The Bethesda Handbook of Clinical Oncology 5th Edition

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Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght Š2005 Li ppi ncott Wi l l i ams & Wi l ki ns > F ro nt o f Bo o k > Edit o rs

Editors Jame A braham MD, FA CP Chi ef Section of Hematology/Oncology; Associate Pr ofessor of Medicine; Medical Dir ector , Mar y Babb Randolph Cancer Center , West Vir ginia Univer sity, Mor gantown, West Vir ginia James L. Gulley MD, PhD, FA CP Di r ector Clinical Immunother apy G r oup, Labor ator y of Tumor Immunology and Biology, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Carmen J. A llegra MD Chi ef Medi cal Offi cer Networ k for Medical Communication and Resear ch, Atlanta, G eor gia

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Contributing Authors Jame A braham MD, FA CP Chi ef Depar tment of Medicine; Associate Pr ofessor , Section of Hematology/Oncology, Medical Dir ector , Mar y Babb Randolph Cancer Center , West Vir ginia Univer sity, Mor gantown, West Vir ginia Manish A graw al MD, MA , MSc Staff Investi gator Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland; Oncologist, Depar tment of Oncology, Associates in Oncology and Hematology, Rockville, Mar yland Carmen J. A llegra MD Chi ef Medi cal Offi cer Networ k for Medical Communication and Resear ch, Atlanta, G eor gia Ramin A ltaha MD Assi stant Pr ofessor Section of Hematology/Oncology, Rober t C. Byr d Health Sciences Center , West Vir ginia Univer sity, Mor gantown, West Vir ginia Christina M. A nnunziata Cl i ni cal Fel l ow Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Philip M. A rlen MD Staff Cl i ni ci an Labor ator y of Tumor Immunology and Biology, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Susan Bates MD Seni or Investi gator Cancer Ther apeutics Br anch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland

Jason R. Beckrow DO Oncol ogy Fel l ow Depar tment of Inter nal Medicine, Michigan State Univer sity, East Lansing, Michigan; Oncology F ellow, Br eslin Cancer Center , Ingham Regional Medical Center , Lansing, Michigan Michael J. Birrer MD, PhD Deputy Branch Chi ef Depar tment of Cell and Cancer Biology, National Cancer Institute, National Institutes of Health, Rockville, Mar yland Marc R. Blackman MD Chi ef Endocr ine Section, Labor ator y of Clinical Investigation, National Center for Complementar y and Alter native Medicine, National Institutes of Health, Bethesda, Mar yland Oscar S. Breathnach MB, FRCPI Cl i ni cal Instr uctor Depar tment of Medicine, Univer sity College Cor k, Cor k, Ir eland; Consultant Medical Oncologist, Depar tment of Oncology, Cor k Univer sity Hospital, Cor k, Ir eland June Cai MD Assi stant Pr ofessor of Psychi atr y Depar tment of Psychiatr y and Human Behavior , Br own Univer sity Medical School, Pr ovidence, Rhode Island; Dir ector , Division of Consulation-Liaison Psychiatr y Ser vice, Depar tment of Psychiatr y, The Mir iam Hospital, Pr ovidence, Rhode Island Jane Carter RN, MSN Resear ch Nur se Speci al i st National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Deborah Charest-Gutierrez RN BSN Cl i ni cal Manager Depar tment of Nur sing, Pr ocedur e, Vascular Access, Conscious Sedation Ser vice, National Institutes of Health, Bethesda, Mar yland Richard W . Childs MD

Seni or Investi gator Tumor Immunology/Stem Cell Tr ansplantation, Hematology Br anch, National Hear t, Lung, Blood Institute, National Institutes of Health, Bethesda, Mar yland Barbara A . Conley MD Pr ofessor and Chi ef Section of Hematology/Oncology, Depar tment of Medicine, Michigan State Univer sity, East Lansing, Michigan Jorge E. Cortes MD Pr ofessor ; Deputy Chai r and Chi ef Chr onic Myelogenous Leukemia Section, Depar tment of Leukemia, M.D. Ander son Cancer Center , The Univer sity of Texas, Houston, Texas Michael Craig MD Fel l ow Section of Hematology/Oncology, Depar tment of Medicine, West Vir ginia Univer sity, Mor gantown, West Vir ginia Gregory Curt MD Seni or Medi cal Di r ector Astr aZeneca Oncology, G ar r ett Par k, Mar yland; G uest Resear cher , Radiation Oncology Br anch, National Institutes of Health Clinical Center , Bethesda, Mar yland W illiam L. Dahut MD Chi ef G enitour inar y Clinical Resear ch Section, Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Suzanne G. Demko PA -C Physi ci an Assi stant; Chi ef; Offi ce of Nur se Practi ti oner s and Physi ci an Assi stants Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Neelima Denduluri MD Cl i ni cal Fel l ow

Medical Oncology, Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Marcel P. Devetten MD Assi stant Pr ofessor Depar tment of Medicine; Dir ector , Blood and Mar r ow Tr ansplantation Pr ogr am, Univer sity of Nebr aska Medical Center , Omaha, Nebr aska Marnie Dobbin MS RD, CNSD Cl i ni cal Resear ch Di eti ti an Depar tment of Nutr ition, National Institutes of Health Clinical Center , Bethesda, Mar yland J. Paul Duic MD Resi dent Depar tment of Emer gency Medicine, Johns Hopkins School of Medicine, Baltimor e, Mar yland Cynthia E. Dunbar MD Head Molecular Hematopoiesis Section, Hematology Br anch, National Hear t, Lung, and Blood Institute, National Institutes of Health, Bethesda, Mar yland How ard A . Fine MD Seni or Investi gator /Branch Chi ef Neur o-Oncology Br anch, National Cancer Institute and National Institute for Neur ologic Disor der s, National Institutes of Health, Bethesda, Mar yland Tito Fojo MD, PhD Seni or Investi gator Cancer Ther apeutics Br anch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland A rlene A . Forastiere MD Pr ofessor of Oncol ogy Depar tment of Oncology, Johns Hopkins Univer sity School of Medicine, Baltimor e, Mar yland Barry L. Gause MD

Seni or Investi gator Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Juan C. Gea-Banacloche MD Staff Cl i ni ci an Exper imental Tr ansplantation and Immunology Br anch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland; Head, Infectious Disease Consult Ser vice, National Institutes of Health Clinical Center , Bethesda, Mar yland David Gius MD, PhD Chi ef Molecular Radiation Oncology, Radiation Oncology Br anch, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Martin E. Gutierrez MD Head Lung Cancer Clinical Resear ch Section and Head, Office of NavyOncology, Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland James L. Gulley MD, PhD, FA CP Di r ector Clinical Immunother apy G r oup, Labor ator y of Tumor Immunology and Biology, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Upendra P. Hegde MD Assi stant Pr ofessor of Medi ci ne Depar tment of Inter nal Medicine, Division of Hematology and Oncology, Univer sity of Connecticut Health Center , John Dempsey Hospital, F ar mington, Connecticut Lee J. Helman Chi ef of Pedi atr i c Oncol ogy; Acti ng Sci enti fi c Di r ector for Cl i ni cal Sci ences Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland

A nne M. Horgan Cl i ni cal Instr uctor Depar tment of Medicine, Univer sity College Cor k, Cor k, Ir eland Thomas E. Hughes PharmD, BCOP Cl i ni cal Phar macy Speci al i st Depar tment of Phar macy, National Institutes of Health Clinical Center , Bethesda, Mar yland W illiam R. Jarnagin MD, FA CS Assi stant Pr ofessor of Sur ger y Depar tment of Sur ger y, Weill Medical College of Cor nell Univer sity, New Yor k, New Yor k; Associate Attending Sur geon, Depar tment of Sur ger y, Memor ial Sloan-Ketter ing Cancer Center , New Yor k, New Yor k Michael J. Keating MD Pr ofessor of Medi ci ne Depar tment of Leukemia M.D. Ander son Cancer Center , The Univer sity of Texas, Houston, Texas David P. Kelsen MD Chi ef G astr ointestinal Oncology Ser vice; Edwar d S. G or den Chair in Medical Oncology, Memor ial Sloan-Ketter ing Cancer Center , New Yor k, New Yor k Hung T. Khong MD Assi stant Pr ofessor Depar tments of Medicine and Phar macology, Head Clinical Immunother apeutics Resear ch Labor ator y, USA Cancer Resear ch Institute, Univer sity of South Alabama, Mobile, Alabama George P. Kim MD Assi stant Pr ofessor Division of Hematology/Oncology; Chief of G astr ointestinal Cancer Section, Mayo Clinic Cancer Center , Jacksonville, F lor ida Christopher Klebanoff Emor y School of Medicine, Atlanta, G eor gia

David R. Kohler PharmD Oncol ogy Cl i ni cal Phar macy Speci al i st Phar macy Depar tment, National Institutes of Health Clinical Center , Bethesda, Mar yland Herbert L. Kotz MD Consul tant Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Barnett S. Kramer MD, MPH Associ ate Di r ector for Di sease Pr eventi on Office of Disease Pr evention, National Institutes of Health, Bethesda, Mar yland; Editor -in-Chief, Jour nal of the National Cancer Institute, Bethesda, Mar yland Pallavi P. Kumar MD Cl i ni cal Fel l ow HIV and AIDS Malignancy Br anch, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Gregory D. Leonard MB, BCH, BA O, Bed Sci The Royal Col l ege of Physi ci ans Dublin, Ir eland; Consultant Medical Oncologist, Old School of Nur sing, Water for d Regional Hospital, Dunmor e Road, Water for d, Ir eland Richard F. Little MD Seni or Cl i ni cal Investi gator HIV and AIDS Malignancy Br anch, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Patrick J. Mansky MD Staff Cl i ni ci an National Center for Complementar y and Alter native Medicine, National Institutes of Health, Bethesda, Mar yland Michael E. Menefee MD Cl i ni cal Fel l ow

Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Richard A . Messmann MD, MHS, MSc Assi stant Pr ofessor Depar tment of Hematology/Oncology, Michigan State Univer sity, East Lansing, Michigan; Dir ector of Cancer Resear ch, G r eat Lakes Cancer Institute, Lansing, Michigan Hamid R. Mirshahidi MD Fel l ow Section of Hematology/Oncology, Depar tment of Medicine, West Vir ginia Univer sity, Mor gantown, West Vir ginia Brian P. Monahan MD, FA CP Chai r and Associ ate Pr ofessor of Medi ci ne Depar tment of Hematology and Medical Oncology, Unifor med Ser vices, Univer sity of the Health Sciences, Bethesda, Mar yland, Pr ogr am Dir ector Hematology and Medical Oncology Division, National Naval Medical Center , Bethesda, Mar yland Manish Monga MD Staff Depar tment of Oncology, Wheeling Hospital, Wheeling, West Vir ginia Sattva S. Neelapu MD Assi stant Pr ofessor Depar tment of Lymphoma and Myeloma, M.D. Ander son Cancer Center , Univer sity of Texas, Houston, Texas Naomi P. O'Grady MD Medi cal Di r ector Depar tment of Cr itical Car e Medicine, Pr ocedur es, Vascular Access and Conscious Sedation Ser vices, National Institutes of Health, Bethesda, Mar yland Eileen M. O'Reilly MD Assi stant Attendi ng/Assi stant Pr ofessor of Medi ci ne Depar tment of Medicine, Memor ial Sloan-Ketter ing Cancer Center , New Yor k, New Yor k

Maryland Pao MD Deputy Cl i ni cal Di r ector National Institute of Mental Health, National Institutes of Health, Bethesda, Mar yland Edw in M. Posadas MD Cl i ni cal Fel l ow Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Muzaffar H. Qazilbash MD Assi stant Pr ofessor Depar tment of Blood and Mar r ow Tr ansplantation, M.D. Ander son Cancer Center , Univer sity of Texas, Houston, Texas Eddie Reed MD Di r ector of Mar y Babb Randol ph Cancer Center ; Laur ence and Jean DeLynn Chai r of Oncol ogy at Rober t C. Byr d Heal th Sci ences Center West Vir ginia Univer sity, Mor gantown, West Vir ginia A vi S. Retter MD Cl i ni cal Fel l ow Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Donald L. Rosenstein MD Chi ef of Psychi atr y Consul tati on-Li ai son Ser vi ce; Deputy Cl i ni cal Di r ector at Offi ce of the Cl i ni cal Di r ector National Institute of Mental Health, National Institutes of Health, Bethesda, Mar yland Kerry Ryan MPH, MSHS, PA -C Physi ci an Assi stant Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland M. W asif Saif MD, MBBS Assi stant Pr ofessor Depar tment of Medicine, Division of Hematology/Oncology and Depar tment of Phar macology/Toxicology, Univer sity of Alabama at Bir mingham, Bir mingham, Alabama

Gisa Schun Assi stant Pr ofessor of Medi ci ne Section of Hematology/Oncology, West Vir ginia Univer sity, Mor gantown, West Vir ginia Muhammad Kamran Siddique MD Fel l ow Division of Hematology/ Oncology, Depar tment of Medicine, Michigan State Univer sity, East Lansing, Michigan; F ellow, Division of Hematology and Oncology, Depar tment of Medicine, Br eslin Cancer Center , Ingham Regional Center , Lansing, Michigan Chris H. Takimoto MD, PhD Di r ector of Phar macol ogy Institute for Dr ug Development, Cancer Ther apy & Resear ch Center , San Antonio, Texas; Clinical Associate Pr ofessor of Medicine Division of Medical Oncology, Univer sity of Texas Health Science Center , San Antonio, Texas Carter Van W aes MD, PhD Seni or Investi gator and Chi ef Head and Neck Sur ger y Br anch, National Institute on Deafness and Other Communication Disor der s, Clinical Resear ch Center , National Institutes of Health, Bethesda, Mar yland; Clinical Dir ector National Institute on Deafness and Other Communication Disor der s, Clinical Resear ch Center , National Institutes of Health, Bethesda, Mar yland Daw n B. W allerstedt RN, CRNP Nur se Practi ti oner Resear ch, National Center for Complementar y and Alter native Medicine, National Institutes of Health, Bethesda, Mar yland W yndham H. W ilson MD, PhD Chi ef Lymphoma Section, Exper imental Tr ansplantation and Immunology Br anch, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Sarah M. W ynne MD Cl i ni cal Fel l ow Labor ator y of Immunor egulation, National Institute of Aller gy and

Infectious Diseases, National Institutes of Health, Bethesda, Mar yland

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > F ro nt o f Bo o k > De dic a t io n

Dedication We dedicate this book to those whose lives ar e touched by cancer and to the car egiver s who spend endless hour s taking car e of them. “May I never for get that the pati ent i s a fel l ow cr eatur e i n pai n. May I never consi der hi m mer el y a vessel of di sease.” — Mai moni des (12th centur y philosopher –physician)

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght Š2005 Li ppi ncott Wi l l i ams & Wi l ki ns > F ro nt o f Bo o k > P re fa c e

Preface The Bethesda Handbook of Clinical Oncology i s a cl ear, conci se, and compr ehensi ve r efer ence book for the busy cl i ni ci an to use i n hi s or her dai l y encounter s wi th pati ents. The book has been compi l ed by cl i ni ci ans who ar e wor ki ng or ar e trai ned at the Nati onal Cancer Insti tute and Nati onal Insti tutes of Heal th as wel l as by schol ar s fr om MD Ander son Cancer Center, Memor i al Sl oan-Ketter i ng Cancer Center, Johns Hopki ns Oncol ogy Center, and other academi c i nsti tuti ons. To l i mi t the si ze of the book, l ess space has been dedi cated to eti ol ogy, pathophysi ol ogy, and epi demi ol ogy and gr eater emphasi s has been pl aced on practi cal cl i ni cal i nfor mati on. For easy accessi bi l i ty to the per ti nent i nfor mati on, l ong descr i pti ons ar e avoi ded, and mor e tabl es, pi ctur es, al gor i thms, and phrases ar e i ncl uded. The Bethesda Handbook of Clinical Oncology i s not i ntended as a substi tute for the many excel l ent oncol ogy r efer ence textbooks essenti al for a mor e compl ete under standi ng of the pathophysi ol ogy and management of compl i cated oncol ogy i n pati ents. We hope that the r eader-fr i endl y for mat of thi s book, wi th i ts compr ehensi ve r evi ew of the management of each di sease and wi th tr eatment r egi mens i ncl udi ng dosage and schedul e, wi l l make thi s book uni que and useful for oncol ogi sts, oncol ogy fel l ows, r esi dents, students, oncol ogy nur ses, and al l i ed heal th pr ofessi onal s. For the second edi ti on, we have updated the secti ons and have added two r el evant topi cs (on tar geted therapy and on compl ementar y and al ter nati ve medi ci ne).

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght Š2005 Li ppi ncott Wi l l i ams & Wi l ki ns > F ro nt o f Bo o k > Ac k no w le dgm e nt s

Acknowledgments We thank al l our fr i ends and col l eagues who wor ked har d to make thi s book possi bl e. We thank Jane Car ter, RN, who wr ote the chapter on end-of-l i fe car e for the book and whose l i fe i s touched by cancer now. Thi s book woul d not have been possi bl e wi thout the str ong and conti nued suppor t of Jonathan Pi ne, the seni or oncol ogy edi tor at Li ppi ncott Wi l l i ams & Wi l ki ns. We thank our wi ves, Shyl a, Tr eni se, and Li nda, for thei r encouragement and suppor t i n thi s endeavor.

TABLE OF CONTENTS

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Section 1 - Head and Neck [+] 1 - Head and Neck Cancer [-]

Section 2 - Thorax [+] 2 - Non–Small Cell Lung Cancer [+] 3 - Small Cell Lung Cancer [-]

Section 3 - Digestive System [+] 4 - Esophageal Cancer [+] 5 - Gastric Cancer [+] 6 - Biliary Tract Cancer [+] 7 - Primary Cancers of the Liver [+] 8 - Colorectal Cancer [+] 9 - Pancreatic Cancer [+] 10 - Anal Cancer [+] 11 - Other Gastrointestinal Tumors [-]

Section 4 - Breast [+] 12 - Breast Cancer [-]

Section 5 - Genitourinary [+] 13 - Renal Cell Cancer [+] 14 - Prostate Cancer [+] 15 - Bladder Cancer [+] 16 - Testicular Carcinoma [-]

Section 6 - Gynecologic [+] 17 - Ovarian Cancer [+] 18 - Endometrial Cancer [+] 19 - Cervical Cancer [+] 20 - Vulvar Cancer [-]

Section 7 - Musculoskeletal [+] 21 - Sarcomas and Malignancies of the Bone [-]

Section 8 - Skin Cancer [+] 22 - Skin Cancers and Melanoma [-]

Section 9 - Hematologic Malignancies [+] 23 - Acute Leukemias [+] 24 - Chronic Leukemias [+] 25 - Myeloid Leukemia [+] 26 - Chronic Myeloproliferative Diseases [+] 27 - Multiple Myeloma [+] 28 - Non-Hodgkin Lymphoma [+] 29 - Hodgkin Lymphoma [+] 30 - Hematopoietic Stem Cell Transplantation [-]

Section 10 - Other Malignancies [+] 31 - Acquired Immunodeficiency Syndrome–Related Malignancies [+] 32 - Carcinoma of Unknown Primary [+] 33 - Central Nervous System Tumors [+] 34 - Endocrine Tumors [-]

Section 11 - Supportive Care [+] 35 - Hematopoietic Growth Factors [+] 36 - Infectious Complications in Oncology [+] 37 - General Principles of Cancer Pain Management [+] 38 - Oncologic Emergencies and Paraneoplastic Syndromes [+] 39 - Psychopharmacologic Management in Oncology [+] 40 - Management of Emesis in Oncology [+] 41 - Nutrition for Oncology Patients [+] 42 - End-of-life Care [-]

Section 12 - Targeted Treatments and Complimentary and Alternative Medicine [+] 43 - Targeted Therapies [+] 44 - Complementary and Alternative Medicine in Oncology [-]

Section 13 - Common Procedures and Chemotherapy Drugs [+] 45 - Central Venous Access Devices [+] 46 - Procedures in Medical Oncology [+] 47 - Anticancer Agents BACK OF BOOK

[-] Appendices [+]

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Appendix Part 1 [+]

Appendix Part 2 [+]

Appendix Part 3

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 1 - He a d a nd Ne c k > 1 - He a d a nd Ne c k C a nc e r

1 Head and Neck Cancer Barbara A . Conley* A rlene A . Forastiere† David Gius‡ Carter VanW aes§ *Depar tment of Medicine, Michigan State Univer sity, East Lansing, Michigan † Depar tment

of Oncology, Johns Hopkins Univer sity School of Medicine, Baltimor e, Mar yland ‡ Radiation

Oncology Br anch, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland § Head

and Neck Sur ger y Br anch, National Institute for Deafness and Other Communicative Disor der s, National Institutes of Health, Bethesda, Mar yland Tumor s of the head and neck ar e the si xth most common mal i gnancy i n the Uni ted States, wi th a year l y i nci dence of 40,000 to 50,000 cases. Ni nety per cent of these cancer s i nvol ve squamous cel l hi stol ogy. The most common si tes ar e the oral cavi ty, phar ynx, l ar ynx, and hypophar ynx. Nasal cavi ty and paranasal si nus cancer s, sal i var y gl and mal i gnanci es, and var i ous sar comas, l ymphomas, and mel anoma ar e l ess common.

EPIDEMIOLOGY The wor l dwi de i nci dence of head and neck squamous cancer i s mor e than 500,000 cases per year, and i n the Uni ted States, i t compr i ses appr oxi matel y 4% to 5% of al l new cancer s and 2% of al l cancer deaths (11,000 per year ) (1). Most pati ents ar e ol der than 50 year s, and i nci dence i ncr eases wi th age; the mal e-to-femal e rati o i s 2.5:1. The age-adjusted i nci dence i s hi gher among bl ack men, and,

stage-for-stage, sur vi val among Afr i can Amer i cans i s l ower overal l than i n whi tes. Appr oxi matel y 34% of oral and phar yngeal cancer s pr esent as l ocal i zed di sease, 46% pr esent as l ocor egi onal (i .e., l ocal l y advanced or i nvol vi ng r egi onal l ymph nodes) di sease, and 10% pr esent as metastati c di sease.

RISK FACTORS Tobacco and al cohol use ar e major r i sk factor s for devel opi ng cancer. Heavy al cohol consumpti on i ncr eases the r i sk twofol d to si xfol d, wher eas smoki ng i ncr eases the r i sk fi vefol d to 25-fol d, dependi ng on gender, race, and the amount of smoki ng. Both factor s together i ncr ease the r i sk 15-fol d to 40-fol d. Smokel ess tobacco and snuff ar e associ ated wi th oral cavi ty cancer s. Case–contr ol studi es show that the r el ati ve r i sk for devel opi ng er ythr opl asi a cancer i n ti ssues i n contact wi th snuff powder (cheek and gum) i s near l y 50fol d (2). In many par ts of Asi a and some par ts of Afr i ca, chewi ng betel wi th or wi thout tobacco and sl aked l i me i s associ ated wi th pr emal i gnant l esi ons and oral squamous cancer s (3,4). Al cohol and tobacco affect the enti r e r espi rator y mucosa, l eadi ng to mul ti focal mucosal abnor mal i ti es known as “fi el d cancer i z ati on” (5). Ther e i s a 2% to 6% per year r i sk for a second head and neck, l ung, or esophageal cancer i n pati ents wi th a hi stor y of cancer i n thi s ar ea. Those who conti nue to smoke have the hi ghest r i sk. Second pr i mar y cancer s r epr esent a major r i sk factor for death among sur vi vor s of an i ni ti al squamous car ci noma of the head and neck (6,7,8). Epstei n-Bar r vi r us (EBV) has been detected i n vi r tual l y al l nonkerati ni z i ng and undi ffer enti ated nasophar yngeal cancer s but l ess consi stentl y i n squamous nasophar yngeal cancer s (r evi ewed i n 9). Cor r el ati on has been obser ved between the pr esence of papi l l omavi r us and oral and or ophar ynx cancer s (10,11,12). Other r i sk factor s i ncl ude sun exposur e (l i p cancer ); occupati onal exposur e to ni ckel (nose and ethmoi ds), radi um (antr um), mustar d gas (sphenoi d), chr omi um (si nuses and nose), l eather (ethmoi ds and nasal cavi ty), and wood dust (ethmoi ds and nasal cavi ty); radi ati on exposur e (thyr oi d and sal i var y gl and cancer ); EBV exposur e (nasophar yngeal cancer ); and, possi bl y, vi tami n A defi ci ency and mar i juana. Di sor der s of DNA r epai r (e.g., Fanconi anemi a) as wel l as or gan transpl antati on wi th i mmunosuppr essi on ar e associ ated wi th i ncr eased r i sk of squamous head and neck

cancer.

PREVENTION AND CHEMOPREVENTION The most i mpor tant r ecommendati on for pr eventi on of head and neck cancer i s to avoi d smoki ng and to l i mi t al cohol i ntake. Pr emal i gnant l esi ons occur r i ng i n the oral cavi ty, phar ynx, and l ar ynx mani fest as l eukopl aki a (a whi te patch that does not scrape off and that has no other obvi ous cause) or er ythr opl aki a (fr i abl e r eddi sh or specked l esi ons) (see Tabl e 1.1.). The r i sk of l eukopl aki as wi thout dyspl asi a pr ogr essi ng to cancer i s about 4% . However, up to 40% of sever e dyspl asi as or er ythr opl asi as pr ogr ess to cancer. Reti noi ds can r ever si bl y i mpr ove pr emal i gnant hi stol ogy. In a smal l randomi zed pl acebo-contr ol l ed tr i al i n pati ents tr eated for a head and neck cancer, i sotr eti noi n decr eased the i nci dence of second pr i mar y tumor s (13). A l ar ger defi ni ti ve randomi zed, pl acebocontr ol l ed tr i al i n pati ents wi th curati vel y tr eated stages I and II head and neck squamous cel l car ci noma fai l ed to fi nd any benefi t of 13-cis-r eti noi c aci d i n pr eventi ng second pr i mar y cancer s or i n sur vi val (14). Eur oscan, a l ar ge Eur opean chemopr eventi on tr i al that randomi zed pati ents wi th stage I to stage III non–smal l cel l l ung cancer or head and neck squamous cancer to ei ther vi tami n A (as r eti nyl pal mi tate) or N-acetyl cystei ne (a fr ee radi cal scavenger ), nei ther dr ug or both dr ugs, al so fai l ed to fi nd pr eventi ve benefi t (15).

TABLE 1.1. Premalignant Lesions Premalignant lesions

Clinical

Leukoplakia

Erythroplakia

Dy

White patch or plaque occurring in surface of mucous membrane

Bright red velvety plaques that cannot be characterized

Ca as le er

features

that does not rub off, once other oral diseases are ruled out

clinically or pathologically as being due to any other condition

or ob m fin

Probability of progression to malignant lesions

4%

15%–30% of dysplastic Lesions

15

Histopathology

Hyperkeratosis associated with variable histologic findings; rarely contain dysplasia or carcinoma. (Invasive or in situ carcinoma found in only 6% of cases)

Mild to moderate dysplasia in 10% of patients; severe dysplasia, in situ or invasive carcinoma in 90% of cases

Tr hi di pl ch in nu nu pr nu

From McFarland M, Abaza NA, El-Mofty S. In: Damj Linder J, eds. Anderson's pathology. St. Louis: Mos with permission. Pr esentl y, ther e i s no effecti ve chemopr eventi on for pati ents at r i sk for head and neck squamous cancer. Chemopr eventi on outsi de a cl i ni cal tr i al i s not r ecommended and i s potenti al l y har mful . Two l ar ge randomi zed chemopr eventi on tr i al s for l ung cancer demonstrated a wor se outcome for those pati ents randomi zed to

Vi tami n A and β-Car otene (CARET study) or to β-Car otene al one (ATBC study) (16,17,18,19).

ANATOMY A si mpl i fi ed depi cti on of extracrani al head and neck anatomy i s pr esented i n F IG . 1.1.

FIG. 1.1. Sagi ttal secti on of the upper aer odi gesti ve tract. (Used wi th the per mi ssi on of the Amer i can Joi nt Commi ttee on Cancer (AJCC), Chi cago, Il l i noi s. The or i gi nal sour ce for thi s mater i al i s the AJCC Cancer Stagi ng Manual , Si xth Edi ti on (2002) publ i shed by Spr i nger-Ver l ag, New Yor k, http://www.spr i nger-ny.com.)

The patter ns of l ymphati c drai nage di vi de the neck i nto several l evel s (see F IG . 1.2). Level I compr i ses the submental or submandi bul ar nodes; l evel II (upper jugul ar l ymph nodes) extends fr om the skul l base to the hyoi d bone; l evel III (mi ddl e jugul ar l ymph nodes) i s the ar ea between the hyoi d bone and the l ower bor der of the cr i coi d car ti l age; l evel IV (l ower jugul ar l ymph nodes) i s the ar ea between the cr i coi d car ti l age and the cl avi cl e; l evel V i s the poster i or tr i angl e; l evel VI i s the anter i or compar tment fr om the hyoi d bone to the supraster nal notch, bounded on each si de by the

medi al car oti d sheath; and l evel VII i s the ar ea of the super i or medi asti num. Masses mor e than 3 cm i n gr eatest di mensi on ar e general l y gr oups of nodes or a si ngl e node, wi th the tumor extendi ng i nto the soft ti ssues (20). Knowl edge of the l ymphati c drai nage of the neck assi sts the sur geon i n pl anni ng the extent of neck r esecti on and i n l ocati ng a pr i mar y tumor when a pal pabl e l ymph node i s the i ni ti al pr esentati on.

FIG. 1.2. Di agram of the neck showi ng l evel s of l ymph nodes. Level I, submandi bul ar ; l evel II, hi gh jugul ar ; l evel III, mi djugul ar ; l evel IV, l ow jugul ar ; l evel V, poster i or jugul ar ; l evel VI, tracheoesophageal ; l evel VIII (super i or medi asti nal ) i s not shown. (Used wi th the per mi ssi on of the Amer i can Joi nt Commi ttee on Cancer (AJCC), Chi cago, Il l i noi s. The or i gi nal sour ce for thi s mater i al i s the AJCC Cancer Stagi ng Manual , Si xth Edi ti on (2002) publ i shed by Spr i nger-Ver l ag, New Yor k, http://www.spr i nger-ny.com.)

STAGING SYSTEM Stagi ng i s based on physi cal exami nati on and i magi ng tests. The

stagi ng system put for th by the Amer i can Joi nt Commi ttee for Cancer (AJCC) (see Tabl e 1.2) and the Uni on Inter nati onal e Contr e l e Cancer (UICC) [tumor, node, metastasi s (TNM)] i s used. The AJCC cl assi fi cati on (20) emphasi zes r esectabi l i ty status by di vi di ng advanced di sease stages i nto stage IVA (r esectabl e), stage IVB (unr esectabl e), and stage IVC (di stant metastati c di sease).

TABLE 1.2. TNM Staging of Head and Neck Tumors Definition of TNM Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

Nasopharynx T1

Tumor confined to the nasopharynx

T2

Tumor extends to soft tissue

T2a

Tumor extends to the oropharynx and/or nasal cavity without parapharyngeal extensiona

T2b

Any tumor with parapharyngeal extension a

T3

Tumor involves bony structures and/or paranasal sinuses

T4

Tumor with intracanial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticator space

Oropharynx T1

Tumor 2 cm or less in greatest dimension

T2

Tumor more than 2 cm but not more than 4 cm in greatest dimension

T3

Tumor more than 4 cm in greatest dimension

T4a

Tumor invades the larynx, deep/extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible

T4b

Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery

Hypopharynx

T1

Tumor limited to one subsite of hypopharynx and 2 cm or less in greatest dimension

T2

Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures more than 2 cm but not more than 4 cm in greatest diameter without fixation of hemilarynx

T3

Tumor more than 4 cm in greatest dimension or with fixation of hemilarynx

T4a

Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus, or central compartment soft tissueb

T4b

Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures

Regional Lymph Nodes (N) Nasopharynx The distribution and the prognostic impact of regional lymph node spread from nasopharynx cancer, particularly of the undifferentiated type, are different from those of other head and neck mucosal cancers and justify the use of a different N classification scheme. NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Unilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossac

N2

Bilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossac

N3

Metastasis in a lymph node(s)c >6 cm and/or to supraclavicular fossa N3a Greater than 6 cm in dimension N3b Extension to the supraclavicular fossa d

Oropharynx and Hypopharynx NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension

N2

Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none

more than 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension.

N2a

Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension

N2b

Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N3

Metastasis in a lymph node more than 6 cm in greatest dimension

Distant Metastasis (M) MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

Stage Grouping: Nasopharynx Stage 0

Ti s

N0

M0

Stage I

T1

N0

M0

Stage IIA

T2a

N0

M0

T1

N1

M0

T2

N1

M0

T2a

N1

M0

T2b

N0

M0

T2b

N1

M0

T1

N2

M0

T2a

N2

M0

T2b

N2

M0

T3

N0

M0

T3

N1

M0

T3

N2

M0

T4

N0

M0

T4

N1

M0

T4

N2

M0

Stage IVB

Any T

N3

M0

Stage IVC

Any T

Any N

M1

Stage IIB

Stage III

Stage IVA

Stage Grouping: Oropharynx, Hypopharynx

Stage 0

Ti s

N0

M0

Stage 1

T1

N0

M0

Stage II

T2

N0

M0

T3

N0

M0

T1

N1

M0

T2

N1

M0

T3

N1

M0

T4a

N0

M0

T4a

N1

M0

T1

N2

M0

T2

N2

M0

T3

N2

M0

T4a

N2

M0

T4b

Any N

M0

Any T

N3

M0

Any T

Any N

M1

Stage III

Stage IVA

Stage IVB

Stage IVC

a

Parapharyngeal extension denotes posterolateral infiltration of tumor beyond the pharyngobasilar fascia. b Central compartment of soft tissues includes

prelaryngeal strap muscles and subcutaneous fat. c Midline nodes are considered ipsilateral nodes. d Supraclavicular zone or fossa is relevant to the staging of nasopharyngeal carcinoma and is the triangular region originally described by Ho. It is defined by three points: (a) the superior margin of the sternal end of the clavicle, (b) the superior margin of the lateral end of the clavicle, (c) the point where the neck meets the shoulder. Note that this would include the caudal portions of levels IV and V. All cases with lymph nodes (whole or part) in the fossa are considered N3b. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag, New York, http://www.springer-ny.com . The T cl assi fi cati on i ndi cates the extent of the pr i mar y tumor. It di ffer s for each si te. For pr i mar y tumor s of the oral cavi ty, hypophar ynx, and or ophar ynx, l esi ons gr eater than 4 cm ar e cl assi fi ed as T3. Vocal cor d paral ysi s wi th a l ar ynx or hypophar ynx pr i mar y i ndi cates at l east T3. Lesi ons wi th l ocal i nvasi on of adjacent str uctur es i ndi cate T4. The N cl assi fi cati on i s uni for m for al l pr i mar y si tes, except nasophar ynx. For al l pr i mar y si tes except nasophar ynx, any cl i ni cal l ymph node i nvol vement i ndi cates at l east stage III, and nodes l ar ger than a si ngl e 3-cm i psi l ateral node ar e cl assi fi ed as stage IV r egar dl ess of T stage. The pr esence of di stant metastasi s (M1) i ndi cates stage IVC di sease. Medi asti nal l ymph node i nvol vement i s consi der ed di stant metastasi s.

Tumor grade has not shown si gni fi cant associ ati on wi th outcome and i s not consi der ed when stagi ng head and neck cancer s.

PRESENTATION Si gns and symptoms ar e usual l y secondar y to mass effect and/or pai n fr om pr i mar y tumor or i nvol ved l ymph nodes and i nvasi on of adjacent str uctur es or ner ves (see Tabl e 1.3) Adul t pati ents wi th any of these symptoms for mor e than 4 weeks shoul d be r efer r ed to an otol ar yngol ogi st. Del ay i n di agnosi s i s common: ei ther pati ent del ay or r epeated cour ses of anti bi oti cs for oti ti s medi a or sor e thr oat, for exampl e. A l ateral i zed fi r m cer vi cal mass i n an el der l y smoker i s hi ghl y suggesti ve of squamous cel l car ci noma. For nasophar yngeal cancer s, the most common pr esenti ng symptom i s a neck mass, someti mes i n the poster i or tr i angl e. In advanced l esi ons, crani al ner ve abnor mal i ti es may be pr esent.

TABLE 1.3. Common Presenting Signs and Symptoms of Head and Neck Cancer Painless neck mass Odynophagia Dysphagia Hoarseness Hemoptysis Trismus Otalgia Otitis media Loose teeth Ill-fitting dentures Cranial nerve deficits Nonhealing oral ulcers

Wi th the excepti on of hypophar yngeal and nasophar yngeal cancer s, di stant metastases ar e uncommon at pr esentati on. The most common si tes of di stant metastases ar e l ung and bone; l i ver i nvol vement i s l ess common.

DIAGNOSIS The hi stor y shoul d i ncl ude: a. tobacco exposur e (pack-year s, amount chewed, and durati on of habi t, cur r ent or for mer ) b. al cohol exposur e (number of dr i nks per day) c. other r i sk factor s menti oned ear l i er d. cancer hi stor y of fami l y e. si gns and symptoms l i sted i n Tabl e 1.3 f. thor ough r evi ew of systems. The physi cal exami nati on shoul d i ncl ude: a. car eful i nspecti on of the scal p, ear s, nose, and mouth; b. pal pati on of the neck and mouth, assessment of tongue mobi l i ty, deter mi nati on of r estr i cti ons i n the abi l i ty to open the mouth (tr i smus), and bi manual pal pati on of the base of the tongue and fl oor of the mouth; c. speci al attenti on shoul d be gi ven to the exami nati on of crani al ner ves. Abnor mal i ti es ar e suggested by asymmetr y i n the physi cal exami nati on. Refer ral for di r ect and i ndi r ect l ar yngoscopy shoul d be str ongl y consi der ed for symptoms of hoar seness or sor e thr oat not cur ed by a si ngl e cour se of anti bi oti cs. F r i abi l i ty (easy bl eedi ng), an i ndi cator of an ear l y mal i gnant pr ocess and er ythr opl aki a (Tabl e 1.1), i s fr equentl y associ ated wi th sever e dyspl asi a or car ci noma in situ and the si te shoul d be bi opsi ed. When neck mass i s the fi r st pr esentati on, the pr i mar y si te can be l ocated and bi opsi ed i n appr oxi matel y 80% of cases. If no pr i mar y si te i s obvi ous, ti ssue di agnosi s

can be obtai ned by fi ne needl e aspi rati on (F NA) bi opsy of the node, wi th sensi ti vi ty and speci fi ci ty appr oachi ng 99% . A nondi agnosti c F NA does not r ul e out the pr esence of tumor. Computer i zed tomography scan (CT scan) r emai ns the pr i mar y i magi ng study for eval uati on of metastati c adenopathy. Magneti c r esonance i magi ng (MRI) may compl ement the CT scan. Posi tr on emi ssi on tomography (PET) scans ar e bei ng used mor e fr equentl y to detect tumor s that ar e not obvi ous on other scans, but thi s techni que i s sti l l under eval uati on (21,22). Lar yngoscopy and nasophar yngoscopy shoul d be per for med. Wi th occul t pr i mar y tumor s, di r ected bi opsi es of the nasophar ynx, tonsi l , base of tongue, and pyr i for m si nus shoul d be per for med (see F IG . 1.3). Bi l ateral tonsi l l ectomy wi l l someti mes r eveal the sour ce of an occul t cancer.

FIG. 1.3. Eval uati on of cer vi cal adenopathy when a pr i mar y cancer of the head and neck i s suspected.

Sur gi cal bi opsy of a neck mass i s contrai ndi cated i f a squamous cel l car ci noma i s suspected. Studi es show that open bi opsy may wor sen l ocal contr ol , i ncr ease the rate of di stant metastases, and decr ease overal l sur vi val rate, possi bl y by spr eadi ng the di sease at the ti me

of the bi opsy. F i nal l y, an open bi opsy does not pr ovi de any i nfor mati on addi ti onal to that obtai ned fr om F NA, and l ar yngoscopy i s sti l l necessar y for tr eatment pl anni ng.

WORK-UP AND STAGING EVALUATION After the di agnosi s of cancer i s establ i shed, the pati ent shoul d be cl i ni cal l y staged by physi cal exami nati on and radi ol ogi c studi es, usual l y by CT scan and/or MRI of the pr i mar y tumor, neck, and chest. CT scan better defi nes the cor ti cal bone and i s better than MRI for eval uati ng metastati c adenopathy. MRI has super i or soft ti ssue contrast, does not i nvol ve radi ati on, and may be better than CT scan for pr i mar y tumor stagi ng. PET scanni ng i s sti l l under goi ng eval uati on for sensi ti vi ty and speci fi ci ty (21,22). A chest radi ograph or chest CT scan i s i ndi cated for al l pati ents because of the r i sk of a second mal i gnancy. Addi ti onal studi es var y accor di ng to the cl i ni cal stage, symptoms, and pr i mar y si te.

PROGNOSIS The most i mpor tant deter mi nant of pr ognosi s i s stage at di agnosi s. The 5-year sur vi val for stage I pati ents exceeds 80% but i s l ess than 40% i n stage III and IV di sease. Most pati ents have l ocal l y advanced di sease i nvol vi ng one or several l ymph nodes on one or both si des of the neck. The pr esence of a pal pabl e l ymph node i n the neck general l y decr eases the sur vi val rate by 50% compar ed to the same T stage wi thout node i nvol vement. Most r el apses occur l ocor egi onal l y. Di stant metastases ar e mor e commonl y seen l ater i n the cour se of the di sease, or as par t of r el apse after successful i ni ti al tr eatment, and pr edomi nantl y i nvol ve l ung, bone, and l i ver. The l i feti me r i sk of devel opi ng a new cancer for a pati ent wi th head and neck cancer i s 20% to 40% (6,8). After 3 year s, devel opment of a new cancer r epr esents the gr eatest sur vi val r i sk (see Tabl es 1.4, 1.5 and 1.6).

TABLE 1.4. Head and Neck Cancer: Natural history and

No

Site

Epidemiology

common presenting symptoms

involv

5%–10

Lip

Alveolar ridge and retromolar trigone

Risk factors are sun exposure and tobacco; 3,600 new cases a year; 10 to 40 times more common in white men than in black men or women (black or white)

10% of all oral cancers; M:F, 4:1

Exophytic mass or ulcerative lesion; more common in lower lip (92%); slowgrowing tumors; pain and bleeding

Exophytic mass or infiltrating tumor, may invade bone; bleeding, pain exacerbated by chewing, loose teeth, and ill-fitting

Midline spread bilatera

Level I commo (subma and submen upper l lesions metast earlier: and als preaur

30% (7 T4)

Levels more c

and ill-fitting dentures 10%–15% of oral cancers, (occurrence 0.6/100,000); Floor of mouth M:F, 3:1; median age, 60 yr

Tongue (anterior two thirds)

Hard palate

6,200 new cases/yr; median age, 60 yr; M:F, 3:1

0.4 cases/100,000 (5% of oral cavity); M:F, 8:1; 50%

Painful infiltrative lesions, may invade bone, muscles of floor of mouth and tongue

Exophytic or infiltrative pain, occasional difficulty in speech and deglutition

Deeply infiltrating or superficially

T1, 12% 30%; T and T4

Levels more c

Greate propen lymph metast oral ca sites; b involve 25%; l more c followe III, and

Less frequen

palate cases squamous, 50% salivary glands

Buccal mucosa

8% of oral cavity cancers in United States; Women > men

spreading pain

Exophytic more often, silent presentation; pain, bleeding, difficulty in chewing

6%–29

10% at diagno Levels more c

M:F, male-to-female ratio.

TABLE 1.5. Head and Neck Cancer: Orophar

Site

Epidemiology

Natural history and common presenting symptoms Advanced at presentation (silent location, aggressive behavior);

N invol

All st 70% 80%

Base of tongue

4,000 new cases annually in the United States; M:F ratio, 3 to 5:1.

Pain, dysphagia, weight loss, and otalgia(from cranial nerve involvement);

Leve III m comm also and V

Neck mass is a frequent presentation

Tonsillar fossa: more advanced at presentation: 75% stage III or IV, pain, dysphagia, weight loss, and neck mass

Tonsil, tonsillar pillar, and soft palate

Tobacco and alcohol are

Soft palate: More indolent, may present as erythroplakia

Tonsi pillar 38%

Tonsi fossa 68% prese N2 o disea

the most significant risk factors

Posterior pharyngeal wall

Advanced at diagnosis (silent location);

Clinic palpa node

Pain, bleeding, and weight loss;

T1, 2

T2, 3 Neck mass is common initial symptom

T3, 6

T4, 7

Bilat invol is co

Over

Supraglottis

35% of laryngeal cancers

Most arise in epiglottis; early lymph node involvement due to extensive lymphatic drainage; two-thirds of patients have nodal

T1, T2, T3, T4,

6 7 7 7

Leve III, a more

metastases at diagnosis

Glottis

Most common laryngeal cancer

Most favorable prognosis; late lymph node involvement; usually well differentiated, but with infiltrative growth pattern; hoarseness is an early symptom, 70% have localized disease at diagnosis; Poorly differentiated, infiltrative growth pattern unrestricted by tissue

comm

Spar lymp drain early rarel meta to ly node Clinic posit T2 <

Leve III, a more comm

T3, T 20%

20% overa

Subglottis

Rare, 1%–8% of laryngeal cancers

barriers; rarely causes hoarseness, may cause dyspnea from airway involvement; two-thirds of patients have metastatic disease at presentation

Pretr and parat node comm invol

M:F, male-to-female ratio.

TABLE 1.6. Head and Neck Cancer: Hypoph Paranasal Sinuses, and Nasop

Site

Epidemiology

Natural history and common presenting symptoms Aggressive, diffuse local spread, early lymph node involvement; occult metastases to

in

Hypopharynx

Nasal cavity and paranasal sinuses

2,500 new cases yearly in United States; etiology: tobacco, alcohol, and nutritional abnormalities

Rare, 0.75/100,000 occurrence in United States Nasal cavity and maxillary sinus, fourfifths of all cases M:F, 2:1 Increased risk with exposure to furniture, shoe, textile industries;

thyroid and paratracheal node chain; pain, neck stiffness (retropharyngeal nodes), otalgia (cranial nerve X), irritation, and mucus retention 50% present as neck mass; high risk of distant metastases

Nonhealing ulcer, occasional bleeding, unilateral nasal obstruction, dental pain, loose teeth, illfitting dentures, trismus, diplopia, proptosis, epiphora, anosmia, and headache,

A ly d U h c p ly a

1 c p n L II c

Nasopharynx

nickel, chromium, mustard gas, isopropyl alcohol, and radium

depending of site of invasion Usually advanced at presentation

Rare (< 1/100,000) except in North Africa, Southeast Asia, and China, far northern hemisphere Associated with EBV, diet, genetic factors

Most common initial presentation: neck mass Other presentations: otitis media, nasal obstruction, tinnitus, pain, and cranial nerve involvement

C p W W II 9

M:F, male-to-female ratio; EBV, Epstein–Barr virus.

SCREENING Car eful exami nati on of the head and neck i s war ranted i n i ndi vi dual s wi th r i sk factor s or suggesti ve symptoms. Mucosal abnor mal i ti es and pal pabl e neck masses shoul d be bi opsi ed (see the secti on, Di agnosi s). The Uni ted States Pr eventi ve Task For ce (http://www.ahcpr.gov/cl i ni c/uspstfi x.htm) does not r ecommend r egul ar scr eeni ng for oral cancer i n the general popul ati on but r ecommends counsel i ng for cessati on of tobacco use and l i mi tati on

of al cohol i ntake. The Amer i can Cancer Soci ety (http://www.cancer.or g) r ecommends oral exami nati on or dental appoi ntments. The oral exami nati on shoul d i ncl ude i nspecti on of al l mucosal ar eas, assessment of range of moti on of tongue, bi manual pal pati on of fl oor of mouth, pal pati on of the tongue, and assessment of dental heal th. Any of the compl ai nts descr i bed ear l i er r equi r e eval uati on, especi al l y i f symptoms per si st for mor e than 4 weeks or after tr eatment for pr esumed i nfecti on.

TREATMENT The management of pati ents wi th head and neck cancer i s compl ex. The choi ce of tr eatment modal i ty depends on the stage and si te of di sease. Pati ents wi th l ocal l y advanced di sease shoul d be eval uated (pr osthodonti cs, nutr i ti on, speech, and swal l owi ng) by a mul ti di sci pl i nar y team i ncl udi ng otol ar yngol ogi st or head and neck sur gi cal oncol ogi st, radi ati on oncol ogi st, medi cal oncol ogi st, denti st, and per sonnel i nvol ved i n r ehabi l i tati on befor e tr eatment i s i ni ti ated. In general , ei ther sur ger y or radi ati on i s effecti ve as si ngl emodal i ty therapy for pati ents wi th ear l y-stage di sease (stage I or II) for most si tes. The choi ce of modal i ty depends on l ocal exper ti se, pati ent pr efer ence, and functi onal r esul t. For the 60% of pati ents wi th l ocal l y advanced di sease (stage III, IV, and M0), combi nedmodal i ty therapy i s i ndi cated.

Surgery The natur e of the sur gi cal pr ocedur e i s deter mi ned pr i mar i l y by the si ze of the tumor and the str uctur es i nvol ved. Extensi ve sur ger i es and those i nvol vi ng functi on of the tongue

fr equentl y r equi r e myocutaneous fl aps or mi cr ovascul ar fr ee fl aps to achi eve a mor e functi onal r econstr ucti on. Resectabi l i ty depends on the exper i ence of the sur geon and the r ehabi l i tati on team. In general , a tumor i s unr esectabl e i f the sur geon bel i eves that al l of the gr oss tumor cannot be r emoved or that l ocal and di stant contr ol wi l l not be achi eved after sur ger y even wi th adjuvant radi ati on therapy. G eneral l y, i nvol vement of the skul l base, pter ygoi d, and deep neck muscul atur e, and of the major

vessel s por tends a poor outcome wi th sur ger y as a pr i mar y modal i ty. Cer vi cal l ymph node di ssecti ons may be el ecti ve or therapeuti c. El ecti ve neck di ssecti ons ar e done at the ti me of sur ger y i n pati ents wi th necks that ar e cl i ni cal l y negati ve when the r i sk of a posi ti ve l ymph node i s at l east 30% . Therapeuti c neck di ssecti ons ar e done for cl i ni cal l y obvi ous masses. Cer vi cal l ymph node di ssecti ons ar e cl assi fi ed as radi cal , modi fi ed radi cal , or sel ecti ve. The radi cal di ssecti on i ncl udes r emoval of al l l ymph nodes i n the neck fr om l evel s I to V ( F i g. 1.2), i ncl udi ng r emoval of the i nter nal jugul ar vei n, spi nal accessor y ner ve, and ster nocl ei domastoi d muscl e. Thi s sur ger y i s now rar el y per for med because of excessi ve mor bi di ty, especi al l y l oss of shoul der functi on. The modi fi ed radi cal di ssecti on pr eser ves one or mor e of the nonl ymphati c str uctur es. In sel ecti ve neck di ssecti ons, onl y cer tai n l evel s of l ymph nodes ar e r emoved on the basi s of the speci fi c l ymphati c drai nage fr om the pr i mar y si te. Wi th no pal pabl e or CT scan evi dence of cl i ni cal nodal i nvol vement, nodal metastases wi l l be pr esent beyond the confi nes of an appr opr i ate sel ecti ve neck di ssecti on l ess than 10% of the ti me. Senti nel l ymph node di ssecti on and PET scanni ng ar e cur r entl y bei ng eval uated for use i n di agnosi ng posi ti ve l ymph nodes i n pati ents wi th necks that ar e cl i ni cal l y negati ve.

Radiation Therapy The use of radi ati on as a si ngl e therapy i n ear l y-stage tumor s (i .e., T1 and T2) i s as effi caci ous as sur ger y. The choi ce of therapy depends on expected qual i ty of l i fe, functi onal outcome, sequel ae of therapy, and opti ons for tr eatment i n case of r ecur r ence. In l ocal l y advanced tumor s (i .e., T3 and T4), radi ati on therapy i s combi ned wi th sur ger y. In general , postoperati ve radi ati on i s pr efer r ed over pr eoperati ve radi ati on accor di ng to the r esul ts of two randomi zed pr ospecti ve studi es that show super i or l ocal contr ol and mi ni mal l y i ncr eased sur vi val i n the postoperati ve radi ati on ar m i n hypophar yngeal cancer pati ents (23). Postoperati ve radi otherapy i s r ecommended for pati ents at hi gh r i sk for l ocal r ecur r ence [i .e., T4 tumor, cl ose or posi ti ve mar gi ns (50%

3p deletions

>80%

Microsatellite alterations

Present

Dominant oncogene abnormalities ras mutations Her-2/neu overexpression

~30% ~30%

myc family amplification

>50%

bcl-2 overexpression

>50%

Telomerase expression

~90%

AUC, area under the curve; i.v., intravenous.

PATHOLOGY Tabl e 2.2 outl i nes the Wor l d Heal th Or gani z ati on WHO cl assi fi cati on of NSCLC. Adenocar ci noma i s the most fr equentl y di agnosed for m of NSCLC i n both men and women, havi ng r epl aced squamous cel l car ci noma. The r eason for thi s i s uncl ear, but the fol l owi ng hypothesi s has been pr oposed. Incr eased str ength and fr equency of i nhal ati on i s r equi r ed to mai ntai n ni coti ne l evel s i n chr oni c smoker s who smoke l ow-tar, fi l ter ed ci gar ettes. Low-tar ci gar ettes ar e l ess

i r r i tati ng to the pr oxi mal br onchi al tr ee, ther eby al l owi ng deeper i nhal ati on, whi ch per mi ts the car ci nogens i n the i nhal ed vapor to penetrate deepl y.

TABLE 2.2. WHO Classification of Non–small Cell Lung Cancer Histologic types of NSCLC: Modified WHO classification 1. Squamous cell carcinoma 1. Epidermoid 2. Spindle cell variant 2. Adenocarcinoma 1. Acinar 2. Papillary 3. Bronchioloalveolar 4. Solid carcinoma with mucin 3. Large cell 1. Giant cell 2. Clear cell 4. Adenosquamous NSCLC, non–small cell lung cancer; WHO, World Health Organization. Br onchi ol oal veol ar car ci noma, al though cur r entl y cl assi fi ed as a subtype of adenocar ci noma, demonstrates cl i ni cal featur es, suggesti ng that i t r epr esents a di sti nct hi stol ogi c for m of NSCLC. These featur es ar e mani fested as a gr eater tendency for occur r ence i n women and nonsmoker s; the devel opment of bi l ateral , mul ti focal

pul monar y i nvol vement, wi th a l esser tendency for extrathoraci c metastases; and a better sur vi val rate than a si mi l ar stage of NSCLC.

SYMPTOMS AND SIGNS OF LUNG CANCER A mi nor i ty of pati ents pr esent wi th an asymptomati c l esi on that i s di scover ed i nci dental l y on a chest radi ograph. Most l ung cancer s ar e di scover ed because of the devel opment of a new symptom or wor seni ng of a cl i ni cal symptom or si gn. No set of si gns or symptoms ar e pathognomoni c of l ung cancer, and so the di agnosi s i s usual l y del ayed. Cl i ni cal si gns and symptoms of l ung cancer may be di vi ded i nto four categor i es: the symptoms (a) r esul ti ng fr om l ocal tumor gr owth, (b) r esul ti ng fr om r egi onal spr ead, (c) caused by di stant metastases, and (d) r el ated to paraneopl asti c syndr omes. Tabl e 2.3 outl i nes the character i sti c symptoms or si gns.

TABLE 2.3. Symptoms and Signs of Lung Cancer

Primary Disease Central or endobronchial tumor growth Cough Sputum production Hemoptysis Dyspnea Wheeze (classically unilateral) Stridor Pneumonitis, with fever and productive cough (secondary to obstruction)

Peripheral tumor growth Pain, from pleural or chest wall involvement Cough Dyspnea Pneumonitis Regional Involvement (Either Direct or Metastatic Spread) Hoarseness (recurrent laryngeal nerve paralysis) Tracheal obstruction Dysphagia (esophageal compression) Dyspnea (pleural effusion, tracheal or bronchial obstruction, pericardial effusion, phrenic nerve palsy, lymphatic infiltration, and superior vena cava obstruction) Horner syndrome (sympathetic nerve palsy) Metastatic Involvement (Common Sites) Bone involvement Pain, exacerbated by movement or weight bearing; often worse at night Fracture Liver metastases Right hypochondrial pain Icterus Altered mentation Brain metastases Altered mental status Seizures Motor and sensory deficits Paraneoplastic Syndromes

Clubbing Hypertrophic pulmonary osteoarthropathy Hypercalcemia Dermatomyositis Eaton-Lambert syndrome Hypercoagulable state Gynecomastia

MAKING THE DIAGNOSIS OR PLANNING THERAPY Once a suspected tumor i s i denti fi ed, i t i s then necessar y to obtai n a hi stol ogi c di agnosi s and accuratel y stage the tumor. The stage of the di sease pr ovi des an i ndex of the pr ognosi s and al l ows sel ecti on of an appr opr i ate therapeuti c appr oach. In some cases, ti ssue di agnosi s may not be establ i shed unti l the ti me of defi ni ti ve sur gi cal r esecti on. Because 30% to 50% of pati ents have metastati c di sease at the ti me of pr esentati on, cl ues to the cl i ni cal stage wi l l often be evi dent fr om the pati ent's cl i ni cal hi stor y and fr om hi s or her physi cal exami nati on. Sputum cytol ogy i s the noni nvasi ve techni que used for the di agnosi s of NSCLC. It i s most sensi ti ve for central l y l ocated tumor s. Other noni nvasi ve methods of tumor eval uati on i ncl ude chest radi ographs, computer i zed tomography scan (CT scan) of chest (i ncl udi ng the l i ver and adr enal s), magneti c r esonance i magi ng (MRI) (par ti cul ar l y for super i or sul cus tumor s), and posi tr on emi ssi on tomography (PET) scanni ng. To eval uate the potenti al l y i nvol ved si tes as di r ected by a pati ent's symptoms, pl ai n radi ographs, radi onucl eoti de bone scans, and CT scan of the brai n ar e often useful . Apar t fr om sputum cytol ogy, these tests can onl y i nfer the pr esence of cancer.

Invasi ve techni ques ar e usual l y r equi r ed to obtai n the ti ssue sampl e(s) to make a concl usi ve hi stol ogi c di agnosi s. These i ncl ude br onchoscopy (wi th br ushi ngs and washi ngs), transthoraci c br onchi al bi opsy, CT scan–gui ded transthoraci c bi opsy, thoracocentesi s (for pl eural effusi ons), and medi asti noscopy wi th medi asti nal node bi opsy. CT scan and MRI can pr ovi de i nfor mati on about hi l ar and medi asti nal nodal i nvol vement of the tumor. Si ze i s the cr i ter i on used to di sti ngui sh nor mal fr om abnor mal nodes, wi th a shor t axi s nodal di ameter of 1 cm bei ng typi cal l y used as the upper l i mi t of nor mal . However, nodal enl ar gement may r el ate to hyper pl asti c r eacti ve nodes, par ti cul ar l y i n pati ents wi th postobstr ucti ve pneumoni a. The accuracy of CT scan and MRI for detecti ng metastati c hi l ar (N1) or medi asti nal di sease i s onl y 62% to 68% and 68% to 74% , r especti vel y. Pati ents wi th cl i ni cal stage I to III di sease wi th a central tumor or per i pheral tumor s gr eater than 2 cm shoul d have a medi asti noscopy wi th medi asti nal node bi opsy, par ti cul ar l y i f the nodes ar e gr eater than 1 cm i n di ameter on radi ol ogi c eval uati on. Recent studi es have shown that 2-[F -18] fl uor o-D-gl ucose– posi tr on emi ssi on tomography (F DG –PET) i magi ng i s mor e accurate i n detecti ng l ymph node metastases. Combi nati on chest CT scan and PET scan may r epl ace the need for medi asti noscopy and hel p avoi d unnecessar y thoracotomi es. Pl ai n fi l ms, CT scan, and MRI fi ndi ngs ar e often suggesti ve of chest wal l or medi asti nal i nvasi on but may not be defi ni ti ve i n confi r mi ng the same unl ess a chest wal l mass, r i b destr ucti on, or gr oss encasement of the medi asti nal str uctur es i s pr esent. An advantage of MRI i n eval uati ng chest i nvasi on i s i ts super i or soft-ti ssue contrast r esol uti on and mul ti pl anar capabi l i ty. The sensi ti vi ty (63% to 90% ) and speci fi ci ty (84% to 86% ) of MRI i n di agnosi ng chest wal l i nvasi on i s si mi l ar to that of CT scan. However, MRI i s the techni que of choi ce i n eval uati ng super i or sul cus tumor s, as CT scan i s l i mi ted by axi al pl ane and str eak ar ti fact fr om the shoul der s. Common si tes of metastati c di sease fr om NSCLC ar e l ymph nodes, brai n, bone, l i ver, and adr enal gl ands. Routi ne radi ol ogi c eval uati on of occul t metastases i n the absence of cl i ni cal or l aborator y fi ndi ngs r emai ns contr over si al and i s not general l y r ecommended. However, i f a per son wi th known NSCLC devel ops

bone pai n, i t i s most i mpor tant to assess the wei ght-bear i ng bones to avoi d the devel opment of pathol ogi c fractur es. Per sons wi th cl i ni cal l y appar ent r esectabl e di sease commonl y have a metastati c wor k-up, i ncl udi ng CT scan of the brai n and bone, to avoi d potenti al l y unnecessar y sur gi cal i nter venti on (see Tabl e 2.4). The TNM stagi ng system fol l owed ear l i er was r evi sed i n June 1997 (see Tabl e 2.5). The r evi sed stagi ng di vi des stage I and stage II i nto A and B categor i es and modi fi es stage IIIA to mor e accuratel y r epr esent the pr ognosti c i mpl i cati ons of the anatomi c extent of di sease. The T1 N0 M0, T2 N0 M0, and T1 N1 M0 anatomi c subsets ar e desi gnated as separate enti ti es and the T3 N0 M0 categor y i s pl aced i n stage IIB to mor e accuratel y r efl ect di ffer ences i n cl i ni cal outcome. Stage IIIB and IV categor i es have r emai ned unchanged, wi th two excepti ons: satel l i te tumor nodul e(s) i n the pr i mar y-tumor l obe ar e desi gnated T4, and separate metastati c tumor nodul e(s) i n the i psi l ateral nonpr i mar y-tumor l obe(s) of the l ung ar e desi gnated M1. However, i t i s sti l l di ffi cul t to separate a si ngl e satel l i te or metastati c nodul e i n the non–tumor-bear i ng l obe fr om a synchr onous pr i mar y l ung cancer unl ess they ar e of di ffer ent hi stol ogi c type. Despi te di ffer ent cl i ni cal outcomes, no di sti ncti on has been made between stage IIIB di sease wi th and wi thout mal i gnant effusi on. Tabl es 2.5, 2.6, and 2.7 pr ovi de TNM descr i pti ons and stages, the pr ognosi s per cl i ni cal and pathol ogi c stage, and the descr i pti on of medi asti nal nodal status, r especti vel y.

TABLE 2.4. Imaging Options Local disease evaluation

Metastatic disease evaluation

Plain radiographs

Bone: plain films and

bone scan CT scan of chest (including adrenals and liver)

Brain: CT scan or MRI

MRI chest

Liver: CT scan (part of the CT scan of chest) Spinal cord: MRI

PET PET: optional CT scan, computerized tomography scan; MRI, magnetic resonance imaging; PET, positron emission tomography.

TABLE 2.5. Staging System for Non–small Cell Lung Cancer Lung cancer staging: TNM classification

TX

Primary tumor cannot be assessed, or tumor is proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Primary tumor 3 cm in greatest dimension

T2

Involves main bronchus, ≥2 cm from carina Invades the visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung Tumor of any size that directly invades any of the following: Chest wall (including superior sulcus tumors) Diaphragm

T3

Mediastinal pleura Parietal pericardium Involves main bronchus Ta ble o f C o nt e nt s > Se c t io n 3 - Dige s t iv e Sy s t e m > 4 - Es o pha ge a l C a nc e r

4 Esophageal Cancer Gregory D. Leonard* David P. Kelsen† Carmen J. A llegra‡ *The Royal College of Physicians, Dublin, Ir eland † G astr ointestinal

Oncology Ser vice, Memor ial Sloan-Ketter ing Cancer Center , New Yor k, New Yor k ‡ Networ k

for Medical Communication and Resear ch, Atlanta, G eor gia

Esophageal cancer i s the ni nth most commonl y occur r i ng cancer wor l dwi de and the si xth most common cause of cancer mor tal i ty (1). It i s hi ghl y curabl e i n i ts ear l i est stages; however, i t usual l y pr esents i n the advanced di sease. Despi te the l ast two decades of pr ogr ess i n cl i ni cal r esear ch, the medi an sur vi val ti me for a pati ent wi th symptoms of a pr i mar y esophageal cancer i s l ess than 18 months. Most r esear ch and contr over sy i n the tr eatment of esophageal cancer cur r entl y focuses on the r ol e of chemoradi otherapy as ei ther adjuvant or as pr i mar y therapy for esophageal cancer.

EPIDEMIOLOGY United States: Esophageal cancer was esti mated to account for 1% of al l mal i gnanci es and 6% of al l gastr oi ntesti nal mal i gnanci es i n 2003 (2). The age-adjusted i nci dence fr om 1996 to 2000 i s 4.5 cases per 100,000 popul ati on (http://www.seer.cancer.gov/csr /1975_2000/). Appr oxi matel y 13,900 new cases and 13,000 deaths wer e esti mated for 2003.

The medi an age at di agnosi s i s 67 year s. Thi s cancer rar el y occur s i n pati ents younger than 25 year s. Esophageal cancer i s two to four ti mes mor e fr equent i n men than i n women. Si ewer t type 1 tumor s [adenocar ci noma (ADC)] ar e ei ght to ni ne ti mes mor e common i n men than i n women. Rates of occur r ence of esophageal cancer ar e appr oxi matel y thr eefol d hi gher among bl acks than among whi tes. Squamous cel l car ci noma (SCC) i s mor e common i n bl ack men; ADC i s mor e common i n whi te men. F i ve-year r el ati ve sur vi val rates wer e 5% fr om 1974 to 1976 and 13% fr om 1992 to 1998. Rest of the w orld: Ther e ar e appr oxi matel y 500,000 cases of esophageal cancer i n the wor l d, but ther e i s mar ked geographi c var i ati on. Regi ons wi th cl uster s of hi gh rates i ncl ude Chi na (e.g., Li nxi an), Iran, F rance, and South Afr i ca. In the 1970s, appr oxi matel y 90% of esophageal cancer s wer e SCCs. The i nci dence of ADCs has i ncr eased dramati cal l y and cur r entl y accounts for appr oxi matel y 60% to 70% of new cases— a rate of accel erati on gr eater than that of any other cancer i n the Uni ted States.

ETIOLOGY A denocarcinoma Bar r ett esophagus Obesi ty G astr oesophageal r efl ux di sease (G ERD), whi ch can be caused by obesi ty and mi ght r esul t i n Bar r ett esophagus. Squamous Cell Carcinoma Tobacco Al cohol Pr edi sposi ng condi ti ons:

Tyl osi s (SCC) Achal asi a Esophageal di ver ti cul a and webs (SCC) Pl ummer–Vi nson syndr ome Human papi l l omavi r us (HPV) Cel i ac di sease Less si gni fi cant causes i ncl ude envi r onmental exposur e and di etar y factor.

BARRETT ESOPHAGUS Bar r ett esophagus, per haps as a r esul t of G ERD, i s the most i mpor tant r i sk factor (100 ti mes r i sk i ncr ease over other factor s) for ADC. Scr eeni ng r ecommendati ons (no randomi zed tr i al data for sur vei l l ance practi ces) ar e as fol l ows: For no dyspl asi a, endoscopy ever y 2 to 3 year s For l ow-grade dyspl asi a, endoscopy ever y 6 months for 12 months and then year l y For hi gh-grade dyspl asi a, esophagectomy or thr ee monthl y endoscopi es or photodynami c therapy (PDT).

CLINICAL PRESENTATION The most common cl i ni cal pr esentati ons of esophageal cancer ar e l i sted i n Tabl e 4.1 and ar e usual l y r el ated to l ocal compr essi on or i nfi l trati on symptoms or general i zed mal ai se and anor exi a.

TABLE 4.1. Clinical presentation of esophageal cancer Symptoms

Patients with symptoms (%)

Dysphagia (solids usually before liquids)

80–96

Weight loss

42–46

Odynophagia

≤50

Epigastric or retrosternal pain

≤20

Cough or hoarseness

≤5

Tracheoesophageal fistula

1–13

The cl assi c tr i ad for pr esentati on of esophageal cancer i s as fol l ows: Astheni a Anor exi a Anal gesi a (for dysphagi a).

DIAGNOSIS Symptoms Dysphagi a or odynophagi a Hematemesi s Dyspepsi a Hoar seness Dyspnea Anor exi a. Si gns (usual l y l ate pr esentati on) Hor ner syndr ome

Left supracl avi cul ar l ymphadenopathy (Vi r chow node) Cachexi a Hepatomegal y Bone metastases (rar e but paraneopl asti c hyper cal cemi a can occur ). Upper gastr oi ntesti nal endoscopy Thi s di agnosti c pr ocedur e i s the gol d standar d. The combi nati on of endoscopi c bi opsi es and br ush cytol ogy has an accuracy of gr eater than 90% i n maki ng a ti ssue di agnosi s of esophageal cancer. Bar i um contrast radi ography Thi s di agnosti c pr ocedur e can document contour and moti l i ty abnor mal i ti es and unexpected ai r way fi stul a and may be useful when the enti r e esophagus has not been vi sual i zed endoscopi cal l y. However, a ti ssue di agnosi s i s needed for defi ni ti ve di agnosi s.

PATHOLOGY Most newl y di agnosed pati ents have ADC, but ther e ar e contrasti ng r epor ts on thei r r el ati ve pr ognosi s. Less than 1% of esophageal tumor s ar e l ymphoma, mel anoma, car ci nosar coma, or smal l cel l car ci noma. F i fty per cent of tumor s ar i se i n the l ower one-thi r d of the esophagus, 25% ar i se i n the upper esophagus, and 25% of tumor s occur i n the mi ddl e one-thi r d of the esophagus (2).

STAGING The Amer i can Joi nt Commi ssi on for Cancer (AJCC) has desi gnated stagi ng of cancer by TNM cl assi fi cati on, whi ch defi nes the anatomi c extent of di sease (3) (see Tabl e 4.2). Of note, cer vi cal adenopathy i n tumor s i n the l ower one-thi r d of esophagus i s M1 as opposed to N1.

TABLE 4.2. Definition of TNM and stage

grouping TNM stage: Primary tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ T1: Tumor invades lamina propria or submucosa T2: Tumor invades muscularis propria T3: Tumor invades adventitia T4: Tumor invades adjacent structures Regional lymph nodes (N)

N1: Regional lymph node metastasis NX: Regional lymph nodes cannot be assessed N0: No regional

Distant metastasis (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis Tumors of the lower thoracic esophagus M1a: Metastasis in celiac lymph nodes M1b: Other distant metastasis Tumors of the midthoracic esophagus M1a: Not applicable M1b: Other distant metastasis Tumors of the upper thoracic esophagus M1a: Metastasis in cervical nodes

lymph node metastasis

M1b: Other distant metastasis

Stage Grouping Stage 0

Ti s

N0

M0

Stage I

T1

N0

M0

Stage IIA

T2

N0

M0

T3

N0

M0

T1

N1

M0

T2

N1

M0

T3

N1

M0

T4

Any N

M0

Stage IV

Any T

Any N

M1

Stage IVA

Any T

Any N

M1a

Stage IVB

Any T

Any N

M1b

Stage IIB

Stage III

The Si ewer t cl assi fi cati on subcl assi fi es gastr oesophageal juncti on tumor s i nto thr ee types accor di ng to thei r anatomi c l ocati on: Type 1 ar e di stal esophagus tumor s, type II ar e car di a tumor s, and type III ar e subcar di a gastr i c tumor s (4). Stagi ng wor k-up can i ncl ude the fol l owi ng: Computerized tomography scan (CT) scan: CT scan of the chest and abdomen can demonstrate evi dence of spr ead of tumor

to l ymph nodes or di stant metastases to the l i ver (35% ), l ungs (20% ), bone (9% ), and adr enal s (5% ). CT scan may under esti mate the depth of tumor i nvasi on and per i -esophageal l ymph node i nvol vement i n up to 50% of cases. Magneti c r esonance i magi ng (MRI) pr ovi des si mi l ar r esul ts to CT. Endoscopic ultrasound (EUS): EUS may be hel pful when metastases ar e not detected by CT or other i magi ng modal i ti es. EUS i s the opti mal techni que for l ocor egi onal stagi ng. A metaanal ysi s demonstrated gr eater than 71% sensi ti vi ty i n stagi ng pr eoperati ve depth of i nvasi on (T) and gr eater than 60% sensi ti vi ty for l ocor egi onal l ymph nodes (N); speci fi ci ty was gr eater than 67% and gr eater than 40% , r especti vel y (5). Positron emission tomography (PET): PET i s useful when CT i s negati ve for metastati c di sease, and the di agnosi s can change management of cancer i n 20% to 25% of pati ents (6). Br onchoscopy i s r equi r ed i n tumor s l ess than 25 to 26 mm fr om the i nci sor s, to excl ude i nvasi on of the poster i or membranous trachea or tracheoesophageal fi stul a.

TREATMENT Surgery Sur ger y al one r emai ns a standar d tr eatment for esophageal cancer wi th r esectabl e l ocal or l ocor egi onal di sease. In 1993, sur ger y was used as a component of tr eatment i n 34% of pati ents. Sur ger y al one was used i n 18% of pati ents (7). Recent i mpr ovements i n stagi ng techni ques and pati ent sel ecti on have i mpr oved sur gi cal mor bi di ty and mor tal i ty. Operati ve mor tal i ty rates ar e now l ess than 5% . Sur gi cal exper ti se i s a major contr i butor to sur vi val , wi th better outcomes i n hi ghvol ume center s. Resecti on i s possi bl e i n appr oxi matel y 50% of pati ents (8). F i ve-year sur vi val i n pati ents wi th sur gi cal r esecti on i s 5% to 25% . Sur gi cal pr i nci pl es i ncl ude a wi de r esecti on of the pr i mar y tumor by ai mi ng for an R0 r esecti on (no r esi dual tumor ), i ncl udi ng mor e than 5-cm r esecti on mar gi ns pl us r egi onal l ymphadenectomy. Intraoperati ve fr ozen secti on can assess for r esi dual di sease, whi ch, i f pr esent, i s consi der ed an R1

(mi cr oscopi c tumor ) or R2 (macr oscopi c tumor ) r esecti on. In general , pati ents wi th cer vi cal car ci noma of the esophagus ar e not consi der ed candi dates for sur gi cal r esecti on; chemoradi ati on i s favor ed i n these pati ents. Sur gi cal appr oaches i ncl ude the fol l owi ng: Transthoracic resection: En bl oc esophagectomy r equi r es l apar otomy and thoracotomy, for exampl e, total thoraci c or transthoraci c (Lewi s) pr ocedur es. A thr ee-fi el d l ymph node di ssecti on (extended l ymphadenectomy) i ncl udes super i or medi asti num and cer vi cal l ymphadenectomy. It i s the tr eatment of choi ce i n Japan but i s associ ated wi th i ncr eased toxi ci ty and has a questi onabl e sur vi val advantage. Transhiatal esophagectomy: Thi s i ncl udes l apar otomy and cer vi cal anastomosi s. Thi s techni que avoi ds thoracotomy.

Chemoradiotherapy (Combined-modality Approach) Al though no l ar ge pr ospecti ve randomi zed tr i al s have di r ectl y compar ed pr i mar y chemoradi ati on wi th sur ger y, defi ni ti ve chemoradi ati on for l ocor egi onal car ci noma of the esophagus i s consi der ed to be an al ter nati ve to sur ger y. Inter est i n chemoradi otherapy i s based on the Radi ati on Therapy Oncol ogy G r oup (RTOG ) 85-01 tr i al (9) that demonstrated a sur vi val advantage (14 ver sus 9 months medi an sur vi val and 27% ver sus 0% 5-year sur vi val ) i n favor of chemoradi otherapy over radi otherapy al one i n i noperabl e pati ents (see Tabl e 4.3). A number of randomi zed tr i al s of chemoradi otherapy ver sus radi otherapy al one have fai l ed to dupl i cate the r esul ts of RTOG 85-01; however, a r ecent Cochrane r evi ew has confi r med the super i or i ty of chemoradi otherapy ver sus radi otherapy i n fi t, moti vated pati ents (10). Chemoradi otherapy i s now the standar d of car e for pati ents wi th unr esectabl e esophageal cancer or an al ter nati ve to sur ger y for pati ents wi th r esectabl e cancer s.

TABLE 4.3. Radiation Therapy Oncology Grou 85-01 trial of chemoradiotherapy versus rad alone in esophageal cancer Number of Histology patients

121

SCC = 88% ADC = 12%

Treatment

Median 5-Ye survival surviv

Cisplatin 75 mg/m2 d 1 5-FU 1,000 mg/m 2 /d d 1–4 50 Gy of radiation wk 1, 5 Cisplatin/5FU wk 8, 11 versus 64 Gy of radiation 2Gy/fx

14.1 mo vs. 9.3 mo

27% vs. 0%

SCC, squamous cell carcinoma; ADC, adenocarcinom 5-fluorouracil; Gy, Gray of radiation; fx, fraction of From Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal long-term follow-up of a prospective randomized tr 85-01). JAMA 1999;281:1623–1627, with permissio

Chemoradiotherapy as Definitive Therapy in Resectable Cancer Upper thoraci c esophageal (above the aor ti c ar ch) tumor s and T4 or N1 tumor s ar e usual l y consi der ed unr esectabl e. The outcomes of chemoradi otherapy i n RTOG 85-01 wer e comparabl e to those found i n sur gi cal therapy (11). Resul ts fr om the randomi zed tr i al s of pr eoperati ve chemoradi otherapy have demonstrated pathol ogi cal compl ete r esponse rates of gr eater than 25% and ar e associ ated wi th an i mpr oved sur vi val . Tr i al s that used sur ger y after chemoradi otherapy i n pati ents who r esponded and hi gher doses of radi ati on for pati ents who di d not r espond fai l ed to show a benefi t for the gr oup r ecei vi ng sur ger y. A better deter mi nant of the r ol e of sur ger y after chemoradi otherapy i s evi dent fr om two r ecent tr i al s: In the fi r st tr i al , pati ents wi th l ocal l y advanced but r esectabl e tumor s wer e tr eated wi th chemoradi otherapy, and pati ents wi th at l east a par ti al r esponse wer e randomi zed to conti nued chemoradi otherapy or sur ger y (12). Ther e was no di ffer ence i n overal l sur vi val (19.3 ver sus 17.7 months, r especti vel y), but ear l y mor tal i ty and durati on of hospi tal stay wer e l ess i n the chemoradi otherapy-onl y ar m. The second tr i al randomi zed pati ents wi th l ocal l y advanced tumor s to ei ther defi ni ti ve chemoradi otherapy or chemoradi otherapy (l ower doses of radi ati on) and sur ger y (13). Ther e was no si gni fi cant di ffer ence i n sur vi val outcomes (15 ver sus 16 months, r especti vel y) between the two gr oups of pati ents. Ther e was i mpr oved sur vi val i n a subgr oup of pati ents r ecei vi ng sur ger y because they di d not r espond to chemoradi otherapy. No pr ospecti ve randomi zed tr i al has compar ed chemoradi ati on to sur ger y al one i n r esectabl e tumor s. Local r ecur r ence rates, however, r emai n gr eater than 45% . Radi ati on dose escal ati on has not pr oved to be benefi ci al . A r ecent tr i al exami ni ng thi s appr oach was cl osed after an i nter i m anal ysi s i ndi cated that ther e woul d be no advantage wi th hi gher doses of radi ati on.

Preoperative Chemoradiotherapy (Trimodality Approach) The rati onal e for pr eoperati ve chemoradi otherapy was fi r st studi ed by Lei chman et al . i n 21 pati ents wi th SCC. Pati ents wer e tr eated wi th 3,000 cG y of radi ati on and wi th two cycl es of concur r ent 5-fl uor ouraci l (5-F U) and ci spl ati n (14). An addi ti onal 2,000 cG y of radi ati on was gi ven postoperati vel y when r esi dual tumor was seen at sur ger y. The pathol ogi cal l y compl ete r esponse was 37% wi th a medi an sur vi val of 18 months. Ei ght pr ospecti ve randomi zed phase III tr i al s (two r epor ted i n abstract for m) have addr essed the i ssue of whether pr eoperati ve chemoradi otherapy offer s any benefi t over sur ger y al one (11). Much debate exi sts about the i nter pr etati on of these tr i al s (see Tabl e 4.4). Onl y Wal sh et al . have demonstrated si gni fi cant benefi ts i n medi an sur vi val (16 ver sus 11 months; p = 0.01) and 3-year sur vi val (32% ver sus 6% ; p = 0.01) of pati ents r ecei vi ng pr eoperati ve chemoradi otherapy (15). However, l i mi tati ons of thi s tr i al i ncl ude poor sur gi cal outcome, smal l number s of pati ents studi ed, and the fact that al l pati ents had ADC. Other tr i al s fai l ed to dupl i cate these r esul ts, al though many showed nonsi gni fi cant medi an sur vi val benefi ts, di sease-fr ee sur vi val benefi ts, and, overal l , showed a tr end towar d an i mpr ovement i n outcome when pr eoperati ve chemoradi otherapy was added. Use of new chemotherapeuti c agents such as pacl i taxel and i r i notecan have shown pr omi se.

TABLE 4.4. Randomized phase III trials of trimodality therapy compared to surgery

Number of

3-Year survival trimodality

Study

Nygaard (16)

evaluable Histology patients

88

therapy vs. surgery

SCC

17% vs. 9% a

Apintop (17)

69

SCC

24% vs. 10% b

Le Prise (18)

86

SCC

19% vs. 14%

Walsh (15)

113

ADC

32% vs. 6%

Bosset (19)

282

SCC

30% vs. 31% c

Urba (20)

100

SCC 25% ADC 75%

30% vs. 16%

505

SCC 29% ADC 61%

21.7 mo vs. 18.5 mo d

NA

28.2 mo vs. 27.3 mo d

Burmeister (21)

Lee (22)

102

SCC, squamous cell carcinoma; ADC, adenocarcinoma; NA, not available.

a

2 × 2 factorial design; b 5-year survival; c median follow-up of 55 mo; d median survival.

