Cancer Management: A Multidisciplinary Approach doc

Department of Radiation OncologyFox Chase Cancer Center Department of Radiation Oncology Wyoming Cancer Center Medical Group Mission Viejo, California Steven T.. Hoskins, MD Curtis and E

Note to the reader

The information in this volume has been carefully reviewed for accuracy ofdosage and indications Before prescribing any drug, however, the clinicianshould consult the manufacturer’s current package labeling for acceptedindications, absolute dosage recommendations, and other information perti-nent to the safe and effective use of the product described This is especiallyimportant when drugs are given in combination or as an adjunct to other forms

of therapy Furthermore, some of the medications described herein, as well

as some of the indications mentioned, had not been approved by the US Foodand Drug Administration at the time of publication This possibility should beborne in mind before prescribing or recommending any drug or regimen

Publishers of

ONCOLOGYOncology News International

The views expressed are the result of independent work and do notnecessarily represent the views or findings of the US Food and DrugAdministration or the United States

Copyright © 2003 by The Oncology Group All rights reserved This book is protected

by copyright No part of it may be reproduced in any manner or by any means, electronic

or mechanical, without the written permission of the publisher

Library of Congress Catalog Card Number 2002111548

ISBN Number 189148317X

For information on obtaining additional copies of this volume, contact the publishers,The Oncology Group, a division of SCP Communications, Inc., 134 West 29th Street,5th Floor, New York, NY 10001-5399

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The Oncology Group

A D I V I S I O N O F

S C P C O M M U N I C AT I O N S , I N C

Department of Radiation Oncology

Fox Chase Cancer Center

Department of Radiation Oncology

Wyoming Cancer Center

Medical Group

Mission Viejo, California

Steven T Brower, MD

Department of Surgical Research

Memorial Medical Center

Dennis S Chi, MD

Gynecology Service Memorial Sloan-Kettering Cancer Center

Contributors

Division of Medical Oncology

Dana-Farber Cancer Institute

Department of Medical Oncology

City of Hope National Medical Center

Lawrence Driver, MD

Pain Symptom Management Section

M D Anderson Cancer Center

Stony Brook University Hospital

and Medical Center

East Setauket, New York

Michael J Gazda, MS

Department of Radiation Oncology North Shore Cancer Center Miami, Florida

Leo I Gordon, MD

Division of Hematology/Oncology Robert H Lurie Comprehensive Cancer Center Feinberg School of Medicine/ Northwestern University

Eric M Horwitz, MD

Department of Radiation Oncology

Fox Chase Cancer Center

William J Hoskins, MD

Curtis and Elizabeth Anderson Cancer

Institute at Memorial Health

University Medical Center

Savannah, Georgia

Mark Hurwitz, MD

Department of Radiation Oncology

Harvard Medical School

Jimmy J Hwang, MD

Department of Hematology/Oncology

Lombardi Cancer Center

James Ito, MD

Department of Infectious Diseases

City of Hope National Medical Center

William Beaumont Hospital

Royal Oak, Michigan

Lori Jardines, MD

Department of Surgery

Cooper Health Services

Camden, New Jersey

and Oncologic Surgery

City of Hope National Cancer Center

Hagop Kantarjian, MD

Division of Medicine

M D Anderson Cancer Center

John J Kavanagh, MD

Section of Gynecologic Medical Oncology

M D Anderson Cancer Center

Mark Kawachi, MD

Department of Urology City of Hope National Medical Center

Fadlo R Khuri, MD

Department of Thoracic/Head and Neck Medical Oncology

M D Anderson Cancer Center

Rachelle M Lanciano, MD

Department of Radiation Oncology Delaware County Memorial Hospital Drexel Hill, Pennsylvania

Charles Loprinzi, MD

Department of Medical Oncology Mayo Clinic

Section of General Medicine

M D Anderson Cancer Center

Kim A Margolin, MD

Department of Medical Oncology

City of Hope National Medical Center

Department of Thoracic Surgery

Cedars Sinai Medical Center

Bone Marrow Transplant

City of Hope National Medical Center

City of Hope National Medical Center

Bert O’Neil, MD

Division of Hematology/Oncology University of North Carolina

at Chapel Hill

Brian O’Sullivan, MD

Department of Radiation Oncology Princess Margaret Hospital Toronto, Ontario, Canada

Ray Page, DO , P h D

Department of Pharmacology University of North Texas Health Science Center

Fort Worth, Texas

I Benjamin Paz, MD

Division of Surgery City of Hope National Medical Center

Richard Pazdur, MD

Division of Oncology Drug Products Center for Drug Evaluation and Research

US Food and Drug Administration

Division of Radiation Oncology

Fox Chase Cancer Center

Stephen P Povoski, MD

Department of Surgery

James Cancer Hospital and Solove

Research Institute at Ohio

State University

Marcus E Randall, MD

Department of Radiation Oncology

Indiana University Medical Center

Department of Adult Oncology

Dana-Farber Cancer Institute

John Andrew Ridge, MD , P h D

Department of Surgical Oncology

Fox Chase Cancer Center

Darrell S Rigel, MD

Department of Dermatology

New York University Medical Center

John M Robertson, MD

Department of Radiation Oncology

William Beaumont Hospital

Steven Rosen, MD

Division of Hematology/Oncology

Robert H Lurie Comprehensive Cancer

Center Feinberg School of Medicine/

Martin G Sanda, MD

Department of Urology University of Michigan Comprehensive Cancer Center

Howard Sandler, MD

Department of Radiation Oncology University of Michigan

Comprehensive Cancer Center

Kim Andrews Sawyer

American Cancer Society Atlanta, Georgia

Roderich E Schwarz, MD , P h D

Department of Surgery Robert Wood Johnson University Hospital New Brunswick, New Jersey

Dong M Shin, MD

Department of Medicine University of Pittsburgh Cancer Institute

Richard T Silver, MD

Division of Hematology/Oncology Weill Medical College

David Straus, MD

Department of Medicine Memorial Sloan-Kettering Cancer Center

Mohan Suntharalingam, MD

Department of Radiation Oncology University of Maryland

Melissa Warner President

James F McCarthy Senior Vice President, Editorial

Gail van Koot Senior Project Manager, Editorial

Terri Gelfand Editorial Administrative Assistant

Jeannine Coronna Director of Operations

Publishing Staff

Catherine Sweeney, MD

Department of Palliative Care

and Rehabilitation Medicine

M D Anderson Cancer Center

Chris Takimoto, MD , P h D

Department of Pharmacology

University of North Texas

Health Science Center

Fort Worth, Texas

Joachim Yahalom, MD

Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center

Alan W Yasko, MD

Division of Surgical Oncology

M D Anderson Cancer Center

The concept for Cancer Management: A Multidisciplinary Approach arose nearly

10 years ago This seventh annual edition reflects the ongoing commitment ofthe authors, editors, and publishers to rapidly disseminate to oncologists themost current information on the clinical management of cancer patients.Each chapter in this seventh edition has been updated to keep pace with themost current diagnostic and treatment recommendations In addition, and inaccordance with the recommendations of users of previous editions of thistreatment handbook, the common chemotherapy regimens have again beenincluded within the treatment sections of each chapter, rather than as a sepa-rate Appendix as in the fifth and previous editions Information on biologicaltherapies, too, is now included in the treatment sections of appropriate chap-ters, rather than as a separate chapter Again, readers tell us this reorganizationmakes the treatment guide easier to use

The current volume also provides information on newly approved drugs, such

as gefitinib (Iressa), lonafarnib (Sarasar), pemetrexed (Alimta), flavorpiridol(cyclin-dependent kinase inhibitor), epirubicin (Ellence), citalopramhydrobromide (Celexa), oxandrolone (Oxandrin), infliximab (Remicade),troxacitabine (Troxatyl), temozolomide (Temodar), tariquidar, antithymocyteglobulin (Atgam), voriconazole (Vfend), micafungin, as well as new indica-tions for alemtuzumab (Campath), capecitabine (Xeloda), darbepoetin alfa(Aranesp), zoledronic acid (Zometa), Actiq (oral transmucosal fentanyl citrate),and rituximab (Rituxan) Reports on newer clinical trials with imatinib mesylate(Gleevec), oxaliplatin (Eloxatin), erlotinib (Tarceva), thalidomide (Thalomid),raloxifene (Evista), anastrozole (Arimidex), letrozole (Femara), and others alsoare included

The 49 chapters, one Addendum, and 2 Appendices in the latest edition sent the efforts of 120 contributors (9 of whom are new) from 60 institutions inthe United States and Canada

Three consistent goals continue to guide our editorial policies:

■ To provide practical information for physicians who manage cancerpatients

■ To present this information concisely, uniformly, and logically, phasizing the natural history of the malignancy, screening and diagno-sis, staging and prognosis, and treatment

em-■ To emphasize a collaborative multidisciplinary approach to patientmanagement that involves surgical, radiation, and medical oncologists,

as well as other health care professionals, working as a cohesive team

As with the first six annual editions, each chapter (as appropriate) in the rent volume has been authored jointly by practicing medical, surgical, andradiation oncologists In some cases, other specialists have been asked to con-tribute their expertise to a particular chapter

cur-All of our contributors personally manage patients using a multidisciplinary proach in their respective institutions Thus, these chapters reflect the recom-mendations of practitioners cognizant that therapies must be based on evidence-based research directed at practical patient care in a cost-effective manner.

ap-To write, edit, and publish a 1,000-page text in less than 6 months requires thededication of all of the authors, as well as a professional publication staff tocoordinate the technical aspects of editing and publishing We, the authors andeditors, are indebted to the following individuals: especially Gail van Koot,senior project manager for the book; Susan Reckling, managing editor of thevolume; Jim McCarthy, Senior Vice-President/Editorial; Cara Glynn, Edito-rial Director; and Melissa Warner, President of The Oncology Group We alsothank Andrea Bovee Caldwell, Angela Cibuls, Jeannine Coronna, ChristinaFennessey, Ed Geffner, Terri Gelfand, Lisa Katz, Andrew Nash, and StaceyCuozzo for their efforts We extend our special thanks to Robert A Smith, PhD,and Kim Andrews Sawyer of the American Cancer Society for their guidance

in helping us to update screening guidelines

We were able to produce this edition in such a short time frame by drawing

on the oncology expertise of the editors of ONCOLOGY and Oncology News

International These periodic publications, the seventh annual edition of this

book, and continuously updated, clinically relevant oncology information can

be accessed, at no charge, at The Oncology Group website, CancerNetwork.com.The background of this text’s cover should look familiar to readers It is iden-

tical to that of ONCOLOGY, the flagship publication of The Oncology Group,

which has provided continuing medical information to oncology professionalsfor the past 16 years and is consistently ranked as the most widely read oncol-ogy journal by an independent readership audit This cover symbolizes theongoing commitment to oncology education of The Oncology Group and theeditors and authors of this text

Duarte, California

The surgeon is often the first specialist to see the patient with a solid nancy, and, in the course of therapy, he or she may be called upon to providediagnostic, therapeutic, palliative, and supportive care In each of these areas,guiding paradigms that are unique to surgical oncology are employed.

malig-In addition, the surgical oncologist must be knowledgeable about all of theavailable surgical and adjuvant therapies, both standard and experimental, for

a particular cancer This enables the surgeon not only to explain the varioustreatment options to the patient but also to perform the initial steps in diagno-sis and treatment in such a way as to avoid interfering with future therapeuticoptions

Invasive diagnostic modalities

As the surgeon approaches the patient with a solid malignancy or abnormalnodal disease or the rare individual with a tissue-based manifestation of a leu-kemia, selection of a diagnostic approach that will have a high likelihood of aspecific, accurate diagnosis is paramount The advent of high-quality invasivediagnostic approaches guided by radiologic imaging modalities has limited theopen surgical approach to those situations where the disease is inaccessible, asignificant amount of tissue is required for diagnosis, or a percutaneous ap-proach is too dangerous (due, for example, to a bleeding diathesis, critical in-tervening structures, or the potential for unacceptable complications, such aspneumothorax)

Lymph node biopsy

The usual indication for biopsy of the lymph node is to establish the diagnosis

of lymphoma or metastatic carcinoma Each situation should be approached

in a different manner

Lymphoma The goal of biopsy in the patient with an abnormal lymph nodeand suspected lymphoma is to make the general diagnosis and to establishthe lymphoma type and subtype Additional analyses of the cells in thenode, its internal architecture, and the subpopulations of cells are critical forsubsequent treatment Although advances in immunocytochemical and his-tochemical analyses have been made, adequate tissue is the key element inaccurate diagnosis.

Consequently, the initial diagnosis of lymphoma should be made on a pletely excised node that has been minimally manipulated to ensure that there

com-is little crush damage When primary lymphoma com-is suspected, the use of needleaspiration does not consistently allow for the complete analyses described aboveand can lead to incomplete or inaccurate diagnosis and treatment delays.When recurrent lymphoma is the primary diagnosis, the analysis of specificcell type is very important for assessing changes in the type of lymphoma andwhether a transformation has occurred In the rare situation in which recurrentHodgkin’s disease is suspected, a core biopsy may be adequate if the classicReed-Sternberg cells are identified However, in the initial and recurrent set-tings, biopsy of an intact node is often required

Carcinoma The diagnosis of metastatic carcinoma often requires less tissuethan is needed for lymphoma Fine-needle aspiration (FNA), core biopsy, orsubtotal removal of a single node will be adequate in this situation For meta-static disease, the surgeon will use a combination of factors, such as location ofthe node, physical examination, and symptoms, to predict the site of primarydisease When this information is communicated to the pathologist, the patho-logic evaluation can be focused on the most likely sites so as to obtain thehighest diagnostic yield The use of immunocytochemical analyses can be suc-cessful in defining the primary site, even on small amounts of tissue

Head and neck adenopathy The head and neck region is a common site ofpalpable adenopathy that poses a significant diagnostic dilemma Nodal zones

in this area serve as the harbinger of lymphoma (particularly Hodgkin’s ease) and as sites of metastasis from the mucosal surfaces of the upperaerodigestive tract, nasopharynx, thyroid, lungs, and, occasionally, from intra-abdominal sites, such as the stomach, liver, and pancreas

dis-Since treatment of these nodal metastases varies widely, and since subsequenttreatments may be jeopardized by inconveniently placed biopsy incisions, thesurgical oncologist must consider the most likely source of the disease prior toperforming the biopsy FNA or core biopsy becomes a very valuable tool inthis situation, as the tissue sample is usually adequate for basic analysis (cyto-logic or histologic), and special studies (eg, immunocytochemical analyses) can

be performed as needed

Biopsy of a tissue-based mass

Several principles must be considered when approaching the seemingly ple task of biopsying a tissue-based mass As each of the biopsy methods hasunique risks, yields, and costs, the initial choice can be a critical factor in the

timeliness and expense of the diagnostic process It is crucial that the physiciancharged with making the invasive diagnosis be mindful of these factors.

Mass in the aerodigestive tract In the aerodigestive tract, biopsy of a lesionshould include a representative amount of tissue taken preferably from theperiphery of the lesion, where the maximum amount of viable malignant cellswill be present Since the treatment of in situ and invasive disease varies greatly,the biopsy must be of adequate depth to determine penetration of the tumors.This is particularly true for carcinomas of the oral cavity, pharynx, and larynx

Breast mass Although previously a common procedure, an open surgicalbiopsy of the breast is rarely indicated today Palpable breast masses that arehighly suspicious (as indicated by physical findings and mammography) can

be diagnosed as malignant with close to 100% accuracy with FNA However,because the distinction between invasive and noninvasive disease is often re-quired prior to the initiation of treatment, a core biopsy, performed eitherunder image guidance (ultrasound or mammography) or directly for palpablelesions, is the method of choice

The spectrum of therapeutic options guides the method of tissue diagnosis Forexample, the woman who chooses preoperative chemotherapy for a breastlesion is best served with a core biopsy This biopsy method establishes thehistologic diagnosis, provides adequate tissue for analyses of hormone-recep-tor levels and other risk factors, causes little or no cosmetic damage, does notperturb sentinal analyses, and does not require extended healing prior to theinitiation of therapy In addition, a small radio-opaque clip can be placed in thetumor to guide the surgical extirpation This is important because excellenttreatment responses can make it difficult for the surgeon to localize the originaltumor site

Mass in the trunk or extremities For soft-tissue or bony masses of the trunk

or extremities, the biopsy technique should be selected on the basis of theplanned subsequent tumor resection The incision should be made along ana-tomic lines in the trunk or along the long axis of the extremity When a sar-coma is suspected, FNA can establish the diagnosis of malignancy, but a corebiopsy will likely be required to determine histologic type and plan neoadjuvanttherapy

Preoperative evaluation

As with any surgical patient, the preoperative evaluation of the cancer patienthinges primarily on the individual’s underlying medical condition(s) Becausemost new cancers occur in older patients, careful attention must be paid toevaluation of cardiovascular risks Adequate information usually can be ob-tained from a standard history, physical examination, and electrocar-diogram (ECG), but any concerns identified should be subjected to a fulldiagnostic work-up

The evaluation should also include a detailed history of previous therapies.Previous use of doxorubicin (Adriamycin and others) may be associated withcardiac dysfunction and the use of bleomycin (Blenoxane) with severe lungsensitivity to oxygen concentrations > 30% Prior radiation therapy is associ-ated with fibrosis and delayed healing An appreciation of potential postopera-tive problems secondary to these factors is important in planning the surgicalextirpation and reconstruction.