Postoperative Chemoradiotherapy Ther e ar e fewdata on the use of postoperati ve chemoradi otherapy i n esophageal cancer. A r ecent tr i al found a stati sti cal l y si gni fi cant sur vi val advantage for postoperati ve chemoradi otherapy compar ed to sur ger y al one i n gastr oesophageal and gastr i c cancer s (see Tabl e 4.5) (23). On the basi s of these data, adjuvant chemoradi otherapy has been r ecommended for ADC tumor s of the l ower esophagus. It i s possi bl e that the sur vi val benefi t associ ated wi th the use of chemoradi otherapy r esul ts fr om r educti ons i n l ocal r ecur r ences and thus compensates for i nadequate sur ger y (onl y 10% of pati ents had the r ecommended D2 r esecti on).

TABLE 4.5. Intergroup-116 trial of adjuva chemoradiotherapy versus surgery alone in g or gastroesophageal adenocarcinomas

Number Median 3-Year of Surgery Treatment survival survival patients D0 54%

Surgery followed by 5-FU 425

36 mo

50%

D1 36%

mg/m 2 /d d 1–5

vs.

vs.

27 mths

41%

LV 20 mg/m 2 /d d 1–5 a

556

D2 10%

4,500 cGy radiation d28,180 cGy/d 5 d/wk for 5 wk vs. surgery alone

5-FU, 5-fluorouracil; LV, leucovorin. a Two further courses of chemotherapy were given apart after radiation. Additional 5-FU 400 mg/m2 an 20 mg/m2 were given on the first 4 d and the last 3 radiotherapy.

Radiation Therapy Radi ati on therapy al one i s general l y consi der ed pal l i ati ve and i s used i n pati ents who ar e unabl e to tol erate chemoradi otherapy. Preoperative Radiotherapy: No randomi zed tr i al s of pr eoperati ve si ngl e-modal i ty radi otherapy have demonstrated a sur vi val benefi t i n pati ents.

Postoperative Radiotherapy: Si mi l ar l y, ther e i s no benefi t of si ngl e-modal i ty postoperati ve radi otherapy i n pati ents.

Chemotherapy Si ngl e-agent chemotherapy demonstrates r esponse rates of 15% to 25% . Combi nati on chemotherapy r esponse rates ar e 25% to 45% , but thi s has not defi ni ti vel y i mpr oved sur vi val i n advanced di sease states. Ci spl ati n wi th 5-F U i s the most fr equentl y used r egi men for both combi ned-modal i ty therapy i n l ocor egi onal di sease and systemi c therapy for pal l i ati on. SCC may be mor e sensi ti ve to chemotherapy, but ther e i s no di ffer ence i n l ong-ter m outcome between SCC and ADC. New chemotherapeuti c agents have demonstrated encouragi ng r esponse rates (see Tabl e 4.6).

TABLE 4.6. New Chemotherapeutic Agents in Esophageal Cancer Dose Combination Chemotherapy ranges chemotherapy

Respons rates (%)

Cisplatin Paclitaxel

50– 200 mg/m 2

Carboplatin Etoposide

60–

Cisplatin

26–100

Docetaxel

Irinotecan

100 mg/m 2 65– 125 mg/m 2

5-FU

18–24

Cisplatin 22–58 5-FU 5-FU

Oxaliplatin

85– 130 mg/m 2

Epirubicin

48–81

Capecitabine Epirubicin

Capecitabine

1,000– 1,250 mg/m 2

5-FU 54 Cisplatin Oxaliplatin

5-FU, 5-fluorouracil. a Some trials included radiation therapy.

Preoperative (Neoadjuvant) Chemotherapy The poor sur vi val , even for pati ents wi th cl i ni cal l y l ocal i zed car ci noma of the esophagus, suggests that occul t metastases ar e pr esent at di agnosi s, ther eby pr ovi di ng the i mpetus to add systemi c therapy ear l y dur i ng pati ent management. In the two l ar gest tr i al s exami ni ng pr eoperati ve chemotherapy, the Inter gr oup (INT 0113) tr i al (24) showed no sur vi val benefi t,

wher eas the Medi cal Resear ch Counci l (MRC) tr i al (25) demonstrated a 3-month medi an sur vi val advantage for chemotherapy over sur ger y al one (see Tabl e 4.7). The fol l owi ng di ffer ences i n the two studi es may have contr i buted to thei r di ffer ent outcomes: Chemotherapy was of l onger durati on and was wi th hi gher doses i n INT 0113. Thi s therapy may have been detr i mental by del ayi ng access to sur ger y and causi ng mor e toxi ci ty. Sur ger y was per for med i n onl y 80% of the pati ents i n the chemotherapy ar m i n INT 0113 compar ed to 92% i n the MRC tr i al . Outcome for sur ger y al one was poor i n the MRC tr i al , ther eby possi bl y exaggerati ng the benefi ts of chemotherapy. Radi ati on therapy off pr otocol (equal l y di str i buted between tr eatment ar ms) was avai l abl e i n the MRC tr i al . A l ar ger sampl e si ze i n the MRC tr i al may have faci l i tated detecti on of a stati sti cal l y si gni fi cant r esul t.

TABLE 4.7. Comparison of the Two Largest Preoperative Chemotherapy Trials

Intergroup 0113

Medical Research Council (MRC)

Patient number

467

802

Histology

ADC = 54%, SCC = 46%

ADC = 66%, SCC = 31%

Cisplatin 100

Cisplatin 80

Treatment

mg/m 2 D1

mg/m 2 D1

5-FU 1,000 mg/m 2 /d d 1–5

5-FU 1,000 mg/m 2 /d d 1–4

for q4wk × 3 followed by surgery vs. surgery alone Postoperative CT to patients with stable disease or response to preoperative CT

For q3wk × 2 followed by surgery vs. surgery alone

Three further cycles but with cisplatin 75 mg/m2 80% CT + surgery

92% CT + surgery

96% surgery alone

97% surgery alone

14.9 mo CT + surgery

16.8 mo CT + surgery

16.1 mo surgery

13.3 mo

Resectability

Median survival

alone

surgery alone

ADC, adenocarcinoma; SCC, squamous cell carcinoma; CT, chemotherapy; 5-FU, 5fluorouracil.

Postoperative Chemotherapy Most tr i al s of postoperati ve chemotherapy al so i nvol ved pr eoperati ve chemotherapy. As wi th pr eoperati ve chemotherapy, ther e i s r enewed i nter est i n thi s appr oach on the basi s of the MRC data, al though i t has yet to be adopted as a standar d appr oach A r ecent tr i al assessed the use of per i operati ve epi r ubi ci n, ci spl ati n, and 5-F U (ECF ) chemotherapy or sur ger y al one i n esophagogastr i c cancer. In 503 pati ents, 15% had esophagogastr i c cancer and 11% had esophageal cancer. Adjuvant chemotherapy i ncr eased pr ogr essi on-fr ee sur vi val and r esectabi l i ty rates and showed a tr end towar d i mpr oved sur vi val (p = 0.06) (26).

Palliation Pal l i ati ve opti ons can be spl i t i nto l ocal or systemi c opti ons. Local therapi es i ncl ude exter nal beam and brachytherapy radi ati on. Thi s appr oach can pal l i ate dysphagi a i n appr oxi matel y 80% of pati ents. PDT has al so been appr oved by the U. S. Food and Dr ug Admi ni strati on (F DA) for thi s i ndi cati on. For rapi d pal l i ati on, l aser or bal l oon di l atati on and stenti ng i s r ecommended. The pl acement of a gastr ostomy or jejunostomy tube may i mpr ove the pati ent's nutr i ti onal status. The systemi c chemotherapy opti ons i n esophageal cancer ar e i mpr ovi ng (Tabl e 4.6). However, no tr i al has i denti fi ed a r efer ence r egi men speci fi c to esophageal cancer.

Ci spl ati n combi ned wi th 5-F U i s the most commonl y used r egi men, but thi s di d not demonstrate a stati sti cal l y si gni fi cant benefi t over ci spl ati n al one when tested i n a randomi zed tr i al of pati ents wi th advanced SCC of the esophagus (27). Most data on chemotherapy i n advanced esophageal cancer ar e extrapol ated fr om tr i al s i n gastr i c cancer that often i ncl ude gastr oesophageal tumor s. In Eur ope, ECF i s fr equentl y used because of i ts super i or sur vi val compar ed to 5-F U, doxor ubi ci n, and methotr exate (FAMTX) i n advanced esophagogastr i c cancer (28). A r ecent tr i al i n metastati c or unr esectabl e gastr i c and gastr oesophageal cancer eval uated docetaxel , ci spl ati n, and 5F U (DCF ) and ci spl ati n and 5-fl uor ouraci l (CF ). Ti me to di sease pr ogr essi on i mpr oved fr om 3.7 months to 5.2 months (haz ar d rati o 1.704), and medi an overal l sur vi val i mpr oved fr om 8.5 months to 10.2 months (p = 0.0053) i n pati ents r ecei vi ng DCF compar ed to those r ecei vi ng CF (29).

DISTRIBUTION, TREATMENT, AND SURVIVAL FOR ESOPHAGEAL CANCER BY STAGE IN THE UNITED STATES The di str i buti on, tr eatment, and sur vi val i n pati ents wi th esophageal cancer accor di ng to stage i n the Uni ted States ar e gi ven i n Tabl e 4.8.

TABLE 4.8. Stage, Distribution, Treatment a Survival of Esophageal Cancers in the Unite States

Stage

Distribution (%)

Treatment

5-Ye relat surv rat (%

Surgery

Localized (I + II)

Chemoradiotherapy if surgery not possible 25

27 Adjuvant chemoradiotherapy indicated for GE or lower esophageal ADC tumors Surgery if possible (e.g., T3 N0 lesions) Definitive chemoradiotherapy

Regional (III)

28

Neoadjuvant chemoradiotherapy followed by surgery Adjuvant chemoradiotherapy indicated for GE or lower esophageal ADC tumors Best supportive care/palliation

13

Local: Radiation therapy or brachytherapy Intraluminal intubation or dilatation Laser or endocoagulation Photodynamic therapy Chemotherapy: Distant (IV)

25

Cisplatin 100 mg/m 2 i.v. d 1 q21d 5-FU 1,000 mg/m2 i.v. d 1–5 continuous q21d treatment until progression or intolerable toxicity Or Epirubicin 50 mg/m 2 i.v. d 1

2

q21d Cisplatin 60 mg/m 2 i.v. d 1 q21d 5-FU 200 mg/m 2 /d i.v. continuous infusion treatment for maximum of 6 mo

ADC, adenocarcinoma; GE, gastroesophageal; 5-FU 5-fluorouracil.

FOLLOW-UP FOR PATIENTS WITH LOCOREGIONAL DISEASE Ther e i s no standar d sur vei l l ance scheme. Hi stor y and physi cal exami nati on, compl ete bl ood count (CBC), ur ea, el ectr ol ytes, and l i ver functi on tests ar e r ecommended ever y 4 months for 1 year, ever y 6 months for 2 year s, and then annual l y (http://www.nccn.or g). Chest radi ograph shoul d be obtai ned as i ndi cated. CT scans of the chest/abdomen shoul d be obtai ned as cl i ni cal l y i ndi cated. Upper gastr oi ntesti nal endoscopy shoul d be per for med as cl i ni cal l y i ndi cated.

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a randomi sed, contr ol l ed tr i al (the MAG IC tr i al , ISRCTN 93793971). Pr oc Am Soc Clin Oncol 2003;22:249 (abstract 998).

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 3 - Dige s t iv e Sy s t e m > 5 - G a s t ric C a nc e r

5 Gastric Cancer M. W asif Saif Univer sity of Alabama at Bir mingham, Bir mingham, Alabama

EPIDEMIOLOGY Wor l dwi de, gastr i c car ci noma r epr esents the second or thi r d most common mal i gnancy. The fr equency of occur r ence of gastr i c car ci noma at di ffer ent si tes wi thi n the stomach has changed i n the Uni ted States over r ecent decades. Cancer of the di stal hal f of the stomach has been decr easi ng i n the Uni ted States si nce the 1930s. However, over the l ast two decades, the i nci dence of cancer of the car di a and gastr oesophageal juncti on has been rapi dl y r i si ng. The i nci dence of thi s cancer has i ncr eased dramati cal l y, especi al l y i n pati ents younger than 40 year s. An esti mated 22,400 new cases and 12,100 deaths fr om gastr i c car ci noma wer e expected i n the Uni ted States i n 2003.

RISK FACTORS Age at onset: fi fth decade Mal e-to-femal e rati o i s 1.67:1.0 Afr i can Amer i can–to-whi te rati o i s 1.5:1 Pr ecur sor condi ti ons i ncl ude chr oni c atr ophi c gastr i ti s and i ntesti nal metapl asi a, per ni ci ous anemi a (10% to 20% i nci dence), par ti al gastr ectomy for beni gn di sease, Helicobacter pylor i i nfecti on (especi al l y chi l dhood exposur e—thr ee- to fi vefol d i ncr ease), Ménétr i er di sease, and gastr i c adenomatous pol yps. These pr ecur sor l esi ons ar e l ar gel y l i nked to di stal (i ntesti nal type) gastr i c car ci noma. Fami l y hi stor y: fi r st degr ee (two- to thr eefol d); the fami l y of

Napol eon Bonapar te i s an exampl e; fami l i al cl uster i ng; pati ents wi th her edi tar y nonpol yposi s col or ectal cancer (Lynch syndr ome II) ar e at i ncr eased r i sk; r ecentl y, ger ml i ne mutati ons of Ecadher i n have been l i nked to the rar e enti ty of fami l i al di ffuse gastr i c cancer. Tobacco use r esul ts i n a 1.5 to thr eefol d i ncr eased r i sk for cancer. Fer menti ng and smoki ng of food r esul ts i n hi gh sal t and ni tr osami nes content. Defi ci enci es of vi tami ns A, C, and E; β-car otene; sel eni um; and fi ber ar e r i sk factor s for cancer. Bl ood type A Al cohol The mar ked r i se i n the i nci dence of gastr oesophageal and pr oxi mal gastr i c adenocar ci noma appear s to be str ongl y cor r el ated to the r i si ng i nci dence of Bar r ett esophagus.

PATHOPHYSIOLOGY Most gastr i c cancer s ar e adenocar ci nomas (mor e than 90% ) of two di sti nct hi stol ogi c types: i ntesti nal and di ffuse. The other gastr i c cancer s ar e pr edomi nantl y non-Hodgki n l ymphomas or l ei omyosar comas. Di ffer enti ati ng between adenocar ci noma and l ymphoma i s cr i ti cal because the pr ognosi s and tr eatment for these two enti ti es di ffer consi derabl y.

Intestinal Type The “epi demi c” for m of cancer i s fur ther di ffer enti ated by gl and for mati on and i s associ ated wi th pr ecancer ous l esi ons, gastr i c atr ophy, and i ntesti nal metapl asi a. The i ntesti nal for m accounts for most di stal cancer s and i s stabl e or i ts i nci dence i s decl i ni ng. These cancer s i n par ti cul ar ar e associ ated wi th H. pylor i i nfecti on, as pr oposed by Cor r ea. In thi s car ci nogenesi s model , the i nter pl ay of envi r onmental factor s l eads to gl andul ar atr ophy, r el ati ve achl or hydr i a, and i ncr eased gastr i c pH. Thi s r esul ts i n bacter i al over gr owth, and H. pylor i and bacter i a pr oduce ni tr i tes and ni tr oso compounds causi ng fur ther devel opment of gastr i c atr ophy and i ntesti nal metapl asi a, ther eby i ncr easi ng the r i sk of cancer. Thi s for m i s mor e common i n ar eas of the wor l d wher e gastr i c

car ci noma i s endemi c. The r ecent decl i ne i n gastr i c car ci noma i n the Uni ted States i s l i kel y the r esul t of a decl i ne i n the i nci dence of i ntesti nal type l esi ons. Intesti nal type l esi ons ar e associ ated wi th an i ncr eased fr equency of over expr essi on of epi der mal gr owth-factor r eceptor, er bB-2 and er bB-3.

Diffuse Type The “endemi c” for m of car ci noma i s mor e common i n younger pati ents and exhi bi ts an undi ffer enti ated si gnet-r i ng hi stol ogy. Ther e i s a pr edi l ecti on for submucosal spr ead because of l ack of cel l cohesi on, l eadi ng to l i ni ti s pl asti ca. Conti guous spr ead of the car ci noma to the per i toneum i s common. Pr ecancer ous l esi ons have not been i denti fi ed, and a car ci nogenesi s model has not been pr oposed al though i t i s al so associ ated wi th H. pylor i i nfecti on. G eneti c pr edi sposi ti ons to endemi c for ms of car ci noma have been r epor ted, as have associ ati ons between car ci noma and i ndi vi dual s wi th type A bl ood. These cancer s occur i n the pr oxi mal stomach wher e i ncr eased i nci dence has been obser ved wor l dwi de; stage for stage, these cancer s have a wor se pr ognosi s than do di stal cancer s. Di ffuse l esi ons have been l i nked to abnor mal i ti es of fi br obl ast gr owth-factor systems, i ncl udi ng the K-sam oncogene (see F i g. 5.1).

FIG. 5.1. Two hi stol ogi cal types of gastr i c adenocar ci noma. A : Intesti nal B: Di ffuse.

Molecular Analysis l oss of heter oz ygosi ty of chr omosomes 5q or APC gene (del eted i n 34% of gastr i c cancer s), 17p, and 18q (DCC gene) mi cr osatel l i te i nstabi l i ty, par ti cul ar l y, of transfor mi ng gr owth factor-ß (TG F ß) type II r eceptor, wi th subsequent gr owthi nhi bi ti on der egul ati on p53 i s mutated i n appr oxi matel y 40% to 60% cases by al l el i c l oss and base transi ti on mutati ons r educed E-cadher i n expr essi on, a cel l adhesi on medi ator, i s obser ved i n di ffuse-type undi ffer enti ated cancer s Her 2/neu and er bB-2/er bB-3 (epi der mal gr owth factor s) ar e over expr essed, especi al l y i n i ntesti nal for ms Epstei n–Bar r vi ral genomes ar e detected r as mutati ons ar e rar el y r epor ted, i n contrast to other gastr oi ntesti nal cancer s.

DIAGNOSIS G astr i c car ci noma, when super fi ci al and sur gi cal l y curabl e, typi cal l y pr oduces no symptoms. Among 18,365 pati ents anal yzed by the Amer i can Col l ege of Sur geons, pati ents pr esented wi th the fol l owi ng symptoms: wei ght l oss (62% ) abdomi nal pai n (52% )

nausea (34% ) anor exi a (32% ) dysphagi a (26% )

mel ena (20% ) ear l y sati ety (18% ) ul cer-type pai n (17% ) and l ower extr emi ty edema (6% ). Cl i ni cal fi ndi ngs at pr esentati on may demonstrate the fol l owi ng symptoms: anemi a (42% ) hypopr otei nemi a (26% ) abnor mal l i ver functi ons (26% ) fecal occul t bl ood (40% ). G astr i c car ci nomas spr ead by di r ect extensi on, i nvadi ng i nto adjacent str uctur es. The di sease may al so spr ead by l ymphati c vessel s: to i ntra-abdomi nal nodes and l eft supracl avi cul ar nodes (Vi r chow node) al ong per i toneal sur faces, r esul ti ng i n a per i umbi l i cal nodul e (Si ster Mar y Joseph node, named after the nur se i n the operati ng r oom of Mayo Cl i ni c, or “per i umbi l i cal l ymph nodes,” whi ch for m as tumor spr eads al ong the fal ci for m l i gament to subcutaneous si tes) to Ir i sh node, a l eft anter i or axi l l ar y l ymph node r esul ti ng fr om the spr ead of pr oxi mal pr i mar y cancer to l ower esophageal and i ntrathoraci c l ymphati cs to enl ar ged ovar y (Kr ukenber g tumor ; ovar i an metastases) to a mass i n the cul -de-sac (Bl umer shel f ), whi ch i s pal pabl e on r ectal exami nati on or to frank per i toneal car ci nomatosi s and mal i gnant asci tes.

The l i ver i s the most common si te of hematogenous di ssemi nati on, al though pul monar y metastases ar e al so seen.

Paraneoplastic Syndromes

Skin Syndromes: Acanthosi s ni gr i cans Der matomyosi ti s Ci r ci nate er ythemas Pemphi goi d Sebor r hei c keratoses: Leser–Tr él at si gn, acute onset. Central Nervous System (CNS) Syndromes: Dementi a Cer ebel l ar ataxi a. Miscellaneous Syndromes: Thr ombophl ebi ti s Mi cr oangi opathi c hemol yti c anemi a Membranous nephr opathy.

Tumor Markers Car ci noembr yoni c anti gen (CEA) i s el evated i n 40% to 50% of cases, useful i n fol l ow-up but not for scr eeni ng α-Fetopr otei n and CA 19-9 ar e el evated i n 30% of pati ents wi th gastr i c cancer Medi cal l y r efractor y per si stent pepti c ul cer may pr ompt bar i um or endoscopi c eval uati on.

Endoscopic Findings Ini ti al upper gastr oi ntesti nal endoscopy and doubl e-contrast bar i um swal l ow i denti fy suggesti ve l esi ons and have di agnosti c accuracy of 95% and 75% , r especti vel y. Computer i zed tomographi c scanni ng i s then useful for assessi ng l ocal extensi on, l ymph node i nvol vement, and pr esence of metastasi s, al though under stagi ng occur s i n most cases.

Endoscopi c ul trasonography assesses the depth of tumor i nvasi on and l ymph node status wi th 80% accuracy, suppl ementi ng pr eoperati ve eval uati ons.

STAGING The Amer i can Joi nt Commi ttee on Cancer (AJCC) has desi gnated stagi ng by TNM cl assi fi cati on (see Tabl e 5.1).

TABLE 5.1. TNM Classification of Cancer Staging Designated by the American Joint Committee on Cancer (AJCC) Primary Tumor Tis: Carcinoma T1: Invasion of T2: Invasion of T3: Invasion of T4: Invasion of

in situ lamina propria or submucosa muscularis propria serosa adjacent structures

Lymph Node Status N0: No regional lymph node involvement N1: Metastases to 1 to 6 regional lymph nodes N2: Metastases to 7 to 15 regional lymph nodes N3: Metastases to more than 15 regional lymph nodes Metastatic Disease M0: No distant metastases M1: Distant metastases present

Stage 0

Tis

N0

M0

IA

T1

N0

M0

T1

N1

M0

T2

N0

M0

T1

N2

M0

T2

N1

M0

T3

N0

M0

T2

N2

M0

T3

N1

M0

T4

N0

M0

T3

N2

M0

T4

N1–3

M0

T1–3

N3

M0

T1–4

N0–2

M1

IB

II

IIIA

IIIB

IV

Two-thirds of patients are first seen with stage III or IV disease. Lymphadenectomy should contain at least 15

lymph nodes for proper staging.

PROGNOSIS a. Pathol ogi cal stagi ng r emai ns the most i mpor tant deter mi nant of pr ognosi s. b. Other pr ognosti c var i abl es that have been r epor ted to be associ ated wi th an unfavorabl e outcome i ncl ude: ol der age l ocati on of tumor (see Tabl e 5.2) wei ght l oss gr eater than 10% di ffuse ver sus i ntesti nal hi stol ogy (5-year sur vi val after r esecti on, 16% ver sus 26% , r especti vel y) hi gh-grade or undi ffer enti ated tumor s four or mor e l ymph nodes i nvol ved aneupl oi d tumor s el evati ons i n epi der mal gr owth factor or P-gl ycopr otei n l evel over expr essi on of thymi dyl ate synthase over expr essi on of ERCC1, p53, and Her-2 l oss of p21 and p27.

TABLE 5.2. Five-year Survival with Respect to Location of Tumor Site Proximal

5-yr survival after surgical resection (%)

stomach

10

Distal stomach

25

Entire stomach

5

MANAGEMENT OF GASTRIC CANCER Standard of Care Al though sur gi cal r esecti on r emai ns the cor ner stone of gastr i c cancer tr eatment, the opti mal extent of nodal r esecti on r emai ns contr over si al , wi th randomi zed studi es fai l i ng to show that the D2 pr ocedur e i mpr oves sur vi val when compar ed wi th D1 di ssecti on. The hi gh rate of r ecur r ence and poor sur vi val of pati ents fol l owi ng sur ger y pr ovi des a rati onal e for the ear l y use of adjuvant tr eatment. Adjuvant chemotherapy or adjuvant radi otherapy, when used al one, does not i mpr ove sur vi val fol l owi ng r esecti on. However, the r esul ts of the Inter gr oup 0116 study ar e pr omi si ng i n showi ng that the combi nati on of 5-fl uor ouraci l (5-F U)–based chemotherapy wi th radi otherapy si gni fi cantl y pr ol ongs di sease-fr ee and overal l sur vi val when compar ed to no adjuvant tr eatment. In advanced gastr i c cancer, chemotherapy enhances qual i ty of l i fe and pr ol ongs sur vi val when compar ed wi th the best suppor ti ve car e. Ther e i s no agr eed standar d of tr eatment i n thi s setti ng. Of the commonl y used r egi mens, epi r ubi ci n pl us ci spl ati n and 5-F U (ECF ) pr obabl y has the str ongest cl ai m to thi s r ol e. However, ther e i s a pr essi ng need for assessi ng new agents, both cytotoxi c and mol ecul ar l y tar geted, i n both the advanced and adjuvant setti ngs.

Surgery Al though compl ete sur gi cal r esecti on of the tumor and adjacent l ymph nodes r emai ns the onl y chance for cur e, up to 80% of gastr i c cancer i n pati ents i n the Uni ted States i s advanced at di agnosi s. Sur gi cal exti r pati on of gastr i c cancer i s i ndi cated i n pati ents wi th stages I, II, and III di sease, wi th mi ni mal l ymph node i nvol vement.

Tumor si ze and l ocati on di ctate the type of sur gi cal pr ocedur e to be used (Tabl e 5.2). Current Issues A re: a. subtotal ver sus total gastr ectomy b. extended l ymphadenectomy c. pr ophyl acti c spl enectomy.

Subtotal versus Total Gastrectomy Subtotal gastr ectomy (SG ) may be per for med i n case of pr oxi mal car di a or di stal l esi ons, pr ovi ded that the fundus or car di oesophageal juncti on i s not i nvol ved. Pr oxi mal gastr ectomy i s associ ated wi th i ncr eased postoperati ve compl i cati ons, mor tal i ty, and qual i ty-of-l i fe decr ement, necessi tati ng thor ough consi derati on of compl ete gastr i c r esecti on. Total gastr ectomy (TG ) i s mor e appr opr i ate i f tumor i nvol vement i s di ffuse and ar i ses i n the body of the stomach, wi th extensi on to wi thi n 6 cm of the car di a (see F i gs. 5.2 and 5.3).

FIG. 5.2. (A and B) Total gastr ectomy (TG ).

FIG. 5.3. (A and B) Subtotal gastr ectomy (SG ).

Extended Lymph Node Dissection The r egi onal l ymph nodes i ncl ude N1 and N2 l ymph node gr oups (l esser and gr eater cur vatur e of per i gastr i c, l eft gastr i c, common

hepati c, spl eni c, and cel i ac axi s nodes). D2 l ymphadenectomy i nvol ves mor e extensi ve N2 l ymph-node–gr oup r esecti on and i s r epor ted to i mpr ove sur vi val i n pati ents wi th T1, T2, and some ser osa-i nvol ved T3 l esi ons. Factor s such as operati ve ti me, hospi tal i z ati on l ength, and transfusi on r equi r ements, and thus mor bi di ty, ar e al l i ncr eased. The gr eatest benefi t of extended l ymph node di ssecti on (ELD) may occur i n ear l y gastr i c cancer l esi ons wi th smal l tumor s and super fi ci al mucosal i nvol vement because up to 20% of such l esi ons have occul t l ymph node i nvol vement. The r outi ne use of D2 l ymphadenectomy conti nues to be studi ed.

Prophylactic Splenectomy Routi ne spl enectomy for tumor s that do not adher e to or i nvade the spl een i s not benefi ci al . Palliative sur ger y i s consi der ed i n pati ents wi th obstr ucti on, bl eedi ng, or pai n, and despi te operati ve mor tal i ti es of 25% to 50% , the r esul ts fr om the gastr ojejunostomy bypass sur ger y al one i ndi cate a twofol d i ncr ease i n mean sur vi val . The sel ecti on of pati ents most l i kel y to benefi t fr om thi s pal l i ati ve effor t r equi r es fur ther eval uati on.

Radiation Therapy G astr i c car ci noma i s r el ati vel y r esi stant to radi otherapy; consequentl y, for pati ents wi th l ocal l y r ecur r ent or metastati c di sease, moderate doses of exter nal -beam i r radi ati on ar e used onl y to pal l i ate symptoms and not to i mpr ove sur vi val . Local or r egi onal r ecur r ence i n the gastr i c or tumor bed, the anastomosi s, or r egi onal l ymph nodes occur i n 40% to 65% of pati ents after gastr i c r esecti on wi th curati ve i ntent (see Tabl e 5.3). The fr equency of such r el apses makes r egi onal radi ati on an attracti ve possi bi l i ty for adjuvant therapy. Thi s modal i ty i s l i mi ted by the techni cal chal l enges i nher ent i n abdomi nal i r radi ati on, opti mal defi ni ti on of fi el ds, and the general l y di mi ni shed per for mance status, i n par ti cul ar, nutr i ti onal state, of potenti al candi dates.

Ser i al studi es of the G astr oi ntesti nal Tumor Study G r oup (G ITSG ) of pati ents wi th l ocal l y unr esectabl e pancr eati c and gastr i c adenocar ci noma have shown that combi ned-modal i ty therapy i s super i or to ei ther opti mal radi otherapy or chemotherapy al one. On the basi s of thi s concept, combi ned chemoradi ati on typi cal l y i n combi nati on wi th 5-F U chemotherapy has been eval uated both i n the neoadjuvant and the adjuvant setti ngs. Pal l i ati ve radi ati on i s i mpor tant i n managi ng pai n, obstr ucti ons, and bl eedi ng. Investi gator s at the Nati onal Cancer Insti tute randomi zed 60 pati ents who under went curati ve r esecti on to ei ther r ecei ve i ntraoperati ve radi otherapy (IORT) or not r ecei ve IORT. IORT fai l ed to affor d a benefi t over conventi onal therapy i n overal l sur vi val .

TABLE 5.3. Failure Areas following Surgery

Failure area

MGH clinical (130) no. (%)

Gastric bed

27 (21%)

58 (55%)

48 (52%)

Anastomosis or stump

33 (25%)

28 (27%)

55 (60%)

11 (8%)

45 (43%)

48 (52%)

Lymph nodes

MINN MCNEER reoperation autopsy (105) no. (92) no. (%) (%)

no., total number of patients; MGH, Mass achusetts general hospital; MINN, Minnesota;

MCNEER, Massey Cancer Center

Adjuvant Chemoradiotherapy In 1993, a meta-anal ysi s of 11 randomi zed, contr ol l ed tr i al s concl uded that postoperati ve chemotherapy offer ed no si gni fi cant sur vi val benefi t beyond that associ ated wi th curati ve r esecti on. However, thi s meta-anal ysi s was l ater cr i ti ci zed for l acki ng suffi ci ent power to detect a di ffer ence and for i ts choi ce of tr i al s. Ther e have been several randomi zed tr i al s publ i shed si nce the meta-anal ysi s of Her mans et al . Ear l e and Mar oun r ecentl y conducted another meta-anal ysi s of al l studi es thr ough 1999. A smal l sur vi val benefi t was noted for pati ents randomi zed to adjuvant therapy [r el ati ve r i sk = 0.94; 95% confi dence i nter val (CI), 0.89 to 1.00]. A pr ospecti ve randomi zed tr i al fr om the Br i ti sh Stomach Cancer G r oup fai l ed to demonstrate a sur vi val benefi t for postoperati ve adjuvant radi ati on al one, al though l ocor egi onal fai l ur es had decr eased fr om 27% to 10.6% . Adjuvant exter nal -beam radi ati on therapy wi th combi ned chemotherapy has been eval uated i n the Uni ted States. In a phase III i nter gr oup tr i al (INT-0166), 556 pati ents wi th compl etel y r esected stage IB to stage IV M0 adenocar ci noma of the stomach and gastr oesophageal juncti on wer e randomi zed to r ecei ve sur ger y al one or sur ger y pl us postoperati ve chemotherapy (5-F U and l eucovor i n) and concur r ent radi ati on therapy (45 G y). A si gni fi cant sur vi val benefi t has been r epor ted for adjuvant combi ned-modal i ty therapy wi th 5-year medi an fol l ow-up. Medi an sur vi val was 36 months for the adjuvant chemoradi ati on gr oup as compar ed to 27 months for the sur ger y al one ar m (P = 0.005). Thr ee-year overal l sur vi val and r el apsefr ee sur vi val wer e 50% and 48% , r especti vel y, for adjuvant chemoradi ati on and 41% and 31% , r especti vel y, for sur ger y al one (P = 0.005).

Neoadjuvant Chemoradiotherapy The avai l abl e data on the r ol e of neoadjuvant pr eoperati ve therapy ar e not yet concl usi ve. Al though neoadjuvant therapy may r educe

the tumor mass i n many pati ents, several randomi zed, contr ol l ed tr i al s have shown that, compar ed wi th pr i mar y r esecti on, a mul ti modal appr oach does not r esul t i n a sur vi val benefi t i n pati ents wi th l ocor egi onal , that i s, potenti al l y r esectabl e, tumor s. In contrast, i n pati ents wi th l ocal l y advanced tumor s (i .e., pati ents i n whom compl ete tumor r emoval wi th pr i mar y sur ger y seems unl i kel y), neoadjuvant therapy i ncr eases the l i kel i hood of compl ete tumor r esecti on on subsequent sur ger y. However, onl y those pati ents wi th objecti ve hi stopathol ogi c r esponse to pr eoperati ve therapy seem to benefi t fr om thi s appr oach.

Chemotherapy The most commonl y admi ni ster ed chemotherapeuti c agents wi th objecti ve r esponse rates i n gastr i c cancer i ncl ude 5-F U, doxor ubi ci n, ci spl ati n, methotr exate, mi tomyci n, etoposi de, and doxor ubi ci n.

Chemotherapy Versus Best Supportive Care Four studi es have randomi zed pati ents wi th metastati c gastr i c cancer to ei ther combi nati on chemotherapy or best suppor ti ve car e (BSC). Two studi es used fl uor ouraci l , doxor ubi ci n, and methotr exate (FAMTX) and two studi es used etoposi de, fl uor ouraci l , and l eucovor i n (ELF ) as the pr i mar y chemotherapeuti c agents. In al l four studi es, a si gni fi cant sur vi val benefi t was noted for pati ents randomi zed to chemotherapy (see Tabl e 5.4).

TABLE 5.4. Chemotherapy Versus Best Supportive Care (BSC) Regimen Patients

Survival BSC (mo)

Survival chemo (mo)

FAMTX

36

3

12

FAMTX

40

3

10

ELF

37

3

7.5+

ELF

18

4

10

BSC, best supportive care; FAMTX, fluorouracil, doxorubicin, and methotrexate; ELF, etoposide, fluorouracil, and leucovorin.

Single Agents Versus Combination Regimens Single Agents Monotherapy wi th si ngl e agents r esul ts i n 15% to 20% r esponse rates. 5-F U i s the most extensi vel y studi ed, pr oduci ng a 20% r esponse rate. In addi ti on, mi tomyci n-C (MMC), adr i amyci n, and car musti ne (BCNU) have shown si mi l ar r esul ts. Mor e r ecent studi es usi ng wel l -defi ned r esponse cr i ter i a, have, however, fai l ed to pr oduce such r esul ts, showi ng r esponse rates of l ess than 10% for 5-F U and adr i amyci n. Ci spl ati n has been used r ecentl y and has shown pr omi si ng r esul ts i n mor e than one study. Compl ete r esponses wi th si ngl e agents ar e, however, rar e, and par ti al r egr essi ons ar e r el ati vel y br i ef. Newer agents bei ng i nvesti gated i ncl ude taxoter e, taxol , oxal i pl ati n, i r i notecan, and oral for ms of 5F U (see Tabl e 5.5).

TABLE 5.5. Single-agent Chemotherapy in Advanced Gastric Cancer Drug

n patients

RR (%)

5-FU

392

21

MMC

211

30

Cisplatin

36

22

CCNU

37

8

MTX

28

11

Adriamycin

68

25

BCNU

23

17

RR, response rate; 5-FU, 5-fluorouracil; MMC, mitomycin-C; CCNU, 1-(2-chloroethyl)-3cyclohexyl-1-nitrosourea; MTX, methotrexate; BCNU, adriamycin, and carmustine.

Combination Chemotherapy Better under standi ng of the phar macol ogy of many chemotherapeuti c agents, i ncl udi ng 5-F U, the mai n dr ug used i n advanced gastr i c cancer, has l ed to the devel opment of combi nati on r egi mens. Var i ous combi nati ons of acti ve agents have been r epor ted to i mpr ove the r esponse rate among pati ents wi th advanced gastr i c car ci noma, appr oachi ng 30% to 60% . However, the Nor th Central Cancer Tr eatment G r oup (NCCTG ) obser ved no differ ence in over all sur vival among 252 pati ents randomi zed to r ecei ve 5-F U, doxor ubi ci n, and semusti ne (methyl -CCNU) (FAMe); 5F U, doxor ubi ci n, and ci spl ati n (FAP); or 5-F U al one. Most commonl y used combi nati on r egi mens i ncl ude FAM (fl uor ouraci l , doxor ubi ci n, mi tomyci n-C), FAP, ECF, ELF, F LAP (fl uor ouraci l , l eucovor i n, doxor ubi ci n, ci spl ati n), PELF (ci spl ati n, epi doxor ubi ci n, l eucovor i n, fl uor ouraci l wi th gl utathi one and fi l grasti m), FAMTX, and F UP (fl uor ouraci l , ci spl ati n) (Tabl es 5.6, 5.7, and 5.8).

TABLE 5.6. Combination regimens Drugs

No. of RR patients (%)

MS

Commen

FAM

656

30

12.5 mo

Until recen was the mo widely prescribed regimen

FAMe

141

28

—

—

FAP

234

34

30 wk

Significant toxicity

EAP

197

46

10– 17 mo

Benefits patients wi more locall advanced disease but less benefic in patients with peritoneal carcinomat and other M disease

Treatmentrelated dea

in 10% of patients

FAMTX

ELF

Taxotere/CDDP

364

>100

47

41

9– 48

53

44

48

25

51

135

45

CDDP/CPT-11

ECF

7– 10 mo

12% compl responders

10 mo

Useful in elderly and renally impaired patients

9 mo

Despite hematologi toxicity, overall well tolerated

9 mo

Active agai both gastri and GEJX —

8.7 m

1-yr surviv 36%

33% compl responders The

MLP-F

82

16 m

percentage complete responders was influen by supplement local therap (i.e., radiat to 50%)

RR, response rate; MS, median survival; FAM, fluorouracil, doxorubicin, mitomycin-C; FAMe, 5-FU doxorubicin, and semustine; FAP, 5-FU, doxorubicin and cisplatin; EAP, Etoposide, doxorubicin, cisplatin FAMTX, fluorouracil, doxorubicin, and methotrexate ELF, etoposide, fluorouracil, and leucovorin; CDDP, cisplatin; CPT-11, irinotecan; ECF, epirubicin plus cisplatin and 5-FU; MLP-F, Methotrexate, Leucovori 5-Fu and cisplatin.

TABLE 5.7. Randomized studies in advanced gastric cancer using second-generation regimens n RR (%) patients FAMTX vs. FAM

213

41 vs. a

MS 42 wk vs. 29 wk a

PELF vs. FAM FAMTX vs. EAP ECF vs. FAMTX

147

43 vs. 15 a

35 wk vs. 23 wk

60

33 vs. 20

7.3 mo vs. 6.1 mo

274

45 vs. 21 a

8.9 mo vs. 5.7 mo a

RR, response rate; MS, median survival; FAMTX, fluorouracil, doxorubicin, and methotrexate; FAM, fluorouracil, doxorubicin, mitomycin-C; PELF, cisplatin, epidoxorubicin, leucovorin, fluorouracil with glutathione and filgrastim; ECF, epirubicin plus cisplatin and 5FU. a Difference is statistically significant.

TABLE 5.8. Regimens and doses of agents Drug combinations

Doses in mg/m 2 /schedule

RR/CR

FAMTX Methotrexate

1,500 d1, h0

Leucovorin

15 PO q6 × 8, starting h0

30%– 70%/12%

5-FU

1,500 d1, h1

Doxorubicin

30 d15

ELF Leucovorin

300 d1–3

Etoposide

120 d1–3

5-FU

500 d1–3

48%/12%

CPT-11/CDDP CPT-11

60 d1, 8, 15, 22

CDDP

25–30 d1, 8, 15, 22

30%– 40%

ECF Epirubicin

50 d1

CDDP

60 d1

5-FU

200 qd by continuous i.v. × 21 wk

37%– 45%/17%

RR, response rate; CR, complete remission.

Newer Agents Newer chemotherapeuti c agents, i ncl udi ng i r i notecan, gemci tabi ne, oxal i pl ati n, and taxanes, show pr omi si ng acti vi ty and ar e cur r entl y bei ng tested i n phase III tr i al s. Taxoter e has al r eady been i nvesti gated i n two phase II cl i ni cal tr i al s. In the Eur opean tr i al , a 24% r esponse rate was r epor ted i n a ser i es of 33 pati ents wi th advanced gastr i c cancer. It i s i nter esti ng that pati ents who had thei r pr i mar y tumor r emoved r esponded better than those pati ents who di d not. In a Japanese study, 20% of pati ents who showed no r esponse to pr evi ous chemotherapy had a par ti al r esponse to 60 mg per m2 of 3- or 4-weekl y doses of taxoter e. Docetaxel has al so been shown to l ack cr oss-r esi stance wi th other dr ugs i n the tr eatment of gastr i c cancer and i s l i kel y to be at l east addi ti ve to ci spl ati n and 5-F U. Phase II r esul ts of docetaxel –ci spl ati n has yi el ded r esponse rates si mi l ar to those achi eved by ECF and PELF. Addi ng 5-F U to docetaxel –ci spl ati n has achi eved an objecti ve r esponse rate (ORR) of 52% ver sus 45% for docetaxel –ci spl ati n al one i n a randomi zed phase II tr i al . Docetaxel based r egi mens demonstrate acceptabl e tol erabi l i ty despi te pr edi ctabl e hematotoxi ci ty. Neutr openi a, the major toxi ci ty, i s manageabl e by dose modi fi cati on or by usi ng pr ophyl acti c granul ocyte col ony sti mul ati ng factor. Several phase III tr i al s ar e now ongoi ng, i ncl udi ng a l ar ge-scal e tr i al of docetaxel –ci spl ati n–5F U ver sus ci spl ati n–5-F U. Ir inotecan (CPT-11) has al so been used al one or i n combi nati on wi th ci spl ati n i n phase I–II cl i ni cal studi es. Response rates of 23% and 41% , r especti vel y, wi th acceptabl e toxi ci ty wer e r epor ted. In the fi r st study, objecti ve r esponses wer e obser ved i n 20% of pr etr eated pati ents (mostl y wi th 5-F U). Usi ng Capecitabine (Xeloda) i nstead of 5-F U i n combi nati on r egi men i s al so under eval uati on i n randomi zed tr i al s. S-1 i s a novel oral fl uor opyr i mi di ne der i vati ve composed of tegafur (5-F U pr odr ug), 5-chl or o-2,4-di hydr oxypyr i di ne (i nhi bi tor of 5-F U degradati on), and potassi um oxonate (i nhi bi tor of gastr oi ntesti nal toxi ci ti es). A phase II tr i al has r eveal ed a r esponse rate of 53.6% , wher eas a r etr ospecti ve study showed an overal l r esponse rate of 32% (44% of pati ents wer e chemo naï ve).

Use of Stents The use of plastic and expansile metal stents has been associ ated wi th successful pal l i ati on of obstr ucti ve symptoms i n mor e than 85% of pati ents wi th tumor s i n the gastr oesophagus and i n the car di a.

TREATMENT OF GASTRIC CANCER ACCORDING TO STAGE Stage 0 Gastric Cancer Stage 0 i ndi cates gastr i c cancer confi ned to the mucosa. On the basi s of exper i ence i n Japan, wher e stage 0 i s di agnosed fr equentl y, i t has been found that mor e than 90% of pati ents tr eated by gastr ectomy wi th l ymphadenectomy wi l l sur vi ve beyond 5 year s. An Amer i can ser i es has confi r med these fi ndi ngs.

Stage I Gastric Cancer a. One of the fol l owi ng sur gi cal pr ocedur es i s r ecommended for stage I gastr i c cancer : di stal SG (i f the l esi on i s not i n the fundus or at the car di oesophageal juncti on) pr oxi mal SG or TG , wi th di stal esophagectomy (i f the l esi on i nvol ves the car di a), of the tumor s that often i nvol ve the submucosal l ymphati cs of the esophagus TG (i f the tumor i nvol ves the stomach di ffusel y or ar i ses i n the body of the stomach and extends to wi thi n 6 cm of the car di a or di stal antr um) r egi onal l ymphadenectomy, whi ch i s r ecommended wi th al l of the pr evi ousl y noted pr ocedur es spl enectomy, whi ch i s not r outi nel y per for med. b. Postoperati ve chemoradi otherapy i s r ecommended for pati ents wi th node-posi ti ve (T1 N1) and muscl e-i nvasi ve (T2 N0) di sease. c. Neoadjuvant chemoradi otherapy i s under cl i ni cal eval uati on.

Stage II Gastric Cancer a. One of the fol l owi ng sur gi cal pr ocedur es i s r ecommended for stage II gastr i c cancer : di stal SG (i f the l esi on i s not i n the fundus or at the car di oesophageal juncti on) pr oxi mal SG or TG (i f the l esi on i nvol ves the car di a) TG (i f the tumor i nvol ves the stomach di ffusel y or ar i ses i n the body of the stomach and extends to wi thi n 6 cm of the car di a) r egi onal l ymphadenectomy i s r ecommended wi th al l of the above pr ocedur es spl enectomy i s not r outi nel y per for med. b. Postoperati ve chemoradi otherapy i s al so r ecommended. c. Neoadjuvant chemoradi otherapy i s under cl i ni cal eval uati on.

Stage III Gastric Cancer a. Radi cal sur ger y: Curati ve r esecti on pr ocedur es ar e confi ned to pati ents who do not have extensi ve nodal i nvol vement at the ti me of sur gi cal expl orati on. b. Postoperati ve chemoradi otherapy i s al so r ecommended. c. Neoadjuvant chemoradi otherapy i s under cl i ni cal eval uati on.

Stage IV Gastric Cancer Patients with No Distant Metastases (M0) Radi cal sur ger y i s per for med i f possi bl e, fol l owed by postoperati ve chemoradi ati on. Neoadjuvant chemoradi ati on therapy i s under cl i ni cal eval uati on.

Patients with Distant Metastases (M1) Al l newl y di agnosed pati ents wi th hematogenous or per i toneal

metastases shoul d be consi der ed as candi dates for cl i ni cal tr i al s i f possi bl e. In some pati ents, chemotherapy may pr ovi de substanti al pal l i ati ve benefi t and occasi onal durabl e r emi ssi on, al though i t does not pr ol ong l i fe or pr ovi de a cur e.

INTRAPERITONEAL SPREAD In appr oxi matel y 50% of pati ents wi th advanced gastr i c cancer, the di sease r ecur s l ocal l y or at an i ntraper i toneal si te, and thi s r ecur r ence has a negati ve effect on sur vi val . Investi gator s have r epor ted thei r exper i ence wi th systemi c and i ntraper i toneal (IP) 5F U and ci spl ati n i n conjuncti on wi th R0 r esecti on of hi gh-r i sk gastr i c cancer. Thi r ty-four pati ents (17 mal e and 17 femal e; medi an age 59 year s, range 26 to 77 year s) r ecei ved an R0 r esecti on (18 pati ents r ecei ved SG , 2 pati ents r ecei ved pr oxi mal gastr ectomy, and 14 r ecei ved TG ) and adjuvant IV or IP 5-F U or ci spl ati n for hi stol ogi cal l y confi r med T2–4 N0–3 gastr i c adenocar ci noma at Memor i al Sl oan-Ketter i ng Cancer Center. Pati ents who r ecei ved radi ati on therapy or pr eoperati ve chemotherapy wer e excl uded. A case-matched anal ysi s of these 32 pati ents and 170 randoml y sel ected matched contr ol s was per for med. The contr ol gr oup was chosen fr om a pool of 614 pati ents who under went r esecti on al one between 1985 and 1997, excl udi ng those pati ents who had M1 di sease or pr eoperati ve chemotherapy. A 5:1 match rati o was used to sel ect pati ents by sex, T stagi ng, and N stagi ng. At a medi an fol l ow-up of 131 months for sur vi vor s, the medi an sur vi val was found to be 25 months i n the IP gr oup ver sus 26 months for the matched-contr ol gr oup. fi ve- and 10-year actuar i al sur vi val was 37% and 37% for the IP gr oup ver sus 30% and 18% for the matched contr ol s. None of these fi ndi ngs wer e stati sti cal l y si gni fi cant. The r ecur r ence rate was 61% i n the IP chemotherapy gr oup, wi th 66% occur r i ng l ocal l y or at an i ntraper i toneal si te, whi ch was not better than the matched contr ol s. Al l pati ents wer e eval uated for toxi ci ty, and ther e was one death fr om car di ac ar r est dur i ng IP chemotherapy tr eatment. Acute grade III or IV toxi ci ty was obser ved i n 14 (44% ) pati ents, consi sti ng of nausea or vomi ti ng, di ar r hea, and hematol ogi c toxi ci ty, but al l the toxi c r esponses r esol ved. It was concl uded that adjuvant IP 5-F U and ci spl ati n can be del i ver ed wi th l ow mor tal i ty and si gni fi cant mor bi di ty. Thi s r egi men di d not al ter sur vi val or al ter the patter n of r ecur r ence. Better agents ar e needed to i mpr ove the effi cacy of thi s mode of therapy. Pati ents at hi gher r i sk, wi th ser osal i nvol vement or conti guous str uctur e i nvasi on, can al so r ecei ve pr ophyl axi s wi th

conti nuous hyper ther mi c per i toneal per fusi on (CHPP) per i operati vel y.

POSTSURGICAL FOLLOW-UP Fol l ow-up i n pati ents fol l owi ng compl ete sur gi cal r esecti on shoul d i ncl ude cl i ni c vi si ts, wi th l i ver functi on tests and CEA measur ements bei ng per for med. A chest radi ograph i s al so war ranted. Inter val s of ever y 3 months for the fi r st 2 year s, then ever y 6 months for 3 year s, and then ever y year have been suggested. If TG i s not per for med, year l y upper endoscopy i s di ctated by a 1% to 2% i nci dence of second pr i mar y tumor s. Vi tami n B1 2 defi ci ency devel ops i n most TG pati ents and 20% of SG pati ents, typi cal l y wi thi n 4 to 10 year s. Vi tami n B1 2 suppl ementati on i s admi ni ster ed at 1,000 µg i ntramuscul ar l y ever y month.

SCREENING In most countr i es, scr eeni ng of the general popul ati ons i s not practi cal because of l ow i nci dence of gastr i c cancer. However, scr eeni ng i s wor thwhi l e i n Japan wher e the i nci dence of gastr i c cancer i s hi gh. Japanese scr eeni ng gui del i nes i ncl ude i ni ti al upper endoscopy at age 50, wi th fol l ow-up endoscopy for abnor mal i ti es. No such gui del i nes ar e avai l abl e i n the Uni ted States.

PRIMARY GASTRIC LYMPHOMA Epidemiology and Pathology Pr i mar y gastr i c l ymphoma (PG L) i s an uncommon mal i gnancy that i s i ncr easi ng i n i nci dence and r epr esents appr oxi matel y 2% to 7% of pr i mar y gastr i c mal i gnanci es. In the Uni ted States, ther e wi l l be an esti mated 22,400 cases of gastr i c mal i gnancy per year, whi ch i ndi cates that an esti mated 448 to 1,568 new cases of gastr i c l ymphoma woul d have occur r ed i n 1997. The i nci dence of PG L has been i ncr easi ng over the l ast 20 year s wi thout any cl ear

expl anati on. Inci dence of PG L i ncr eases wi th age, wi th a peak i n the si xth to seventh decades. A sl i ght mal e pr edomi nance has been r epor ted i n several ser i es. Ther e ar e thr ee types of gastr i c l ymphomas: a. PG L i s defi ned as an extranodal l ymphoma ar i si ng i n the stomach, whi ch i s the most common si te of extranodal l ymphoma. PG L can spr ead to r egi onal l ymph nodes and can become di ssemi nated. Most PG Ls ar e of B cel l or i gi n, al though occasi onal cases of T-cel l and Hodgki n l ymphoma ar e seen. b. Secondar y gastr i c l ymphoma i ndi cates i nvol vement of the stomach as a par t of a di ffuse l ymphoma ar i si ng el sewher e. In an autopsy ser i es, pati ents who di ed fr om di ssemi nated nonHodgki n l ymphoma (NHL) showed i nvol vement of the gastr oi ntesti nal tract i n 50% to 60% of cases. c. Ter ti ar y gastr i c l ymphoma i s r ecur r ent l ymphoma i nvol vi ng the stomach after tr eatment of a nodal l ymphoma and i s uncommon.

Pathology Most gastr i c l ymphomas ar e B-cel l l ymphoma, most commonl y havi ng di ffuse, l ar ge cel l featur es. Most gastr i c l ymphomas appear to ar i se i n the l ami na pr opr i a fr om whi ch they i nfi l trate i nto the submucosa, eventual l y spr eadi ng to r egi onal l ymph nodes. Up to 40% of gastr i c l ymphomas ar e l ow-grade mucosa-associ ated l ymphoi d ti ssue (MALT) l ymphomas. These i ndol ent, l ow-grade l ymphomas ar e character i zed by aggr egates of l ymphoi d ti ssue i n mucosal si tes wi th the fol l owi ng featur es: l ar ge r eacti ve fol l i cl es, pr omi nent mar gi nal zones contai ni ng cel l s wi th angul ar nucl ei r emi ni scent of centr ocytes, i nfi l trati on of the gastr i c epi thel i um by l ymphoi d cel l s, and pl asma cel l s under l yi ng the super fi ci al epi thel i um. Heavy- and l i ght-chai n gene r ear rangements of monocl onal i mmunogl obi n ar e i denti fi ed i n the l ymphomas.

Clinical Presentation Symptoms of PG L that ar e most common at pr esentati on ar e abdomi nal pai n and wei ght l oss. Bl eedi ng i s l ess common, and pati ents rar el y pr esent wi th per forati on. Stage IE and stage IIE PG L pr esent i n pati ents wi th an equal pr eval ence. Stage IE di sease i s seen i n 36% to 72% of pati ents at

pr esentati on and stage IIE di sease i s seen i n 28% to 64% of pati ents. Pr esentati on wi th hi gh-grade and l ow-grade di sease i s al so equal , wi th 34% to 65% of di sease pr esenti ng as hi gh-grade l ymphoma, 12% to 17% pr esenti ng as i nter medi ate-grade l ymphoma, and 35% to 65% pr esenti ng as l ow-grade l ymphoma.

Diagnosis Di agnosi s of PG L by endoscopi c eval uati on has mar kedl y i mpr oved over the l ast decade. In r ecent ser i es, successful endoscopi c di agnosi s of l ymphoma was made i n 92% to 100% of the pati ents. A l ar ge r evi ew of 3,157 pati ents wi th PG L r epor ted data on the sensi ti vi ty of endoscopi c di agnosi s for 848 pati ents. A di agnosi s of cancer was made i n 79% of pati ents, wi th a di agnosi s of l ymphoma made i n onl y 54% . Thi s i ndi cates that 25% of the pati ents wer e di agnosed wi th cancer that was not thought to be l ymphoma. The r evi ew al so stated that the success of endoscopi c eval uati on and bi opsy i n di agnosi ng gastr i c l ymphoma has i mpr oved mar kedl y i n r ecent decades. In a r evi ew of pati ents tr eated fr om 1980 to 1990, the cor r ect pr eoperati ve di agnosi s was made i n onl y 57% of pati ents, but an i mpr ovement was noted over ti me. A di agnosi s rate of 44% was seen between 1980 and 1984 compar ed wi th 64% fr om 1985 to 1990. Other ser i es r epor t a cor r ect di agnosi s by endoscopy i n 38% to 92% of pati ents. Techni ques that have l ed to a hi gher rate of success i ncl ude the use of l ar ger bi opsy for ceps, mul ti pl e bi opsi es, and the use of br ushi ngs. If an ul cer i s pr esent, the bi opsy shoul d be at the edge of the ul cer crater at mul ti pl e si tes.

Staging Stagi ng of gastr i c l ymphoma based upon the Ann Ar bor system i ncl udes stage IE, whi ch i ndi cates a di sease l i mi ted to the stomach, wi thout nodal spr ead. Stage IIE1 i s a tumor i n the stomach that spr eads to adjacent conti guous l ymph nodes. Stage IIE2 i s a tumor i n the stomach that spr eads to l ymph nodes that ar e nonconti guous wi th the pr i mar y tumor.

Treatment Tr eatment of PG L i s hi ghl y var i abl e, wi th no consensus establ i shed

on the most effecti ve therapy. To date, onl y one randomi zed cl i ni cal tr i al compar i ng tr eatments has been publ i shed. Tr eatment deci si ons must, ther efor e, be based on r etr ospecti ve studi es that addr ess the tr eatment of thi s uncommon mal i gnancy. These r etr ospecti ve studi es ar e di ffi cul t to compar e and mostl y r epr esent nonrandomi zed data wi th si gni fi cant stage and grade var i ati on. Sel ecti on bi as i s evi dent i n some ser i es; pati ents wi th mor e advanced di sease and mor e aggr essi ve hi stol ogy r ecei ve mor e aggr essi ve therapy. Ther e i s a need for pr ospecti ve randomi zed tr i al s to eval uate the di ffer ent tr eatments of thi s mal i gnancy.

Impact of Association with H. Pylori on Treatment of PGL Evi dence for a str ong associ ati on between gastr i c l ymphoma and gastr i c i nfecti on by Helicobacter pylor i has been shown. A si mpl i fi ed tr eatment al gor i thm that outl i nes the tr eatment of l ow-grade l ymphoma i s shown i n F i g. 5.4.

FIG. 5.4. Si mpl i fi ed al gor i thm outl i ni ng the tr eatment of l owgrade l ymphoma.

Treatment of Low-grade and High-grade

Primary Gastric Lymphoma The i ni ti al therapy i s based upon the type of PG L. Low-grade MALT l ymphoma i s tr eated i ni ti al l y by eradi cati ng H. pylor i. Compl ete r egr essi on after pr oven eradi cati on i s fol l owed wi th ser i al endoscopi es. For pati ents wi th stages IE and IIE1 non-MALT l ymphoma and l ow-grade MALT l ymphoma not r espondi ng to tr eatment of H. pylor i i nfecti on, sur gi cal r esecti on i s i ndi cated. Sur gi cal r esecti on has the advantage of al l owi ng accurate stagi ng, gradi ng, and cur e wi th sur ger y al one. Thi s al l ows chemotherapy to be gi ven onl y to those pati ents wi th hi gh-grade l ymphoma and avoi ds chemotherapy i n those pati ents wi th favorabl e hi stol ogy. Chemotherapy after sur gi cal r esecti on i s i ndi cated i n those pati ents wi th posi ti ve l ymph nodes, r esi dual di sease, and hi gh-grade l ymphoma found i n the pathol ogi c speci men. We feel that al l hi ghgrade l ymphomas, both MALT and non-MALT i n or i gi n, shoul d be tr eated i ni ti al l y wi th chemotherapy. Thi s i s shown i n F i g. 5.5.

FIG. 5.5. Mucosa-associ ated l ymphoi d ti ssue (MALT) and nonMALT shoul d be i ni ti al l y tr eated wi th chemotherapy.

SELECTED READINGS Adachi Y, Yasuda K, Inomata M, et al . Pathol ogy and pr ognosi s of

gastr i c car ci noma: wel l ver sus poor l y di ffer enti ated type. Cancer 2000;89(7):1418–1424. Bonenkamp JJ, Her mans J, et al . Extended l ymph-node di ssecti on for gastr i c cancer : Dutch G astr i c Cancer G r oup. N Engl J Med 1999;340:908–914.

Chang HM, Jung KH, Ki m TY, et al . A phase III randomi zed tr i al of 5-fl uor ouraci l , doxor ubi ci n, and mi tomyci n C ver sus 5-fl uor ouraci l and mi tomyci n C ver sus 5-fl uor ouraci l al one i n curati vel y r esected gastr i c cancer. Ann Oncol 2002;13(11):1779–1785. Cul l i nan SA, Moer tel CG , Wi ear d HS, et al . Contr ol l ed eval uati on of thr ee dr ug combi nati on r egi mens ver sus fl uor ouraci l al one for the therapy of advanced gastr i c cancer : Nor th Central Cancer Tr eatment G r oup. J Clin Oncol 1994;12:412–416. Ear l e CC, Mar oun JA, Adjuvant chemotherapy after curati ve r esecti on for gastr i c cancer non-Asi an pati ents: r evi si ti ng a meta-anal yses of randomi sed tr i al s. Eur J Cancer 1999;35(7):1059–1064. G astr oi ntesti nal Tumor Study G r oup. A compar i son of combi nati on chemotherapy and combi ned modal i ty therapy for l ocal l y advanced gastr i c car ci noma. Cancer 1982;49:1771–1777. G under son LL, Sosi n H. Adenocar ci noma of the stomach: ar eas of fai l ur e i n a r e-operati on ser i es (second or symptomati c l ook) cl i ni copathol ogi c cor r el ati on and i mpl i cati ons for adjuvant therapy. Int J Radiat Oncol Biol Phys 1982;8(1):1–11. Her mans J, Bonenkamp JJ, Boon MC. et al . Adjuvant therapy after curati ve r esecti on for gastr i c cancer : meta-anal ysi s of randomi zed tr i al s. J Clin Oncol 1993;11:1441–1447. Macdonal d JS, Smal l ey SR, Benedetti J, et al . Chemoradi otherapy after sur ger y compar ed wi th sur ger y al one for adenocar ci noma of the stomach or gastr oesophageal juncti on. N Engl J Med 2001;345(10):725–730.

Stephens J, Smi th J. Tr eatment of pr i mar y gastr i c l ymphoma and gastr i c mucosa-associ ated l ymphoi d ti ssue l ymphoma. J Am Coll Sur g 1998;187(3):312–320. Water s JS, Nor man A, Cunni ngham D, et al . Long-ter m sur vi val after epi r ubi ci n, ci spl ati n and fl uor ouraci l for gastr i c cancer : r esul ts of a randomi zed tr i al . Br J Cancer 1999;80(1-2):269–272.

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 3 - Dige s t iv e Sy s t e m > 6 - Bilia ry Tra c t C a nc e r

6 Biliary Tract Cancer Gregory D. Leonard* Eileen M. O'Reilly† Carmen J. A llegra‡ *The Royal College of Physicians, Dublin, Ir eland † Depar tment

of Medicine, Memor ial Sloan-Ketter ing Cancer Center , New Yor k, New Yor k ‡ Networ k

for Medical Communication and Resear ch Atlanta, G eor gia

Car ci nomas of the bi l i ar y tract i ncl ude those cancer s ar i si ng ei ther i n the gal l bl adder or the bi l e duct. Ther e wer e esti mated to be 6,800 new cases of gal l bl adder and bi l i ar y tract cancer s (excl udi ng i ntrahepati c bi l i ar y tract cancer ) and 3,500 deaths fr om these cancer s i n 2003 (1). G al l bl adder cancer i s twi ce as common as chol angi ocar ci noma. The ter m chol angi ocar ci noma was i ni ti al l y used to desi gnate tumor s of the i ntrahepati c bi l e ducts, but, mor e r ecentl y, i t r efer s to the enti r e spectr um of tumor s ar i si ng i n the i ntrahepati c, per i hi l ar, and di stal bi l e ducts. The epi demi ol ogy, cl i ni cal featur es, stagi ng, and sur gi cal tr eatment ar e di sti nct for car ci nomas ar i si ng i n the gal l bl adder and bi l e duct, and these ar e descr i bed separatel y. The pal l i ati ve tr eatment opti ons ar e si mi l ar and ar e di scussed together at the end of the chapter.

CARCINOMA OF THE GALLBLADDER Epidemiology The age-adjusted i nci dence of car ci noma of gal l bl adder i s 1.2 per 100,000 popul ati on i n the Uni ted States fr om 1996 to 2000 (http://www.seer.cancer.gov/csr /1975_2000/). It affects women two to si x ti mes mor e commonl y than men and

has a 50% gr eater i nci dence i n whi tes as compar ed to bl ack i ndi vi dual s (2). The hi ghest i nci dence i s among Nati ve Amer i cans and i n South Amer i ca (par ti cul ar l y Chi l e), Japan, and Easter n Eur ope, and the l owest i nci dence i s i n Si ngapor e, Ni ger i a, and the Uni ted States. The mean age at di agnosi s of the car ci noma i s 65 year s.

Etiology Cholelithiasis (gallstones): Of pati ents wi th gal l bl adder car ci noma, 65% to 90% have gal l stones, wher eas onl y 1% to 3% of pati ents wi th gal l stones devel op gal l bl adder cancer. The r i sk i ncr eases wi th i ncr ease i n si ze of the stones. Infection: Salmonella typhi, Escher ichia coli, and Helicobacter pylor i i nfecti ons al so cause gal l bl adder car ci nomas. Gallbladder polyps or porcelain gallbladder: Pol yps >1 cm di ameter have the gr eatest mal i gnancy potenti al . Por cel ai n gal l bl adder due to extensi ve cal ci um deposi ti on i n the wal l i s a pathol ogi cal fi ndi ng and can be associ ated wi th car ci noma i n l ess than 20% of pati ents. Miscellaneous: Anomal ous pancr eati cobi l i ar y duct juncti on r esul ti ng i n backfl ow of pancr eati c jui ce and bi l i ar y stasi s may cause gal l bl adder cancer. Obesi ty, estr ogens, and chemi cal s fr om the r ubber i ndustr y have al so been associ ated wi th thi s di sease.

Clinical Features Pai n (82% ) Wei ght l oss (72% ) Anor exi a (74% ) Nausea or vomi ti ng (68% ) Mass i n the r i ght upper quadrant (65% ) Jaundi ce (44% ) Abdomi nal di stensi on (30% ) Pr ur i tus (20% )

Inci dental (15% to 20% ) Cour voi si er l aw states that i f the gal l bl adder i s enl ar ged and i f the pati ent has pai nl ess jaundi ce, the cause i s unl i kel y to be gal l stones. In el der l y pati ents, gal l bl adder cancer may pr esent as chol ecysti ti s.

Diagnosis Abnor mal ser ol ogy can occur wi th el evati ons i n l evel s of al kal i ne phosphatase, γ-gl utamyl transpepti dase, bi l i r ubi n, car ci noembr yoni c anti gen (CEA), or CA 19-9, but these factor s ar e mor e commonl y el evated i n chol angi ocar ci noma. Pl ai n radi ograph of the abdomen may detect cal ci fi cati ons fr om por cel ai n gal l bl adder. Ul trasound i s usual l y abnor mal (thi ckened wal l , mass, and l oss of gal l bl adder or l i ver i nter face) but may not be speci fi c for gal l bl adder cancer. Computer i zed tomography (CT) scan gi ves better vi sual i z ati on of the extent of tumor gr owth and nodal status and i s useful i n gal l bl adder cancer wher e di stant metastases ar e common. Magneti c r esonance chol angi opancr eatography (MRCP) and chol angi ography by endoscopi c r etr ograde chol angi opancr eatography (ERCP) ar e the opti mal i magi ng modal i ti es to outl i ne l ocal anatomy for pr eoperati ve pl anni ng (2). Bi opsi es pr i or to sur ger y may r esul t i n tumor seedi ng; ther efor e, the di agnosi s i s usual l y made at the ti me of sur ger y.

Pathology Adenocar ci noma accounts for mor e than 85% of cases. It i s subcharacter i zed i nto papi l l ar y, tubul ar, muci nous, or si gnet cel l type. Other hi stol ogi es i ncl ude anapl asti c, squamous cel l , smal l cel l , and car ci noi d car ci noma.

Staging G al l bl adder cancer s have been cl assi fi ed by Nevi n et al . (3) or by usi ng the TNM stagi ng system (4) (see Tabl e 6.1). A stagi ng l apar oscopy i s a useful adjunct to i magi ng modal i ti es because i t may detect i ntra-abdomi nal metastases, ther eby spar i ng radi cal and potenti al l y mor bi d sur ger y i n pati ents.

TABLE 6.1. Staging Systems for Gallbladder Cancer AJCC 6th Edition TNM Stage Stage IA

T1 N0 M0

Stage IB

T2 N0 M0

T2: invades perimuscular connective tissue

Stage IIA

T3 N0 M0

T3: perforates the serosa and/or directly invades the liver or one other adjacent organ

Stage IIB

T1– 3 N1 M0

N1: metastases in cystic duct, choledochal, and/or hilar lymph nodes

T4 N0– 1

T4: tumor invades portal vein or hepatic artery or multiple

Stage III

T1a: invades lamina propria T1b: invades the muscle layer

Stage IV

M0

extrahepatic organs or structures

Any T any N M1

M1: distant metastases

Nevin stage Stage I

Intramucosal only

Stage II

Extends to muscularis

Stage III

Extends through serosa

Stage IV

Transmural involvement and cystic lymph nodes are involved

Stage V

Direct extension to liver or distant metastases

Treatment Surgery Onl y 10% to 30% of pati ents can be consi der ed for potenti al l y curati ve sur ger y (2). Sur ger y can be a si mpl e chol ecystectomy or a radi cal (extended)

chol ecystectomy. A radi cal pr ocedur e i nvol ves wedge r esecti on of the gal l bl adder bed, exci si on of the supraduodenal extrahepati c bi l e duct, en bl oc di ssecti on of r egi onal l ymph nodes, and r esecti on of segments V and IVB of the l i ver (some physi ci ans advocate pancr eati coduodenectomy) (5). Stage I di sease can be tr eated successful l y wi th a si mpl e chol ecystectomy, wi th sur vi val rate bei ng gr eater than 85% , but some physi ci ans advocate radi cal sur ger y (Tabl e 6.2). Up to 40% of stage IIA (for mer l y stage II) cancer s ar e found to have l ymph node i nvol vement at sur ger y, upstagi ng them to pathol ogi cal stage IIB (for mer l y stage III). Because of thi s upstagi ng, most sur geons advocate radi cal sur ger y for stage II and above. Many studi es have demonstrated i mpr ovements i n sur vi val i n pati ents r eoperated wi th a radi cal pr ocedur e compar ed to those r ecei vi ng onl y a si mpl e chol ecystectomy (6). Some author s have r epor ted extended sur vi val s wi th radi cal sur ger y even i n stage IV pati ents studi ed by Nevi n et al . (7).

TABLE 6.2. Treatment and 5-year Survival of Gallbladder Cancers According to Stage TNM stage

Treatment

5-yr Median survival survival (%)

Simple cholecystectomy I

19 mo Radical cholecystectomy Radical

60–100

cholecystectomy II

+/- Radiation therapy (not standard)

7 mo

10–20

4 mo

5

2 mo

0

Radical cholecystectomy III

+/- Radiation therapy (not standard) Palliation with stent placement

IV

Surgery or radiation or chemotherapy or combination of these

Radiation In pati ents wi th unr esectabl e tumor s, radi ati on al one i s rar el y a successful pal l i ati ve pr ocedur e (8). A number of r epor ts have documented i mpr ovements i n sur vi val rates i n cases of i ntraoperati ve or postoperati ve adjuvant radi otherapy. No pr ospecti ve randomi zed contr ol l ed tr i al s have been per for med to addr ess thi s i ssue.

Chemotherapy and Palliation The benefi ts and opti ons avai l abl e for chemotherapy and pal l i ati on

of car ci noma of the gal l bl adder ar e the same as those for chol angi ocar ci noma and ar e di scussed i n the secti ons Chemother apy and Palliation.

Survival The var i ous aspects of sur vi val fol l owi ng tr eatment of gal l bl adder cancer s accor di ng to stage ar e gi ven i n Tabl e 6.2.

CARCINOMA OF THE BILE DUCTS (CHOLANGIOCARCINOMA) Epidemiology Chol angi ocar ci noma i s subdi vi ded i nto pr oxi mal extrahepati c (per i hi l ar or Kl atski n tumor ; 50% to 60% ), di stal extrahepati c (20% to 25% ), i ntrahepati c (per i pheral tumor ; 20% to 25% ), and mul ti focal (5% ) tumor s (9). The i nci dence of i ntrahepati c bi l e duct tumor s was 0.9 cases per 100,000 popul ati on between 1996 and 2000 and for other bi l i ar y tumor s was 1.5 cases per 100,000 popul ati on. The i nci dence has i ncr eased, par tl y because of i ncr eased r ecogni ti on of the i ntrahepati c for m of the di sease. Chol angi ocar ci noma i s mor e common i n men (10).

Etiology Inflammatory conditions: Pr i mar y scl er osi ng chol angi ti s i s associ ated wi th a 5% to 15% l i feti me r i sk. Ul cerati ve col i ti s and chr oni c i ntraductal gal l stone di sease al so i ncr ease r i sk. Bile duct abnormalities: Car ol i di sease (cysti c di l atati on of i ntrahepati c ducts), bi l e duct adenoma, bi l i ar y papi l l omatosi s, and chol edochal cysts i ncr ease r i sk. Infection: In Southeast Asi a, r i sk can be i ncr eased 25- to 50fol d by parasi ti c i nfestati on fr om Opisthor chis viver r ini and Clonor chis sinensis. Hepati ti s C ci r r hosi s i s al so a r i sk factor. Miscellaneous: Smoki ng, thor otrast (a radi ol ogi c contrast agent), asbestos, radon, and ni tr osami nes ar e al so known to i ncr ease r i sk (5).

Clinical Features Intrahepati c chol angi ocar ci noma may pr esent as a mass, be asymptomati c, or pr oduce vague symptoms such as pai n, anor exi a, wei ght l oss, ni ght sweats, and mal ai se. Extrahepati c chol angi ocar ci noma usual l y pr esents wi th symptoms and si gns of chol estasi s (i cter us, pal e stool s, dar k ur i ne, and pr ur i tus or chol angi ti s, whi ch i ncl udes pai n, i cter us, and fever ).

Diagnosis A chol estati c ser ol ogi c pi ctur e (as di scussed i n gal l bl adder cancer ) may be seen. A val ue of CA 19-9 >100 U per mL i s hi ghl y suggesti ve of mal i gnancy and i s el evated i n up to 85% of pati ents wi th chol angi ocar ci noma (9). Ul trasonography i s the fi r st-l i ne i nvesti gati on for suspected chol angi ocar ci noma. Bi l i ar y di l atati on i s usual l y seen. Thi s techni que can often over l ook masses and i s poor at del i neati ng anatomy. CT scan i s better at defi ni ng anatomy and can be used to di r ect CT scan–gui ded bi opsi es. MRCP i s the opti mal i magi ng modal i ty. ERCP pr ovi des anatomi cal i nfor mati on (chol angi ography) that i s useful for pl anni ng sur ger y, but, mor e i mpor tantl y, i t may pr ovi de a ti ssue di agnosi s. However, because these tumor s ar e desmopl asti c, cytol ogy br ushi ngs have a l ow yi el d (30% ) i n maki ng the di agnosi s. When br ushi ngs and bi opsy ar e combi ned, the yi el d i mpr oves to 40% to 70% . Endoscopi c ul trasound and posi tr on emi ssi on tomography (PET) may pr ovi de fur ther i nfor mati on on l ocal and di stant di sease, r especti vel y. The di agnosi s of chol angi ocar ci noma i s fr equentl y made on the basi s of the cl i ni cal scenar i o, ser ol ogy, and radi ol ogy but wi thout hi stol ogi c confi r mati on, but such a di agnosi s i n the absence of ti ssue shoul d be made onl y after effor ts ar e taken to pr ove the di agnosi s by use of cytol ogi c or pathol ogi c eval uati on pr eoperati vel y.

Pathology Adenocar ci nomas account for 95% of tumor s.

Staging Up to 50% of pati ents have l ymph node i nvol vement at pr esentati on and 10% to 20% have per i toneal i nvol vement. In one ser i es, l apar oscopy pr evented unnecessar y sur ger y i n one thi r d of pati ents (11). Stagi ng i s based on the TNM cl assi fi cati on (4). Other cl assi fi cati ons such as the cl assi fi cati on by Bi smuth et al . (12) defi ne the extent of ductal i nvol vement (Tabl e 6.3).

TABLE 6.3. Staging systems for Extrahepatic Bile Duct Cancers AJCC 6th Edition TNM Classification Stage IA

T1 N0 M0

T1: tumor confined to the bile duct

Stage IB

T2 N0 M0

T2: tumor invades beyond the bile duct wall

Stage IIA

T3 N0 M0

T3: Tumor invades liver, gallbladder, pancreas, unilateral branches of portal vein, or hepatic artery

Stage IIB

T1– 3 N1 M0

N1: Regional lymph node

Stage III

T4 any N M0

T4: tumor invades main portal vein or bilateral branches, common hepatic artery or other adjacent structures

Stage IV

Any T any N M1

M1: distant metastases

Intrahepatic cancers are classified as per liver tumors Ampulla of Vater cancers have a separate staging classification (4) Bismuth classification Type I

Tumors below the confluence of left and right hepatic ducts

Type II

Tumors reaching the confluence but not involving the left or right hepatic ducts

Type III

Tumors occluding the common hepatic duct and either the right or left hepatic

duct Tumors that are multicentric or that involve the confluence of the right and left hepatic ducts

Type IV

Treatment Surgery Sur ger y i s the onl y curati ve opti on and may be possi bl e i n 30% to 60% of pati ents (10). The goal s of sur ger y ar e (a) tumor r emoval and (b) establ i shi ng or r estor i ng bi l i ar y drai nage. Sur ger y for extrahepati c hi l ar chol angi ocar ci nomas i s based on the stage of di sease, and the goal of sur gi cal i nter venti on i s to obtai n a tumor-fr ee mar gi n >5 cm (see Tabl e 6.4). Long-ter m sur vi val has been r epor ted after l i ver transpl antati on i n thr ee studi es, but transpl antati on i s not a standar d appr oach (5).

TABLE 6.4. Treatment and Survival o Cholangiocarcinomas According to Locat

Location

Treatment Type I + II En bloc resection of extrahepaticbile ducts,

Median survival

Extrahepatic (hilar)

gallbladder, regionallymphadenectomy, and Roux-en-Y hepaticojejunostomy Type III

12–24 mo

As above plus right/left hepatectomy Type IV As above plus extended right/left hepatectomy Extrahepatic (distal)

Pancreaticoduodenectomy

12–24 mo

Intrahepatic

Resect involved segments or lobe of liver

18–30 mo

Radiation In pati ents wi th unr esectabl e di sease, ther e have been r epor ts of l ong-ter m sur vi val wi th combi ned-modal i ty chemoradi otherapy. One r epor t documented a medi an sur vi val of 21 months i n pati ents wi th unr esectabl e cancer or those wi th r esi dual di sease after sur ger y (13). Adjuvant radi ati on i s not r ecommended because ther e i s l i mi ted and confl i cti ng data on thi s subject. One r etr ospecti ve ser i es r epor ted a si gni fi cant i mpr ovement i n 5-year sur vi val for those tr eated wi th radi ati on therapy and sur ger y compar ed to sur ger y al one (39% ver sus 13% ) (14). However, the mor tal i ty wi th sur ger y i n the sur ger y al one gr oup was 10% .

Chemotherapy Chemotherapy appear s to pr ovi de pal l i ati ve benefi t to pati ents wi th bi l i ar y tract cancer, al though defi ni ti ve pr oof of a sur vi val benefi t i s l acki ng (15). Ther e ar e now many chemotherapy opti ons for chol angi ocar ci noma and gal l bl adder cancer (5,16). Many of these tr i al s ar e r epor ted i n abstract for m or sampl e si zes ar e smal l , so the tr eatment of choi ce has not been establ i shed. Usual r esponse rates ar e between 10% and 20% , and hi gh r esponse rates found i n si ngl e-i nsti tuti on studi es have not been r epr oduci bl e i n l ar ger mul ti -i nsti tuti on tr i al s. Hi stor i cal l y, fl uor opyr i mi di nes have been the cytotoxi c therapy of choi ce, but the l i kel i hood of r esponse i s l ess than 10% . Incr easi ngl y, gemci tabi ne i s consi der ed as the standar d of car e. G emci tabi ne combi nati ons, for exampl e, ci spl ati n and gemci tabi ne, have demonstrated hi gh r esponse rates of 20% to 60% and medi an sur vi val up to 20 months, but as yet ther e have been no randomi zed compar i sons showi ng cl ear-cut super i or i ty over si ngl e-agent therapy. Mi tomyci n, as a si ngl e-agent or as combi nati on therapy, has demonstrated r esponse rates of up to 47% and medi an sur vi val s of 9.5 months. Other si ngl e agents wi th acti vi ty i ncl ude docetaxel , i r i notecan, ral ti tr exed, anthracycl i nes, car bopl ati n, and oxal i pl ati n.

Palliation Pati ents wi th unr esectabl e or metastati c di sease may benefi t fr om pal l i ati ve sur ger y, radi ati on, or chemotherapy, or a combi nati on of these. Bi l i ar y drai nage can be achi eved by Roux-en-Y chol edochojejunostomy, bypass of the si te of obstr ucti on to l eft or r i ght hepati c duct, or endoscopi c or per cutaneousl y pl aced stents (metal -wal l stents have a l ar ger di ameter and ar e l ess pr one to occl usi on or mi grati on and ar e pr eferabl y used i n pati ents wi th a

l i fe expectancy of gr eater than 6 months and/or i n those who have unr esectabl e di sease). Cel i ac pl exus bl ock or photodynami c therapy ar e other opti ons (17).

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10. de G r oen PC, G or es G J, LaRusso NF, et al . Bi l i ar y tract cancer s. N Engl J Med 1999;341:1368–1378. 11. Cor vera CU, Weber SM, Jar nagi n WR. Rol e of l apar oscopy i n the eval uati on of bi l i ar y tract cancer. Sur g Oncol Clin Nor th Am 2002;11:877–891. 12. Bi smuth H, Castai ng D, Traynor O, et al . Resecti on or pal l i ati on: pr i or i ty of sur ger y i n the tr eatment of hi l ar cancer. Wor ld J Sur g 1988;12:39–47. 13. Mor ganti AG , Tr odel l a L, Val enti ni V, et al . Combi ned modal i ty tr eatment i n unr esectabl e extrahepati c bi l i ar y car ci noma. Int J Radiat Biol Phys 2000;46:913–999. 14. Todor oki T, Ohara K, Kawamoto T, et al . Benefi ts of adjuvant radi otherapy after radi cal r esecti on of l ocal l y advanced mai n hepati c duct car ci noma. Int J Radiat Biol Phys 2000;46:581–587. 15. G l i mel i us B, Hoffman K, Sjoden PO, et al . Chemotherapy i mpr oves sur vi val and qual i ty of l i fe i n advanced bi l i ar y and pancr eati c cancer. Ann Oncol 1996;7(6):793–600. 16. Henja M, Pr uckmayer M, Rader er M. The r ol e of chemotherapy and radi ati on i n the management of bi l i ar y cancer : a r evi ew of the l i teratur e. Eur J Cancer 1998;34:977–986. 17. Ber r F, Wi edmann M, Tannapfel A, et al . Photodynami c therapy for advanced bi l e duct cancer : evi dence for i mpr oved pal l i ati on and extended sur vi val . Hepatology 2000;31:291–298.

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 3 - Dige s t iv e Sy s t e m > 7 - P rim a ry C a nc e rs o f t he Liv e r

7 Primary Cancers of the Liver Gregory D. Leonard* W illiam R. Jarnagin† Carmen J. A llegra‡ *The Royal College of Physicians, Dublin, Ir eland † Depar tment

of Sur ger y Weill Medical College of Cor nell Univer sity, New Yor k, New Yor k ‡ Networ k

for Medical Communication and Resear ch, Atlanta, G eor gia

Pr i mar y l i ver cancer s ar i se pr edomi nantl y fr om the par enchymal l i ver cel l s or hepatocytes (90% ) and ar e cal l ed hepatocellular car cinoma (HCC). Tumor s ar i si ng fr om the i ntrahepati c bi l e ducts (10% ) ar e cal l ed cholangiocar cinomas and ar e di scussed pr i mar i l y i n Chapter 6. HCC i s the fi fth l eadi ng cause of cancer i n the wor l d, wi th an annual i nci dence of one mi l l i on cases (1). The i nci dence i n the Uni ted States has i ncr eased by appr oxi matel y 75% i n the l ast decade, l i kel y because of i ncr eases i n i nci dence of chr oni c hepati ti s i nfecti on (2). Resear ch on vacci nati ons for hepati ti s B and i ts consequences have pr evented the devel opment of HCC i n many r egi ons of the wor l d. F ur ther pr ogr ess i n the tr eatment of HCC i s necessar y to si gni fi cantl y r educe mor tal i ty fr om thi s common gl obal di sease.

EPIDEMIOLOGY In the Uni ted States, the i nci dence of cl i ni cal l y si gni fi cant metastati c car ci noma to the l i ver i s 20 ti mes mor e common than pr i mar y l i ver cancer. The age-adjusted i nci dence of HCC fr om 1996 to 2000 i s 5 per 100,000 popul ati on (http://www.seer.cancer.gov/csr /1975_2000/). In 2003, 17,300

(i ncl udes i ntrahepati c bi l e duct cancer s) new cases of pr i mar y l i ver cancer and 14,400 deaths fr om thi s di sease wer e esti mated i n the Uni ted States (3). Ther e i s mar ked geographi c var i ati on i n the i nci dence of HCC, wi th the hi ghest i nci dences of up to 30 per 100,000 popul ati on occur r i ng i n sub-Saharan Afr i ca and Asi a. Men ar e affected twi ce as often as women. The mean age at di agnosi s i s between 50 and 60 year s.

ETIOLOGY Ci r r hosi s i s pr esent i n 80% of pati ents wi th HCC. Ther efor e, r i sk factor s for ci r r hosi s ar e al so r i sk factor s for HCC. Hepati ti s B vi r us (HBV) i nfecti on i ncr eases the r i sk of devel opi ng HCC by 100-fol d. HBV causes 80% of HCC i n the wor l d. HCC devel ops fr om chr oni c hepati ti s due to HBV at a rate of 0.5% per year. Hepati ti s C vi r us (HCV) i nfecti on accounts for 30% to 50% of HCC i n the Uni ted States. HCC devel ops fr om HCV at a rate of 5% per year. Al cohol i c ci r r hosi s accounts for 15% of of HCC. Hemochr omatosi s, her edi tar y tyr osi nemi a, and autoi mmune chr oni c acti ve hepati ti s ar e other causes of ci r r hosi s and ar e associ ated wi th a si gni fi cant r i sk for devel opi ng HCC (6). Ther e i s l ess convi nci ng evi dence for the r i sk of devel opi ng HCC fr om: Afl atoxi n B1 (chemi cal pr oduct of Asper gi l l us) Andr ogeni c ster oi ds Thor otrast (radi ol ogy contrast agent) and Oral contracepti ves.

CLINICAL FEATURES The most common symptoms or si gns of HCC ar e (7): Pai n (91% )

Wei ght l oss (35% ) Vomi ti ng (8% ) Hepatomegal y (89% ) Abdomi nal swel l i ng (43% ) and Jaundi ce (7% to 41% ). Paraneopl asti c mani festati ons can al so occur. They i ncl ude hypogl ycemi a, hyper cal cemi a, car ci noi d, er ythr ocytosi s, hyper chol ester ol emi a, hyper thyr oi di sm, and osteopor osi s.

DIAGNOSIS Ser ol ogi c tests may r eveal abnor mal i ti es i n the l i ver pr ofi l e. αFetopr otei n (AF P) i s el evated i n 50% to 90% of pati ents wi th HCC but can al so be el evated i n other l i ver abnor mal i ti es. AF P val ues >400 µg per dL i n pati ents wi thout hepati ti s or >4,000 µg per mL i n pati ents posi ti ve for hepati ti s B sur face anti gen and wi th radi ographi c abnor mal i ti es suggest the di agnosi s of HCC (http://www.nccn.or g). If sur ger y i s pl anned i n these pati ents, an open bi opsy at l apar otomy i s usual l y pr efer r ed to decr ease the r i sk of tumor seedi ng, bl eedi ng, or r uptur e. Des-γcar boxy pr othr ombi n pr otei n, i nduced by the absence of vi tami n K, i s i ncr eased i n about 91% of pati ents wi th HCC, but i s al so el evated i n other causes of hepati ti s. Car ci noembr yoni c anti gen (CEA) i s l ess useful i n HCC and i s mor e l i kel y to be el evated i n chol angi ocar ci noma. Ul trasonography i s consi der ed the best scr eeni ng tool i n conjuncti on wi th AF P for hi gh-r i sk popul ati ons. Tr i phasi c computer i zed tomography (not contrast enhanced, ar ter i al phase, and por tal phase) pr ovi des better defi ni ti on, can assess for metastati c di sease, and i s used to gui de per cutaneous bi opsi es. G adol i ni um-enhanced magneti c r esonance (MR) i magi ng may i mpr ove character i z ati on of smal l l esi ons. MR angi ography i s used to pl an for sur ger y. Lapar oscopy i s r ecommended to i mpr ove stagi ng and to pr event unnecessar y l apar otomy (10).

PATHOLOGY

Ther e ar e many hi stol ogi c types of HCC i ncl udi ng trabecul ar, pseudogl andul ar or aci nar, compact, sci r r hous, cl ear cel l , and fi br ol amel l ar. F i br ol amel l ar car ci noma i s a hi stol ogi c var i ant accounti ng for 1% of HCC. It occur s mor e commonl y i n women, i s not associ ated wi th ci r r hosi s, and has a better pr ognosi s than HCC.

STAGING The TNM stagi ng system (see Tabl e 7.1) has been cr i ti ci zed because i t does not eval uate the under l yi ng l i ver di sease, whi ch i s cl ear l y a major pr ognosti c factor i n pati ents r egar dl ess of tumor stage (11). The Chi l d-Pugh gradi ng system has been i ncor porated i nto the management of HCC because i t eval uates the status of the under l yi ng l i ver functi on and i nfl uences tr eatment (12) (see Tabl e 7.2).

TABLE 7.1. The American Joint Committee on Cancer (AJCC) 6th edition TNM stage groupings Stage I

T1 N0 M0

T1: solitary tumor with no vascular invasion

Stage II

T2 N0 M0

T2: solitary tumor with vascular invasion or multiple tumors none >5 cm

Stage IIIA

T3 N0 M0

T3: multiple tumors >5 cm or involving a major branch of the portal or hepatic vein

Stage IIIB

T4 N0 M0

T4: tumor directly invading adjacent organs other than gallbladder or perforating visceral peritoneum

Stage IIIC

Any T N1 M0

N1: regional lymph node metastases

Stage IV

Any T any N M1

M1: distant metastases

TABLE 7.2. Child-Pugh scoring system Chemical and biochemical parameters

Score attributed to each parameter 1

2

3

Encephalopathy

None

1–2

3–4

Ascites

None

Slight

Moderate

Albumin (g/dL)

>3.5

2.8– 3.5

6

Bilirubin (mg/dL)

1–2

2–3

>3

Class A = 5–6 points, Class B = 7–9 points, Class C = 10–15 points.

TREATMENT Surgery Sur ger y r emai ns the onl y possi bl i ty for cur e i n HCC. The tr eatment al gor i thm for HCC i s deter mi ned by two factor s: Tumor extent and the sever i ty of the under l yi ng hepati c par enchymal di sease (F i g. 7.1). Partial hepatectomy: Hepati c r esecti on r emai ns the mai nstay of sur gi cal therapy for thi s di sease. Onl y 13 to 35% ar e sur gi cal candi dates. The major i ty have ei ther di sease that i s beyond sur gi cal cor r ecti on or have poor hepati c r eser ve or both. Smal l tumor s have the best outcomes. Recur r ence i s most commonl y seen i n the r emnant l i ver. Repeat hepatectomy i s possi bl e i n 10 to 29% of pati ents. Operati ve mor tal i ty i s 5cm) has been shown to be associ ated wi th ver y hi gh l ocal r ecur r ence rates. Per cutaneous ethanol i njecti on i nto tumor s causes cel l ul ar dehydrati on, coagul ati ve necr osi s and l ocal i zed ti ssue i schemi a. It i s fr equentl y used for up to thr ee l ocal i zed tumor s of Se c t io n 3 - Dige s t iv e Sy s t e m > 8 - C o lo re c t a l C a nc e r

8 Colorectal Cancer George P. Kim* Chris H. Takimoto† Carmen J. A llegra‡ *G astr ointestinal Cancer Section, Mayo Clinic Cancer Center , Jacksonville, F lor ida † Institute

for Dr ug Development, Cancer , Ther apy & Resear ch Center , San Antonio, Texas ‡ Networ k

for Medical Communication and Resear ch, Atlanta, G eor gia

EPIDEMIOLOGY Col or ectal cancer (CRC) i s the second overal l , that i s, men and women combi ned, l eadi ng cause of cancer death i n the Uni ted States and i s the thi r d most common cause of cancer, separatel y, i n men and i n women. It was esti mated that appr oxi matel y 146,940 new cases of CRC woul d have been di agnosed i n 2004 i n the Uni ted States, and one-thi r d of pati ents woul d have di ed as a r esul t of the di sease (1). The l i feti me r i sk of devel opi ng CRC i s 1:18. Sur ger y wi l l cur e al most 50% of al l di agnosed pati ents, al though al most 80,000 peopl e devel op metastati c CRC each year. The i nci dence of col on cancer i s hi gher i n the mor e economi cal l y devel oped r egi ons, such as the Uni ted States or Wester n Eur ope, than i n Asi a, Afr i ca, or South Amer i ca. Between 1973 and 1998, the U.S. i nci dence of CRC conti nued to decl i ne, and so di d mor tal i ty, whi ch decl i ned by 23.5% dur i ng thi s i nter val .

RISK FACTORS Al though cer tai n condi ti ons pr edi spose pati ents to devel op col on cancer, up to 70% of pati ents have no i denti fi abl e r i sk factor s: A ge: Mor e than 90% of col on cancer occur i n pati ents ol der than 50 year s. Gender: The i nci dence of col on cancer i s hi gher i n women, wher eas r ectal cancer i s mor e common i n men. Ethnicity: The occur r ence of cancer i s mor e common i n Afr i can Amer i cans than i n whi tes, and mor tal i ty i ncr eases by 32% i n Afr i can Amer i cans. History of colorectal cancer or adenomas: –tubul ar adenomas (l owest r i sk) –tubul ovi l l ous adenomas (i nter medi ate r i sk) –vi l l ous adenomas (hi ghest r i sk). Tobacco use: About 2.5-fol d i ncr eased r i sk of adenomas i s obser ved i n smoker s. Obesity Dietary factors: hi gh-fi ber, l ow cal or i c i ntake, and l ow ani mal -fat di ets may r educe the r i sk of cancer. Calcium deficiency: Dai l y i ntake of 1.25 to 2.0 g of cal ci um was associ ated wi th a r educed r i sk of r ecur r ent adenomas i n a randomi zed pl acebo-contr ol l ed tr i al . Micronutrient deficiency: Fol ate and vi tami n E and D defi ci ency may i ncr ease the r i sk of cancer. Inflammatory bow el disease: Ul cerati ve col i ti s i ncr eases r i sk by 7-fol d to 11-fol d, especi al l y wi th the durati on of col i ti s (8 to 12 year s) and wi th the detecti on of dyspl asi a. Cr ohn di sease i s associ ated wi th a twofol d i ncr eased r i sk of CRC. Nonsteroidal antiinflammatory drugs: An Amer i can Cancer Soci ety study r epor ted 40% l ower mor tal i ty i n r egul ar aspi r i n user s, and si mi l ar r educti ons i n mor tal i ty wer e seen i n pr ol onged nonster oi dal anti i nfl ammator y dr ug (NSAID) use i n pati ents wi th r heumatol ogi c di sor der s. The cycl ooxygenase-2 (COX-2) i nhi bi tor cel ecoxi b i s appr oved by the U.S. Food and Dr ug Admi ni strati on (F DA) for adjuncti ve tr eatment of pati ents wi th fami l i al adenomatous pol yposi s (FAP). Its r ol e i n the pr eventi on of cancer devel opment i n nonher eti dar y cohor ts i s

under i nvesti gati on. Family history: In the general popul ati on, i f one fi r st-degr ee r el ati ve devel ops cancer, i t i ncr eases the r el ati ve r i sk for other fami l y member s to 1.72, and i f two r el ati ves ar e affected, the r el ati ve r i sk i ncr eases to 2.75; i ncr eased r i sk i s al so obser ved when a fi r st-degr ee r el ati ve devel ops an adenomatous pol yp befor e age 60. Tr ue her edi tar y for ms of cancer account for onl y 6% of CRCs.

Familial Adenomatous Polyposis Syndrome FAP i s an autosomal -domi nant i nher i ted syndr ome wi th mor e than 90% penetrance, mani fested by hundr eds of pol yps devel opi ng by l ate adol escence. The r i sk of devel opi ng i nvasi ve cancer over ti me i s vi r tual l y 100% . G er ml i ne mutati ons i n the adenomatous pol yposi s col i (APC) gene on chr omosome 5q21 have been i denti fi ed. The l oss of the APC gene r esul ts i n al ter ed si gnal transducti on wi th i ncr eased transcr i pti onal acti vi ty of ß-cateni n. A ttenuated FA P: These FAPs ar e fl at adenomas that ar i se at an ol der age than FAPs do; mutati ons tend to occur i n the pr oxi mal and di stal por ti ons of the APC gene. Gardner syndrome: Thi s syndr ome i s associ ated wi th desmoi d tumor s, l i pomas, and fi br omas of the mesenter y or abdomi nal wal l . Turcot syndrome: Thi s syndr ome i nvol ves tumor s of the central ner vous system (CNS). Peutz–Jeghers syndrome: Thi s syndr ome shows nonneopl asti c hamar tomatous pol yps thr oughout the gastr oi ntesti nal tract and per i oral mel ani n pi gmentati on. Juvenile polyposis: These ar e hamar tomas i n col on, smal l bowel , and stomach.

Hereditary Nonpolyposis Colorectal Cancer The Lynch syndr omes, named after Henr y T. Lynch, i ncl ude Lynch I or the col oni c syndr ome, whi ch i s an autosomal -domi nant trai t character i zed by di sti nct cl i ni cal featur es i ncl udi ng pr oxi mal col on i nvol vement, muci nous or poor l y di ffer enti ated hi stol ogy, pseudodi pl oi dy, and the pr esence of synchr onous or metachr onous tumor s. Incr eased sur vi val has been obser ved i n pati ents despi te col on cancer devel opi ng befor e 50 year s, wi th a l i feti me r i sk of

cancer appr oxi mati ng 75% . The Lynch II or extracol oni c i ndi vi dual s ar e suscepti bl e to mal i gnanci es i n the endometr i um, ovar y, stomach, hepatobi l i ar y tract, smal l i ntesti ne, and geni tour i nar y tract. The “Amster dam Cr i ter i a” wer e establ i shed to i denti fy potenti al ki ndr eds and i ncl ude: Hi stol ogi cal l y ver i fi ed CRC i n at l east thr ee fami l y member s, one bei ng a fi r st-degr ee r el ati ve of the other two member s CRC i nvol vi ng at l east two successi ve generati ons and At l east one fami l y member bei ng di agnosed by 50 year s. Incl usi on of extracol oni c tumor s and cl i ni copathol ogi cal and age modi fi cati ons wer e i ntr oduced by the “Bethesda Cr i ter i a” i n 1997. G er ml i ne defects i n DNA mi smatch-r epai r genes (hMSH2, hMLH1, hPMS1, and hPMS2) have been detected, and r esul tant mi cr osatel l i te i nstabi l i ty (MSI) can be i denti fi ed i n vi r tual l y al l her edi tar y nonpol yposi s col or ectal cancer (HNPCC) ki ndr eds and i n 15% to 20% of sporadi c col on cancer s.

SCREENING The Amer i can Cancer Soci ety has devel oped scr eeni ng gui del i nes for the ear l y detecti on of col on cancer. Ther e ar e a var i ety of avai l abl e ear l y detecti on tests for col on cancer. Star ti ng at age 50, both men and women shoul d di scuss the ful l range of testi ng opti ons wi th thei r physi ci ans and choose one of the fol l owi ng: Year l y fecal occul t bl ood test (F OBT) F l exi bl e si gmoi doscopy ever y 5 year s Year l y F OBT and fl exi bl e si gmoi doscopy ever y 5 year s (pr efer r ed over ei ther F OBT al one or fl exi bl e si gmoi doscopy al one) Doubl e-contrast bar i um enema ever y 5 year s Col onoscopy ever y 10 year s. It shoul d be noted that al l posi ti ve tests shoul d be fol l owed up wi th col onoscopy. Indi vi dual s wi th a fami l y or per sonal hi stor y of col on

cancer or pol yps or a hi stor y of chr oni c i nfl ammator y bowel di sease shoul d be tested ear l i er and may need to under go testi ng mor e often.

Virtual Colonoscopy A vi r tual col onoscopy or computer i zed tomographi c col onography i s an emer gi ng technol ogy i n whi ch a spi ral computer i zed tomography (CT) scan of the col on i s obtai ned and thr ee-di mensi onal i mages ar e cr eated and r evi ewed by a radi ol ogi st. A r ecent study demonstrated comparabl e sensi ti vi ty to conventi onal col onoscopy (88.7% ver sus 92.3% for pol yps at l east 6 mm i n di mensi on). Ear l i er studi es usi ng two-di mensi onal technol ogy and i nexper i enced radi ol ogi sts obser ved equi vocal r esul ts. Pati ents sti l l r equi r e bowel pr eparati on and col oni c di stensi on as wel l as i ngesti on of oral contrast. Addi ti onal studi es ar e r equi r ed befor e thi s techni que can be used r outi nel y.

Carcinoembryonic Antigen Car ci noembr yoni c anti gen (CEA) i s not useful for general CRC scr eeni ng pur poses. CEA has a l ow posi ti ve pr edi cti ve val ue wher eby appr oxi matel y 60% of cancer s ar e mi ssed.

K-ras Detection The K-r as gene i s mutated i n 50% of CRCs, and i ts detecti on i n stool r epr esents a potenti al power ful scr eeni ng strategy. Thi s i s cur r entl y an acti ve ar ea of cl i ni cal i nvesti gati on.

PATHOPHYSIOLOGY Col on car ci nogenesi s i nvol ves pr ogr essi on fr om hyper pr ol i ferati ve mucosa to pol yp for mati on, wi th dyspl asi a, and transfor mati on to noni nvasi ve l esi ons and subsequent tumor cel l s wi th i nvasi ve and metastati c capabi l i ti es. CRC i s a uni que model of mul ti step car ci nogenesi s r esul ti ng fr om the accumul ati on of mul ti pl e geneti c al terati ons. Stage-by-stage mol ecul ar anal ysi s has r eveal ed that thi s pr ogr essi on i nvol ves several types of geneti c i nstabi l i ty, i ncl udi ng l oss of heter oz ygosi ty, wi th chr omosomes 8p, 17p, and 18q r epr esenti ng the most common chr omosomal l osses. The 17p del eti on accounts for l oss of p53 functi on, and 18q contai ns the tumor-suppr essor genes del eted i n col on cancer (i .e., DCC) and the gene del eted i n pancr eati c 4 (i .e., DPC4). The l oss of heter oz ygosi ty of chr omosome 18q has pr ognosti c si gni fi cance.

Col on car ci nogenesi s al so occur s as a consequence of defects i n the DNA mi smatch r epai r system. The l oss of hMLH1 and hMSH2, pr edomi nantl y, i n sporadi c cancer s l eads to accel erated accumul ati on of addi ti ons or del eti ons i n r epeati ng DNA nucl eoti de uni ts. Thi s MSI contr i butes to the l oss of gr owth i nhi bi ti on medi ated by transfor mi ng gr owth factor-ß (TG F -ß) due to a mutati on i n the type II r eceptor. Mutati ons i n the APC gene on chr omosome 5q21 ar e r esponsi bl e for FAP and ar e i nvol ved i n cel l si gnal i ng and i n cel l ul ar adhesi on, wi th bi ndi ng of ß-cateni n. Al terati ons i n the APC gene occur ear l y i n tumor pr ogr essi on. Mutati ons i n the pr otooncogene r as fami l y, i ncl udi ng K-r as and N-r as, ar e i mpor tant for transfor mati on and al so ar e common i n ear l y tumor devel opment. Mor e than 90% of CRCs ar e adenocar ci nomas, wi th pr oxi mal tumor s becomi ng i ncr easi ngl y mor e common. Left-si ded cancer s tend to be annul ar, l eadi ng to obstr ucti on, wher eas r i ght-si ded cancer s ar e mor e commonl y pol ypoi d and cl i ni cal l y si l ent. One-thi r d of pati ents wi l l i ni ti al l y be seen wi th metastati c di sease, wher eas 50% wi l l eventual l y devel op metastases.

DIAGNOSIS Signs and Symptoms Abdomi nal pai n, typi cal l y i nter mi ttent and vague Wei ght l oss Bowel changes, such as penci l stool s Ear l y sati ety G astr oi ntesti nal bl eedi ng Fati gue Obstr ucti on, per forati on, acute or chr oni c bl eedi ng, or l i ver metastasi s, al l of whi ch contr i bute to symptom devel opment Unusual pr esentati ons i ncl udi ng pati ents wi th deep venous thr ombosi s, Str eptococcus bovis bacter emi a, and nephr oti c-range pr otei nur i a Cl i ni cal fi ndi ngs i ncl udi ng anemi a, wei ght l oss, el ectr ol yte abnor mal i ti es, and l i ver enz yme el evati ons.

Diagnostic Evaluation A doubl e-contrast bar i um enema may be mor e cost effecti ve as an i ni ti al eval uati on, but endoscopi c studi es pr ovi de hi stol ogi c i nfor mati on, potenti al therapeuti c i nter venti on, and overal l gr eater sensi ti vi ty and speci fi ci ty. Basi c l aborator y studi es i ncl udi ng compl ete bl ood count, el ectr ol ytes, and l i ver and r enal functi on tests, chest radi ograph, and CT scan of the abdomen and pel vi s ar e useful i n i ni ti al cancer di agnosi s, al though the r el ati ve contr i buti ons of these var i ous modal i ti es ar e undefi ned. CEA el evati ons occur i n non–cancer-r el ated condi ti ons, r educi ng the speci fi ci ty of CEA measur ements i n the i ni ti al detecti on of col on cancer.

STAGING The Amer i can Joi nt Commi ttee on Cancer (AJCC) (1) stagi ng of col on cancer usi ng the TNM cl assi fi cati on was updated i n 2003 (see F i g. 8.1). Pati ents wi th stage II and III di sease have been fur ther strati fi ed, and vascul ar or l ymphati c i nvasi on has been i ncl uded (see Tabl e 8.1). The tumor desi gnati on, or T stage, defi nes the extent of bowel wal l penetrati on, as opposed to tumor si ze. The AJCC stagi ng system accounts for the number of l ymph nodes i nvol ved as a si gni fi cant pr edi ctor of sur vi val . Four or mor e posi ti ve l ymph nodes or gr oss ver sus mi cr oscopi c bowel wal l penetrati on l ead to di mi ni shed sur vi val . Some pati ents wi th stage II di sease exhi bi t a heter ogeneous outcome and ar e at hi gh r i sk for r el apse, wi th outcomes si mi l ar to those of node-posi ti ve pati ents (see Tabl e 8.2).

FIG. 8.1. Stagi ng cl assi fi cati on of col or ectal cancer. Cl assi fi cati on i s based on modi fi cati ons of Dukes' system. Stages B3 and C3 (not shown) si gni fy i nvasi on of conti guous or gans or str uctur es (T4). Pr ognosi s i s al so deter mi ned by the number of posi ti ve l ymph nodes: mor e than four (N2) l ymph nodes pr edi cts a wor se outcome than one to thr ee (N1) l ymph nodes, and a poor hi stopathol ogi cal di ffer enti ati on, vascul ar or l ymphati c i nvasi on, and a posi ti ve pr eoperati ve CEA val ue of >5 ng per mL i mpl i es a wor se outcome. Accor di ng to the r evi sed TNM cl assi fi cati on system, stage I equal s T1 or T2 N0 (Dukes' stage A and B1 ); stage II equal s T3 or T4 N0 (Dukes' stage B2 and B3 ); stage III equal s any T pl us N1, N2, or N3 (Dukes' stage C1 , C2 and C3 ); and stage IV equal s any T any N pl us M1 (Dukes' stage D).

TABLE 8.1. American Joint Committee on Cancer (AJCC) Staging Classification (2003) Primary tumor: T

TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ—intraepithelial or invasion of the lamina propriaa T1: Tumor invades submucosa T2: Tumor invades muscularis propria T3: Tumor invades through the muscularis propria into the subserosa or into nonperitonealized pericolic or perirectal tissues T4: Tumor directly invades other organs or structures, and/or perforates visceral peritoneum b , c Regional lymph nodes: Nd NX: Regional nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis in 1 to 3 regional lymph nodes N2: Metastasis in 4 or more regional lymph nodes Distant metastases: M MX: Presence of distant metastases cannot be assessed M0: No distant metastases M1: Distant metastases are present. Metastasis in the external iliac or common iliac lymphnode is classified as M1 Stage grouping Stage 0:

Dukes'/MAC Tis N0 M0

Stage I

T1 N0 M0—A A T2 N0 M0—A B1

Stage IIA

T3 N0 M0—B B2

Stage IIB

T4 N0 M0—B B3

Stage IIIA

T1—T2 N1 M0—C C1

Stage IIIB

T3–T4 N1 M0—C C2/C3

Stage IIIC

Any T N2 M0—C C1/C2/C3

Stage IV

Any T Any N M1—D

Stage group II is subdivided into IIA and IIB on the basis of whether the primary tumor is T3 or T4, respectively Stage III is subdivided into IIIA (T1–2 N1 M0), IIIB (T3–4 N1 M0), or IIIC (any T N2 M0) Stage at initial diagnosis: Stage I

14%

Stage II/III

65%

Stage IV

21%

a

Tis includes cancer cells confined within the

glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa. b Direct invasion in T4 includes invasion of other segments of the colorectum through the serosa, for example, invasion of the sigmoid colon by a carcinoma of the cecum. c Tumor that is macroscopically adherent to other organs or structures is classified T4. However, if no tumor is present in the adhesion microscopically, the classification should be pT3. The V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion. d Smooth metastatic nodules in the pericolic or perirectal fat are considered lymph node metastases and will be counted in the N staging. In contrast, irregularly contoured metastatic nodules in the peritumoral fat are considered as a vascular invasion and will be coded as an extension of the T category as either V1 (microscopic vascular invasion) if it is only microscopically visible or as V2 (macroscopic vascular invasion) if it is grossly visible.

TABLE 8.2. Five-year Survival Prognosis by Stage

Stage 0–I

>90%

Stage II

70–85%

Stage III

55–70%

Stage IV

0.2 mm

pN0(mol-):

No regional lymph node metastasis histologically, negative molecular finding (RT-PCR)

pN0(mol+):

No regional lymph node metastasis histologically, positive molecular finding (RT-PCR)

pN1:

Metastasis in 1–3 axillary lymph node(s) and/or in internal mammary node(s), with microscopic disease detected by sentinel lymph node dissection but not clinically apparenta

pN1mi:

Only micrometastasis (>0.2 mm, 2.0 mm)

pN2b:

Metastasis in clinically apparentb internal mammary lymph nodes in the absence of axillary lymph node metastasis Metastasis in ten or more axillary lymph nodes, or in infraclavicular

pN3:

lymph nodes, or clinically apparent b ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes, with clinically microscopic metastasis in internal mammary lymph nodes or in ipsilateral supraclavicular lymph nodes

pN3a:

Metastasis in ten or more axillary lymph nodes (at least one tumor deposit>2.0 mm), or metastasis to the infraclavicular lymph nodes

pN3b:

Metastasis in clinically apparentb ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes, with microscopic disease detected by sentinel lymph node dissection but not clinically apparenta

pN3c:

Metastasis in ipsilateral supraclavicular lymph nodes

Distant metastasis (M)

MX:

Presence of distant metastasis cannot be assessed

M0:

No distant metastasis

M1:

Distant metastasis present

IHC, immunohistochemistry; RT-PCR, reversetranscription polymerase chain reaction. a Not clinically apparent is defined as not being detected by imaging studies (excluding lymphoscintigraphy) or clinical examination, or by not being grossly visible on histopathologic evaluation. b Clinically apparent is defined as being detected by imaging studies (excluding lymphoscintigraphy) or clinical examination, or by being grossly visible pathologically. From AJCC Cancer Staging Manual. Sixth Edition 2002. Springer Publication, with permission.

TABLE 12.4. American Joint Committee on Cancer Stage Groupings Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

T0

N1

M0

Stage IIA

T1

N1

M0

T2

N0

M0

T2

N1

M0

T3

N0

M0

T0

N2

M0

T1

N2

M0

T2

N2

M0

T3

N1

M0

T3

N2

M0

Stage IIIB

T4

N0—N2

M0

Stage IIIC

Any T

N3

M0

Stage IV

Any T

Any N

M1

Stage IIB

Stage IIIA

From AJCC Cancer Staging Manual. Sixth Edition 2002, Springer Publication, with permission.

Prognostic Factors

1. Number of posi ti ve axi l l ar y l ymph nodes Thi s i s one of the most power ful pr ognosti c i ndi cator s. 2. Tumor si ze Tumor s smal l er than 1 cm have a good pr ognosi s i n pati ents wi thout l ymph node i nvol vement. 3. Hi stol ogi c or nucl ear grade Pati ents wi th poor l y di ffer enti ated hi stol ogy and hi gh nucl ear grade have a wor se pr ognosi s than other s. Scar ff–Bl oom–Ri char dson (SBR) gradi ng system and F i sher nucl ear grade ar e commonl y used systems. 4. ER/PR status ER- and or PR-posi ti ve tumor has better pr ognosi s. 5. Hi stol ogi c tumor type Pr ognoses of i nfi l trati ng ductal and l obul ar car ci noma ar e si mi l ar. Muci nous (col l oi d) and typi cal medul l ar y and tubul ar hi stol ogi es have good pr ognosi s i f the si ze i s 5 cm. Two randomi zed tr i al s showed i mpr ovement i n overal l sur vi val (OS) for postmastectomy radi ati on i n pati ents wi th one to thr ee posi ti ve l ymph nodes, and i t i s bei ng eval uated i n mor e cl i ni cal tr i al s. New er Radiation Techniques under Investigation: 1. Partial breast irradiation (PBI) i s under i nvesti gati on and may be used i n cl i ni cal tr i al at thi s poi nt. 2. Partial breast brachytherapy (PBB) or i nter sti ti al brachytherapy i s al so under goi ng cl i ni cal tr i al s i n stage I and II pati ents wi th fr ee r esected mar gi ns and zer o to thr ee posi ti ve

l ymph nodes. In the PBB method, pati ents r ecei ve ten fracti ons of radi ati ons of 3.4 G y wi thi n 5 days. 3. Mammosite Radiation Therapy System (RTS) was appr oved by the U.S. Food and Dr ug Admi ni strati on (F DA) on May 6, 2002, for pati ents wi th T2 N0 M0 br east cancer. Radi ati on of 34-G y i s del i ver ed i n ten fracti ons wi thi n 5 days thr ough a bal l oon i nser ted at the l umpectomy si te dur i ng sur ger y.

Systemic Treatment for Early Breast Cancer Chemotherapy i s r ecommended for most of the pati ents wi th nodeposi ti ve di sease. For node-negati ve pati ents, the tr eatment i s based on many factor s, such as the tumor si ze, ER/PR status, nucl ear or hi stol ogi c grade (Tabl e 12.5).

TABLE 12.5. Risk Categories for Patients with Node-negative Breast Cancer

Factors

Min/low risk (all factors)

Intermediate risk (between the two categories)

High risk (at least one factor)

Tumor size

≤1 cm

1–2 cm

>2 cm

ER and/or PR status

Positive

Positive

Negative

Grade 1 (uncertain

Grade

Grade

relevance for tumors ≤1 cm)

Age

>35

Grade 1–2

2–3

Ta ble o f C o nt e nt s > Se c t io n 5 - G e nit o urina ry > 1 3 - Re na l C e ll C a nc e r

13 Renal Cell Cancer Hung T. Khong* Christopher Klebanoff† Susan Bates‡ *USA Cancer Resear ch Institute, Univer sity of South Alabama, Mobile, Alabama † Emor y

School of Medicine, Atlanta, G eor gia

‡ Cancer

Ther apeutics Br anch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland

EPIDEMIOLOGY In the year 2003, ther e was an esti mated 3% of adul t mal i gnanci es, wi th 31,900 new cases and 11,900 deaths fr om r enal cancer. The mal e-to-femal e rati o for r enal cancer i s 2:1. In the Uni ted States, the i nci dence rates for r enal cel l car ci noma (RCC) ar e hi gher among bl acks than among whi tes (Tabl e 13.1). Age at di agnosi s i s usual l y gr eater than 40 year s, wi th the medi an age i n the mi d-60s. Cancer of the r enal tubul ar epi thel i um accounts for 90% of al l mal i gnanci es ar i si ng i n the ki dney. Most of the r emai ni ng cases ar e transi ti onal cel l car ci noma of the r enal pel vi s. Sur vei l l ance, Epi demi ol ogy, and End Resul ts (SEER) data i ndi cate that the i nci dence and mor tal i ty rates for RCC have i ncr eased steadi l y i n al l race and sex gr oups fr om 1975 thr ough 1995 (F i gs. 13.1 and 13.2; Tabl e 13.1).

FIG. 13.1. Age-adjusted i nci dence rates for r enal cel l car ci noma.

FIG. 13.2. Age-adjusted mor tal i ty rates for r enal cel l car ci noma.

TABLE 13.1. Age-adjusted Incidence Rates per 100,000 Person-years Race/Sex

Incidence rate (%)

% increase/yr

White men

9.6

2.3

White women

4.4

3.1

Black men

11.1

3.9

Black women

4.9

4.3

ETIOLOGY AND RISK FACTORS Tobacco use contr i butes to one thi r d of al l cases of RCC i n the Uni ted States—cur r ent smoker s exhi bi t 40% hi gher r i sk than nonsmoker s; the r i sk i ncr eases per pack-year hi stor y. Hi gh consumpti on of fr i ed or sautéed meat i s another r i sk factor. Obesi ty, par ti cul ar l y i n women, contr i butes to the r i sk for devel opi ng RCC. Exposur e to asbestos and petr ol eum pr oducts i ncr eases the chances of devel opi ng RCC. End-stage r enal di sease wi th devel opment of acqui r ed cysti c di sease of the ki dney i s a major r i sk factor ; pati ents wi th cysti c changes i n the ki dney who under go di al ysi s exhi bi t a 30-ti mes hi gher r i sk than the general popul ati on. Her edi tar y di sease: 1. von Hi ppel -Li ndau (VHL) di sease i s a fami l i al syndr ome wi th an autosomal domi nant i nher i tance patter n, associ ated wi th r eti nal hemangi omas, central ner vous system (CNS) hemangi obl astomas, r enal cysts and RCC, pheochr omocytoma, and epi di dymal cysts. RCC i s found to devel op i n 25% of VHL pati ents (data have been col l ected fr om l i teratur e r evi ews: total number of VHL pati ents i s 706 and total number of RCC cases r epor ted i s 176). The mean age at onset i s 44 year s. 2. Her edi tar y nonpapi l l ar y RCC devel ops because of transl ocati on between the shor t ar m of chr omosome 3 (3p) and chr omosome 6, 8, or 11, as i s seen i n some fami l i al RCC ki ndr eds. 3. Her edi tar y papi l l ar y RCC (HPRCC) type I i s associ ated wi th a mutati on of the aMET pr otooncogene at 7q31.3. aMET encodes a transmembrane r eceptor tyr osi ne ki nase.

4. Her edi tar y l ei omyomatosi s and r enal cel l cancer (HLRCC) i s an autosomal domi nant di sor der character i zed by smoothmuscl e tumor s of the ski n and uter us and/or r enal cancer that was r ecentl y l i nked to mutati ons i n the fumarate hydratase (F H) gene. The r enal cancer s may have ei ther type II papi l l ar y or col l ecti ng duct mor phol ogy 5. Renal chr omophobe and oncocytoma i s l i nked to the Bi r t– Hogg–Dubé syndr ome, a der matol ogi c di sor der character i zed by cutaneous hai r fol l i cl e tumor s (fi br ofol l i cul omas), pul monar y cysts, and r enal tumor s. The Bi r t–Hogg–Dubé syndr ome gene has been found at 17p11.2 and i s associ ated wi th chr omophobe (34% ), oncocytoma (5% ), hybr i d chr omophobe–oncocytomas (50% ), cl ear cel l car ci noma (9% ), and papi l l ar y r enal cancer (2% ).

PATHOLOGIC CLASSIFICATION For pathol ogi c cl assi fi cati on, see Tabl e 13.2.

TABLE 13.2. Pathologic Classification of Rena Cell Carcinoma Type of carcinoma

Clear cell

Frequency (%)

Genetic changes

5-yr surviva (%)

70–80

3p (81%– 98%), von HippelLindau (VHL) gene mutation (57%) a

55–60

Trisomies

Papillary

Chromophobe

10–15

5

Collecting duct

7 cm. From one recent study, stage I is reported to be 45%, and stage II 13%, as per the 1997 version.

TABLE 13.4. Common Presenting Symptoms or Laboratory Abnormality

Symptom/lab finding

% of patients

Hematuria

56–59

Pain

38–41

Abdominal mass

36–45

Weight loss

28

Anemia

21

Fever

11

Nonmetastatic hepatic dysfunction (Stauffer syndrome)

7

Polycythemia

Ta ble o f C o nt e nt s > Se c t io n 6 - G y ne c o lo gic > 1 7 - O va ria n C a nc e r

17 Ovarian Cancer Eddie Reed* Ramin A ltaha† *Mar y Babb Randolph Cancer Center , Rober t C. Byr d Health Sciences Center , West Vir ginia Univer sity, Mor gantown, West Vir ginia † Section

of Hematology/Oncology, Rober t C. Byr d Health Sciences Center , West Vir ginia Univer sity, Mor gantown, West Vir ginia Ovar i an cancer i s di vi ded i nto thr ee br oad hi stol ogi c categor i es: epi thel i al car ci nomas, ger m cel l tumor s, and str omal cel l tumor s. Appr oxi matel y 90% of al l cases of ovar i an cancer ar e of the epi thel i al var i ety. Thi s chapter i s devoted to epi thel i al ovar i an car ci noma, except for the secti on on fal l opi an tube car ci noma and extraovar i an per i toneal car ci noma. The number of esti mated new cases of ovar i an cancer i n 2003 was 25,400 i n the Uni ted States, the esti mated number of deaths fr om thi s di sease total ed 14,300. Ovar i an cancer r epr esents appr oxi matel y 25% of the total number of cancer cases i nvol vi ng the femal e geni tal tract. However, unl i ke cer vi cal cancer or endometr i al cancer, the most ovar i an cancer cases pr esent as stage III or stage IV. The overal l sur vi val rate had i mpr oved fr om appr oxi matel y 35% i n the 1970s, to mor e than 50% i n the 1990s. Thi s decr ease i s bel i eved to have r esul ted fr om the i ntr oducti on of pl ati num-based therapy for management of thi s di sease. F ur ther i mpr ovements i n sur vi val have been obser ved wi th the i ntr oducti on of pacl i taxel and other agents that have been r ecentl y appr oved for use i n thi s di sease by the U.S. Food and Dr ug Admi ni strati on (F DA). Some r epor ts suggest that the i ntr oducti on of ci spl ati n and car bopl ati n i nto chemotherapeuti c r egi mens not onl y r esul ted i n i mpr oved sur vi val stati sti cs but may al so be associ ated wi th emer gi ng patter ns of metastati c spr ead suggesti ve of mor e aggr essi ve di sease.

TUMOR MARKERS The best tumor mar ker for thi s di sease i s CA125. CA125 i s a hi gh– mol ecul ar-wei ght gl ycopr otei n that i s el evated i n up to 50% of stage I tumor s and el evated i n 80% to 90% of stage II, III, or IV tumor s. Mi nor el evati ons i n CA125 l evel s ar e not speci fi c for ovar i an cancer and can be seen i n endometr i osi s, beni gn tumor s, fi br oi ds, and i n pr egnant or postpar tum women. In addi ti on, moderate el evati ons i n CA125 l evel s can be seen i n other adenocar ci nomas such as br east cancer and endometr i al cancer. However, CA125 l evel s gr eater than 2,000, wi th the appr opr i ate cl i ni cal hi stor y, shoul d be consi der ed to r epr esent epi thel i al ovar i an cancer unti l pr oved other wi se. Once the di agnosi s of ovar i an cancer has been made, CA125 i s useful i n fol l owi ng the di sease. It i s a useful sur r ogate for tumor r esponse but does not pr edi ct compl ete r esponse. A per si stentl y r i si ng CA125 fol l owi ng di sease r esponse i s r epr esentati ve of tumor r ecur r ence. Some r epor ts suggest that CA125 pl us transvagi nal ul trasound may be effecti ve i n scr eeni ng for pr evi ousl y undi agnosed di sease. Other bi ochemi cal enti ti es have been suggested as possi bl e mar ker s for pr evi ousl y undi agnosed ovar i an cancer. They i ncl ude OVX-1, l ysophosphati di c aci d, and an advanced pr oteomi c anal ysi s method per for med on pati ent pl asma.

SCREENING The Nati onal Cancer Insti tute (NCI) r ecommends scr eeni ng for ovar i an cancer i n women wi th known geneti c syndr omes associ ated wi th thi s di sease and for women wi th a par ti cul ar l y str ong fami l y hi stor y of the di sease r egar dl ess of the pr esence of a r ecogni zed geneti c syndr ome. A r ecent study randomi zed 20,000 women wi thout a fami l y hi stor y of ovar i an cancer to scr eeni ng and to no scr eeni ng. CA125 was the fi r st scr eeni ng test, fol l owed by ul trasound for pati ents wi th an el evated CA125. Ther e was no di ffer ence between the two gr oups i n the abi l i ty to detect ear l y stage di sease nor was ther e any di ffer ence i n the number of deaths fr om ovar i an cancer. Ther efor e, r outi ne scr eeni ng of women wi thout a fami l y hi stor y of ovar i an cancer i s not r ecommended.

RISK FACTORS AND PREVENTION Ovar i an cancer r i sk i ncr eases wi th age and wi th a fami l y hi stor y of ovar i an cancer. Al though most cases of ovar i an cancer occur i n women wi thout any known r i sk factor s, ther e ar e several geneti c

syndr omes that ar e str ongl y associ ated wi th thi s di sease. These syndr omes i ncl ude the her edi tar y br east and ovar i an cancer syndr omes associ ated wi th BRCA1 and BRCA2 and wi th the her edi tar y nonpol yposi s col or ectal cancer syndr ome (Lynch II syndr ome). In each of these geneti c syndr omes, var i abl e penetrance has been obser ved. Recent studi es show that pr ophyl acti c total abdomi nal hyster ectomy and bi l ateral sal pi ngo-oophor ectomy (TAH/BSO), can be effecti ve i n r educi ng the pr edi cted occur r ence of ovar i an cancer i n women wi th BRCA1 or BRCA2 mutati ons. In addi ti on, studi es suggest that oral contracepti ves may have a pr eventi ve effect on thi s di sease, whi ch appear s to i ncr ease wi th the durati on of contracepti ve use. It shoul d be noted that the newer, l ow-estr ogen for mul ati ons have not yet pr oved to have the same pr otecti ve effect. Other maneuver s that ar e associ ated wi th a r educti on i n the number of ovul ati ons (i .e., pr egnancy, nur si ng after pr egnancy, etc.) appear to have pr otecti ve effects as wel l .

PATHOLOGY Epi thel i al hi stol ogi es account for about 90% of al l ovar i an cancer s. These i ncl ude the hi stol ogi es of ser ous, muci nous, endometr i oi d, transi ti onal , and cl ear cel l s. Among these cel l types, cl ear cel l appear s to have a consi stentl y wor se pr ognosi s. Tumor s of l ow mal i gnant potenti al (bor der l i ne tumor s) may exi st wi thi n each of the above fi ve hi stol ogi c types. Mi xed Mül l er i an tumor i s pr obabl y of epi thel i al or i gi n and i s al so associ ated wi th cl i ni cal r esi stance to therapy. G eneral l y, any of the afor ementi oned tumor hi stol ogi es may be wel l di ffer enti ated, moderatel y di ffer enti ated, or poor l y di ffer enti ated. Cl i ni cal pr ognosi s wor sens wi th poor l y di ffer enti ated cel l s. Rar el y, a tumor may cl ear l y be an ovar i an cancer but may be suffi ci entl y undi ffer enti ated so that i t cannot be assi gned to any of the si x cel l types noted. The ger m cel l tumor s ar e cl assi fi ed as dysger mi noma, endoder mal si nus tumor, mal i gnant teratoma, embr yonal car ci noma, or pr i mar y chor i ocar ci noma. Str omal tumor s ar e mesenchymal i n or i gi n and consi st of granul osa tumor s or Ser tol i -Leydi g cel l tumor s.

DIAGNOSIS AND WORKUP Cl i ni cal l y, the natur e of the thr ee br oad cl asses of tumor s i s di r ectl y

r el ated to the cl i ni cal pr esenti ng symptoms of the di sease. Tumor s of epi thel i al hi stol ogy tend to pr esent i n the advanced stage (i .e., III or IV) and ar e associ ated wi th abdomi nal di scomfor t, l ow back pai n, bl oati ng, and abdomi nal di stensi on. G er m cel l tumor s tend to behave cl i ni cal l y i n a manner si mi l ar to that of ger m cel l tumor s i n men. Ser tol i -Leydi g cel l tumor s pr oduce vi r i l i z ati on i n affected i ndi vi dual s. G ranul osa cel l tumor s may cause pr ecoci ous puber ty i n pr emenar chal women, amenor r hea i n women of r epr oducti ve age, and vagi nal bl eedi ng i n postmenopausal women. A smal l per centage of women of r epr oducti ve age i n whom sur ger y i s per for med for a pel vi c mass wi l l have a mal i gnant tumor, wi th the l i kel i hood of the mal i gnancy i ncr easi ng wi th age. Appr oxi matel y 50% of the postmenopausal women i n whom sur ger y i s per for med for a pel vi c mass wi l l have a mal i gnant neopl asm. Pr eoperati ve wor kup of a pati ent suspected to have an ovar i an mass may i ncl ude any or al l of the fol l owi ng: bl ood chemi str i es, l i ver functi on tests (LF Ts), r enal functi on tests, compl ete bl ood counts (CBCs), ul trasonography, CA125, computer i zed tomography (CT) scan of the abdomen and pel vi s, α-fetopr otei n, and β-human chor i oni c gonadotr opi n (β-HCG ). Addi ti onal studi es may be per for med, as appr opr i ate. A summar y of the suggested pr eoperati ve wor kup i s gi ven i n Tabl e 17.1.

TABLE 17.1. The workup for patients suspected of having an ovarian malignancy Personal and family history and physical examination Liver function tests, BUN, creatinine, LDH CBC with platelets, PT, PTT, INR Tumor markers (CA125, AFP, and β-HCG)

CT scan of abdomen and pelvis, and CXR. CT of chest if CXR is abnormal. Radiographic tests of unclear utility: MRI of abdomen and pelvis, PET scan BUN, blood urea nitrogen; LDH, lactate dehydrogenase; CBC, complete blood count; PT, prothrombin time; PTT, partial thromboplastin time; INR, international normalized ratio; AFP, α-fetoprotein; HCG, human chorionic gonadotropin; CT, computerized tomography; CXR, chest x-ray; MRI, magnetic resonance imaging; PET, positron emission tomography. Consider possible abnormal hormone secretion syndromes. Consider possible concurrent malignancies from other sites. Consider possible metastases to the ovary, from other sites (breast, colon, etc.). Sur ger y shoul d be per for med by a gynecol ogi c oncol ogi st or a sur gi cal oncol ogi st—pr eferabl y the for mer. The G ynecol ogi c Oncol ogy G r oup (G OG ) has defi ned the appr opr i ate sur gi cal pr ocedur e for ovar i an cancer and has i nsi sted that sur gi cal pr otocol shoul d be fol l owed i n ever y pati ent under goi ng sur ger y for thi s di sease. The pr ognosti c i mpor tance of maxi mal sur gi cal debul ki ng has been demonstrated i n mul ti pl e studi es over the l ast 4 decades. Favorabl e pr ognosti c factor s i ncl ude younger age at the ti me of di agnosi s (younger than 65 year s), good per for mance status, cel l type other than cl ear cel l , stage I or II di sease, wel l -di ffer enti ated tumor, di pl oi d tumor s, no over expr essi on of HER2, l ow vascul ar endothel i al gr owth factor (VEG F ) expr essi on, and opti mal tumor debul ki ng dur i ng sur ger y to 3 cm after sur ger y, and aneupl oi dy.

STAGING Ovar i an cancer may exi st i n stage I, II, III, or IV. Thi s deter mi nati on can be made onl y after appr opr i ate abdomi nopel vi c sur ger y. Stage IV di sease can someti mes be di agnosed wi thout i nvasi on of the abdomi nopel vi c space. However, r ecent studi es show that tumor debul ki ng favorabl y affects pr ognosi s, even i n stage IV di sease. Cur r ent Federati on Inter nati onal e de G ynecogi e et d'Obstetr i que (F IG O) stagi ng cr i ter i a ar e l i sted i n Tabl e 17.2.

TABLE 17.2. Federation Internationale de Gynecogie et d'Obstetrique (FIGO) staging of ovarian cancer Stage I

Growth limited to one or both ovaries

IA

Growth limited to one ovary; no ascites; no tumor on the external surfaces; capsule intact

IB

Growth limited to both ovaries; no ascites; no tumor on the external surfaces; capsule intact

IC

Tumor either stage IA or IB but with tumor on the surface of one or both ovaries; capsule ruptured; ascites present containing malignant cells; or

positive peritoneal washings Stage II

Growth involving one or both ovaries with pelvic extension

IIA

Extension and/or metastases to the uterus and/or fallopian tubes

IIB

Extension to other pelvic organs

IIIC

Tumor either stage IIA or IIB but with tumor on the surface of one or both ovaries; capsule(s) ruptured; ascites present containing malignant cells; or positive peritoneal washings

Stage III

Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes: metastases to the surface of the liver equals stage III; tumor is limited to the true pelvis but with histologically verified malignant extension to the small bowel or omentum

IIIA

Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces

IIIB

Tumor of one or both ovaries; histologically confirmed implants of abdominal peritoneal surfaces, none >2 cm in diameter; node negative

IIIC

Abdominal implants >2 cm in diameter and/or positive retroperitoneal or inguinal nodes

Stage IV

Growth involving one or both ovaries and with distant metastases; if pleural effusion is present, there must be positive cytologic test results to allot a case to stage IV; parenchymal liver metastasis equals stage IV

Stage I di sease i s confi ned to one or both ovar i es. Mal i gnant asci tes, but no i mpl ants, may be pr esent on the abdomi nopel vi c wal l . Stage II i nvol ves one or both ovar i es, wi th extensi on to the pel vi c vi scera. As i n the case of stage I di sease, ther e may be mal i gnant asci tes, but no i mpl ants on the abdomi nopel vi c wal l . Stage III di sease i s associ ated wi th i mpl ants on the abdomi nopel vi c wal l or the ser osal sur face of the l i ver or i nvol ves the smal l bowel or omentum. Stage IV di sease shows metastasi s to par enchymal l i ver, l ung, the pl eural cavi ty, or other demonstrated metastases outsi de the abdomi nopel vi c space.

TREATMENT OF OVARIAN CANCER Surgery Upon i ni ti al pr esentati on, sur ger y i s the pr i mar y tool i n the tr eatment and stagi ng of the di sease. When sur geons fol l ow the speci fi c sur gi cal pr otocol desi gned by the G OG , the di sease can be

defi ni ti vel y staged. Stage I di sease wi th favorabl e pr ognosti c featur es can be tr eated by sur ger y al one. Stage II di sease wi th favorabl e pr ognosti c featur es can be tr eated by sur ger y fol l owed by a l i mi ted cour se of pl ati num-based chemotherapy (thr ee to four cycl es). For the i ni ti al pr esentati on of the di sease, al l other setti ngs of ovar i an cancer of epi thel i al hi stol ogy r equi r e appr opr i ate sur ger y fol l owed by at l east si x cycl es of pacl i taxel and car bopl ati n. Cur r entl y, ther e i s debate over the potenti al val ue of fol l owi ng thi s r egi men wi th two or mor e addi ti onal cycl es of pacl i taxel as a si ngl e agent. The pr i mar y goal of ovar i an cancer sur ger y i s to r emove al l vi si bl e di sease, i f possi bl e. Retr ospecti ve anal yses show that pati ents wi th no vi si bl e di sease after sur ger y, as a gr oup, show si gni fi cant r ecover y, fol l owed by pati ents wi th vi si bl e di sease of 3 toxicity

Gemcitabine

1,000 mg/m2 /dose i.v. over 30 min, on d 1 and d 8; Repeat q21d depending on WBC recovery;

Hexamethylmelamine

Several different regimens are commonly used; 260 mg/m2 /day, PO, divided into 4 doses, after meals; each day for 14 consecutive d; then 7 or 14 d off; Repeat q21 or 28 d

Liposomal doxorubicin

40 mg/m2 or 50 mg/m 2 /dose, one 1-hr i.v. infusion; repeat q21 d Several different regimens are commonly used;

Oral etoposide

(VP16)

100 mg/dose, PO, daily, × 14 d, followed by 7 or 14 d off; repeat q21 or 28 d

Tamoxifen

20 mg/dose, PO, b.i.d, continuously

Taxotere

70 mg/m2 or 80 mg/m 2 /dose; one 1-hr i.v. infusion; repeat q21d

Topotecan

1.5 mg/m2 /dose; i.v., daily × 5; do not exceed 7.5 mg/m2 total dose/cycle; Repeat q21d

Weekly paclitaxel

70 mg/m2 /dose or 80 mg/m 2 /dose, one 1-hr i.v. infusion, weekly; 3 wk on, 1 wk off; Repeat q28d

WBC, white blood cell. The fi r st step for pati ents wi th r ecur r ent or per si stent di sease i s to deter mi ne whether the pati ent's di sease i s pl ati num sensi ti ve or pl ati num r esi stant. G eneral l y, i f a pati ent has per si stent or

pr ogr essi ve di sease whi l e r ecei vi ng ci spl ati n- or car bopl ati n-based therapy, the di sease shoul d be consi der ed pl ati num r esi stant. In addi ti on, i f the pati ent appear s to r espond but has di sease r ecur r ence or pr ogr essi on wi thi n 6 months of the most r ecent dose of pl ati num, the di sease shoul d be consi der ed pl ati num r esi stant. If di sease r ecur s mor e than 1 year after the most r ecent dose of pl ati num, the di sease may be consi der ed to be pl ati num sensi ti ve. Data suggest that the l i kel i hood of a second cl i ni cal r esponse to r etr eatment wi th pl ati num i s mor e than 70% i n pati ents who have been gi ven thei r l ast pl ati num dose mor e than 2 year s pr i or to the r etr eatment. F ur ther mor e, data suggest that thi s pr i nci pl e may hol d tr ue for pacl i taxel i n thi s di sease. Recur r ent ovar i an cancer i s now consi der ed a chr oni c di sease by most medi cal and gynecol ogi c oncol ogi sts. Thi s i s because thi s i l l ness wi l l usual l y r espond to a ser i es of di ffer ent tr eatment r egi mens over ti me, commonl y r esul ti ng i n a 5- to 10-year ti me frame of di sease per si stence wi th good qual i ty of l i fe. Accompl i shi ng thi s, however, r equi r es ski l l ful uti l i z ati on of cur r entl y accepted pr i nci pl es of cl i ni cal dr ug r esi stance and the tr eatment appr oaches used to counter dr ug r esi stance. For exampl e, a pati ent who r ecei ves i ni ti al therapy wi th car bopl ati n and pacl i taxel may exper i ence a cl i ni cal compl ete r emi ssi on i ni ti al l y and exhi bi t di sease r ecur r ence several year s l ater. In such i nstances, r etr eatment wi th car bopl ati n and pacl i taxel woul d be appr opr i ate. One can expect a l i kel i hood of mor e than 70% that the di sease wi l l r espond agai n. When the di sease becomes pl ati num r esi stant, a non–cr oss-r esi stant medi cati on such as l i posomal doxor ubi ci n must be used for tr eatment. Once r esi stance devel ops to thi s new agent, the pati ent shoul d be tr eated wi th an agent that i s non–cr oss-r esi stant wi th any of the pr evi ous thr ee medi cati ons, such as gemci tabi ne. The next r egi men used mi ght be topotecan, pr obabl y fol l owed by oral VP16, and so on. Wi th use of thi s type of appr oach, the di sease can be contr ol l ed i n some pati ents for several year s, wi th acceptabl e toxi ci ty and wi th good qual i ty of l i fe. For pati ents wi th di sease r ecur r ence but few or no symptoms, the use of tamoxi fen at 20 mg PO b.i .d. shoul d be consi der ed. Thi s can be done for bi ochemi cal r ecur r ence of the CA125 onl y or for radi ographi c r ecur r ence of di sease wi thout physi cal symptoms.

Common Toxicities from Treatment Tabl e 17.5 l i sts a range of toxi ci ti es that commonl y occur wi th chemotherapy tr eatment r egi mens for ovar i an cancer. Wi th the excepti on of thr ombocytopeni a, the myel osuppr essi on caused by these r egi mens can be r eadi l y tr eated wi th cur r entl y appr oved cytoki nes, such as granul ocyte col ony sti mul ati ng factor (G -CSF ) and er ythr opoi eti n. Nausea and vomi ti ng shoul d be appr oached i n a pr eventati ve manner. Aggr essi ve pr eventi ve anti nausea therapy shoul d be used for pl ati num-contai ni ng r egi mens. Once nausea and vomi ti ng ar e wel l establ i shed i n a pati ent, i t i s usual l y ver y di ffi cul t to contr ol .

TABLE 17.5. Common toxicities from the treatment of epithelial ovarian cancer Associated with all the agents listed in this chapter, except tamoxifen Myelosuppression

All three lineages affected; persistent thrombocytopenia is associated with the platinum compounds Preventive treatment is very important; delayed nausea and vomiting is very common

Nausea and vomiting

Steroids, HT3 inhibitor, and substance P inhibitor all are

recommended for routine use with platinumcontaining regimens Seen with cisplatin and with carboplatin; usually more clinical significant with cisplatin

Renal dysfunction

Serum creatinine may be normal, in the face of a markedly reduced creatinine clearance; this is important because the use of other renally cleared drugs may be needed (antibiotics, etc.); Platinum-related renal insufficiency is nonoliguric; vigilance is required Clinically occurs before detectable changes on EMG/NCTs; stocking-andglove distribution;

Neurotoxicity

Usually progressive with repeated platinum doses, and can become severe; cisplatin is more likely to cause this problem than

carboplatin

Fatigue/weakness

Altered sexual function

May be related to anemia but is a frequent side effect of several newer agents including gemcitabine, topotecan, irofulven, and others Common side effect; seldom discussed spontaneously by the patient; can be an underlying contributing factor to family disruption, and clinical reactive depression; Usually is a combined function of surgery, and effect of neuroactive anticancer agent (platinum, etc.)

Clinical depression

Common side effect; many patients will request a medication for this; sometimes a severe problem Acute hypersensitivity to paclitaxel; acute hypersensitivity to

Rare toxicities

cisplatin/carboplatin (usually after six–eight cycles of therapy, when it occurs); Desensitization is occasionally appropriate and can be successful. On most occasions, switch to another agent right away

Renal dysfuncti on i s fr equentl y under esti mated i n pati ents who have r ecei ved ei ther ci spl ati n or car bopl ati n i n the past. Substanti al r educti ons i n cr eati ni ne cl earance can coexi st wi th a nor mal bl ood ur ea ni tr ogen (BUN) and ser um cr eati ni ne after substanti al doses of ei ther agent. Neur otoxi ci ty i s common, and mi l d, when cur r entl y accepted doses of car bopl ati n and/or pacl i taxel ar e used. When sever e neur otoxi ci ty devel ops (grade 3 or gr eater ), thi s can be ver y di ffi cul t to manage and tends to r esol ve sl owl y. Dr ug-i nduced fati gue (as opposed to anemi a-r el ated fati gue) i s a fr equentl y over l ooked si de effect and shoul d be consi der ed when symptoms devel op. Al ter ed sexual functi on i s a fr equent, but not fr equentl y di scussed, cl i ni cal pr obl em. Thi s may contr i bute to fami l y di scor d, and cl i ni cal depr essi on, i n some si tuati ons. Thi s pr obl em i s cur r entl y under studi ed. Rar e but sever e si de effects (usi ng cur r ent tr eatment and suppor ti ve r egi mens) i ncl ude hyper sensi ti vi ty to pacl i taxel and/or pl ati num compounds and acute l eukemi a.

Experimental THERAPY G eneral l y, pati ents shoul d be encouraged to par ti ci pate i n contr ol l ed cl i ni cal tr i al s appr oved by the NCI and/or the F DA. Cooperati ve gr oups such as the G OG r outi nel y conduct phase III tr i al s for i ndi vi dual s who ar e di agnosed for the fi r st ti me. It i s thr ough car eful l y per for med cl i ni cal phase III tr i al s that i mpr ovements on cur r ent tr eatment appr oaches can be made. For al l pati ents beyond thei r i ni ti al di agnosi s, effor ts shoul d be made to i denti fy phase III

or phase II cl i ni cal tr i al s that ar e appr opr i ate. Phase I cl i ni cal tr i al s ar e r easonabl e tr eatment opti ons for some pati ents. Exper i mental therapi es that ar e bei ng tested, or have r ecentl y been tested, i ncl ude gene therapy appr oaches, hi gh-dose chemotherapy wi th bone mar r ow transpl antati on, anti angi ogenesi s therapi es, i mmunotherapi es, effor ts to r ever se r esi stance to standar d dr ugs, novel combi nati ons of dr ugs, and novel smal l mol ecul es. G eneral l y, hi gh-dose chemotherapy wi th bone mar r ow transpl antati on i s not cur r entl y r ecommended i n thi s di sease. In addi ti on, i ntraper i toneal therapy, once consi der ed to have gr eat pr omi se, i s cur r entl y not i n general use.

FALLOPIAN TUBE CARCINOMA AND EXTRAOVARIAN PERITONEAL CARCINOMA These ar e two var i ants of adenocar ci noma that occur i n women, whi ch cl i ni cal l y behave and r espond to therapy i n a manner si mi l ar to epi thel i al ovar i an cancer. The stagi ng pr ocess i s ver y si mi l ar to ovar i an cancer for both mal i gnanci es, and the tr eatment appr oaches ar e i denti cal , stage for stage.

SUPPORTIVE CARE Among those cl i ni cal si tuati ons that may occur as a di r ect r esul t of uncontr ol l ed di sease, bowel obstr ucti on and ur i nar y tract obstr ucti on ar e the most tr oubl esome. In the setti ng of the i ni ti al pr esentati on of the i l l ness, ever y effor t shoul d be made to sur gi cal l y r el i eve thi s pr obl em and shoul d be i mmedi atel y fol l owed by systemi c therapy. In r ecur r ent or per si stent di sease, i f ther e i s a str ong l i kel i hood of cl i ni cal dr ug sensi ti vi ty, sur gi cal r emedy of ei ther pr obl em shoul d agai n be attempted i mmedi atel y. As stated pr evi ousl y, nausea and vomi ti ng shoul d be tr eated pr eventi vel y. Cl i ni cal depr essi on can someti mes i nter fer e wi th a pati ent's adher ence to therapy and shoul d be taken ser i ousl y. Par ti ci pati on of the pati ent i n cancer suppor t gr oups can someti mes be ver y hel pful to the affected i ndi vi dual , and thi s can be of assi stance to the heal th car e pr ovi der.

SUGGESTED READINGS Ber ek JS. Epi thel i al ovar i an cancer. In: Ber ek JS, Hacker NF, eds. Pr actical gynecologic oncology, 3r d ed. Phi l adel phi a, PA:

Li ppi ncott Wi l l i ams & Wi l ki ns, 2000:457–522. Cal ver t AH, Newel l DR, G umbr el l LA, et al . Car bopl ati n dosage; pr ospect of eval uati on of a si mpl e for mul a based on r enal functi on. J Clin Oncol 1989;7:1748–1756. Cor nel i son TL, Reed E. Nephr otoxi ci ty and hydrati on management for ci spl ati n, car bopl ati n, and or mapl ati n: a r evi ew. G ynecol Oncol 1993;50:147–158. Hoski ns WJ, McG ui r e WP, Brady MF, et al . The effect of di ameter of l ar gest r esi dual di sease on sur vi val after pr i mar y cytor educti ve sur ger y i n pati ents wi th subopti mal r esi dual epi thel i al ovar i an car ci noma. Am J Obstet G ynecol 1994;170:974–979. Jacobs I, Skates SJ, MacDonal d N, et al . Scr eeni ng for ovar i an cancer : a pi l ot randomi zed contr ol l ed tr i al . Lancet 1999;353:1207–1210. Kohn EC, Sar osy G , Davi s P, et al . A phase I/II study of dosei ntense pacl i taxel wi th ci spl ati n and cycl ophosphami de as i ni ti al therapy of poor-pr ognosi s advanced-stage epi thel i al ovar i an cancer. G ynecol Oncol 1996;62:181–191. Li nk C, Bi cher A, Kohn E, et al . F l exi bl e G -CSF dosi ng i n ovar i an cancer pati ents r ecei vi ng dose i ntense taxol therapy. Blood 1994;83:1188–1192.

McG ui r e WP, Hoski ns WJ, Brady MF, et al . Taxol and ci spl ati n i mpr ove outcome i n pati ents wi th advanced ovar i an cancer as compar ed to cytoxan/ci spl ati n. N Engl J Med 1996;334:1–6. Ozol s RF, Bundy BN, G r eer BE et al , G ynecol ogi c Oncol ogy G r oup. Phase III tr i al of car bopl ati n and pacl i taxel compar ed wi th ci spl ati n and pacl i taxel i n pati ents wi th opti mal l y r esected stage III ovar i an cancer : a G ynecol ogi c Oncol ogy G r oup study. J Clin Oncol 2003;21:3194–3200. Ozol s RF, Schwar tz PE, Ei fel PJ. Ovar i an cancer, fal l opi an tube

car ci noma, and per i toneal car ci noma. In: DeVi ta VT Jr, Hel l man S, Rosenber g SA, eds. Cancer pr inciples and pr actice of oncology, 6th ed. Phi l adel phi a, PA: Li ppi ncott Wi l l i ams & Wi l ki ns, 2001:1597–1532. Reed E. Ci spl ati n and anal ogs. In: Chabner BA, Longo D, eds. Cancer chemother apy and biother apy pr inciples and pr actice, Chapter 15, 3r d ed. Phi l adel phi a, PA: Li ppi ncott Wi l l i ams & Wi l ki ns, 2001:447–465. Reed E, Evans MK. Acute l eukemi a fol l owi ng ci spl ati n-based chemotherapy i n a pati ent wi th ovar i an cancer. J Natl Cancer Inst 1990;82:431–432. Reed E, Jacob J. Car bopl ati n and r enal dysfuncti on. Ann Inter n Med 1989;110:409. Reed E, Zer be CS, Brawl ey OW, et al . Anal ysi s of autopsy eval uati ons of ovar i an cancer pati ents tr eated at the Nati onal Cancer Insti tute, 1972-1988. Am J Clin Oncol 2000;28:107–116. Sar osy G , Reed E. Autol ogous stem cel l transpl antati on i n ovar i an cancer : i s mor e better ? Ann Inter n Med 2000;133:555–556.

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 6 - G y ne c o lo gic > 1 8 - Endo m e t ria l C a nc e r

18 Endometrial Cancer Christina M. A nnunziata* Michael J. Birrer† *Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland † Depar tment

of Cell and Cancer Biology, National Cancer Institute, National Institutes of Health, Rockville, Mar yland

EPIDEMIOLOGY Endometr i al cancer i s the most common pel vi c gynecol ogi c mal i gnancy i n women (6% of al l cancer s i n women). In 2002, 39,300 new cases wer e di agnosed (the i nci dence of endometr i al cancer was 22 cases per 100,000 popul ati on i n the 1980s and has been constant si nce then). An esti mated 6,400 deaths due to thi s mal i gnancy ar e pr edi cted year l y (accounti ng for 2% of al l cancer deaths). The mor tal i ty rate has conti nued to decl i ne si nce 1989, l i kel y because of i ncr eased awar eness of symptoms (abnor mal vagi nal bl eedi ng). Mor tal i ty i s twi ce as hi gh i n Afr i can Amer i can women than i n whi te women. However, the i nci dence i s 1.4 ti mes hi gher i n whi te women than i n Afr i can Amer i can women. Peak i nci dence i s i n the si xth and seventh decades of l i fe (5% of cases ar e di agnosed befor e the age of 40; 20% to 25% of pati ents ar e di agnosed befor e menopause).

RISK FACTORS

Endogenous estr ogen excess Pol ycysti c ovar y di sease Anovul ator y menstr ual cycl es Obesi ty: bei ng over wei ght by mor e than 20 to 50 l b i ncr eases the r i sk thr eefol d and bei ng over wei ght by mor e than 50 l b i ncr eases the r i sk 10-fol d G ranul osa cel l tumor of the ovar y (or other estr ogen-secr eti ng tumor s) Advanced l i ver di sease Endogenous pr ol onged estr ogen exposur e: ear l y menar che and l ate menopause; menopause i n women ol der than 52 year s i ncr eases the r i sk by 2.4-fol d. Ir r egul ar menses, i nfer ti l i ty, and nul l i par i ty: nul l i par ous women have twi ce the r i sk of devel opi ng uter i ne cancer compar ed to women wi th one chi l d and thr i ce the r i sk when compar ed to women who gi ve bi r th to fi ve or mor e chi l dr en Exogenous unopposed estr ogen sour ces, i ncl udi ng tamoxi fen (TAM), a weak estr ogen that i ncr eases the r el ati ve r i sk (RR) of devel opi ng endometr i al cancer to 2.3 Type 2 di abetes mel l i tus (DM), possi bl y r el ated to the effects of hyper i nsul i nemi a Hyper tensi on Fami l y hi stor y: hi stor y of endometr i al cancer i n a fi r st-degr ee r el ati ve i ncr eases the r i sk by thr eefol d, and hi stor y of a col or ectal cancer i n a fi r st-degr ee r el ati ve i ncr eases the r i sk of an endometr i al cancer by twofol d Per sonal hi stor y of br east, ovar i an, or col or ectal cancer ; per sonal or fami l y hi stor y consi stent wi th her edi tar y nonpol yposi s col or ectal cancer (HNPCC) (Lynch II syndr ome).

PROTECTIVE FACTORS Oral contracepti ves: Ther e i s a 50% decr ease i n RR when oral contracepti ves ar e used for at l east 12 months. Thi s pr otecti on l asts for at l east 10 year s after di sconti nuati on. Ci gar ette smoki ng: Ther e appear s to be a modest pr otecti ve r ol e

of ci gar ette smoki ng. However, thi s i s str ongl y outwei ghed by the si gni fi cant i ncr eased r i sk of l ung cancer and other major heal th haz ar ds.

DIAGNOSIS AND SCREENING Routi ne scr eeni ng for endometr i al cancer i s not r equi r ed i n asymptomati c women. Women taki ng TAM shoul d have a gynecol ogi c eval uati on accor di ng to the same gui del i nes as for women who ar e not taki ng thi s dr ug. Endometr i al bi opsy shoul d be done when the pati ent i s symptomati c (vagi nal bl eedi ng or spotti ng).

SIGNS AND SYMPTOMS Abnor mal vagi nal bl eedi ng i s a common symptom of endometr i al cancer (seen i n appr oxi matel y 90% of cases). Pr emenopausal women wi th pr ol onged and/or heavy menses, or i nter menstr ual spotti ng, shoul d under go endometr i al bi opsy. Al l postmenopausal women wi th vagi nal bl eedi ng shoul d be eval uated for endometr i al cancer (20% of these pati ents wi l l ul ti matel y be di agnosed wi th the mal i gnancy). Bi opsy i s al so r ecommended i n women taki ng estr ogen therapy for menopausal symptoms who may have wi thdrawal bl eedi ng. Asymptomati c pati ents wi th abnor mal gl andul ar ti ssue on Papani col aou smear shoul d be eval uated for endometr i al cancer (appr oxi matel y 10% of uter i ne cancer cases ar e detected by a Papani col aou smear ). Papani col aou smear, however, i s not an adequate tool for detecti on of endometr i al mal i gnancy. Pal pabl e, l ocal l y advanced tumor detected on pel vi c exami nati on i s suggesti ve of endometr i al cancer. Si gns and symptoms of advanced di sease (mani festati on i n Ta ble o f C o nt e nt s > Se c t io n 8 - Sk in C a nc e r > 2 2 - Sk in C a nc e rs a nd M e la no m a

22 Skin Cancers and Melanoma Upendra P. Hegde* Barry Gause† *Division of Hematology/Oncology, Univer sity of Connecticut Health Center , F ar mington, Connecticut † Medical

Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland The ski n i s the l ar gest or gan of the human body. It i s embr yol ogi cal l y der i ved fr om the neur oectoder m and the mesoder m. It consi sts of thr ee l ayer s: epi der mi s, der mi s, and subcuti s. Ski n cancer s can ar i se fr om var i ous cel l types and str uctur es i n var i ous l ayer s of the ski n (1). The exposur e of the ski n to the envi r onment has a speci al r el evance because a wi de var i ety of car ci nogens can i nteract di r ectl y wi th the geneti c components of ski n cel l s. Such exposur e has i ncr eased the i nci dence of ski n cancer s. The cel l s of or i gi n i n var i ous types of ski n cancer s ar e outl i ned i n Tabl es 22.1 and 22.2. The ski n cancer s ar e best di vi ded i nto mel anoma and nonmel anoma.

TABLE 22.1. Cells of Epidermis and Respective Tumor Type Cells of epidermis Melanocyte

Tumor type Melanoma

Incidence (%) 5–7

Epidermal basal cell

Basal cell carcinoma

60

Keratinocyte

Squamous cell carcinoma

30

Merkel cell

Merkel cell tumor

1–2

Langerhans cell

Histiocytosis X

4 mm). The effect of i nter fer on on di sease-fr ee sur vi val has been eval uated i n thi s setti ng (see Tabl e 22.12) (14).

TABLE 22.12. Use of Adjuvant Interferon Study group (accrual)

Treatment regimen

Outcomes analysis

Interferon α-2b, 20 Favored

million units/m 2 /dose i.v., 5 d/wk × 4 wk (total dose/wk, 100 million units/m 2 ), ECOG E1684 (287 patients with stage IIB or stage III malignant melanoma AJCC stage)

interferon therapy overall survival, 0.047

followed by Interferon α-2b, 10 million units/m 2 s.c., three times/wk for 48 wk (total dose/wk, 30 million units/m 2 ) vs. Observation Interferon α-2b, 20 million units/m 2 /dose i.v., 5 d/wk × 4 wk (total dose/wk, 100

Relapsefree survival, p = 0.004 Significant toxicity of interferon observed.

million units/m 2 ), followed by

ECOG 1690 (642 patients)

Interferon α-2b, 10 million units/m 2 s.c., three times/wk for 48 wk (total dose/wk, 30 million units/m 2 ) vs. Low-dose interferon: Interferon α-2b, 3 million units/m 2 s.c., three times/wk for 104 wk (total dose/wk, 9 million units/m 2 ) vs.

Survival benefit for high-dose interferon Relapsefree survival p = 0.05 in both nodepositive & nodenegative patients greatest in those with 2– 3 nodes (p = 0.02) No overall 5-yr survival benefit

Observation

ECOG E 1697 (1,444 patients AJCC stage II A) The aim is to know the impact of interferon on relapse-free survival and overall survival in the adjuvant setting in stage IIA disease

UKCCCR Study (1,000 patients AJCC stage II or III)

Interferon α-2b, 20 million units/m 2 /dose i.v., 5 d/wk × 4 wk (total dose/wk, 100 million units/m 2 ),

Ongoing

OR Observation Interferon α-2a, 3 million units/m 2 s.c., three times/wk for 2 yr (total dose/wk, 9 million units/m 2 ), OR Observation

Ongoing

Interferon α-2b, 10million units/m 2 /dose s.c. 5 d/wk for 4 wk (total dose/wk, 50 million units/m 2 ), EORTC study (18952) (1,000 patients AJCC stage II or III disease) for interferon in adjuvant setting. The goal is to see the impact of the two lower doses and subcutaneously administered interferon on the disease

followed by Interferon α-2b, 10 million units/m 2 s.c., three times/wk for 1 yr (total dose/wk, 30 million units/m 2 ), OR Interferon α-2b, 5 million units/m 2 s.c., three times/wk for

Ongoing

2 yr (total dose/wk, 15 million units/m 2 ) ECOG, Eastern Cooperative Oncology Group; AJCC, American Joint Committee for Cancer; UKCCCR, The UK Coordinating Committee on Cancer Research; EORTC, European Organization for the Research and Treatment of Cancer; i.v. intravenous; s.c., subcutaneous; vs., versus. Adapted from Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon α-2b adjuvant therapy of high risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 1996;14:7– 17, with permission.

Interleukin-2 Therapy for Metastatic Melanoma IL-2, fi r st i denti fi ed as a T-cel l gr owth factor i n 1976, i s pr oduced pr i mar i l y by T-hel per cel l s. It i s a 15-kD gl ycopr otei n and i nteracts wi th IL-2 r eceptor s expr essed on acti vated T cel l s, r esul ti ng i n pr ol i ferati on and di ffer enti ati on of both B and T cel l s and of cytotoxi c cel l s, and sti mul ates the cascade of cytoki nes i ncl udi ng var i ous i nter l euki ns, i nter fer ons, and tumor necr osi s factor s. The anti tumor effects of IL-2 ar e medi ated by i ts abi l i ty to cause pr ol i ferati on of natural ki l l er cel l s (NKs), l ymphoki ne-acti vated ki l l er cel l s (LAKs), and other cytotoxi c cel l s. IL-2 Doses and Administr ation Methods: The U.S. Food and Dr ug Admi ni strati on (F DA)–appr oved dosage for tr eatment of metastati c mel anoma i s 600,000 IU per kg admi ni ster ed as a bol us over 15

mi nutes ever y 8 hour s for a maxi mum of 14 doses. Fol l owi ng a r est per i od of about 5 to 9 days, the r egi men i s r epeated i f tol erated by the pati ent. Imagi ng studi es ar e r epeated at the end of two cour ses, and i f tumor r esponses or di sease stabi l i z ati on i s documented, the tr eatment i s r epeated, wi th per i odi c assessment of di sease r esponse. The overal l r esponse rate i s about 16% and a compl ete r esponse rate of 6% , and r esponses have been noted i n al l the di sease si tes (15,16). Pati ents who achi eved compl ete r esponses had the hi ghest chances of achi evi ng pr ol onged di sease-fr ee sur vi val . Pati ents wi th good basel i ne per for mance status and chemonai ve status wer e most l i kel y to r espond to the hi gh-dose IL-2 tr eatment. The toxi ci ty pr ofi l e of IL-2 i s dose, r oute, and admi ni strati on dependent. Common toxi ci ty pr ofi l e i nvol ves gastr oi ntesti nal system (i .e., nausea and vomi ti ng), car di ovascul ar system (i .e., hypotensi on or ar r hythmi as), l ung (i .e., hypoxemi a and pl eural effusi ons), ki dneys (i .e., azotemi a), and central ner vous system (i .e., confusi on and del i r i um) i n addi ti on to fever and fl ui d r etenti on, most of whi ch ar e the mani festati ons of the capi l l ar y l eak syndr ome. Toxi ci ty i s accentuated i n pati ents wi th basel i ne pul monar y, car di ac, and metabol i c di sease. Hi ghl y ski l l ed nur si ng and sel ecti on of the r i ght pati ents for hi gh-dose IL-2 have si gni fi cantl y r educed mor tal i ty i n pati ents tr eated wi th hi gh-dose IL2. Because hi gh-dose IL-2 therapy causes si gni fi cant toxi ci ty, i t i s al so admi ni ster ed ei ther subcutaneousl y or as a conti nuous i ntravenous i nfusi on at 9 to 18 mi l l i on IU/m2 /day for 4 to 5 days, and dosages up to 24 mi l l i on IU/m2 /day i n pati ents not el i gi bl e for hi gh dose of IL-2. Al though total r esponse rates as hi gh as 16.8% have been r epor ted, compl ete r esponses ar e l ower than those r epor ted wi th hi gh-dose IL-2. Combination IL-2 r egimens: Pr ecl i ni cal data have suggested syner gi sti c i mmunol ogi c effects of combi ni ng IL-2 wi th i nter fer on-α and chemotherapeuti c agents. These obser vati ons have r esul ted i n combi nati ons of IL-2 and i nter fer ons that di d not show a si gni fi cant advantage i n in vivo studi es. Concur r ent or sequenti al combi nati on of chemotherapeuti c agents wi th IL-2 and/or i nter fer on-α (bi ochemotherapy) pr oduces l ess toxi ci ty than hi gh-dose IL-2 and shows mi xed r esul ts, wi th overal l r esponses rangi ng fr om 25.3% to 50% (17). Pr esentl y, the use of bi ochemotherapy i s exper i mental unti l the fi nal r esul ts of a l ar ge i nter gr oup study compar i ng bi ochemotherapy and chemotherapy i n metastati c mel anoma ar e

r epor ted.