For example, in a patient who requires mastectomy after failed ing surgery, the zone of tissue damage from the original radiation therapy can

breast-conserv-be assessed by reviewing the port and boost site films or by examining theirradiated site for tattoo marks used to align the radiation field Plans for re-section of heavily irradiated tissues should be made preoperatively in concertwith the reconstructive surgeon, and the relative increased risk of postopera-tive problems should be discussed with the patient This evaluation shouldinclude the type of tissue to be transferred, analysis of potential donor andrecipient sites and vessels, and assurance that the appropriate microvascularequipment is available, in the event that it is needed during surgery

Pathologic confirmation of the diagnosis

The treatment of cancer is based almost exclusively on the organ of origin and,

to a lesser degree, on the histologic subtype Unless the operative procedure isbeing performed to make a definitive diagnosis, review of the pathologic mate-rial is needed to confirm the diagnosis preoperatively

There are few exceptions to this doctrine, and it behooves the surgeon to have

a confirmed diagnosis, including the in situ or invasive nature of the cancer,prior to performing an operation This tenet assumes paramount importancewhen one is performing procedures for which there is no recourse once thespecimen is removed, eg, laryngectomy, mastectomy, removal of the analsphincter, and extremity amputation

Ironically, in some situations, a preoperative or intraoperative diagnosis not be confirmed, despite the fact that the preoperative and intraoperativephysical findings, laboratory data, and radiologic studies (pre- and intraop-erative) overwhelmingly suggested the cancer diagnosis The classic example

can-of this dilemma is the jaundiced patient with a firm mass in the pancreatichead The Whipple procedure (pancreaticoduodenectomy) causes significantmorbidity but is required to make the diagnosis and treat the cancer In any ofthese situations, the preoperative discussion with the patient must include thepossibility that the final diagnosis may be a benign lesion

Resection

The principles of resection for malignant disease are based on the surgical goal(complete resection vs debulking), degree of functional significance of the in-volved organ or structure, and the ability to reconstruct the involved and sur-rounding structures Also important are the technical abilities of the surgeon

or availability of a surgical team, adequacy of adjuvant and neoadjuvant pies, and the biological behavior (local and systemic) of the disease The defi-nition of “resectable” varies, and this term can be defined only in the context

thera-of the aforementioned modifying parameters

Wide excision

A wide excision includes the removal of the tumor itself and a margin of mal tissue, usually exceeding 1 cm in all directions from the tumor The mar-gin is quite variable in a large, complex (multiple tissue compartments) speci-men, and the limiting point of the resection is defined by the closest approxi-mation of cancerous tissue to the normal tissue excised

nor-Wide margins are recommended for tumors with a high likelihood of localrecurrence (eg, dermatofibrosarcoma protuberans) and for tumors without anyreliable adjuvant therapeutic options

Breast The use of adjuvant radiation therapy has permitted the use ofbreast-conserving surgery, which limits the excision of wide margins ofnormal breast tissue

Colon and rectum For carcinoma of the colon and rectum, the width of sion is defined by the longitudinal portion of the bowel and the inclusion ofadjacent nodal tissue The principles of wide resection of normal bowelinclude at least 5 cm of uninvolved tissue, the associated mesenteric leaf,and adjacent rectal soft tissue (mesorectum)

exci-This general principle has been modified in the distal rectum, where nal bowel margins of 2 cm are accepted This modification reflects the empha-sis on functional results (ie, maintenance of anal continence) and the availabil-ity of adequate adjuvant radiation therapy to improve local control

longitudi-No touch technique

This principle is based on the concept that direct contact with the tumor duringresection can lead to an increase in local implantation and embolization oftumor cells Theoretically, the metastatic potential of the primary lesion would

be enhanced by the mechanical extrusion of tumor cells into local lymphaticand vascular spaces There may be some validity to this theory with respect totumors that extend directly into the venous system (eg, renal cell tumors withextension to the vena cava) or that extensively involve local venous drainage(eg, large hepatocellular carcinomas)

Extensive palpation and manipulation of a colorectal primary have been shown

to result in direct shedding of tumor cells into the lumen of the large bowel.The traditional strategy to lessen this risk was to ligate the proximal and distallumen of the segment containing the tumor early in the resection These areaswere then included in the resection, limiting the contact of shed tumor cellswith the planned anastomotic areas

Neither of the above theoretical situations (ie, manipulation of the tumor anddirect contact of the tumor with the anastomotic area) has been definitively

tested in controlled, prospective, randomized trials However, the risk-benefitratio clearly favors adherence to the general principles of minimal tumor ma-nipulation, protection of the anastomotic areas, and exclusion of the resectionbed from potential implantation with tumor cells.

Lymphadenectomy

Early surgical oncologic theory proposed that breast cancer progressed fromthe primary site to the axillary lymph nodes to the supraclavicular nodes andnodes of the neck This theory led to the radical surgical approach that in-cluded resection of all of the breast tissue and some or all of the above-noteddraining nodal basins (ie, modified radical or radical mastectomy)

Absent in this approach was an appreciation of the nodes not only as a deposit

of regional metastatic disease but also as a predictor of systemic disease ern treatment approaches view nodal dissection as having a triple purpose: thesurgical removal of regional metastases, the prediction of prognosis, and theplanning of adjuvant therapy

Mod-The surgical technique for lymphadenectomy is based on nodal basins that aredefined by consistent anatomic structures For example, dissection of the neck

is defined by the mandible, anterior strap muscles of the neck, clavicle, zius muscle, carotid artery, vagus nerve, brachial plexus, and fascia overlyingthe deep muscles of the neck

trape-Modifications of classic techniques Each of the classic anatomic adenectomies has been modified along lines that consider the predicted posi-tivity and functional impact of the dissection To use the example of radicalneck dissection, the modifications include supraomohyoid dissection for tu-mors of the floor of the mouth (a high-risk zone) and sparing of the spinalaccessory nerve (functional prevention of shoulder drop and loss of full ab-duction of the shoulder)

lymph-As alluded to in the previous paragraphs, lymph node dissection has peutic value only in patients with positive nodes In individuals with pathol-ogically negative nodes, the benefit is limited to prediction of prognosis anddocumentation of pathologic negativity Therefore, in the pathologically nega-tive nodal basin, there is minimal benefit to outweigh the risks and untowardsequelae of the dissection

thera-Sentinel node biopsy

Technique The technique of sentinel node identification is being developed toaddress clinically negative nodal basins With this technique, node or nodesthat preferentially drain a particular primary tumor are identified by mappingand then surgically excised The mapping agents include radiolabeled materi-als and vital dyes that are specifically taken up by, and transported in, thelymphatic drainage systems These mapping and localizing agents, used alone

or in combination, are critical in defining the unique flow patterns to specificlymph node(s) and in defining ambiguous drainage patterns (eg, a truncal mela-noma that may drain to the axilla, supraclavicular, or inguinal spaces)

Unresolved issues As this field of directed diagnostic node biopsy and tion develops, many technical issues related to the timing and location of theinjections are being evaluated In addition, the type of pathologic evaluation(ie, the number of sections examined per node, and the use of immunohis-tochemical analysis) is undergoing intense scrutiny.

dissec-A study of 200 consecutive patients who had sentinel lymph node biopsiesperformed for breast cancer examined the concepts of injecting dye and radio-active tracer into either the breast or the overlying dermis The authors be-lieved that the technical aspects of intradermal injection were simpler and moreeasily reproduced than those of injections into the breast Injections were per-formed in group 1 intraparenchymally, and in group 2 intradermally The com-bination of blue dye and isotope localization produced a 92% success rate

in group 1 and a 100% success rate in group 2 The authors concluded thatdermal and parenchymal lymphatics of the breast drain to the same lymphnode and that the more simple approach of dermal injection may simplify andoptimize sentinel lymph node localization

For melanoma, for which these techniques were originally developed, researchersare studying the feasibility and clinical relevance of evaluating nodal materialwith polymerase chain reaction (PCR) techniques These techniques also arebeing studied in breast cancer, where the clinical relevance of the presence ofmicrometastases or PCR-only metastases is highly controversial and, therefore,questions the need for this intense level of pathologic scrutiny

Elective lymph node dissection has limited value in intermediate-thicknessmelanoma In clinically node-negative patients, the use of the sentinel nodetechnique can avoid postoperative complications, increase confidence aboutthe better prognosis, and avoid the significant side effects of adjuvant immu-nologic therapy However, the identification of histologically positive nodesvia sentinel node biopsy technique is expected to have significant benefit, as itwill result in a complete therapeutic dissection and adjuvant therapy with in-terferon-α (Intron A, Roferon-A)