CONCLUSIONS Hi gh-dose i nter fer on r emai ns the most acti ve adjuvant agent eval uated to date for hi gh-r i sk mel anoma. It pr ol ongs the r el apse-fr ee sur vi val , but i ts i mpact on overal l sur vi val i s l ess cl ear. A summar y of the management opti ons of mel anoma i n advanced tumor stage i s found i n Tabl e 22.13. Chemotherapy agents and thei r r esponse rates i n metastati c mel anoma ar e l i sted i n Tabl e 22.14. Combi nati on chemotherapy i n metastati c mel anoma i s descr i bed i n Tabl e 22.15.

TABLE 22.13. Management Options Management

Metastatic site

Comments

Combination chemotherapy

Systemic metastasis

Palliative in nature, dacarbazine is the drug of choice

Surgical resection

Brain, soft tissue, lung, or liver

Isolated single legion

Radiation therapy

Brain, bone, or symptomatic systemic

Treatment of symptomatic lesions

metastasis

Combination chemotherapy + biologic therapy (interleukin-2 and/or interferon α)

Systemic metastatic disease

Promising and effective. Regression of visceral metastasis is seen with possible survival advantage

Immunotherapies

Systemic metastatic disease Experimental

Experimental

TABLE 22.14. Chemotherapy Agents and Response Rates Chemotherapeutic agent

Response rates (%)

Dacarbazine

15–25

Temozolomide (DTIC analog)

21

Nitrosoureas

Cisplatin

10–20

Carboplatin Vinca alkaloids Vincristine 15–25 Vinblastine Vindesine Taxoids Paclitaxel

18

Docetaxel Piritrexim

23

DTIC, dacarbazine.

TABLE 22.15. Description of Chemotherapy Regimens Chemotherapy regimens

Treatment description Cisplatin, 25

Response rates (%)

mg/m 2 /d i.v. for 3 d, d 1–3 (total dose/cycle, 75 mg/m 2 )

CBDT, the “Dartmouth regimen”*

Carmustine, 150 mg/m 2 i.v. d 1 on every oddnumbered cycle (i.e., every 43 d) (total dose every two cycles, 150 mg/m 2 ) Dacarbazine, 220 mg/m 2 /d i.v. for 3 d, d 1–3 (total dose/cycle, 660 mg/m 2 ) Tamoxifen, 10 mg twice daily PO during the therapy Cycle repeated every 21 d Cisplatin, 20 mg/m 2 /d i.v. for 4 d, d 2–5 (total dose/cycle, 80 mg/m 2 )

19–55

CVD (MD Anderson Cancer Center)†

Vinblastine, 1.6 mg/m 2 /d i.v. for 5 d, d 1–5 (total dose/cycle, 8 mg/m 2 ) Dacarbazine, 800 mg/m 2 i.v. on d 1 (total dose/cycle, 800 mg/m2 ) Cycle repeats every 21 d

* From Del Prete SA, Maurer LH, O'Donnell I, et al. Combination chemotherapy with cisplatin, carmustine, dacarbazine, and tamoxifen in metastatic melanoma. Cancer Treat Rep 1984;68: 1403–1405, with permission. † From Legha SS, Ring S, Papadopoulos N, et al. A prospective evaluation of a triple-drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanoma. Cancer 1989;64:2024–2029. A r ecent phase III mul ti center randomi zed tr i al of dacar baz i ne al one ver sus the Dar tmouth r egi men (i .e., ci spl ati n, car musti ne, dacar baz i ne, and tamoxi fen) i n pati ents wi th metastati c mel anoma fai l ed to show a stati sti cal di ffer ence i n sur vi val or tumor r esponse i n pati ents wi th mel anoma (EORTC study) (18). Combination of Chemotherapy Regimen and Biologic Therapy

(Biochemotherapy) Rationale: Anti cancer effects of the combi nati on therapy ar e addi ti ve or syner gi sti c Ther e ar e di ffer ent mechani sms of acti on for di ffer ent r egi mens Nonover l appi ng toxi ci ty No cr oss r esi stance Ther e i s a suggesti on that bi ol ogi c agents may pr oduce l ongter m sur vi val s. Combi nati on chemotherapy wi th bi ol ogi c agents i s descr i bed i n Tabl e 22.16.

TABLE 22.16. Combination Chemotherapy with Biologic Agents

Treatment Dacarbazine, 1,000 mg/m2 as a continuous infusion over 24 h (total dose/cycle, 1,000 mg/m2 ) Recombinant interleukin-2, administered i.v. over 30 min on an outpatient basis on days 15–19 and d 22–26. The dose of interleukin-2 was 24 MIU/m2 for 10 doses, d 1–5 and 8–12 (total dose/cycle, 240 MIU/m 2 ) Dacarbazine was repeated once every 28 d and supportive treatment given during this protocol

Response rates (%)

22

Dacarbazine, 200 mg/m2 i.v. for 5 d, start every wk 4 Interferon α-2b, 15 MU/m2 i.v. daily for 5 d/wk for 3 wk, and thereafter, 10 MU/m2 s.c. 3 times/wk. Cycle repeats every 28 d

53

Cisplatin, 100 mg/m2 i.v. on d 1 (total dose/cycle, 100 mg/m2 ) Interferon α-2a, 10 MU/d s.c. on d 1–5 (total dose/cycle, 50 MU) Interleukin-2 given as continuous infusion for 6 d (d 3–8) in a decrescendo schedule, starting on d 3 with 18 MU/m2 every 6 h, followed by 18 MU/m2 every 12 h, 18 MU/m2 every 24 h, and a maintenance dose of 4.5 MU/m2 every 24 h for 72 h (total dose/cycle, 139.5 MU/m2 ). Cycle repeats every 28 d

33 (overall response rate)

CVD regimen

64 (overall response rate)

Cisplatin, 20 mg/m2 /d i.v. for 4 d, d 2–5 (total dose/cycle, 80 mg/m2 ) Vinblastine, 1.6 mg/m2 /d i.v. for 5 d, d 1–5 (total dose/cycle, 8 mg/m 2 ) Dacarbazine, 800 mg/m2

i.v. on d 1 (total dose/cycle, 8 mg/m 2 ) PLUS Interleukin-2, 9 million units/m2 /d continuous i.v. infusion for 4 d, d 6–9 (total dose/cycle, 36 million units/m 2 ) Interferon α, 5 million units/m 2 /dose s.c. for 5 d, d 6–10 (total dose/cycle, 25 million units/m 2 ) Note: The therapy schedule with the biologic agents either immediately precedes or follows the CVD regimen. Cycle repeats every 21 d Cisplatin, 25 mg/m2 i.v. 2-h infusion on d 1–3 and 22–25 (total dose/cycle, 175 mg/m2 ) Carmustine, 150 mg/m2 i.v. 1-h infusion on d 1 (total dose/cycle, 150 mg/m2 ) Dacarbazine, 220 mg/m 2 i.v. 2-h infusion on d 1–3 and 22–25 (total dose/cycle, 1,540 mg/m 2 ) Tamoxifen, 10-mg tablet PO b.i.d. for 6 wk and begin on d 1 Interleukin-2, 1.5 million units/m2 administered i.v. every 8 h, starting d 4 for 15 doses, d 4–8 and 17–21 (total dose/cycle, 45 million

55

units/m 2 ) PLUS Interferon α-2b, 6 million units/m 2 /d s.c. for 10 d, d 4–8 and 17–21 (total dose/cycle, 60 million units/m 2 ). Cycle repeats every 6 wk MIU, million international units; MU, million units.

Vaccine Therapy in Malignant Melanoma Immuni z ati on pr i nci pal l y i nvol ves r ecogni ti on of tumor-speci fi c pepti de by cytotoxi c T cel l s when pr esented by anti gen-pr esenti ng cel l s bound to major hi stocompati bi l i ty compl ex (MHC) mol ecul es. A number of tumor-associ ated pepti de anti gens ar e pur i fi ed and ei ther admi ni ster ed i ntrader mal l y wi th an i mmune adjuvant (19) or the pepti de i s “pul sed” onto autol ogous anti gen-pr esenti ng cel l s, and the combi nati on i s i njected i ntrader mal l y (20). Di F r onzo et al . (21) have used pol yval ent mel anoma vacci ne der i ved fr om the mel anoma cel l cul tur es i n pati ents wi th AJCC stage II mel anoma and have r epor ted enhanced humoral i mmune r esponse to cor r el ate wi th i mpr oved di sease-fr ee sur vi val and overal l sur vi val . The semi nal obser vati on that heatshock pr otei ns i sol ated fr om cancer cel l s of mi ce and rats el i ci ted speci fi c i mmuni ty to the cancer s fr om whi ch they wer e der i ved l ed to the di scover y that heat-shock pr otei ns ar e associ ated wi th pepti des, i ncl udi ng anti geni c tumor-speci fi c pepti des, and el i ci t potent tumor-speci fi c T-cel l i mmuni ty when i njected back. Pr el i mi nar y phase I and II studi es of heat-shock pr otei ns pur i fi ed fr om the autol ogous mel anoma tumor s i n humans have shown cl i ni cal l y r el evant si gni fi cant tumor-speci fi c i mmune r esponses (22).

A mul ti i nsti tuti onal phase III study i s ongoi ng to el uci date the cl i ni cal si gni fi cance of heat-shock pr otei n vacci ne der i ved fr om the autol ogous tumor cel l s. Other appr oaches i ncl ude gene therapy for appr opr i ate pepti de expr essi on i n the anti gen-pr esenti ng cel l s, whi ch then pr ocess the pepti de i ntracel l ul ar l y and bi nd ti ghtl y to the appr opr i ate human l eukocyte anti gen (HLA) mol ecul e for pr esentati on to cytotoxi c T cel l s. Some of the mel anoma-associ ated anti gen epi topes ar e l i sted i n Tabl e 22.17. Var i ous studi es ar e i n pr ogr ess, and fi nal r esul ts ar e awai ted.

TABLE 22.17. Melanoma-associated Antigen Epitopes Antigen

HLA restriction

Cellular location

MAGE-1

A1/Cw 1601

Cytoplasm

MAGE-3

A1/A2

Cytoplasm

MART1/MelaA

A2

Cytoplasm

Tyrosinase

A2/A24

Melanosomal

NONMELANOMA SKIN CANCER Ther e ar e two major types of nonmel anoma ski n cancer s: basal cel l car ci noma and squamous cel l car ci noma. Together they account for near l y one thi r d of al l the cancer s i n the Uni ted States.

Basal Cell Carcinoma Basal cel l car ci noma i s the most common cancer i n the U.S.

whi te popul ati on. It accounts for 77% of 77,000 new cases of nonmel anoma ski n cancer s seen i n the Uni ted States. Common Clinical Presentations of Basal Cell Carcinoma Include the Follow ing: Shi ny ski n, col or ed pi nk, wi th transl ucent papul e wi th tel angi ectasi a Nodul ar var i ant consi sts of nodul e wi th central depr essi on and r ol l ed mar gi ns and may bl eed fr om trauma. Usual l ocati on i s head and neck ar ea Pi gmented basal cel l car ci noma: Nodul ar wi th br own to bl ack pi gment. Scl er osi ng or mor phea-type basal cel l car ci noma: Yel l owi sh, i nfi l trated, wi th i ndi sti nct bor der s, may not be di agnosed for a l ong ti me. Mohs sur ger y may be appr opr i ate for tr eatment. Other l ess common pr esentati ons i ncl ude hyper keratoti c type car ci noma: Usual l y i nvol ves head and neck ar ea, exhi bi ts sessi l e gr owth on the l ower tr unk, i s mul ti centr i c on face wi th ul cer and scar ti ssues, and i s of the gi ant exophyti c type and the cysti c type that pr esents as a bl ue–gray nodul e on the face.

Squamous Cell Carcinoma Squamous Cell Carcinoma Involving the Skin has the Follow ing Characteristics: Usual l y found i n el der l y whi te men wi th sun-damaged ski n Common si tes i ncl ude back of the hand, for ear m, face, and neck; si ngl e or mul ti pl e l esi ons F i r m, i ndurated, expandi ng nodul e, often at the si te of acti ni c keratosi s The nodul e may be ul cerated, and r egi onal l ymph nodes may be enl ar ged.

Squamous Cell Carcinoma of a Mucocutaneous Site:

El der l y men wi th chr oni c hi stor y of smoki ng, al cohol use, or chewi ng tobacco or betel nut Common si tes i ncl ude mouth and l ower l i p Lesi ons usual l y star t as an er osi on or a nodul e that ul cerates. Other Sites Include the Follow ing: Sol e of the foot, ver r ucous for m Mal e geni tal i a: human papi l l omavi r us (HPV) r el ated, under l yi ng condyl omata of Buschke– Lowenstei n (see Tabl e 22.18).

TABLE 22.18. Premalignant Lesions of the Epidermis Actinic keratosis Chemical keratosis: arsenic, tar, polycyclic aromatic hydrocarbons, thermal keratosis Radiation dermatitis Bowen disease Erythroplasia of Queyrat Bowenoid papulosis Epidermodysplasia verruciformis Leukoplakia Keratoacanthoma Tabl e 22.19 l i sts the comparati ve featur es of basal and squamous cel l car ci nomas of the ski n.

TABLE 22.19. Features of Basal and Squamous Cell Carcinomas of Skin

Characteristics

Basal cell carcinoma

Squamous cell carcinoma

Incidence

Most common cancer of the skin in whites

Next most common skin cancer in whites

Cell of origin

Basal cells of epidermis and hair follicles

Epidermal keratinocytes

Site of tumor

Sunexposed areas of head and neck, ear, and extremities

Sun-exposed areas of head, neck, face, forearm, and dorsum of the hand

Ethnic background

Fair skin

Fair skin

Sun exposure

Continuous cumulative exposure

Continuous cumulative exposure

Male/female ratio

Common in men

Common in men

Growth and prognosis

Slow growing and good prognosis

Mucosal origin

None

Slow growing and good prognosis

Involves lip and mouth

Diagnosis of Nonmelanoma Skin Cancer Hi stor y shoul d i ncl ude durati on of the l esi on, symptoms l i ke pai n/i tchi ng, and r ecent changes of the sur face: Hi stor y of sun exposur e, and r ecr eati onal and occupati onal hi stor y Ethni c backgr ound and the type of the ski n Hi stor y of radi ati on exposur e, ar seni c exposur e, chr oni c ul cer /bur n scar, or osteomyel i ti s.

Complete Skin Examination Includes the Follow ing: Exami nati on of scal p, ear s, pal ms, sol es, i nter di gi tal ar eas, and mucous membranes. Eval uati on of the extent of sun damage to ski n (i .e., sol ar el astosi s, scal i ng, er ythema, tel angi ectasi a, and sol ar l enti gi nes). The ski n shoul d be eval uated for enl ar gement of the l ocor egi onal and di stant metastases. Ski n bi opsy shoul d be per for med, ei ther exci si onal when the tumor i s smal l , or i nci si onal when the tumor i s l ar ge. A shave bi opsy wi th a scal pel may be used i n nodul oul cerati ve, cysti c, or super fi ci al type.

Treatment Principles Sur ger y i s the pr i mar y mode of tr eatment.

Exci si on of the tumor wi th negati ve mar gi ns of appr oxi matel y 4 to 6 mm i s suffi ci ent. The pr ocedur e i s per for med under l ocal anesthesi a. Local l y drai ni ng nodes ar e exami ned and r emoved onl y i f they ar e enl ar ged. Pl asti c sur ger y may be needed to cl ose the defects pr oduced by exci si on of the tumor. Mohs sur ger y: Thi s i s a pr ogr essi ve exci si on techni que that al l ows exci si on of the tumor unti l the negati ve mar gi ns ar e achi eved. Mohs mi cr ographi c sur ger y uses the fr esh-ti ssue techni que wi th the use of fr ozen secti on and i s l ess ti meconsumi ng than the or i gi nal sur ger y.

Role of Radiation THERAPY Radi ati on therapy del i ver s x-rays at a total dose of 2,000 to 3,000 cG y that penetrate up to 2 to 5 mm, wher e most of the basal cel l and squamous cel l car ci nomas i nfi l trate. The total dose i s di vi ded i nto mul ti pl e fracti ons, usual l y over 3 to 4 weeks, to r educe si de effects (see Tabl e 22.20).

TABLE 22.20. Radiation Therapy Radiation therapy in nonmelanoma skin cancer Advantages

Common side effects

Most skin tumors are radiosensitive

Loss of hair follicles and sweat glands

Indicated for skin cancer in elderly patients who have high

Skin atrophy and

risk for surgery and large and bulky tumors

telangiectasia

Tumors located on the nose, eye, lip, eyelid, and inner and outer canthi of the eye as well as skin cancer along the embryonal fusion planes

Radiation dermatitis

Cure rate for squamous cell carcinoma and basal cell carcinoma are >90%

Radiationinduced precancerous lesions of the skin

Var i ous other types of tr eatments ar e l i sted i n Tabl e 22.21.

TABLE 22.21. Other Types of Treatment Treatment method

Characteristic features Advantages Useful to treat basal cell carcinoma, superficial squamous cell carcinoma, Bowen disease, and

1.

Curettage and electrodesiccation preceded by a shave biopsy

keratoacanthoma actinic keratosis Cure rates in selected patients, 77%–97% Disadvantages Not suitable for tumors in highrisk areas, histologically aggressive tumors, or morphea-type tumors Advantages

2.

Cryotherapy kills tumor cells by freezing Liquid nitrogen (-195.5°C) causes tissue necrosis

Suitable for small tumors of the eyelids, nose, chest, back, or morphea-type basal cell carcinoma Simple procedure; no anesthesia necessary Disadvantages

Cannot be used in patients with Raynaud phenomenon or tumors >3 cm in diameter Advantages

3.

Fluorouracil cream, 1% or 5%, applied topically to cover the lesions twice daily for a few weeks. An inflammatory response id desired; if it does not occur, the drug concentration or frequency of applications or treatment duration should be increased. Typical treatment duration is 2–6 wk longer

Suitable for basal cell carcinoma on the face and extremities, and on superficial tumors Disadvantages Photosensitivity, allergic reactions, and not useful in other cancers of skin. Occlusive dressings may increase the incidence of inflammatory reactions in adjacent normal skin. Porous gauze dressings may be used to cover

application sites.

4.

5.

Fluorouracil plus 2,4dinitrochlorobenzene

Selected cases of Bowen disease and in situ epidermoid cancer.

Combination chemotherapy fluorouracil plus cisplatin

As a palliative treatment in metastatic skin cancer when surgery is not curative.

Other Cancers of the Skin Mer kel cel l car ci noma ar i ses fr om the neopl asti c pr ol i ferati on of the Mer kel cel l s. Characteristics of the Merkel Cell: Ar i ses fr om the neural cr est cel l s and i s a member of the ami ne pr ecur sor uptake and decar boxyl ati on (APUD) cel l system Si tuated i n the basal l ayer of the epi der mi s and hai r fol l i cl es Impor tant for tacti l e sensati ons i n l ower ani mal s F uncti ons as a mechanor eceptor i n humans. Characteristics of Merkel Cell Tumor: Rar e tumor seen i n el der l y whi tes wi th sun-exposur e hi stor y Invol ves ski n of the head and neck and found l ess commonl y i n the extr emi ti es and geni tal s Pr esents as i ntracutaneous bl ui sh, fi r m, and nontender nodul e

about 0.5 to 1 cm Hi stol ogi cal l y, a smal l r ound cel l tumor, contai ni ng neur osecr etor y cytopl asmi c granul es Neur on-speci fi c enol aseposi ti ve and anti cytokerati n anti body, CAM 5.2, posi ti ve Di ffer enti al di agnosi s i ncl udes smal l cel l car ci noma of l ung and l ymphoma Ear l y spr ead by l ymphati cs and hematogenousl y to the di stant si te Sur gi cal exci si on i s the pr i mar y tr eatment, and radi ati on i s used i n the adjuvant setti ng. Tumors A rising from the Skin A ppendages, Pilosebaceous Complex: Hai r fol l i cl e Sebaceous gl and Ar r ector pi l i muscl e Apocr i ne sweat gl and. Most of these tumor s ar e beni gn, and car ci nomas ar e rar e. Significance: Of i nter est to der matopathol ogi st.

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Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 9 - He m a t o lo gic M a ligna nc ie s > 2 3 - Ac ut e Le uk e m ia s

23 Acute Leukemias Michael Craig* Jame A braham† Brian P. Monahan‡ *Section of Hematology/Oncology, West Vir ginia Univer sity, Mor gantown, West Vir ginia † Mar y

Babb Randolph Cancer Center , West Vir ginia Univer sity, Mor gantown, West Vir ginia ‡ Depar tment

of Hematology and Medical Oncology, Unifor med Ser vices, Univer sity of the Health Sciences, Bethesda, Mar yland Acute l eukemi a r epr esents a ver y aggr essi ve, mal i gnant transfor mati on of an ear l y hematol ogi c pr ecur sor. The mal i gnant cl one i s ar r ested i n an i mmatur e, bl ast for m; pr ol i ferates abnor mal l y; and no l onger has the abi l i ty to under go maturati on. In contrast, the chr oni c l eukemi as ar e character i zed by r esi stance to apoptosi s and by accumul ati on of nonfuncti onal cel l s. Accumul ati on of the bl asts wi thi n the bone mar r ow r esul ts i n pr ogr essi ve hematopoi eti c fai l ur e, wi th associ ated i nfecti on, anemi a, and thr ombocytopeni a. It i s these compl i cati ons that often pr ompt eval uati on i n newl y di agnosed pati ents. Acute l eukemi a conti nues to pr esent a grave di agnosi s because of i ts rapi d cl i ni cal cour se. Pati ents r equi r e aggr essi ve and ur gent eval uati on and tr eatment i ni ti ati on. As a general r ul e, tr eatment i s expected to i mpr ove qual i ty of l i fe and pr ol ong sur vi val . Unfor tunatel y, many pati ents pr esent at an advanced age and wi th comor bi d condi ti ons, maki ng cytotoxi c tr eatment di ffi cul t. El der l y or unwel l pati ents who ar e gi ven the best suppor ti ve car e sur vi ve onl y for a few months. The i mmatur e, cl onal l y pr ol i ferati ng cel l s that for m bl asts may be der i ved fr om myel oi d or l ymphoi d cel l l i nes. Transfor mati on of

granul ocyte, RBC, or pl atel et (myel oi d) pr ecur sor s r esul ts i n acute myel ogenous l eukemi a (AML). Acute l ymphobl asti c l eukemi a (ALL) or i gi nates fr om B or T l ymphocytes. Thi s general di vi si on has i mpl i cati ons for di ffer ent tr eatment and di agnosti c appr oaches. It i s the fi r st step i n cl assi fyi ng the l eukemi c pr ocess occur r i ng i n the pati ent.

EPIDEMIOLOGY Esti mated new cases i n the Uni ted States i n 2003 wer e 10,500 for AML and 3,600 for ALL (age-adjusted esti mates). AML accounts for 7,800 deaths and ALL accounts for 1,400 deaths annual l y i n the Uni ted States (age-adjusted esti mates). The r i sk of devel opi ng AML i ncr eases wi th advanced age, the medi an age bei ng 60 to 69. Seventy-fi ve per cent of newl y di agnosed pati ents wi th AML ar e ol der than 60. AML i s the most common l eukemi a i n adul ts (80% of cases). ALL i s mor e common i n chi l dr en; 60% of cases ar e found i n pati ents younger than 20 year s. A smal l decr ease and a pl ateau i n the i nci dence of new cases has been obser ved si nce 1995.

RISK FACTORS Most pati ents wi l l have no i denti fi abl e r i sk for devel opi ng l eukemi a. Tabl e 23.1 l i sts the condi ti ons that ar e i denti fi ed wi th an i ncr eased r i sk for devel opi ng acute l eukemi a. Most studi es have eval uated the r el ati onshi p between the r i sk factor s and AML. The condi ti ons that ar e most associ ated wi th AML ar e chr oni c benzene exposur e, exposur e to i oni z i ng radi ati on, and pr evi ous chemotherapy. In the case of chr oni c l ymphocyti c l eukemi a (CLL), the her bi ci de fr om the Vi etnam War era, Agent Orange, has been associ ated wi th at l east compensabl e r i sk.

TABLE 23.1. Risk Factors for Acute Leukemia

Exposure: ionizing radiation, benzene, cytotoxic drugs, alkylating agents, cigarette smoking, ethanol use by the mother Acquired disorders: myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, polycythemia vera, chronic myelogenous leukemia, myeloproliferative disorders, idiopathic myelofibrosis, aplastic anemia, eosinophilic fasciitis, myeloma, primary mediastinal germ cell tumor (residual teratoma elements evolve into myeloid progenitors that evolve into AML years later) Genetic predisposition: Down syndrome, Fanconi anemia, Diamond-Blackfan anemia, Kostmann syndrome, Klinefelter syndrome, Chromosome 21q disorder, Wiskott-Aldrich syndrome, ataxia-telangiectasia, dyskeratosis congenita, combined immunodeficiency syndrome, von Recklinghausen disease, neurofibromatosis 1, Shwachman syndrome Familial: nonidentical sibling (1:800), monozygotic twin (1:5), first-degree relative (three times increased risk). Infection: human T-cell leukemia virus and Tcell ALL AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia.

Ionizing Radiation Exposure Explored in

Atomic Bomb Survivors Ioni z i ng radi ati ons have a l atency per i od of 5 to 20 year s and a peak per i od of 5 to 9 year s i n atomi c bomb sur vi vor s. They exhi bi t a 20- to 30-fol d i ncr eased r i sk of AML and chr oni c myel ogenous l eukemi a (CML).

Chemotherapy Therapy-r el ated AML may account for 10% to 20% of new cases. It i s r epor ted i n Hodgki n and non-Hodgki n l ymphoma; br east, smal l cel l , ger m cel l , and ovar i an tumor s; as wel l as i n pati ents who have r ecei ved hi gh-dose therapy. Leukemi a associ ated wi th al kyl ati ng agents may be associ ated wi th cytogeneti c changes of chr omosomes 5, 7, and 13. Often ther e i s a mul ti year l atent-phase myel odyspl asti c syndr ome pr ecedi ng the devel opment of AML. Topoi somerase II agents, often wi th an abnor mal chr omosome 11q23 i n the bl asts, can rapi dl y evol ve after i ni ti al therapy. Usual l y, these ar e pr eceded by onl y a br i ef myel odyspl asti c state rapi dl y evol vi ng to AML. Pr evi ous hi gh-dose therapy wi th autol ogous transpl ant l eads to a cumul ati ve r i sk of 2.6% by 5 year s, especi al l y wi th total body i r radi ati on (TBI)–contai ni ng r egi mens.

CLINICAL SIGNS AND SYMPTOMS 1. Ineffecti ve hematopoi esi s—r esul ts fr om mar r ow i nfi l trati on by the mal i gnant cel l s Anemi a: pal l or, fati gue, and shor tness of br eath Thr ombocytopeni a: epi staxi s, petechi ae, and easy br ui si ng Neutr openi a: fever and pyogeni c i nfecti on. 2. Infi l trati on of other or gans Ski n: l eukemi a cuti s i n 10%

G um hyper tr ophy: especi al l y i n monocyti c l eukemi a (AML M5) G ranul ocyti c sar coma: l ocal i zed tumor composed of bl ast cel l s; i t i mpar ts poor er pr ognosi s; these sar comas ar e occasi onal l y extramedul l ar y l eukemi a masses associ ated wi th 8;21 transl ocati on Li ver, spl een, and l ymph nodes: common i n ALL, occasi onal l y i n monocyti c l eukemi a (AML M5) Thymi c mass: pr esent i n 15% of ALL i n adul ts Testi cul ar i nfi l trati on: al so a si te of r el apse for ALL Reti nal i nvol vement: may occur i n ALL. 3. Central ner vous system (CNS) and meni ngeal i nvol vement F i ve per cent to 10% of cases at di agnosi s, mai nl y ALL, i nv(16) [F r ench–Amer i can– Br i ti sh (FAB) M4Eo], and hi gh bl ast count Anal ysi s and pr ophyl axi s ar e gi ven i n ALL to decr ease CNS r el apse Symptoms: headache and crani al ner ve pal sy, but mostl y asymptomati c. 4. Di ssemi nated i ntravascul ar coagul ati on (DIC) and bl eedi ng Ver y common wi th pr omyel ocyti c l eukemi a t(15;17); mechani sm i s r el ated to ti ssue factor r el ease by granul es and fi br i nol ysi s; i t wor sens wi th cytotoxi c tr eatment and i mpr oves wi th al l -trans r eti noi c aci d (ATRA) Can be pr esent i n AML i nv(16) or monocyti c l eukemi a or can be r el ated to sepsi s. 5. Leukostasi s Occur s wi th el evated bl ast count; 25% of pati ents wi th ALL pr esent wi th whi te bl ood cel l (WBC) count gr eater than 50,000 Symptoms r esul t fr om capi l l ar y pl uggi ng by l eukemi c cel l s; i t i s associ ated wi th l ar ge nondefor mabl e bl asts i n AML and ALL and i s rar el y seen i n CLL Common si gns: dyspnea, headache, confusi on, and hypoxi a Ini ti al tr eatment i ncl udes l eukapher esi s, aggr essi ve hydrati on, and chemotherapy to rapi dl y l ower the ci r cul ati ng bl ast per centage wi th dr ugs (e.g., oral hydr oxyur ea or

i ntravenous cycl ophosphami de) Transfusi ons shoul d be avoi ded because these may i ncr ease vi scosi ty Leukapher esi s i s r epeated dai l y i n conjuncti on wi th chemotherapy unti l the bl ast count i s l ess than 50,000.

DIAGNOSTIC EVALUATION Hi stor y and physi cal exami nati on ar e an essenti al par t of di agnosi s of acute l eukemi a. Compl ete bl ood count (CBC) and di ffer enti al , manual exami nati on of per i pheral smear, and per i pheral bl ood fl ow cytometr y ar e consi der ed when ci r cul ati ng bl asts ar e suffi ci entl y abundant to establ i sh a di agnosi s wi thout need for bone mar r ow bi opsy. Coagul ati on tests i ncl ude pr othr ombi n ti me (PT), par ti al thr ombopl asti n ti me (PTT), D-di mer, and fi br i nogen. El ectr ol ytes wi th cal ci um, magnesi um, phosphor us, and ur i c aci d. Low gl ucose, potassi um, and PO2 (par ti al pr essur e of oxygen) can occur wi th del ay i n anal ysi s of hi gh bl ast count. Bone mar r ow bi opsy and aspi rate (wi th anal ysi s for mor phol ogy), cytogeneti cs, fl ow cytometr y, and cytochemi cal stai ns (Sudan bl ack, myel oper oxi dase, aci d phosphatase, and speci fi c and nonspeci fi c esterase) ar e used for di agnosi s. Human l eukocyte anti gen (HLA) testi ng of pati ents who ar e transpl ant candi dates—the test i s per for med befor e the pati ent becomes cytopeni c. Speci men r equi r ements ar e mi ni mal when DNA-based HLA typi ng i s per for med. Hepati ti s B and C, cytomegal ovi r us, her pes si mpl ex vi r us, human T-cel l l eukemi a vi r us, and human i mmunodefi ci ency vi r us anti body ti ter s ar e obtai ned. Typi ng and scr eeni ng of bl ood pr oducts of pati ents wi th thei r consent: Bl ood pr oduct sel ecti on shoul d pr ospecti vel y consi der the al l ogenei c transpl ant candi dacy needs of cytomegal ovi r us CMV conver si on r educti on and i r radi ati on to i ncapaci tate donor l ymphocytes fr om contami nati ng pr oducts.

Pr egnancy test (β-human chor i oni c gonadotr opi n). El ectr ocar di ogram (ECG ) and anal ysi s of car di ac ejecti on fracti on shoul d be done pr i or to tr eatment wi th anthracycl i nes. Lumbar punctur e—per for med when si gns and symptoms of ALL or monocyti c l eukemi a ar e pr esent. Low pl atel ets shoul d be cor r ected. The pr ocedur e may be per for med after r educti on of per i pheral bl ast count to avoi d i nocul ati on of bl asts i nto uni nvol ved cer ebr ospi nal fl ui d (CSF ). Obtai n cel l count, openi ng pr essur e, pr otei n l evel , and submi t cytocentr i fuge speci men for cytol ogy. Central venous access shoul d be obtai ned usi ng dual -l umen tunnel catheter or tr i pl e-l umen l i ne. An i mpl anted por t-type catheter i s not r ecommended. Coagul ati on abnor mal i ti es shoul d be cor r ected i f pr esent. It i s often possi bl e to i ni ti ate i nducti on therapy wi th nor mal per i pheral vei ns and awai t subsi dence of coagul opathy to r educe r i sk of pr ocedural compl i cati ons. Suppl emental testi ng of fl uor escent in situ hybr i di z ati on (F ISH) assay for 15;17 transl ocati on i s per for med when acute pr omyel ocyti c l eukemi a (APL) i s suspected, and BCR-ABL test i s per for med when de novo CML or bl ast cr i si s transfor mati on i s suspected to be cr i ti cal . Cytogeneti c anal ysi s of bl asts wi l l contr i bute dramati cal l y to subsequent pr efer r ed management.

INITIAL MANAGEMENT The i ni ti al management of acute l eukemi a i nvol ves the fol l owi ng: Hydrati on wi th i .v. fl ui ds, 1,500 to 2,000 mL per day. Tumor l ysi s pr ophyl axi s shoul d be star ted. Bl ood pr oduct suppor t suggesti ons for pr ophyl acti c transfusi ons ar e hemogl obi n l evel l ess than 8 and pl atel et l evel l ess than 10,000. Pl atel et tr i gger thr eshol d can be hi gher i n the context of fever or bl eedi ng (l ess than 20,000 suggested), cr yopr eci pi tate can be used i f fi br i nogen l evel i s l ess than 100, and fr esh fr ozen pl asma (F F P) can be used for si gni fi cantl y el evated l evel s of PT and PTT. The mi ni mum “safe” pl atel et l evel r equi r ed to pr event spontaneous hemor r hage i s not known. Addi ti onal pl atel et opti mi z ati on strategi es i ncl ude avoi dance of cycl ooxygenase-2 (COX-2)–sel ecti ve nonster oi dal anti i nfl ammator y dr ug (NSAID), aspi r i n, and cl opi dogr el -l i ke

agents. WBC fi l ter (i f CMV-negati ve bl ood i nventor y i s not avai l abl e) shoul d be used and bl ood pr oducts shoul d be i r radi ated i n those pati ents who ar e futur e al l ogenei c transpl ant candi dates. Fever and neutr openi a r equi r e bl ood and ur i ne cul tur es, fol l owed by tr eatment wi th appr opr i ate anti bi oti cs (see Chapter 36), and i magi ng. Therapeuti c anti coagul ati on shoul d be gi ven wi th extr eme cauti on i n pati ents dur i ng per i ods of extr eme thr ombocytopeni a. Adjustment of pr ophyl acti c pl atel et transfusi on thr eshol ds or anti coagul ants i s r equi r ed. Suppr essi on of menses Medr oxypr ogester one (Pr overa) 10 mg dai l y or twi ce dai l y.

Tumor Lysis Syndrome Tumor l ysi s syndr ome can be spontaneous or can be i nduced by chemotherapy. Ri sk factor s i ncl ude el evated ur i c aci d, hi gh WBC count, el evated l actate dehydr ogenase (LDH), hi gh tumor bur den, and those factor s that ar e al r eady pr esent spontaneousl y i n tumor l ysi s at pr esentati on. Laborator y tests i ndi cate el evated cr eati ni ne, l ow cal ci um, hi gh phosphor us, aci dosi s, and coagul opathy. The pati ents shoul d be i ni ti ated on al l opur i nol 300 mg twi ce dai l y for 3 days, fol l owed by once dai l y unti l r i sk i s r esol ved. For hydrati on, al kal i ni z i ng fl ui ds (0.5N sal i ne wi th 50 mEq sodi um bi car bonate 2,000 mL per day) shoul d be consi der ed. Rasbur i case (El i tek) 0.15 mg per kg i .v. dai l y shoul d be used for up to 5 days i f the pati ent i s i n tumor l ysi s at pr esentati on or has r i si ng cr eati ni ne l evel or hyper ur i cemi a dur i ng i nducti on. Hemodi al ysi s may be r equi r ed i n r efractor y cases or ur gentl y i n the setti ng of l i fe-thr eateni ng hyper kal emi a, or vol ume over l oad i f ol i gur i c (see Chapter 38).

CLASSIFICATION OF ACUTE MYELOGENOUS LEUKEMIA Ther e ar e two cur r ent systems to cl assi fy AML. One system has been suggested by the Wor l d Heal th Or gani z ati on (WHO) and i ncor porates r ecur r ent cytogeneti c abnor mal i ti es and pr ognosti c gr oups (see Tabl e 23.2). Mar r ow bl asts shoul d make up 20% of the nucl eated cel l s wi thi n the aspi rate unl ess t(8;21) or i nv(16) i s pr esent. The F r ench-Amer i can-Br i ti sh (FAB) cl assi fi cati on i s al so used and cl assi fi es AML i nto ei ght subtypes. The bl asts may be character i zed as myel oi d l i neage by the pr esence of Auer r ods; a posi ti ve myel oper oxi dase, Sudan bl ack, or nonspeci fi c esterase stai n; and the i mmunophenotype shown by fl ow cytometr y. Cel l sur face mar ker s associ ated wi th myel oi d cel l l i nes i ncl ude CD13, CD33, CD34, c-ki t, and HLA-DR. Monocyti c mar ker s i ncl ude CD64, CD11b, and CD14. CD41 (pl atel et gl ycophor i n) i s associ ated wi th megakar yocyti c l eukemi a, and gl ycophor i n A i s pr esent on er ythr obl asts. HLA-DR– negati ve bl ast phenotype i s uni quel y seen i n APL and ser ves as a rapi dl y avai l abl e test i n confi r mi ng the suspi ci on of thi s subtype r equi r i ng a speci fi c i nducti on therapy.

TABLE 23.2. The World Health Organization (WHO) and French–American–British (FAB) Classification of Myeloid Leukemia AML with recurrent genetic abnormalities AML with t(8;21) (usually FAB M2) AML with abnormal bone marrow eosinophils and inv(16) or t(16;16) (usually FAB M4Eo) Acute promyelocytic leukemia with t(15;17) (FAB M3) AML with 11q23 abnormalities

AML with multilineage dysplasia Following MDS or myeloproliferative disorder Without prior MDS but with dysplasia in 50% cells in two cell lines

AML and MDS, therapy related Alkylating agent or radiation related Topoisomerase II related Others AML not otherwise categorized AML minimally differentiated (FAB M0) AML without maturation (FAB M1) AML with maturation (FAB M2) Acute myelomonocytic leukemia (FAB M4) Acute monocytic leukemia (FAB M5) Acute erythroid leukemia (FAB M6) Acute megakaryocytic leukemia (FAB M7) Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma AML, acute myelogenous leukemia; MDS, myelodysplasia.

CLASSIFICATION OF ACUTE LYMPHOBLASTIC LEUKEMIA The WHO cl assi fi cati on of ALL di vi des the di sease i nto pr ecur sor Bcel l , pr ecur sor T-cel l , and Bur ki tt-cel l l eukemi a. Immunophenotypi ng of B-l i neage ALL r eveal s l ymphoi d mar ker s (CD19, CD20, CD10, TdT, and i mmunogl obul i n). T-cel l mar ker s i ncl ude TdT, CD2, CD3, CD4, CD5, and CD7. Bur ki tt-cel l l eukemi a i s character i zed by a transl ocati on between chr omosome 8 (the c-myc gene) and chr omosome 14 (i mmunogl obul i n heavy chai n), or chr omosome 2 or 22 (l i ght chai n) r egi ons.

PROGNOSTIC GROUPS IN ACUTE MYELOGENOUS LEUKEMIA Those pati ents who ar e ol der (ol der than 60) and those wi th an el evated bl ast count at di agnosi s (>20,000) have a wor se pr ognosi s. Chemotherapy-r el ated AML and pr i or hi stor y of myel odyspl asi a (MDS) i mpar ts a l ower chance of obtai ni ng compl ete r emi ssi on (CR) and l ong-ter m sur vi val . A hi stor y of tr i somy 21 may i mpar t a good pr ognosi s. Tabl e 23.3 i l l ustrates the pr ognosti c gr oups accor di ng to cytogeneti cs.

TABLE 23.3. Cytogenetic Risk Groups in Treated Adult Acute Myelogenous Leukemia (AML) Cases Favorable risk (5-yr survival with therapy as high as 40%) t(15;17) inv(16), del(16q), t(16;16) t(8;21) with or without complex karyotype and del(9q)

Standard risk (5-yr survival with therapy approximately 20%) no cytogenetic abnormality identified (i.e., normal) all other cytogenetic abnormalities not associated with a specific prognosis Poor risk (5-yr survival with therapy 100,000]. Pati ents typi cal l y have a l eukemi a cel l bur den of appr oxi matel y 10 × 101 5 that i s r educed to appr oxi matel y 10 × 101 2 by i nducti on. Addi ti onal i ntensi ve “consol i dati on” cycl es of chemotherapy ar e gi ven to fur ther r educe thi s r esi dual bur den i n the hope that host i mmune mechani sms can suppr ess the r esi dual l eukemi a popul ati on, ther eby l eadi ng to sustai ned CR. The general appr oach to i nducti on chemotherapy for adul ts i s shown i n Tabl e 23.5. Pati ents shoul d be consi der ed for cl i ni cal tr i al s i f avai l abl e.

TABLE 23.5. Standard Induction for Acute Myelogenous Leukemia (AML) “7 + 3,” 7 d of cytarabine and 3 d of anthracycline: Cytarabine 100–200 mg/m2 daily as continuous infusion × 7 d with Idarubicin 12 mg/m2 daily bolus for 3 d Or Daunorubicin 45–60 mg/m2 daily bolus for 3 d Or Mitoxantrone 12 mg/m2 daily bolus for 3 d

In general : Idar ubi ci n may be the pr efer r ed anthracycl i ne agent i n AML. Addi ti on of hi gh-dose cytarabi ne (HDAC) or etoposi de has been eval uated i n publ i shed r egi mens for i nducti on that may benefi t some pati ents younger than 60. These addi ti ons have not been demonstrated to be concl usi vel y super i or to 3 days of anthracycl i ne and 7 days of cytarabi ne al one. Mul ti pl e r egi mens ar e avai l abl e; Tabl e 23.6 shows a choi ce eval uated i n a randomi zed tr i al . Bone mar r ow aspi rati on shoul d be r epeated at appr oxi matel y 14 days. If r esi dual bl asts ar e pr esent (>5% ), i nducti on chemotherapy shoul d be r epeated (consi der ‘5 + 2’ i n Tabl e 23.7). If si gni fi cant di sease i s pr esent (4 mg/dL Methotrexate reduced to 25% if creatinine

1.5–2 mg/dL, reduce to 50% if creatinine >2 mg/dL HIDAC decreased to 1 g/m2 if patient >60 yr, creatinine >2 mg/dL, or MTX level >20 µmol/L May need to decrease MTX/HIDAC doses for toxicity G-CSF, granulocyte colony stimulating factor; CNS, central nervous system; POMP, 6mercaptopurine–methotrexate–vincristine– prednisone; HIDAC, high-dose cytosine arabinoside; MTX/HIDAC, methotrexate/highdose cytosine arabinoside. a Dosing interval based on risk stratification (see text). b Maintenance therapy was not given in Burkittcell leukemia/lymphoma.

TABLE 23.10. The Larson Regimen Course I: Induction (4 wk). Cyclophosphamide 1,200 mg/m2 i.v. d 1a Daunorubicin 45 mg/m2 i.v. d 1–3 a Vincristine 2 mg i.v. d 1, 8, 15, 22 Prednisone 60 mg/m2 /d PO d 1–21 a L-Asparaginase (Escherichia coli) 6,000

IU/m 2 s.c./i.m. d 5, 8, 11, 15, 18, 22 G-CSF 5 µg/kg/d subcutaneously (s.c.) starting d 4 Course IIA (4 wk; repeat once for Course IIB) Methotrexate 15 mg intrathecal (IT) d 1 Cyclophosphamide 1,000 mg/m2 i.v. d 1 6-Mercaptopurine 60 mg/m2 /d PO d 1–14 Cytarabine 75 mg/m2 /d s.c. d 1–4 and 8–11 Vincristine 2 mg i.v. d 15 and 22 (two doses) L-Asparaginase (E. coli) 6,000 IU/m2 s.c./i.m. d 15, 18, 22, 25 (four doses) G-CSF 5 µg/kg/d s.c. starting d 4. Course III: CNS prophylaxis and interim maintenance (12 wk) IT Methotrexate 15 mg d 1, 8, 15, 22, 29 Cranial irradiation 2,400 cGy (fractionated) d 1–12 6-Mercaptopurine 60 mg/m2 /d PO d 1–70 Methotrexate 20 mg/m2 PO d 36, 43, 50, 57, 64 Course IV: Late intensification (8 wk) Doxorubicin 30 mg/m2 i.v. d 1, 8, 15 Vincristine 2 mg i.v. d 1, 8, 15

Dexamethasone 10 mg/m2 /d PO d 1–14 Cyclophosphamide 1,000 mg/m2 i.v. d 29 6-Thioguanine 60 mg/m2 /d PO d 29–42 Cytarabine 75 mg/m2 /d s.c. d 29–32 and 36– 39 Course V: Prolonged maintenance (until 24 mo from diagnosis) Vincristine 2 mg i.v. d 1 of every 4 wk Prednisone 60 mg/m2 /d PO d 1–5 of every 4 wk 6-Mercaptopurine 60 mg/m2 /d PO d 1–28 Methotrexate 20 mg/m2 PO d 1, 8, 15, 22 CNS, central nervous system. a Dosage reductions for age >60 yr: cyclophosphamide 800 mg/m2 d 1, daunorubicin 30 mg/m2 i.v. d 1–3, and prednisone 60 mg/m 2 /d PO d 1–7.

SUPPORTIVE CARE The r egi mens descr i bed pr evi ousl y i ncor porate gr owth factor s to r educe neutr openi a and al l ow mor e schedul ed chemotherapy to pr oceed. Al l pati ents wi l l r equi r e bl ood pr oduct suppor t at some poi nt dur i ng the tr eatment. Those pati ents tr eated wi th hyper-CVAD r ecei ve pr ophyl acti c anti mi cr obi al s (i .e., l evofl oxaci n 500 mg dai l y, fl uconazol e 200 mg dai l y, and val acycl ovi r 500 mg dai l y). Pr ophyl acti c tr i methopr i m–sul famethoxazol e and val acycl ovi r 500 mg wer e gi ven thr ee ti mes per week dur i ng the fi r st 6 months of

mai ntenance.

THERAPY FOR CENTRAL NERVOUS SYSTEM DISEASE CNS i s a sanctuar y si te. CNS di sease i s di agnosed by the pr esence of neur ol ogi c defi ci ts at di agnosi s or by 5 or mor e bl asts per mi cr ol i ter of CSF. Therapy for CNS di sease i s radi ati on (fracti onated to 2,400 to 3,000 cG y) and i ntrathecal (IT) methotr exate (MTX) or cytarabi ne (Ara-C). Pr ophyl axi s decr eases CNS r el apse fr om 30% to l ess than 5% . The pr ophyl acti c radi ati on and chemotherapy schedul e i ntensi ty ar e dependent on the r el apse r i sk. Radi ati on and IT MTX ar e equi val ent to systemi c hi gh-dose chemotherapy and IT chemotherapy. Ther e ar e potenti al l ateter m cogni ti ve toxi ci ti es i n tr eated subjects. In the hyper-CVAD r egi men, pati ents wi th hi gh-r i sk di sease (i .e., LDH l evel >600, matur e B-cel l di sease, or el evated pr ol i ferati ve i ndex) r ecei ve 16 IT tr eatments, those wi th l owr i sk di sease (no factor s) r ecei ve 4 IT tr eatments, and those wi th unknown di sease r ecei ve 8 IT doses.

TREATMENT OF RELAPSED ACUTE LYMPHOBLASTIC LEUKEMIA Mar r ow i s the most common si te of r el apse but r el apse can occur i n testes, eye, and CNS. Pati ents wi th l ate r el apse (mor e than 1 year fr om i nducti on) may r espond to r ei nducti on wi th the or i gi nal r egi men. Ear l y r el apse or r efractor y di sease wi l l r equi r e transpl antati on or changi ng tr eatment pl an. Several opti ons ar e avai l abl e, i ncl udi ng: hi gh-dose cytarabi ne wi th i dar ubi ci n, mi toxantr one, or fl udarabi ne dose escal ati on of i mati ni b [Phi l adel phi a-posi ti ve (Ph-posi ti ve)]

hyper-CVAD, i f not gi ven i ni ti al l y.

USE OF MONOCLONAL ANTIBODIES IN ACUTE LYMPHOBLASTIC LEUKEMIA 1. Ri tuxi mab (Ri tuxan) Anti -CD20 chi mer i c mur i ne–human monocl onal anti body May have a r ol e i n addi ti on to the pr evi ousl y noted r egi mens i n fr ont-l i ne therapeuti c combi nati ons Pal l i ati on i n those pati ents who ar e not abl e to tol erate i ntensi ve r egi mens. 2. Al emtuz umab (Campath-1H) Anti -CD52 chi mer i c monocl onal anti body empl oyed i n r el apsed CLL Li mi ted exper i ence i n r el apsed and r efractor y di sease, but may have a r ol e i n pal l i ati on Si de effects i ncl ude fever, r i gor, nausea wi th i nfusi on, and pr ol onged l ymphopeni a. 3. G emtuz umab ozogami ci n (Myl otar g) Anti -CD33 monocl onal anti body conjugated wi th cal i cheami ci n (dose l i sted i n pr ecedi ng text) 30% of ALL pati ents may expr ess CD33 (55% Ph-posi ti ve cases).

TRANSPLANTATION Autologous Transplant Autol ogous transpl ant i s a fur ther consol i dati on for pati ents wi th poor-r i sk di sease who have no donor s for al l ogenei c transpl ant. It may be per for med after i ntensi ve consol i dati on chemotherapy. It may be per for med i n ol der pati ents (as ol d as 60 to 70). It may i ncr ease di sease-fr ee sur vi val .

Allogeneic Transplant Al l ogenei c transpl ant has the added benefi t of “graft ver sus l eukemi a” effect. Its i ncr eased shor t-ter m toxi ci ty may l i mi t the abi l i ty to pr oceed wi th the transpl antati on. In the setti ng of unr el ated donor sear ches, the pr ol onged ti me needed to i denti fy a donor needs to be consi der ed at the ti me of di agnosi s. It i s consi der ed for al l pati ents wi th r el apsed or r efractor y di sease, as i t i s the opti on that may yi el d l ong-ter m sur vi val . It i s per for med i n the fi r st CR or ear l y i n the cour se for those pati ents wi th poor r i sk cytogeneti cs, t(9;21), or MDS, especi al l y wi th a matched-r el ated donor. It may be associ ated wi th i ncr eased fai l ur e-fr ee sur vi val . When transpl anted i n fi r st CR, overal l sur vi val i s 60% ; i t decr eases to l ess than 35% when per for med for pati ents wi th r el apsed di sease, and i s l ower than 10% for pati ents wi th r efractor y di sease. Nonmyel oabl ati ve transpl antati on i s bei ng expl or ed for those pati ents unabl e to pr oceed wi th abl ati ve tr eatment secondar y to age or i l l ness.

PROGNOSIS AND SURVIVAL Adul ts wi th acute l eukemi a r emai n at hi gh r i sk for di sease-r el ated and tr eatment-r el ated compl i cati ons. In AML, the pr ognosti c character i sti cs of the di sease ar e associ ated wi th sur vi val . Hi gh-r i sk AML i s associ ated wi th 80% to 90% CR rate, and l ong-ter m di seasefr ee sur vi val i s 60% to 70% i n younger pati ents tr eated wi th HDAC. Poor-r i sk featur es ar e associ ated wi th onl y a 50% to 60% chance of obtai ni ng a CR, and a hi gh r i sk of r el apse i s obser ved i n those pati ents who enter CR. CR and l ong-ter m outcome have i mpr oved for adul t pati ents wi th ALL who wer e r ecei vi ng i ntensi ve cour ses of chemotherapy. Wi th the Lar son r egi men, 85% obtai ned CR (39% ol der than 60 year s). The hyper-CVAD cour se yi el ded a CR of 91% (79% for pati ents ol der

than 60 year s). Medi an durati on of CR was 30 months wi th Lar son r egi men and was 33 months wi th hyper-CVAD. F i ve-year sur vi val was appr oxi matel y 40% .

SUGGESTED READINGS Beutl er E, Li chtman M, Col l er B, et al ., eds. Wi l l i ams hematol ogy, 6th ed. New Yor k: McG raw-Hi l l , 2001. Bl oomfi el d C, Lawr ence D, Byr d J, et al . F r equency of pr ol onged r emi ssi on durati on after hi gh-dose cytarabi ne i n acute myel oi d l eukemi a var i es by cytogeneti c subtype. Cancer Res 1998;58:4173–4179. Byr d J, Mr ozek K, Dodge R, et al . Pr etr eatment cytogeneti c abnor mal i ti es ar e pr edi cti ve of i nducti on success, cumul ati ve i nci dence of r el apse, and overal l sur vi val i n adul t pati ents wi th de novo acute myel oi d l eukemi a: r esul ts fr om Cancer and Leukemi a G r oup B (CALG B 8461). Blood 2002;100:4325–4336. Cor tes J, Estey E, O'Br i en S, et al . Hi gh-dose l i posomal daunor ubi ci n and hi gh-dose cytarabi ne combi nati on i n pati ents wi th r efractor y or r el apsed acute myel ogenous l eukemi a. Cancer 2001;92:7–14. Estey E. Therapeuti c opti ons for acute myel ogenous l eukemi a. Cancer 2001;92:1059–1073. Fer rando A, Look AT. Cl i ni cal i mpl i cati ons of r ecur r i ng chr omosomal and associ ated mol ecul ar abnor mal i ti es i n acute l ymphobl asti c l eukemi a. Semin Hematol 2000;37:381–395. G ar ci a-Maner o G , Kantar ji an HM. The hyper-CVAD r egi men i n adul t acute l ymphocyti c l eukemi a. Hematol Oncol Clin Nor th Am 2000;14:1381–1396. G ar ci a-Maner o G , Thomas D. Sal vage therapy for r efractor y or r el apsed acute l ymphocyti c l eukemi a. Hematol Oncol Clin Nor th Am 2001;15:163–205.

G r i mwade D, Wal ker H, Har r i son G , et al . The pr edi cti ve val ue of hi erar chi cal cytogeneti c cl assi fi cati on i n ol der adul ts wi th acute myel oi d l eukemi a (AML): anal ysi s of 1065 pati ents enter ed i nto the Uni ted Ki ngdom Medi cal Resear ch Counci l AML11 tr i al . Blood 2001;98:1312–1320. Hoel zer D, G okbuget N, et al . Outcome of adul t pati ents wi th Tl ymphobl asti c l ymphoma tr eated accor di ng to pr otocol s for acute l ymphobl asti c l eukemi a. Blood 2002;99:4379–4385. Hoffman R, Benz E, Shatti l S, et al ., eds. Hematol ogy, 3r d ed. New Yor k: Chur chi l l Li vi ngstone, 2000. Jaffe E, Har r i s N, Stei n H, et al ., eds. Wor l d heal th or gani z ati on cl assi fi cati on tumor s: pathol ogy and geneti cs of tumour s of haemotopoi eti c and l ymphoi d ti ssues. Lyon: IARC Pr ess, 2001. Lar son RA. Recent cl i ni cal tr i al s i n acute l ymphobl asti c l eukemi a by the Cancer and Leukemi a G r oup B. Hematol Oncol Clin Nor th Am 2000;14:1367–1379. Lar son RA, Dodge RK, Li nker CA, et al . A randomi zed contr ol l ed tr i al of fi l grasti m dur i ng r emi ssi on i nducti on and consol i dati on chemotherapy for adul ts wi th acute l ymphobl asti c l eukemi a: CALG B Study 9111. Blood 1998;92:1556–1564. Leone G , Voso MT, Si ca S, et al . Therapy r el ated l eukemi as: suscepti bi l i ty, pr eventi on, and tr eatment. Leuk Lymphoma 2001;41:255–276. Mar i s M, Ni eder wi eser D, Sandmai er B, et al . HLA-matched unr el ated donor hematopoi eti c cel l transpl antati on after nonmyel oabl ati ve condi ti oni ng for pati ents wi th hematol ogi c mal i gnanci es. Blood 2003;102:2021–2030. Monti l l o M, Mi r to S, Petti MC, et al . F l udarabi ne, cytarabi ne, and G -CSF (F LAG ) for the tr eatment of poor r i sk acute myel oi d l eukemi a. Am J Hematol 1998;58:105–109. Si ever s EL, Lar son RA, Stadmauer EA, et al . Effi cacy and safety

of gemtuz umab ozogami ci n i n pati ents wi th CD33-posi ti ve acute myel oi d l eukemi a i n fi r st r el apse. J Clin Oncol 2001;19:3244– 3254. Sl ovak ML, Kopecky KJ, Cassi l eth PA, et al . Kar yotypi c anal ysi s pr edi cts outcome of pr er emi ssi on and postr emi ssi on therapy i n adul t acute myel oi d l eukemi a: a Southwest Oncol ogy G r oup/Easter n cooperati ve Oncol ogy G r oup Study. Blood 2000;96:4075–4083.

Soi gnet SL, F rankel SR, Douer D, et al . Uni ted States mul ti center tr i al of ar seni c tr i oxi de i n r el apsed acute pr omyel ocyti c l eukemi a. J Clin Oncol 2001;19:3852–3860. Tal l man M, Nabhan C, Feusner J, et al . Acute pr omyel ocyti c l eukemi a: evol vi ng therapeuti c strategi es. Blood 2002;99:759– 767. Wei ck J, Kopecky K, Appel baum F, et al . A randomi zed i nvesti gati on of hi gh-dose ver sus standar d-dose cytosi ne arabi nosi de wi th daunor ubi ci n i n pati ents wi th pr evi ousl y untr eated acute myel oi d l eukemi a: a Southwest Oncol ogy G r oup Study. Blood 1996;88:2841–2851.

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 9 - He m a t o lo gic M a ligna nc ie s > 2 4 - C hro nic Le uk e m ia s

24 Chronic Leukemias Muzaffar H. Qazilbash Michael J. Keating M.D. Ander son Cancer Center , Univer sity of Texas, Houston, Texas Chr oni c l ymphocyti c l eukemi a (CLL) accounts for mor e than one thi r d of al l l eukemi as, and because of i ts pr eval ence i n hematol ogi c practi ce, i t i s the focus of thi s chapter. Addi ti onal chr oni c l eukemi as di scussed i n thi s chapter i ncl ude pr ol ymphocyti c l eukemi a (PLL) and hai r y cel l l eukemi a (HCL) (see Tabl es 24.1 and 24.2).

TABLE 24.1. Chronic Lymphocytic Leukemia CLL

Comments

Origin

B-cell malignancy (>95%)

Incidence

10,000 cases annually in the United States

Median age

55 yr

M:F

2:1

Etiology

No known causes; slight increased risk of CLL and B-cell

malignancies in family members

Molecular

Accumulation of clonal lymphocytes, possibly a result of overexpression of bcl-2, which can interfere with apoptosis

Cytogenetic abnormalities

Trisomy 12; abnormalities in chromosomes 11 and 17; Deletion of 13q14

CLL, chronic lymphocytic leukemia.

TABLE 24.2. Clinical and Laboratory Features Comments

Symptoms

Fatigue, weight loss, fever in the absence of active infection, night sweats, unusually severe local reactions to insect bites, increased frequency of bacterial and viral infections

Physical examination

Lymphadenopathy and splenomegaly Lymphocytosis (5–500 × 103 /

Laboratory features

µL), appear as normal lymphocytes by light microscopy with presence of scant cytoplasm; presence of smudge cells (artifact of blood smear preparation); absolute neutrophil count can be low, normal, or increased; anemia or thrombocytopenia may be present

Bone marrow

Demonstrates nodular or diffuse infiltration of small- to medium-sized lymphocytes with mature features and normal myeloid components

Lymph nodes

Infiltrates of small- to mediumsized lymphocytes with condensed mature-appearing chromatin and an occasional nucleolus; larger lymphocytes with more prominent nucleoli are usually present and are termed prolymphocytes, can be clustered as pseudofollicles

Immunologic features

The hallmark is the coexpression of CD5, CD19, CD20, and CD23 surface antigens that are detected by flow cytometry

DIAGNOSIS Var i ous di agnosti c cr i ter i a have been pr oposed for CLL; two of the most commonl y used cr i ter i a ar e the gui del i nes of the Nati onal Cancer Insti tute–sponsor ed wor ki ng gr oup (NCI-WG ) and of the Inter nati onal Wor kshop on Chr oni c Lymphocyti c Leukemi a (IWCLL). The NCI-WG gui del i nes r equi r e (a) an absol ute l ymphocytosi s (≥5 × 10 3 per µL), wi th cel l s havi ng a mor phol ogi cal l y matur e appearance sustai ned for 4 weeks; (b) a nor mocel l ul ar or hyper cel l ul ar bone mar r ow wi th l ymphocyte count ≥30% ; and (c) monocl onal B-cel l phenotype expr essi ng CD5, wi th a l ow-l evel sur face i mmunogl obul i n (Ig) expr essi on. The IWCLL r ecommends si mi l ar cr i ter i a but r equi r es a l ymphocyte count of ≥10 × 103 per µL i f faci l i ti es for obtai ni ng phenotypi ng ar e not avai l abl e.

STAGING AND PROGNOSIS Ther e ar e several stagi ng methods for CLL. The thr ee most commonl y used stagi ng methods ar e the Rai , modi fi ed Rai (see Tabl e 24.3), and the Bi net stagi ng systems. Pr ognosi s based on Rai stagi ng system i s outl i ned i n Tabl e 24.4.

TABLE 24.3. Staging Rai Modified Rai

Criteria

0

Low risk

Lymphocytosis only (≥15 × 10 3 /µL in peripheral blood)

1

Intermediate risk

Lymphocytosis with enlarged nodes

2

Intermediate risk

Lymphocytosis with increased splenic or hepatic size

3

4

High risk

Lymphocytosis with anemia (Hb ≤11 g/dL)

High risk

Lymphocytosis with thrombocytopenia (≤100 × 10 3 /µL)

Hb, hemoglobin.

TABLE 24.4. Prognosis Modified Rai stage Median survival (yr) Low risk

>10

Intermediate risk

7

High risk

3

A number of newl y i denti fi ed pr ognosti c factor s pr edi ct an i nfer i or outcome. These factor s i ncl ude an el evated ser um β-2-mi cr ogl obul i n l evel , hi gh-sol ubl e CD23 l evel , nai ve B cel l s that l ack Ig gene hyper mutati on, and el evated CD38 l evel .

TREATMENT CLL i s cl ear l y an i ndol ent hematol ogi c mal i gnancy often not r equi r i ng tr eatment at di agnosi s. In general , tr eatment i s i ni ti ated after the occur r ence of one of the fol l owi ng compl i cati ons: (a) si gni fi cant and per si stent fati gue; (b) wei ght l oss; (c) fever wi thout i nfecti on; (d) ni ght sweats; (e) si gni fi cant anemi a (hemogl obi n l evel Se c t io n 9 - He m a t o lo gic M a ligna nc ie s > 2 5 - M y e lo id Le uk e m ia

25 Myeloid Leukemia Muzaffar H. Qazilbash Jorge E. Cortes M.D. Ander son Cancer Center , Univer sity of Texas, Houston, Texas

EPIDEMIOLOGY Ever y year, appr oxi matel y 5,000 to 7,000 i ndi vi dual s ar e di agnosed wi th chr oni c myel oi d l eukemi a (CML) i n the Uni ted States. The annual i nci dence of CML i s one to two cases per 100,000 i ndi vi dual s. The medi an age at pr esentati on r epor ted fr om l ar ge cohor t studi es i s 45 to 55 year s. Mor e than 80% of pati ents ar e di agnosed i n the chr oni c phase, often i nci dental l y dur i ng r outi ne tests. CML rar el y occur s i n chi l dr en (2% to 3% of chi l dhood l eukemi as).

PATHOPHYSIOLOGY The hal l mar k of CML i s the Phi l adel phi a chr omosome (Phchr omosome), a r eci pr ocal transl ocati on between the l ong ar ms of chr omosomes 9 and 22 [i .e., t(9;22)]. The transl ocati on r esul ts i n the transfer of the Abel son (ABL) gene to an ar ea of chr omosome 22 ter med the br eakpoi nt cl uster r egi on (BCR), pr oduci ng the BCR-ABL fusi on gene. Thi s fusi on gene gi ves r i se to a chi mer i c pr otei n, p210 BC R-ABL , wi th tyr osi ne ki nase acti vi ty, whi ch i s bel i eved to pl ay a pathogeni c r ol e i n thi s di sease.

STAGING AND PROGNOSIS CML typi cal l y pr ogr esses over ti me fr om i ts chr oni c phase to an accel erated phase and then to a bl ast phase (see Tabl e 25.1). 1. Bl ast cr i si s: An abr upt transi ti on to a bl ast phase i s cal l ed bl ast cr i si s. Featur es of a bl ast cr i si s i ncl ude fever, mal ai se,

pr ogr essi ve and pai nful spl enomegal y and/or hepatomegal y, bone pai n, wor seni ng anemi a and thr ombocytopeni a, and thr omboti c or bl eedi ng compl i cati ons. 2. Pr ognosi s: The chr onic phase typi cal l y l asts 3 to 4 year s, wi th the annual rate of pr ogr essi on to a bl ast phase bei ng 5% to 10% i n the fi r st 2 year s and 20% i n the subsequent year s. The pr ognosi s for pati ent i n the chr oni c phase i s 5 to 6 year s, wi th some pati ents sur vi vi ng as l ong as 10 year s. For pati ents i n the acceler ated phase, sur vi val i s usual l y l ess than 1 year, and for blast phase, the sur vi val i s a few months. A shor ter chr oni c phase may be pr edi cted by character i sti c featur es at di agnosi s, such as ol der age, mal e sex, i ncr eased l actate dehydr ogenase (LDH) l evel , mul ti pl e cytogeneti c abnor mal i ti es, hi gh per centage of i mmatur e myel oi d cel l s, basophi l i a, eosi nophi l i a, thr ombocytosi s, and anemi a. A useful pr edi cti ve model usi ng these mul ti pl e r i sk factor s i s the Sokal r i sk i ndex. A r ecentl y modi fi ed ver si on of thi s i ndex that pr edi cts pati ents who do best wi th chemotherapy or i nter fer on (IF N)-α i s i l l ustrated i n Tabl e 25.2.

TABLE 25.1. Chronic Myeloid Leukemia Stages and Prognosis Stage Chronic phase

Accelerated

Features 5% blasts and

Median survival 5–6 yr

phase

promyelocytes in PB or BM, worsening thrombocytopenia, cytogenetic clonal evolution, and >20% peripheral basophils

Blast phase

30% blasts and promyelocytes in the PB and BM, with features of accelerated phase, as described earlier

2 × 106 per µL i s a r i sk factor for hemor r hage.

DIAGNOSIS AND CLINICAL FEATURES Excluding Secondary Causes of Polycythemia or Thrombocytosis In the absence of a di sease-speci fi c posi ti ve mar ker for PV, the Pol ycythemi a Vera Study G r oup (PVSG ), an i nter nati onal study gr oup, has publ i shed the di agnosti c cr i ter i a that i ncl ude demonstrati on of i ncr eased r ed cel l mass i n the pr esence of nor mal hemogl obi n oxygen saturati on, suppor ted by other di agnosti c cr i ter i a such as spl enomegal y, l eukocytosi s, thr ombocytosi s, el evated l eukocyte al kal i ne phosphatase, and i ncr eased ser um vi tami n B1 2 l evel s. The appl i cati on of these di agnosti c cr i ter i a may excl ude some cases of PV; ther efor e, an al gor i thmi c appr oach usi ng ser um EPO and hi stol ogi c character i sti cs of the bone mar r ow i s useful i n for mul ati ng a wor ki ng di agnosi s of PV (see F i g. 26.2). Kar yotype abnor mal i ti es ar e i nfr equent and nonspeci fi c i n PV; they i ncl ude tr i somi es of chr omosomes 8 and 9 and del eti ons of l ong ar ms of chr omosomes 13 and 20. PVSG has al so establ i shed the di agnosti c cr i ter i a for ET (see Tabl e 26.2).

TABLE 26.2. Diagnostic Criteria for Essential Thrombocytopenia

1. Platelets >600 × 103 /µL 2. Hct 500/mm3 ) or thrombocytopenia (platelet count >25,000/mm 3 ).

Highly Aggressive NHL B Cell Precursor B lymphoblastic lymphoma/leukemia i s mostl y a di sease found i n chi l dr en and pr esents as l eukemi a i n 80% and as l ymphoma i n 20% of cases. Invol vement of nodes, ski n,

bone and/or BM may be seen. Poor pr ognosti c factor s i ncl ude

transl ocati ons of t(1;19), t(9;22), and 11q13 abnor mal i ti es, and tumor s that l ack expr essi on of CD10, CD34, and CD24. Pati ents wi th mor e than 50 chr omosomes have a better pr ognosi s. The EF S at 5 year s i s 85% and 64% for l ocal i zed and advanced di sease, r especti vel y. Burkitt lymphoma occur s pr i mar i l y i n chi l dr en, al though occasi onal cases, whi ch ar e often cal l ed Bur ki tt-l i ke l ymphoma, ar e seen i n adul ts. Bur ki tt and Bur ki tt-l i ke l ymphomas ar e bel i eved to be si mi l ar di seases, wi th the l atter showi ng some “atypi cal ” pathol ogi c featur es. The di sease was i ni ti al l y i denti fi ed i n equator i al Afr i ca, wher e i t was found to be associ ated wi th EBV and transl ocati on of the c-myc oncogene, and i s r egar ded as the endemi c for m of l ymphoma. In the wester n countr i es, a sporadi c “nonendemi c” for m, whi ch i s i nfr equentl y associ ated wi th EBV, occur s commonl y, and Bur ki tt l ymphoma often i nvol ves mesenter i c LN and the di stal i l eum and cecum. Bur ki tt l ymphoma i s hi ghl y curabl e wi th aggr essi ve chemotherapy, wi th PF S bei ng mor e than 90% (see Tabl es 28.10 and 28.11).

TABLE 28.10. Adults and Children with Burkitt and Burkitt-like Non-Hodgkin Lymphoma have Similar Outcomes when Treated with Cyclophosphamide, Vincristine, Doxorubicin, High-dose Methotrexate/Ifosfamide, Etoposide, and High-dose Cytarabine (CODOX-M/IVAC) Regimen Number Children: 21 Adults: 20

CR (%)

EFS at 2 yr (%)

90

85

100

100

Total: 41

95

92

Adapted from Magrath I, Adde M, Shad A, et al. Adults and children with small noncleaved cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 1996;14(3):925–934, with permission.

TABLE 28.11. Estimate of 1-year Event-free Survival for Subgroups of High-risk Patients Treated With Cyclophosphamide, Vincristine, Doxorubicin, High-dose Methotrexate/Ifosfamide, Etoposide, and High-dose Cytarabine (CODOX-M/IVAC) Regimen Variable

n

1-yr EFS (%)

(95% CI)

Log-rank P value

International Prognostic Index score 0–1

2

6

83.3

(53.5– 99.0)

—

19

63.2

(41.5– 84.9)

—

3

14

57.1

(31.2– 83.1)

0.8852

From Mead GM, Sydes MR, Walewski J, et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 2002;13:1264–1274, with permission.

T Cell Precursor T-lymphoblastic lymphomas/leukemias ar e most common i n young adul t men i n thei r thi r d decade of l i fe. In chi l dr en, these cancer s consti tute 40% of al l l ymphomas and 15% of l ymphobl asti c l eukemi as. Pati ents often have a rapi dl y enl ar gi ng medi asti nal mass, wi th or wi thout per i pheral LN i nvol vement. The di sti ncti on between l ymphoma and l eukemi a i s based on the per centage i nvol vement of the BM, wi th 25% to 30% defi ni ng the di sease as a l eukemi a. The EF S at 5 year s i s 85% and 64% for l ocal i zed and advanced di sease, r especti vel y.

Treatment Principles The most hi ghl y aggr essi ve l ymphomas ar e curabl e by chemotherapy and shoul d be tr eated expedi ti ousl y and wi th appr opr i ate therapy. A number of aggr essi ve r egi mens have shown equal r esul ts and ar e outl i ned i n Tabl es 28.12, 28.13, and 28.14. The aggr essi ve tr eatment of adul ts wi th Bur ki tt l ymphoma has achi eved r esul ts si mi l ar to those obtai ned i n chi l dr en and justi fi es the hi gher toxi ci ty associ ated wi th these r egi mens. However, ol der pati ents often tol erate these aggr essi ve r egi mens poor l y.

TABLE 28.12. Hyper CVAD Alternating with Hi and Ara-C

Cycle

Odd number cycles 1, 3, 5, and 7

Day

Drug

Dose

1–3

Cyclophosphamide

300 mg/m 2 (total dose 1,800 mg/m 2 )

i.v.

1–3

Mesna

600 mg/m 2

Contin i.v.

Doxorubicin

50 mg/m 2

i.v.

Vincristine

2 mg

i.v.

Dexamethasone

40 mg/d

PO or

4 4 and 11

4– 11 and 11–

10

Rou

14

Even number cycles

G-CSF

Methotrexate

1 Leucovorin

2, 4, 6, and 8

µg/kg

s.c.

1 g/m2

Contin i.v.

50 mg i.v. or PO is given

i.v. or

Ara-C,

3 g/m2

i.v.

5 µg/kg,

s.c.

2–3 G-CSF

CNS prophylaxis: Methotrexate 12 mg intrathecal o intrathecal on d 8 of each cycle for 16 intrathecal t patients; four intrathecal treatments in low-risk pa

TABLE 28.13. Cyclophosphamide, Vincris Doxorubicin, High-dose Methotrexate (COD Regimen Day

Drug

Dose

Cyclophosphamide

800 mg/m 2

Route i.v.

Vincristine

1.5 mg/m 2 (max 2 mg)

i.v.

Doxorubicin

40 mg/m 2

i.v.

Cytarabine

70 mg

Intrathecal

Cyclophosphamide

200 mg/m 2

i.v.

Cytarabine

70 mg

Intrathecal

Vincristine

1.5 mg/m 2 (max 2 mg)

i.v.

1,200 mg/ 2

i.v.

Ove

240 mg/m 2

i.v.

Eac 23 h

192 mg/m 2

i.v.

At h

i.v.

Eve unti leve

1

2– 5 3

8

10

11

Dail

Methotrexate

Leucovorin 12

mg/m 2

10 –

13

G-CSF

5 µg/kg

s.c.

15

Methotrexate

12 mg

Intrathecal

16

Leucovorin

15 mg

PO

Dail AGC

24 h intr met

MTX, methotrexate; G-CSF, granulocyte colony stim factor; AGC, absolute granulocyte count; ANC, abso neutrophil count. Next cycle should be started on the day the unsupp ANC is >1.0 × 109 /L, and unsupported platelet >75 10 9 /L.

TABLE 28.14. Ifosfamide, etoposide, and high cytarabine (IVAC) regimen Day

Drug Etoposide

Ifosfamide

Dose

Route

T

60 mg/m2

i.v.

Daily 1 h

1,500 mg/m 2

i.v.

Daily 1 h

1– 5 Mesna

1 and 2 5

6

7

360 mg/m 2 (mixed with ifosfamide) followed by 360 mg/m 2

i.v.

Cytarabine

2 g/m2

i.v.

Methotrexate

12 mg

Intrathecal

Leucovorin

G-CSF

15 mg

5 µg/kg

3 ho (sev dose h pe

Over 12 h (tota four dose

PO

24 h intra MTX

s.c.

Daily AGC × 10

MTX, methotrexate; G-CSF, granulocyte colonystimulating factor; AGC, absolute granulocyte coun Next cycle should start (CODOX-M) on the day the unsupported ANC is >1.0 × 109 /L, and unsupported platelet is >75 ×109 /L.

SUGGESTED READINGS Ar mi tage JO, Vose JM, Bi er man PJ. Sal vage therapy for pati ents wi th non-Hodgki n's l ymphoma. J Natl Cancer Inst 1990;10:39–43. Bagl ey CM Jr, Devi ta VT Jr, Berar d CW, et al . Advanced l ymphosar coma: i ntensi ve cycl i cal combi nati on chemotherapy wi th cycl ophosphami de, vi ncr i sti ne, and pr edni sone. Ann Inter n Med 1972;76:227–234. Cabani l l as F, Hagemi ster F, McLaughl i n P, et al . Resul ts of MIME sal vage r egi men for r ecur r ent or r efractor y l ymphoma. J Clin Oncol 1987;5:407–412.

Chabner BA, Longo D. Cancer chemotherapy and bi otherapy pr i nci pl es and practi ce, 2nd ed. Phi l adel phi a, PA: Li ppi ncott– Raven Publ i sher s, 1996:1–16. Chao NJ, Rosenber g SA, Hor ni ng SJ. CEPP(B): an effecti ve and wel l -tol erated r egi men i n poor-r i sk, aggr essi ve non-Hodgki n's l ymphoma. Blood 1990;76:1293–1298. Coi ffi er B, Lepage E, Br i er e J, et al . CHOP chemotherapy pl us r i tuxi mab compar ed wi th CHOP al one i n el der l y pati ents wi th di ffuse l ar ge-B-cel l l ymphoma. N Engl J Med 2002;346:235–242. Cz ucz man MS, G r i l l o-Lopez AJ, Whi te CA, et al . Tr eatment of pati ents wi th l ow-grade B-cel l l ymphoma wi th the combi nati on of chi mer i c anti -CD20 monocl onal anti body and CHOP chemotherapy. J Clin Oncol 1999;17:268. Dana B, Dahl ber g S, Mi l l er T, et al . m-BACOD tr eatment for i nter medi ate-and hi gh-grade mal i gnant l ymphomas: a Southwest Oncol ogy G r oup phase II tr i al . J Clin Oncol 1990;8:1155–1162. Danhauser L, Pl unkett W, Keati ng M, et al . 9-beta-Darabi nofuranosyl -2-fl uor oadeni ne 5'-monophosphate phar macoki neti cs i n pl asma and tumor cel l s of pati ents wi th r el apsed l eukemi a and l ymphoma. Cancer Chemother Phar macol

1986;18:145–152. G ol dstei n L, G al aski H, Fojo A, et al . Expr essi on of a mul ti dr ug r esi stance gene i n human cancer s. J Natl Cancer Inst 1989;81:116–120. G uti er r ez M, Chabner BA, Pear son D, et al . Rol e of a doxor ubi ci ncontai ni ng r egi men i n r el apsed and r esi stant l ymphomas: an 8year fol l ow-up of study of EPOCH. J Clin Oncol 2000;18:3633– 3642. Her sh MR, Kuhn JG , Phi l l i ps JL, et al . Phar macoki neti c study of fl udarabi ne phosphate (NSC 312887). Cancer Chemother Phar macol 1986;17:277–280. Hohenstei n M, Augusti ne S, Rutar F, et al . Establishing an institutional model for the administr ation of tositumomab and iodine I 131 tosi tumomab. Semin Oncol 2003;30:39–49. Hutton JJ, Von Hoff DD, Kuhn J, et al . Phase I clinical investigation of 9-beta-D-arabi nofuranosyl -2-fl uor oadeni ne 5'monophosphate (NSC 312887), a new pur i ne anti metabol i te. Cancer Res 1984;44:4183–4186. Kai ser U, Uebel acker I, Abel U, et al . Randomi zed study to eval uate the use of hi gh-dose therapy as par t of pr i mar y tr eatment for “aggr essi ve” l ymphoma. J Clin Oncol 2002;20(22):4413–4419. Kewal ramani T, Zel enetz AD, Ni mer SD, et al . Ri tuxi mab and ICE (RICE) as second-l i ne therapy pr i or to autol ogous stem cel l transpl antati on for r el apsed or pr i mar y r efractor y di ffuse l ar ge Bcel l l ymphoma. Blood 2004;103:3684–3688. Ki tada S, Ander sen J, Reed JC, et al . Expr essi on of apoptosi sr egul ati ng pr otei ns i n chr oni c l ymphocyti c l eukemi a: cor r el ati ons wi th i n vi tr o and i n vi vo chemor esponses. Blood 1998;91:3379– 3389. Kl i mo P, Connor s J. MACOP-B chemotherapy for the tr eatment of

di ffuse l ar ge cel l l ymphoma. Ann Inter n Med 1985;102:596–602. Legha SS, Benjami n RS, MacKay B, et al . Reducti on of doxor ubi ci n car di otoxi ci ty by pr ol onged conti nuous i ntravenous i nfusi on. Ann Inter n Med 1982;96:133–139. Magrath I, Adde M, Shad A, et al . Adul ts and chi l dr en wi th smal l noncl eaved cel l l ymphoma have a si mi l ar excel l ent outcome when tr eated wi th the same chemotherapy r egi ment. J Clin Oncol 1996;14:925–934. McKel vey EM, G ottl i eb JA, Wi l son HE, et al . Hydr oxyl daunomyci n (Adr i amyci n) combi nati on chemotherapy i n mal i gnant l ymphoma. Cancer 1976;38:1484–1493. McLaughl i n P, G r i l l o-Lopez AJ, Li nk BK, et al . Ri tuxi mab chi mer i c anti -CD20 monocl onal anti body therapy for r el apsed i ndol ent l ymphoma: hal f of pati ents r espond to a four-dose tr eatment pr ogram. J Clin Oncol 1998;16:2825–2833. Mead G M, Sydes MR, Wal ewski J, et al . An i nter nati onal eval uati on of CODOX-M and CODOX-M al ter nati ng wi th IVAC i n adul t Bur ki tt's l ymphoma: r esul ts of Uni ted Ki ngdom Lymphoma G r oup LY06 study. Ann Oncol 2002;13:1264–1274. Non-Hodgki n's Lymphoma Cl assi fi cati on Pr oject. A cl i ni cal eval uati on of the i nter nati onal l ymphoma study gr oup cl assi fi cati on of non-Hodgki n's l ymphoma. N Engl J Med 1993;329:987. Reed JC. Dysr egul ati on of apoptosi s i n cancer. Cancer J Sci Am 1999;4:S8–S13. Rosenwal d A, Wr i ght G , Chan WC, et al . The use of mol ecul ar pr ofi l i ng to pr edi ct sur vi val after chemotherapy for di ffuse l ar geB-cel l l ymphoma. N Engl J Med 2002;346:1937–1947. Thomas DA, Cor tes J, O'Br i en S, et al . Hyper-CVAD pr ogram i n Bur ki tt's-type adul t acute l ymphobl asti c l eukemi a. J Clin Oncol 1999;17:2461–2470.

Vel asquez WS, Cabani l l as F, Sal vador P, et al . Effecti ve sal vage therapy for l ymphoma wi th ci spl ati n i n combi nati on wi th hi ghdose Ara-C and dexamethasone (DHAP). Blood 1988;71:117–122. Vel asquez WS, McLaughl i n P, Tucker S, et al . ESHAP—an effecti ve chemotherapy r egi men i n r efractor y and r el apsi ng l ymphoma: a 4-year fol l ow-up study. J Clin Oncol 1994;12:1169–1176. Vose JM, Li nk BK, G r ossbar d ML, et al . Phase II study of r i tuxi mab i n combi nati on wi th CHOP chemotherapy i n pati ents wi th pr evi ousl y untr eated, aggr essi ve non-Hodgki n's l ymphoma. J Clin Oncol 2001;19:389–397.

Wagner HN Jr, Wi seman G A, Mar cus CS, et al . Admi ni strati on gui del i nes for radi oi mmunotherapy of non-Hodgki n's l ymphoma wi th 90Y-l abel ed anti -CD20 monocl onal anti body. J Nucl Med 2002;43:267–272. Wei ck J, Dahl ber g S, F i sher R, et al . Combi nati on chemotherapy of i nter medi ate-grade and hi gh-grade non-Hodgki n's l ymphoma wi th MACOP-B: a Southwest Oncol ogy G r oup study. J Clin Oncol 1991;9:748–753. Wi l son WH, G r ossbar d ML, Pi ttal uga S, et al . Dose-adjusted EPOCH chemotherapy for untr eated l ar ge B-cel l l ymphomas: a phar macodynami c appr oach wi th hi gh effi cacy. Blood 2002;99:2685–2693.

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 9 - He m a t o lo gic M a ligna nc ie s > 2 9 - Ho dgk in Ly m pho m a

29 Hodgkin Lymphoma Gisa Schun* Jame A braham† Marcel P. Devetten‡ *Section of Hematology/Oncology, West Vir ginia Univer sity, Mor gantown, West Vir ginia † Section

of Hematology/Oncology, Mar y Babb Randolph Cancer Center , West Vir ginia Univer sity, Mor gantown, West Vir ginia ‡ Depar tment

of Medicine, Univer sity of Nebr aska Medical Center , Omaha, Nebr aska

EPIDEMIOLOGY Hodgki n l ymphoma (HL) i s among the most common mal i gnanci es of young adul ts. It consti tutes appr oxi matel y 1% of al l mal i gnanci es and 18% of al l l ymphomas, and, i n the Uni ted States, 3 of ever y 100,000 peopl e devel op thi s condi ti on. In Eur ope and Nor th Amer i ca, ther e i s a bi modal age di str i buti on, wi th an i ncr easi ng fr equency between the second and thi r d decades, and a second peak i n the seventh decade.

ETIOLOGY AND RISK FACTORS The eti ol ogy of HL i s uncl ear and may be mul ti factor i al . Same-sex si bl i ngs of pati ents wi th HL have a ten ti mes hi gher r i sk of devel opi ng HL than si bl i ngs of a di ffer ent sex. Thi s associ ati on may be caused by geneti c factor s and/or envi r onmental factor s. Appr oxi matel y 40% to 50% of the cases of “cl assi c” HL have cl onal i ntegrati on of Epstei n–Bar r vi r us (EBV) i n the Reed– Ster nber g (RS) cel l s.

Smoki ng has r ecentl y been l i nked to HL.

PATHOLOGY HL i s a neopl asti c di sor der of the l ymphoi d system, usual l y ar i si ng fr om B l ymphocytes. Typi cal l y, a smal l number of scatter ed gi ant neopl asti c cel l s (RS cel l s) ar e sur r ounded by an i nfl ammator y backgr ound.

Reed–Sternberg Cells or Variants The RS cel l i s a l ymphoi d cel l , and i n most of the cases studi ed, i t i s a cl onal B cel l . Cytol ogi cal l y, the RS cel l i s a mul ti nucl eated gi ant cel l wi th l ar ge eosi nophi l i c i ncl usi on-l i ke nucl eol i , wi th a thi ck, wel l defi ned nucl ear membrane and pal e-stai ni ng chr omati n. The cl assi c RS cel l has two mi r r or-i mage nucl ei , whi ch ar e often descr i bed as “owl 's eyes.” A backgr ound of l ymphocytes, eosi nophi l s, and hi sti ocytes i s usual l y pr esent (see F i g. 29.1).

FIG. 29.1. A : Di agnosti c Reed–Ster nber g cel l , seen i n cl assi c types of Hodgki n l ymphomas (mi xed cel l ul ar i ty, nodul ar scl er osi s, l ymphocyte depl eti on). B: Var i ants of Reed–Ster nber g cel l s seen i n nodul ar l ymphocyte-pr edomi nant Hodgki n l ymphomas: popcor n cel l s or L and H cel l s (l ymphocyti c or hi sti ocyti c pr edomi nance). Reed–Ster nber g cel l s of the cl assi c type general l y ar e not seen i n a nodul ar l ymphocytepr edomi nant Hodgki n l ymphoma.

Histopathologic Classification In 1994, the Inter nati onal Lymphoma Study G r oup i ntr oduced a cl assi fi cati on i ncor porati ng i mmunol ogi c and mol ecul ar data as par t of a Revi sed Eur opean–Amer i can Lymphoma cl assi fi cati on (REAL) for HL, whi ch r epl aced the ol der Rye cl assi fi cati on. The REAL cl assi fi cati on was i ncor porated i n the cl assi fi cati on of the Wor l d Heal th Or gani z ati on (WHO) i n 2001 (see Tabl e 29.1).

TABLE 29.1. Classification systems REAL Classification, 1994

Lymphocyte predominance Classic Hodgkin lymphoma

Rye Classification, 1965 Lymphocyte predominance, nodular Lymphocyte predominance, diffuse (most cases)

Lymphocyte-rich classic HL

Lymphocyte predominance, nodular (some cases)

Nodular sclerosis (NSHL)

Nodular sclerosis (NSHL)

Mixed cellularity (MCHL)

Mixed cellularity (MCHL)

Lymphocyte depletion

Lymphocyte depletion

REAL, Revised European–American Lymphoma. The REAL/WHO cl assi fi cati on r ecogni zes two di sti nct di seases wi th di sti ngui shi ng hi stopathol ogi c featur es and i mmunophenotypes: 1. Cl assi c Hodgki n Lymphoma (CHL) 2. Lymphocyte-pr edomi nant Hodgki n Lymphoma (LPHL). Featur es and i mmunophenotypes of cl assi c HL and LPHL ar e descr i bed i n Tabl e 29.2.

TABLE 29.2. Features and immunophenotypes of Hodgkin lymphomas Cells/Antigen

Classic HL

Lymphocytepredominant HL

Diagnostic RS cells

Always present

Rare to absent

Lymphocytes (background)

T > B cells

B > T cells

CD30 (Ki-1)

Usually positive

Often positive

CD15 (Leu M1)

Usually positive

Negative

CD45 (LCA)

Usually negative

Positive

CD20 (L26)

Usually negative

Positive

EBV

40%–50% positive

Usually negative

HL, Hodgkin lymphoma.

CLINICAL FEATURES Mor e than 80% of pati ents pr esent wi th cer vi cal l ymph node enl ar gement, and mor e than 50% have medi asti nal adenopathy. Lymph nodes ar e usual l y nontender, fi r m, and r ubber y. Consti tuti onal symptoms (“B” symptoms): Unexpl ai ned fever (temperatur e, >38°C) Dr enchi ng ni ght sweats Unexpl ai ned wei ght l oss (>10% of body wei ght, mor e than 6 months befor e the di agnosi s) Other symptoms ar e i mpor tant to note but ar e not consi der ed “B” symptoms: fati gue, weakness, anor exi a, al cohol -i nduced nodal pai n, and pr ur i tus. Stagi ng [Ann Ar bor /Amer i can Joi nt Commi ttee for Cancer (AJCC) and Cotswol d] i s outl i ned i n Tabl e 29.3.

TABLE 29.3. Staging

Stage I

Involvement of single lymph node region or lymphoid structure (spleen, thymus, Waldeyer ring), or involvement of a single extralymphatic site (IE)

Stage II

Involvement of two or more lymph node regions on the same side of the diaphragm (II), which may be accompanied by localized contiguous involvement of an extralymphatic organ or site (IIE). The number of anatomic sites may be indicated by numeric subscript

Stage III

Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an associated extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIIE+S)

Stage IV

Disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement Each stage is divided into A and B categories: B for those with defined systemic symptoms, and A for those without

X

A mass >10 cm or a mediastinal mass larger than one third of the thoracic diameter

E

Involvement of a single extranodal site contiguous to a known nodal site

CS

Clinical staging

PS

Pathologic staging

Pretreatment Evaluation 1. Exci si onal bi opsy of an enl ar ged l ymph node: eval uati on of the speci men by a hematopathol ogi st, i ncl udi ng i mmunophenotypi ng. G eneral l y, needl e bi opsi es ar e i nsuffi ci ent for a pr oper di agnosi s. 2. Hi stor y wi th attenti on to B symptoms. 3. Compl ete physi cal exami nati on and documentati on of measurabl e di sease. 4. Laborator y tests i ncl ude: Compl ete bl ood count (CBC), er ythr ocyte sedi mentati on rate (ESR) Bi ochemi cal tests of l i ver functi on, r enal functi on, and ser um ur i c aci d, l actate dehydr ogenase (LDH), ser um al bumi n. 5. Radi ol ogi c studi es: Chest radi ograph and computer i zed tomography (CT) scan of the chest, abdomen, and pel vi s ar e used for eval uati on. CT scan of the neck i s useful , par ti cul ar l y i f the neck or upper chest i s i nvol ved. Basel i ne gal l i um scans or posi tr on emi ssi on tomography (PET) scans can be useful . PET scan i s i ncr easi ngl y favor ed for stagi ng because of evi dence of hi gher sensi ti vi ty and accuracy, par ti cul ar l y i n the spl een. Bone scan or radi ographs ar e used i f bone pai n or tender ness i s pr esent. 6. Bone mar r ow bi opsy of at l east one poster i or i l i ac cr est for those wi th abnor mal CBC or cl i ni cal stage IIB, III, or IV.

Stagi ng l apar otomy and spl enectomy wer e done r outi nel y i n the past for pati ents wi th ear l y stage di sease above the di aphragm and for whom defi ni ti ve radi ati on tr eatment was consi der ed. Now, wi th newer radi ol ogi c testi ng such as PET scans, i t i s rar el y used.

Unfavorable Prognostic Features The most i mpor tant unfavorabl e pr ognosti c featur es ar e advanced stage, B symptoms, and pr esence of bul ky di sease. 1. Advanced stage (IIIB and IV) 2. Pr esence of B symptoms (i .e., fever, wei ght l oss, and dr enchi ng ni ght sweats) 3. Bul ky di sease defi ned as >10-cm di ameter, par ti cul ar l y i n the medi asti num (mor e than one thi r d of chest di ameter ) 4. Extranodal i nvol vement (l i ver, spl een, and bone mar r ow) 5. Pati ents ol der than 40 year s 6. Incr eased ESR (B symptoms + ESR >30, or no B symptoms and ESR >70) 7. Hi stol ogy Unfavorabl e: mi xed cel l ul ar i ty and l ymphocyte depl eti on Favorabl e: l ymphocyte-pr edomi nant and nodul ar scl er osi s 8. Low ser um al bumi n.

MANAGEMENT OF NEWLY DIAGNOSED HODGKIN LYMPHOMA HL i s tr eated wi th a curati ve i ntent. In vi ew of the hi gh cur e rates, studi es have i ncr easi ngl y addr essed l ong-ter m toxi ci ti es to defi ne best tr eatment strategi es. Tr eatment sel ecti on i s ther efor e not onl y i nfl uenced by stage and unfavorabl e pr ognosti c factor s but al so by toxi ci ty.

Risk Stratification and PROGNOSIS Two major r i sk gr oups ar e di sti ngui shed, ear l y and advanced di sease:

1. Stages I and II wi thout B symptoms or bul ky di sease ar e consi der ed “favorabl e ear l y stage” and ar e at l ow r i sk for r ecur r ence. Cur e rate i s gr eater than 90% . 2. Stage IIB and stages I to IIB wi th bul k ar e var i abl y consi der ed “ear l y” or “advanced” by di ffer ent study gr oups. Most U.S. gr oups tr eat them as “unfavorabl e ear l y di sease.” Cur e rate i s gr eater than 80% . 3. Stages III and IV ar e consi der ed “advanced stage” and ar e at si gni fi cant r i sk for r ecur r ence. Cur e rate i s about 60% to 70% . Other cr i ter i a mi ght be i ncl uded to subdi vi de the two major r i sk gr oups fur ther to avoi d under- or over tr eatment of pati ents wi th ear l y stage di sease. For exampl e, the Canada Cl i ni cal Tr i al s G r oup and the Easter n Cooperati ve Oncol ogy G r oup (ECOG ) separate ear l y stage Hodgki n Di sease HD i nto: Low risk: i ncl udes nodul ar l ymphocyte-pr edomi nant Hodgki n di sease (NLPHD) and nodul ar scl er osi ng hi stol ogy, affects i ndi vi dual s younger than 40 year s, ESR i s l ess than 50, and thr ee or l ess di sease-si te r egi ons ar e i nvol ved. High risk: i ncl udes al l other di seases i n stages I to II, excl udi ng bul ky di sease >10 cm.

Radiation Treatment Radi ati on i s the most effecti ve si ngl e therapeuti c modal i ty for HL. In general , the management of HL wi th radi ati on therapy consi sts of tr eati ng r egi ons of known di sease (“i nvol ved fi el d”). An “extended fi el d” tr eats unaffected adjacent nodal gr oups i n addi ti on to the i nvol ved r egi ons (see Tabl e 29.4).

TABLE 29.4. Radiation guidelines Tumoricidal dose

40–45 By at the rate of 10 Gy/wk

Clinically negative nodal regions

35 Gy

Consolidation (after chemotherapy)

15–20 Gy

Radi ati on cover i ng extended fi el ds i s used to thr ee major fi el ds, known as the mantl e, paraaor ti c, and pel vi c or i nver ted-Y fi el ds (see F i g. 29.2).

FIG. 29.2. Radi ati on therapy fi el ds used i n tr eati ng Hodgki n di sease (A , B, C, and D). When the fi el ds shown i n C and D ar e combi ned, thi s i s commonl y cal l ed total nodal i r radi ati on (TNI). (F r om Haskel l CM. Cancer Tr eatment. 4th ed. Phi l adel phi a: WB Saunder s, 1995:965, wi th per mi ssi on.)

The usual dose of radi ati on i s 25 to 30 G y to uni nvol ved ar eas and 35 to 44 G y to the i nvol ved fi el d. Radi ati on doses can be l ower when used i n conjuncti on wi th chemotherapy Radi ati on therapy al one i s r eser ved for ear l y stages of HL wi thout unfavorabl e pr ognosti c featur es. In pati ents wi th advanced di sease, radi ati on contr i butes to di sease-fr ee sur vi val shown for bul ky di sease and nodul ar scl er osi s hi stol ogy, but whether i t pr ol ongs overal l sur vi val i s not evi dent. Addi ng l ong-ter m toxi ci ty wi th radi ati on r emai ns a concer n because of the hi gh cur e rate even i n advanced di sease. When choosi ng modal i ti es, one shoul d consi der the hi gher r i sk of young women (younger than 27 year s ol d) for br east cancer and the hi gher r i sk of l ung cancer i n smoker s as l ate toxi ci ty fr om radi ati on to the chest. Pati ents who r el apse after tr eatment wi th radi ati on therapy al one ar e fr equentl y sal vaged successful l y wi th combi nati on chemotherapy.

Chemotherapy The fi r st “curati ve r egi men” was mechl or ethami ne, Oncovi n, pr ocar baz i ne, pr edni sone (MOPP), whi ch r esul ted i n a 70% compl ete r emi ssi on i n pati ents wi th stage III and stage IV cancer. Subsequentl y, many r egi mens have been devel oped, i ncl udi ng MOPP var i ants, doxor ubi ci n (Adr i amyci n), bl eomyci n, vi nbl asti ne, and dacar baz i ne (ABVD) and i ts var i ants, and hybr i ds of MOPP/ABVD.

Choosing between MOPP, ABVD, and MOPP/ABVD In a randomi zed study, the Cancer and Leukemi a G r oup B (CALG B) showed ABVD and MOPP/ABVD to be super i or to MOPP al one i n ter ms of r emi ssi on, fr eedom fr om pr ogr essi on, and sur vi val . At 10 year s, the r i sk of devel opi ng tr eatment-r el ated l eukemi a wi th the MOPP r egi men i s 2% to 3% , wher eas i t i s 0.7% wi th ABVD.

Infer ti l i ty rates ar e much l ower wi th ABVD than wi th MOPP (see Tabl e 29.5).

TABLE 29.5. Cancer and Leukemia Group B study comparing combination treatments Complete response rate (%)

Survival rate (%)

MOPP

67

64

ABVD

82

72

MOPP/ABVD

83

73

Regimen

MOPP, mechlorethamine, Oncovin, procarbazine, and prednisone; ABVD, doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine. A r ecent randomi zed i nter gr oup tr i al demonstrated that MOPP/ABV i s associ ated wi th a gr eater i nci dence of acute toxi ci ty, myel odyspl asi a (MDS), and l eukemi a than ABVD i s, wi th no di ffer ence i n fai l ur e-fr ee sur vi val or overal l sur vi val at 5 year s. ABVD shoul d be consi der ed the standar d r egi men for tr eatment of advanced HD (see Tabl e 29.6).

TABLE 29.6. Commonly used treatment regimens ABVD

Doxorubicin, 25 mg/m2 /dose i.v. push for two doses, d 1 and 15 (total dose/cycle, 50 mg/m2 ) Bleomycin, 10 units/m2 /dose i.v. push for two doses, d 1 and 15 (total dose/cycle, 20 units/m 2 ) Vinblastine, 6 mg/m2 /dose i.v. push for two doses, d 1 and 15 (total dose/cycle, 12 mg/m2 ) Dacarbazine, 375 mg/m2 /dose i.v. infusion for two doses, d 1 and 15 (total dose/cycle, 750 mg/m 2 ) Treatment cycle repeats every 28 d MOPP Mechlorethamine, 6 mg/m2 /dose i.v. push for two doses, d 1 and 8 (total dose/cycle, 12 mg/m 2 ) Vincristine, 1.4 mg/m2 /dose i.v. push for two doses, d 1 and 8 (total dose/cycle, 2.8 mg/m2 ) Procarbazine, 100 mg/m2 /d PO for 14 doses, d 1–14 (total dose/cycle, 1,400 mg/m2 ) Prednisone, 40 mg/m2 /d PO for 14 doses, d 1– 14 (cycles 1 and 14 only) (total dose/cycle, 560 mg/m 2 )

Treatment cycle repeats every 28 d Alternating MOPP/ABVD Alternate MOPP and ABVD cycles by 28 d MOPP/ABV hybrid Mechlorethamine, 6 mg/m2 i.v. push d 1 (total dose/cycle, 6 mg/m2 ) Vincristine, 1.4 mg/m2 i.v. push d 1 (total dose/cycle, 1.4 mg/m2 ; maximal dose, 2 mg) Procarbazine, 100 mg/m2 /d PO for 7 doses, d 1–7 (total dose/cycle, 700 mg/m2 ) Prednisone, 40 mg/m2 /d PO for 14 doses, d 1– 14 (total dose/cycle, 560 mg/m2 ) Doxorubicin, 25 mg/m2 i.v. push d 8 (total dose/cycle, 25 mg/m2 ) Hydrocortisone, 100 mg i.v. d 8, before bleomycin (total dose/cycle, 100 mg) Bleomycin, 10 units/m2 i.v. push d 8 (total dose/cycle, 10 units/m2 ) Vinblastine, 6 mg/m2 i.v. push d 8 (total

dose/cycle, 6 mg/m2 ) Treatment cycle repeats every 28 d Stanford V Mustard, 6 mg/m2 i.v. wk 1, 5, 9 Vincristine, 1.4 mg/m2 i.v. wk 2, 4, 6, 8, 10, 12 (maximal dose, 2 mg) Prednisone, 40 mg/m2 /d PO every other d wk 1–9, taper Doxorubicin, 25 mg/m2 i.v. wk, 1, 3, 5, 7, 9, 11 Bleomycin, 5 units/m2 i.v. wk 2, 4, 6, 8, 10, 12 Vinblastine, 6 mg/m2 i.v. wk, 1, 3, 5, 7, 9, 11 VP-16 60 mg/m2 i.v. × 2 wk 3, 7, 11 1. The maximum dose of vincristine is 2 mg 2. All drugs are administered on d 1, except for VP-16, which is given on d 1 and 2 3. Taper prednisone by 10 mg of the total dose q.o.d. (every other day) on wk 10 and 11 4. Reduce the dose of vinblastine to 4 mg/m2 if on wk 9 and 11 for patients over the age of 50 yr old 5. Reduce the dose of vincristine to 1 mg on wk 10 and 12 for patients over the age of 50 yr

6. If mustard is not available, a substitution with 650 mg/m2 of cyclophosphamide can be made on wk 1, 5, 9 7. Patients will receive total of 12 wk of treatment.

Combined Modality Treatment A meta-anal ysi s of 23 tr i al s of pati ents wi th ear l y stage HD showed that the 10-year rate of fr eedom fr om r el apse was hi gher wi th combi ned modal i ty therapy than wi th radi ati on, but sur vi val rates wer e not si gni fi cantl y di ffer ent.

Primary Treatment Options 1. Favorabl e ear l y di sease a. Two to four cycl es ABVD wi th i nvol ved fi el d radi ati on to fol l ow b. Extended fi el d radi ati on al one. 2. Unfavorabl e ear l y di sease a. Four to si x cycl es ABVD wi th i nvol ved or extended fi el d radi ati on. One Eur opean randomi zed tr i al showed no di ffer ence i n fr eedom fr om tr eatment fai l ur e or overal l sur vi val when extended fi el d radi ati on was r epl aced by i nvol ved fi el d radi ati on (30 G y to fi el d, 10 G y to bul k). 3. Advanced di sease a. ABVD for si x to ei ght cycl es i s the cur r ent standar d. Tr eatment i s usual l y conti nued two cycl es after r esol uti on of di sease by i magi ng studi es. b. Addi ti on of i nvol ved fi el d radi ati on i s usual l y consi der ed, par ti cul ar l y for bul ky di sease. Recent evi dence fr om a randomi zed tr i al suggests ther e may be no need to add radi ati on, i f a compl ete r esponse can be achi eved wi th combi nati on chemotherapy. c. Stanfor d V i s an effecti ve r egi men wi th shor ter tr eatment

durati on (3 months) and i s cur r entl y under goi ng randomi zed compar i son wi th ABVD-based tr eatment i n i nter gr oup tr i al E2496. 4. Lymphocyte-pr edomi nant Hodgki n l ymphoma: Thi s subtype has the pr opensi ty to cause mul ti pl e r el apses even up to 15 year s. a. Ear l y stages of LPHL wi thout r i sk factor s ar e tr eated wi th radi ati on al one. b. Advanced stages ar e rar e at di agnosi s and car r y a poor pr ognosi s. They ar e tr eated l i ke nodul ar scl er osi ng hi stol ogy. c. Phase II tr i al s show si ngl e-agent acti vi ty of r i tuxi mab for the usual l y CD20-posi ti ve LPHL. It i s possi bl y effecti ve i n the chemotherapy-r efractor y setti ng, al though the effect i s of shor t durati on. The use of r i tuxi mab has to be consi der ed i nvesti gati onal and affected pati ents shoul d be r efer r ed for tr i al s because of the rar i ty of the di sease.

High-dose Therapy and Autologous Stem Cell Transplantation Hi gh-dose therapy wi th autol ogous transpl ant has no defi ned r ol e for consol i dati on i n the tr eatment pr ograms for newl y di agnosed unfavorabl e-r i sk HL that r espond to standar d chemotherapy. One randomi zed tr i al fr om the Uni ted Ki ngdom demonstrated no advantage i n pati ents wi th hi ghl y unfavorabl e pr ognosi s i n achi evi ng compl ete r esponse wi th the Eur opean r egi men PVACEBOP.

Evaluation of Treatment Response with Positron Emission Tomography PET i s a new tool i n managi ng pati ents wi th l ymphomas. A negati ve PET scan at compl eti on of therapy i ndi cates a favorabl e pr ognosi s. Per si stentl y posi ti ve PET scans at the end of chemotherapy seem to have a hi gh sensi ti vi ty for pr edi cti ng subsequent r el apse and need cl ose fol l ow-up; however, some of those pati ents may r emai n i n pr ol onged r emi ssi on. Mor e pr ospecti ve studi es ar e needed to defi ne the useful ness and l i mi tati ons of PET scans mor e pr eci sel y.

TREATMENT OF RELAPSED HODGKIN LYMPHOMA In general , r el apsed HL i s sti l l curabl e. Rel apses usual l y occur wi thi n 2 to 3 year s after pr i mar y therapy. Ther e ar e cur r entl y no cl ear parameter s to pr edi ct the 15% to 20% of pati ents who wi l l pr ogr ess dur i ng tr eatment or r el apse ear l y. Pati ents wi th r el apse wi thi n 1 year of pr i mar y tr eatment or wi th a second r el apse have a sur vi val of l ess than 20% at 5 year s. For successful choi ce of management, one shoul d consi der the fol l owi ng: 1. Si tes of r el apse (i .e., pr i or radi ated ar ea, si ngl e or mul ti pl e nodes, extranodal , bul ky). 2. Detai l s of pr evi ous tr eatment. If the r el apse i s due to i nadequate i ni ti al tr eatment, r etr eatment wi th chemotherapy or radi ati on i s consi der ed. Rel apse after pr i mar y radi ati on i s best managed wi th chemotherapy. 3. Achi evement and durati on of fi r st r emi ssi on: Early relapse ( Ta ble o f C o nt e nt s > Se c t io n 9 - He m a t o lo gic M a ligna nc ie s > 3 0 - He m a t o po ie t ic St e m C e ll Tra ns pla nt a t io n

30 Hematopoietic Stem Cell Transplantation Michael Craig* Jame A braham† Richard W . Childs‡ *Section of Hematology/Oncology, Depar tment of Medicine, West Vir ginia Univer sity, Mor gantown, West Vir ginia † Mar y

Babb Randolph Cancer Center , West Vir ginia Univer sity, Mor gantown, West Vir ginia ‡ National

Hear t, Lung, and Blood Institute, National Institutes of Health, Bethesda, Mar yland Hematopoi eti c stem cel l transpl antati on (HSCT) r emai ns an effecti ve tr eatment opti on for many pati ents wi th a wi de range of mal i gnant and nonmal i gnant condi ti ons. In addi ti on to autol ogous and matched r el ated donor al l ogenei c transpl antati ons, many pati ents may be offer ed unr el ated donor, nonmyel oabl ati ve, or cor d bl ood transpl antati on. An esti mated 40,000 to 50,000 transpl antati ons wer e per for med wor l dwi de i n 2002. Al though transpl antati on may be associ ated wi th si gni fi cant mor bi di ty and mor tal i ty, r ecent advances i n suppor ti ve car e, human l eukocyte anti gen (HLA) typi ng, and tr eatments for graft ver sus host di sease (G VHD) have l ed to i mpr oved outcomes for pati ents under goi ng the pr ocedur e. An over vi ew of autol ogous and al l ogenei c transpl antati on i s pr ovi ded i n thi s chapter, al ong wi th a di scussi on of the compl i cati ons and thei r management.

HEMATOPOIETIC STEM CELLS Hematopoi eti c stem cel l s (HSCs) ar e i mmatur e pr ecur sor cel l s r esi di ng wi thi n the mar r ow space that ar e capabl e of gi vi ng r i se to

most of the cel l ul ar el ements wi thi n the bl ood, i ncl udi ng l ymphoi d, er ythr oi d, and myel oi d l i nes. These cel l s ar e defi ned by thei r abi l i ty to r escue l ethal l y i r radi ated ani mal s fr om mar r ow apl asi a. In humans, most HSCs expr ess the CD34 anti gen and l ack l i neagespeci fi c mar ker s, al though a popul ati on of CD34- stem cel l s has al so been descr i bed. The number of CD34+ cel l s that ar e pr esent i n the graft has an i mpact on transpl ant outcome; i n the al l ogenei c setti ng, fewer CD34+ cel l s ar e associ ated wi th a hi gher r i sk of transpl ant-r el ated mor tal i ty and del ays i n the ti me to hematopoi eti c r ecover y i n contrast to mor e CD34+ cel l s wher e transpl ant-r el ated mor tal i ty and the r i sk of di sease r el apse i s decr eased. HSCs can be obtai ned fr om per i pheral bl ood, bone mar r ow, or umbi l i cal cor d bl ood (di scussed i n subsequent text).

Peripheral Blood Stem Cell Collection G r owth factor s [granul ocyte col ony sti mul ati ng factor (G -CSF ) or granul ocyte-macr ophage col ony sti mul ati ng factor (G M-CSF )] ar e used to “mobi l i ze” or i ncr ease the number of HSCs and pr ogeni tor cel l s i n the per i pheral bl ood. Cel l s ar e col l ected by apher esi s pr ocedur e on day 5 or 6. In the autol ogous transpl ant setti ng, chemotherapy may be gi ven (pr ovi di ng an addi ti onal anti neopl asti c effect) befor e gr owth factor s, wi th apher esi s bei ng per for med dur i ng hematopoi eti c r ecover y. Fewer compl i cati ons and mor bi di ty ar e exper i enced by the donor. Per i pheral bl ood stem cel l (PBSC) grafts r esul t i n mor e rapi d engraftment than mar r ow grafts. The mi ni mum goal of PBSC col l ecti on i s 2 × 106 CD34 + cel l s per kg (range 2.0 to 8.0). Mor e T cel l s (CD3+ ) ar e col l ected i n the al l ogenei c setti ng.

Bone Marrow Harvest Tradi ti onal sour ce of HSCs; used l ess often than per i pheral bl ood grafts. Bone mar r ow i s har vested fr om poster i or i l i ac cr ests under general anesthesi a.

A har vest of 15 mL per kg of aspi rated mar r ow i s general l y consi der ed safe to the donor. The goal cel l dose i s 2.0 × 108 mononucl ear cel l s per kg of r eci pi ent wei ght. Compl i cati ons to the donor may i ncl ude pai n, neur opathy, and anemi a. Sever e compl i cati ons occur i n l ess than 0.5% of pr ocedur es.

CURRENT INDICATIONS FOR TRANSPLANTATION Many mal i gnant and nonmal i gnant di sor der s have been tr eated successful l y wi th HSCT [the Nati onal Mar r ow Donor Pr ogram (NMDP) cur r entl y l i sts mor e than 70 di seases]. Most transpl antati ons ar e per for med for mal i gnant condi ti ons, i ncl udi ng acute myel oi d and l ymphocyti c l eukemi as, chr oni c myel ogenous l eukemi a (CML), mul ti pl e myel oma, non-Hodgki n l ymphoma, and Hodgki n l ymphoma. Stem cel l di sor der s (e.g., apl asti c anemi a and par oxysmal noctur nal hemogl obi nur i a), i nher i ted i mmune-system defects (e.g., sever e combi ned i mmunodefi ci ency and Wi skott-Al dr i ch syndr ome), er ythr ocyte di sor der s (e.g., si ckl e cel l anemi a and β-thal assemi a), and congeni tal metabol i c di seases have been cur ed by al l ogenei c HSCT.

PRETRANSPLANTATION EVALUATION Pr i or to tr eatment, a thor ough di scussi on hi ghl i ghti ng the transpl antati on pr ocedur e i tsel f as wel l as r i sks and benefi ts associ ated wi th the pr ocedur e shoul d take pl ace between the physi ci an and the pati ent. 1. Human l eukocyte anti gen testi ng (HLA typi ng) of the pati ent and a sear ch for a HLA-matched donor (begi nni ng wi th si bl i ngs) i s r equi r ed i f an al l ogenei c transpl ant i s bei ng consi der ed. 2. Medi cal hi stor y and eval uati on Revi ew of or i gi nal di agnosi s and pr evi ous tr eatments, i ncl udi ng radi ati on Concomi tant medi cal pr obl ems Cur r ent medi cati ons and al l er gi es

Deter mi nati on of cur r ent di sease status (i .e., i n r emi ssi on, r el apse, mi ni mal r esi dual di sease, etc.) Restagi ng and confi r mati on of metastati c spr ead Transfusi on hi stor y and compl i cati ons, as wel l as ABO typi ng Psychosoci al eval uati on and del i neati on of a car egi ver. 3. Physi cal exami nati on Thor ough physi cal exami nati on Eval uati on of oral cavi ty and denti ti on Neur ol ogi c eval uati on i f di sease coul d i nvol ve the central ner vous system Kar nofsky per for mance status (pr efer r ed val ue >70% ). 4. Or gan functi on anal ysi s Renal functi on: cr eati ni ne cl earance >60 mL per mi nute Hepati c functi on: al ani ne ami notransferase (AST) and aspar tate ami notransferase (ALT) l ess than twi ce the upper l evel of nor mal and bi l i r ubi n 40% ] Chest x-ray and pul monar y functi on testi ng i ncl udi ng di ffusi ng capaci ty of l ung for car bon monoxi de (DLCO) and for ced vi tal capaci ty (F VC). 5. Infecti ous di sease eval uati on Ser ol ogy for cytomegal ovi r us (CMV), human i mmunodefi ci ency vi r us (HIV), and hepati ti s Ser ol ogy for her pes si mpl ex vi r us (HSV), Epstei n–Bar r vi r us (EBV), and var i cel l a Assess for pr i or hi stor y of i nvasi ve fungal (asper gi l l us) i nfecti on. 6. Consi derati on of r efer ral to r epr oducti ve center for sper m banki ng or in vitr o fer ti l i z ati on.

AUTOLOGOUS STEM CELL TRANSPLANTATION

Hi gh-dose chemotherapy (HDCT) wi thout stem cel l r escue may r esul t i n pr ol onged cytopeni as. Autol ogous stem cel l s ar e col l ected and ar e r ei nfused i nto the pati ent after the compl eti on of HDCT to r econsti tute the hematopoi eti c system. Autol ogous transpl antati on i s most effecti ve i n chemotherapysensi ti ve tumor s or as a consol i dati on therapy for pati ents i n r emi ssi on. HDCT may al so over come i ntr i nsi c tumor r esi stance to chemotherapy. Most grafts use PBSCs col l ected by apher esi s. The pr oduct i s fr ozen vi abl y i n di methyl sul foxi de (DMSO) and thawed just pr i or to i nfusi on. Reacti ons dur i ng transfusi on ar e rar e and may i ncl ude br onchospasm, fl ushi ng, or hypotensi on secondar y to DMSO. Pancytopeni a typi cal l y per si sts for 10 to 20 days and i s shor tened usi ng PBSC and gr owth factor s. Anti mi cr obi al s and bl ood pr oducts ar e typi cal l y gi ven to suppor t the pati ent i n the fi r st few weeks fol l owi ng transpl antati on. Infecti ous compl i cati ons may occur as a consequence of the pati ent bei ng pr ofoundl y i mmunosuppr essed. New pr otocol s ar e cur r entl y expl or i ng tandem autol ogous transpl ants (two stem cel l r escues after HDCT) and autol ogous fol l owed by nonmyel oabl ati ve al l ogenei c transpl antati on. Late toxi ci ti es i ncl ude the devel opment of myel odyspl asi a, especi al l y i n r egi mens wi th total body i r radi ati on (TBI).

ALLOGENEIC STEM CELL TRANSPLANTATION Introduction Al l ogenei c stem cel l transpl antati on has pr ogr essed fr om a tr eatment of l ast r esor t to fi r st-l i ne therapy for some pati ents. Extensi ve pl anni ng and coor di nati on of car e i s r equi r ed for al l transpl antati on candi dates, usual l y i nvol vi ng a networ k of physi ci ans and suppor t staff. The NMDP i s an i nval uabl e r esour ce for physi ci ans and thei r pati ents for the pur pose of transpl antati on. The NMDP Web si te i s http://www.mar r ow.or g. Al l physi ci ans may

per for m a fr ee i ni ti al sear ch for an HLA-matched unr el ated donor i n the NMDP, whi ch mai ntai ns a r egi str y of mor e than 5 mi l l i on potenti al donor s.

Graft versus Malignancy The mai n therapeuti c benefi t of al l ogenei c transpl ant depends on the potenti al of the donor 's i mmune system to r ecogni ze and eradi cate the mal i gnant or abnor mal stem cel l cl one [the so cal l ed graft-ver sus-l eukemi a (G VL) or graft-ver sus-tumor (G VT) effect]. Thi s i mmune effect i s evi denced by the l ower r el apse rate of hematol ogi c mal i gnanci es i n pati ents who under go al l ogenei c transpl antati on than i n those who under go autol ogous transpl antati on, as wel l as by an i ncr eased r el apse rate i n pati ents r ecei vi ng a transpl ant fr om a syngenei c (i denti cal twi n) donor or an al l ograft that has under gone T-cel l depl eti on. In addi ti on, pati ents who devel op G VHD have a l ower r i sk of r el apse than those who do not, and those who r el apse after transpl antati on may be i nduced i nto a second r emi ssi on wi th a donor l ymphocyte i nfusi on (DLI). CML, l ow-grade l ymphoma, and acute myel ogenous l eukemi a (AML) ar e most suscepti bl e to the G VT effect, wher eas acute l ymphobl asti c l eukemi a and hi gh-grade l ymphomas ar e r el ati vel y r esi stant to G VT. G VL i s pr edomi nantl y medi ated by donor-der i ved T cel l s, al though new evi dence suppor ts a potenti al contr i buti on fr om nonspeci fi c cytoki nes (both host and/or donor der i ved) and donor-der i ved natural ki l l er (NK) cel l s i n some setti ngs.

Sources of Donor Hematopoietic Progenitor Cells Matched Related Donor The pr obabi l i ty of HLA-i denti ty between si bl i ngs i s 25% . In the Uni ted States, appr oxi matel y 30% of pati ents wi l l have an HLA-matched si bl i ng. The r i sk of G VHD i ncr eases as the HLA di spar i ty between the pati ent and donor i ncr eases; ther efor e, most transpl ant center s pr efer a 6/6 or 5/6 HLA match.

Syngeneic Donor Rar el y, an i denti cal twi n can ser ve as the donor. Because G VHD does not occur, posttranspl antati on i mmunosuppr essi on i s not r equi r ed (al though the r i sk of di sease r el apse i s hi gher i n thi s setti ng).

Matched Unrelated Donor Sear ch thr ough the NMDP for appr opr i ate HLA match. Ti me fr om i denti fyi ng a pr el i mi nar y donor to col l ecti ng the al l ograft i s typi cal l y 3 to 4 months. Seventy per cent of whi tes wi l l have an HLA-matched donor. It i s mor e di ffi cul t to fi nd matched donor s for cer tai n mi nor i ty gr oups. Thi r ty per cent of sear ches thr ough the NMDP r esul t i n a transpl ant. The r i sk of G VHD and graft fai l ur e i ncr eases wi th i ncr easi ng HLA mi smatches.

Umbilical Cord Transplantation Umbi l i cal cor ds ar e obtai ned fr om umbi l i cal vessel s at del i ver y and ar e cr yopr eser ved; a r egi str y r ecor ds the HLA type of the donor. Lymphocytes fr om cor d grafts ar e i mmunol ogi cal l y i mmatur e, whi ch appear s to decr ease the r i sk of G VHD that i s associ ated wi th usi ng an HLA-mi smatched graft. Low stem cel l number s i n the graft l ead to i ncr eased r i sk of graft fai l ur e and a pr ol onged i nter val to hematopoi eti c r ecover y.

Haploidentical Donor Par ent or si bl i ng may ser ve as donor, wi th HLA match r estr i cted to thr ee l oci .

Lar ge number s of CD34+ cel l s i ncr ease the chances of engraftment. T-cel l depl eti on of the al l ograft i s r equi r ed to r educe the r i sk of l ethal G VHD. The pr ocess r equi r es pr ol onged i mmunosuppr essi on, whi ch i ncr eases the r i sk of i nfecti on.

Donor Evaluation Car eful donor sel ecti on and eval uati on i s an i ntegral par t of the pr etranspl antati on wor kup. The donor must be heal thy and abl e to wi thstand the apher esi s pr ocedur e or a bone mar r ow har vest. 1. Donor HLA typi ng 2. ABO typi ng 3. Hi stor y-r el evant i nfor mati on of the donor Any pr evi ous mal i gnancy wi thi n 5 year s except nonmel anoma ski n cancer (absol ute excl usi on cr i ter i a) Car di ac or cor onar y ar ter y di sease Compl i cati ons to anesthesi a Hi stor y of l ung di sease Back or spi ne di sor der s Medi cati ons 4. Infecti on exposur e HIV, human T-l ymphotr opi c vi r us (HTLV), hepati ti s, CMV, HSV, and EBV. 5. Pr egnancy.

Human Leukocyte Antigen Typing The HLA system i s a ser i es of cel l sur face pr otei ns, whi ch pl ay an i mpor tant r ol e i n i mmune functi on. The system i s i nti matel y i nvol ved i n cel l -to-cel l i nteracti ons and r ecogni ti on. The genes encodi ng the HLA system ar e l ocated on chr omosome 6 and ar e codomi nantl y expr essed. A str i ki ng featur e of the HLA system i s i ts

enor mous di ver si ty. HLA cl ass I mol ecul es i ncl ude HLA-A, HLA-B, and HLA-C l oci . HLA cl ass II mol ecul es ar e made up of mor e than 15 anti gens, wi th HLA-DR havi ng the gr eatest i mpact on transpl antati on outcome. F ur ther compl exi ty of the HLA system was r eveal ed wi th the advent of mol ecul ar-based HLA typi ng, showi ng that HLA anti gens pr evi ousl y i denti fi ed by ser ol ogi c testi ng wer e actual l y di ver se when cl assi fi ed by DNA anal ysi s. Cur r ent r ecommendati ons i ncl ude matchi ng of the donor and r eci pi ent at the al l el e l evel for HLA-A, HLA-B, and HLA-DRB1 l oci .

Stages of Transplant Conditioning (“The Preparative Regimen”) The goal s of the condi ti oni ng r egi men i ncl ude i mmunosuppr essi on of the r eci pi ent to pr event graft r ejecti on and to eradi cate r esi dual di sease or abnor mal cel l popul ati ons. Condi ti oni ng strategi es can be categor i zed as myel oabl ati ve (conventi onal condi ti oni ng) or nonmyel oabl ati ve (see secti on on nonmyel oabl ati ve transpl ants) strategi es. Several myel oabl ati ve condi ti oni ng r egi mens ar e cur r entl y bei ng used, wi th the most common r egi mens i ncor porati ng hi gh-dose cycl ophosphami de combi ned wi th ei ther TBI or busul fan. The choi ce of a par ti cul ar condi ti oni ng r egi men i s gui ded by factor s such as the sensi ti vi ty of the mal i gnancy to dr ugs i n the r egi men, the toxi ci ti es i nher ent to i ndi vi dual condi ti oni ng agents, and the age and per for mance status of the pati ent. Ini ti al si de effects of the transpl antati on pr ocedur e that ar e r el ated to the pr eparati ve r egi men i ncl ude mucosi ti s, nausea, di ar r hea, al opeci a, pancytopeni a, and sei z ur es (wi th busul fan). Late effects of transpl ant condi ti oni ng i ncl ude l ung toxi ci ty, gr owth r etar dati on, and second mal i gnancy.

Transplantation Phase The transpl antati on phase usual l y star ts 24 hour s after compl eti ng the pr eparati ve r egi men. Infusi on of donor pr oduct i s usual l y wel l tol erated by the r eci pi ent.

The day of transpl antati on i s tradi ti onal l y r efer r ed to as “Day 0.”

Engraftment Engraftment i s defi ned as ti me to devel op a sustai ned absol ute granul ocyte count of >500 cel l s per µL Pl atel et r ecover y usual l y l ags behi nd granul ocyte r ecover y. Durati on of condi ti oni ng-i nduced cytopeni as depends on the CD34 + cel l count i n the graft, use of gr owth factor s, and agents used for G VHD pr ophyl axi s.

Supportive Care Phase Hematol ogi c suppor t i s pr ovi ded wi th bl ood pr oducts. Infecti on pr ophyl axi s and tr eatment for m a par t of thi s phase. G VHD and other transpl antati on-r el ated compl i cati ons occur i n thi s phase.

Infections Infecti on r emai ns a major cause of mor bi di ty for pati ents under goi ng HSC transpl antati on. F i gur e 30.1 di spl ays an over vi ew of potenti al pathogens. Indwel l i ng catheter s ar e a common sour ce of i nfecti ons, and sepsi s may occur dur i ng the neutr openi a phase of the transpl antati on. Cur r ent appr oaches to mi ni mi ze the r i sk of l i fethr eateni ng i nfecti ons i ncl ude the use of pr ophyl acti c anti mi cr obi al , anti fungal , and anti vi ral agents, as wel l as aggr essi ve scr eeni ng for common transpl antati on-associ ated i nfecti ons.

FIG. 30.1. Phases of oppor tuni sti c i nfecti ons among al l ogeni c HSCT r eci pi ents. *wi thout standar d pr ophyl axi s; Δ pr i mar i l y among per sons who ar e ser oposi ti ve befor e transpl ant. (F r om Center s for Di sease Contr ol and Pr eventi on. G ui del i nes for pr eventi ng oppor tuni sti c i nfecti ons among hematopoi eti c stem cel l transpl ant r eci pi ents: r ecommendati ons of CDC, the Infecti ous Di sease Soci ety of Amer i ca, and the Amer i can Soci ety of Bl ood and Mar r ow Transpl antati on. MMWR Mor b Mor tal Wkl y Rep 200;49(No. RR-10):[1–60], wi th per mi ssi on.)

Neutropenic Fever See Chapter 36 for over vi ew of management of neutr openi c fever.

Cytomegalovirus Infection Cytomegal ovi r us i nfecti on i s a major cause of mor bi di ty and mor tal i ty, especi al l y pneumoni a. In addi ti on to pneumoni a, symptoms may i ncl ude fever, hepati ti s, enter i ti s, and mar r ow suppr essi on. CMV i nfecti on most commonl y occur s as a r esul t of the r eacti vati on of a pr i or i nfecti on i n the pati ent or because of the transfer of an i nfecti on fr om the donor (rar e). The i nfecti on usual l y occur s after engraftment and may coi nci de wi th G VHD or wi th the use of i mmunosuppr essi ve agents used to tr eat G VHD. The wi ndow of r i sk for vi ral r eacti vati on i s gr eatest fr om the day of engraftment to 100 days after transpl antati on. Scr eeni ng for vi ral r eacti vati on i s per for med weekl y after transpl antati on by measur i ng the CMV anti gen l evel s or by pol ymerase chai n r eacti on (PCR). Ini ti al tr eatment i s wi th i ntravenous ganci cl ovi r ± i ntravenous i mmunogl obul i n tr eatment. Foscar net i s an al ter nati ve tr eatment (especi al l y i n pati ents wi th cytopeni as).

Invasive Fungal Infection Invasi ve fungal i nfecti on i s another cause of si gni fi cant mor bi di ty, wi th pr esentati on of pneumoni a, si nusi ti s, cel l ul i ti s, or bl ood i nfecti on. Common agents ar e Asper gillus, F usar ium, Zygomycetes, as wel l as Candida speci es. Expanded sel ecti on of anti fungal agents may i mpr ove outcome. Candida fungal pr ophyl axi s wi th fl uconazol e i s used by many center s.

Hematologic Support Hematol ogi c suppor t i s pr ovi ded by r epl acement of bl ood and pl atel et pr oducts as needed. Al l bl ood pr oducts shoul d be i r radi ated pr i or to i nfusi on. Leukocyte r educti on fi l ter s ar e i ndi cated to r educe CMV transmi ssi on and to r educe febr i l e r eacti ons.

Venoocclusive Disease Hepati c venooccl usi ve di sease (VOD) i s character i zed by jaundi ce, tender hepatomegal y, and unexpl ai ned wei ght gai n or asci tes. VOD r emai ns extr emel y di ffi cul t to tr eat, wi th the r i sk for thi s compl i cati on i ncr easi ng wi th the use of busul fan-contai ni ng pr eparati ve r egi mens. Tr eatment typi cal l y i nvol ves suppor ti ve car e measur es focused on mai ntai ni ng r enal functi on, the coagul ati on system, and fl ui d bal ance. Moni tor i ng busul fan dr ug l evel s wi th appr opr i ate dose adjusti ng appear s to decr ease the i nci dence of thi s compl i cati on. Defi br oti de, an i nvesti gati onal agent, has r ecentl y been used wi th success to tr eat sever e VOD.

Pulmonary Toxicity Bacter i al , vi ral , or fungal or gani sms may cause pneumoni a. Di ffuse al veol ar hemor r hage (usual l y condi ti oni ng r el ated) may r espond to hi gh-dose ster oi ds. Inter sti ti al pneumoni ti s wi th fever, di ffuse i nfi l trates, and hypoxi a may occur i n 10% to 20% of pati ents; al though commonl y i di opathi c, CMV needs to be excl uded as the cause i n al l the cases. The need for venti l ator suppor t i s associ ated wi th poor outcome.

Graft Versus Host Disease G VHD r emai ns a mai n toxi c effect associ ated wi th al l ogenei c transpl antati on. Thi s cl i ni cal condi ti on r esul ts when donor-der i ved T

cel l s r ecogni ze and r eact agai nst nor mal r eci pi ent ti ssues. Acute G VHD occur s most commonl y wi thi n the fi r st 100 days of the transpl antati on, wher eas chr oni c G VHD occur s most commonl y mor e than 100 days after transpl antati on. Up to 50% of matched si bl i ng al l ogenei c transpl ants ar e compl i cated by acute G VHD. Cur r ent appr oaches to l essen the r i sk i ncl ude the use of pr ophyl acti c phar macol ogi c agents and T-cel l depl eti on of the graft. The cl i ni cal pr esentati on of G VHD may be var i abl e but the most commonl y affected or gans ar e ski n, l i ver, and the gastr oi ntesti nal system. The stagi ng system for G VHD i s pr esented i n Tabl e 30.1. Ri sk factor s for acute G VHD ar e shown i n Tabl e 30.2.

TABLE 30.1. Staging System for Graft versus Host Disease (GVHD) Level of injury

Skin

Liver (bilirubin)

Gut

2–3 mg/dL

500– 1,000 mL liquid stool/d

2

Maculopapular rash 25%– 50% of body surface

3–6 mg/dL

1,000– 1,500 mL liquid stool/d

3

Generalized erythroderma

6–16 mg/dL

>1,500 mL liquid stool/d

1

Maculopapular rash 15 mg/dL

abdominal pain with or without ileus

Level of injury Clinical grade

Skin

Liver

GI tract

I

1 or 2

None

none

II

1–3

1

1

III

2 or 3

2 or 3

2 or 3

IV

2–4

2–4

2–4

GI, gastrointestinal.

TABLE 30.2. Risk factors for Acute Graft versus Host Disease (GVHD) Level of HLA mismatch Infection (e.g., CMV, varicella, etc.) Use of unrelated donors

Older patients Donor with a prior history of pregnancy Sex-mismatched transplant (female allografts into male recipients) Intensive conditioning regimens HLA, human leukocyte antigen; CMV, cytomegalovirus.

Prevention of Acute Graft Versus Host Disease T-cel l depl eti on of the al l ograft or combi nati ons of cycl ospor i ne, methotr exate, tacr ol i mus, pr edni sone, or mycophenol ate mofeti l pr event acute G VHD. A common r egi men for si bl i ng donor transpl ants i s cycl ospor i ne, PO or i .v., and methotr exate i .v. on days 1, 3, 6, and 11. Cycl ospor i ne dose 5 mg/kg/day, di vi ded i n two doses; the goal i s to mai ntai n bl ood l evel s of cycl ospor i ne at 150 to 300 ng per mL. Tacr ol i mus dose 0.05 to 0.1 mg/kg/day, di vi ded i n two doses; the goal i s to mai ntai n l evel s at 5 to 15 ng per mL. Many medi cati ons may i nteract wi th i mmunosuppr essant dr ugs. Donor T-cel l depl eti on pr i or to transpl ant decr eases r i sk of G VHD but may i ncr ease the r i sk of r el apse. T-cel l depl eti on may be accompl i shed by var i ous methods, such as CD34+ sel ecti on of the graft or the use monocl onal anti bodi es di r ected agai nst T-cel l anti gens.

Treatment of Acute Graft versus Host Disease Ini ti al l y, methyl pr edni sol one shoul d be gi ven at a dose of 1 to 2 mg/kg/day. For those pati ents who do not r espond or for those who have a par ti al r esponse, addi ti onal agents can be added wi th var i abl e success (see Tabl e 30.3); cl i ni cal tr i al s shoul d be consi der ed.

TABLE 30.3. Treatments that May be Useful for Acute Graft versus Host Disease (GVHD) Treatment Methylprednisolone Cyclosporine/tacrolimus Azathioprine Daclizumab Infliximab Muromonab-CD3 (OKT3) Photopheresis Antithymocyte globulin

Chronic Graft versus Host Disease Chr oni c G VHD typi cal l y occur s after 100 days fr om

transpl antati on. Pr i or hi stor y of acute G VHD and the use of PBSC al l ografts ar e r i sk factor s. Chr oni c G VHD pr esents wi th var i abl e or gan i nvol vement and symptoms, i ncl udi ng cl i ni cal pr esentati ons that may r esembl e autoi mmune di sor der s (i .e., l i chenoi d ski n changes, si cca syndr ome, scl er oder ma-l i ke ski n changes, chr oni c hepati ti s, and br onchi ol i ti s obl i terans). Chr oni c G VHD i s often accompani ed by cytopeni as and i mmunodefi ci ency. Tr eatment i nvol ves pr ol onged cour ses of ster oi ds and other i mmunosuppr essi ve agents as wel l as pr ophyl acti c anti bi oti cs (e.g., peni ci l l i n). Some tr i al s have shown a benefi t fr om thal i domi de, mycophenol ate mofeti l , photopher esi s, and Psoral en-UV-A (PUVA) (for chr oni c ski n G VHD).

Relapse after Transplant Rel apse of mal i gnant di sease after al l ogenei c transpl ant i s an omi nous event. Most r el apses occur wi thi n 2 year s of transpl antati on. Immunosuppr essi on i s typi cal l y wi thdrawn to enhance a G VT effect, and i n some cases, a DLI i s gi ven (l ymphocytes fr om the or i gi nal stem cel l donor ). Thi s fr equentl y r esul ts i n G VHD, whi ch may al so be associ ated wi th a G VT r esponse. The most favorabl e r esponses to DLI have been seen i n pati ents wi th CML, especi al l y those i n the mol ecul ar or chr oni c phase of r el apse.

Nonmyeloablative Transplantation Nonmyel oabl ati ve transpl antati on (NST) r el i es pr i nci pal l y on the graft ver sus mal i gnancy effect. Instead of i ntense myel oabl ati ve pr eparati ve r egi mens, thi s techni que i ncor porates i mmunosuppr essi on to al l ow for engraftment of donor cel l s. The most common pr eparati ve r egi men consi sts of fl udarabi ne combi ned wi th an al kyl ati ng agent or l ow-dose TBI. Nonmyel oabl ati ve transpl ants may be per for med i n ol der adul ts (i .e., ol der than 60 year s) because r egi men-r el ated toxi ci ti es ar e l ess i n thi s case. A mi xtur e of donor and r eci pi ent hematopoi eti c cel l s i s pr esent just after transpl ant (cal l ed mixed chimer ism). As i mmune suppr essi on i s

r emoved, the sur vi vi ng r eci pi ent cel l s ar e gradual l y eradi cated by the donor i mmune system, ul ti matel y r esul ti ng i n ful l donor engraftment. G VT effects have been obser ved to occur i n CML, AML, chr oni c l ymphocyti c l eukemi a (CLL), l ymphoma, mul ti pl e myel oma, as wel l as i n sel ect metastati c sol i d tumor s. A number of smal l studi es have r ecentl y r epor ted that G VT effects may be obser ved i n pati ents wi th cytoki ne-r efractor y metastati c r enal cel l car ci noma. Di sease r egr essi on i s usual l y del ayed, occur r i ng 4 to 6 months after transpl antati on fol l owi ng the wi thdrawal of i mmunosuppr essi on and occur r i ng fr equentl y i n associ ati on wi th ei ther acute or chr oni c G VHD. Cl i ni cal tr i al s i nvesti gati ng G VT effects i n r enal cel l car ci noma and a var i ety of other metastati c sol i d tumor s ar e ongoi ng.

CONCLUSION HSC transpl antati on has dramati cal l y i mpr oved over the l ast several decades i nto an effecti ve therapeuti c tr eatment for a var i ety of mal i gnant and nonmal i gnant condi ti ons. The number of pati ents who benefi t fr om thi s pr ocedur e wi l l l i kel y i ncr ease as futur e transpl antati on strategi es conti nue to evol ve that l i mi t compl i cati ons whi l e maxi mi z i ng benefi ci al donor i mmune-medi ated graft-ver sus-mal i gnancy effects.

SUGGESTED READINGS Amer i can Soci ety of Bl ood and Mar r ow Transpl antati on. Web si te http://www.asbmt.or g 2004. Bar r ett AJ, Rez vani K, Sol omon S, et al . New devel opments i n al l otranspl ant i mmunol ogy. In: Br oudy V, Pr chal J, Tr i cot G , eds. Hematology 2003: the Amer i can Soci ety of Hematol ogy educati on pr ogram book. Washi ngton, DC: Amer i can Soci ety of Hematol ogy, 2003:350–371. http://www.hematol ogy.or g. Bensi nger W, Mar ti n P, Stor er B, et al . Transpl antati on of bone mar r ow as compar ed to per i pheral -bl ood cel l s fr om HLA-i denti cal r el ati ves i n pati ents wi th hematol ogi cal cancer s. N Engl J Med 2001;344:175–181.

Center s for Di sease Contr ol and Pr eventi on. G ui del i nes for

pr eventi ng oppor tuni sti c i nfecti ons among hematopoi eti c stem cel l transpl ant r eci pi ents: r ecommendati ons of the CDC, the Infecti ous Di sease Soci ety of Amer i ca, and the Amer i can Soci ety of Bl ood and Mar r ow Transpl antati on. MMWR Mor b Mor tal Wkly Rep 2000;49(No. RR-10):1–125. Champl i n R, Khour i I, Kor nbl au S, et al . Al l ogenei c hematopoi eti c stem cel l transpl antati on as adopti ve i mmunotherapy: i nducti on of graft-ver sus-mal i gnancy as pr i mar y therapy. Hematol Oncol Clin Nor th Am 1999;13:1041–1057. Chi l ds R, Cher noff A, Contenti n N, et al . Regr essi on of metastati c r enal -cel l car ci noma after nonmyel oabl ati ve al l ogenei c per i pheral -bl ood stem-cel l transpl antati on. N Engl J Med 2000;343:750–758. Hur l ey C, Lowe L, Logan B, et al . Nati onal Mar r ow Donor Pr ogram HLA-matchi ng gui del i nes for unr el ated mar r ow transpl ants. Biol Blood Mar r ow Tr ansplant 2003;9:610–615. Inter nati onal Bone Mar r ow Transpl ant Regi str y. Web si te http://www.i bmtr.or g 2004. Nati onal Mar r ow Donor Pr ogram. Web si te http://www.mar r ow.or g. 2004

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 1 0 - O t he r M a ligna nc ie s > 3 1 - Ac quire d Im m uno de fic ie nc y Sy ndro m e – Re la t e d M a ligna nc ie s

31 Acquired Immunodeficiency Syndrome– Related Malignancies Pallavi P. Kumar Richard F. Little HIV and AIDS Malignancy Br anch, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Indi vi dual s wi th human i mmunodefi ci ency vi r us (HIV) i nfecti on ar e at i ncr eased r i sk for devel opi ng neopl asti c di sease. The cl i ni cal behavi or of speci fi c mal i gnanci es i s often mar kedl y al ter ed i n the setti ng of HIV i nfecti on as compar ed to the HIV-negati ve counter par t. Thr ee neopl asms ar e consi der ed as acqui r ed i mmunodefi ci ency syndr ome (AIDS)–defi ni ng condi ti ons when they occur i n HIVi nfected pati ents: 1. Kaposi sar coma (KS) 2. Aggr essi ve B-cel l non-Hodgki n l ymphoma, both per i pheral and pr i mar y central ner vous system (CNS) l ymphomas 3. Cer vi cal cancer. A number of other cancer s that ar e not consi der ed AIDS-defi ni ng occur wi th i ncr easi ng fr equency i n HIV-i nfected pati ents, i ncl udi ng Hodgki n di sease (HD), mul ti centr i c Castl eman di sease, angi osar coma, mul ti pl e myel oma, brai n cancer, l ung cancer, and semi noma. Hi ghl y acti ve anti r etr ovi ral therapy (HAART) for HIV i nfecti on has r esul ted i n fewer AIDS compl i cati ons, i ncl udi ng mal i gnanci es.

1. Ther e i s no cur e for AIDS, but HAART i ncr eases l ongevi ty, ther eby i ncr easi ng the pr eval ence of peopl e l i vi ng wi th HIV and AIDS. 2. Cancer pr eval ence i n the HIV-i nfected popul ati on may be expected to i ncr ease over ti me.

KAPOSI SARCOMA Epidemiology KS was fi r st descr i bed i n 1872 by Mor i tz Kaposi . KS i s the most common HIV-associ ated tumor. Ther e ar e four epi demi ol ogi c for ms of KS: 1. Cl assi c KS a. Thi s i s found pr edomi natel y i n el der l y men of the Medi ter ranean and Easter n Eur ope. 2. Epi demi c KS a. In Afr i ca, especi al l y i n the Ni l e–Congo water shed, KS i s the most commonl y di agnosed tumor. b. KS can be aggr essi ve i n chi l dr en, i nvol vi ng the l ymph nodes, i nter nal or gans, and ski n. c. The ser opr eval ence of Kaposi sar coma–associ ated her pesvi r us (KSHV) exceeds 60% i n some par ts of subSaharan Afr i ca (see subsequent text). 3. AIDS-r el ated KS a. AIDS-r el ated KS heral ded the emer gi ng AIDS epi demi c i n 1981. i. Thi s pr evi ousl y rar e tumor was suddenl y seen wi th an unexpectedl y hi gh pr eval ence i n young gay men, a popul ati on pr evi ousl y unaffected by thi s di sease. i i. Coi nfecti on wi th HIV i ncr eases the r i sk of KS by mor e than 100,000 ti mes, and the cl i ni cal cour se can be mor e aggr essi ve than that of cl assi cal KS. b. In the devel oped wor l d, the i nci dence of KS i s hi ghest among men who have sex wi th other men (MSM) and wi th thei r femal e sex par tner s. In the ear l y stages of the

epi demi c, KS was the AIDS-defi ni ng di agnosi s i n near l y 50% of HIV-i nfected MSM. c. Cur r entl y, KS i s the AIDS-defi ni ng di agnosi s i n l ess than 11% of HIV-i nfected MSM; the r easons for thi s i ncl ude i. a change i n the case defi ni ti on of AIDS i n 1992 that i ncl uded l ess than 200 CD4 cel l s per mm3 i i. safer sex practi ces possi bl y l eadi ng to a decr ease i n KSHV transmi ssi on i i i. i nducti on of i mmune r econsti tuti on by HAART, whi ch can l ower the r i sk of devel opi ng AIDS-r el ated KS. 4. Immune suppr essi on fr om other causes (e.g., i atr ogeni c i mmune suppr essi on i n sol i d or gan transpl antati on) can al so i ncr ease the r i sk of KS i n i ndi vi dual s i nfected wi th KSHV.

Pathophysiology of Kaposi Sarcoma Kaposi sar coma i s an angi opr ol i ferati ve l esi on caused by KSHV, al so known as human her pesvi r us 8 (HHV-8). Thi s novel gammaher pes vi r us was di scover ed i n 1994. It encodes for a number of vi ral mi mi cs of human cytoki nes and other factor s i nvol ved i n KS pathogenesi s. Inter l euki n 6 (IL-6), macr ophage i nhi bi tor y pr otei n, and i nter fer on r egul ator y factor upr egul ates vascul ar endothel i al gr owth factor (VEG F ) and i ts r eceptor s. KSHV-i nfected spi ndl e-shaped cel l s ar e most l i kel y of vascul ar endothel i al or i gi n. KSHV-dr i ven pr oangi ogeni c factor s pr omote endothel i al cel l hyper pr ol i ferati on and spi ndl e-l i ke mor phogenesi s. KS endothel i al /spi ndl e cel l s r espond to i. basi c fi br obl ast gr owth factor (bF G F ) i i. VEG F Most cel l s ar e l atentl y i nfected and expr ess l atencyassoci ated nucl ear anti gen (LANA). LANA pr omotes cel l sur vi val by i nteracti ng wi th the tumor suppr essor pr otei n p53. LANA i nteracts wi th p53 and i nhi bi ts i ts abi l i ty to pr omote apoptosi s, ther eby contr i buti ng to vi ral per si stence

and oncogenesi s i n KS. Some cel l s show l yti c i nfecti on. Transmi ssi on r outes have not been establ i shed. The possi bi l i ti es i ncl ude mother to i nfant, chi l d to chi l d, and sexual transmi ssi on. Sal i va contai ns hi gh concentrati ons of KSHV. KSHV appear s to be transmi tted i neffi ci entl y by transfusi on of bl ood pr oducts. It i s an angi opr ol i ferati ve neopl asti c di sease. The vascul ar i ty of the l esi on gi ves i t a pur pl i sh appearance. The l esi ons can be fl at or nodul ar. Lymphadenopathy and edema may be pr esent i n the absence of cutaneous i nvol vement. KS ar i ses si mul taneousl y i n mul ti pl e nonmetastati c si tes. Ski n i nvol vement i s typi cal , but vi r tual l y any i nter nal or gan except the brai n can be affected.

Diagnosis KS i s di agnosed usi ng the fol l owi ng techni ques: A 4- to 6-mm ski n punch bi opsy: Extensi ve sur gi cal exci si on i s not r equi r ed and may not be cl i ni cal l y useful . Di ffer enti al di agnosi s: Baci l l ar y angi omatosi s, mel anoma, granul omatous condi ti ons, or pr omi nent vascul ar i ty i n the l ymph nodes. HIV ser ol ogy shoul d be obtai ned whenever KS i s suspected.

Clinical Presentation Var i abl e cl i ni cal cour se Indol ent waxi ng and wani ng of cutaneous i nvol vement. Rel entl ess pr ogr essi on wi th ul cerati on, sever e tumorassoci ated edema, pai n, and di sfi gur ement. Pati ents wi th mi ni mal KS may r equi r e no tr eatment unl ess the

psychol ogi cal i mpact, whi ch can be sever e, war rants therapy. Extensi ve pul monar y i nvol vement may be associ ated wi th a par ti cul ar l y poor pr ognosi s (medi an sur vi val l ess than 7 months i n the pr e-HAART era). Substanti al mor bi di ty and death can ensue fr om i nvol vement of other vi scera (e.g., gastr oi ntesti nal tract).

Kaposi Sarcoma Staging The TIS stagi ng system (see Tabl e 31.1), devi sed by the AIDS Cl i ni cal Tr i al s G r oup Oncol ogy Commi ttee, i s commonl y used. 1. T r efer s to tumor extent 2. I r efer s to i mmune status 3. S r efer s to other AIDS-r el ated systemi c i l l ness. The TIS system stages pati ents, overal l , as bei ng ei ther at good r i sk, desi gnated by the subscr i pt 0, or at poor r i sk, desi gnated by the subscr i pt 1, the summar y taki ng the for m T0 o r 1 I 0 o r 1 S 0 o r 1. In the HAART era, two di ffer ent r i sk categor i es have been i denti fi ed 1. G ood r i sk (T0 S 0 , T1 S 0 , T0 S 1 ) 2. Poor r i sk (T1 S 1 ). The i mmune status of the two r i sk categor i es appear s not to be pr edi cti ve. Thi s most l i kel y depends on the effecti veness of HAART; the or i gi nal TIS may be mor e appl i cabl e for pati ents wi th mul ti dr ug-r esi stant HIV i nfecti on. The stagi ng of KS i ncl udes (a) enumerati on and bi di r ecti onal measur ement of cutaneous and oral l esi ons; (b) basel i ne chest x-ray: i f thi s i s abnor mal , computer i zed tomography (CT) scan of the chest shoul d be per for med; (c) CD4 cel l count; (d) endoscopy i f symptoms r eferabl e to the gastr oi ntesti nal (G I) tract ar e pr esent. 1. Lesi ons shoul d be character i zed as a. fl at or nodul ar b. l esi ons wi th or wi thout tumor-associ ated edema.

2. If ther e ar e mor e than 50 cutaneous l esi ons, r epr esentati ve ar eas contai ni ng at l east 20 l esi ons ar e desi gnated for i ndi vi dual l esi on assessment for r esponse to therapy. 3. Abnor mal i ti es on chest CT may i ndi cate pul monar y i nvol vement by KS. Br onchoscopi c eval uati on can establ i sh the di agnosi s of pul monar y KS i f l esi ons ar e vi sual i zed i n the ai r ways. Endobr onchi al or open l ung bi opsy shoul d be avoi ded, because of r i sk of hemor r hage.

TABLE 31.1. Revised Acquired Immunodeficiency Syndrome Clinical Trial Group (ACTG) staging classification for Kaposi sarcomaa

Good risk (0) (all of the following)

Tumor (T)

Immune system (I) (May not

Confined to skin and/or lymph nodes and/or nonnodular oral disease confined to the palate

Poor risk (1) (any of the following) Tumorassociated edema or ulceration Extensive oral KS Nonnodal viscera

be predictive in those responding to HAART b )

Systemic illness (S)

CD4 count ≥150/mm 3

CD4 count 10% involuntary weight loss, or diarrhea) persisting for more than 2 wk. Performance status Se c t io n 1 0 - O t he r M a ligna nc ie s > 3 3 - C e nt ra l Ne rv o us Sy s t e m Tum o rs

33 Central Nervous System Tumors Patrick J. Mansky* J. Paul Duic† How ard A . Fine‡ *National Center for Complementar y and Alter native Medicine, National Institutes of Health Bethesda, Mar yland † Depar tment

of Emer gency Medicine, Johns Hopkins Univer sity Baltimor e, Mar yland ‡ Neur o-Oncology

Br anch, National Cancer Institute and National Institute of Neur ologic Disor der s, National Institutes of Health Bethesda, Mar yland Pr i mar y brai n tumor s r epr esent a di ver se spectr um of di seases that uni for ml y pose a uni que pr obl em to the practi ti oner because of thei r i ntracrani al l ocati on. Brai n tumor s r epr esent the second most common neur ol ogi c cause of death after str oke, but onl y the tenth most common cause of death fr om cancer. Never thel ess, they ar e a major cause of mor tal i ty fr om cancer i n young adul ts and chi l dr en. Most adul t brai n tumor s occur i n the cer ebral hemi spher es, but two thi r ds of al l pedi atr i c brai n tumor s ar e i nfratentor i al . Dur i ng autopsy, metastati c brai n tumor s can be found i n 25% to 40% of pati ents wi th systemi c cancer. Ear l y detecti on and accuracy of di agnosi s have mar kedl y i mpr oved because of advances i n computer i zed tomography (CT) and magneti c r esonance i magi ng (MRI). Despi te the i mpr ovements, the pr ognosi s for most for ms of mal i gnant brai n tumor s r emai ns extr emel y poor. The mai nstays of therapy r emai n sur ger y and radi ati on, wher eas chemotherapy i s benefi ci al onl y i n a sel ect gr oup of tumor s.

EPIDEMIOLOGY

Accor di ng to the Sur vei l l ance, Epi demi ol ogy, and End Resul ts (SEER) r egi str y for 1973 thr ough 1987, the range of i nci dence of brai n tumor s i s 2 to 19 cases per 100,000 per sons per year, dependi ng on age at di agnosi s. Peak age: 0 to 4 year s, 3.1 per 100,000 per sons Pl ateau: 65 to 79 year s, 17.9 to 18.7 per 100,000 per sons 17,000 to 20,000 new cases per year Pr i mar y brai n tumor s compr i se 2% of newl y di agnosed mal i gnanci es per year i n the Uni ted States.

Distribution The most common central ner vous system (CNS) tumor s ar e der i ved fr om gl i al pr ecur sor s. The di str i buti on of tumor fr equency by age i s demonstrated i n Tabl e 33.1.

TABLE 33.1. Distribution of Tumor Frequ Age (yr) Histology

0–9

10– 19

20– 29

30– 39

Astrocytoma

60%

59%

76%

81%

Low-grade

10%

7%

5%

5%

Anaplastic

47%

43%

51%

55%

GBM

1%

7%

14%

18%

Mixed glioma

3%

4%

5%

6%

Oligodendroglioma

1%

4%

5%

6%

Ependymoma

9%

3%

4%

2%

21%

10%

6%

2%

Embryonal/teratoid

1%

1%

0%

0%

Meningioma

0%

0%

1%

2%

Medulloblastoma

GBM, glioblastoma multiforme. From DeVita VT Jr, Hellman S, Rosenberg SA, eds. and practice of oncology, 6th ed. Philadelphia: Lipp 2001, with permission.

Mortality Ther e ar e an esti mated 13,000 deaths fr om pr i mar y brai n tumor s per year. CNS tumor s ar e the most pr eval ent sol i d tumor s i n chi l dhood. In chi l dr en younger than 15 year s, brai n tumor s ar e the most fr equent cancer-r el ated causes of death. In the age gr oup 15 to 59 year s, CNS tumor s ar e the thi r d l eadi ng cause of cancer-r el ated deaths. However, 80% of al l pr i mar y brai n tumor– r el ated deaths occur i n pati ents ol der than 59 year s.

CLINICAL DIAGNOSIS Common Symptoms (By Decr easi ng F r equency): Headache Sei z ur e Cogni ti ve/per sonal i ty changes Focal weakness Nausea/vomi ti ng

Speech abnor mal i ti es Al ter ed consci ousness Common Si gns (By Decr easi ng F r equency): Hemi par esi s Crani al ner ve pal si es Papi l l edema Cogni ti ve dysfuncti on Sensor y defi ci ts Hemi anesthesi a Hemi anopi a Dysphasi a

DIFFERENTIAL DIAGNOSIS Tumor s of the cer ebr um may be di ffer enti ated by l ocati on accor di ng to age at onset of symptoms (see Tabl e 33.2 and F i g. 33.1).

FIG. 33.1. Topol ogi c di str i buti on and pr efer r ed si tes of pr i mar y central ner vous system tumor s. (F r om Bur ger PC, Schei thauer BW, Vogel F S. Sur gi cal pathol ogy of the ner vous system and i ts cover i ngs, 3r d ed. New Yor k: Chur chi l l Li vi ngstone, 1991, wi th per mi ssi on.)

TABLE 33.2. Differential Diagnosis Location

Adult

Chil

Metastatic disease

Astrocytom

Glioblastoma

Glioblastom

Astrocytoma

Oligodendr

Meningioma

Sarcoma

Oligodendroglioma

Neuroblast

Mixed glioma

Mixed gliom

Metastatic disease

Astrocytom

Astrocytoma

Medullobla

Glioblastoma

Ependymom

Supratentorial

Infratentorial

Ependymoma Brainstem Brainstem glioma Pituitary tumor

Craniophar

Meningioma

Optic gliom

Sellar/parasellar

Neurinoma Meningioma Base of skull

Chordoma

Epidermoid

Carcinoma Dermoid/epidermoid

Acute Complications of Intracranial Tumors Because the skul l 's r i gi d natur e does not al l ow for pr ocesses associ ated wi th i ntracrani al expansi on, brai n l esi ons r outi nel y r esul t i n str uctural di spl acement and l i fe-thr eateni ng consequences. Fol l owi ng the path of l east r esi stance, tentor i al or foramen magnum her ni ati on may ensue. Neur ol ogi c fi ndi ngs ar e descr i bed i n Tabl es 33.3 and 33.4.

TABLE 33.3. Neurologic Findings Tentorial/temporal lobe herniation Pupillary dilation Ptosis Ipsilateral hemiplegia Contralateral hemiplegia Homonymous hemianopia Midbrain syndrome Coma with rising blood pressure/bradycardia

TABLE 33.4. Neurologic Findings Cerebellar/foramen magnum herniation Head tilt Stiff neck Neck paresthesias Tonic tensor spasms of limbs and body Coma Respiratory arrest

PRIMARY BRAIN TUMORS VERSUS BRAIN METASTASES Primary BrainTumors Gliomas Four major types of gl i omas have been r ecogni zed on the basi s of thei r pr esumed nor mal gl i al cel l of or i gi n: 1. Astr ocytoma 2. Ol i godendr ocytoma 3. Ol i goastr ocytoma (mi xed gl i oma) 4. Ependymoma

Grading The pathol ogi c cl assi fi cati on of pr i mar y brai n tumor s has been a contr over si al and constantl y changi ng ar ea secondar y to the l ack of pr ognosti c r el evance for most cl assi fi cati on systems. In addi ti on, the consi derabl e i ntraobser ver var i abi l i ty between neur opathol ogi sts i n assessi ng the speci fi c hi stol ogi c subtypes of a gi ven tumor, secondar y to the subjecti ve cr i ter i a of each pathol ogi c cl assi fi cati on schema, has made the cl assi fi cati on of brai n tumor s even mor e confusi ng. A pathol ogi c gradi ng system r ecentl y pr oposed by the Wor l d Heal th Or gani z ati on (WHO) has been general l y accepted by most neur opathol ogi sts and i ncor porates the fol l owi ng featur es for deter mi ni ng the grade (l evel of aggr essi veness) of each hi stol ogi c subtype of tumor : Cel l ul ar atypi a Mi toti c acti vi ty Degr ee of cel l ul ar i ty Vascul ar pr ol i ferati on Degr ee of necr osi s A general cl assi fi cati on of pr i mar y brai n tumor s can be found i n the subsequent text: Grade 1 Pi l ocyti c astr ocytoma G i ant cel l astr ocytoma G angl i ogl i oma Dysembr yopl asti c neur oepi thel i al tumor s Grade 2 Wel l -di ffer enti ated l ow-grade astr ocytomas Ol i godendr ogl i omas Ependymomas Grade 3

Anapl asti c astr ocytomas (AAs) Anapl asti c ol i godendr ogl i omas Anapl asti c ependymal tumor s Grade 4 G l i obl astoma mul ti for me (G BM) Embr yonal tumor s

Epidemiology G l i omas compr i se 45% of al l i ntracrani al tumor s, wi th peak age i n the seventh decade. Tabl e 33.5 shows the pr eval ence of the pathol ogi c subtypes of gl i omas i n r el ati on to other mor e common pr i mar y brai n tumor s.

TABLE 33.5. Epidemiology Type

%

Glioblastoma

55.0

Astrocytoma

20.5

Ependymoma

6.0

Medulloblastoma

6.0

Oligodendroglioma

5.0

Choroid plexus papilloma

2.0

Colloid cyst

2.0

Molecular Genetics of Gliomas G eneti c al terati ons for m a conti nuum of pr ogr essi ve anapl asi a i n gl i omas (see Tabl e 33.6). Wher eas secondar y or pr ogr essi ve gl i omas often har bor mutati ons of p53 and over expr essi on of the pl atel et-der i ved gr owth factor (PDG F ) r eceptor, they sel dom show ampl i fi cati on of epi der mal gr owth factor r eceptor (EG F R). By contrast, pr i mar y or de novo G BM usual l y l ack p53 mutati ons and contai n an ampl i fi ed EG F R. To date, none of the mol ecul ar parameter s has demonstrated any si gni fi cant associ ati on wi th pati ent sur vi val i n G BM.

TABLE 33.6. Molecular Genetics of Glioma Genetic alteration

Anaplasia

Glio vari

TP53 mutation PDGF overexpression

Low-grade

Loss of chromosome 17p and 22q CDKN2/p16 deletion RB mutation CDK4 amplification Loss of chromosome 9p, 19q, 11p

Anaplastic astrocytoma

Low-gr astrocy

MDM2 amplification/overexpression EGFR amplification rearrangements

High-grade GBM

PTEN mutation Loss of chromosome 10 GBM, glioblastoma multiforme; EGFR, epidermal gr factor receptor.

Glioblastoma Multiforme G BM i s the most common adul t pr i mar y brai n tumor, accounti ng for 10% to 15% of i ntracrani al tumor s. The age of peak i nci dence i s 45 to 55 year s; overal l i nci dence i s two to thr ee per 100,000 popul ati on; sex di str i buti on, mal e-tofemal e rati o i s 3:2. Medi an sur vi val i s 6 months.

Localization G BM occur s equal l y ever ywher e i n the brai n and i s pr opor ti onal to the vol ume of brai n ti ssue i n that par ti cul ar anatomi c l ocati on. It i s mor e l i kel y to be bi hemi spher i c than other types of tumor s ar e.

Development Devel opment of G BM i s de novo (“pr i mar y”) or i s a pr ogr essi on fr om a l ower grade pr ecur sor l esi on (“secondar y”).

Genetics p53 mutati ons EG F R ampl i fi cati on Loss of heter oz ygosi ty (LOH) on chr omosome 10; phosphatase and tensi n homol og (PTEN) del eti ons LOH on chr omosome 17p Si gni fi cant aneupl oi dy

Imaging Characteristics on Magnetic Resonance Imaging Heter ogeneous hypoi ntense or i soi ntense mass on CT scan or on Tesl a 1 (T1, r el axati on ti me 1) MRI. Heter ogeneousl y contrast-enhanci ng mass Hyper vascul ar appearance Cal ci fi cati ons ar e rar e

Differential Diagnosis Brai n metastasi s Cer ebral abscess Demyel i nati ng/i nfl ammator y pr ocess (i .e., mul ti pl e scl er osi s) Radi ati on necr osi s Si ngl e photon emi ssi on computer i zed tomography (SPECT) and MR cer ebral per fusi on i magi ng may be used to di sti ngui sh radi ati on necr osi s (hypovascul ar ) fr om tumor r ecur r ence (hyper vascul ar ) MR spectr oscopy i s bei ng i ncr easi ngl y used to hel p di sti ngui sh tumor fr om other pr ocesses that ar e vi sual i zed on MRI. G l i osar coma i s a var i ant, wi th a mesenchymal component and a gr eater tendency for dural i nvasi on.

G BMs ar e character i sti cal l y i nfi l trati ve wi thi n brai n par enchyma but rar el y show extracer ebral metastasi s.

Therapy Cur r ent tr eatment r ecommendati ons for mal i gnant gl i omas (i .e., hi gh-grade astr ocytomas and G BM) i ncl ude sur gi cal r esecti on, adjuvant radi otherapy, and, i n sel ect pati ents, the addi ti on of chemotherapy. Secondar y to the i nfi l trati ve gr owth character i sti cs of mal i gnant gl i omas, tumor s r ecur even after gr oss total pr i mar y r esecti on. An anal ysi s of several Radi ati on Therapy Oncol ogy G r oup (RTOG ) tr i al s cr eated the sur vi val categor i es accor di ng to pati ent character i sti cs, as shown i n Tabl e 33.7.