Palliation

In the continuum of care for the cancer patient, aspects of palliation, or thereduction of suffering, are delegated to the surgeon This text includes manyexamples of palliative surgical procedures: venous access, surgical relief of as-cites with shunt procedures, neurosurgical intervention for chronic pain, fixa-tion of pathologic fractures, and placement of feeding tubes to deliver foodand medications The surgeon must be versed in the techniques of and indica-tions for such interventions and discuss their risks and benefits with the patient,caregivers, and referring physician The barriers to the initiation and practice

of palliative surgery include the reluctance of patients, family and referringphysicians, health care system administrative obstacles, and cultural factors

Resuscitation issues An ethical issue of resuscitation must be addressed whenconsidering palliative surgical intervention Some may take the position that if

a patient is to have surgery, he or she must be willing to undergo full tion if required That tenet may be set aside in the palliative setting, in whichthe operative intervention is planned only to relieve suffering In such a situa-tion, a frank discussion with the patient and appropriate family members canavoid the distressing situation of the patient being placed on unwanted, fruit-less life support Again, the surgeon is called upon not only to provide a tech-nical service but also to achieve a comprehensive understanding of the diseaseprocess and how it affects each individual cancer patient.

resuscita-Suggested reading

Fortner JG: Inadvertent spread of cancer at surgery J Surg Oncol 53:191–196, 1993

Krouse RS, Nelson RA, Farrell BR, et al: Surgical palliation at a cancer center ArchSurg 136:773–778, 2001

McCahill LE, Krouse R, Chu D, et al: Indications and use of palliative surgery–results ofSociety of Surgical Oncology survey Ann Surg Oncol 9:104–112, 2002

McIntosh SA, Purushotham AD: Lymphatic mapping and sentinel node biopsy in breastcancer Br J Surg 85:1347–1356, 1998

CHAPTER 2

Principles of

radiation therapy

Michael J Gazda, MS, and Lawrence R Coia, MD

This chapter provides a brief overview of the principles of radiation therapy.The topics to be discussed include the physical aspects of how radiation works(ionization, radiation interactions) and how it is delivered (treatment machines,treatment planning, and brachytherapy) Recent relevant techniques of radia-tion oncology, such as conformal and stereotactic radiation, also will be pre-sented These topics are not covered in great technical detail, and no attempt ismade to discuss the radiobiological effects of radiation therapy It is hoped that

a basic understanding of radiation treatment will benefit those practicing inother disciplines of cancer management

How radiation works

IONIZING RADIATION

Ionizing radiation is energy sufficiently strong to remove an orbital electronfrom an atom This radiation can have an electromagnetic form, such as ahigh-energy photon, or a particulate form, such as an electron, proton, neu-tron, or alpha particle

High-energy photons By far, the most common form of radiation used inpractice today is the high-energy photon Photons that are released from thenucleus of a radioactive atom are known as gamma rays When photons arecreated electronically, such as in a clinical linear accelerator, they are known asx-rays Thus, the only difference between the two terms is the origin of thephoton

Inverse square law The intensity of an x-ray beam is governed by the inversesquare law This law states that the radiation intensity from a point source isinversely proportional to the square of the distance away from the radiationsource In other words, the dose at 2 cm will be one-fourth of the dose at 1 cm

Electron volt Photon absorption in human tissue is determined by theenergy of the radiation, as well as the atomic structure of the tissue inquestion The basic unit of energy used in radiation oncology is the elec-tron volt (eV); 103 eV = 1 keV, 106 eV = 1 MeV

colli-An example of this interaction in practice can be seen on a diagnostic x-rayfilm Since the atomic number of bone is 60% higher than that of soft tissue,bone is seen with much more contrast and detail than is soft tissue The energyrange in which the photoelectric effect predominates in tissue is about 10-25 keV.

Compton effect The Compton effect is the most important photon-tissueinteraction for the treatment of cancer In this case, a photon collides with a

“free electron,” ie, one that is not tightly bound to the atom Unlike the toelectric effect, in the Compton interaction both the photon and electron arescattered The photon can then continue to undergo additional interac-tions, albeit with a lower energy The electron begins to ionize with theenergy given to it by the photon

pho-The probability of a Compton interaction is inversely proportional to the ergy of the incoming photon and is independent of the atomic number of thematerial When one takes an image of tissue using photons in the energy range

en-in which the Compton effect domen-inates (~25 keV-25 MeV), bone and tissue interfaces are barely distinguishable This is a result of the atomic num-ber independence

soft-The Compton effect is the most common interaction occurring clinically, asmost radiation treatments are performed at energy levels of about 6-20 MeV.Port films are films taken with such high-energy photons on the treatmentmachine and are used to check the precision and accuracy of the beam; be-cause they do not distinguish tissue densities well, however, they are not equal

to diagnostic films in terms of resolution

Pair production In this process, a photon interacts with the nucleus of anatom, not an orbital electron The photon gives up its energy to the nucleusand, in the process, creates a pair of positively and negatively charged elec-trons The positive electron (positron) ionizes until it combines with a freeelectron This generates two photons that scatter in opposite directions.The probability of pair production is proportional to the logarithm of the en-ergy of the incoming photon and is dependent on the atomic number of thematerial The energy range in which pair production dominates is ≥ 25 MeV.This interaction does occur to some extent in routine radiation treatment withhigh-energy photon beams

ELECTRON BEAMS

With the advent of high-energy linear accelerators, electrons have become aviable option in treating superficial tumors up to a depth of about 5 cm Elec-tron depth dose characteristics are unique in that they produce a high skindose but exhibit a falloff after only a few centimeters

Electron absorption in human tissue is greatly influenced by the presence ofair cavities and bone The dose is increased when the electron beam passesthrough an air space and is reduced when the beam passes through bone

Common uses The most common clinical uses of electron beams include thetreatment of skin lesions, such as basal cell carcinomas, and boosting of (givingfurther radiation to) areas that have previously received photon irradiation,such as the postoperative lumpectomy or mastectomy scar in breast cancerpatients, as well as select nodal areas in the head and neck

MEASURING RADIATION ABSORPTION

The dose of radiation absorbed correlates directly with the energy of the beam

An accurate measurement of absorbed dose is critical in radiation treatment.The deposition of energy in tissues results in damage to DNA and diminishes

or eradicates the cell’s ability to replicate indefinitely

Gray The basic unit of radiation absorbed dose is the amount of energy (joules)absorbed per unit mass (kg) This unit, known as the gray (Gy), has replacedthe unit of rad used in the past (100 rads = 1 Gy; 1 rad = 1 cGy)

Exposure In order to measure dose in a patient, one must first measure theionization produced in air by a beam of radiation This quantity is known asexposure One can then correct for the presence of soft tissue in the air andcalculate the absorbed dose in Gy

Percentage depth dose The dose absorbed by tissues due to these actions can be measured and plotted to form a percentage depth dosecurve As energy increases, the penetrative ability of the beam increases andthe skin dose decreases

inter-How radiation is delivered

TREATMENT MACHINES

Linear accelerators

High-energy radiation is delivered to tumors by means of a linear accelerator

A beam of electrons is generated and accelerated through a waveguide thatincreases their energy to the keV to MeV range These electrons strike a tung-sten target and produce x-rays

X-rays generated in the 10–30-keV range are known as grenz rays, whereasthe energy range for superficial units is about 30–125 keV Orthovoltage unitsgenerate x-rays from 125–500 keV

Orthovoltage units continue to be used today to treat superficial lesions; infact, they were practically the only machines treating skin lesions before therecent emergence of electron therapy The maximum dose from any of theselow-energy units is found on the surface of patients; thus, skin becomes thedose-limiting structure when treating patients at these energies The depth atwhich the dose is 50% of the maximum is about 7 cm Table 1 lists the physicalcharacteristics of several relevant x-ray energies.