TABLE 33.7. Survival Categories by Patient Characteristics Patient characteristics Age 50 yr, KPS >70, symptoms >3 mo Age 50 yr, symptoms 50 yr

Age 70 Age >50 yr, KPS Ta ble o f C o nt e nt s > Se c t io n 1 0 - O t he r M a ligna nc ie s > 3 4 - Endo c rine Tum o rs

34 Endocrine Tumors Michael E. Menefee* Tito Fojo† *Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland † Cancer

Ther apeutics Br anch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Endocr i ne tumor s ar e r el ati vel y uncommon. These tumor s may cause mor bi di ty and mor tal i ty not onl y by l ocal and di stant spr ead of tumor cel l s but al so thr ough medi ator s pr oduced by the tumor cel l s that may have systemi c effects. The tumor s ar e often di ffi cul t to di agnose and tr eat effecti vel y. Thi s chapter di scusses 1. thyr oi d cancer 2. cancer of the parathyr oi d gl and 3. adr enocor ti cal cancer 4. pheochr omocytoma 5. pancr eati c endocr i ne tumor s 6. car ci noi d tumor s 7. mul ti pl e endocr i ne neopl asi a (MEN). The epi demi ol ogy of endocr i ne tumor s i s outl i ned i n Tabl e 34.1.

TABLE 34.1. Incidence and Proportion of all Endocrine Cancers and Relative Proportions

of Different Primary Thyroid Cancer Subtypes Total (%)

Number All endocrine cancers Thyroid

18,100

91

Endocrine pancreas

800

4

Adrenal

550

2.8

Thymus

425

2.1

Pineal gland

128

0.6

Pituitary gland

77

0.4

Parathyroid

48

0.2

Carotid body, paraganglia

33

0.16

Primary thyroid cancers Well differentiated

87–90

Papillary

75

Follicular

10

Hörthle cell

2–4

Anaplastic

1–2

Medullary thyroid cancer

5–9

Sporadic

6

Familial

3

Lymphoma

1–3

Sarcoma and others

45 yr Any T, any N,

Medullary Anaplastic

Age 3 cm, suggesti ve of car ci noma El evated parathyr oi d hor mone l evel s Vocal cor d paral ysi s i n mor e advanced di sease Si tes of metastases: l ungs, cer vi cal l ymph nodes, and l i ver.

Diagnostic Evaluation Di ffer enti al i ncl udes parathyr oi d adenoma and hyper pl asi a, wi th car ci noma bei ng suggested by a l ar ge neck mass and mar kedl y el evated cal ci um l evel s. Most cases ar e di agnosed at sur ger y; however, some cases ar e not di agnosed unti l after the i ni ti al r esecti on has been compl eted or unti l the ti me of l ocal r ecur r ence or metastases. F i ne needl e aspi rati on (F NA) i s i nappr opr i ate for di agnosi s.

Treatment Sur gi cal Pr i mar y modal i ty consi sts of an en bloc r esecti on of the tumor and i nvol ved str uctur es, as wel l as of the i psi l ateral l obe of thyr oi d. Recur r ent tumor and ol i gometastases shoul d be r esected as wel l . Medi cal Chemotherapy i s of l i mi ted val ue. Agents wi th acti vi ty i ncl ude DTIC (dacar baz i ne); 5fl uor ouraci l ; cycl ophosphami de. Management of hyper cal cemi a i s essenti al whi l e tr eati ng parathyr oi d car ci noma. Radi ati on Tumor s ar e general l y radi oi nsensi ti ve. Radi ati on onl y has a pal l i ati ve benefi t.

ADRENAL CORTICAL CARCINOMA Epidemiology Adr enal cor ti cal car ci noma i s rar e; i t accounts for 0.05% to 0.2% of al l cancer s. It shows a bi modal age di str i buti on, wi th the fi r st peak i n chi l dr en younger than 5 year s and wi th a second peak i n adul ts i n thei r four th to fi fth decade.

Natural History The 5-year sur vi val rate i s 23% . The 10-year sur vi val rate i s 10% . The pr ognosi s i s better i n chi l dr en. The common si tes of di stant spr ead ar e l i ver, l ungs, l ymph nodes, and bone.

Etiology The eti ol ogy of adr enal cor ti cal car ci noma i s not known.

Pathology Di ffer enti ati on between adenomas and car ci nomas can r epr esent a hi stol ogi c chal l enge. However, car ci nomas wi l l tend to di spl ay mi toti c acti vi ty, aneupl oi dy, and venous i nvasi on. Car ci nomas may al so secr ete abnor mal amounts of andr ogens and 11-deoxyster oi ds.

Staging MacFar l ane cl assi fi cati on of var i ous stages of adr enal cor ti cal car ci noma i s gi ven i n F i g. 34.3.

FIG. 34.3. MacFar l ane cl assi fi cati on. F r om DeVi ta VT, Hel l man JS, Rosenber g SA. Cancer : pr i nci pl es and practi ces of oncol ogy, 6th ed. Phi l adel phi a: Li ppi ncott-Raven, wi th per mi ssi on.

Clinical Manifestations Endocr i ne dysfuncti on: Featur es of hyper cor ti sol i sm Vi r i l i z ati on/femi ni z ati on Mi neral ocor ti coi d excess. Appr oxi matel y 50% of pati ents pr esent wi th evi dence of hor monal excess. Symptoms ar i si ng fr om l ocal mass effect or di stant metastases ar e evi dent.

Diagnostic Evaluation Adr enal i nci dental omas ar e bei ng detected mor e often, wi th i mpr oved qual i ty and wi th mor e fr equent uti l i z ati on of i magi ng studi es. See F i g. 34.4.

FIG. 34.4. Eval uati on of an adr enal mass i n a pati ent wi th suspected pheochr omocytoma. F r om DeVi ta VT, Hel l man JS, Rosenber g SA. Cancer : pr i nci pl es and practi ces of oncol ogy, 6th ed. Phi l adel phi a: Li ppi ncott-Raven, wi th per mi ssi on.

Bi ochemi cal eval uati on i s per for med i f cl i ni cal l y war ranted (i .e., ur i nar y ster oi ds, suppr essi on tests).

Treatment En bloc r esecti on i s appr opr i ate for al l stages i ni ti al l y, and fur ther sur gi cal r esecti on shoul d be attempted for l ocal r ecur r ence and for metastati c di sease whenever feasi bl e. Radi ofr equency abl ati on may be i mpl emented for l ocal contr ol or metastases i n pati ents wi th unr esectabl e di sease. Mi totane has i nduced hor monal r esponse rates i n up to 75% of pati ents wi th functi onal tumor s, wi thout any change i n overal l

sur vi val . Other acti ve agents i ncl ude doxor ubi ci n, etoposi de, and ci spl ati n.

PHEOCHROMOCYTOMA Epidemiology Pheochr omocytoma i s found i n l ess than 0.2% of al l pati ents wi th hyper tensi on. Cl assi cal l y, appr oxi matel y 10% of pheochr omocytomas ar e mal i gnant; however, the tr ue number may be hi gher. Appr oxi matel y 10% of pheochr omocytomas ar e bi l ateral ; i t tends to occur mor e fr equentl y i n the fami l i al syndr omes. Appr oxi matel y 10% of the di sease i s extraadr enal ; mal i gnancy i s mor e l i kel y to be found i n extraadr enal tumor s. Appr oxi matel y 10% of the di sease i s associ ated wi th a fami l i al geneti c syndr ome [e.g., MEN-2 or von Hi ppel –Li ndau (VHL)].

Natural History Pheochr omocytomas general l y ar e i ndol ent tumor s. It metastasi zes most commonl y to the l ungs, brai n, and bone. Mor bi di ty and mor tal i ty i s r el ated to the secr etor y pr oducts of the tumor.

Etiology The eti ol ogy of pheochr omocytoma i s not known.

Pathology Pheochr omocytomas ar i se fr om chr omaffi n cel l s, most of whi ch nest i n the adr enal medul l a.

Both mal i gnant and beni gn tumor s have the capabi l i ty of vascul ar i nvasi on and extensi on i nto the cor tex. The onl y absol ute cr i ter i on for mal i gnancy i s the pr esence of secondar y tumor s i n si tes wher e chr omaffi n cel l s do not usual l y exi st.

Clinical Manifestations The cl i ni cal featur es of pheochr omocytomas ar e summar i zed i n Tabl e 34.7.

TABLE 34.7. Clinical Features Mild labile hypertension to hypertensive crisis; sustained hypertension is also common Myocardial infarction Cerebral infarction Classic pattern of paroxysmal hypertension occurs in 30%–50% of cases Spells of paroxysmal headache Pallor or flushing Tremor Apprehension

Palpitation Orthostasis Mild weight loss Diaphoresis

Diagnostic Evaluation Metabol i c assessment: Twenty-four-hour ur i nar y catechol ami nes, vani l l yl mandel i c aci d (VMA), and metanephr i ne (most speci fi c) Cl oni di ne suppr essi on test i s r ecommended for i nter medi ate catechol ami ne l evel s. Catechol ami ne l evel s wi l l not be suppr essed i n pati ents wi th pheochr omocytoma. Radi ol ogi c assessment: Both computer i zed tomography (CT) scan and magneti c r esonance i magi ng (MRI) ar e equal l y sensi ti ve. Label ed metai odobenz yl guani di ne (1 3 1 I-MIBG ) i s str uctural l y si mi l ar to nor epi nephr i ne and i s taken up and concentrated i n adr ener gi c ti ssue. It i s hi ghl y sensi ti ve and speci fi c, par ti cul ar l y for mal i gnant tumor s and the fami l i al syndr omes. Bone scan i s super i or to metastases.

1 3 1 I-MIBG

i n detecti ng bone

Di agnosti c eval uati on hel ps to di ffer enti ate between beni gn and mal i gnant tumor s (Tabl e 34.7).

Treatment Surgical Sur ger y i s the mai nstay of tr eatment and shoul d be consi der ed

for pr i mar y, r ecur r ent, and metastati c di sease. Appr opr i ate pr eoperati ve eval uati on and α ± β-bl ockade ar e r equi r ed to mi ni mi ze r i sk of a hyper tensi ve cr i si s. The l apar oscopi c appr oach i s acceptabl e i f no obvi ous tumor i nvasi on or metastases ar e vi sual i zed dur i ng i magi ng studi es (see F i g. 34.5).

FIG. 34.5. Di agnosi s and tr eatment of pheochr omocytoma. (F r om Abel off MD, et al . Cl i ni cal oncol ogy, 3r d ed. Phi l adel phi a: El sevi er Chur chi l l Li vi ngstone, wi th per mi ssi on.)

Medical Chemotherapy Cycl ophosphami de, vi ncr i sti ne, and dacar baz i ne (CVD) Bi ochemi cal r esponse of 79%

F i fty-seven per cent r educti on i n measurabl e di sease Medi an durati on of r esponse i s gr eater than 20 months Smal l study (14 pati ents).

Radiation Radi ati on has a l i mi ted r ol e; i t may be used for bone metastases and soft-ti ssue metastases.

NEUROENDOCRINE TUMORS Neur oendocr i ne tumor s ar e rar e tumor s that ar e di sti ngui shed fr om many other sol i d tumor s by thei r abi l i ty to pr oduce bi ol ogi cal l y acti ve mol ecul es that can pr oduce systemi c syndr omes. The two pr i mar y subgr oups of neur oendocr i ne tumor s ar e car ci noi d tumor s and pancr eati c endocr i ne tumor s.

Carcinoid Tumors Epidemiology The i nci dence of car ci noi d tumor s i n the Uni ted States i s 1 to 2 cases per 100,000 i ndi vi dual s.

Natural History Abdomi nal and r ectal car ci noi ds tend to pr esent wi th tumor s of smal l si ze ( Ta ble o f C o nt e nt s > Se c t io n 1 1 - Suppo rt iv e C a re > 3 5 - He m a t o po ie t ic G ro w t h Fa c t o rs

35 Hematopoietic Growth Factors Philip M. A rlen James L. Gulley Labor ator y of Tumor Immunology and Biology, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Labor ator y of Tumor Immunology and Biology, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Hematol ogi c toxi ci ty fr om chemotherapy i s the most pr eval ent ser i ous si de effect encounter ed i n medi cal oncol ogy cl i ni cal practi ce. Reducti on i n al l thr ee cel l l i neages (i .e., whi te bl ood cel l s, r ed bl ood cel l s, and pl atel ets) can l ead to compl i cati ons such as fever, whi ch compl i cates neutr openi a and r equi r es pati ent hospi tal i z ati on, and sever e anemi a or thr ombocytopeni a, whi ch may necessi tate transfusi on. Al l thr ee cel l l i nes ar i se fr om di ffer enti ati on of toti potent hematopoi eti c stem cel l s; the ful l y di ffer enti ated cel l s ar e matur e l eukocytes, er ythr ocytes, or pl atel ets (the br eakdown pr oduct of megakar yoctes). Hematopoi eti c gr owth factor s ar e the r egul ator y mol ecul es for al l thr ee cel l l i nes. Several hematopoi eti c gr owth factor s have been i denti fi ed, synthesi zed, and appr oved for use i n cl i ni cal practi ce to mi ti gate hematol ogi c toxi ci ty caused by chemotherapy. Recommendati ons i n thi s chapter come pr i mar i l y fr om the evi dence-based cl i ni cal practi ce gui del i nes of the Amer i can Soci ety of Cl i ni cal Oncol ogy (ASCO) (1,2,3). In many cl i ni cal si tuati ons, hematopoi eti c gr owth factor i s used both judi ci ousl y (4) and i n a cost-effecti ve manner (5,6). New agents conti nue to be sought, devel oped, and eval uated i n cl i ni cal tr i al s.

MYELOID GROWTH FACTORS: GRANULOCYTE COLONY-STIMULATING FACTOR AND GRANULOCYTE MACROPHAGE COLONYSTIMULATING FACTOR Cur r entl y, two myel oi d gr owth factor s have been appr oved for cl i ni cal use by the U.S. Food and Dr ug Admi ni strati on (F DA). They ar e fi l grasti m (granul ocyte col ony-sti mul ati ng factor [G -CSF; Neupogen and Neul asta (Pegfi l grasti m)]; Amgen, Inc. and sar gramosti m (granul ocyte macr ophage col ony-sti mul ati ng factor [G M-CSF, Leuki ne; Ber l ex Laborator i es (Scher i ng AG )]. Wher eas G CSF i s speci fi c for the pr oducti on of neutr ophi l s, G M-CSF sti mul ates the pr oducti on of monocytes and eosi nophi l s i n addi ti on to neutr ophi l s. Ther e i s no fi r m cl i ni cal evi dence to i ndi cate that one agent pr oduces a super i or cl i ni cal benefi t over the other. Al though exogenous myel oi d gr owth factor decr eases the durati on of absol ute neutr openi a, i t does not affect the extent of the neutr openi a. F DAr ecommended doses of gr owth factor s ar e l i sted i n Tabl e 35.1.

TABLE 35.1. Summary of Growth Factor Indications Drug/FDArecommended dosing

Filgrastim 5 µg/kg/d s.c.— initiated 24 h after completion of chemotherapy— continued daily until the postchemotherapy

Indications

Cancer pts receiving myelosuppressive chemotherapy. Pts with nonmyeloid malignancy following BMT Pts with severe

ANC is = 10 × 109 cells/L—may require as many as 10–14 daily injections. For stem cell mobilization and transplant—10 µg/kg/d s.c. may be used.

Pegfilgrastim Single 6-mg fixed dose, once per chemotherapy cycle

Sargramostim Dose for chemotherapy-induced neutropenia is 250 µg/m 2 /d s.c Following autologous bone marrow transplant—250 µg/m 2 /d given by a 2hour i.v. infusion

chronic neutropenia following induction chemotherapy for AML mobilization of stem cells for transplant

Cancer pts receiving myelosuppressive chemotherapy

Following autologous BMT Delay or failure of BMT engraftment Following induction chemotherapy for AML in older pts Mobilization of stem cells for transplant

Epoetin α chemotherapy for nonmyeloid malignancies current FDA-approved recommended dose— 150 U/kg s.c. three times a wk—can be increased to 300 U/kg three times weekly if an adequate response (rise in hemoglobin = 1 g/dL) does not occur after 4 wk of therapy. 40,000 units s.c. weekly—well tolerated and as effective as a three times a week dosing. Darbopoetin α approved recommended starting dose is 2.25 µg/kg s.c. —dose should be adjusted to maintain a target hemoglobin

Chemotherapy induced anemia

Same as epoetin α

level – for a < 1.0 g/dL increase in hemoglobin after 6 wk of therapy, dose should be increased up to 4.5 µg/kg – if hemoglobin increases by more than 1.0 g/dL in a 2-wk period or exceeds 12 g/dL, the dose should be reduced by 25% – if hemoglobin exceeds 13 g/dL, doses should be temporarily withheld until the hemoglobin falls to 12 g/dL

Oprelvekin dose in adult is 50 µg/kg s.c. once daily therapy begins 6–24 h after chemotherapy is completed continues until the postnadir platelet count is = 50,000 µL.

Pts undergoing myelosuppressive chemotherapy for nonmyeloid malignancies who are at high risk for developing severe thrombocytopenia

FDA, U.S. Food and Drug Administration; pts, patients; ANC, absolute neutrophil count; BMT, bone marrow transplant; AML, acute myelogenous leukemia.

INDICATIONS Primary Prophylaxis Myel oi d gr owth factor s wer e i ni ti al l y r ecommended as pr i mar y pr ophyl axi s after a fi r st cycl e of chemotherapy for pati ents wi th a mor e than 40% pr obabi l i ty of exper i enci ng febr i l e neutr openi a (F N). Thi s was based upon the Lyman study that exami ned the cost of hospi tal i z ati on and the poi nt at whi ch G -CSF became a costeffecti ve opti on i n pr eventi ng F N (5). ASCO gui del i nes ar e cur r entl y bei ng updated to r efl ect the thr eshol d val ue of the pr obabi l i ty of exper i enci ng F N as bei ng gr eater than 20% to 25% , the val ue at whi ch i t cur r entl y becomes cost effecti ve to use gr owth factor s to pr event hospi tal i z ati on. Thi s pr obabi l i ty i ncl udes pati ents who ar e r ecei vi ng hi gh-dose chemotherapeuti c r egi mens. The use of gr owth factor s may be str ongl y consi der ed i n pati ents who ar e thought to be at hi gher r i sk for chemotherapy-i nduced i nfecti ous compl i cati ons because of (a) pr eexi sti ng neutr openi a caused by di sease, (b) extensi ve ear l i er chemotherapy, (c) pr evi ous i r radi ati on to ar eas contai ni ng l ar ge amounts of bone mar r ow, (d) a hi stor y of F N dur i ng ear l i er myel osuppr essi ve tr eatments that have been equal l y or l ess myel osuppr essi ve, or (e) condi ti ons that potenti al l y i ncr ease the r i sk of a ser i ous i nfecti on (e.g., poor per for mance status, decr eased i mmune functi on, open wounds, and pr eexi sti ng acti ve ti ssue i nfecti ons).

Secondary Prophylaxis To date, ther e have been no publ i shed r egi mens demonstrati ng a benefi t of ei ther di sease-fr ee sur vi val or overal l sur vi val to pati ents when CSF suppor t i s i mpl emented as a secondar y pr ophyl axi s al ong wi th dose-i ntense chemotherapy. Ther efor e, i n the absence of cl i ni cal data or other compel l i ng r easons for mai ntai ni ng the dose

i ntensi ty of chemotherapy, CSF suppor t shoul d be admi ni ster ed fol l owi ng F N or sever e or pr ol onged neutr openi a after a pr evi ous chemotherapy cycl e whi l e i mpl ementi ng conventi onal chemotherapy doses.

Treatment of Neutropenic Patients A number of cl i ni cal tr i al s str ongl y suppor t the r ecommendati on that gr owth factor s shoul d not be used r outi nel y for uncompl i cated fever and neutr openi a, whi ch ar e defi ned as fever for at l east 10 days; when ther e i s no evi dence of pneumoni a, cel l ul i ti s, abscess, si nusi ti s, hypotensi on, mul ti or gan dysfuncti on, or i nvasi ve fungal i nfecti on; and i n the absence of uncontr ol l ed mal i gnanci es (7,8,9,10,11,12,13,14). Al though a decr ease i n the per i od of neutr openi a [absol ute neutr ophi l count (ANC) 3 6 - Infe c t io us C o m plic a t io ns in O nc o lo gy

36 Infectious Complications in Oncology Sarah M. W ynne* Juan C. Gea-Banacloche † *Labor ator y of Immunor egulation, National Institute of Aller gy and Infectious Diseases, National Institutes of Health, Bethesda, Mar yland † Exper imental

Tr ansplantation and Immunology Br anch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland

FEVER IN NONNEUTROPENIC CANCER PATIENTS Pati ents wi th cancer may have fever for many r easons other than i nfecti on, i ncl udi ng the under l yi ng mal i gnancy, medi cati ons, bl ood pr oducts, and graft-ver sus-host di sease. Infecti ons, however, ar e a si gni fi cant pr obl em i n pati ents, r egar dl ess of the type of mal i gnancy and the stage of tr eatment. In addi ti on to neutr openi a, ther e ar e several other factor s that contr i bute to i ncr eased suscepti bi l i ty to i nfecti on. Local factor s i ncl ude br eakdown of bar r i er s (i .e., mucosi ti s and sur ger y) that pr ovi de a por tal of entr y for bacter i a, and obstr ucti on (i .e., bi l i ar y obstr ucti on, ur eteral obstr ucti on, and br onchi al obstr ucti on) that faci l i tates l ocal i nfecti on (e.g., chol angi ti s, pyel onephr i ti s, and postobstr ucti ve pneumoni a). Intravascul ar devi ces, drai nage tubes, or stents may become col oni zed by mi cr oor gani sms and may l ead to l ocal i nfecti on, bacter emi a, or fungemi a. Spl enectomy i ncr eases the suscepti bi l i ty to i nfecti on caused by Str eptococcus pneumoniae and other encapsul ated bacter i a.

Defi ci enci es of humoral i mmuni ty (e.g., mul ti pl e myel oma and chr oni c l ymphoi d l eukemi a) l ead to i ncr eased suscepti bi l i ty to encapsul ated or gani sms such as S. pneumoniae and Haemophilus influenz ae. Defects i n cel l -medi ated i mmuni ty (e.g., l ymphoma, hai r y cel l l eukemi a, tr eatment wi th ster oi ds, fl udarabi ne and other dr ugs, and T-cel l –depl eted hematopoi eti c stem cel l transpl antati on) i ncr ease the suscepti bi l i ty to oppor tuni sti c i nfecti ons fr om Legionella pneumophila, Mycobacter ium speci es, Cr yptococcus neofor mans, Pneumocystis jir oveci, cytomegal ovi r us (CMV), var i cel l a-zoster vi r us (VZV), and other pathogens.

Antibiotic Therapy in Nonneutropenic Cancer Patients Anti bi oti cs shoul d be admi ni ster ed empi r i cal l y i n cases of fever i n pati ents wi th cancer who do not exhi bi t neutr openi a onl y when a bacter i al i nfecti on i s consi der ed l i kel y. In the absence of l ocal i z i ng si gns and symptoms, bacter emi a shoul d be consi der ed, par ti cul ar l y i n pati ents wi th i ntravascul ar devi ces. Many author i ti es r ecommend empi r i c anti bi oti cs (e.g., l evofl oxaci n and ceftr i axone) unti l bacter emi a i s r ul ed out. Cl i ni cal l y documented i nfecti ons and sepsi s shoul d be tr eated wi th anti bi oti cs as war ranted by the cl i ni cal scenar i o. Whenever anti bi oti cs ar e star ted, a pl an wi th speci fi c endpoi nts shoul d be for mul ated to avoi d unnecessar y toxi ci ty, super i nfecti on, and devel opment of r esi stance.

FEVER IN NEUTROPENIC CANCER PATIENTS Neutr openi a i s the most i mpor tant r i sk factor for devel opi ng bacter i al i nfecti on i n pati ents wi th cancer. The r i sk of devel opi ng i nfecti on i ncr eases wi th the rapi di ty of onset and wi th the degr ee and durati on of neutr openi a. Pati ents wi th febr i l e neutr openi a r equi r e i mmedi ate eval uati on and pr ompt i ni ti ati on of empi r i c anti bi oti cs (see F i g. 36.1). Empi r i c br oad-spectr um anti bi oti cs wi th acti vi ty agai nst Pseudomonas aer uginosa must be i ni ti ated as soon as the cl i ni cal eval uati on i s compl eted.

FIG. 36.1. Appr oach to pati ents wi th fever and neutr openi a, wi thout cl i ni cal l y or mi cr obi ol ogi cal l y documented i nfecti on. For speci fi c i nfecti ons, see text and Tabl e 36.2. *Vancomyci n shoul d be di sconti nued after 48–72 hour s i f ther e i s no bacter i ol ogi cal documentati on of a pathogen r equi r i ng i ts use, except i n softti ssue or tunnel i nfecti ons. † Thi s “r escue” anti bacter i al r egi men wi l l var y between i nsti tuti ons dependi ng on the l ocal patter ns of anti bi oti c r esi stance. Car bapenem + fl uor oqui nol one/ami nogl ycosi de + vancomyci n i s typi cal . ‡ For a detai l ed di scussi on of anti fungal therapy opti ons, see text. MRSA, methi ci l l i n (oxaci l l i n)-r esi stant Staphylococcus aur eus; PRSP, peni ci l l i n-r esi stant Str eptococcus pneumoniae; ANC,

absol ute neutr ophi l count.

Definitions Fever : an oral temperatur e hi gher than 38.3C or two oral temperatur es >38°C measur ed 1 hour apar t. Neutr openi a: an absol ute neutr ophi l count (ANC) 3 7 - G e ne ra l P rinc iple s o f C a nc e r Pa in M a na ge m e nt

37 General Principles of Cancer Pain Management Jason R. Beckrow* Richard A . Messmann† *Depar tment of Inter nal Medicine, Michigan State Univer sity, East Lansing, Michigan † Depar tment

of Hematology/Oncology, Michigan State Univer sity, East Lansing, Michigan Inappr opr i ate or i nadequate pai n management i s a consi derabl e pr obl em that r esul ts i n suffer i ng and decr eased qual i ty of l i fe for pati ents wi th cancer. Most pati ents wi th advanced cancer, and up to 60% of pati ents wi th any stage of cancer di agnosi s, exper i ence consi derabl e pai n. The pr obl em i s not tr i vi al , and unr el i eved pai n i s a r i sk factor for sui ci de i n pati ents wi th cancer. Thi s chapter i s desi gned to hel p cl i ni ci ans focus on the thr ee major components of any compr ehensi ve pai n-management pl an: (a) i ni ti al pati ent assessment fol l owed by (b) anal gesi c therapy, and (c) r eassessment. The chapter i s not i ntended to be an exhausti ve r evi ew of pai n management, but i t may act as a hel pful gui de to faci l i tate an under standi ng of pai n assessment and contr ol .

INITIAL PATIENT ASSESSMENT The i ni ti al assessment of any pati ent wi th cancer who i s i n pai n shoul d i ncl ude a compr ehensi ve hi stor y, wi th documentati on of the fol l owi ng: The pr i mar y cancer di agnosi s and cur r ent extent of di sease: Thi s may hel p defi ne the eti ol ogy of the pai nful sti mul i (e.g., pr ostate cancer and bone pai n).

Any cur r ent or ear l i er tr eatment of pai n: Is the pati ent opi ate naï ve? Ear l i er anal gesi c i nter venti ons and documentati on of outcomes may affect dosi ng consi derati ons. The type(s) of anal gesi cs bei ng used by the pati ent as wel l as the admi ni strati on r oute (Is the del i ver y of the medi cati on opti mi zed?), dose (Is the dose suffi ci ent for anal gesi a?), schedul e (Is ther e appr opr i ate r egul ar l y schedul ed “ar ound-thecl ock” coverage? Is the dosi ng i nter val consi stent wi th the durati on of acti on of the pr escr i bed dr ug?), and change i n effecti veness of cur r ent r egi men (Is ther e a tol erance devel opi ng to the cur r ent r egi men?) shoul d be i denti fi ed. Locati on of pai n: Identi fy the speci fi c ar ea, depth or si te fr om whi ch the pai n or i gi nates. Date of onset: Is thi s an acute or a chr oni c pr obl em? Qual i ty of pai n: Character i z ati on may hel p el uci date the eti ol ogy of pai n. Is the pai n crampi ng, bur ni ng, achi ng, dul l , or shar p? Character of pai n: Is the pai n waxi ng or wani ng? What ar e the aggravati ng and al l evi ati ng factor s? Is i t constant or i nter mi ttent? Intensi ty and sever i ty of pai n: A vi sual anal og scal e (VAS) and a numer i c scal e (see F i g. 37.1) shoul d be used to quanti fy and document the i ntensi ty of pai n. The pati ent's subjecti ve i nter pr etati on of the l evel of pai n shoul d be bel i eved. Chr oni c cancer pai n may not be accompani ed by sympatheti c sti mul ati on, whi ch i s nor mal l y mani fested as tachypnea or tachycar di a, despi te sever e pai n.

FIG. 37.1. Pai n i ntensi ty scal es: (Top) Vi sual anal og scal e (VAS). (Bottom) Si mpl e descr i pti ve pai n i ntensi ty scal e.

Psychosoci al eval uati on (any concomi tant major str esses?): Psychol ogi cal dependency on pr escr i pti on or i l l i ci t dr ugs, and on al cohol , shoul d be i denti fi ed. Per ti nent medi cal hi stor y shoul d be documented. Physi cal exami nati on: The physi cal exami nati on shoul d character i ze the mani festati ons of pai n, such as atr ophy, muscl e weakness, and tr i gger poi nts. A thor ough neur ol ogi c exami nati on i s essenti al , especi al l y i f neur opathi c pai n i s suspected. Appr opr i ate l aborator y and i magi ng studi es shoul d be obtai ned. These basel i ne fi ndi ngs shoul d be documented i n the pati ent's char t to faci l i tate futur e management.

PHARMACOLOGIC THERAPY The si x pr i nci pl es of phar macol ogi c pai n management modi fi ed fr om the Wor l d Heal th Or gani z ati on (WHO) r epor t ar e as fol l ows: 1. By the mouth: The oral r oute i s the pr efer r ed r oute whenever possi bl e (for the sake of the pati ent's conveni ence and to avoi d pai nful i .m. i njecti ons). 2. By the clock: Basal anal gesi c admi ni strati on shoul d be based on a fi xed schedul e— “ar ound the cl ock” (ATC) and not on an “as needed” (p.r.n.) basi s. A rati onal l y desi gned, r egul ar l y schedul ed

ATC dosi ng avoi ds the peak-and-tr ough effect of pr n dosi ng, i n whi ch hi gh ser um l evel s of the anal gesi c cor r el ate wi th adver se effects such as nausea, pr ur i tus, or somnol ence, and l ow l evel s cor r espond to per i ods of subopti mal anal gesi a. Pati ents shoul d not r el y on pr n anal gesi cs to cover basal pai n-contr ol r equi r ements. However, pr n anal gesi cs shoul d al ways be or der ed for br eakthr ough pai n contr ol . 3. W HO three-step ladder (see F i g. 37.2):

FIG. 37.2. Thr ee-step Wor l d Heal th Or gani z ati on (WHO) anal gesi c l adder. (F r om Cancer pai n r el i ef, 2nd ed. G eneva: Wor l d Heal th Or gani z ati on, 1996, wi th per mi ssi on.)

Step 1: For mi l d pai n, use nonopi oi d anal gesi cs (see Tabl e 37.1) wi th or wi thout adjuvant therapy (see Tabl e 37.2), at r ecommended dose and fr equency.

TABLE 37.1. Select Nonopioid Analg Generic drug name

Usual dose and administration schedule

Maximum daily dosea Usually ≤4,000 mg

Ana ant

daily

and

Therapeutic salicylate concentration range, 150– 300 µg/mL

Irre inh agg irri mu cau ble trig rea ina

Ana ant be hig in c use

Aspirin

325–650 mg PO every 4–6 h

APAP

325–650 mg PO every 4–6 h, or 975– 1,000 mg PO every 4–6 h

Limit total daily APAP dose to ≤4,000 mg

200–400 mg PO every 4–6 h

Limit total daily Ibuprofen dose to ≤3,200 mg

Ibuprofen

Naproxen immediate release: 250– 500 mg PO

Limit total daily dose to ≤4,000 mg naproxen Limit total

See gen sta

every 12 h

Naproxen

daily dose to ≤1,375 mg naproxen sodium

See gen sta

Naproxen delayed release: 375– 500 mg PO every 12 h Naproxen controlled release: 750– 1,000 mg PO once daily

Naproxen sodium: 275– 550 mg PO every 12 h

Limit total daily ketorolac dose to ≤40 mg PO, ≤120 mg i.v./i.m.

Parenterally Age Ta ble o f C o nt e nt s > Se c t io n 1 1 - Suppo rt iv e C a re > 3 9 - P s y c ho pha rm a c o lo gic M a na ge m e nt in O nc o lo gy

39 Psychopharmacologic Management in Oncology Donald L. Rosenstein* Maryland Pao† June Cai‡ *National Institute of Mental Health, National Institutes of Health, Bethesda, Mar yland † National

Institute of Mental Health, National Institutes of Health, Bethesda, Mar yland ‡ Depar tment

of Pyschiatr y and Human Behavior , Br own Univer sity Medical School, Pr ovidence, Rhode Island Psychi atr i c syndr omes, pr edomi nantl y depr essi on and anxi ety, occur commonl y i n pati ents wi th cancer, and, i f mi sdi agnosed or poor l y managed, can have a pr ofoundl y negati ve effect on opti mal oncol ogi c car e. The compr ehensi ve psychi atr i c car e of pati ents wi th cancer i ncl udes psychosoci al , behavi oral , and psychoeducati onal i nter venti ons as wel l as phar macol ogi c and psychotherapeuti c tr eatment. Thi s chapter focuses on the psychophar macol ogi c management of the major psychi atr i c syndr omes encounter ed i n the oncol ogy setti ng and concl udes wi th speci fi c r ecommendati ons for psychophar macol ogi c management i n pedi atr i c oncol ogy.

CONSIDERATIONS BEFORE PRESCRIBING PSYCHOPHARMACOLOGIC AGENTS 1. Psychi atr i c symptoms ar e often mani festati ons of an under l yi ng medi cal di sor der or ar e compl i cati ons of i ts tr eatment (see Tabl e 39.1). For exampl e, speci fi c mal i gnanci es (e.g., l ung, br east,

gastr oi ntesti nal , r enal , and pr ostate cancer s) ar e pr one to metastasi ze to the central ner vous system (CNS). In addi ti on, any advanced cancer can r esul t i n str uctural or metabol i c CNS i nsul ts that pr eci pi tate psychi atr i c symptoms. For those pati ents whose psychi atr i c symptoms fai l to r espond to psychophar macol ogi c tr eatment, CNS i nvol vement shoul d be r econsi der ed, even i n mal i gnanci es that do not commonl y metastasi ze to the brai n.

TABLE 39.1. Medical Conditions in Oncologic and Other Disorders Associated with Anxiety and Depression Neoplasms Brain tumors Insulinoma Lymphoma

Cardiovascular Ischemic heart disease Arrhythmias Congestive heart failure

Small cell carcinoma Pancreatic cancer

Metabolic

Leukemia

Electrolyte disturbances Uremia

Endocrinologic

Vitamin B12 or folate deficiency

Cushing syndrome Adrenal insufficiency Hypopituitarism Pheochromocytoma Thyroid dysfunction

Other Substance abuse and withdrawal Pain (uncontrolled) Hematologic (e.g., anemia)

2. Medi cal l y i l l pati ents ar e par ti cul ar l y suscepti bl e to CNS adver se effects of medi cati ons. Speci fi c exampl es of medi cati ons associ ated wi th mood, cogni ti ve, and behavi oral symptoms i ncl ude the fol l owi ng: cor ti coster oi ds, i nter l euki n-2, i nter fer onα, nar coti cs, and dopami ne-bl ocki ng anti emeti cs. For pati ents who devel op psychi atr i c symptoms after tr eatment wi th such agents, i t i s often mor e pr udent to l ower the dose or to di sconti nue the use of a cur r entl y pr escr i bed medi cati on than to i ntr oduce yet another agent (i .e., a psychotr opi c) that mi ght exacer bate psychi atr i c symptoms. 3. Pol yphar macy i s often unavoi dabl e i n pati ents wi th cancer ; however, most cl i ni cal l y si gni fi cant i nteracti ons wi th psychotr opi c agents ar e pr edi ctabl e and can be avoi ded by choosi ng al ter nati ve agents or by maki ng dose adjustments. The use of monoami ne oxi dase i nhi bi tor s (MAOIs) wi th ei ther meper i di ne (Demer ol ) or sel ecti ve ser otoni n r euptake i nhi bi tor s (SSRIs) i s l i fe thr eateni ng. Up-to-date dr ug i nteracti on r esour ces can be found at several i nter net websi tes (e.g., http://www.medi ci ne.i upui .edu/fl ockhar t/). 4. Inadequate pai n contr ol fr equentl y i nduces symptoms of anxi ety,

i r r i tabi l i ty, or depr essi on. It i s essenti al to have pai n wel l contr ol l ed so that the appr opr i ate psychi atr i c di agnosi s and tr eatment can pr oceed (see Chapter 37). One note of cauti on i n thi s r egar d concer ns the combi ned use of SSRIs and tr i cycl i c anti depr essants (TCAs), whi ch ar e fr equentl y used i n the tr eatment of neur opathi c pai n. Some SSRIs (e.g., fl uoxeti ne, par oxeti ne, and fl uvoxami ne) i nhi bi t the metabol i sm of TCAs, whi ch can i n tur n pr ol ong the cor r ected QT i nter val (QTc) i nter val .

COMMON PSYCHIATRIC SYNDROMES IN THE ONCOLOGY SETTING 1. Adjustment disor der : Thi s i s a ti me-l i mi ted, mal adapti ve r eacti on to a speci fi c str essor that typi cal l y i nvol ves symptoms of depr essi on, anxi ety, or behavi oral changes and i mpai r s psychosoci al functi oni ng. The di agnosti c cr i ter i a i ncl ude the onset of symptoms wi thi n 3 months of the str essor but the durati on of symptoms i s no mor e than 6 months. The di ffer enti al di agnosi s i ncl udes the fol l owi ng di sor der s: Ber eavement Posttraumati c str ess di sor der Other mood and anxi ety di sor der s Management: The i ni ti al tr eatment appr oach consi sts of cr i si s i nter venti on and br i ef psychotherapy. Ti me-l i mi ted symptom management wi th medi cati ons may be i ndi cated. For exampl e, anxi ety, tear ful ness, and i nsomni a ar e fr equent r eacti ons to the di agnosi s of a new or r ecur r ent mal i gnancy. Shor t-ter m tr eatment of these symptoms wi th benzodi azepi nes (BZDs) (e.g., l orazepam and cl onazepam) i s appr opr i ate, effecti ve, and rar el y associ ated wi th the devel opment of abuse or dependence. 2. Major depr ession: Major depr essi on and subsyndr omal depr essi ve di sor der s ar e common i n pati ents wi th cancer. Pr eval ence rates var y between 5% and 50% dependi ng on how depr essi on i s defi ned, whether study sampl es ar e drawn fr om outpati ent cl i ni cs or hospi tal war ds, and the type of cancer i nvol ved. Untr eated depr essi on has been cor r el ated to poor compl i ance wi th medi cal car e, i ncr eased pai n and di sabi l i ty, and a gr eater l i kel i hood to consi der euthanasi a and physi ci an-assi sted sui ci de.

A major di agnosti c task i n the oncol ogy setti ng i s assor ti ng symptoms attr i butabl e to depr essi on fr om those symptoms that ar e caused by the cancer or i ts tr eatment. The pati ent wi th di ssemi nated cancer who i s under goi ng chemotherapy i s l i kel y to exper i ence fati gue, anor exi a, wei ght l oss, and i nsomni a, whether a cl i ni cal depr essi on i s pr esent or absent. Our practi ce i s to i nsti tute empi r i c tr i al s of anti depr essants usi ng a tar geted symptom r educti on appr oach. In bor der l i ne cases, a per sonal or fami l y hi stor y of depr essi on and symptoms of excessi ve gui l t, poor sel f-esteem, anhedoni a, and r umi nati ve thi nki ng str engthen the ar gument for a medi cati on tr i al . F ur ther mor e, because the number of wel l tol erated, safe, and effecti ve anti depr essants has gr own, we have l ower ed our thr eshol d for tr eati ng subsyndr omal depr essi on i n the oncol ogy setti ng. Par ti cul ar attenti on shoul d be pai d to symptoms of hopel essness, hel pl essness, and sui ci dal i deati on, accompani ed by consi derabl e i ncr eases i n anxi ety, because pati ents wi th cancer have an i ncr eased r i sk of sui ci de compar ed wi th the general popul ati on. The i nci dence of cancer at cer tai n si tes (e.g., head and neck, l ung, gastr oi ntesti nal tract, ur ogeni tal tract, and br east) i s associ ated wi th an even gr eater r i sk of sui ci de (see Tabl e 39.2).

TABLE 39.2. Risk Factors for Suicide in Patients with Cancer Historical considerations

Clinical descriptors

Prior suicide attempts

Elderly men

Family history of suicide

Recent loss and poor social support

Prior

psychiatric illness

Current depression, anxiety, substance abuse

History of substance abuse

Advanced cancer, pain, poor prognosis

Impulsive behavior

Delirium, psychosis, illogical thoughts

Di ffer enti al di agnosi s of major depr essi on: Adjustment di sor der Dysthymi c di sor der Del i r i um Dementi a Substance abuse Bi pol ar di sor der Ber eavement Mood di sor der caused by a medi cal di sor der or medi cati on (Tabl e 39.1). Management: Tr eatment modal i ti es i ncl ude phar macotherapy (see Tabl e 39.3), psychotherapy, and el ectr oconvul si ve therapy (ECT). Sel ecti on of an anti depr essant shoul d be based on a number of consi derati ons such as pr i or tr eatment r esponse, an opti mal match between the pati ent's tar get symptoms and the si de-effect pr ofi l e of the anti depr essant (e.g., usi ng a sedati ng agent for the pati ent wi th anxi ety and i nsomni a), and the potenti al for dr ug i nteracti ons. Mi r taz api ne (Remer on) has several pr oper ti es that make i t a par ti cul ar l y attracti ve anti depr essant choi ce i n pati ents wi th cancer : i t i s sedati ng, causes wei ght gai n, has few si gni fi cant dr ug i nteracti ons, and i s a par ti al 5HT-3 r eceptor antagoni st (i .e., has anti emti c pr oper ti es).

TABLE 39.3. Commonly used Antidepressants in Patients with Cancer

Generic names (brand names)

Dose range (mg)

Important adverse effects and comments

SSRIs

Fluoxetine (Prozac) a , d

Sertraline (Zoloft) a , d

5–60

Sexual dysfunction, diarrhea, weight changes, insomnia, agitation, anxiety, hyponatremia, night sweats

12.5– 200

Sedation, weight gain, GI symptoms, sexual dysfunction, hyponatremia Sexual dysfunction, sedation,

Paroxetine (Paxil)c , d

Citalopram (Celexa) d

Escitalopram (Lexapro)

Fluvoxamine (Luvox) a

10–60

akathisia, anticholinergic effects, hyponatremia, withdrawal syndrome

10–60

Nausea, dry mouth, somnolence, ejaculation disorder, weak inhibition of CYP isoenzymes

5–40

Nausea, dry mouth, somnolence, ejaculation disorder, weak inhibition of CYP isoenzymes

25– 300

Night sweats, sexual dysfunction, potent inhibitor of CYP1A2 and 3A3/4

Novel antidepressants

Venlafaxine (Effexor) c

Mirtazapine (Remeron) b

Bupropion (Wellbutrin) c

18.75– 300

GI distress, sexual dysfunction, sedation, anticholinergic effects, hypertension at dose >225 mg

7.5–45

Sedation, dry mouth, increased appetite and weight gain, constipation, asthenia, dizziness

37.5– 450

GI distress, tremor, excitement, seizure at high dose or with brain tumors Sedation,

Trazodone (Desyrel)

25– 200

anticholinergic effects, orthostatic hypotension, priapism, useful for anxiety and insomnia at low doses

CNS stimulants

Methylphenidate (Ritalin) a , c

Dextroamphetamine (Dexedrine) a , c

2.5–40

Insomnia, agitation, GI distress, headache, tics, rebound depression

2.5–30

Insomnia, agitation, confusion, delusion, psychosis, tics, rebound depression

Tricyclic antidepressants Dry mouth, sedation,

weight gain, ECG changes, orthostatic hypotension, anticholinergic effects

Amitriptyline (Elavil) a

25– 150

Desipramine (Norpramin)

25– 150

Dry mouth, tachycardia, ECG changes

25– 150

Tremor, confusion, anticholinergic effects

Nortriptyline (Pamelor)

SSRI, selective serotonin reuptake inhibitor; GI, gastrointestinal; CYP, cytochrome P-450; CNS, central nervous system; ECG, electrocardiogram. a FDA approval for use in children/adolescents. b Orally disintegrating tablets or wafers available. c Sustained release and extended release formulations available. d Liquid formulation available. 3. Anxiety disor der s: Many medi cal condi ti ons seen i n the oncol ogy setti ng, such as hear t fai l ur e, r espi rator y compr omi se, sei z ur e di sor der s, pheochr omocytoma, and chemotherapy-i nduced ovar i an fai l ur e, may cause anxi ety. Addi ti onal condi ti ons that

may cause both anxi ety and depr essi on ar e l i sted i n Tabl e 39.1. Si mi l ar l y, anxi ety i s an adver se effect of numer ous medi cati ons. In par ti cul ar, dopami ne-bl ocki ng anti emeti cs such as metocl oprami de (Regl an), pr ochl or peraz i ne (Compaz i ne), and pr omethaz i ne (Phener gan) fr equentl y cause akathi si a, an adver se effect character i zed by subjecti ve r estl essness and i ncr eased motor acti vi ty, whi ch i s commonl y mi sdi agnosed as anxi ety. The di ffer enti al di agnosi s of anxi ety di sor der s i n the oncol ogy setti ng i ncl udes the fol l owi ng: Exacer bati on of medi cal i l l ness Agi tated depr essi on

Adver se effects of medi cati ons Substance or al cohol abuse or wi thdrawal Adjustment di sor der Del i r i um. Management of anxi ety: In addi ti on to behavi oral therapy and psychotherapy, BZDs ar e the medi cati ons that ar e most fr equentl y used for the shor t-ter m tr eatment of anxi ety (see Tabl e 39.4). For anxi ety that per si sts beyond a few weeks, tr eatment wi th an anti depr essant (Tabl e 39.3) i s i ndi cated. If the pati ent has al r eady been taki ng an SSRI, i t i s i mpor tant to not di sconti nue an SSRI (wi th the excepti on of fl uoxeti ne because of i ts l ong hal f-l i fe) abr uptl y to avoi d r ebound anxi ety fr om wi thdrawal . Low-dose atypi cal anti psychoti cs ar e often useful for sever e and per si stent anxi ety or for condi ti ons such as anxi ety secondar y to ster oi ds and del i r i um (see Tabl e 39.5).

TABLE 39.4. Preferred BZDs in the Oncology Setting Lorazepam (Ativan) a

Clonazepam (Klonopin)

Dose equivalency

1 mg

0.25 mg

Dose range

0.25–2 mg PO, sublingual, i.m. or i.v. routes, every 1–6 h (maximum daily dose, 8 mg)

0.25–1 mg PO route only, every 12 h

Rapid onset of action

Less frequent dosing than with lorazepam

Advantages

BZD, benzodiazepines; PO, orally; i.m., intramuscularly; i.v., intravenously. a Liquid formulation available.

TABLE 39.5. Commonly Used Neuroleptics Setting Initial Administrative dose routes and (mg) schedules haloperidol a , b (Haldol)

0.25– 1 PO,

every 2–12 h s.c., i.m.,

Maxim dail dos (mg

20

or i.v.

chlorpromazine (Thorazine)

12.5– 50 PO, i.m. or i.v.

every 4–12 h

300

risperidone a , b (Risperdal)

0.25– 3 PO

every 12 h

6

olanzapine (Zyprexa)

2.5– 10 PO

every 12–24 h

20

quetiapine (Seroquel)

25– 50 PO

every 12–24 h

800

EPS, extrapyramidal symptoms; PO, orally; s.c., i.m., intramuscularly; i.v., intravenously. a FDA approval for use in children/adolescents. b Liquid formulation available. The fol l owi ng i ssues associ ated wi th BZD use r equi r e attenti on: BZDs ar e the tr eatment of choi ce for del i r i um caused by al cohol or sedati ve–hypnoti c wi thdrawal , but typi cal l y wor sen other types of del i r i um. In pati ents wi th hepati c fai l ur e, l orazepam, temazepam, or oxazepam ar e the pr efer r ed BZDs.

BZDs may r esul t i n “di si nhi bi ti on,” especi al l y i n del i r i um, substance abuse, or gani c di sor der s, and pr eexi sti ng per sonal i ty di sor der s. The abr upt di sconti nuati on of BZDs wi th shor t hal f-l i ves [e.g., al prazol am (Xanax) and tr i azol am (Hal ci on)] can cause r ebound anxi ety and pr eci pi tate a wi thdrawal syndr ome. 4. Delir ium: Del i r i um i s an acute confusi onal state character i zed by a fl uctuati ng cour se of cogni ti ve i mpai r ment, per ceptual di stur bances, mood changes, del usi ons, and sl eep–wake cycl e di sr upti on. Pati ents can have a hyperacti ve (agi tated) or hypoacti ve (qui et) del i r i um. Vi r tual l y any psychi atr i c symptom can be a mani festati on of del i r i um, among whi ch anxi ety and/or l abi l e mood ar e common pr esentati ons often mi sdi agnosed as “depr essi on.” Pati ents who ar e el der l y, who ar e on mul ti pl e medi cati ons, or who have under l yi ng brai n pathol ogy ar e mor e pr one to del i r i um. Del i r i um i n ter mi nal l y i l l pati ents i s common and often under di agnosed. The di ffer enti al di agnosi s i ncl udes the fol l owi ng: Dementi a Affecti ve di sor der s wi th psychosi s (mani a or depr essi on) Psychoti c di sor der s Medi cati on effects or substance or al cohol abuse or wi thdrawal . Management: The fi r st steps i n the management of del i r i um ar e the i denti fi cati on and tr eatment of pr eci pi tati ng factor s and the di sconti nuati on of nonessenti al medi cati ons. Hal oper i dol (Hal dol ) conti nues to be the tr eatment of choi ce for del i r i um i n most cases (Tabl e 39.5). Newer atypi cal anti psychoti cs have fewer si de effects and can be used as wel l , such as ol anz api ne (Zypr exa), queti api ne (ser oquel ) and r i sper i done (Ri sper dal ). Del i r i um secondar y to BZD, or sedati ve–hypnoti c and al cohol wi thdrawal shoul d be tr eated wi th BZDs.

ADDITIONAL CONSIDERATIONS FOR PSYCHOPHARMACOLOGIC MANAGEMENT IN PEDIATRIC ONCOLOGY Cancer i s the four th l eadi ng cause of death, and the l eadi ng cause

of nonacute death among chi l dr en. Li fe-thr eateni ng i l l ness i n a chi l d or an adol escent i s traumati c and can be associ ated wi th anxi ety and depr essi on. Al though many pati ents cope wel l wi th and adapt to the trauma, symptoms of depr essi on such as fati gue, cogni ti ve i mpai r ment, decr eased soci al i nteracti on and expl orati on, and anor exi a may be par t of a cytoki ne or i mmunol ogi c r esponse to cancer and i ts tr eatments. Psychotr opi c medi cati ons can dramati cal l y i mpr ove the qual i ty of l i fe for chi l dr en wi th cancer. These medi cati ons do not r epl ace compr ehensi ve, mul ti modal , mul ti di sci pl i nar y car e, but ar e adjuncts to decr ease di scomfor t and i mpr ove functi oni ng of medi cal l y i l l chi l dr en.

Assessment and Diagnosis in Pediatric Oncology A thor ough psychi atr i c assessment i s needed to make a cor r ect di agnosi s and to i nsti tute tr eatment. Typi cal l y, thi s assessment i s based on mul ti pl e br i ef exami nati ons of the chi l d and i nfor mati on gather ed fr om addi ti onal sour ces i ncl udi ng fami l y, staff, and teacher s. A pati ent's bi ol ogi c vul nerabi l i ty to depr essi on and anxi ety may be i nfer r ed fr om (a) a fami l y hi stor y of a mood or anxi ety di sor der, or other psychi atr i c di sor der, and (b) pr evi ous psychi atr i c symptoms or psychi atr i c tr eatment. Common compl ai nts i n medi cal l y i l l chi l dr en i ncl ude: anxi ety pai n di ffi cul ty i n sl eepi ng fati gue feel i ng “bor ed.”

Adul t psychi atr i c syndr omes of adjustment di sor der, major depr essi on, anxi ety, and del i r i um appl y to chi l dr en as wel l , but anxi ety, rather than depr essi on, i s the most fr equent di agnosi s. Impor tant deter mi ni ng factor s for phar macol ogi c i nter venti on ar e sever i ty and durati on of psychi atr i c symptoms.

Psychopharmacologic Treatment of Pediatric Patients

In 1994, manufactur er s and federal l y funded r esear cher s wer e mandated to study medi cati ons such as anti depr essants i n chi l dr en. Al though ther e have been no wel l -contr ol l ed anti depr essant tr i al s i n depr essed medi cal l y i l l chi l dr en, and the dose of psychi atr i c medi cati ons for chi l dr en wi th cancer has not been systemati cal l y studi ed, anti depr essants have been useful for tr eati ng anxi ety and depr essi on. Body wei ght, Tanner stagi ng, cl i ni cal status, and potenti al for medi cati ons to i nteract ar e wei ghed i n deci di ng doses. See Tabl es 39.3 and 39.5 for psychotr opi cs wi th U.S. Food and Dr ug Admi ni strati on (F DA) appr oval for use i n chi l dr en and adol escents. BZDs, such as l orazepam, used i n l ow doses i n conjuncti on wi th nonphar macol ogi c di stracti on techni ques, may be appr opr i ate for pr ocedur es that i nduce consi derabl e anxi ety i n chi l dr en. Cl onazepam i s l onger acti ng and may be hel pful wi th mor e per vasi ve and pr ol onged anxi ety symptoms. BZDs can cause sedati on, confusi on, and behavi oral di si nhi bi ti on. Thei r use shoul d be car eful l y moni tor ed, especi al l y i n those pati ents wi th CNS dysfuncti on. BZD wi thdrawal pr eci pi tated by abr upt di sconti nuati on occur s most fr equentl y on transfer r i ng the pati ent fr om i ntensi ve car e setti ngs. Anti hi stami nes have been used to sedate anxi ous chi l dr en. Di phenhydrami ne, hydr oxyz i ne, and pr omethaz i ne may be hel pful for occasi onal i nsomni a. However, anti hi stami nes ar e not hel pful for per si stent anxi ety and thei r anti chol i ner gi c pr oper ti es can pr eci pi tate or wor sen del i r i um. Intravenous di phenhydrami ne may be sought because i t can i nduce euphor i a when gi ven by i .v. push; ver y hi gh doses can pr ovoke sei z ur es. F l uoxeti ne i s the onl y F DA-appr oved SSRI for depr essi on i n chi l dr en ol der than 6 year s. F l uoxeti ne and ser tral i ne ar e appr oved for obsessi ve-compul si ve di sor der i n chi l dr en ol der than 6 year s; fl uvoxami ne i s appr oved for those who ar e 8 year s and ol der. F l uoxeti ne, wi th i ts acti ve metabol i te nor fl uoxeti ne, and fl uvoxami ne ar e potent i nhi bi tor s of cytochr ome P-450 (CYP) 3A3 and 3A4. They ar e contrai ndi cated wi th macr ol i de anti bi oti cs, azol e anti fungal agents, and several other medi cati ons. Ami tr i ptyl i ne i s appr oved for depr essi on i n chi l dr en who ar e 12 year s or ol der. TCAs ar e useful for tr eati ng i nsomni a, wei ght l oss, anxi ety, and some pai n syndr omes. Some anti depr essants may contr i bute to sui ci dal thi nki ng i n chi l dr en and adol escents. Thi s possi bi l i ty war rants car eful moni tor i ng of al l chi l dr en tr eated wi th anti depr essants. Use of non-

F DA appr oved psychophar macol ogi c agents i n chi l dr en wi th cancer may be consi der ed i n extr eme or pr ol onged di str ess and poor functi oni ng, but must be moni tor ed cl osel y. It i s unusual for chi l dr en wi th cancer to be sui ci dal i n the absence of pr emor bi d depr essi on or i nadequate pai n management. Chi l dr en and adol escents who cannot tol erate anti depr essants may benefi t fr om sti mul ants for depr essi on and apathy. Psychosti mul ants ar e general l y wel l tol erated and have a rapi d onset of acti on. Chi l dr en wi th del i r i um, hal l uci nati ons, sever e agi tati on, or aggr essi on may be safel y tr eated wi th l ow-dose anti psychoti cs such as hal oper i dol or atypi cal neur ol epti cs such as r i sper i done. Al though ther e i s a dear th of r esear ch i n pedi atr i c cancer psychophar macol ogy, chi l d psychi atr y consul tati on may consi derabl y i mpr ove the qual i ty of l i fe for chi l dr en under goi ng cancer tr eatment and deal i ng wi th cancer sur vi val . Routi ne psychol ogi cal scr eeni ng of chi l dr en wi th cancer and sur vi vor s can detect ongoi ng di str ess. Psychophar macol ogi c consul tati on may al so hel p chi l dr en wi th postradi ati on or postchemotherapy condi ti ons r el ated to attenti on, mood, and anxi ety di sor der s.

SUMMARY Psychi atr i c syndr omes ar e fr equentl y mi sdi agnosed and poor l y tr eated i n pati ents wi th cancer. Befor e i ni ti ati ng psychophar macol ogi c therapy, under l yi ng medi cal di sor der s and adver se effects of medi cati on must be addr essed and potenti al dr ug i nteracti ons anti ci pated. Psychi atr i c symptoms shoul d then be tr eated pr omptl y and aggr essi vel y. Consul tati on fr om a psychi atr i st i s i ndi cated i n the fol l owi ng ci r cumstances when the pati ent (a) has a compl ex psychi atr i c hi stor y and i s taki ng mul ti pl e psychotr opi c medi cati ons; (b) exhi bi ts depr essi ve symptoms associ ated wi th extr eme gui l t, anxi ety, and/or sui ci dal thoughts; (c) i s confused, hal l uci nati ng, agi tated, or vi ol ent; and (d) i s noncompl i ant wi th tr eatment or r ejects tr eatment and seeks physi ci an-assi sted sui ci de.

SUGGESTED READINGS Academy of Psychosomati c Medi ci ne. Psychi atr i c aspects of excel l ent end-of-l i fe car e: a posi ti on statement of the Academy of Psychosomati c Medi ci ne. Avai l abl e at: http://www.apm.or g/eol car e.html . Accessed Mar ch 14, 2005.

Amer i can Psychi atr i c Associ ati on. Di agnosti c and stati sti cal manual of mental di sor der s, 4th ed. Washi ngton, DC: Amer i can Psychi atr i c Associ ati on, 1994. Cassem EH. Depr essi ve di sor der s i n the medi cal l y i l l : an over vi ew. Psychosomati cs 1995;36:S2–S10. Cl eel and CS, Bennett G J, Dantzer R, et al . Ar e the symptoms of cancer and cancer tr eatment due to a shar ed bi ol ogi c mechani sm? A cytoki ne-i mmunol ogi c model of cancer symptoms. Cancer 2003;97:2919. Coyl e N, Adel har dt J, Fol ey KM, et al . Character of ter mi nal i l l ness i n the advanced pati ent wi th cancer : pai n and other symptoms dur i ng the l ast four weeks of l i fe. J Pai n Symptom Manage 1990;5:83. Emanuel EJ, Fai r cl ough DL, Dani el s ER, et al . Euthanasi a and physi ci an-assi sted sui ci de: atti tudes and exper i ences of oncol ogy pati ents, oncol ogi sts, and the publ i c. Lancet 1996;347:1805. Endi cott J. Measur ement of depr essi on i n pati ents wi th cancer. Cancer 1984;53:2243. Fawz y I, G r eenbur g D. Oncol ogy. Textbook of consul tati on-l i ai son psychi atr y. Washi ngton, DC: Amer i can Psychi atr i c Pr ess, 2001. G ol dman LS, Wi se TN, Br ody DS. Psychi atr y for pr i mar y car e physi ci ans. Washi ngton, DC: Amer i can Psychi atr i c Pr ess, 1997. Hol l and J. Psycho-oncol ogy. New Yor k: Oxfor d Uni ver si ty Pr ess, 1998. Li psett DR, Payne EC, Cassem NH. On death and dyi ng. Di scussi on. J G er i atr Psychi atr y 1974;7:108. Lynch ME. The assessment and pr eval ence of affecti ve di sor der s i n advanced cancer. J Pal l i at Car e 1995;11:10.

McDani el JS, Mussel man DL, Por ter MR, et al . Depr essi on i n pati ents wi th cancer : di agnosi s, bi ol ogy, and tr eatment. Ar ch G en Psychi atr y 1995;52:89. Reckl i ti s C, O'Lear y T, Di l l er L. Uti l i ty of r outi ne psychol ogi cal scr eeni ng i n the chi l dhood cancer sur vi vor cl i ni c. J Cl i n Oncol 2003;21:787. Spi egel D, Sands S, Koopman C. Pai n and depr essi on i n pati ents wi th cancer. Cancer 1994;74:2570. Spi egel L. Pedi atr i c psychophar macol ogy. Psycho-oncol ogy. New Yor k: Oxfor d Uni ver si ty Pr ess, 1998; Wi se TN. The physi ci an and hi s pati ent wi th cancer. Pr i m Car e 1974;1:407.

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 1 1 - Suppo rt iv e C a re > 4 0 - M a na ge m e nt o f Em e s is in O nc o lo gy

40 Management of Emesis in Oncology David R. Kohler Phar macy Depar tment, National Institutes of Health, Clinical Center , Bethesda, Mar yland

TYPES OF TREATMENT-RELATED EMETIC SYMPTOMS Radi ati on- and chemotherapy-associ ated emeti c symptoms ar e categor i zed as acute, del ayed, or anti ci pator y (see F i g. 40.1) (1).

FIG. 40.1. Emeti c symptom phases and anti emeti c acti vi ty compar i son. Top: The temporal r el ati on between the star t of emetogeni c tr eatment [hour zer o (0)] and emeti c symptom phases. For each phase, shaded bar s i ndi cate general l y the per i ods dur i ng whi ch nausea and emesi s occur ; depth of shadi ng cor r el ates di r ectl y wi th the i nci dence of symptoms. Bottom: The

most hi ghl y acti ve dr ug categor i es ar e ranked by thei r r el ati ve effecti veness dur i ng the acute (0–24 hour s) and del ayed (after 24 hour s) emeti c phases.

Acute-phase symptoms cor r el ate wi th ser otoni n (5-HT) r el ease fr om enter ochr omaffi n cel l s. Emeti c si gnal s ar e pr opagated at l ocal 5-HT 3 r eceptor s and transmi tted al ong affer ent vagus ner ve fi ber s, and a di ffuse ser i es of effector nucl ei ar e acti vated i n the medul l a obl ongata (the so-cal l ed “vomi ti ng center ”). Thi s i n tur n i ntegrates affer ent emeti c si gnal s and subsequentl y acti vates and coor di nates motor nucl ei that pr oduce the physi ol ogi c changes associ ated wi th vomi ti ng. Al though an eti ol ogy for del ayed symptoms r emai ns el usi ve, such symptoms may be r el ated to acti vati on of neur oki ni n type 1 r eceptor s (NK1 ) for whi ch substance P i s the natural l i gand. Del ayed-phase symptoms have been associ ated wi th numer ous chemotherapeuti c r egi mens (see Tabl e 40.1). Symptoms may occur as ear l y as 16 to 18 hour s after emetogeni c tr eatment, wi th the per i od of most fr equent i nci dence between 24 and 96 hour s after tr eatment (2,3).

TABLE 40.1. Antineoplastic Drugs Implicated in Causing Delayed Emesis Carboplatin ≥300 mg/m2 (± other cytotoxic agents) Cisplatin ≥50 mg/m2 Cyclophosphamide ≥600 mg/m2 Cyclophosphamide ± other cytotoxic agents Cyclophosphamide + anthracycline combinations Doxorubicin ≥50 mg/m2 Del ayed emesi s may occur i n pati ents who do not exper i ence

symptoms acutel y, but i ts i nci dence character i sti cal l y decr eases i n pati ents who achi eve compl ete contr ol dur i ng the acute phase. Al though the sever i ty of emesi s dur i ng the del ayed phase i s typi cal l y l ess than that whi ch occur s dur i ng the acute phase, the sever i ty of nausea i s r epor tedl y si mi l ar dur i ng both phases. Repeated anti neopl asti c tr eatments that ar e character i zed by poor emeti c contr ol gi ve r i se to anti ci pator y emeti c symptoms, whi ch ar e an aver si ve condi ti oned r esponse. Consequentl y, compl ete contr ol thr oughout anti neopl asti c tr eatment r emai ns the best pr eventi ve strategy agai nst devel opi ng symptoms. Al though anxi ol yti c amnesti c dr ugs ar e hel pful i n pr eventi ng the devel opment of anti ci pator y symptoms, behavi or-modi fi cati on and cogni ti ve-di stracti on techni ques become the pr i mar y modal i ti es of i nter venti on after symptoms occur. After symptoms devel op, the r ol e of medi cal i nter venti on dur i ng subsequent emetogeni c tr eatment i s l i mi ted to pr eventi ng r ei nfor cement of condi ti oned sti mul us, whi ch may exacer bate anti ci pator y symptoms.

EMETIC (EMETOGENIC) POTENTIAL The potenti al for pr oduci ng emesi s and the patter ns i n whi ch symptoms mani fest var y among anti neopl asti c medi cati ons and radi ati on therapy techni ques. Acute Emeti c Symptoms: G eneral l y, onset of emesi s i s wi thi n 1 to 3 hour s after commenci ng chemotherapy admi ni strati on (see Tabl e 40.2).

TABLE 40.2. Time to Onset after Commencement of Chemotherapy Administration and Duration of Emesis Drug name Aldesleukin

Time to onset (h)

Duration (h)

0–6

—

Altretamine

3–6

—

Asparaginase

1–3

—

Bleomycin

3–6

—

Carboplatin

6–8

>24

Carmustine

2–6

4–24

48–72

—

1–6

24 to >48

Cyclophosphamide

6–18

6 to >24

Cytarabine

6–12

3–5

Dacarbazine

1–5

1–24

Dactinomycin

2–6

12–24

Daunorubicin

2–6

24

Doxorubicin

4–6

6 to >24

Etoposide

3–8

6–12

Fluorouracil

3–6

3–4

Hydroxyurea

6–12

—

1–6

6–12

Chlorambucil Cisplatin

Ifosfamide

Irinotecan

2–6

6–12

Lomustine

2–6

4–12

Mechlorethamine

0.5–2

1–24

Melphalan

6–12

—

4–8

—

4–12

3–12

1–6

3–12

Mitotane

Long latency

Persistent

Paclitaxel

3–8

3–8

Pentostatin

Long latency

Persistent, >24

Plicamycin

4–6

12–24

Procarbazine

24–27

Variable

Streptozocin

1–4

12–24

Teniposide

3–8

6–12

Thioguanine

4–8

—

Mercaptopurine Methotrexate Mitomycin

Thiotepa

6–12

Variable

Vinblastine

4–8

—

Vincristine

4–8

—

Vinorelbine

4–8

—

From Borison HL, McCarthy LE. Neuropharmacology of chemotherapyinduced emesis. Drugs 1983;25(suppl 1):8– 17 and Aapro M. Methodological issues in antiemetic studies. Invest New Drugs 1993;11:243–253, with permission (4,5). Excepti ons i ncl ude mechl or ethami ne (ni tr ogen mustar d), cycl ophosphami de, and car bopl ati n. Most fr equent i nci dence of emesi s occur s dur i ng a 2- to 6-hour per i od after tr eatment. Emesi s may per si st or r ecur i nter mi ttentl y for 12 hour s or l onger after tr eatment. Among anti neopl asti c dr ugs, the dose admi ni ster ed most often affects emetogeni c potenti al and the durati on for whi ch symptoms occur. The number of emetogeni c dr ugs admi ni ster ed i n combi nati on, admi ni strati on schedul e, tr eatment durati on, and r oute of dr ug admi ni strati on ar e al so mi ti gati ng factor s. Emeti c potenti al i s often a functi on of tr eatment durati on; i t may be decr eased or el i mi nated by attenuati ng dr ug del i ver y over hour s or days and i s often i ncr eased by rapi d admi ni strati on, by r epeti ti ous emetogeni c tr eatment, and by br i ef i nter val s between r epeated doses. For i oni z i ng radi ati on, emeti c potenti al cor r el ates di r ectl y wi th the amount of radi ati on admi ni ster ed per dose and the dose rate. Lar ge tr eatment vol umes and fi el ds i ncl udi ng the upper abdomen, the upper hemi thorax, and the whol e body ar e pr omi nent r i sk factor s

for sever e emesi s. G eneral l y, emeti c r i sk i s i ncr eased when radi ati on and chemotherapy ar e admi ni ster ed concomi tantl y.

PATIENT RISK FACTORS THAT AFFECT EMETIC CONTROL It i s general l y mor e di ffi cul t to pr event and contr ol emesi s i n women than i n men, par ti cul ar l y among women wi th a hi stor y of per si stent or sever e emeti c symptoms dur i ng pr egnancy chi l dr en and young adul ts than i n ol der pati ents pati ents wi th a hi stor y of i ncompl ete anti emeti c contr ol dur i ng ear l i er tr eatments, whether (a) acutel y, (b) dur i ng the del ayed phase, or (c) dur i ng both per i ods. Pati ents i n the categor y (c) ar e at gr eatest r i sk for poor anti emeti c contr ol dur i ng subsequent tr eatments (6). Decr eased per for mance status and a pr edi sposi ti on to moti on si ckness have al so been associ ated wi th poor emeti c contr ol . In contrast, pati ents who have chr oni cal l y consumed al cohol i c beverages (general l y, >100 g ethanol per day for several year s) ar e mor e l i kel y to have compl ete emeti c contr ol than “nondr i nker s,” even i f the for mer ar e not usi ng al cohol now. For a mi nor i ty of pati ents who r ecei ve tr eatment-appr opr i ate anti emeti c pr ophyl axi s, effecti ve emeti c contr ol i s beyond the scope of evi dence-based gui del i nes and r equi r es a rati onal empi r i c appr oach. Unfor tunatel y, empi r i c i nter venti ons pr edi spose pati ents to a r i sk of over tr eatment that may adver sel y affect thei r safety and unjusti fi abl y i ncr ease tr eatment costs. In compar i son, under tr eatment i s equal l y unsati sfactor y because i t pl aces pati ents at r i sk for emesi s and debi l i tati ng mor bi di ty that may adver sel y affect thei r safety, comfor t, and qual i ty of l i fe, and i t compl i cates thei r car e.

PRIMARY ANTIEMETIC PROPHYLAXIS To pr event emeti c symptoms dur i ng each emetogeni c tr eatment, tr eatment-appr opr i ate anti emeti c pr ophyl axi s shoul d pr ecede

tr eatment and pr oceed on a fi xed schedul e. Unschedul ed medi cati ons r equi r e pati ents to r ecogni ze pr odr omes or devel op symptoms befor e an anti emeti c i s admi ni ster ed. It i s essenti al that pati ents who r ecei ve emetogeni c tr eatments ar e not l eft to r el y on unschedul ed anti emeti cs; however, i t i s al so rati onal to pr ovi de a suppl y of anti emeti c medi cati ons that pati ents can sel f-admi ni ster for symptoms that sur mount (i .e., “br eakthr ough”) pr i mar y pr ophyl axi s.

TREATMENT FOR BREAKTHROUGH SYMPTOMS Up to 50% of pati ents r ecei vi ng hi ghl y emetogeni c therapy may exper i ence br eakthr ough symptoms. Consequentl y, pati ents who r ecei ve moderatel y or mor e hi ghl y emetogeni c tr eatment shoul d r ecei ve a suppl y of medi cati on to tr eat br eakthr ough symptoms and cl ear i nstr ucti ons about how to modi fy thei r pr ophyl acti c r egi men. Cycl i c emetogeni c tr eatments pr esent an oppor tuni ty to eval uate a pati ent's subopti mal r esponse to anti emeti c pr ophyl axi s: Does an unsuccessful pr ophyl axi s strategy consti tute an adequate tr i al ? Can emeti c contr ol be i mpr oved wi th the same dr ugs by escal ati ng doses or by shor teni ng admi ni strati on i nter val s? Al ter nati vel y, i t may be pr eferabl e to “r escue” a pati ent fr om a subopti mal r esponse by addi ng one or mor e agents fr om a phar macol ogi c cl ass that compl ements or potenti ates dr ugs al r eady i n use r epl aci ng a dr ug wi th a mor e potent agent fr om the same phar macol ogi c cl ass. Ei ther one or both strategi es may be uti l i zed wi th cycl i c tr eatment or to i nter vene when r esponse to pr ophyl axi s i s unsati sfactor y. Mi ti gati ng factor s to be consi der ed i n devel opi ng a tr eatment strategy for br eakthr ough symptoms i ncl ude the fol l owi ng: Di mi ni shed gastr oi ntesti nal moti l i ty and i mpai r ed dr ug absor pti on fr om the gut ar ound ti mes when emeti c symptoms occur

Some pati ents may be too i l l to swal l ow and r etai n oral medi cati ons Rectal supposi tor i es ar e a practi cal al ter nati ve, but cl i ni ci ans shoul d ascer tai n whether a pati ent fi nds that r oute of admi ni strati on acceptabl e befor e anti ci pati ng compl i ance. Avoi d sustai ned-r el ease dr ug pr oducts for tr eati ng acute symptoms Br eakthr ough symptoms r equi r e a rapi dl y acti ng i nter venti on for whi ch sustai ned-r el ease dr ug pr oducts ar e i l l sui ted.

ANTIEMETIC COMBINATIONS Anti emeti cs i n combi nati on can be mor e effecti ve than si ngl e agents. The rati onal e for combi ni ng anti emeti c agents i s to i mpr ove neur otransmi tter bl ockade by tar geti ng mul ti pl e r eceptor types decr ease the adver se effects associ ated wi th (a) a pati ent's mal i gnant di sease (e.g., anxi ety), (b) anti neopl asti c tr eatment (e.g., di ar r hea), and (c) other anti emeti c agents (e.g., sedati on, extrapyrami dal effects), whi ch may i mpr ove thei r overal l comfor t and abi l i ty to tol erate tr eatment devel op si mpl e anti emeti c strategi es sui tabl e for outpati ents that decr ease the durati on of hospi tal i z ati on and the amount of ti me spent i n an ambul ator y car e setti ng. Numer ous studi es have demonstrated that acute-phase emeti c contr ol i s consi derabl y i mpr oved when 5-HT 3 r eceptor antagoni sts and gl ucocor ti coi ds ar e combi ned. An NK1 r eceptor antagoni st, apr epi tant, al so contr i butes to anti emeti c acti vi ty and augments symptom contr ol dur i ng the acute phase when i t i s used i n combi nati on wi th a 5-HT 3 r eceptor antagoni st and gl ucocor ti coi d. Del ayed-phase contr ol i s i mpr oved by gl ucocor ti coi ds or apr epi tant or both dr ugs combi ned; however, medi cati on use can be compl i cated by apr epi tant, whi ch may al ter the metabol i sm and el i mi nati on of other dr ugs. In cases i n whi ch pr ophyl axi s agai nst del ayed-phase symptoms i s i ndi cated but apr epi tant may adver sel y i nteract wi th other medi cati ons, gl ucocor ti coi ds al one or i n

combi nati on wi th ei ther metocl oprami de or a 5-HT 3 antagoni st and per haps wi th dopami ne (D2 ) r eceptor antagoni sts may pr ovi de adequate contr ol .

PLANNING ANTIEMETIC PROPHYLAXIS Pl anni ng effecti ve anti emeti c pr ophyl axi s for chemotherapy entai l s eval uati ng each agent's emeti c potenti al ; the sever i ty, onset, and durati on of symptoms; and how dr ug dosage, schedul e, and r oute of admi ni strati on may affect those factor s. An exper t panel has devel oped a method for categor i z i ng the emeti c potenti al of dr ugs (see Tabl e 40.3) and an al gor i thm wi th whi ch one may pr edi ct the cumul ati ve emeti c potenti al of dr ug combi nati ons (see Tabl e 40.4) (7,8,9,10,11).

TABLE 40.3. Emetic Potential as a Function of Drug, Dosage, and Route of Administration Emetic potential

Drug name and dosage range

Incidence of emesis a

Carmustine (>250 mg/m 2 ) Cisplatin (≥50 mg/m2 ) Cyclophosphamide (>1,500 mg/m2 ) Level 5 (very high)

Dacarbazine Lomustine (>60

>90%

mg/m 2 ) Mechlorethamine Streptozocin Amifostine (>500 mg/m 2 ) Busulfan (>4 mg/kg/d) Carboplatin Carmustine (≤250 mg/m 2 ) Cisplatin (750–≤1,500 mg/m 2 )

Level 4 (high)

Cytarabine (>1,000 mg/m 2 ) Dactinomycin (>1.5 mg/m 2 ) Doxorubicin (>60 mg/m 2 )

60%– 90%

Epirubicin (>90 mg/m 2 ) Melphalan (i.v., >50 mg/m 2 ) Methotrexate (>1,000 mg/m 2 ) Mitoxantrone (>15 mg/m 2 ) Procarbazine Aldesleukin (>12–15 Million International Units/m 2 ) Altretamine Amifostine (>300– ≤500 mg/m2 ) Arsenic trioxide Cyclophosphamide (≤750 mg/m2 ) Cyclophosphamide (oral, for multiple consecutive days)

Dactinomycin (≤1.5 mg/m 2 ) Daunorubicin

Level 3 (moderate)

Doxorubicin (20–60 mg/m 2 ) Epirubicin (≤90 mg/m 2 ) Idarubicin Ifosfamide Irinotecan Lomustine (75 mg/m 2 ) Pentostatin Plicamycin

30%– 60%

Amifostine (≤300 mg/m 2 ) Asparaginase Bexarotene Capecitabine Cytarabine (5 scheduled feedings/day, reliance on nutritious liquids (quenching thirst) without need for appetite Nausea: ↓ fat foods/supplements (e.g., Biocare, Boost, Resource drink) Malabsorption: semi-elemental palatable products (e.g., Propeptide oral formulation) Diarrhea: ↓ lactose, ↓ fat, ↓ insoluble fiber, ↓ soluble fiber (e.g., Benefiber and Ensure light) Fat malabsorption: ↓ fat diet and MCT5,000 (IU)/d, B6 >200 mg/d, chromium >200 mg/d Vitamin D >1,600 IU/d, Fe >15 mg/d (unless Fe deficiency clear), Zn >25 mg/d. Vitamin C >250 mg/d may alter renal excretion of chemotherapy. Any single antioxidant taken in excess (e.g., α-carotene) may cause a pro-oxidant state or malabsorption of other antioxidants (Vitamin E Ta ble o f C o nt e nt s > Se c t io n 1 2 - Ta rge t e d Tre a t m e nt s a nd C o m plim e nt a ry a nd Alt e rna t iv e M e dic ine > 4 3 - Ta rge t e d The ra pie s

43 Targeted Therapies James L. Gulley* Gregory Curt† *Labor ator y of Tumor Immunology and Biology, Center for Cancer Resear ch, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland † Astr aZeneca

Oncology, G ar r ett Par k, Mar yland

The i deal phar maceuti cal agent acts on the tar get ti ssue wi thout bei ng toxi c to other ti ssues, ther eby havi ng a wi de therapeuti c i ndex. Ini ti al anti cancer agents fel l far shor t of thi s i deal , wi th l i mi ted anti tumor acti vi ty and consi derabl e toxi ci ty to nor mal ti ssues. Newer cl asses of pr omi si ng dr ugs that tar get mol ecul ar str uctur es or pathways uni que to tumor s ar e bei ng devel oped. Thi s chapter pr ovi des a br i ef over vi ew on U.S. Food and Dr ug Admi ni strati on (F DA)–appr oved tar geted therapi es.

MONOCLONAL ANTIBODIES Monocl onal anti bodi es (MABs) take advantage of the exqui si te speci fi ci ty i nher ent i n the i mmune system. The fi r st generati on of mur i ne MABs had di sappoi nti ng cl i ni cal r esul ts despi te the abi l i ty to tar get tumor s appr opr i atel y. Thi s was caused by a l ack of effector functi on of mur i ne anti bodi es i n humans (i .e., i nabi l i ty to faci l i tate anti body-dependent cel l ul ar cytotoxi ci ty or to compl ement medi ated l ysi s) that was attr i butabl e to l ack of mur i ne F c (constant fragment of an anti body mol ecul e) functi onal i ty i n humans and to si gni fi cant i nducti on of human anti –mouse-anti bodi es (HAMAs). Thi s was over come ei ther by addi ng functi onal i ty to the anti bodi es (e.g., addi ng a radi oi sotope or toxi n) or by “humani z i ng” the anti body to gai n effector functi on and to decr ease i mmunogeni ci ty. Some MABs ar e compl etel y human except for sel ect segments of the

hyper var i abl e domai n of the anti body (see F i g. 43.1). Several MABs have been F DA appr oved for ei ther di agnosti c testi ng or cancer therapy (see Tabl e 43.1).

TABLE 43.1. U.S. Food and Drug Administration (FDA)-approved Monoclonal Antibodies (MABs) for Cancer Treatment Generic name

Rituximab

Tositumomab and I-131 tositumomab a

(90)Yibritumomab tiuxetan b

Trade name

Rituxan

Bexxar

Zevalin

Target

FDA indication

CD20

Relapsed or refractory, low-grade or follicular, CD20 + NHL

CD20

Refractory to rituximab, relapsed, CD20 + follicular NHL

CD20

Relapsed or refractory, low-grade, or transformed B-cell lymphoma

Alemtuzumab

Gemtuzumab ozogamicin

Trastuzumab

Bevacizumab

Cetuximab

Campath1H

Mylotarg

Herceptin

Avastin

Erbitux

CD52

Salvage Bcell CLL

CD33

Relapsed acute myeloid leukemia

HER2/neu

HER-2+ metastatic breast cancer

VEGF

Metastatic colorectal cancer, frontline with 5-FU

EGFR

Second line for metastatic colorectal cancer in combination with irinotecan

NHL, non-Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; VEGF, vascular endothelial growth factor; 5-FU, 5-fluorouracil;

EGFR, epidermal growth factor receptor. a Unlabeled antibody is given first followed by labeled antibody. (131)I is both a β and γ emitter. b Rituxumab is given first then (111)In labeled antibody (to assess biodistribution), then therapeutic (90)Y labeled antibody. (90)Y is a β emitter.

FIG. 43.1. F ul l y human and ful l y mur i ne anti bodi es have al l r egi ons fr om thei r r especti ve speci es. Chi mer i c anti bodi es general l y have the constant r egi ons fr om humans and var i abl e r egi ons fr om other speci es, wher eas humani zed anti bodi es general l y have onl y sel ect r egi ons (such as the hyper var i abl e r egi on) fr om another speci es.

The nomencl atur e of MABs has a few uni que r ul es. G ener i c names of MABs or fragments end i n “mab.” In addi ti on, an MAB wi th the suffi x “omab” i ndi cates a mur i ne anti body, “xi mab” i ndi cates a chi mer i c anti body, and “z umab” i ndi cates a humani zed anti body.

Rituximab (Rituxan) Ri tuxi mab (Ri tuxan) i s a chi mer i c MAB that tar gets CD20, a mar ker found on B cel l s.

It i s i ndi cated for r el apsed or r efractor y, l ow-grade or fol l i cul ar, CD20 + non-Hodgki n l ymphoma (NHL). Overal l r esponse (OR) rate of si ngl e-agent r i tuxi mab was 48% , wi th 6% compl ete r esponse (CR) i n a mul ti center, open-l abel , si ngl e-ar m study of 166 pati ents wi th r el apsed or r efractor y l owgrade or fol l i cul ar B-cel l NHL (1). The medi an durati on of r esponse was 11.2 months (range, 1.9 to mor e than 42.1 months). See Chapter 28 for detai l s about use. Toxi ci ti es i ncl ude astheni a, di z z i ness, headache, nausea, vomi ti ng, pr ur i tus, and rash (common), and i nfecti on and hematol ogi c, car di ac, and r enal toxi ci ty (ser i ous).

Trastuzumab (Herceptin) Trastuz umab (Her cepti n) i s a humani zed anti body that tar gets the human epi der mal gr owth factor r eceptor (HER-2), whi ch i s over expr essed i n a var i ety of cancer s. It i s i ndi cated i n pati ents wi th br east cancer who over expr ess HER-2, ei ther i n combi nati on wi th pacl i taxel as up-fr ont tr eatment for di sease, or as a si ngl e agent for those who have fai l ed ear l i er chemotherapy. In a pi votal phase III tr i al of 469 pati ents wi th HER-2–posi ti ve br east cancer who had not pr evi ousl y r ecei ved chemotherapy for metastases, the pati ents wer e randomi zed to r ecei ve chemotherapy wi th or wi thout traz tuz umab. In contrast to the ar m that r ecei ved chemotherapy wi thout traz tuz umab, the combi nati on ar m had a l onger medi an ti me to di sease pr ogr essi on (TTP) (7.4 ver sus 4.6 months; p 3 d Administration of total parenteral nutrition

Need for frequent blood sampling

Several di ffer ent types of central VADs ar e avai l abl e for use i n pati ents wi th cancer (1,2,3,4,5,6). Indi vi dual ci r cumstances wi l l deter mi ne the type of VAD that i s best for a par ti cul ar pati ent. Pl aci ng and mai ntai ni ng any central VAD i s mor e compl ex, however, than i s the case wi th a si mpl e per i pheral i .v. catheter. It i s ver y i mpor tant to r ecogni ze and mi ni mi ze the potenti al for mechani cal compl i cati ons and i nfecti ons associ ated wi th the use of central VADs.

CLASSIFICATION AND APPLICATION OF DIFFERENT CENTRAL VASCULAR ACCESS DEVICES The cl assi fi cati on of central VADs i s based, i n l ar ge par t, on the fol l owi ng parameter s: the character i sti cs of each catheter 's composi ti on (e.g., pol yur ethane or si l i cone), i ts l ocati on (i .e., central or per i pheral ), and the method of i nser ti on (i .e., per cutaneous, tunnel ed, or i mpl anted). These parameter s ar e associ ated wi th both advantages and di sadvantages, whi ch ar e outl i ned i n Tabl e 45.2. A per cutaneous catheter i s i nser ted di r ectl y thr ough the ski n i nto the vessel . In tunnel ed pl acement, a par t of a catheter i s pl aced i n the subcutaneous ti ssue between the si tes of i nser ti on at the ski n (usual l y mi dway between the ni ppl e and ster num on the anter i or chest) and the vei n (subcl avi an or i nter nal jugul ar ). A Dacr on cuff posi ti oned several i nches above the exi t si te pr omotes fi br ous i ngr owth, better secur i ng the tunnel ed catheter and possi bl y decr easi ng bacter i al col oni z ati on of the catheter bel ow the cuff. Impl anted VADs have a stai nl ess steel , ti tani um, or pl asti c por t at thei r pr oxi mal end, whi ch i ncl udes a Si l asti c sel f-seal i ng septum. Once the catheter i s i nser ted, the por t i s pl aced i n a subcutaneous pocket that i s sutur ed. The Si l asti c septum of the por t can be accessed by a needl e i ntr oduced thr ough the ski n and septum, i nto the por t chamber i tsel f. Thi s i s fr equentl y done wi th a Huber needl e, whi ch has been desi gned wi th a si de hol e to mi ni mi ze damage (cor i ng) to the Si l asti c septum. Por t housi ngs ar e desi gned to pr ovi de mi ni mal di stor ti on ar ti fact on magneti c r esonance i magi ng (MRI) or

computer i zed tomography (CT) scans.

TABLE 45.2. Advantages and Disadvantages of Different Catheter Compositions, Locations, and Methods of Insertion Type

Advantages

Disadvantages

Polyurethane

• Durable • Easy to position

• Increased vascular injury

Silicone

• Decreased vascular injury

• Easily broken • More difficult to position

Composition

Location of insertion

Peripheral (basilic veins)

• Limited central insertion • Insertion by nurse

• Migration with movement or cephalic complication • Mechanical phlebitis • Maximum of two lumens • Insertion by physician

• Limited tip

Central insertion

migration • More than two lumens possible

(internal jugular or subclavian veins) • Greater central insertion complications

Methods of insertion

• Bedside placement • Easy to remove

• Increased risk of infection • Activity restrictions • Frequent maintenance

Tunneled

• Decreased risk of infection • Easy to remove

• Radiologist or surgeon insertion • Activity restrictions • Frequent maintenance

Implanted

• Decreased risk of infection • No activity restrictions • Infrequent maintenance

• Insertion by surgeon • Maximum of two lumens • Removal by surgeon

Percutaneous

The parameter s outl i ned i n Tabl e 45.2 deter mi ne, i n l ar ge par t, the appl i cabi l i ty of a par ti cul ar type of catheter for a par ti cul ar pati ent. Pol yur ethane per cutaneous catheter s, al though r el ati vel y easy to pl ace at ei ther central or per i pheral si tes, ar e general l y not sui tabl e for l ong-ter m use, gi ven the gr eater r i sk of i nfecti on and vascul ar trauma associ ated wi th thei r use. Tunnel ed and i mpl anted Si l asti c catheter s, however, al though mor e di ffi cul t to pl ace, may be associ ated wi th l ower r i sk of i nfecti on and vascul ar i njur y and can be used over l onger per i ods. The ease of car e and l i mi ted r estr i cti ons associ ated wi th i mpl anted catheter s make thei r use most desi rabl e i n pati ents who wi l l r equi r e fr equent catheter use over pr ol onged per i ods. The opti mal durati on of use for per cutaneous or Si l asti c catheter s l ocated central l y or per i pheral l y has not been adequatel y defi ned. Wi th car e and pr ompt r emoval when cl i ni cal l y i ndi cated, these catheter s may be mai ntai ned i n some pati ents for several months. Other character i sti cs of central VADs may make one type of catheter mor e appl i cabl e for an i ndi vi dual pati ent than another. For exampl e, catheter s l ocated central l y ar e usual l y l ar ger i n gauge (4 to 12 F r ) than those pl aced per i pheral l y (2 to 6 F r ) and per mi t hi gher fl ow rates and easi er drawi ng of bl ood. Lar ger-gauge catheter s can al so be constr ucted wi th mor e l umens. Al though most central VADs ar e open at the end or ti p, the G r oshong catheter (Bar d Access Systems) has a cl osed end wi th a thr ee-way sl i t val ve to r educe the potenti al backfl ow of bl ood i nto the catheter. F i gur e 45.1 shows an al gor i thm for deter mi ni ng the type of catheter most appr opr i ate for a par ti cul ar pati ent. Tabl e 45.3 shows exampl es of the di ffer ent catheter types fr equentl y used at the Nati onal Insti tutes of Heal th (NIH) War r en G . Magnuson Cl i ni cal Center.

TABLE 45.3. Examples of Frequently Insert Vascular Access Devices at the National Insti of Health Warren G. Magnuson Clinical Cen Catheter type and

Composition

Size (Fr)

Lumens

Ty dur

manufacturer

ins

Nontunneled CVCa 4, 5, 7, or 8

3

3–3

12 c

2

2–1

Silicone

5

2

6–8

Bard Rad PICC

Silicone

5

2

6–8

Quinton Mahurkar

Silicone

11.5 c

2

2–1

Polyurethane

4

1

4–8

5

2

4

1

5

2

7

2

Arrow

Bard Hohn

Polyurethane

PICC b Arrow

Bard Groshong

Silicone

Tunneled CVC Bard

Silicone

≤1

Hickman

Bard Groshong

10

2

10

3

Silicone

9.5

2

Silicone

9.6

1

Implanted ports Bard MRI

≤2

CVC, central venous catheter; PICC, peripherally inserted central venous catheter. a Centrally inserted central venous catheter. b Peripherally inserted CVC. c Used for dialysis or apheresis.

FIG. 45.1. Al gor i thm for deter mi ni ng the appr opr i ate type of catheter.

COMPLICATIONS WITH INSERTION Inser ti on of any central VAD, whether at the bedsi de, i n radi ol ogy, or i n sur ger y, i s associ ated wi th the r i sk of mechani cal compl i cati ons or i nfecti on (1,2,3,5,6). Mechani cal compl i cati ons most commonl y ar i se when catheter pl acement r esul ts i n i njur y to central vascul ar str uctur es (e.g., venous or ar ter i al per forati on) or to the l ungs (e.g., pneumo-, hemo-, or hydr othorax). The occur r ence of these types of compl i cati ons or thei r sequel ae can be r educed by ensur i ng: fi r st, that abnor mal i ti es of anatomy r el ated to pr evi ous therapy (e.g., sur ger y, radi ati on, or ear l i er VADs) or di sease (e.g., tumor ) ar e r ecogni zed befor e VAD pl acement; second, that the pati ent's coagul ati on pr ofi l e has been opti mi zed (i .e., pl atel et count br ought to >50,000 per mL and pr othr ombi n and par ti al thr ombopl asti n ti mes cor r ected); and thi r d, that car eful attenti on i s gi ven to i denti fi cati on of compl i cati ons that may become appar ent onl y several hour s after VAD pl acement (e.g., pneumo-, hemo-, or hydr othorax). In some pati ents, i n whom compl ete cor r ecti on of the coagul ati on pr ofi l e i s not possi bl e, VAD pl acement

may sti l l be done whi l e the appr opr i ate r epl acement pr oducts ar e i nfused thr ough an addi ti onal catheter. Because of the di ffi cul ti es associ ated wi th compr essi ng subcl avi an vascul ar str uctur es, per cutaneous or tunnel ed catheter i nser ti ons shoul d general l y not be per for med at thi s si te unl ess an adequate coagul ati on pr ofi l e can be achi eved. Compl i cati ons ar i si ng fr om i nfecti on fr om i nser ti on can be r educed by ensur i ng that the operator s use a str i ct ster i l e techni que and ful l bar r i er pr ecauti ons.

CARE AND MAINTENANCE Once the central VADs have been i nser ted, thei r car e and mai ntenance i ncl ude r egul ar fl ushi ng wi th a sal i ne and hepar i n sol uti on and changi ng of dr essi ngs (i .e., gauze or transpar ent) and catheter i njecti on caps. No cl ear standar d has been establ i shed wi th r espect to the vol ume, dose, and fr equency of hepar i n fl ushi ng; the type and fr equency of dr essi ng changes; or the fr equency of cap changes. However, general gui del i nes do exi st, and successful mai ntenance of a central VAD i s the r esul t of an establ i shed car e r outi ne (7,8,9). Most central VADs ar e fl ushed dai l y wi th a quanti ty of sal i ne (5 to 10 mL) and hepar i n (1 to 5 mL of a 10 to 1,000 U per mL) sol uti on equi val ent to two ti mes the vol ume of the catheter and any addi ti onal i nfusi on devi ces i n ser i es wi th the catheter. Impl anted VADs ar e fl ushed monthl y wi th sal i ne and hepar i n when not accessed. G r oshong catheter s ar e fl ushed weekl y, or after each use, wi th sal i ne onl y. G auze and transpar ent dr essi ngs ar e changed ever y 2 days and 7 days, r especti vel y. Catheter caps ar e changed after wi pi ng wi th cl eansi ng sol uti on at l east ever y 7 days, or whenever they ar e damaged or contai n r esi dual bl ood. A 2% chl or hexi di ne-based pr eparati on i s r ecommended for catheter si te car e. Al ter nati vel y, i f the pati ent cannot tol erate chl or hexi di ne, povi done–i odi ne (10% ), al cohol (70% to 92% ) sol uti ons, and hydr ogen per oxi de can be used. Whenever a central VAD i s accessed, pr ecauti ons must be taken to pr event the entr y of ai r i nto the catheter and ther eby i nto the ci r cul ati on (i .e., ai r embol us). The central VAD shoul d be cl amped between the poi nt of access and the pati ent. If a catheter does have to r emai n open for shor t per i ods, such as dur i ng i ni ti al wi r e r emoval at i nser ti on, the pati ent shoul d be i n the Tr endel enbur g posi ti on.

COMPLICATIONS AFTER INSERTION Mai ntai ni ng a central VAD for any per i od i s associ ated wi th the r i sk of i nfecti on, thr omboti c or nonthr omboti c catheter obstr ucti on, vascul ar i njur y, or fai l ur e of the VAD i tsel f. These compl i cati ons may occur at any ti me. The r epor ted i nci dence of i nfecti on r el ati ng to central VADs ranges fr om 3% to 60% but i s usual l y l ess than 10% (1,2,3,4,5,9,10,11,12). Thi s i nci dence may be hi gher i n pati ents wi th cancer who have neutr openi a r el ated to therapy or di sease. Infecti ons wi th central VADs can occur l ocal l y (i .e., exi t si te or tunnel or pocket i nfecti ons) or systemi cal l y [i .e., catheter-r el ated bl oodstr eam i nfecti ons (CR-BSIs)]. Defi ni ti ons devel oped by the Center s for Di sease Contr ol and Pr eventi on (CDC) ar e shown i n Tabl e 45.4 ( 9). Di ffer ent types of i nfecti ons wi th VADs wi l l be managed di ffer entl y (1,3,4,5,6,10,11,12,13). Exi t-si te i nfecti ons, most fr equentl y r el ated to Staphylococcus epider midis, can be tr eated i ni ti al l y wi th l ocal wound car e and oral anti bi oti cs wi thout r emovi ng the catheter. However, exi t-si te i nfecti ons r esul ti ng i n bacter emi a may r equi r e catheter r emoval , especi al l y i n cases of i nfecti ons wi th Staphylococcus aur eus. Tunnel or pocket i nfecti ons ar e most fr equentl y r el ated to S. epider midis or S. aur eus and al most al ways r equi r e systemi c anti bi oti c tr eatment and catheter r emoval , wi th sur gi cal drai nage of the i nfected si te. A defi ni ti ve di agnosi s of CR-BSI, al though not al ways possi bl e, r equi r es that the same pathogen be cul tur ed i n the bl ood drawn fr om both the central VAD and another si te. Documented or suspected CR-BSI shoul d al ways be tr eated wi th systemi c anti bi oti cs. These i nfecti ons, most fr equentl y r el ated to S. epider midis and S. aur eus, may al so be caused by ei ther the gramnegati ve bacter i a or fungal speci es to whi ch i mmunosuppr essed pati ents wi th cancer ar e suscepti bl e. The i ni ti ati on of empi r i c anti bi oti c coverage i n such pati ents must take these other or gani sms i nto account. CR-BSI can someti mes be tr eated wi th systemi c anti bi oti cs al one, but evi dence of wor seni ng i nfecti on or the pr esence of S. aur eus or candi dal i nfecti on cal l s for pr ompt r emoval of the catheter. Some central VADs ar e i mpr egnated wi th anti mi cr obi al agents [chl or hexi di ne and si l ver sul fadi az i ne (Ar r owguar d Bl ue; Ar r ow Inter nati onal ) or mi nocycl i ne and r i fampi n (Cook Spectr um; Cook Cr i ti cal Car e)] or have an attached anti mi cr obi al cuff [si l ver i on (Vi ta Cuff; Vi taphor e)]. The overal l

effecti veness of such agents i n pr eventi ng i nfecti on over the l i feti me of a central VAD conti nues to be studi ed (13,14,15,16,17,18). At pr esent, data suppor t the use of anti septi ci mpr egnated catheter s. The effecti veness of anti mi cr obi al cuffs i s not yet cl ear.

TABLE 45.4. Centers for Disease Control and Prevention (CDC) Clinical and Surveillance Definitions for Catheter-related Infections Colonized catheter

Growth of a microorganism from the catheter tip, subcutaneous segment or hub

Microbiologic exit-site infection

Erythema or induration within 2 cm of exit site without purulent drainage or bloodstream infection

Clinical exitsite or tunnel infection

Tenderness, erythema, and/or induration >2 cm from the exit site and along the subcutaneous tunnel without a bloodstream infection

Pocket infection

Erythema and necrosis of the skin over the reservoir of a total implanted device, or purulent exudate in the subcutaneous pocket containing the reservoir, in the absence of a bloodstream infection

Infusaterelated bloodstream infection

Growth of the same organism from the infusate and blood cultures with no other identifiable source of infection

CR-BSI

At least one positive blood culture from a peripheral vein, with clinical symptoms of infection and no other apparent source of infection; or the isolation of the same organism from a semiquantitative or quantitative culture of a catheter segment and from the peripheral blood; or simultaneous quantitative blood cultures with a ≥5:1 ratio of catheter vs. peripheral blood; or a differential time period of catheter culture vs. peripheral blood of >2 h.

CR-BSI, catheter-related bloodstream infections. Obstr ucti on of a VAD can be r el ated to thr omboti c or nonthr omboti c causes (10,19,20,21,22). Thr omboti c obstr ucti ons can be cl assi fi ed as those pr esent wi thi n (i ntral umi nal ) or ar ound the outsi de of (fi br i n sheath) the catheter i tsel f and those i n associ ati on wi th the vessel wal l (mural thr ombus). A catheter may someti mes become encased i n a mural thr ombus. Nonthr omboti c obstr ucti on of a central VAD can be a r esul t of mal posi ti oni ng of a catheter ti p agai nst a vessel wal l , catheter ki nki ng, l umi nal occl usi on caused by

dr ug pr eci pi tati on, or fractur e of the catheter. These types of obstr ucti on may r equi r e ei ther r eposi ti oni ng or r emoval of the catheter. When di agnosi ng the cause of an obstr ucti on, i t i s hel pful to fi r st deter mi ne whether the obstr ucti on i nter fer es wi th wi thdrawal or wi th i nfusi on or both. An al gor i thm to ai d i n the di agnosi s and tr eatment of catheter obstr ucti on i s shown i n F i g. 45.2.

FIG. 45.2. Al gor i thm to ai d i n the di agnosi s and tr eatment of catheter obstr ucti on. *Thr ombol ysi s therapy: •Ur oki nase •Str eptoki nase •r tPTA. †Jugul ar vei n di stenti on, evi dence of col l ateral ci r cul ati on, uni l ateral ar m swel l i ng. ‡Chemi cal occl usi on therapy: •Al cohol for l i pi d pr eci pi tates •0.1 Hydr ochl or i c aci d for nonl i pi d pr eci pi tates.

Vascul ar i njur y r esul ti ng i n actual per forati on of a vessel wal l i s not commonl y found wi th the fl exi bl e central VADs now i n use. Never thel ess, catheter ti ps shoul d not be posi ti oned per pendi cul ar to an adjacent vessel , such as i n the i nnomi nate vei n at i ts juncti on wi th the SVC. Because of the smal l er di ameter s of the basi l i c and cephal i c vei ns, mechani cal phl ebi ti s can someti mes occur after PICC i nser ti on. Thi s usual l y mani fests i tsel f wi thi n 1 to 7 days of i nser ti on wi th er ythema, tender ness, i ndurati on, and a pal pabl e venous cor d al ong the vessel tract. Tr eatment i s wi th moi st heat, ar m el evati on, mi l d range-of-moti on exer ci ses, and an anti i nfl ammator y agent. Mechani cal phl ebi ti s shoul d r espond to tr eatment wi thi n 24 to 48 hour s. If such a r esponse i s not noted, the catheter shoul d be r emoved, l ocal tr eatment shoul d be conti nued, and consi derati on shoul d be gi ven to a cour se of anti bi oti c therapy. Wi th use, VADs may themsel ves fai l . In per cutaneous catheter s, the sutur es or anchor i ng devi ce may l oosen, and the catheter may be pul l ed out par ti al l y or compl etel y. Any catheter that has been par ti al l y pul l ed out shoul d not be r eadvanced. If a chest radi ograph does not show the catheter ti p i n the SVC, the catheter shoul d be r emoved. The exter nal par ts of a catheter that ar e fr equentl y mani pul ated may br eak. Some catheter s have r epai r ki ts avai l abl e fr om the manufactur er s and can be safel y r epai r ed. If no r epai r ki ts ar e avai l abl e, the catheter shoul d be r emoved. In rar e i nstances, an i nter nal par t of a VAD may br eak and embol i ze. Thi s pr obl em, whi ch may be r ecogni zed onl y when the catheter i s r emoved, shoul d be addr essed i mmedi atel y wi th i nter venti onal radi ol ogy.

REMOVAL OF CENTRAL VASCULAR ACCESS DEVICES VADs that ar e nei ther tunnel ed nor i mpl anted can be r emoved at the bedsi de. Whenever r esi stance i s encounter ed dur i ng r emoval , car e shoul d be taken to avoi d sever i ng the catheter. A radi ograph or fl uor oscopy shoul d be used to deter mi ne whether the catheter has become ki nked or knotted. In some cases, especi al l y wi th PICC VADs, thr ombosi s may devel op, pr eventi ng catheter r emoval . When a VAD has been i n pl ace for a pr ol onged per i od, especi al l y i n the case of central l y pl aced pol yur ethane catheter s, a fi stul a, l ar ge enough to per mi t ai r entr y after catheter r emoval , may devel op.

After VAD r emoval , the si te shoul d be dr essed to pr event thi s fr om happeni ng. Tunnel ed Si l asti c catheter s can al so be r emoved at the bedsi de. However, i f a tunnel ed catheter has a cuff (or cuffs) associ ated wi th i t, any r esul tant adhesi ons may necessi tate i nci si on and di ssecti on for catheter r emoval . Impl anted catheter s r equi r e sur gi cal r emoval .

References 1. Al exander HR. Vascul ar access and speci al i zed techni ques of dr ug del i ver y. In: DeVi ta VT Jr, Hel l man S, Rosenber g SA, eds. Cancer : pr inciples and pr actice of oncology, 5th ed. Phi l adel phi a, PA: Li ppi ncott–Raven Publ i sher s, 1997:725–734. 2. Lucas AB, Stei nhaus EP, Tor osi an MH. Long ter m venous access catheter s and i mpl anted por ts. In: HR Al exander, ed. Vascular access in the cancer patient: devices, inser tion techniques, maintenance, and pr evention and management of complications, Phi l adel phi a, PA: JB Li ppi ncott Co, 1994:3–35. 3. G ar ci a JP, Osteen RT. Vascul ar access for cancer therapy. In: Macdonal d JS, Hal l er DG , Mayer RJ, eds. Manual of oncologic ther apeutics, 3r d ed. Phi l adel phi a, PA: JB Li ppi ncott Co, 1995:67–70. 4. Lucas AB. A cr i ti cal r evi ew of venous access devi ces: the nur si ng per specti ve. In: Hubbar d SM, G r een PE, Knobf MT, eds. Cur r ent issues in cancer nur sing pr actice, Phi l adel phi a, PA: JB Li ppi ncott Co, 1991:1–10. 5. Raaf J. Vascul ar access, catheter technol ogy and i nfusi on pumps. In: Moosa AR, Schi mpff SC, Robson MC, eds. Compr ehensive textbook of oncology, 2nd ed., Vol 1. Bal ti mor e, MD: Wi l l i ams & Wi l ki ns, 1991:583–589. 6. Shoemaker WC. Intravascul ar access and l ong-ter m catheter mai ntenance. In: Ayr es SM, G r envi k A, Hol br ook PR et al , eds. Textbook of cr itical car e, 3r d ed. Phi l adel phi a, PA: WB Saunder s, 1995:234–252. 7. Intravenous Nur si ng Soci ety. Standar ds of practi ce

suppl ement. J Intr aven Nur s 2000;21:1S. 8. Oncol ogy Nur si ng Soci ety. Access device guidelines module: catheter s: r ecommendations for nur sing education and pr actice. Pi ttsbur gh, PA: Oncol ogy Nur si ng Pr ess, 1995. 9. Center s for Di sease Contr ol and Pr eventi on. G uidelines for pr evention of intr avascular infections. Atl anta, G A. 2002. 10. Hoch JR. Management of compl i cati ons of l ong-ter m venous access. Semin Vasc Sur g 1997;10:135–143. 11. G r oeger JS, Lucas AB, Thal er HT, et al . Infecti ous mor bi di ty associ ated wi th l ong-ter m use of venous access devi ces i n pati ents wi th cancer. Ann Inter n Med 1993;119:1168–1174. 12. Lucas AB, Stei nhaus EP, Tor osi an MH. Types of catheter r el ated i nfecti ons. In: Al exander HR, ed. Vascular access in the cancer patient, devices, inser tion techniques, maintenance, and pr evention and management of complications, Phi l adel phi a, PA: JB Li ppi ncott Co, 1994:113–127. 13. Tol tz i s P, G ol dmann DA. Cur r ent i ssues i n central venous catheter i nfecti on. Annu Rev Med 1990;41:169–176. 14. G r oeger JS, Lucas AB, Coi t D, et al . A pr ospecti ve, randomi zed eval uati on of the effect of si l ver i mpr egnated subcutaneous cuffs for pr eventi ng tunnel ed chr oni c venous access catheter i nfecti ons i n cancer pati ents. Ann Sur g 1993;218:206– 210. 15. Maki DG , Cobb L, G ar man JK, et al . An attachabl e si l veri mpr egnated cuff for the pr eventi on of i nfecti on wi th central venous catheter s: a pr ospecti ve randomi zed mul ti center tr i al . Am J Med 1988;85:307–314. 16. Dar oui che RO, Raad II, Hear d SO, et al . A compar i son of two anti mi cr obi al -i mpr egnated central venous catheter s. N Engl J Med 1999;340:1–8.

17. Maki DG , Stol z SM, Wheel er S, et al . Pr eventi on of central venous catheter-r el ated bl oodstr eam i nfecti on by use of an anti septi c-i mpr egnated catheter. Ann Inter n Med 1997;127:257– 266. 18. Raad II, Dar oui che R, Dupui s J, et al . Central venous catheter s coated wi th mi nocycl i ne and r i fampi n for the pr eventi on of catheter-r el ated col oni z ati on and bl oodstr eam i nfecti ons. Ann Inter n Med 1997;127:267–274.

19. Rumsey K, Ri char dson D. Management of i nfecti on and occl usi on associ ated wi th vascul ar access devi ces. Semin Oncol Nur s 1995;11:174–183. 20. Wi l l i ams E. Catheter-r el ated thr ombosi s. Clin Car diol 1990;13:34–36. 21. Lucas AB, Stei nhaus EP, Tor osi an MH. Catheter occl usi on and per si stent wi thdrawal occl usi on. In: Al exander HR, ed. Vascular access in the cancer patient: devices, inser tion techniques, maintenance, and pr evention and management of complications, Phi l adel phi a, PA: JB Li ppi ncott Co, 1994:91–107. 22. Reed T, Phi l l i ps D. Management of central venous catheter occl usi ons and r epai r s. J Intr aven Nur s 1996;19:289–294.

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 1 3 - C o m m o n P ro c e dure s a nd C he m o t he ra py Drugs > 4 6 - P ro c e dure s in M e dic a l O nc o lo gy

46 Procedures in Medical Oncology Suzanne G. Demko Kerry Ryan Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland Medical Oncology Clinical Resear ch Unit, National Cancer Institute, National Institutes of Health, Bethesda, Mar yland As i n other subspeci al ti es, pr ocedur es per for med i n an oncol ogy setti ng can ser ve the dual pur poses of di agnosi s and tr eatment. Thi s chapter outl i nes those medi cal oncol ogy pr ocedur es that ar e commonl y per for med and br i efl y di scusses any speci al consi derati ons or techni ques that may be of assi stance i n per for mi ng these pr ocedur es rapi dl y, wi th confi dence, and wi th an eye towar d pati ent comfor t and educati on.

INFORMED CONSENT Wr i tten i nfor med consent, or a l egal l y suffi ci ent substi tute, must be obtai ned befor e ever y pr ocedur e and shoul d be fi l ed i n the pati ent's medi cal r ecor d.

ANESTHESIA Local anesthesi a shoul d be used for al l pr ocedur es, and pr emedi cati on wi th a nar coti c and benzodi azepi ne [pr eferabl y, fentanyl and mi dazol am (Ver sed)] shoul d be consi der ed for cer tai n pati ents and pr ocedur es. Li docai ne, 1% mi xed i n a 3:1 or 5:1 rati o wi th sodi um bi car bonate, wi l l ensur e pr oper anestheti c effect and wi l l al so vi r tual l y el i mi nate the typi cal sti ng of l i docai ne.

INSTRUMENTATION

Most offi ces and hospi tal s ar e equi pped wi th ster i l e trays or sel fcontai ned di sposabl e ki ts that ar e speci fi c to each pr ocedur e. Wher e addi ti onal i nstr uments ar e needed because of operator pr efer ence or other consi derati ons, they may be added.

PROCEDURES Bone Marrow Aspirate/Bone Marrow Biopsy Indications Di agnosti c: for the anal ysi s of abnor mal i ty i n pr oducti on of bl ood cel l s and for the pur pose of stagi ng i n hematol ogi c and nonhematol ogi c mal i gnanci es.

Contraindications Sever e thr ombocytopeni a (pl atel ets 1 mL wi l l be di l uted by per i pheral bl ood. Spi cul es of bone mar r ow wi l l be pr esent unl ess si gni fi cant fi br osi s i s pr esent or the mar r ow i s packed wi th l eukemi c or other mal i gnant cel l s. If no speci men i s obtai ned, r epl ace the obturator and car eful l y advance the needl e 2mm to 3 mm. Repeat the aspi rati on pr ocess. Pr epar e smear s for eval uati on. Poster i or super i or i l i ac cr est aspi rati on and bi opsy: 1. In general , an 11-gauge Jamshi di -type needl e i s used to obtai n bi opsy speci mens. Under speci al ci r cumstances (e.g., spongy bone mar r ow or easi l y compr essed mar r ow), a l ar gergauge needl e (8-gauge) may be used to obtai n an adequate bi opsy speci men. 2. The pati ent may be posi ti oned pr one; however, the l ateral decubi tus posi ti on may be used i nstead for better i denti fi cati on of anatomi c si tes or for pati ent comfor t. For al l but the most obese pati ents, these posi ti ons may be used for aspi rati on and bi opsy. For extr emel y obese pati ents or for those who have had radi ati on to the pel vi s, the anter i or i l i ac cr est may be used for sampl i ng. 3. Once the si te has been pr epar ed and anestheti zed, advance

the needl e i nto the cor tex of the bone unti l i t i s fi xed. Attempt aspi rati on and, i f unsuccessful , advance the needl e sl i ghtl y and attempt agai n. 4. Once the aspi rate i s obtai ned, advance the needl e usi ng a twi sti ng moti on, wi thout the obturator i n pl ace, to obtai n the bi opsy speci men. A 1.5- to 2-cm speci men i s r ecommended. To ensur e that the speci men i s col l ected when the needl e i s r emoved, fi r st r otate the needl e br i skl y i n one di r ecti on and then i n the other di r ecti on, and then “r ock” gentl y by exer ti ng pr essur e per pendi cul ar to the shaft of the needl e i n four di r ecti ons wi th the needl e capped. Then gentl y r emove the needl e whi l e r otati ng i n a cor kscr ew manner. Remove the speci men fr om the needl e by pushi ng i t up thr ough the hub wi th a styl et pr ovi ded for thi s pur pose, taki ng car e to avoi d needl esti ck i njur i es whi l e r emovi ng the speci men. Jamshi di needl e ki ts pr ovi de a smal l , cl ear pl asti c gui de to faci l i tate thi s pr ocess.

Aftercare A pr essur e dr essi ng i s pl aced over the si te, and exter nal pr essur e i s appl i ed for 5 to 10 mi nutes. Di r ect pr essur e i s the pr efer r ed method to avoi d pr ol onged bl eedi ng and hematoma for mati on. The pr essur e dr essi ng shoul d r emai n i n pl ace for 24 hour s. The pati ent may r emove the pr essur e dr essi ng and shower after 24 hour s; however, the pati ent shoul d avoi d i mmer si on of the si te i n water for 1 week after the pr ocedur e i n or der to avoi d i nfecti on.

Complications Infecti on and hematoma for mati on ar e the most common compl i cati ons after bone mar r ow bi opsy and aspi rati on, and can be mi ni mi zed by usi ng car eful techni ques dur i ng and after the pr ocedur e.

Documentation Pr epar e a pr ocedur e note.

Lumbar Puncture

Indications Di agnosti c [anal ysi s of cer ebr ospi nal fl ui d (CSF ) to assess adequacy of tr eatment] CSF pr essur e measur ement to assess adequacy of tr eatment Admi ni strati on of i ntrathecal chemotherapy

Contraindications Incr eased i ntracrani al pr essur e Coagul opathy Infecti ous pr ocess near the pl anned access si te

Anatomy The conus medul l ar i s rar el y ends bel ow L3 (i .e., L1 to L2 i n adul ts and L2 to L3 i n chi l dr en), and i nter spaces above thi s shoul d be avoi ded (see F i g. 46.2).

FIG. 46.2. Anatomy of the l umbar spi ne. (F r om Chestnut MS, Dewar TN, Locksl ey RM, et al . Lumbar punctur e. In: Chestnut MS, Dewar TN, Locksl ey RM, eds. Offi ce & bedsi de pr ocedur es. Nor wal k, CT: Appl eton & Lange, 1992:391, wi th per mi ssi on.)

The L4 spi nous pr ocess or the L4-5 i nter space l i es i n the center of the supracr i stal pl ane (a l i ne drawn between the poster i or super i or i l i ac cr ests). Ther e ar e ei ght l ayer s fr om the ski n to the subarachnoi d space; they ar e ski n, supraspi nous l i gament, i nter spi nous l i gament, l i gamentum fl ava, epi dural space, dura, subarachnoi d membrane, and subarachnoi d space.

Procedure 1. Descr i be the pr ocedur e to the pati ent and assur e hi m or her that you wi l l expl ai n what you ar e about to do befor e you do i t. 2. Posi ti on the pati ent i n the l ateral decubi tus posi ti on at the edge of the tabl e or bed, wi th knees pul l ed upwar d and head fl exed downwar d towar d chest (see F i g. 46.3). If the spi nal col umn appear s to be mi sal i gned, pl ace a pi l l ow beneath the pati ent to assur e pr oper al i gnment. Thi s posi ti on may be substi tuted wi th the seated posi ti on i f the pati ent i s obese or has di ffi cul ty r emai ni ng i n the l ateral decubi tus posi ti on for any r eason.

FIG. 46.3. Lateral decubi tus posi ti on for l umbar punctur e. (F r om Chestnut MS, Dewar TN, Locksl ey RM, et al . Lumbar punctur e. In: Chestnut MS, Dewar TN, Locksl ey RM, eds. Offi ce & bedsi de pr ocedur es. Nor wal k, CT: Appl eton & Lange, 1992:390, wi th per mi ssi on.)

3. Assess the anatomi c l andmar ks and i denti fy the i nter space to be used for the pr ocedur e. 4. Usi ng ster i l e techni que, pr epar e the ar ea and one i nter space above or bel ow i t wi th povi done–i odi ne sol uti on. Drape the pati ent, establ i shi ng a ster i l e fi el d. 5. Usi ng 1% l i docai ne–bi car bonate mi xtur e, anestheti ze the ski n and deeper ti ssues, bei ng car eful to avoi d admi ni ster i ng epi dural or spi nal anesthesi a. 6. Inser t the spi nal needl e i nto the anestheti zed ski n and i nto the spi nous l i gament, keepi ng the needl e paral l el to the bed or tabl e. Immedi atel y change the angl e of the needl e to between 30 and 45 degr ees, di r ecti ng the needl e cephal ad. The bevel of the needl e shoul d be posi ti oned to face the pati ent's fl anks to al l ow the needl e to spr ead rather than cut the dural sac. Begi n to advance the needl e i n smal l i ncr ements thr ough the l ayer s and r emove the styl et to check for CSF befor e each new advance of the needl e. Wi th practi ce, the operator may be abl e to i denti fy the “pop” thr ough the dura i nto the subarachnoi d space, but even an exper i enced operator woul d be wi se to check for CSF befor e each advance of the needl e.

7. Havi ng confi r med the pr esence of CSF, attach a manometer to measur e the openi ng pr essur e. Col l ect appr opr i ate sampl es of CSF. Send the sampl es i n the fol l owi ng or der : tube 1, cul tur es; tube 2, chemi str i es (especi al l y gl ucose and pr otei n); tube 3, cel l count and di ffer enti al ; and tube 4, cytopathol ogi c or other speci al studi es (fl ow cytometr y, cytogeneti cs, etc.). Typi cal l y, a total of 8 to 15 mL of CSF i s r emoved dur i ng l umbar punctur es (LPs). However, i f speci al studi es ar e r equi r ed, 40 mL of fl ui d can be r emoved safel y. If i ntrathecal chemotherapy i s to be admi ni ster ed, attach the syr i nge to the spi nal needl e, tube adapter, or stopcock, and admi ni ster by sl ow push. 8. Wi thdraw the needl e, obser ve the si te for CSF l eak or hemor r hage, and pl ace an appr opr i ate bandage over the si te. 9. Transfer the pati ent to a r ecumbent posi ti on and ask the pati ent to r emai n i n thi s posi ti on for 5 to 10 mi nutes. Ther e appear s to be no r el ati on between postpr ocedur e posi ti oni ng and spi nal headache; however, a r el ati onshi p does exi st for needl e si ze, CSF l eak, and spi nal headache. The pati ent shoul d be i nstr ucted to dr i nk 2 to 3 L of fl ui d over the next 24 hour s, i n or der to r epl eni sh the CSF r emoved.

Complications Spi nal headache can occur i n appr oxi matel y 20% of pati ents after LP. It i s a character i sti c headache, i n that i t i s pr esent as a poundi ng ache i n the occi pi tal r egi on when the pati ent i s upr i ght and r esol ves when the pati ent l i es down. Cer tai n categor i es of pati ents ar e mor e l i kel y to have a post-LP headache. Femal e pati ents, those wi th a hi stor y of headache pr i or to LP, or those of a younger age gr oup (peak age 20 to 40 year s) ar e associ ated wi th the hi ghest i nci dence of post-LP headache. F l ui d i ntake shoul d be encouraged, over-the-counter anal gesi cs shoul d be suggested, and the pati ent shoul d be i nstr ucted to r emai n r ecumbent, i f possi bl e. Spi nal headaches can be qui te sever e and may l ast for about 1 week. If thi s i s the case, str onger anal gesi a, caffei ne, or a bl ood patch pr ocedur e may be i ndi cated. Ner ve r oot trauma can occur, but i t does so onl y i nfr equentl y.

Thi s compl i cati on can be avoi ded by choosi ng a l ow i nter space as the entr y si te. Cer ebel l ar or medul l ar her ni ati on occur s onl y rar el y, i n some pati ents who have i ncr eased i ntracrani al pr essur e. If r ecogni zed ear l y, thi s pr ocess can be r ever sed. Infecti ons, i ncl udi ng meni ngi ti s, can al so occur. Bl eedi ng r esul ti ng i n a smal l number of r ed bl ood cel l s (RBCs) i n the CSF i s a common occur r ence i n pati ents under goi ng an LP. However, ser i ous bl eedi ng can r esul t i n spi nal compr omi se i n appr oxi matel y 1% to 2% of pati ents. Ser i ous bl eedi ng usual l y occur s onl y i n pati ents who have thr ombocytopeni a or bl eedi ng di sor der s, or who have r ecei ved anti coagul ants befor e or after under goi ng an LP.

Paracentesis Indications Pati ents wi th asci tes as a r esul t of tumor metastasi s or obstr ucti on often benefi t fr om therapeuti c paracentesi s. Wher e the di agnosi s i s i n doubt, or to assess di agnosti c mar ker s, di agnosti c paracentesi s can be per for med.

Contraindications Ther e ar e few si tuati ons i n whi ch one woul d hesi tate to per for m a paracentesi s. The compl i cati on rate for thi s pr ocedur e i s mi nuscul e (about 1% ), and the benefi t der i ved by the pati ent can be qui te r emar kabl e. Thi s i s especi al l y tr ue of therapeuti c paracentesi s. Even i n the event of a coagul opathy, the benefi t outwei ghs the r i sks i n per for mi ng thi s pr ocedur e.

Anatomy One shoul d i denti fy the ar ea of gr eatest dul l ness i n the abdomen by per cussi on. As an al ter nati ve, one can have the asci tes

“mar ked” by havi ng the pati ent under go an ul trasound. Car e shoul d be taken to avoi d the abdomi nal vascul atur e and vi scera.

Procedure 1. Pl ace the pati ent i n a comfor tabl e supi ne posi ti on on the edge of the bed or tabl e. 2. Identi fy the ar ea of the abdomen to be accessed (see F i g. 46.4).

FIG. 46.4. Si tes for di agnosti c paracentesi s. (F r om Chestnut MS, Dewar TN, Locksl ey RM, et al . G astr oi ntesti nal pr ocedur es. In: Chestnut MS, Dewar TN, Locksl ey RM, eds. Offi ce & bedsi de pr ocedur es. Nor wal k, CT: Appl eton & Lange, 1992:269, wi th per mi ssi on.)

3. Pr epar e the ar ea wi th povi done–i odi ne sol uti on and establ i sh a ster i l e fi el d by drapi ng the pati ent. 4. Anestheti ze the ar ea wi th 1% l i docai ne–bi car bonate mi xtur e. 5. For di agnosti c paracentesi s, i nser t a 22- to 25-gauge needl e attached to a ster i l e syr i nge i nto the ski n, and pul l the ski n l ateral l y befor e advanci ng the needl e i nto the abdomen. After

r el easi ng the tensi on on the ski n, advance the needl e i n the per i toneal cavi ty, wi thdraw an appr opr i ate amount of fl ui d, and send for testi ng. The ski n-r etracti on method cr eates a “Z” tract i nto the per i toneal cavi ty, and thi s mi ni mi zes the r i sk of asci ti c l eak after the pr ocedur e (see F i g. 46.5).

FIG. 46.5. “Z-tracki ng” techni que for needl e i nser ti on i nto the per i toneal cavi ty. (F r om Chestnut MS, Dewar TN, Locksl ey RM, et al . Bone mar r ow aspi rati on & bi opsy. In: Chestnut MS, Dewar TN, Locksl ey RM, eds. Offi ce & bedsi de pr ocedur es. Nor wal k, CT: Appl eton & Lange, 1992:381, wi th per mi ssi on.)

6. For therapeuti c paracentesi s, use the Z-tract method wi th a mul ti pl e-por t fl exi bl e catheter over a gui de needl e. When the catheter i s i n pl ace, evacuate the asci tes i nto mul ti pl e contai ner s. One must, however, be car eful that the pati ent r emai ns hemodynami cal l y stabl e dur i ng the r emoval of l ar ge amounts of asci tes. 7. When the pr ocedur e has been compl eted, wi thdraw the needl e or catheter and pl ace a pr essur e bandage over the si te. Look for any bl eedi ng or asci ti c l eak befor e pl aci ng the bandage. 8. After a therapeuti c paracentesi s i s per for med, the pati ent shoul d r emai n i n a supi ne posi ti on unti l al l vi tal si gns ar e stabl e and shoul d be assi sted when r i si ng fr om the bed or tabl e for the fi r st ti me after the pr ocedur e. 9. If the pati ent becomes or thostati c, standar d medi cal measur es

shoul d be used to r ever se thi s pr ocess, and he or she must be hemodynami cal l y stabl e befor e bei ng al l owed to l eave.

Complications Al though the sel ecti on of an adequate si te for paracentesi s vi r tual l y el i mi nates compl i cati ons, the fol l owi ng have been r epor ted: hemor r hage, asci ti c l eak, i nfecti on, and per forated abdomi nal vi scus.

Thoracentesis Indications For r emoval of pl eural fl ui d for di agnosti c or therapeuti c pur poses

Contraindications Ther e ar e no absol ute contrai ndi cati ons to di agnosti c thoracentesi s i f i t i s deci ded that the i nfor mati on gai ned fr om pl eural fl ui d anal ysi s i s needed for di agnosi s and/or therapy. The r el ati ve contrai ndi cati ons ar e as fol l ows: Coagul opathy (the coagul ati on abnor mal i ty shoul d be cor r ected) Bul l ous emphysema (associ ated wi th i ncr eased r i sk of pneumothorax) Car di ovascul ar di sease (car di ac dysr hythmi as) Pati ents wi th a mi ni mal amount of pl eural fl ui d posi ti ve endexpi rator y pr essur e (PEEP) ar e not at i ncr eased r i sk for devel opi ng pneumothorax when compar ed wi th nonventi l ated pati ents. Mechani cal l y venti l ated pati ents, however, ar e at i ncr eased r i sk for devel opi ng tensi on physi ol ogy or a per si stent ai r l eak, i f pneumothorax does occur. Inabi l i ty of pati ent to cooperate Cel l ul i ti s, i f the thoracentesi s r equi r es penetrati ng the i nfl amed

ti ssue.

Important Preprocedure Considerations Car e must be taken to ascer tai n the l ocati on of the di aphragm befor e the pr ocedur e i n or der to avoi d acci dental i njur y to the abdomi nal or gans and vi scera. Chest radi ographs shoul d be vi ewed by the per son who i s per for mi ng the pr ocedur e and, i f l ocul ati on of fl ui d i s suspected, decubi tus fi l ms and, possi bl y, computer i zed tomography scan or ul trasonography may be hel pful befor e thoracentesi s i s attempted.

Anatomy The pr ocedur e may be per for med wi th the pati ent i n a si tti ng posi ti on, wi th ar ms r esti ng on a pi l l ow pl aced on a tabl e. Thi s al l ows the pati ent to l ean for war d 10 to 15 degr ees, al l owi ng the i nter costal spaces to spr ead. The pr ocedur e i s per for med thr ough the seventh or ei ghth i nter costal space i n the poster i or axi l l ar y l i ne. Wi th fl uor oscopi c, sonographi c, or computer i zed tomographi c gui dance, the pr ocedur e may be per for med bel ow the fi fth r i b anter i or l y, the seventh r i b l ateral l y, and the ni nth r i b poster i or l y. Wi thout such gui dance, the under l yi ng or gans may be i njur ed. Assessi ng the si ze of the pl eural effusi on by physi cal exami nati on i nvol ves the detecti on of decr eased tacti l e fr emi tus and dul l ness to per cussi on over the pl eural effusi on. The per cussi on i s begun at the top of the chest, l i steni ng for any change i n the sound of per cussi on whi l e movi ng downwar d. When the change i n sound i s fi r st noted, i t shoul d be compar ed wi th the per cussi on note i n the same i nter space and wi th the l ocati on on the opposi te si de of the chest. Thi s i ndi cates the hi ghest l evel of the pl eural effusi on.

Procedure

1. Wi th the pati ent i n the pr oper posi ti on, cl ean the si te wi th anti septi c sol uti on and begi n l ocal anesthesi a. Infi l trate the ski n wi th 1% l i docai ne usi ng a 25-gauge needl e. Infi l trati on to the deeper ti ssues i s achi eved usi ng a 22-gauge needl e, advanci ng the needl e sl owl y, at a r i ght angl e to the chest wal l i n the center of the i nter costal space. Di r ect the needl e i nto the i nter costal space just above the r i b to avoi d i njur y to the i nter costal ner ve and vessel s that may r un just bel ow the r i b. Aspi rate fr equentl y to ensur e that no vessel has been enter ed and to deter mi ne the di stance fr om the ski n to the pl eural fl ui d. Once the pl eural fl ui d has been obtai ned, r emove the anesthesi a needl e and note the depth. 2. A smal l ski n i nci si on may be needed to ease the passage of a l ar ger-gauge thoracentesi s needl e i nto the pl eural space. G eneral l y, a 16- to 19-gauge needl e wi th i ts i ntracath i s i ntr oduced just to the l evel of obtai ni ng pl eural fl ui d. If, at thi s ti me, the fl ui d i s bl oody or di ffer ent i n appearance fr om that i denti fi ed wi th the anesthesi a needl e, vessel i njur y must be suspected, and the pr ocedur e must be stopped. If the fl ui d appear s to be the same as i t was when pr evi ousl y aspi rated, advance a fl exi bl e i ntracath and wi thdraw the needl e to avoi d punctur e of the l ung as the fl ui d i s drai ned. The pl acement of a fl exi bl e i ntracath wi th a thr ee-way stopcock al l ows the r emoval of l ar ge vol umes of fl ui d wi th a l ower r i sk of pneumothorax. (For sampl i ng smal l amounts of pl eural fl ui d wi thout the need to drai n l ar ge amounts of i t, a 22-gauge needl e connected to an ai r ti ght, thr ee-way stopcock wi l l suffi ce.) Attach tubi ng to the thr ee-way stopcock and r emove fl ui d by hand or by vacutai ner. Moni tor the hemodynami c status car eful l y when wi thdrawi ng mor e than 1,000 mL per pr ocedur e. 3. A chest radi ograph shoul d be per for med after the pr ocedur e to deter mi ne the amount of fl ui d that r emai ns, to l ook for the pr esence of pneumothorax, and to assess the l ung par enchyma. A smal l pneumothorax does not need tr eatment, wher eas a major pneumothorax (>50% l ung col l apse) does (see F i g. 46.6).

FIG. 46.6. Tr ocar techni que for i nser ti ng a chest tube. A : Inser ti on of chest tube. B: Advancement of the chest tube off the tr ocar i nto the pl eural space. (F r om Chestnut MS, Dewar TN, Locksl ey RM, et al . Bone mar r ow aspi rati on & bi opsy. In: Offi ce & bedsi de pr ocedur es. Nor wal k, CT: Appl eton & Lange, 1992:221, wi th per mi ssi on.)

Complications Pneumothorax Ai r embol i sm (rar e) Infecti on Pai n at punctur e si te Bl eedi ng Spl een or l i ver punctur e.

SUGGESTED READINGS Butl er E, Li chtman M, G i l er B, et al . Williams hematology, 5th ed. New Yor k: McG raw-Hi l l , 1995. Evans RW, Ar mon C, F r ohman EM, et al . Assessment: pr eventi on of post-l umbar punctur e headaches: r epor t of the therapeuti cs and technol ogy assessment subcommi ttee of the Amer i can Academy of Neur ol ogy. Neur ology 2000;149:1087. Issel bacher K, Braunwal d E, Wi l son JD, et al . Har r ison's pr inciples of inter nal medicine, 13th ed. New Yor k: McG raw-Hi l l , 1994. Jashi di K, Swai m WR. Bone mar r ow bi opsy wi th unal ter ed ar chi tectur e: a new bi opsy devi ce. J Lab Clin Med 1971;77:335. Kuntz KM, Kokmen E, Stevens JC, et al . Post-l umbar punctur e headaches: exper i ence i n 501 consecuti ve pr ocedur es. Neur ology 1992;42:1884. LeMense JP, Sahn SA. Safety and val ue of thoracentesi s i n medi cal ICU pati ents. J Intensive Car e Med 1998;13:144.

McCar tney JE, Adams JS II, Haz ar d PP. Safe pr ocedur e i n mechani cal l y venti l ated pati ents. Chest 1993;103:1920. Rohl i ng BM, Webb WR, Schl obom RM. Venti l ator-r el ated extraal veol ar ai r. Radiology 1976;121:25. Zi mmer man JE, Dunbar BS, Kl i ngenmai er CH. Management of subcutaneous emphysema, pneumomedi asti num, and pneumothorax dur i ng r espi rator y therapy. Cr it Car e Med 1975;3:69.

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ta ble o f C o nt e nt s > Se c t io n 1 3 - C o m m o n P ro c e dure s a nd C he m o t he ra py Drugs > 4 7 - Ant ic a nc e r Age nt s

47 Anticancer Agents Thomas E. Hughes Depar tment of Phar macy, National Institutes of Health Clinical Center , Bethesda, Mar yland Al l i nfor mati on has been obtai ned fr om the cur r ent pr oduct l abel i ng as of June 1, 2004.

NOTES AND ABBREVIATIONS Single-agent Dose The doses l i sted for each agent ar e fr om the package i nser ts and appl y when the agent i s gi ven al one, unl ess other wi se noted. The doses ar e expr essed i n accor dance wi th the nomencl atur e gui del i nes fr om Kohl er et al . (1).

Abbreviations Listed under Adverse Reactions CNS: central ner vous system CV: car di ovascul ar system DERM: ski n and i ntegument system ELECTRO: el ectr ol yte abnor mal i ti es ENDO: endocr i ne system G I: gastr oi ntesti nal system G U: geni tour i nar y system HEMAT: hematopoi eti c system

INF US: i nfusi on-r el ated r eacti ons OCULAR: ocul ar system PULM: pul monar y system LF Ts: l i ver functi on tests Cr : ser um cr eati ni ne Cr Cl : cr eati ni ne cl earance N/V Lx: Nausea and vomi ti ng graded i nto 5 l evel s (x = 1 or 2 or 3, etc., up to 5) accor di ng to Hesketh et al . (2). (Note: The emetogeni c potenti al based on the expected fr equency of acute emesi s i s as fol l ows: Level 1: 90% .)

ALDESLEUKIN (PROLEUKIN) Mechanism of Action Al desl euki n acti vates cel l ul ar i mmuni ty.

U.S. Food and Drug Administration–Approved Indications Metastati c r enal cel l car ci noma and metastati c mel anoma

U.S. Food and Drug Administration–Approved Dosage Doses of 600,000 IU per kg of Al desl euki n i .v. over 15 mi nutes ever y 8 hour s for a maxi mum of 14 doses The dosage may be r epeated after 9 days of r est for a maxi mum of 28 doses per cour se

Dose Modification Criteria In the event of toxi ci ty a dose may be wi thhel d or i nter r upted.

Adverse Reactions CNS: confusi on, somnol ence, anxi ety, and di z z i ness; CV:

hypotensi on, tachycar di a, and ar r hythmi a; DERM: rash and pr ur i tus; G I: di ar r hea, N/V L3, mucosi ti s, and anor exi a; G U: ol i gur i a and acute r enal fai l ur e; HEMAT: myel osuppr essi on; PULM: dyspnea and pul monar y edema; OTHER: pai n, fever, chi l l s, and mal ai se.

Comments Use may be r estr i cted to pati ents wi th nor mal car di ac and pul monar y functi on Pati ents to be moni tor ed for capi l l ar y-l eak syndr ome Agent i s associ ated wi th i mpai r ed neutr ophi l functi on; consi der anti bi oti c pr ophyl axi s for pati ents wi th i ndwel l i ng central l i nes

ALEMTUZUMAB (CAMPATH) Mechanism of Action Al emtuz umab i s a humani zed monocl onal anti body di r ected agai nst the cel l sur face pr otei n, CD52. The CD52 anti gen i s expr essed on the sur face of nor mal and mal i gnant B and T l ymphocytes, natural ki l l er (NK) cel l s, monocytes, macr ophages, and a subpopul ati on of granul ocytes. The pr oposed mechani sm of acti on of al emtuz umab i s the anti body-dependent l ysi s of l eukemi c cel l s fol l owi ng bi ndi ng to the cel l sur face.

U.S. Food and Drug Administration–Approved Indications B-cel l chr oni c l ymphocyti c l eukemi a (CLL): It i s used for second-l i ne therapy i n pati ents who have been tr eated wi th al kyl ati ng agents and i n those who have fai l ed fl udarabi ne therapy.

U.S. Food and Drug Administration–Approved Dosage Al emtuz umab i s dose-escal ated i n a stepwi se manner to a mai ntenance dose of 30 mg. The i ni ti al r ecommended dosage i s 3 mg i .v. over 2 hour s dai l y. When thi s dosage i s tol erated (i nfusi on-r el ated toxi ci ti es ar e grade 2 or l ess), i t shoul d be

escal ated to 10 mg i .v. over 2 hour s dai l y and conti nued unti l tol erated. When the 10-mg dose i s tol erated, the mai ntenance dose of 30 mg may be i ni ti ated. The mai ntenance dosage i s 30 mg i .v. over 2 hour s admi ni ster ed 3 ti mes per week (i .e., Monday, Wednesday, and F r i day) for up to 12 weeks. In most pati ents, the escal ati on to 30-mg dose can be accompl i shed i n 3 to 7 days. If therapy i s i nter r upted for 7 or mor e days, al emtuz umab shoul d be r ei ni ti ated wi th gradual dose escal ati on. Pati ents shoul d be pr emedi cated wi th an anti hi stami ne (e.g., di phenhydrami ne 50 mg PO or i .v.) and acetami nophen (650 mg PO) 30 mi nutes pr i or to al emtuz umab to amel i orate or avoi d i nfusi on-r el ated toxi ci ty. Anti emeti cs, meper i di ne, and cor ti coster oi ds have al so been used to pr event or tr eat i nfusi onr el ated toxi ci ti es.

Dose Modification Criteria Dose to be modi fi ed i n cases of myel osuppr essi on.

Adverse Reactions CNS: headache, dysthesi a, and di z z i ness; CV: hypotensi on and edema or per i pheral edema; DERM: rash, ur ti car i a, and pr ur i tus; G I: N/V L2–3, di ar r hea, anor exi a, and mucosi ti s or stomati ti s; HEMAT: myel osuppr essi on and l ymphopeni a; INF US: r i gor s, fever, chi l l s, N/VL2–3, hypotensi on, dyspnea, br onchospasm, headache, rash, and ur ti car i a; PULM: dyspnea, cough, br onchi ti s, pneumoni a, and br onchospasm; OTHER: oppor tuni sti c i nfecti ons, sepsi s, fati gue, astheni a, and pai n.

Comments Pati ents tr eated wi th al emtuz umab ar e at r i sk of oppor tuni sti c i nfecti ons caused by pr ofound l ymphopeni a. Anti -i nfecti ve pr ophyl axi s i s r ecommended upon i ni ti ati on of therapy and for a mi ni mum of 2 months fol l owi ng the l ast dose of al emtuz umab or unti l the CD4 count i s equal to 200 cel l s per µL or mor e. Pr ophyl axi s di r ected agai nst Pneumocystis car inii pneumoni a (PCP) (e.g., tr i methopr i m–sul famethoxazol e) and her pesvi r us i nfecti ons (e.g., famci cl ovi r or equi val ent) shoul d be uti l i zed. Al emtuz umab shoul d not be admi ni ster ed as an i ntravenous push

or bol us. Car eful moni tor i ng of bl ood pr essur e and hypotensi on i s r ecommended, especi al l y i n pati ents wi th i schemi c hear t di sease and i n pati ents tr eated wi th anti hyper tensi ve medi cati ons. Pati ents who have r ecentl y been tr eated wi th al emtuz umab shoul d not be i mmuni zed wi th l i ve vi ral vacci nes.

ALTRETAMINE (HEXALEN) Mechanism of Action Al tr etami ne has an unknown mechani sm of acti on, but str uctur e i s si mi l ar to an al kyl ati ng agent.

U.S. Food and Drug Administration–Approved Indications Ovar i an cancer : second-l i ne therapy; pal l i ati ve therapy for per si stent or r ecur r ent ovar i an cancer

U.S. Food and Drug Administration–Approved Dosage 65 mg per m2 PO q.i .d. (4 ti mes dai l y; total dai l y dose: 260 mg per m 2 ) for 14 or 21 consecuti ve days, ever y 28 days

Dose Modification Criteria Dose modi fi ed i n case of myel osuppr essi on and nonhematol ogi c toxi ci ty (i .e., G I i ntol erance and pr ogr essi ve neur otoxi ci ty).

Adverse Reactions CNS: per i pheral sensor y neur opathy, mood di sor der s, ataxi a, and di z z i ness; G I: N/V L3; HEMAT: myel osuppr essi on [whi te bl ood cel l s (WBCs), r ed bl ood cel l s (RBCs), pl atel ets].

Comments Pati ents to be moni tor ed for neur ol ogi c toxi ci ty

ANASTROZOLE (ARIMIDEX) Mechanism of Action Anastr ozol e i s a sel ecti ve, nonster oi dal ar omatase i nhi bi tor.

U.S. Food and Drug Administration–Approved Indications Br east Cancer : Adjuvant tr eatment: Postmenopausal women wi th hor moner eceptor–posi ti ve ear l y br east cancer F i r st-l i ne therapy: Postmenopausal women wi th hor moner eceptor–posi ti ve or hor mone-r eceptor–unknown l ocal l y advanced or metastati c br east cancer Second-l i ne therapy (after tamoxi fen): Postmenopausal women wi th advanced br east cancer

U.S. Food and Drug Administration–Approved Dosage 1 mg PO dai l y (no r equi r ement for gl ucocor ti coi d or mi neral ocor ti coi d r epl acement therapy)

Dose Modification Criteria Renal i mpai r ment: no dose modi fi cati on; hepati c i mpai r ment (mi l d to moderate): no dose modi fi cati on; hepati c i mpai r ment (sever e): no data avai l abl e

Adverse Reactions CNS: headache; CV: hot fl ashes/fl ushi ng; G I: nausea, di ar r hea, and el evated LF T val ues (i n pati ents wi th l i ver metastases); PULM: dyspnea; OTHER: astheni a, pai n, back pai n, and vagi nal bl eedi ng.

Comments Pati ents wi th estr ogen-r eceptor (ER)–negati ve di sease and pati ents who do not r espond to tamoxi fen rar el y r espond to anastr ozol e.

ARSENIC TRIOXIDE (TRISENOX) Mechanism of Action The mechani sm of acti on of ar seni c tr i oxi de i s not compl etel y defi ned. It i nduces apoptosi s i n NB4 human pr omyel ocyti c l eukemi a cel l s in vitr o and damages or degrades the fusi on pr otei n PML/RAR α.

U.S. Food and Drug Administration–Approved Indications Acute pr omyel ocyti c l eukemi a (APL): second-l i ne therapy for the i nducti on of r emi ssi on and for consol i dati on of APL pati ents who ar e r efractor y to, or have r el apsed fr om, r eti noi d and anthracycl i ne chemotherapy.

U.S. Food and Drug Administration–Approved Dosage For APL i nducti on: 0.15 mg per kg i .v. over 1 to 2 hour s dai l y unti l bone mar r ow r emi ssi on. Total i nducti on dose shoul d not exceed 60 doses. For APL consol i dati on: 0.15 mg per kg i .v. over 1 to 2 hour s dai l y × 25 doses over a per i od of up to 5 weeks. Consol i dati on tr eatment shoul d begi n 3 to 6 weeks after compl eti on of i nducti on therapy.

Dose Modification Criteria Renal i mpai r ment: no data avai l abl e (use wi th cauti on); hepati c i mpai r ment: no data avai l abl e.

Adverse Reactions CNS: headache, di z z i ness, and par esthesi as; CV: QT i nter val pr ol ongati on, compl ete atr i oventr i cul ar bl ock, tor sade de poi ntes– type ventr i cul ar ar r hythmi a, atr i al dysr hythmi as, tachycar di a, hypotensi on, and edema; DERM: rash, der mati ti s, dr y ski n, and pr ur i tus; ENDO: hyper gl ycemi a, hypokal emi a, and hypomagnesemi a;

G I: N/V L3, di ar r hea, abdomi nal pai n, anor exi a, consti pati on, and el evated LF T val ues; HEMAT: l eukocytosi s and myel osuppr essi on; PULM: dyspnea and cough; OTHER: fati gue, ar thral gi a, myal gi a, pai n, and APL di ffer enti ati on syndr ome or r eti noi c aci d acute pr omyel ocyti c l eukemi a (RA-APL) syndr ome (RA-APL syndr ome: fever, dyspnea, wei ght gai n, radi ographi c pul monar y i nfi l trates, and pl eural or per i car di al effusi on).

Comments The APL di ffer enti ati on syndr ome (RA-APL syndr ome) occur s i n some pati ents tr eated wi th ar seni c tr i oxi de. Ear l y r ecogni ti on and hi gh-dose cor ti coster oi ds (dexamethasone 10 mg i .v. ever y 12 hour s × 3 days or unti l the r esol uti on of symptoms) have been used for the management of thi s syndr ome. Befor e star ti ng tr eatment wi th ar seni c tr i oxi de, a 12-l ead el ectr ocar di ogram (ECG ) shoul d be per for med and ser um el ectr ol ytes (potassi um, cal ci um, and magnesi um) and cr eati ni ne l evel s shoul d be assessed; pr eexi sti ng el ectr ol yte abnor mal i ti es shoul d be cor r ected. Concomi tant dr ugs that may pr ol ong the QT i nter val shoul d be avoi ded. Dur i ng therapy wi th ar seni c tr i oxi de, nor mal potassi um and magnesi um concentrati ons shoul d be moni tor ed and mai ntai ned as outl i ned i n the package i nser t. The r i sk factor s for QT pr ol ongati on and subsequent ar r hythmi as i ncl ude other QT-pr ol ongi ng dr ugs, a hi stor y of tor sades de poi ntes, pr eexi sti ng QT pr ol ongati on, congesti ve hear t fai l ur e (CHF ), admi ni strati on of potassi um-wasti ng di ur eti cs, or other dr ugs or condi ti ons that r esul t i n hypokal emi a or hypomagnesemi a.

ASPARAGINASE (ELSPAR) Mechanism of Action Asparagi nase depl etes asparagi ne, an ami no aci d r equi r ed by some l eukemi c cel l s.

U.S. Food and Drug Administration–Approved Indications

For acute l ymphobl asti c l eukemi a (ALL): i nducti on therapy wi th asparagi nase (pr i mar i l y i n combi nati on wi th other agents)

U.S. Food and Drug Administration–Approved Dosage Cur r ent l i teratur e to be consul ted for doses ALL: Inducti on therapy i n combi nati on wi th pr edni sone and vi ncr i sti ne—1,000 IU per kg of asparagi nase i .v. dai l y × 10 days, star ti ng day 22 or 6,000 IU per m2 i .m. ever y 3 days for ni ne doses, star ti ng day 4 of i nducti on (day 1 i s the fi r st day of chemotherapy).

Dose Modification Criteria No data avai l abl e

Adverse Reactions DERM: ski n rash; ENDO: hyper gl ycemi a; G I: N/V L2, pancr eati ti s, i ncr eased LF T val ues, i ncr eased bi l i r ubi n l evel s, and decr eased ser um al bumi n; G U: pr er enal azotemi a; HEMAT: coagul opathy; CNS: a var i ety of changes i n mental status; OTHER: hyper sensi ti vi ty, anaphyl acti c r eacti ons, and hyper ther mi a.

Comments [i ncr eased bi l i r ubi n l evel s] Asparagi nase i s contrai ndi cated i n pati ents wi th acti ve pancr eati ti s or wi th a hi stor y of pancr eati ti s. Hyper sensi ti vi ty and anaphyl acti c r eacti ons can occur dur i ng therapy. Package i nser t may be consul ted for test doses and desensi ti z ati on schedul es. i .m. admi ni strati on i s pr efer r ed over i .v. admi ni strati on (l ower i nci dence of anaphyl axi s). i .v. i nfusi ons shoul d be over a per i od of at l east 30 mi nutes.

AZACITIDINE (VIDAZA) Mechanism of Action Az aci ti di ne i s an anti metabol i te; a pyr i mi di ne nucl eosi de anal og of cyti di ne. It causes hypomethyl ati on of deoxyr i bonucl ei c aci d (DNA) and pr oduces di r ect cytotoxi ci ty on abnor mal hematopoi eti c cel l s i n the bone mar r ow.

U.S. Food and Drug Administration–Approved Indications Myel odyspl asti c syndr ome (MDS): The speci fi c subtypes of MDS for whi ch az aci ti di ne i s i ndi cated i ncl ude r efractor y anemi a or r efractor y anemi a wi th r i nged si der obl asts (i f accompani ed by neutr openi a or thr ombocytopeni a or when tranfusi ons ar e r equi r ed), r efractor y anemi a wi th excess bl asts, r efractor y anemi a wi th excess bl asts i n transfor mati on, and chr oni c myel omonocyti c l eukemi a.

U.S. Food and Drug Administration–Approved Dosage MDS: The r ecommended star ti ng dosage i s 75 mg per m2 by s.c. i njecti on, dai l y for 7 consecuti ve days, ever y 4 weeks. The dose may be i ncr eased to 100 mg per m2 i f no benefi ci al effect i s seen after two tr eatment cycl es and i f no toxi ci ty other than nausea and vomi ti ng occur s. Durati on: r ecommended mi ni mum durati on of four tr eatment cycl es; compl ete or par ti al r esponse may take mor e than four tr eatment cycl es; i t may be conti nued as l ong as the pati ent conti nues to benefi t.

Dose Modification Criteria Renal i mpai r ment: no data avai l abl e (to be used wi th cauti on); Hepati c: no data avai l abl e (to be used wi th cauti on); Myel osuppr essi on: dose to be modi fi ed; nonhematol ogi c toxi ci ty (i .e., r enal tubul ar aci dosi s and r enal toxi ci ty): dose to be modi fi ed.

Adverse Reactions

CNS: headache and di z z i ness; DERM: i njecti on-si te er ythema or pai n, ecchymosi s, rash, and pr ur i tus; ELECTRO: r enal tubul ar aci dosi s (i .e., al kal i ne ur i ne, fal l i n ser um bi car bonate concentrati on, and hypokal emi a); G I: N/V L1, di ar r hea, consti pati on, anor exi a, abdomi nal pai n, and hepatotoxi ci ty; G U: i ncr eased Cr and bl ood ur ea ni tr ogen (BUN) concentrati on, and r enal fai l ur e; HEMAT: anemi a, neutr openi a, and thr ombocytopeni a; PULM: cough and dyspnea; OTHER: fever, r i gor s, fati gue, weakness, and per i pheral edema.

Comments Teratogeni c (pr egnancy categor y D): Women of chi l dbear i ng potenti al shoul d be advi sed to avoi d becomi ng pr egnant whi l e r ecei vi ng az aci ti di ne. Men shoul d be advi sed to not father a chi l d whi l e r ecei vi ng az aci ti di ne. Az aci ti di ne shoul d be used wi th cauti on i n pati ents wi th l i ver di sease. It i s potenti al l y hepatotoxi c i n pati ents wi th pr eexi sti ng hepati c i mpai r ment. Az aci ti di ne and i ts metabol i tes ar e pr i mar i l y el i mi nated r enal l y. Pati ents wi th r enal i mpai r ment shoul d be cl osel y moni tor ed for toxi ci ty. Renal toxi ci ty has been r epor ted rar el y wi th i ntravenous az aci ti di ne i n combi nati on wi th other chemotherapeuti c agents for non-MDS condi ti ons.

BACILLE CALMETTE-GUÉRIN LIVE (INTRAVESICAL) (THERACYS, TICE BCG) Mechanism of Action Baci l l e Cal mette-G uér i n has l ocal i nfl ammator y and i mmune r esponse effect.

U.S. Food and Drug Administration–Approved Indications Tr eatment and pr ophyl axi s of car ci noma in situ of the ur i nar y bl adder and for the pr ophyl axi s of pr i mar y or r ecur r ent stage Ta and/or T1 papi l l ar y tumor s fol l owi ng transur ethal r esecti on (TUR).

U.S. Food and Drug Administration–Approved Dosage TheraCys [each vi al contai ns 81 mg (dr y wei ght) or 10.5 ± 8.7 × 10 8 col ony-for mi ng uni ts and comes wi th a 3-mL di l uent vi al ]: One r econsti tuted vi al (81 mg per 3 mL), di l uted i n 50 mL of ster i l e, pr eser vati ve-fr ee nor mal sal i ne (0.9% sodi um chl or i de i njecti on), i s i nsti l l ed i nto bl adder for as l ong as possi bl e (for up to 2 hour s) once weekl y for 6 weeks (i nducti on therapy), fol l owed by one tr eatment at 3, 6, 12, 18, and 24 months each after the i ni ti al tr eatment (mai ntenance therapy). Ti ce BCG [each vi al contai ns 50 mg (wet wei ght) or 1–8 × 108 col ony-for mi ng uni ts]: One r econsti tuted vi al (50 mg per mL), di l uted i n a total vol ume of 50-mL pr eser vati ve-fr ee nor mal sal i ne (0.9% sodi um chl or i de i njecti on), i s i nsti l l ed i nto bl adder for as l ong as possi bl e (for up to 2 hour s) once weekl y for 6 weeks, fol l owed by once monthl y for 6 to 12 months.

Dose Modification Criteria Wi thhol d Baci l l e Cal mette-G uér i n (BCG ) l i ve i n case of any suspi ci on of systemi c i nfecti on.

Adverse Reactions CNS: mal ai se, fever, and chi l l s; G U: i r r i tati ve bl adder symptoms; OTHER: i nfecti ous compl i cati ons (uncommon).

Comments BCG l i ve may compl i cate tuber cul i n ski n test i nter pr etati on. BCG l i ve pr oducts contai n l i ve, attenuated mycobacter i a. Because of the potenti al r i sk of transmi ssi on, i t shoul d be pr epar ed, handl ed, and di sposed of as a bi ohaz ar d mater i al .

BEVACIZUMAB (AVASTIN)

Mechanism of Action Bevaci z umab i s a r ecombi nant humani zed monocl onal i mmunogl obul i n (Ig)G 1 anti body that bi nds to and i nhi bi ts the bi ol ogi c acti vi ty of human vascul ar endothel i al gr owth factor (VEG F ).

U.S. Food and Drug Administration–Approved Indications Metastati c car ci noma of the col on or r ectum: fi r st-l i ne therapy i n combi nati on wi th i ntravenous 5-fl uor ouraci l –based chemotherapeuti c agents.

U.S. Food and Drug Administration–Approved Dosage Metastati c col or ectal cancer : 5 mg per kg i .v. i nfusi on ever y 14 days unti l di sease pr ogr essi on i s detected Do not administer as an i.v. push or bolus. The i ni ti al bevaci z umab dose shoul d be del i ver ed over 90 mi nutes as an i .v. i nfusi on fol l owi ng chemotherapy. If the fi r st i nfusi on i s wel l tol erated, the second i nfusi on may be admi ni ster ed over 60 mi nutes. If the 60-mi nute i nfusi on i s wel l tol erated, al l subsequent i nfusi ons may be admi ni ster ed over 30 mi nutes.

Dose Modification Criteria Renal i mpai r ment: no dose modi fi cati on; hepati c i mpai r ment: no dose modi fi cati on; myel osuppr essi on: no dose modi fi cati on; nonhematol ogi c toxi ci ty: dose to be modi fi ed.

Adverse Reactions CNS: headache; CV: hyper tensi on, hyper tensi ve cr i si s, and CHF; G I: N/VL1, di ar r hea, abdomi nal pai n, gastr oi ntesti nal per forati on, and wound dehi scence; G U: pr otei nur i a and nephr oti c syndr ome; INF US: fever, chi l l s, wheez i ng, and str i dor ; PULM: dyspnea and wheez i ng str i dor ; OTHER: epi staxi s and other mi l d to moderate hemor r hagi c events, ser i ous hemor r hagi c events, wound heal i ng compl i cati ons, deep vei n thr ombosi s or other thr omboembol i c events, and astheni a.

Comments Bevaci z umab can r esul t i n the devel opment of gastr oi ntesti nal per forati on and wound dehi scence and other wound heal i ng compl i cati ons. The appr opr i ate i nter val between ter mi nati on of bevaci z umab and subsequent el ecti ve sur ger y that i s r equi r ed to avoi d the r i sks of wound heal i ng or wound dehi scence has not been deter mi ned. Pr oduct l abel i ng suggests that bevaci z umab shoul d not be i ni ti ated for at l east 28 days fol l owi ng major sur ger y, and the sur gi cal i nci si on shoul d be ful l y heal ed befor e star ti ng therapy. Bl eedi ng compl i cati ons secondar y to bevaci z umab occur i n two di sti nct patter ns: mi nor hemor r hage (most commonl y, grade 1 epi staxi s) and ser i ous, and i n some cases fatal , hemor r hagi c events. Pati ents wi th squamous cel l non–smal l cel l l ung cancer (NSCLC) appear to be at hi gher r i sk for ser i ous hemor r hagi c events. The r i sk of CNS bl eedi ng i n pati ents wi th CNS metastases who ar e r ecei vi ng bevaci z umab has not been eval uated. Bl ood pr essur e shoul d be moni tor ed ever y 2 to 3 weeks dur i ng therapy and mor e fr equentl y i n pati ents who devel op hyper tensi on. Ur i nal ysi s shoul d be done ser i al l y for pr otei nur i a; pati ents wi th a 2+ or gr eater ur i ne di psti ck r eadi ng shoul d under go fur ther assessment (e.g., a 24-hour ur i ne col l ecti on). Teratogeni c (pr egnancy categor y C): Angi ogenesi s i s cr i ti cal to fetal devel opment and bevaci z umab has been shown to be teratogeni c i n rabbi ts.

BEXAROTENE (TARGRETIN) Mechanism of Action Bexar otene i s a r eti noi d that sel ecti vel y bi nds and acti vates r eti noi d X r eceptor (RXR) subtypes. Once acti vated, these r eceptor s functi on as transcr i pti on factor s that r egul ate the expr essi on of genes that contr ol cel l ul ar di ffer enti ati on and pr ol i ferati on.

U.S. Food and Drug Administration–Approved Indications Cutaneous T-cel l l ymphoma (CTCL): second-l i ne therapy for the cutaneous mani festati ons of CTCL i n pati ents who ar e r efractor y to at l east one pr i or systemi c therapy

U.S. Food and Drug Administration–Approved Dosage 300 mg per m2 PO dai l y wi th a meal

Dose Modification Criteria Renal i mpai r ment: no dose modi fi cati on (cauti on as a r esul t of possi bl e pr otei n bi ndi ng al terati ons); hepati c i mpai r ment: use wi th cauti on; toxi ci ty: dose to be modi fi ed.

Adverse Reactions CNS: headache; CV: per i pheral edema; DERM: dr y ski n, photosensi ti vi ty, rash, and pr ur i tus; ENDO: hypothyr oi di sm and hypogl ycemi a (di abeti c pati ents); G I: nausea, pancr eati ti s, el evated LF T val ues, and abdomi nal pai n; HEMAT: l eukopeni a and anemi a; OCULAR: cataracts; OTHER: l i pi d abnor mal i ti es (i .e., el evated tr i gl ycer i des, el evated total and LDL chol ester ol , and decr eased HDL chol ester ol ), astheni a, and i nfecti on.

Comments Fasti ng bl ood l i pi d l evel s shoul d be moni tor ed befor e i ni ti ati on of bexar otene and weekl y after i ni ti ati on of therapy unti l the l i pi d r esponse i s establ i shed (usual l y occur s wi thi n 2 to 4 weeks) and then at 8-week i nter val s ther eafter. LF T r esul ts shoul d be moni tor ed befor e i ni ti ati on of bexar otene and then after 1, 2, and 4 weeks of tr eatment and, i f stabl e, at l east ever y 8 weeks ther eafter for the tr eatment per i od. Compl ete bl ood count and thyr oi d functi on tests to be moni tor ed at basel i ne, and per i odi cal l y ther eafter. Bexar otene i s a teratogen (pr egnancy categor y X) and may cause har m to fetus when admi ni ster ed to a pr egnant woman.

Bexar otene must not be gi ven to a pr egnant woman or to a woman who i ntends to become pr egnant. Women of chi l dbear i ng potenti al shoul d obtai n a negati ve pr egnancy test wi thi n 1 week befor e star ti ng bexar otene therapy, and the test shoul d be r epeated at monthl y i nter val s whi l e the pati ent r emai ns on therapy. Effecti ve contracepti on (two r el i abl e for ms used si mul taneousl y) must be used for 1 month befor e i ni ti ati on of therapy, dur i ng therapy, and for at l east 1 month fol l owi ng di sconti nuati on of therapy. Bexar otene may i nduce the metabol i sm of hor monal contracepti ves and r educe thei r effecti veness; ther efor e, one for m of contracepti on shoul d be nonhor monal .

BICALUTAMIDE (CASODEX) Mechanism of Action Bi cal utami de has anti andr ogeni c acti vi ty.

U.S. Food and Drug Administration–Approved Indications Pal l i ati on of advanced pr ostate cancer (stage D2) i n combi nati on wi th a l utei ni z i ng hor mone–r el easi ng hor mone (LH-RH) agoni st.

U.S. Food and Drug Administration–Approved Dosage 50 mg PO dai l y

Dose Modification Criteria Renal i mpai r ment: no dose modi fi cati on; hepati c i mpai r ment (mi l d to moderate): no dose modi fi cati on; hepati c i mpai r ment (sever e): use wi th cauti on.

Adverse Reactions ENDO: l oss of l i bi do, hot fl ashes, and gynecomasti a; G I: nausea, di ar r hea, and consti pati on; G U: i mpotence.

Comments

Moni tor LF T r esul ts befor e tr eatment, at r egul ar i nter val s for the fi r st 4 months, and per i odi cal l y ther eafter.

BLEOMYCIN (BLENOXANE) Mechanism of Action The mechani sm of acti on of bl eomyci n i s unknown, but i t may i nhi bi t DNA and r i bonucl ei c aci d (RNA) synthesi s.

U.S. Food and Drug Administration–Approved Indications Squamous cel l cancer s, non-Hodgki n l ymphoma, testi cul ar cancer, Hodgki n di sease, and mal i gnant pl eural effusi ons

U.S. Food and Drug Administration–Approved Dosage A test dose (2 U or l ess) for the fi r st two doses i s r ecommended i n pati ents wi th l ymphoma. The dosage i s 0.25 to 0.50 U per kg (10 to 20 U per m2 ) i .v. or i .m. or s.c. weekl y or twi ce weekl y. Mal i gnant pl eural effusi ons: 60 U as a si ngl e i ntrapl eural bol us dose.

Dose Modification Criteria Renal i mpai r ment: use wi th cauti on (dose modi fi cati on gui del i nes ar e not pr ovi ded wi thi n package i nser t but ar e avai l abl e fr om other r efer ences).

Adverse Reactions DERM: er ythema, rash, str i ae, vesi cul ati on, hyper pi gmentati on, ski n tender ness, al opeci a, nai l changes, pr ur i tus, and stomati ti s; PULM: pul monar y fi br osi s (i ncr eases at cumul ati ve doses >400 U, but can occur at l ower total doses) and pneumoni ti s; Other : fever ; chi l l s; i di osyncrati c r eacti on consi sti ng of hypotensi on, mental confusi on, fever, chi l l s, and wheez i ng has been r epor ted i n 1% of l ymphoma

pati ents; and l ocal pai n wi th i ntrapl eural admi ni strati on.