Megavoltage units The megavoltage linear accelerator has been the standardradiotherapy equipment for the past 20-30 years Its production of x-rays isidentical to that of lower-energy machines However, the energy range ofmegavoltage units is quite broad—from 4 to 20 MeV The depth of the maxi-mum dose in this energy range is 1.5-3.5 cm The dose to the skin is about30%-40% of the maximum dose

Most megavoltage units today also have electron-beam capabilities, usually inthe energy range of about 5-20 MeV In order to produce an electron beam,the tungsten target is moved away from the path of the beam The originalelectron beam that was aimed at the tungsten target is now the electron beamused for treatment Unlike that of photons, the electron skin dose is quite high,about 80%-95% of the maximum dose A rule of thumb regarding the depth ofpenetration of electrons is that 80% of the dose is delivered at a depth (in cm)corresponding to one-third of the electron energy (in MeV) Thus, a 12-MeVbeam will deliver 80% of the dose at a depth of 4 cm

Altering beam intensity and field size When measurements are made at thepoint just past the target, the beam is more intense in the center than at theedges Optimal treatment planning is obtained with a relatively constant inten-sity across the width of the beam This process is accomplished by placing aflattening filter below the target

In order for the radiation beam to conform to a certain size, high atomic ber collimators are installed in the machine They can vary the field size from

num-4 × num-4 cm to num-40 × num-40 cm at a distance of 100 cm from the target, which is thedistance at which most treatments are performed

TABLE 1: Depth dose characteristics for clinical

If it is decided that a beam should be more intense on one side than the other,high atomic number filters, known as wedges, are placed in the beam Thesefilters can shift the dose distribution surrounding the tumor by 15º-60º Wedgescan also be used to optimize the dose distribution if the treatment surface iscurved or irregular.

Shielding normal tissue Once the collimators have been opened to the sired field size that encompasses the tumor, the physician may decide to blockout some normal tissue that remains in the treatment field This is accomplished

de-by placing blocks (or alloy), constructed of a combination of bismuth, tin, mium, and lead, in the path of the beam In this way, normal tissues are shielded,and the dose can be delivered to the tumor at a higher level than if the normalstructures were in the field These individually constructed blocks are used inboth x-ray and electron treatments A more modern technique involves multileafcollimators mounted inside the gantry They provide computerized, custom-ized blocking instead of having to construct a new block for each field (See

cad-“Intensity-modulated radiation therapy.”)

PRETREATMENT PROCEDURES

Certain imaging procedures must be done before radiation therapy is begun:

Pretreatment CT Before any treatment planning can begin, a pretreatment

CT scan is often performed This scan allows the radiation oncologist to tify both tumor and surrounding normal structures

iden-Simulation The patient is then sent for a simulation The patient is placed on

a diagnostic x-ray unit that geometrically simulates an actual treatment chine With use of the CT information, the patient’s treatment position is simu-lated by means of fluoroscopy A series of orthogonal films are taken, andblock templates that will shield any normal structures are drawn on the films.These films are sent to the mold room, where technicians construct the blocks

ma-to be used for treatment CT simulation is a modern alternative ma-to tional” simulation and is described later in this chapter

“conven-Guides for treatment field placement Small skin marks, or tattoos, areplaced on the patient following proper positioning in simulation Thesetattoos will guide the placement of treatment fields and give the physician

a permanent record of past fields should the patient need additional ment in the future

treat-It is imperative that the patient be treated in a reproducible manner each day

In order to facilitate this, Styrofoam casts that conform to the patient’s contourand place the patient in the same position for each treatment are constructed.Lasers also help line up the patient during treatment

TREATMENT PLANNING AND DELIVERY

Determining optimal dose distribution The medical physicist or dosimetristuses the information from CT and simulation to plan the treatment on a com-puter A complete collection of machine data, including depth dose and beamprofile information, is stored in the computer The physics staff aids the radia-

tion oncologist in deciding the number of beams (usually two to four) andangles of entry The goal is to maximize the dose to the tumor while minimiz-ing the dose to surrounding normal structures.

Several treatment plans are generated, and the radiation oncologist choosesthe optimal dose distribution The beam-modifying devices discussed earlier,such as blocks and wedges, may be used to optimize the dose distributionaround the tumor

Establishing the treatment plan The planning computer will calculate theamount of time each beam should be on during treatment All pertinent data,such as beam-on time, beam angles, blocks, and wedges, are recorded in thepatient’s treatment chart and sent to the treatment machine The radiation thera-pist will use this information, as well as any casts, tattoos, and lasers, to set upand treat the patient consistently and accurately each day

Port films As part of departmental quality assurance, weekly port films are

taken for each beam They ensure that the beams and blocks are consistentlyand correctly placed for each treatment Port films are images generated by thelinear accelerator at energies of 6-20 MeV Because of the predominance of theCompton effect in this energy range, these images are not as detailed as those atdiagnostic film energies (as mentioned earlier), but they still add important infor-mation on treatment accuracy and ensure the quality of setup and treatment

BRACHYTHERAPY

Brachytherapy is the term used to describe radiation treatment in which the diation source is in contact with the tumor This therapy contrasts with external-beam radiotherapy, in which the radiation source is 80-100 cm away from thepatient

ra-In brachytherapy, dose distribution is almost totally dependent on the verse square law because the source is usually within the tumor volume Be-cause of this inverse square dependence, proper placement of radiation sources

Isotopes Table 2 lists commonly used isotopes and their properties In the past,radium was the primary isotope used in brachytherapy Recently, because of itslong half-life and high energy output, radium has been replaced with cesium(Cs), gold (Au), and iridium (Ir) These isotopes have shorter half-lives than ra-dium and can be shielded more easily because of their lower energies.

Types of implants Brachytherapy procedures can be performed with eithertemporary or permanent implants Temporary implants usually have long half-lives and higher energies than permanent implants These sources can be manu-factured in several forms, such as needles, seeds, and ribbons

All temporary sources are inserted into catheters that are placed in the tumorduring surgery A few days after surgery, the patient is brought to the radiationclinic and undergoes pretreatment simulation Wires with nonradioactive metalseeds are threaded into these catheters Several films are taken, and the images

of the seed placement can be digitized into a brachytherapy treatment ning computer

plan-Once the treatment plan is complete and the physician has chosen the optimaldose rate (usually 50-60 cGy/h), the sources can be implanted The actual im-plantation takes place in the patient’s private room The duration of treatment isusually 1-3 days The majority of temporary implants are loaded interstitially

Common uses Interstitial low-dose-rate (LDR) brachytherapy is commonlyused for cancer of the oral cavity and oropharynx and sarcoma Prostate can-cer is probably the most common site for which LDR brachytherapy “seeds”are used today Intracavitary LDR brachytherapy is frequently used in gyne-cologic applications High-dose-rate (HDR) brachytherapy is used with remoteafterloading techniques, as described below

Remote afterloading brachytherapy

Because brachytherapy requires numerous safety precautions and entails necessary exposure of personnel and family members to radiation, remote after-loading of temporary implants has become popular in recent years The twotypes of remote afterloading that can be used for treatment are LDR and HDRsources The most popular LDR source used today is Cs-137, which has a doserate of about 1 cGy/min The most widely used HDR source is Ir-192 Thisisotope has a dose rate of about 100 cGy/min

un-General procedures The pretreatment brachytherapy procedures outlinedabove are also implemented in remote afterloading brachytherapy Once thetreatment plan has been approved by the physician, the patient is brought intothe treatment room The LDR cesium source or HDR iridium source is con-nected to the end of a cable inside its respective afterloading unit This unit isprogrammed with the data from the planning computer The cable is sent outfrom the unit into one of the patient’s catheters Several catheters can be con-nected to the unit Each catheter is irradiated, one at a time, until the pre-scribed dose has been delivered

The motor that drives the source out of the treatment unit is connected tronically to the door of the treatment room If the treatment must be stoppedfor any reason, simply opening the door triggers an interlock that draws thesource back into the unit Because of this device, oncology personnel will not

elec-be exposed to any radiation should they need to see the patient during ment This interlock is the main safety advantage of remote afterloading overmanual afterloading

treat-LDR treatment Uterine cancer is the most popular site for intracavitary ment with LDR remote afterloading brachytherapy These procedures are per-formed in the patient’s room The interlock is connected to the patient’s door

treat-so that nurses can take vital signs and give medication and family members canvisit the patient without risk of radiation exposure

HDR treatment The most common applications of HDR brachytherapy arefor tumors of the vaginal apex, esophagus, lungs, and, most recently, breastand prostate Most HDR treatments are performed on an outpatient basis.Allowing the patient to return home the same day after therapy is one advan-tage of HDR afterloading brachytherapy Patients with prostate cancer are theexception They may remain in the hospital for 2-3 days during the treatment

Recent advances in planning and treatment

CT SIMULATION

Until recently, CT and simulation were separate pretreatment procedures Withinthe past decade, many cancer centers have combined CT and simulation into asingle diagnostic-treatment planning unit, known as a CT-simulator The majoradvantage of this combination is that both procedures can be performed by oneunit and, thus, the patient does not have to make two separate visits to the clinic.Also, CT simulation is bringing the radiation clinic into the digital age, with hos-pitals reporting an increase in speed, efficiency, and accuracy of treatment plan-ning and delivery

Procedure In brief, in the first step of this new procedure, the patient is placed

on the CT-simulator table and undergoes a normal CT study The physicianhas the capability of outlining the tumor and any normal structures on each