Comments Pati ent shoul d be moni tor ed for fi ne ral es as an ear l y i ndi cati on of pul monar y toxi ci ty. Pul monar y toxi ci ty i s i ncr eased when oxygen i s used dur i ng sur ger y.

BORTEZOMIB (VELCADE) Mechanism of Action Bor tezomi b i s a r ever si bl e i nhi bi tor of the 26S pr oteosome, a l ar ge pr otei n compl ex that degrades ubi qui ti nated pr otei ns. Inhi bi ti on of the 26S pr oteosome pr events tar geted pr oteol ysi s, whi ch can effect mul ti pl e si gnal i ng cascades wi thi n the cel l . Thi s di sr upti on of nor mal homeostati c mechani sms can l ead to cel l death.

U.S. Food and Drug Administration–Approved Indications Mul ti pl e myel oma: second-l i ne therapy i n pati ents wi th mul ti pl e myel oma who have r ecei ved at l east two ear l i er therapi es and have demonstrated di sease pr ogr essi on dur i ng the l ast therapy.

U.S. Food and Drug Administration–Approved Dosage The dosage i s 1.3 mg per m2 i .v. as a bol us i njecti on admi ni ster ed twi ce weekl y for 2 weeks (days 1, 4, 8, and 11), fol l owed by a 10day r est per i od (days 12 to 21). Thr ee weeks (21 days) i s consi der ed to be a tr eatment cycl e. At l east 72 hour s shoul d el apse between consecuti ve doses of bor tezomi b.

Dose Modification Criteria Renal i mpai r ment: no data ar e avai l abl e (use wi th cauti on); Hepati c i mpai r ment: no data ar e avai l abl e (use wi th cauti on); Myel osuppr essi on: dose to be modi fi ed; nonhematol ogi c toxi ci ty (e.g., neur opathy and neur opathi c pai n): dose to be modi fi ed

Adverse Reactions CNS: per i pheral neur opathy, neur opathi c pai n, di z z i ness, and headache; CV: hypotensi on (i ncl udi ng or thostati c hypotensi on and syncope) and edema; DERM: rash; G I: N/V L2–3, di ar r hea, anor exi a, and consti pati on; HEMAT: myel osuppr essi on (thr ombocytopeni a mor e sever e than anemi a, whi ch i s mor e sever e than neutr openi a); OCULAR: di pl opi a and bl ur r ed vi si on; PULM: dyspnea; OTHER: astheni a, fati gue, fever, i nsomni a, and ar thral gi a.

BUSULFAN (MYLERAN); BUSULFAN INJECTION (BUSULFEX) Mechanism of Action Busul fan i s an al kyl ati ng agent.

U.S. Food and Drug Administration–Approved Indications Oral busul fan: Pal l i ati ve tr eatment of chr oni c myel ogenous l eukemi a (CML). Par enteral (i .v.) busul fan: Condi ti oni ng r egi men (i n combi nati on wi th cycl ophosphami de) befor e al l ogenei c hematopoi eti c pr ogeni tor cel l transpl antati on for CML.

U.S. Food and Drug Administration–Approved Dosage Oral busul fan: i nducti on: 4 to 8 mg PO dai l y; mai ntenance: 1 to 3 mg PO dai l y. Par enteral (i .v.) busul fan: Pr emedi cate pati ents wi th phenytoi n befor e busul fan admi ni strati on. For nonobese pati ents, use i deal body wei ght (IBW) or actual body wei ght, whi chever i s l ower. For obese or sever el y obese pati ents, use adjusted IBW

(AIBW). AIBW shoul d be cal cul ated as fol l ows: AIBW = IBW + 0.25 × (actual wei ght – IBW). Dosage i s 0.8 mg per kg over 2 hour s ever y 6 hour s × 16 doses (total dose: 12.8 mg per kg) wi th cycl ophosphami de.

Dose Modification Criteria Myel osuppr essi on: dose to be modi fi ed

Adverse Reactions CNS: sei z ur es; DERM: hyper pi gmentati on; G I: N/V oral L1, i .v. L4; HEMAT: sever e myel osuppr essi on; HEPATIC: venooccl usi ve di sease (VOD); PULM: pul monar y fi br osi s and VOD.

Comments Phenytoi n r educes pl asma ar ea under the cur ve (AUC) of busul fan by 15% . Use of other anti convul sants may r esul t i n hi gher pl asma AUCs of busul fan and an i ncr eased r i sk of VOD or sei z ur es. Moni tor pl asma busul fan exposur e i f other anti convul sants ar e used. Hi gh-dose oral busul fan r egi mens have al so been uti l i zed for condi ti oni ng r egi mens i n the al l ogenei c stem cel l transpl antati on setti ng. Consul t cur r ent l i teratur e for dosi ng r egi mens.

CAPECITABINE (XELODA) Mechanism of Action Capeci tabi ne i s an anti metabol i te that i s enz ymati cal l y conver ted to fl uor ouraci l i n tumor s.

U.S. Food and Drug Administration–Approved Indications Col or ectal cancer : fi r st-l i ne therapy for pati ents wi th metastati c col or ectal car ci noma when tr eatment wi th fl uor opyr i mi di ne therapy al one i s pr efer r ed. Combi nati on therapy for br east cancer : capeci tabi ne combi ned

wi th docetaxel i s i ndi cated for the tr eatment of pati ents wi th metastati c br east cancer after fai l ur e wi th ear l i er anthracycl i necontai ni ng chemotherapy. Monotherapy for br east cancer : Thi r d-l i ne therapy for metastati c br east cancer (after pacl i taxel and an anthracycl i ne-contai ni ng chemotherapeuti c r egi men), or second-l i ne (after pacl i taxel ) therapy i f anthracycl i ne i s not i ndi cated.

U.S. Food and Drug Administration–Approved Dosage The dosage i s 1,250 mg per m2 PO twi ce dai l y (total dai l y dose: 2,500 mg per m2 ) at the end of a meal for 2 weeks, fol l owed by a 1week r est per i od, gi ven as 3-week cycl es. Pr oduct l abel i ng may be consul ted for a dosi ng char t.

Dose Modification Criteria Renal (mi l d i mpai r ment; Cr Cl 51 to 80 mL per mi nute): no modi fi cati on to dosage; r enal (moderate i mpai r ment; Cr Cl 30 to 50 mL per mi nute): dosage to be modi fi ed; hepati c (mi l d-to-moderate i mpai r ment because of l i ver metastases): no modi fi cati on of dosage; toxi ci ty (grade 2 toxi ci ty or hi gher ): dosage to be modi fi ed. Pr oduct l abel i ng may be consul ted for dose modi fi cati on gui del i nes.

Adverse Reactions CNS: fati gue or weakness, par esthesi a, and per i pheral sensor y neur opathy; DERM: hand and foot syndr ome (pal mar–pl antar er ythr odysesthesi a) and der mati ti s; G I: N/V L2, di ar r hea, mucosi ti s, abdomi nal pai n, anor exi a, and hyper bi l i r ubi nemi a; HEMAT: myel osuppr essi on.

CARBOPLATIN (PARAPLATIN) Mechanism of Action Car bopl ati n i s an al kyl ati ng-l i ke agent pr oduci ng i nter strand DNA cr oss-l i nks.

U.S. Food and Drug Administration–Approved

Indications Advanced ovar i an cancer : F i r st-l i ne therapy (i n combi nati on wi th other agents). Second-l i ne therapy (i ncl udi ng pati ents who have pr evi ousl y r ecei ved ci spl ati n).

U.S. Food and Drug Administration–Approved Dosage Wi th cycl ophosphami de: 300 mg per m2 i .v. × one dose on day 1 of the cycl e; cycl es to be r epeated ever y 4 weeks × si x cycl es. Si ngl e agent: 360 mg per m2 i .v. × one dose ever y 4 weeks. For mul a dosi ng may be used as an al ter nati ve to dosi ng based on body sur face ar ea (BSA). Cal ver t For mul a for Car bopl ati n Dosi ng: Total dose i n mi l l i grams = (tar get AUC) × [gl omer ul ar fi l trati on rate (G F R) + 25]. The tar get AUC of 4 to 6 mg/mL/mi nute usi ng si ngl e-agent car bopl ati n appear s to pr ovi de the most appr opr i ate dose range i n pr evi ousl y tr eated pati ents. The Cal ver t for mul a was based on studi es wher e G F R was measur ed by 5 1 Cr–EDTA cl earance. Al ter nati vel y, many cl i ni ci ans commonl y use esti mated Cr Cl equati ons to deter mi ne G F R.

Dose Modification Criteria Renal i mpai r ment: dosage i s to be modi fi ed; Myel osuppr essi on: dosage i s to be modi fi ed.

Adverse Reactions CNS: neur opathy; G I: N/V L4, i ncr eased LF T val ues; ELECTRO: Mg, Na, Ca, and K al terati ons; G U: Incr eased Cr and BUN; HEMAT: myel osuppr essi on (thr ombocytopeni a gr eater than l eukopeni a and anemi a); OTHER: anaphyl acti c r eacti ons; pai n and astheni a.

Comments Not to be confused wi th ci spl ati n for dosi ng or dur i ng pr eparati on.

CARMUSTINE (BICNU) Mechanism of Action Car musti ne i s an al kyl ati ng agent.

U.S. Food and Drug Administration–Approved Indications Indi cated as pal l i ati ve therapy ei ther as a si ngl e agent or i n establ i shed combi nati on therapy wi th other appr oved chemotherapeuti c agents i n the fol l owi ng: brai n tumor s, mul ti pl e myel oma, Hodgki n di sease, and non-Hodgki n l ymphomas.

U.S. Food and Drug Administration–Approved Dosage Si ngl e agent i n pr evi ousl y untr eated pati ents: 150 to 200 mg per m 2 i .v. × one dose ever y 6 weeks, or 75 to 100 mg per m2 i .v. dai l y × two doses ever y 6 weeks.

Dose Modification Criteria Myel osuppr essi on: dosage to be modi fi ed.

Adverse Reactions G I: N/V L5 for dosage >250 mg per m2 , and L4 for dosage ≤250 mg per m2 ; i ncr eased LF T val ues; G U: nephr otoxi ci ty wi th l ar ge cumul ati ve doses; HEMAT: myel osuppr essi on (can be del ayed); OCULAR: r eti nal hemor r hages; PULM: pul monar y fi br osi s (acute and del ayed).

Comments Ri sk of pul monar y toxi ci ty i ncr eases wi th cumul ati ve total doses >1,400 mg per m2 and i n pati ents wi th a hi stor y of l ung di sease, radi ati on therapy, or concomi tant bl eomyci n.

CETUXIMAB (ERBITUX)

Mechanism of Action Cetuxi mab i s a r ecombi nant chi mer i c monocl onal anti body that bi nds to the extracel l ul ar domai n of the human epi der mal gr owth factor r eceptor (EG F R) on both nor mal and tumor cel l s, and competi ti vel y i nhi bi ts the bi ndi ng of epi der mal gr owth factor (EG F ) and other l i gands, ther eby bl ocki ng the phosphor yl ati on and acti vati on of r eceptor-associ ated ki nases.

U.S. Food and Drug Administration–Approved Indications Metastati c col or ectal car ci noma (second-l i ne therapy): cetuxi mab i s i ndi cated for use i n combi nati on wi th i r i notecan i n EG F R-expr essi ng metastati c col or ectal car ci noma i n pati ents who ar e r efractor y to i r i notecan-based chemotherapy, and as monotherapy i n pati ents who ar e i ntol erant to i r i notecan-based chemotherapy.

U.S. Food and Drug Administration–Approved Dosage In the tr eatment of metastati c col or ectal car ci noma (combi ned wi th i r i notecan or as monotherapy): 400 mg per m2 i .v. i nfusi on over 120 mi nutes as an i ni ti al l oadi ng dose (fi r st i nfusi on) fol l owed by a weekl y mai ntenance dose of 250 mg per m2 i .v. i nfusi on over 60 mi nutes. Pr emedi cati on wi th an H1 antagoni st (e.g., 50 mg of di phenhydrami ne i .v.) i s r ecommended.

Dose Modification Criteria Renal i mpai r ment: no dosage modi fi cati on; hepati c i mpai r ment: no dosage modi fi cati on; symptoms of non-hematol ogi c toxi ci ty (der matol ogi c toxi ci ty): dosage to be modi fi ed.

Adverse Reactions DERM: acnefor m rash, ski n dr yi ng and fi ssur i ng, and nai l toxi ci ty; G I: nausea, consti pati on, and di ar r hea; INF US: chi l l s, fever, dyspnea, ai r way obstr ucti on (br onchospasm, str i dor, hoar seness), ur ti car i a, and hypotensi on; PULM: i nter sti ti al l ung di sease; OTHER: astheni a, mal ai se, and fever.

Comments Pati ents enr ol l ed i n the cl i ni cal studi es of cetuxi mab for metastati c col or ectal car ci noma wer e r equi r ed to have i mmunohi stochemi cal evi dence of posi ti ve EG F R expr essi on. Response rate di d not cor r el ate wi th ei ther the per centage of posi ti ve cel l s or the i ntensi ty of EG F R expr essi on. G rade 1 and 2 i nfusi on r eacti ons (chi l l s, fever, and dyspnea) ar e common (16% to 23% ) usual l y on the fi r st day of i ni ti al dosi ng. Sever e i nfusi on r eacti ons have been obser ved i n appr oxi matel y 3% of pati ents and ar e character i zed by a rapi d onset of ai r way obstr ucti on, ur ti car i a, and/or hypotensi on. Sever e i nfusi on r eacti ons r equi r e i mmedi ate i nter r upti on of the cetuxi mab i nfusi on and per manent di sconti nuati on fr om fur ther tr eatment. An acnefor m rash i s common (appr oxi matel y 90% overal l , 10% grade 3) wi th cetuxi mab therapy and i s most commonl y obser ved on the face, upper chest, and back. Dr yi ng and fi ssur i ng of the ski n ar e common and can be associ ated wi th sequel ae of i nfl ammator y r esponses or i nfecti ons. Inter r upti on of therapy and dose modi fi cati on i s r ecommended for sever e der matol ogi c toxi ci ty (pr oduct l abel i ng may be consul ted). Inter sti ti al l ung di sease has rar el y been r epor ted wi th cetuxi mab therapy. In the event of acute onset or wor seni ng pul monar y symptoms, cetuxi mab therapy shoul d be i nter r upted and symptoms shoul d be pr omptl y i nvesti gated. Pr egnancy Categor y C: No ani mal r epr oducti on studi es have been conducted and effects i n pr egnant women ar e unknown. However, EG F R has been i mpl i cated i n the contr ol of pr enatal devel opment and human i mmunogl obul i n (Ig)G 1 i s known to cr oss the pl acental bar r i er.

CHLORAMBUCIL (LEUKERAN) Mechanism of Action Al kyl ati ng agent

U.S. Food and Drug Administration–Approved Indications

Pal l i ati on of CLL, Hodgki n di sease, and non-Hodgki n l ymphomas

U.S. Food and Drug Administration–Approved Dosage Ini ti al and shor t cour ses of therapy: 0.1 to 0.2 mg per kg PO dai l y for 3 to 6 weeks as r equi r ed. Usual l y the 0.1 mg/kg/day dosage i s used except for Hodgki n di sease, i n whi ch 0.2 mg/kg/day i s used. Al ter nate r egi men i n tr eatment of CLL (i nter mi ttent, bi weekl y, or once monthl y pul ses): Ini ti al si ngl e dose of 0.4 mg per kg PO × one dose. Dose may be i ncr ease by 0.1 mg per kg unti l contr ol of l ymphocytosi s i s achi eved. Mai ntenance: Not to exceed 0.1 mg/kg/day.

Dose Modification Criteria Myel osuppr essi on: dose to be modi fi ed

Adverse Reactions CNS: sei z ur es, confusi on, twi tchi ng, and hal l uci nati ons; DERM: rash and rar e r epor ts of pr ogr essi ve ski n hyper sensi ti vi ty r eacti ons; G I: N/V L1 and i ncr eased LF T val ues; HEMAT: myel osuppr essi on and l ymphopeni a; PULM: pul monar y fi br osi s; OTHER: al l er gi c r eacti ons, secondar y acute myel omonocyti c l eukemi a (AML) (l ong-ter m therapy), and ster i l i ty.

Comments Radi ati on and cytotoxi c dr ugs r ender the bone mar r ow mor e vul nerabl e to damage; chl orambuci l shoul d be used wi th cauti on wi thi n 4 weeks of a ful l cour se of radi ati on therapy or chemotherapy.

CISPLATIN (PLATINOL) Mechanism of Action Ci spl ati n i s an al kyl ati ng-l i ke agent that pr oduces i nter strand DNA

cr oss-l i nks.

U.S. Food and Drug Administration–Approved Indications Metastati c testi cul ar tumor s (i n combi nati on wi th other agents) Metastati c ovar i an tumor s (i n combi nati on wi th other agents) Advanced transi ti onal cel l bl adder cancer that i s no l onger amenabl e to l ocal tr eatments such as sur ger y and/or radi otherapy

U.S. Food and Drug Administration–Approved Dosage In the tr eatment of metastati c testi cul ar tumor s: 20 mg per m2 i .v. dai l y × 5 days ever y 4 weeks (i n combi nati on wi th other agents) In tr eatment of metastati c ovar i an tumor s: 75 to 100 mg per m2 i .v. × one dose (i n combi nati on wi th cycl ophosphami de) ever y 4 weeks, or as si ngl e-agent therapy: 100 mg per m2 i .v. × one dose ever y 4 weeks Advanced bl adder cancer : 50 to 70 mg per m2 i .v. × one dose ever y 3 to 4 weeks (si ngl e-agent therapy)

Dose Modification Criteria Renal i mpai r ment: dose to be modi fi ed; myel osuppr essi on: dose to be modi fi ed

Adverse Reactions CNS: neur opathy, par esthesi a, and ototoxi ci ty; ELECTRO: Mg, Na, Ca, and K al terati ons; G I: N/V (for dose ≥50 mg per m2 : L5, for dose 1,500 mg per m2 : L5, between 750 mg per m2 and 1,500 mg per m 2 : L4, 1 g per m2 L4), anor exi a, di ar r hea, mucosi ti s, i ncr eased LF T val ues and pancr eati ti s (i n pati ents who have pr evi ousl y r ecei ved asparagi nase); HEMAT: myel osuppr essi on; OCULAR: conjuncti vi ti s (general l y seen wi th hi gh-dose r egi mens); OTHER: cytarabi ne (AraC) syndr ome (i ncl udes fever, myal gi a, bone pai n, rash, conjuncti vi ti s, and mal ai se); acute r espi rator y di str ess syndr ome r epor ted wi th hi gh-dose r egi mens.

Comments Appr opr i ate pr ophyl axi s may be consi der ed for tumor l ysi s syndr ome when tr eati ng acute l eukemi as. Local cor ti coster oi d eye dr ops may be consi der ed to pr ovi de pr ophyl axi s for conjuncti vi ti s when empl oyi ng hi gh-dose r egi mens of cytarabi ne. Therapy to be wi thhel d i f acute CNS toxi ci ty occur s wi th hi ghdose r egi mens.

CYTARABINE LIPOSOME INJECTION (DEPOCYT) Mechanism of Action Cytarabi ne l i posome i s an anti metabol i te.

U.S. Food and Drug Administration–Approved Indications Intrathecal tr eatment of l ymphomatous meni ngi ti s.

U.S. Food and Drug Administration–Approved Dosage G i ven onl y by i ntrathecal r oute ei ther by an i ntraventr i cul ar r eser voi r or di r ectl y i nto the l umbar sac over a per i od of 1 to 5 mi nutes. Pati ents shoul d be star ted on dexamethasone, 4 mg PO or i .v. twi ce dai l y × 5 days begi nni ng on the day of the cytarabi ne l i posome i njecti on. Inducti on: 50 mg i ntrathecal l y ever y 14 days × two doses (weeks 1 and 3). Consol i dati on: 50 mg i ntrathecal l y ever y 14 days × thr ee doses (weeks 5, 7, and 9) fol l owed by an addi ti onal dose at week 13. Mai ntenance: 50 mg i ntrathecal l y ever y 28 days × four doses (weeks 17, 21, 25, 29).

Dose Modification Criteria Neur otoxi ci ty: dose to be modi fi ed.

Adverse Reactions CNS: Chemi cal arachnoi di ti s, headache, astheni a, confusi on, and somnol ence.

DACARBAZINE (DTIC-DOME) Mechanism of Action Mechani sm of dacar baz i ne i s unknown.

U.S. Food and Drug Administration–Approved Indications Metastati c mal i gnant mel anoma, Hodgki n di sease (second-l i ne therapy).

U.S. Food and Drug Administration–Approved

Dosage Mal i gnant mel anoma: 2 to 4.5 mg per kg i .v. dai l y × 10 days; r epeat ever y 4 weeks, or 250 mg per m2 i .v. dai l y × 5 days; r epeat ever y 3 weeks. Hodgki n di sease: 150 mg per m2 i .v. dai l y × 5 days, r epeat ever y 4 weeks (i n combi nati on wi th other agents), or 375 mg per m2 i .v. on day 1, r epeat ever y 15 days (i n combi nati on wi th other agents).

Adverse Reactions DERM: al opeci a, rash, faci al fl ushi ng, and faci al par esthesi a; G I: N/V L5, anor exi a, di ar r hea, i ncr eased LF T val ues, and hepati c necr osi s; OTHER: pai n and bur ni ng at i nfusi on, anaphyl axi s, fever, myal gi as, and mal ai se.

DACTINOMYCIN (COSMEGEN) Mechanism of Action Dacti nomyci n i s an i nter cal ati ng agent.

U.S. Food and Drug Administration–Approved Indications Indi cated as par t of a combi nati on chemotherapy or mul ti -modal i ty tr eatment r egi men for the fol l owi ng mal i gnanci es: Wi l ms tumor ; chi l dhood r habdomyosar coma; Ewi ng sar coma; and metastati c, nonsemi nomatous testi cul ar cancer. Indi cated as a si ngl e agent or as par t of a combi nati on r egi men for gestati onal tr ophobl asti c neopl asi a. Indi cated as a component of r egi onal per fusi on i n the tr eatment of l ocal l y r ecur r ent or l ocor egi onal sol i d mal i gnanci es.

U.S. Food and Drug Administration–Approved Dosage For obese or edematous pati ents, the dosage shoul d be based on BSA. Dose i ntensi ty shoul d not exceed 15 µg per kg i .v. dai l y × 5 days

or 400 to 600 µg per m2 i .v. dai l y × 5 days, r epeated ever y 3 to 6 weeks. Cur r ent l i teratur e to be consul ted for dosage r egi mens and gui del i nes.

Dose Modification Criteria Myel osuppr essi on: dose to be modi fi ed.

Adverse Reactions DERM: al opeci a, er ythema, ski n er upti ons, radi ati on r ecal l , and ti ssue damage or necr osi s, wi th extravasati on; ELECTRO: hypocal cemi a; G I: N/V (>1.5 mg per m2 : L4, ≤1.5 mg per m2 : L3), mucosi ti s, anor exi a, dysphagi a, i ncr eased LF T val ues, and hepatotoxi ci ty; HEMAT: myel osuppr essi on; OTHER: fever, fati gue, myal gi a, and secondar y mal i gnanci es.

Comments Vesi cant

DAUNORUBICIN (CERUBIDINE) Mechanism of Action Daunor ubi ci n i s an i nter cal ati ng agent that i nhi bi ts topoi someraseII.

U.S. Food and Drug Administration–Approved Indications In adul t ANLL or ALL (chi l dr en and adul ts) i n combi nati on wi th other agents for r emi ssi on i nducti on.

U.S. Food and Drug Administration–Approved Dosage ANLL: i n combi nati on wi th cytarabi ne Age 300 mg per m 2 i n chi l dr en), ar r hythmi as; DERM: nai l hyper pi gmentati on, rash, al opeci a, ti ssue damage or necr osi s, wi th extravasati on; G I: N/V L3, mucosi ti s; HEMAT: myel osuppr essi on; Other : r ed-ti nged ur i ne, fever, chi l l s, and secondar y mal i gnanci es.

Comments Vesi cant Consi der appr opr i ate pr ophyl axi s for tumor l ysi s syndr ome when tr eati ng acute l eukemi as.

DAUNORUBICIN CITRATE LIPOSOME INJECTION (DAUNOXOME) Mechanism of Action

Daunor ubi ci n i s an i nter cal ati ng agent that i nhi bi ts topoi someraseII.

U.S. Food and Drug Administration–Approved Indications Advanced human i mmunodefi ci ency vi r us (HIV)-associ ated Kaposi sar coma (fi r st-l i ne therapy).

U.S. Food and Drug Administration–Approved Dosage 40 mg per m2 i .v. over 60 mi nutes × one dose ever y 2 weeks.

Dose Modification Criteria Hepati c: dose i s to be modi fi ed; r enal i mpai r ment: dose i s to be modi fi ed; myel osuppr essi on: dose i s to be modi fi ed.

Adverse Reactions CV: CHF, ar r hythmi as; DERM: nai l , al opeci a, hyper pi gmentati on, and rash; G I: N/V L2, mucosi ti s, and di ar r hea; HEMAT: myel osuppr essi on; INF US: back pai n, fl ushi ng, and chest ti ghtness (i nfusi on-r el ated r eacti ons usual l y subsi de wi th i nter r upti on of the i nfusi on, and general l y do not r ecur i f the i nfusi on i s then r esumed at a sl ower rate); OTHER: r ed-ti nged ur i ne, fever, chi l l s, and fati gue.

Comments Not to be confused wi th nonl i posomal for ms of daunor ubi ci n. Li posomal for mul ati ons of the same dr ug may not be equi val ent. In anthracycl i ne-naï ve pati ents, car di ac functi on i s to be eval uated by hi stor y and physi cal exami nati on i n each cycl e and l eft ventr i cul ar ejecti on fracti on (LVEF ) functi on i s to be deter mi ned at total cumul ati ve doses of daunor ubi ci n ci trate l i posome i njecti on of 320 mg per m2 and at ever y 160 mg per m2 ther eafter. Pati ents wi th pr eexi sti ng car di ac di sease, wi th a hi stor y of radi otherapy encompassi ng the hear t, or wi th pr evi ousl y r ecei ved anthracycl i nes (doxor ubi ci n >300 mg per m2 or equi val ent) shoul d have car di ac functi on (LVEF ) moni tor ed

befor e daunor ubi ci n ci trate l i posome i njecti on therapy and befor e ever y 160 mg per m2 ther eafter.

DENILEUKIN DIFTITOX (ONTAK) Mechanism of Action Deni l euki n di fti tox i s a fusi on pr otei n composed of di phther i a toxi n fragments l i nked to i nter l euki n 2 (IL-2) sequences; i nteracts wi th IL-2 cel l sur face r eceptor s and i nhi bi ts cel l ul ar pr otei n synthesi s.

U.S. Food and Drug Administration–Approved Indications Tr eatment of per si stent or r ecur r ent CTCL i n pati ents whose mal i gnant cel l s expr ess the CD25 component of the IL-2 r eceptor.

U.S. Food and Drug Administration–Approved Dosage Cel l s shoul d be tested for CD25 befor e admi ni strati on. 9 or 18 µg per kg i .v. over at l east 15 mi nutes dai l y × 5 days; cycl es shoul d be r epeated ever y 21 days. Infusi on shoul d be stopped or i nfusi on rate shoul d be r educed for sever e i nfusi onr el ated r eacti ons.

Adverse Reactions CNS: di z z i ness; CV: vascul ar l eak syndr ome (hypotensi on and edema hypoal bumi nemi a), hypotensi on, and thr omboti c events; DERM: rash, pr ur i tus; G I: N/V L3, anor exi a, di ar r hea, and i ncr eased LF T val ues; HEMAT: anemi a; INF US: acute hyper sensi ti vi ty-type r eacti ons consi sti ng of one or mor e of the fol l owi ng: hypotensi on, back pai n, dyspnea, vasodi l ati on, rash, chest pai n or ti ghtness, tachycar di a, dysphagi a, syncope, al l er gi c r eacti ons, or anaphyl axi s; PULM: dyspnea and cough; OTHER: fl u-l i ke syndr ome consi sti ng of one or mor e of the fol l owi ng: fever and/or chi l l s, astheni a, di gesti ve symptoms, myal gi as, and ar thral gi as (appear s several hour s to days after dose i nfusi on).

Comments Pr emedi cati on wi th anti pyr eti cs and anti hi stami nes to be consi der ed; emer gency medi cati ons and r esusci tati ve equi pment to be r eadi l y avai l abl e dur i ng admi ni strati on. Wei ght, bl ood pr essur e, and ser um al bumi n l evel shoul d be moni tor ed for vascul ar l eak syndr ome. Pati ents wi th pr eexi sti ng l ow ser um al bumi n l evel s may be pr edi sposed to the syndr ome. Pati ents shoul d be moni tor ed car eful l y for i nfecti on.

DOCETAXEL (TAXOTERE) Mechanism of Action Docetaxel has the effect of mi cr otubul e assembl y stabi l i z ati on.

U.S. Food and Drug Administration–Approved Indications Unr esectabl e, l ocal l y advanced, or metastati c NSCLC: fi r st-l i ne therapy i n combi nati on wi th ci spl ati n and second-l i ne therapy as si ngl e agent after fai l ur e of pr i or pl ati num-based chemotherapy. Local l y advanced or metastati c br east cancer (after fai l ur e of ear l i er chemotherapy). Andr ogen-i ndependent (hor mone-r efractor y) metastati c pr ostate cancer (i n combi nati on wi th pr edni sone).

U.S. Food and Drug Administration–Approved Dosage Pr emedi cati on for hyper sensi ti vi ty r eacti ons and fl ui d r etenti on: dexamethasone, 8 mg PO twi ce dai l y for 3 days star ti ng 1 day befor e docetaxel admi ni strati on. NSCLC: F i r st-l i ne therapy (combi ned wi th ci spl ati n): 75 mg per m2

i .v. over 1 hour × one dose ever y 3 weeks (admi ni ster ed i mmedi atel y pr i or to ci spl ati n) Second-l i ne therapy (si ngl e agent): 75 mg per m2 i .v. over 1 hour × one dose ever y 3 weeks. Br east cancer : 60 to 100 mg per m2 i .v. over 1 hour × one dose ever y 3 weeks. Pr ostate cancer : 75 mg per m2 i .v. over 1 hour × one dose ever y 3 weeks. Pr edni sone 5 mg oral l y twi ce dai l y i s admi ni ster ed conti nuousl y.

Dose Modification Criteria Hepati c: dose to be modi fi ed; myel osuppr essi on: dose to be modi fi ed; nonhematol ogi c toxi ci ty: dose to be modi fi ed (package l abel i ng to be consul ted for dose modi fi cati on gui del i nes)

Adverse Reactions CNS: per i pheral neur osensor y toxi ci ty (par esthesi a, dysesthesi a, and pai n), fever, and astheni a; DERM: rash wi th l ocal i zed ski n er upti ons, er ythema and pr ur i tus, nai l changes (pi gmentati on, onychol ysi s, and pai n), and al opeci a; G I: N/V L2, di ar r hea, mucosi ti s, and i ncr eased LF T val ues; HEMAT: myel osuppr essi on; INF US: acute hyper sensi ti vi ty-type r eacti ons consi sti ng of hypotensi on and/or br onchospasm or general i zed rash/er ythema; OTHER: sever e fl ui d r etenti on and myal gi a.

Comments Pati ents wi th pr eexi sti ng hepati c dysfuncti on ar e at i ncr eased r i sk of sever e toxi ci ty. Pati ents wi th pr eexi sti ng effusi ons shoul d be cl osel y moni tor ed fr om the fi r st dose for the possi bl e exacer bati on of the effusi ons. Lower dose, weekl y dosage r egi mens ar e commonl y uti l i zed. Cur r ent l i teratur e to be consul ted for dose gui del i nes. Non–di ethyl hexyl phthal ate (DEHP) pl asti ci zed sol uti on contai ner s and admi ni strati on sets to be used.

DOXORUBICIN (ADRIAMYCIN AND OTHERS) Mechanism of Action Doxor ubi ci n i s an i nter cal ati ng agent and i nhi bi ts topoi somerase-II.

U.S. Food and Drug Administration–Approved Indications ALL, acute nonl ymphocyti c l eukemi a; Wi l ms tumor ; neur obl astoma; soft ti ssue and bone sar coma; br east, ovar i an, thyr oi d, br onchi ogeni c, gastr i c cancer and transi ti onal cel l bl adder cancer ; Hodgki n di sease; mal i gnant l ymphoma.

U.S. Food and Drug Administration–Approved Dosage Many dosi ng r egi mens r epor ted. Cur r ent l i teratur e may be consul ted. Common dose r egi mens l i sted bel ow. Si ngl e agent: 60 to 75 mg per m2 i .v. × one dose r epeated ever y 3 weeks. In combi nati on wi th other agents: 40 to 60 mg per m2 i .v. × one dose, r epeated ever y 3 to 4 weeks.

Dose Modification Criteria Hepati c: dose to be modi fi ed; myel osuppr essi on: dose to be modi fi ed.

Adverse Reactions CV: CHF, (r i sk of car di otoxi ci ty i ncr eases rapi dl y wi th total l i feti me cumul ati ve doses >450 mg per m2 ) and ar r hythmi as; DERM: nai l hyper pi gmentati on, onychol ysi s, al opeci a, radi ati on r ecal l , ti ssue damage or necr osi s wi th extravasati on; G I: N/V (>60 mg per m2 : L4, 20 to 60 mg per m2 : L3, 900 mg per m2 ), ar r hythmi as; DERM: al opeci a, radi ati on r ecal l , ti ssue damage or necr osi s wi th extravasati on; G I: N/V (>90 mg per m2 : L4, ≤90 mg per m2 : L3), and mucosi ti s; HEMAT: myel osuppr essi on; OTHER: faci al fl ushi ng, and secondar y mal i gnanci es.

Comments Vesi cant

ESTRAMUSTINE (EMCYT) Mechanism of Action Estramusti ne i s an al kyl ati ng agent, an estr ogen, and i nduces mi cr otubul e i nstabi l i ty.

U.S. Food and Drug Administration–Approved Indications Pal l i ati ve tr eatment of metastati c and/or pr ogr essi ve car ci noma of the pr ostate.

U.S. Food and Drug Administration–Approved

Dosage 4.67 mg per kg PO thr ee ti mes dai l y (t.i .d.) or 3.5 mg per kg PO four ti mes dai l y (q.i .d.); total dai l y dose: 14 mg per kg. Admi ni ster wi th water, 1 hour befor e or 2 hour s after meal s. Avoi d the si mul taneous admi ni strati on of mi l k, mi l k pr oducts, and cal ci um-r i ch foods and dr ugs.

Dose Modification Criteria Hepati c i mpai r ment: to be admi ni ster ed wi th cauti on, no speci fi c dose modi fi cati ons

Adverse Reactions CV: Edema, fl ui d r etenti on, and venous thr omboembol i sm; ENDO: hyper gl ycemi a, gynecomasti a, and i mpotence; G I: di ar r hea, nausea, and el evated LF T val ues [especi al l y gl utami c-oxal oaceti c transami nase (SG OT) or l actate dehydr ogenase (LDH)]; PULM: dyspnea.

ETOPOSIDE (VEPESID) Mechanism of Action Etoposi de l eads to topoi somerase-II i nteracti on.

U.S. Food and Drug Administration–Approved Indications Refractor y testi cul ar cancer ; smal l cel l l ung cancer (SCLC, fi r st-l i ne therapy i n combi nati on wi th other agents).

U.S. Food and Drug Administration–Approved Dosage Testi cul ar cancer : 50 to 100 mg per m2 i .v. over 30 to 60 mi nutes dai l y × 5 days (days 1 to 5), r epeated ever y 3 to 4 weeks or 100 mg per m2 i .v. over 30 to 60 mi nutes on days 1, 3, and 5,

r epeated ever y 3 to 4 weeks (i n combi nati on wi th other appr oved agents). Cur r ent l i teratur e may be consul ted for dose r ecommendati ons. SCLC: 35 to 50 mg per m2 i .v. over 30 to 60 mi nutes dai l y × 4 to 5 days, r epeated ever y 3 to 4 weeks (i n combi nati on wi th other agents). Cur r ent l i teratur e to be consul ted for dose r ecommendati ons. Oral capsul es: In SCLC, the r ecommended dose of etoposi de capsul es i s two ti mes the i .v. dose r ounded to the near est 50 mg.

Dose Modification Criteria Renal i mpai r ment: dose to be modi fi ed.

Adverse Reactions DERM: al opeci a, rash, ur ti car i a, and pr ur i tus; G I: N/V L2, mucosi ti s, and anor exi a; HEMAT: myel osuppr essi on; INF US: hypotensi on (i nfusi on-rate r el ated), anaphyl acti c-l i ke r eacti ons (character i zed by chi l l s, fever, tachycar di a, br onchospasm, dyspnea, and/or hypotensi on); OTHER: secondar y mal i gnanci es.

ETOPOSIDE PHOSPHATE (ETOPHOS) Mechanism of Action Etoposi de phosphate i s rapi dl y and compl etel y conver ted to etoposi de i n pl asma, l eadi ng to topoi somerase-II i nteracti on.

U.S. Food and Drug Administration–Approved Indications Refractor y testi cul ar cancer ; SCLC, fi r st-l i ne therapy i n combi nati on wi th other agents.

U.S. Food and Drug Administration–Approved Dosage Testi cul ar cancer : 50 to 100 mg per m2 i .v. dai l y × 5 days (days

1 to 5), r epeated ever y 3 to 4 weeks or 100 mg per m2 i .v. on days 1, 3, and 5, r epeated ever y 3 to 4 weeks (i n combi nati on wi th other appr oved agents). Cur r ent l i teratur e may be consul ted for dose r ecommendati ons. SCLC: 35 to 50 mg per m2 i .v. dai l y × 4 to 5 days, r epeated ever y 3 to 4 weeks (i n combi nati on wi th other agents). Cur r ent l i teratur e may be consul ted for dose r ecommendati ons. Hi gher rates of i ntravenous admi ni strati on have been uti l i zed and tol erated by pati ents wi th etoposi de phosphate compar ed to etoposi de. Etoposi de phosphate can be admi ni ster ed at i nfusi on rates fr om 5 to 210 mi nutes (general l y i nfusi on durati ons of 5 to 30 mi nutes have been uti l i zed).

Dose Modification Criteria Renal i mpai r ment: dose to be modi fi ed.

Adverse Reactions DERM: al opeci a, rash, ur ti car i a, and pr ur i tus; G I: N/V L2, mucosi ti s, and anor exi a; HEMAT: myel osuppr essi on; INF US: hypotensi on (i nfusi on-rate r el ated) and anaphyl acti c-l i ke r eacti ons (character i zed by chi l l s, fever, tachycar di a, br onchospasm, dyspnea, and/or hypotensi on); OTHER: secondar y mal i gnanci es.

Comments Etoposi de phosphate i s a water-sol ubl e ester of etoposi de. The water sol ubi l i ty of etoposi de phosphate l essens the potenti al for pr eci pi tati on fol l owi ng di l uti on and dur i ng i ntravenous admi ni strati on. Enhanced water sol ubi l i ty al so al l ows for l ower di l uti on vol umes and mor e rapi d i ntravenous admi ni strati on compar ed to conventi onal etoposi de.

EXEMESTANE (AROMISAN) Mechanism of Action Exemestane i s an i r r ever si bl e ster oi dal ar omatase i nacti vator.

U.S. Food and Drug Administration–Approved Indications

Advanced br east cancer after tamoxi fen fai l ur e i n postmenopausal women.

U.S. Food and Drug Administration–Approved Dosage 25 mg PO dai l y after a meal .

Dose Modification Criteria Renal i mpai r ment: no dose modi fi cati on; hepati c i mpai r ment: no dose modi fi cati on. Note: Dr ug exposur e i s i ncr eased wi th hepati c and/or r enal i nsuffi ci ency. The safety of chr oni c dosi ng i n these setti ngs has not been studi ed. On the basi s of exper i ence wi th exemestane at r epeated doses up to 200 mg dai l y that demonstrated a moderate i ncr ease i n non–l i fe-thr eateni ng adver se effects, dosage adjustment does not appear to be necessar y.

Adverse Reactions CNS: depr essi on, i nsomni a, and anxi ety; CV: hot fl ashes and edema; G I: nausea or i ncr eased appeti te; HEMAT: l ymphocytopeni a; OTHER: tumor si te pai n, astheni a, fati gue, i ncr eased sweati ng, and fever.

FLOXURIDINE Mechanism of Action F l oxur i di ne i s an anti metabol i te catabol i zed to fl uor ouraci l .

U.S. Food and Drug Administration–Approved Indications Pal l i ati ve management of gastr oi ntesti nal adenocar ci noma metastasi s to the l i ver when gi ven by conti nuous r egi onal i ntraar ter i al i nfusi on i n car eful l y sel ected pati ents who ar e consi der ed i ncurabl e by sur ger y or other means.

U.S. Food and Drug Administration–Approved Dosage

0.1 to 0.6 mg/kg/day by conti nuous ar ter i al i nfusi on. The hi gher dose ranges (0.4 to 0.6 mg/kg/day) ar e usual l y empl oyed for hepati c ar ter y i nfusi on because the l i ver metabol i zes the dr ug, ther eby r educi ng the potenti al for systemi c toxi ci ty. Therapy may be gi ven unti l adver se r eacti ons appear ; when toxi ci ti es have subsi ded, therapy may be r esumed. Pati ents may be mai ntai ned on therapy as l ong as r esponse to fl oxur i di ne conti nues.

Dose Modification Criteria Renal i mpai r ment: no dose modi fi cati on; hepati c i mpai r ment: no dose modi fi cati on; myel osuppr essi on: dose to be modi fi ed; nonhematol ogi c toxi ci ty: dose to be modi fi ed

Adverse Reactions CV: myocar di al i schemi a; DERM: al opeci a, der mati ti s, and rash; G I: N/VL1–2, stomati ti s, di ar r hea, enter i ti s, gastr oi ntesti nal ul cerati on and bl eedi ng, and el evated LF T val ues; HEMAT: myel osuppr essi on; INF US: pr ocedural compl i cati ons of r egi onal ar ter i al i nfusi on: ar ter i al aneur ysm, ar ter i al i schemi a, ar ter i al thr ombosi s, embol i sm, fi br omyosi ti s, thr ombophl ebi ti s, hepati c necr osi s, abscesses, i nfecti on at catheter si te, bl eedi ng at catheter si te, catheter bl ocked, di spl aced or l eaki ng; OTHER: fever, l ethar gy, mal ai se, and weakness.

FLUDARABINE (FLUDARA) Mechanism of Action F l udarabi ne i s an anti metabol i te.

U.S. Food and Drug Administration–Approved Indications B-cel l CLL (second-l i ne after al kyl ati ng agent therapy)

U.S. Food and Drug Administration–Approved Dosage 25 mg per m2 i .v. over 30 mi nutes dai l y × 5 days, r epeated ever y 28 days.

Dose Modification Criteria Renal i mpai r ment: dose to be modi fi ed

Adverse Reactions CNS: weakness, agi tati on, confusi on, vi sual di stur bances, coma (sever e neur otoxi ci ty general l y seen wi th hi gh-dose r egi mens but have been r epor ted rar el y at r ecommended doses), and per i pheral neur opathy; CV: edema; DERM: rash; G I: N/V L1, di ar r hea, and anor exi a; HEMAT: myel osuppr essi on, autoi mmune hemol yti c anemi a, and l ymphopeni a; PULM: pneumoni ti s and cases of sever e pul monar y toxi ci ty have been r epor ted; OTHER: myal gi a, tumor l ysi s syndr ome, and fati gue.

Comments Moni tor for hemol yti c anemi a. A hi gh i nci dence of fatal pul monar y toxi ci ty was seen i n a tr i al i nvesti gati ng the combi nati on of fl udarabi ne wi th pentostati n. The combi ned use of fl udarabi ne and pentostati n i s not r ecommended. Transfusi on-associ ated graft ver sus host di sease has been obser ved rar el y after transfusi on of noni r radi ated bl ood i n fl udarabi ne-tr eated pati ents. Usi ng onl y i r radi ated bl ood pr oducts shoul d be consi der ed i f transfusi ons ar e necessar y i n pati ents under goi ng tr eatment wi th fl udarabi ne. Moni tor for tumor l ysi s syndr ome and consi der pr ophyl axi s for pati ents wi th CLL wi th a l ar ge tumor bur den who ar e i ni ti ated on fl udarabi ne.

FLUOROURACIL (ADRUCIL AND OTHERS) Mechanism of Action F l uor ouraci l i s an anti metabol i te.

U.S. Food and Drug Administration–Approved Indications

Pal l i ati ve management of cancer of col on, r ectum, br east, stomach, and pancr eas.

U.S. Food and Drug Administration–Approved Dosage Cur r ent l i teratur e may be consul ted.

Adverse Reactions CNS: Acute cer ebel l ar syndr ome, nystagmus, headache, vi sual changes, and photophobi a; CV: angi na and i schemi a; DERM: dr y ski n, photosensi ti vi ty, hand-foot syndr ome (pal mar–pl antar er ythr odysesthesi a), al opeci a, der mati ti s, and thr ombophl ebi ti s; G I: N/V L2, mucosi ti s, di ar r hea, anor exi a, and gastr oi ntesti nal ul cerati on and bl eedi ng; HEMAT: myel osuppr essi on; OTHER: anaphyl axi s and general i zed al l er gi c r eacti ons.

Comments F l uor ouraci l may be gi ven by conti nuous i ntravenous i nfusi on or by rapi d i .v. admi ni strati on (i .v. bol us or push). The method of admi ni strati on wi l l change the toxi ci ty pr ofi l e of fl uor ouraci l (e.g., gr eater potenti al for G I toxi ci ti es such as mucosi ti s and di ar r hea wi th conti nuous i .v. i nfusi ons and mor e hematol ogi c toxi ci ty wi th bol us admi ni strati on).

FLUTAMIDE (EULEXIN) Mechanism of Action F l utami de i s an anti andr ogen.

U.S. Food and Drug Administration–Approved Indications Stage D2 metastati c pr ostate car ci noma [i n combi nati on wi th l utei ni z i ng hor mone r el easi ng hor mone (LHRH) agoni sts] or l ocal l y confi ned stage B2–C pr ostate car ci noma (i n combi nati on wi th LHRH agoni sts and radi ati on therapy).

U.S. Food and Drug Administration–Approved Dosage

Stage D2 metastati c pr ostate car ci noma: 250 mg PO t.i .d. (ever y 8 hour s). Stage B2–C pr ostate cancer : 250 mg PO t.i .d. (ever y 8 hour s) begi nni ng 8 weeks befor e and conti nui ng thr ough radi ati on.

Adverse Reactions DERM: Rash; G I: nausea, di ar r hea, consti pati on, i ncr eased LF T val ues (LF T r esul ts to be moni tor ed per i odi cal l y because of rar e associ ati ons wi th chol estati c jaundi ce, hepati c necr osi s, and encephal opathy); G U: i mpotence; ENDO: l oss of l i bi do, hot fl ashes, and gynecomasti a.

Comments Interacts wi th war far i n; i nter nati onal nor mal i zed rati o (INR) to be moni tor ed cl osel y.

FULVESTRANT (FASLODEX) Mechanism of Action F ul vestrant i s an ER antagoni st.

U.S. Food and Drug Administration–Approved Indications Br east cancer : second-l i ne therapy for hor mone-r eceptor–posi ti ve metastati c br east cancer i n postmenopausal women wi th di sease pr ogr essi on fol l owi ng anti estr ogen therapy.

U.S. Food and Drug Administration–Approved Dosage 250 mg i .m. i njecti on × one dose and r epeated at 1-month i nter val s.

Dose Modification Criteria Renal i mpai r ment: no dosage modi fi cati on; hepati c (mi l d i mpai r ment): no dosage modi fi cati on; hepati c (moderate-to-sever e i mpai r ment): no data avai l abl e, to be used wi th cauti on.

Adverse Reactions CNS: headache; CV: per i pheral edema; ENDO: hot fl ashes; G I: nausea, consti pati on, di ar r hea, abdomi nal pai n, and anor exi a; OTHER: pai n, phar yngi ti s, i njecti on-si te r eacti ons, and astheni a.

GEFITINIB (IRESSA) Mechanism of Action G efi ti ni b i s an i nhi bi tor of mul ti pl e tyr osi ne ki nases, i ncl udi ng those associ ated wi th the EG F R.

U.S. Food and Drug Administration–Approved Indications NSCLC: second-l i ne monotherapy for the tr eatment of pati ents wi th l ocal l y advanced or metastati c NSCLC after fai l ur e of both pl ati numbased and docetaxel chemotherapi es.

U.S. Food and Drug Administration–Approved Dosage 250 mg PO dai l y

Dose Modification Criteria Renal i mpai r ment: no dose modi fi cati on; hepati c i mpai r ment: no dose modi fi cati on.

Adverse Reactions DERM: rash, acne, dr y ski n, and pr ur i tus; G I: nausea, di ar r hea, anor exi a, and el evated LF T val ues; OCULAR: eye pai n, cor neal er osi on or ul cer (someti mes i n associ ati on wi th aber rant eyel ash gr owth); PULM: i nter sti ti al l ung di sease (i nter sti ti al pneumoni a, pneumoni ti s, and al veol i ti s); OTHER: astheni a, and wei ght l oss.

Comments For pati ents who pr esent wi th acute onset or wor seni ng of pul monar y symptoms (dyspnea, cough, and fever ), gefi ti ni b therapy shoul d be i nter r upted and a pr ompt i nvesti gati on of

these symptoms shoul d occur. Fatal i ti es r el ated to i nter sti ti al l ung di sease have been r epor ted. G efi ti ni b i s extensi vel y hepati cal l y metabol i zed, pr edomi nantl y by cytochr ome P450 (CYP) 3A4. Pati ents shoul d be moni tor ed for potenti al dr ug i nteracti ons wi th ei ther potent i nhi bi tor s or i nducer s of CYP 3A4. A dose i ncr ease of gefi ti ni b to 500 mg per day may be consi der ed when gi ven concomi tantl y wi th a potent CYP 3A4 enz yme i nducer such as phenytoi n or r i fampi n. G efi ti ni b may potenti al l y i nteract wi th war far i n, l eadi ng to an el evated pr othr ombi n ti me (PT) and INR and bl eedi ng events; PT/INR to be moni tor ed r egul ar l y wi th concomi tant use.

GEMCITABINE (GEMZAR) Mechanism of Action G emci tabi ne i s an anti metabol i te.

U.S. Food and Drug Administration–Approved Indications Pancr eati c Cancer : fi r st-l i ne therapy for pati ents wi th l ocal l y advanced (nonr esectabl e stage II or stage III) or metastati c (stage IV) adenocar ci noma of the pancr eas and i n pati ents wi th pancr eati c cancer who wer e pr evi ousl y tr eated wi th fl uor ouraci l . NSCLC: fi r st-l i ne therapy (i n combi nati on wi th ci spl ati n) for pati ents wi th i noperabl e, l ocal l y advanced (stage IIIa or IIIb) or metastati c (stage IV) NSCLC. Metastati c br east cancer : fi r st-l i ne therapy (i n combi nati on wi th pacl i taxel ) for pati ents wi th metastati c br east cancer after fai l ur e of pr i or anthracycl i ne-contai ni ng adjuvant chemotherapy, unl ess anthracycl i nes wer e cl i ni cal l y contrai ndi cated.

U.S. Food and Drug Administration–Approved Dosage Pancr eati c cancer (si ngl e agent use): 1,000 mg per m2 i .v. over

30 mi nutes once weekl y for up to 7 weeks, fol l owed by 1 week of r est fr om tr eatment. Subsequent cycl es shoul d consi st of 1,000 mg per m2 i .v. over 30 mi nutes once weekl y for 3 consecuti ve weeks out of ever y 4 weeks. NSCLC (combi nati on therapy wi th ci spl ati n): 4-week schedul e: 1,000 mg per m2 i .v. over 30 mi nutes on days 1, 8, and 15 of each 28-day cycl e. Ci spl ati n (100 mg per m 2 i .v. × one dose) shoul d be admi ni ster ed after gemci tabi ne onl y on day 1. or 3-week schedul e: 1,250 mg per m2 i .v. over 30 mi nutes on days 1 and 8 of each 21-day cycl e. Ci spl ati n (100 mg per m2 i .v. × one dose) shoul d be admi ni ster ed after gemci tabi ne onl y on day 1. Metastati c br east cancer (combi nati on therapy wi th pacl i taxel ): 1,250 mg per m2 i .v. over 30 mi nutes on days 1 and 8 of each 21-day cycl e. Pacl i taxel shoul d be admi ni ster ed at 175 mg per m 2 i .v. over 3 hour s × one dose (day 1 onl y) befor e gemci tabi ne admi ni strati on.

Dose Modification Criteria Renal i mpai r ment: dose to be used wi th cauti on; hepati c i mpai r ment: dose to be used wi th cauti on; myel osuppr essi on: dose to be modi fi ed; nonhematol ogi c toxi ci ty: dose to be modi fi ed.

Adverse Reactions DERM: rash and al opeci a; G I: N/V L2, consti pati on, di ar r hea, mucosi ti s, i ncr eased LF T val ues and bi l i r ubi n, and rar e r epor ts of sever e hepatotoxi ci ty; G U: pr otei nur i a, hematur i a, and hemol yti cur emi c syndr ome; HEMAT: myel osuppr essi on; PULM: dyspnea, rar e r epor ts of sever e pul monar y toxi ci ty (pneumoni ti s, pul monar y fi br osi s, pul monar y edema, and acute r espi rator y di str ess syndr ome); OTHER: fever, pai n, and rar e r epor ts of vascul ar toxi ci ty (vascul i ti s).

Comments Cl earance i n women and el der l y i s r educed.

Intravenous admi ni strati on rate has been shown to i nfl uence both effi cacy and toxi ci ty. Publ i shed l i teratur e shoul d be r efer r ed to for the appr opr i ate rate of admi ni strati on for a speci fi c r egi men.

GEMTUZUMAB OZOGAMICIN (MYLOTARG) Mechanism of Action G emtuz umab i s a humani zed monocl onal anti body di r ected at the CD33 cel l sur face anti gen conjugated wi th a cytotoxi c anti tumor anti bi oti c, cal i cheami ci n. Bi ndi ng of the anti -CD33 anti body por ti on of gemtuz umab ozogami ci n r esul ts i n the i nter nal i z ati on and r el ease of the cal i cheami ci n, whi ch subsequentl y causes DNA doubl e strand br eakage and cel l death.

U.S. Food and Drug Administration–Approved Indications AML: second-l i ne therapy for pati ents wi th CD33-posi ti ve AML who ar e i n fi r st r el apse, who ar e 60 year s of age or ol der, and who ar e not consi der ed candi dates for other cytotoxi c chemotherapy.

U.S. Food and Drug Administration–Approved Dosage 9 mg per m2 i .v. over 2 hour s × one dose. The r ecommended tr eatment cour se i s a total of two doses wi th 14 days between the doses. Consi der l eukor educti on wi th hydr oxyur ea or l eukapher esi s to r educe the per i pheral whi te bl ood cel l count to 50 to 1,000 mg per m2 L4), mucosi ti s/stomati ti s, di ar r hea, i ncr eased LF T val ues, and acute and chr oni c hepatotoxi ci ty; G U: r enal fai l ur e (hi gh-dose therapy) and cysti ti s; HEMAT: myel osuppr essi on; PULM: i nter sti ti al pneumoni ti s; OTHER: fever, mal ai se, chi l l s, fati gue, teratogeni c, and tumor l ysi s syndr ome.

Comments Cl earance i s r educed i n pati ents wi th i mpai r ed r enal functi on or thi r d-space fl ui d accumul ati ons (e.g., asci tes and pl eural effusi ons). Methotr exate di str i butes to thi r d-space fl ui d accumul ati ons, wi th subsequent sl ow and del ayed cl earance, l eadi ng to pr ol onged ter mi nal pl asma hal f-l i fe and toxi ci ty. Nonster oi dal anti -i nfl ammator y dr ugs and aci di c dr ugs i nhi bi t methotr exate cl earance. Mul ti pl e potenti al dr ug i nteracti ons; cur r ent l i teratur e may be r evi ewed. Use vi gor ous hydrati on, ur i nar y al kal i ni z ati on, and l eucovor i n r escue wi th hi gh-dose therapy. Pr eser vati ve-fr ee pr oduct and di l uents to be used when

admi ni ster i ng i ntrathecal l y or wi th hi gh-dose i .v. r egi mens.

MITOMYCIN C (MUTAMYCIN) Mechanism of Action Mi tomyci n C i nduces DNA cr oss-l i nks thr ough al kyl ati on; i nhi bi ts DNA and RNA synthesi s.

U.S. Food and Drug Administration–Approved Indications Di ssemi nated gastr i c cancer or pancr eati c cancer (i n combi nati on wi th other agents and as pal l i ati ve tr eatment when other modal i ti es have fai l ed).

U.S. Food and Drug Administration–Approved Dosage Si ngl e-agent therapy: 20 mg per m2 i .v. × 1 dose r epeated ever y 6 to 8 weeks. Cur r ent l i teratur e may be r efer r ed to for al ter nati ve dosi ng r egi mens and combi nati on r egi mens.

Dose Modification Criteria Renal i mpai r ment: dose to be modi fi ed; myel osuppr essi on: dose to be modi fi ed.

Adverse Reactions CV: CHF (pati ents wi th pr i or doxor ubi ci n exposur e); DERM: al opeci a, pr ur i tus, ti ssue damage or necr osi s wi th extravasati on; G I: anor exi a, N/V L2, mucosi ti s, and di ar r hea; G U: i ncr eased Cr ; HEMAT: myel osuppr essi on (may be cumul ati ve); PULM: nonpr oducti ve cough, dyspnea, and i nter sti ti al pneumoni a; OTHER: fever, hemol yti c ur emi c syndr ome, mal ai se, and weakness.

Comments Vesi cant.

MITOTANE (LYSODREN) Mechanism of Action Mi totane i s an adr enal cytotoxi c agent.

U.S. Food and Drug Administration–Approved Indications Inoperabl e, functi onal , and nonfuncti onal adr enal cor ti cal car ci noma.

U.S. Food and Drug Administration–Approved Dosage Ini ti al dose: 2 to 6 g PO per day i n thr ee to four di vi ded doses. Doses ar e usual l y i ncr eased i ncr emental l y to 9 to 10 g per day or unti l maxi mum tol erated dose i s achi eved. Maxi mum tol erated dose range var i es fr om 2 to 16 g per day but has usual l y been 9 to 10 g per day. Total dai l y doses shoul d be admi ni ster ed i n thr ee to four di vi ded doses.

Adverse Reactions CNS: ver ti go, depr essi on, l ethar gy, somnol ence, and di z z i ness; DERM: transi ent ski n rashes; G I: anor exi a, nausea, and di ar r hea; OTHER: adr enal i nsuffi ci ency.

Comments Adr enal i nsuffi ci ency pr ecauti ons to be i nsti tuted. Pati ents shoul d be counsel ed r egar di ng the common CNS si de effects, and ambul ator y pati ents shoul d be cauti oned about dr i vi ng, operati ng machi ner y, and other haz ar dous pur sui ts r equi r i ng mental and physi cal al er tness.

MITOXANTRONE (NOVANTRONE) Mechanism of Action Mi toxantr one i nteracts wi th DNA and i s an i nter cal ati ng agent and a

topoi somerase-II i nhi bi tor.

U.S. Food and Drug Administration–Approved Indications ANLL (myel ogenous, pr omyel ocyti c, monocyti c, and er ythr oi d acute l eukemi a) i n adul ts (i ni ti al therapy i n combi nati on wi th other agents) Advanced hor mone-r efractor y pr ostate cancer (i n combi nati on wi th cor ti coster oi ds) Other i ndi cati ons: Mul ti pl e scl er osi s.

U.S. Food and Drug Administration–Approved Dosage ANLL: Inducti on, 12 mg per m2 i .v. dai l y × 3 days (days 1, 2, and 3) i n combi nati on wi th cytarabi ne; consol i dati on, 12 mg per m 2 i .v. dai l y × 2 days (days 1 and 2) i n combi nati on wi th cytarabi ne. Pr ostate cancer : 12 to 14 mg per m2 i .v. × one dose ever y 21 days wi th pr edni sone or hydr ocor ti sone.

Dose Modification Criteria Renal i mpai r ment: no data avai l abl e; hepati c i mpai r ment: to be used wi th cauti on; dose adjustment may be consi der ed.

Adverse Reactions CV: CHF (cl i ni cal r i sk i ncr eases after a l i feti me cumul ati ve dose of 140 mg per m2 ), tachycar di a, el ectr ocar di ographi c changes, and chest pai n; DERM: rash, al opeci a, ur ti car i a, nai l bed changes; G I: N/V (>15 mg per m2 : L4, ≤15 mg per m2 : L3), mucosi ti s, consti pati on, anor exi a, and i ncr eased LF T val ues; HEMAT: myel osuppr essi on; PULM: dyspnea; OTHER: bl ui sh gr een ur i ne, scl era may tur n bl ui sh, phl ebi ti s (i r r i tant), fati gue, secondar y l eukemi as, and tumor l ysi s syndr ome.

Comments Appr opr i ate pr ophyl axi s may be consi der ed for tumor l ysi s syndr ome when tr eati ng acute l eukemi as.

NILUTAMIDE (NILANDRON) Mechanism of Action Ni l utami de i s an anti andr ogen.

U.S. Food and Drug Administration–Approved Indications Metastati c pr ostate cancer (stage D2; i n combi nati on therapy wi th sur gi cal castrati on). Dosi ng shoul d begi n on same day or day after sur gi cal castrati on.

U.S. Food and Drug Administration–Approved Dosage G i ve 300 mg PO dai l y × 30 days, and then 150 mg PO dai l y (wi th or wi thout food).

Adverse Reactions CNS: di z z i ness; CV: hyper tensi on, and angi na; ENDO: hot fl ashes, i mpotence, and decr eased l i bi do; G I: nausea, anor exi a, i ncr eased LF T val ues (LF T r esul ts to be moni tor ed per i odi cal l y because of rar e associ ati ons wi th chol estati c jaundi ce, hepati c necr osi s, and encephal opathy), and consti pati on; OCULAR: vi sual di stur bances and i mpai r ed adaptati on to dar k; PULM: i nter sti ti al pneumoni ti s and dyspnea.

Comments Basel i ne chest x-ray to be obtai ned befor e i ni ti ati ng therapy (wi th consi derati on of basel i ne pul monar y functi on tests). Pati ents shoul d be i nstr ucted to r epor t any new or wor seni ng shor tness of br eath and i f symptoms occur, ni l utami de shoul d be i mmedi atel y di sconti nued.

LF T r esul ts shoul d be moni tor ed at basel i ne and at r egul ar i nter val s × 4 months and then per i odi cal l y ther eafter.

OXALIPLATIN (ELOXATIN) Mechanism of Action Oxal i pl ati n i s an al kyl ati ng-l i ke agent pr oduci ng i nter strand DNA cr oss-l i nks.

U.S. Food and Drug Administration–Approved Indications Advanced or metastati c col or ectal cancer : F i r st-l i ne therapy i n combi nati on wi th i nfusi onal fl uor ouraci l and l eucovor i n i n pati ents wi th advanced col or ectal cancer. Second-l i ne therapy i n combi nati on wi th i nfusi onal fl uor ouraci l and l eucovor i n i n pati ents wi th metastati c col or ectal cancer whose di sease has r ecur r ed or pr ogr essed wi thi n 6 months of compl eti on of fi r st-l i ne therapy wi th the combi nati on of bol us fl uor ouraci l /l eucovor i n and i r i notecan.

U.S. Food and Drug Administration–Approved Dosage Combi ned therapy wi th i nfusi onal fl uor ouraci l and l eucovor i n (F OLF OX r egi men) Day 1: Oxal i pl ati n 85 mg per m2 i .v. over 120 mi nutes × 1 dose gi ven concur r entl y wi th Leucovor i n 200 mg per m2 i .v. over 120 mi nutes × 1 dose fol l owed by F l uor ouraci l 400 mg per m2 i .v. bol us over 2 to 4 mi nutes × 1 dose fol l owed by F l uor ouraci l 600 mg per m2 i .v. conti nuous i nfusi on over 22 hour s.

Day 2: Leucovor i n 200 mg per m2 i .v. over 120 mi nutes × 1 dose, fol l owed by F l uor ouraci l 400 mg per m2 i .v. bol us over 2 to 4 mi nutes × 1 dose, fol l owed by F l uor ouraci l 600 mg per m2 i .v. conti nuous i nfusi on over 22 hour s. Cycl es ar e r epeated ever y 2 weeks.

Dose Modification Criteria Renal i mpai r ment: no data avai l abl e (to be used wi th cauti on); myel osuppr essi on: dose to be modi fi ed; nonhematol ogi c toxi ci ty: dose to be modi fi ed.

Adverse Reactions CNS: per i pheral sensor y neur opathi es (detai l s fol l ow under “Comments”), headache; CV: edema, thr omboembol i c events; DERM: i njecti on-si te r eacti ons; G I: N/V L3, di ar r hea, mucosi ti s or stomati ti s, abdomi nal pai n, anor exi a, taste per ver si on, and el evated LF T val ues; G U: el evated ser um cr eati ni ne; HEMAT: myel osuppr essi on; PULM: pul monar y fi br osi s, dyspnea, and cough; OTHER: fati gue, fever, back pai n, pai n, and hyper sensi ti vi ty r eacti on.

Comments Oxal i pl ati n i s associ ated wi th two types of per i pheral neur opathy: 1. An acute, r ever si bl e, pr i mar i l y per i pheral , sensor y neur opathy that i s of ear l y onset (fr om wi thi n hour s to 1 to 2 days of dosi ng), that r esol ves wi thi n 14 days, and that fr equentl y r ecur s wi th fur ther dosi ng. The symptoms i ncl ude transi ent par esthesi a, dysesthesi a, and hypoesthesi a i n the hands, feet, per i oral ar ea, or thr oat. Symptoms may be pr eci pi tated or exacer bated by exposur e to col d temperatur e or col d objects. Pati ents shoul d be i nstr ucted to avoi d col d

dr i nks and use of i ce, and shoul d cover exposed ski n pr i or to exposur e to col d temperatur e or col d objects. 2. A per si stent (>14 days), pr i mar i l y per i pheral , sensor y neur opathy usual l y character i zed by par esthesi as, dysesthesi as, hypoesthesi as, but may al so i ncl ude defi ci ts i n pr opr i ocepti on that can i nter fer e wi th dai l y acti vi ti es. Dose modi fi cati ons ar e r ecommended for per si stent grade 2 neur otoxi ci ty and di sconti nuati on of therapy i s r ecommended for per si stent grade 3 neur otoxi ci ty.

PACLITAXEL (TAXOL) Mechanism of Action Pacl i taxel stabi l i zes mi cr otubul e assembl y.

U.S. Food and Drug Administration–Approved Indications Advanced ovar i an cancer (fi r st-l i ne and subsequent therapy). As fi r st-l i ne therapy, pacl i taxel i s i ndi cated i n combi nati on wi th ci spl ati n. Br east cancer Adjuvant tr eatment of node-posi ti ve br east cancer (admi ni ster ed sequenti al l y to standar d doxor ubi ci n-contai ni ng combi nati on chemotherapy) Second-l i ne therapy for br east cancer (after fai l ur e of combi nati on chemotherapy for metastati c di sease or r el apse wi thi n 6 months of adjuvant therapy) NSCLC (fi r st-l i ne therapy i n combi nati on wi th ci spl ati n) i n pati ents who ar e not candi dates for potenti al l y curati ve sur ger y and/or radi ati on therapy. AIDS-r el ated Kaposi sar coma (second-l i ne therapy).

U.S. Food and Drug Administration–Approved Dosage

Pati ents ar e to be pr emedi cated wi th dexamethasone, di phenhydrami ne (or i ts equi val ent), and H2 antagoni sts (e.g., ci meti di ne or rani ti di ne) to pr event sever e hyper sensi ti vi ty r eacti ons. Suggested package l i teratur e pr emedi cati on r egi men: dexamethasone 20 mg PO × two doses admi ni ster ed appr oxi matel y 12 and 6 hour s befor e pacl i taxel ; di phenhydrami ne 50 mg i .v. 30 to 60 mi nutes befor e pacl i taxel ; and ci meti di ne 300 mg i .v. or rani ti di ne 50 mg i .v. 30 to 60 mi nutes befor e pacl i taxel . Cur r ent l i teratur e may be consul ted for al ter nati ve pr emedi cati on r egi mens. F i r st-l i ne ovar i an cancer : 135 mg per m2 i .v. conti nuous i nfusi on over 24 hour s or 175 mg per m2 i .v. over 3 hour s (fol l owed by ci spl ati n 75 mg per m2 i .v.) ever y 3 weeks. Second-l i ne ovar i an cancer : 135 mg per m2 or 175 mg per m2 i .v. over 3 hour s ever y 3 weeks. Cur r ent l i teratur e may be consul ted for al ter nati ve r egi mens. Adjuvant therapy of node-posi ti ve br east cancer : 175 mg per m2 i .v. over 3 hour s ever y 3 weeks × four cycl es (admi ni ster ed sequenti al l y wi th doxor ubi ci n-contai ni ng chemotherapy). Second-l i ne br east cancer : 175 mg per m2 i .v. over 3 hour s ever y 3 weeks. NSCLC: 135 mg per m2 i .v. conti nuous i nfusi on over 24 hour s (fol l owed by ci spl ati n 75 mg per m2 i .v.) ever y 3 weeks. AIDS-r el ated Kaposi sar coma: 135 mg per m2 i .v. over 3 hour s ever y 3 weeks or 100 mg per m2 i .v. over 3 hour s ever y 2 weeks. (Note: r educe the dose of dexamethasone pr emedi cati on dose to 10 mg PO per dose i nstead of the suggested 20 mg PO dose).

Dose Modification Criteria Hepati c i mpai r ment: dose to be modi fi ed; myel osuppr essi on: dose to be modi fi ed; nonhematol ogi c toxi ci ty (neur opathy): dose to be modi fi ed.

Adverse Reactions CNS: per i pheral neur osensor y toxi ci ty (par esthesi a, dysesthesi a, and pai n); CV: hypotensi on, bradycar di a, and el ectr ocar di ographi c

changes; DERM: al opeci a, onychol ysi s (mor e common wi th weekl y dosi ng), and i njecti on-si te r eacti ons; G I: N/V L2, di ar r hea, and mucosi ti s; HEMAT: myel osuppr essi on; INF US: acute hyper sensi ti vi ty-type r eacti ons; OTHER: ar thral gi a, and myal gi a.

Comments Use non-DEHP pl asti ci zed sol uti on contai ner s and admi ni strati on sets. Inl i ne fi l trati on (0.22-µ fi l ter ) r equi r ed dur i ng admi ni strati on. Lower dose, weekl y dosage r egi mens ar e commonl y uti l i zed. Cur r ent l i teratur e may be consul ted for dose gui del i nes.

PEGASPARGASE (ONCASPAR) Mechanism of Action Pegaspar gase i s a modi fi ed (pegyl ated) ver si on of the enz yme Lasparagi nase. L-asparagi nase depl etes asparagi ne, an ami no aci d r equi r ed by some l eukemi c cel l s.

U.S. Food and Drug Administration–Approved Indications Pati ents wi th ALL who ar e hyper sensi ti ve to nati ve for ms of Lasparagi nase.

U.S. Food and Drug Administration–Approved Dosage The pr efer r ed r oute i s i .m.; i .v. admi ni strati on shoul d be over 1 to 2 hour s. Combi nati on or sol e i nducti on therapy: Adul ts and chi l dr en, wi th BSA ≥0.6 m2 : 2,500 IU per m2 i .m. or i .v. × one dose ever y 14 days. Chi l dr en wi th BSA 3,000 cel l s per mm3 (package i nser t to be consul ted for schema). Ini ti al (pedi atr i c): 2.5 mg per m2 i .v. weekl y. May i ncr ease weekl y dose up to 12.5 mg per m2 to mai ntai n WBC >3,000 cel l s per mm3 (package i nser t to be consul ted for schema). Cur r ent l i teratur e may be consul ted for al ter nati ve dosi ng r egi mens.

Dose Modification Criteria Renal i mpai r ment: no dosage modi fi cati on; hepati c i mpai r ment: dose to be modi fi ed; myel osuppr essi on: dose to be modi fi ed.

Adverse Reactions CNS: per i pheral neur opathy, par esthesi as, l oss of deep tendon r efl exes, and SIADH; CV: hyper tensi on; DERM: al opeci a, ti ssue damage or necr osi s wi th extravasati on; G I: N/V L1, stomati ti s, consti pati on, and i l eus; G U: ur i nar y r etenti on and pol yur i a; HEMAT: myel osuppr essi on; OTHER: bone pai n, jaw pai n, tumor pai n, weakness, mal ai se, and Raynaud phenomenon.

Comments Vesi cant. To be admi ni ster onl y by the i ntravenous r oute. Fatal i ti es have been r epor ted when other vi nca al kal oi ds have been gi ven i ntrathecal l y. Syr i nge to be l abel ed: “Admi ni ster onl y i .v.; fatal i f gi ven i ntrathecal l y.” Outer wrap (i f used) shoul d r ead: “Do not r emove cover i ng unti l moment of i njecti on. Fatal i f gi ven i ntrathecal l y. For i ntravenous use onl y.”

VINCRISTINE (ONCOVIN AND OTHERS) Mechanism of Action Vi ncr i sti ne i nhi bi ts mi cr otubul e for mati on.

U.S. Food and Drug Administration–Approved Indications Acute l eukemi a; Vi ncr i sti ne has been shown to be useful i n combi nati on wi th other agents for Hodgki n di sease, non-Hodgki n l ymphoma, neur obl astoma, Wi l ms' tumor, r habdomyosar coma.

U.S. Food and Drug Administration–Approved Dosage Adul ts: 1.4 mg per m2 i .v. × one dose. Doses may be r epeated at weekl y i nter val s. Some cl i ni ci ans wi l l l i mi t (“cap”) i ndi vi dual doses to a maxi mum of 2 mg. Pedi atr i cs: 1.5 to 2 mg per m2 i .v. × one dose. For pedi atr i c pati ents wei ghi ng 10 kg or l ess: 0.05 mg per kg i .v. × one dose. Doses may be r epeated at weekl y i nter val s. Some cl i ni ci ans wi l l l i mi t (“cap”) i ndi vi dual doses to a maxi mum of 2 mg.

Dose Modification Criteria Renal i mpai r ment: no dosage modi fi cati on; hepati c i mpai r ment: dose to be modi fi ed.

Adverse Reactions CNS: per i pheral neur opathy, par esthesi as, numbness, l oss of deep tendon r efl exes, and SIADH; DERM: al opeci a, ti ssue damage or necr osi s wi th extravasati on; G I: N/V L1, stomati ti s, anor exi a, di ar r hea, consti pati on, and i l eus; G U: ur i nar y r etenti on, OCULAR: ophthal mopl egi a, extraocul ar muscl e par esi s; PULM: phar yngi ti s; OTHER: jaw pai n.

Comments Vesi cant. To be admi ni ster ed onl y by the i ntravenous r oute. Fatal i ti es have been r epor ted when other vi nca al kal oi ds have been gi ven i ntrathecal l y. Syr i nge to be l abel ed: “Admi ni ster onl y i .v.; fatal i f gi ven i ntrathecal l y.” Outer wrap (i f used) shoul d r ead: “Do not r emove cover i ng unti l moment of i njecti on. Fatal i f gi ven i ntrathecal l y. For i ntravenous use onl y.” A r outi ne pr ophyl acti c r egi men agai nst consti pati on i s r ecommended for al l pati ents r ecei vi ng vi ncr i sti ne.

VINORELBINE (NAVELBINE) Mechanism of Action Vi nor el bi ne i nhi bi ts mi cr otubul e for mati on.

U.S. Food and Drug Administration–Approved Indications NSCLC: F i r st-l i ne therapy as a si ngl e agent (stage IV) or i n combi nati on wi th ci spl ati n (stage III or IV) for ambul ator y pati ents wi th unr esectabl e, advanced NSCLC.

U.S. Food and Drug Administration–Approved Dosage Si ngl e agent: 30 mg per m2 i .v. over 6 to 10 mi nutes, weekl y Vi nor el bi ne i n combi nati on wi th ci spl ati n: Vi nor el bi ne 25 mg per m2 i .v. over 6 to 10 mi nutes weekl y, pl us Ci spl ati n 100 mg per m2 i .v. ever y 4 weeks or Vi nor el bi ne 30 mg per m2 i .v. over 6 to 10 mi nutes weekl y, pl us ci spl ati n 120 mg per m2 i .v. × one dose on days 1 and 29, then

ever y 6 weeks Li ne to be fl ushed wi th 75 to 125 mL of fl ui d (e.g., 0.9% sodi um chl or i de) after admi ni strati on of vi nor el bi ne.

Dose Modification Criteria Renal i mpai r ment: no dosage modi fi cati on; hepati c i mpai r ment: dose to be modi fi ed; neur otoxi ci ty: dose to be modi fi ed; myel osuppr essi on: dose to be modi fi ed.

Adverse Reactions CNS: per i pheral neur opathy, and l oss of deep tendon r efl exes; CV: thr omboembol i c events, and chest pai n; DERM: al opeci a, vei n di scol orati on, venous pai n, chemi cal phl ebi ti s, ti ssue damage or necr osi s wi th extravasati on; G I: N/V L1–2, stomati ti s, anor exi a, consti pati on, i l eus, and el evated LF T val ues; HEMAT: myel osuppr essi on (granul ocytopeni a gr eater than thr ombocytopeni a or anemi a); PULM: i nter sti ti al pul monar y changes, and shor tness of br eath; OTHER: jaw pai n, tumor pai n, fati gue, and anaphyl axi s.

Comments Vesi cant. To be admi ni ster ed onl y by the i ntravenous r oute. Fatal i ti es have been r epor ted when other vi nca al kal oi ds have been gi ven i ntrathecal l y.

REFERENCES 1. Kohl er DR, Montel l o MJ, G r een L, et al . Standar di z i ng the expr essi on and nomencl atur e of cancer tr eatment r egi mens. Am J Health Syst Phar m 1998;55:137–144. 2. Hesketh PJ, Kr i s MG , G r unber g SM, et al . Pr oposal for cl assi fyi ng the acute emetogeni ci ty of cancer chemotherapy. J Clin Oncol 1997;15:103–109. 3. Dor r RT, Al ber ts DS, Sobl e M. Lack of exper i mental vesi cant

acti vi ty for the anti cancer agents ci spl ati n, mel phal an, and mi toxantr one. Cancer Chemother . Phar macol. 1986;16(2):91–94.

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght Š2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ba c k o f Bo o k > Appe ndic e s > Appe ndix Pa rt 1

Appendix Part 1

Performance Status Scales/Scores: Perfor Criteria ECOG (Zubrod) Score

0

Description

Fully active, able to carry on all predisease performance without restriction

Restricted in physically

Karnofsky Score

Description

100

Normal, no complaints, no evidence of disease

90

Able to carry on normal activity; minor signs or symptoms of disease

80

Normal activity with effort; some signs or symptoms of

S

1

1

2

strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework/office work

Ambulatory and capable of all self-care but unable to carry out any activities related to work. Up and about more than 50% of waking hours.

disease

70

Cares for self, unable to carry on normal activity or do active work

60

Requires occasional assistance, but is able to care for most of his/her needs

50

Requires considerable assistance and frequent medical care

40

Disabled, requires special care

3

4

Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

Completely disabled. Cannot carry on any self-care; totally confined to bed or chair

and assistance

30

Severely disabled, hospitalization indicated; death not imminent

20

Very sick, hospitalization indicated; death not imminent

10

Moribund, fatal processes progressing rapidly

ECOG, Eastern Cooperative Oncology Group. Karnofsky and Lansky performance scores are inten multiples of 10. a The conversion of the Lansky to ECOG scales is in National Cancer Institute reporting purposes only.

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght ©2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ba c k o f Bo o k > Appe ndic e s > Appe ndix Pa rt 2

Appendix Part 2

World Health Organization (WHO) and R Evaluation Criteria in Solid Tumors (RECIST) Response Characteristic

Measurability of lesions at baseline

WHO

1. Me un (L wi co 1. Measurable, twote dimensional (product of m LD and greatest co to perpendicular diameter)a ≥1 2. Nonmeasurable/evaluable 2. No (e.g., lymphangitic al pulmonary metastases le abdominal masses) in le is

re

Objective response

1. Ta [c of m pe 10 (m or CR di of le 1. Measurable disease co (change in sum of ≥4 products of LDs and PR greatest perpendicular de diameters; no maximum ba number of lesions co specified) ≥4 CR: disappearance of all PD known disease, in confirmed at ≥4 wk sm PR: ≥50% decrease from ta baseline, confirmed at ob ≥4 wk ap PD: ≥25% increase of ne one or more lesions, or SD appearance of new no lesions

NC: neither PR nor PD criteria met 2. Nonmeasurable disease CR: disappearance of all unknown disease, confirmed at ≥4 wk PR: estimated decrease ≥50%, confirmed at ≥4 wk PD: estimated increase ≥25% in existent lesions NC: neither PR nor PD criteria met

m 2. No le CR di of le no tu co ≥4 PD pr no le ap ne No pe on no le tu ab lim

1. Be re m di

Overall response

1. Best response recorded in measurable disease 2. NC in nonmeasurable lesions will reduce a CR in measurable lesions to an overall PR 3. NC in nonmeasurable lesions will not reduce in a PR in measurable lesions

1. CR From: date CR criteria first met To: date PD first noted 2. Overall response From: date of start of

tr to pr re 2. No no le re ta le ov 3. No no le no in le

1. Ov Fr cr m To re di no 2. Ov re Fr or

Duration of response

treatment To: date PD first noted 3. In patients who achieve only a PR, only the period of overall response should be recorded

fir (w st fir To re di fir 3. SD Fr st tr To fir

WHO, World Health Organization; RECIST, Response Criteria in Solid Tumors; LD, longest diameter; CR, response; PR, partial response; PD, progressive dis change; SD, stable disease. a Lesions that can only be measured unidimensiona considered to be measurable (e.g., mediastinal ade malignant hepatomegaly). From J Natl Cancer Inst 2000;92:179–181, with pe

Editors: A braham, Jame; Gulley, James L.; A llegra, Carmen J. Title: Bethesda Handbook of Clinical Oncology, 2nd Edition Copyr i ght Š2005 Li ppi ncott Wi l l i ams & Wi l ki ns > Ba c k o f Bo o k > Appe ndic e s > Appe ndix Pa rt 3

Appendix Part 3

F i gur e. No Capti on Avai l abl e.

F r om Crawfor d JD, Ter r y ME, Roar ke G M. Pedi atr i on 1950; 5:783, wi th per mi ssi on.

Body surface area Amputee (approximate surface area of amputated part): Hand and five fingers

3%

Foot

3%

Arm, lower

4%

Leg, lower

6%

Arm, upper

6%

Leg, thigh

12%

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