CT slice A computer performs a three-dimensional (3D) transformation of the

CT slices and creates a digitally reconstructed radiograph (DRR)

The DRR resembles a normal diagnostic film, except that it is digital and can

be manipulated to achieve better contrast and detail than regular film Theoutlines of the tumor and organs are displayed on the DRRs for any viewingangle The physician can then draw blocks on the DRRs with a more accurateidea of where the tumor and normal tissues actually lie

The DRRs are digitized into the treatment planning computer, and any CTslices and their contours drawn by the physician are transferred as well TheseDRRs are either sent to the mold room for block construction or are trans-

ferred to the treatment planning software for multileaf collimator tion Treatment plans are generated as discussed earlier.

optimiza-At the time of the patient’s first treatment, DRRs and port films are digitizedand saved on a local area network (LAN) Physicians can then call up theseimages on their desktop computers for weekly patient quality assurance

CONFORMAL RADIATION THERAPY

Conformal radiation therapy is a geometric shaping of the radiation beam thatconforms with the beam’s eye view of the tumor Conformal therapy utilizes theoutlining capabilities of the CT-simulator The physician outlines the tumor vol-ume, generates DRRs, and draws an appropriate margin from 1-2 cm around thetumor These fields conform closely to the shape of the tumor and, thus, shieldmore critical structures than do normal blocks The margin allows for setup er-rors of a few millimeters each day Appropriate immobilization of the target vol-ume must be achieved in each patient through the use of devices that constrainmovement (“casts”) so that the target is accurately localized

These films are sent to the mold room for block construction Since the fieldsare “tighter” around the tumor, the prescribed dose can be increased Cliniciansbelieve that by increasing the dose to the tumor, local control will be improved

Intensity-modulated radiation therapy (IMRT), an extension of conformaltherapy, allows for shaping of the intensity of the radiation beam This is animportant improvement, especially when the target is not well separated fromnormal tissues

A uniform dose distribution can be created around the tumor by either lating the intensity of the beam during its journey through the linear accelera-tor or by the use of multileaf collimators Multileaf collimators consist of 80 ormore individual collimators, or “leaves,” located at the head of the linear ac-celerator, which can be adjusted to the shape of the tumor (For a technicaldescription, the reader is referred to the text by Khan; see “Suggested Reading.”)Both of these methods alter the fluence of radiation exiting the accelerator.The final result is a uniform dose distribution around the tumor and minimaldose to the surrounding normal tissues, often below tolerance levels This im-proves the risk-benefit ratio

modu-The clinical use of IMRT has grown as computer power increases and costsdecline Preliminary clinical data have shown that prostate doses can be in-creased significantly without increasing the complication rate IMRT must

be administered within a closely monitored program with rigorous qualityassurance since it can potentially cause significant injury if not appropriatelyapplied

Several types of IMRT delivery are now becoming standard in radiation cology clinics Dynamic conformal therapy with multileaf collimators is beingused routinely in hospitals around the country With this approach, collima-tors conform to the tumor volume with the beam on while the treatment unit is

on-rotating around the patient This is an example of totally computer-controlledradiation delivery.

Another method of IMRT delivery—serial tomotherapy—is an enhancement of

the method described above An accelerator is equipped with mini-multileafcollimators that form a “slit” of radiation (normally 2 × 20 cm) The gantry isrotated through an entire arc around the patient while the mini-multileaf colli-mators are driven in and out of the field, thus modulating the intensity of thebeam The treatment couch is advanced by a few millimeters and the next arc

is treated An entire treatment is given once all the adjoining arcs have beendelivered

Instead of treating the patient on a normal linear accelerator, with helicaltomotherapy the patient travels continuously through a modified CT ring This

CT ring has the capability of administering 6-mV x-rays, as in a standard linearaccelerator, while at the same time performing a conventional diagnostic CTscan Any anatomic or position changes that might require replanning can beperformed before that day’s treatment Following treatment, a daily, real-timeimage of the dose distribution can be obtained

PROTON THERAPY

Protons, a form of particulate radiation, have been investigated recently as ameans to improve tumor control A proton has a charge of +1, is a stableparticle, and, together with the neutron, makes up the atomic nucleus.Protons are delivered to the tumor in the same manner as are photons andelectrons The dose deposited by protons remains relatively constant as theytravel through the normal tissues proximal to the target

The kinetic energy of the protons is transferred to the tumors by electronsknocked out of atoms These electrons ionize DNA, and their biological ef-fectiveness resembles that of megavoltage photons

Bragg peak At the end of the path, biological effectiveness increases sharply

as the protons slow down and eventually stop This increase in dose is calledthe Bragg peak The size of the Bragg peak is usually smaller than the tumor,however This problem can be resolved by scanning the Bragg peak throughthe tumor volume by sequentially irradiating the target with lower energies.The dose falloff of the Bragg peak is sharp enough that the normal tissues distal

to the tumor receive a negligible radiation dose

Current clinical applications Uveal melanomas and skull-base sarcomas jacent to CNS tissues are two areas that have been under clinical study withpromising results Clinical studies have also begun recently in treating non–small-cell lung, hepatocellular, and paranasal sinus carcinomas

ad-STEREOTACTIC RADIOSURGERY

Stereotactic radiosurgery is a 3D technique that delivers the radiation dose inone fraction Specially designed collimators are attached to a linear accelera-tor, which delivers a high dose of radiation to a small volume, usually about

3 cm in diameter Several stationary beams or multiple arc rotations trate the radiation dose to the lesion while sparing surrounding normal tissue.

concen-Use in treating arteriovenous malformations Stereotactic radiosurgery isused to treat certain patients with arteriovenous malformations These in-tracranial lesions arise from the abnormal development of arteries and venoussinuses Surgical excision is the standard treatment of choice for operable le-sions, but stereotactic radiosurgery has become a viable option for inoperablemalformations

Use in treating brain tumors As with conformal radiotherapy, clinical trialsinvolving stereotactic radiosurgery for brain tumors are being conducted atmajor cancer centers However, based on positive early results, many commu-nity centers have begun instituting a stereotactic radiosurgery program, eitherwith a dedicated cobalt unit (gamma knife) or a linear accelerator–based sys-tem Small (< 4 cm) tumors of the brain, whether primary, metastatic, or recur-rent, may benefit from this treatment technique

SUGGESTED READING

Coia LR, Schultheiss TE, Hanks GE: A Practical Guide to CT Simulation Madison,Wisconsin, Advanced Medical Publishing, 1995

IMRT CWG: Intensity modulated radiotherapy: Current status and issues of interest Int

J Radiat Biol Phys 51:880–914, 2001

Khan FM: Treatment Planning in Radiation Oncology Baltimore, Maryland, Williams &Wilkins, 1998

Perez CA, Brady LW: Principles and Practice of Radiation Oncology Philadelphia,Lippincott-Raven, 1998

Suit H: The Gray Lecture: Coming technical advances in radiation oncology Int J Radiat

Biol Phys 53:798–809, 2002

Van Dyk J: The Modern Technology of Radiation Oncology Madison, Wisconsin, cal Physics Publishing, 1999

Medi-CHAPTER 3

Principles of

chemotherapy

Ray Page, DO, PhD, and Chris Takimoto, MD, PhD

The effective use of cancer chemotherapy requires an understanding of theprinciples of tumor biology, cellular kinetics, pharmacology, and drug resis-tance Thanks to the development of new, effective chemotherapeutic agents,coupled with our expanding knowledge about the administration and combi-nation of these agents, we now are able to cure almost 20% of all new cases ofcancer through chemotherapy alone

This chapter focuses on the principles responsible for the development of ern combination chemotherapy regimens This discussion is followed by de-scriptions of the major classes of chemotherapeutic drugs and their mecha-nisms of action

mod-Cellular kinetics

Cytokinetic studies have shown how the kinetics of cellular growth defines thecharacteristics of tumor growth and, in part, explains the biological behaviorand heterogeneity of tumors

Normal cell cycle

Inherent to cytokinetic principles is the concept of the cell cycle Daughtercells formed as a result of mitosis consist of three subpopulations: (1) cells thatare nondividing and terminally differentiated, (2) cells that are continually pro-liferating, and (3) cells that are resting but may be recruited into the cell cycle(ie, stem cells) All three populations exist simultaneously in tumors

The cell cycle is composed of four phases during which the cell prepares forand effects mitosis Cells that are committed to divide again enter the G1 phase.Preliminary synthetic cellular processes occur that prepare the cell to enter theDNA synthetic (S) phase Specific protein signals regulate the cell cycle andallow replication of the genome where the DNA content becomes tetraploid(4N) After completion of the S phase, the cell enters a second resting phase,

G2,prior to undergoing mitosis The cell progresses to the mitotic (M) phase,

in which the chromosomes condense and separate and the cell divides, ducing two daughter cells

pro-Chemotherapeutic agents can be classified according to the phase of thecell cycle in which they are active (Table 1) Agents that are cell-cycle-phase–

nonspecific (eg, alkylating agents) have a linear dose-response curve; that is,the greater the dose of drug, the greater is the fraction of cell kill However,cell-cycle-phase–specific drugs have a plateau with respect to cell killing abil-ity, and cell kill will not increase with further increases in drug dosage.

Tumor kinetics

The rate of growth of a tumor is a reflection of the proportion of actively ing cells (the growth fraction), the length of the cell cycle (doubling time), andthe rate of cell loss Variations in these three factors are responsible for thevariable rates of tumor growth observed among tumors of differing histolo-gies, as well as among metastatic and primary tumors of the same histology.Tumors characteristically exhibit a sigmoid-shaped Gompertzian growth curve,

divid-in which tumor doubldivid-ing time varies with tumor size Tumors grow most idly at small tumor volumes As tumors become larger, growth slows based on acomplex process dependent on cell loss and tumor blood and oxygen supply

rap-TABLE 1: Cell-cycle-phase–specific drugs

a Have greatest effects in S phase and possibly late G 2 phase; cell blockade or death, however, occurs in early mitosis.

Adapted, with permission, from Dorr RT, Von Hoff DD (eds): The Cancer Chemotherapy Handbook, 2nd

ed, p 5 East Norwalk, Connecticut, Appleton & Lange, 1993.

In order to have the best chance for cure, chemotherapy must achieve a tional cell kill in a logarithmic fashion (ie, 1-log-kill is 90% of cells, 2-log-kill is99% of cells) From these concepts, chemotherapy models have been devel-oped utilizing alternating non–cross-resistant therapies, induction-intensifica-tion approaches, and adjuvant chemotherapy regimens.

frac-Principles of combination chemotherapy

Using kinetic principles, a set of guidelines for designing modern combinationchemotherapy regimens have been derived Combination chemotherapy ac-complishes three important objectives not possible with single-agent therapy:(1) It provides maximum cell kill within the range of toxicity tolerated by thehost for each drug; (2) it offers a broader range of coverage of resistant celllines in a heterogeneous tumor population; and (3) it prevents or slows thedevelopment of new drug-resistant cell lines

Selection of drugs for combination regimens

The following principles have been established to guide drug selection in bination regimens:

com-■ Drugs known to be active as single agents should be selected for binations Preferentially, drugs that induce complete remissions should

al-■ Drugs should be used in their optimal dose and schedule

■ Drugs should be given at consistent intervals The treatment-free terval between cycles should be the shortest possible time for recovery

in-of the most sensitive normal tissue

■ Drugs with different patterns of resistance should be combined to mize cross-resistance

mini-Terminology used in describing chemotherapy

Chemotherapy is administered with a variety of treatment schedules designedaccording to the intent and responsiveness of therapy Definitions of chemo-therapy are generally based on the purpose of achieving certain therapeuticgoals as described in Table 2

Definitions of response

Tumors can be classified according to their general sensitivity to chemotherapy.Response to chemotherapy is defined precisely as complete response, partialresponse, minimal response (stable disease), and progression Complete re-sponse is defined as the disappearance of all evidence of disease and no ap-

pearance of new disease for a specified interval (usually 4 weeks) Partial sponse is defined as a reduction by at least 50% in the sum of the products ofthe two longest diameters of all lesions, maintained for at least one course oftherapy, with no appearance of new disease Minimal response is any responseless than a partial response and is usually not reported in clinical trials Progres-sion is defined as growth of existing disease or appearance of new disease dur-ing chemotherapy.

re-The NCI (National Cancer Institute) has adopted standardized response ria and is requiring their use by all cooperative groups These criteria, calledRECIST (Response Evaluation Criteria in Solid Tumors), were developed andrecently revised by the World Health Organization (WHO) The goals areconsistency of evaluation and comparison of regimens within a single trial andregimens of different trials A comparison of RECIST and WHO guidelines islisted in Table 3

crite-Dose intensity

Kinetic principles predict that, for drug-sensitive cancers, the factor limitingthe capacity to cure is proper dosing Reduction in dose is associated with adecrease in cure rate before a significant reduction in the complete remissionrate occurs A dose reduction of approximately 20% can lead to a loss of up to

TABLE 2: Terminology used in describing chemotherapy

Induction: High-dose, usually combination, chemotherapy given with the intent of inducing

complete remission when initiating a curative regimen The term is usuallly applied tohematologic malignancies but is equally applicable to solid tumors

Consolidation: Repetition of the induction regimen in a patient who has achieved a complete

remission after induction, with the intent of increasing cure rate or prolonging remission

Intensification: Chemotherapy after complete remission with higher doses of the same agents

used for induction or with different agents at high doses with the intent of increasing curerate or remission duration

Maintenance: Long-term, low-dose, single or combination chemotherapy in a patient who has

achieved a complete remission, with the intent of delaying the regrowth of residual tumorcells

Adjuvant: A short course of high-dose, usually combination chemotherapy in a patient with

no evidence of residual cancer after surgery or radiotherapy, given with the intent ofdestroying a low number of residual tumor cells

Neoadjuvant: Adjuvant chemotherapy given in the preoperative or perioperative period Palliative: Chemotherapy given to control symptoms or prolong life in a patient in whom cure

is unlikely

Salvage: A potentially curative, high-dose, usually combination, regimen given in a patient who

has failed or recurred following a different curative regimen

From: Yarbro J: The scientific basis of cancer chemotherapy, in Perry MC (ed): The Chemotherapy Sourcebook, p 12 Baltimore, MD, Lippincott, Williams and Wilkins, 1996.

50% of the cure rate Conversely, a twofoldincrease in dose can be associated with a 10-fold (1-log) increase in tumor cell kill in ani-mal models.

Overcoming chemotherapy resistance

There are multiple reasons for chemotherapyfailure in cancer patients, involving a variety

of anatomic, pharmacologic, and cal mechanisms Tumor sanctuary sites (brain,testes) and blood flow to the tumor representanatomic barriers; pharmacologic and bio-chemical explanations include altered drug ac-tivation/inactivation in normal tissues, decreased drug accumulation, increasedrepair of drug-induced damage to the cell, altered drug targets, and alteredgene expression

biochemi-Overexpression of the MDR1 (multidrug resistance) gene is the most notable

mediator of drug resistance and encodes a 170-kd transmembrane tein p-Glycoprotein is an energy-dependent pump that serves to remove tox-

p-glycopro-ins or endogenous metabolites from the cell A high level of MDR1 sion is reliably correlated with resistance to cytotoxic agents Tumors that in-trinsically express the MDR1 gene prior to chemotherapy characteristicallydisplay poor durable responses

expres-TABLE 3: Comparison of RECIST and WHO guidelines

Objective response (LD Target lesions (change in Measurable disease

is the longest diameter) sum of LDs, maximum 5 per (change in the sum of the

organ up to 10 total products of LDs and[more than one organ]) greatest perpendicular

diameters, no maximumnumber of lesions specified)Complete response (CR) Disappearance of all target Disappearance of all known

lesions, confirmed at disease, confirmed at

Partial response (PR) ≥ 30% decrease from ≥ 50% decrease from

base-baseline, confirmed at line, confirmed at ≥ 4 weeks

≥ 4 weeksProgressive disease (PD) ≥ 20% increase over smallest ≥ 25% increase in one or

sum observed or appearance more lesions or appearance

of new lesions of new lesionsStable disease (SD) Neither PR nor PD criteria Neither PR nor PD criteria

Tariquidar (XR9576) is an

investigational intravenous drug

that is a potent p-glycoprotein

inhibitor that reverses MDR

associated with common

chemotherapy drugs It can be

safely and conveniently

adminis-tered with full doses of paclitaxel,

doxorubicin, and vinorelbine with

no compromise of

pharmacokinet-ics Phase III studies in lung cancer

are ongoing to evaluate the efficacy

and response of tariquidar in

combination therapy (Boniface G,

Ferry D, Atsmon J, et al: Proc Am Soc

Clin Oncol [abstract] 21:90b, 2002).

RECIST = Response Evaluation Criteria in Solid Tumors; WHO = World Health Organization

Chemotherapy agents subject to MDR1- mediated resistance include theanthracyclines, vinca alkaloids, taxanes, and topoisomerase inhibitors Targeted

therapies that inhibit p-glycoprotein are under evaluation in combination with

cytotoxic drugs subject to MDR (see sidebar on previous page)

Liposomal formulations of chemotherapeutic drugs are a promising newapproach to overcoming these resistance mechanisms Liposomes are well-defined lipid and lipoprotein vesicles that offer immense potential for target-ing drugs to tumors The advantages of these drug carriers over the conventionaladministration of chemotherapy agents are described in Table 4

FDA-approved liposomal preparations of doxorubicin (Doxil), daunorubicin(DaunoXome), cytarabine (DepoCyt), and amphotericin B (Abelcet) have proven

to be attractive, less toxic alternatives to the conventional drug formulations.Liposomal daunorubicin and amphotericin B have clearly shown less cardiacand renal damage, respectively Daunorubicin liposomal is efficacious in in-duction regimens for acute leukemia; cytarabine liposomal appears to be supe-rior to intrathecal cytarabine for treatment of CNS leukemia and lymphoma

An additional advantage of the liposomal delivery system is the ability to capsulate and stabilize very hydrophobic molecules such as paclitaxel (Taxol).Nanoparticle, albumin-stabilized paclitaxel has allowed much higher doses ofdrug to be given with far fewer side effects than paclitaxel which contains thetoxic carrier material cremophor Currently, a phase III randomized studycomparing the efficacy of nanoparticle paclitaxel with conventional paclitaxel

en-in metastatic breast cancer is under way

Several liposomal formulations of conventional anticancer drugs are currently

in phase I/ II evaluation, including liposomal vincristine, platinum,

mitoxantrone, all-trans retinoic acid (ATRA), and lurtotecan There is a strong

probability that these drug carriers will allow better administration of poorly

soluble cancer drugs, enhance drug delivery and uptake in the tumor, andboost dose intensity, subsequently improving antitumor response, overcomingdrug resistance, and decreasing chemotherapy toxicities

TABLE 4: Advantages of liposomal drug delivery

• Provides selective passive targeting to tumor sites

• Increases efficacy and therapeutic index

• Improves delivery of hydrophobic molecules

• Reduces the toxicities of the encapsulated agent

• Avoids accumulation in vital organs and tissues

• Improves pharmacokinetics (reduced elimination, increased drug exposure time)

• Increases stability via encapsulation

• Enhances intracellular drug delivery to overcome drug resistance

Text continues on page 35

TABLE 5: Alkylating agents and their uses, dosages,

and toxicities

Drug and its uses a Dosages Toxicities b

Nitrogen mustards

Chlorambucil 0.1-0.2 mg/kg PO daily for Bone marrow depression,

CLL, HD, NHL, 3-6 wk as required (usually gonadal dysfunction,

ovarian cancer, 4-10 mg/d) or intermittent leukemia, hyperuricemia,choriocarcinoma, 0.4 mg/kg every 3-4 wk; pulmonary fibrosis

lymphosarcoma increase by 0.1 mg/kg until

control of disease or toxicity

Cyclophosphamide 40-50 mg/kg IV in divided Bone marrow depression, AML, ALL, CLL, HD, doses over 2-5 d to start, hemorrhagic cystitis, im-

and NHL, multiple followed by 10-15 mg/kg munosuppression, alopecia,

myeloma, mycosis IV every 7-10 d; or 3-5 stomatitis, SIADH

fungoides, neuroblas- mg/kg IV twice weekly;

toma, ovarian and or 1-5 mg/kg/d PO

Mechlorethamine 0.4 mg/kg ideal body Bone marrow depression,

HD, NHL, CML, CLL, weight given as single nausea and vomiting,

mycosis fungoides, dose or in divided doses local phlebitis, severe skin

bronchogenic carcin- of 0.1-0.2 mg/kg/d necrosis if extravasated,

oma, lymphosarcoma, gonadal dysfunction

polycythemia vera, malignant

effusions (intracavitary)

Melphalan Continuous therapy: 6 mg Bone marrow depression, Multiple myeloma, PO daily for 2-3 wk, no anorexia, nausea and

breast and ovarian cancers, therapy for 2-4 wk, then vomiting, gonadal testicular

sarcoma, testicular maintenance with 2-4 mg dysfunction, leukemiaand lung cancers PO daily

Pulse: 10 mg/m2 PO dailyfor 4 d every 4-6 wk

a FDA-approved uses in italics; neoplasms are carcinomas unless otherwise indicated

b Dose-limiting effects in italics

continued on following page

TABLE 5: Alkylating agents and their uses, dosages,

and toxicities (continued)

Drug and its uses a Dosages Toxicities b

Aziridine

Thiotepa IV: 0.3-0.4 mg/kg by rapid Bone marrow depression, Ovarian, breast, and IV infusion nausea and vomiting,

superficial bladder Intravesical: 60 mg/60 mL mucositis, skin rashes

cancers, HD, CML, CLL, sterile water instilled and

bronchogenic carcinoma, retained in bladder for 2 h;

malignant effusions (intra- repeat weekly for 4 wk

cavitary), BMT for refrac- Intracavitary: 0.6-0.8 mg/kg

tory leukemia, lymphomas

Alkyl sulfonate

Busulfan 2-8 mg PO daily for Bone marrow depression, CML, BMT for refractory remission induction; pulmonary fibrosis,

leukemia, lymphomas adjust dosage to WBC aplastic anemia,

amen-count; 1-3 mg PO daily for orrhea, gynecomastia,maintenance; withhold skin hyperpigmentationinduction if WBC count

< 15,000/µL; resumetherapy when WBCcount > 50,000/µL

Nitrosoureas

Carmustine 150-200 mg/m2 IV Delayed bone marrow

Brain tumor, multiple every 6-8 wk depression, nausea and myeloma, HD, NHL, vomiting, reversible hepato-

Gliadel wafers Up to 8 wafers placed Fever, pain, and abnormal

Glioblastoma multiforme in the brain cavity created healing

by tumor removal

Lomustine 130 mg/m2 PO every 6 wk; Delayed bone marrow

Brain tumors, HD, adjust dose in combination depression, nausea and

GI carcinomas, NSCLC chemotherapy vomiting, reversible

hepato-toxicity, pulmonary andrenal damage, neurologicreactions, leukemia

Streptozocin Daily: 500 mg/m2 IV for 5 d Renal damage, nausea and Pancreatic islet-cell, every 6 wk until maximum vomiting, diarrhea, alteredcarcinoid, colon, hepatoma, benefit or toxicity glucose metabolism, liverNSCLC, HD Weekly: 1,000 mg/m2 IV dysfunction

weekly for first 2 wk, thenescalate dose to response

or toxicity, not to exceed asingle dose of 1,500 mg/m2

Drug and its uses Dosages Toxicities

Platinum complexes

Carboplatin Single agent: 360 mg/m2 Bone marrow depression, Ovarian cancer, endo- IV every 4 wk nausea and vomiting, periph-metrial, head and neck, Combination: 300 mg/m2 eral neuropathy, ototoxicitylung, testicular, and IV every 4 wk

breast cancers, relapsed Calvert formula:

acute leukemia, NHL Total dose (mg) = Target

Oxaliplatin

Colorectal (second-line) 85 mg/m2 IV over 120 min Bone marrow depression,

on d 1 followed by diarrhea, nausea and vomiting,

infusional 5-FU and leuco- neuropathies exacerbated byvorin on d 1-2, every 2 wk cold exposure, pharyn-

golaryngeal dysesthesia

Nonclassic alkylators

Altretamine 4-12 mg/kg/d or 260 mg/m2, Nausea and vomiting,

Ovarian, lung, breast, PO divided in 3-4 doses for bone marrow depression,and cervical cancers, NHL 14-21 d of a 28-d regimen paresthesias, CNS toxicity

Dacarbazine Melanoma: 2.0-4.5 mg/kg/d Bone marrow depression, Malignant melanoma, IV for 10 d every 4 wk; or nausea and vomiting, flulike

HD, soft-tissue sarcomas, 250 mg/m2/d IV for 5 d syndrome, transient neuroblastoma every 3 wk toxicity, local irritation,

hepato-HD: 375 mg/m2 IV on d 1, facial flushing, alopeciarepeated every 15 d (single

agent); 150 mg/m2/d IVfor 5 d every 4 wk(combination therapy)

Procarbazine Single agent: 4-6 mg/kg/d Bone marrow depression,

HD, NHL, brain tumors, PO until maximum nausea and vomiting,

HD (MOPP): 100 mg/m2/d paresthesias, headache,

Temozolomide 150 mg/m2/d PO Bone marrow depression, Anaplastic astrocytoma for 5 d every 28 d nausea and vomiting

(relapsed), renal cell cancer,

melanoma

ALL = acute lymphoblastic leukemia; AML = acute myelogenous leukemia; AUC = area under the curve; BMT = bone marrow transplantation; CLL = chronic lymphocytic leukemia; CML = chronic myelogenous leukemia; CMML = chronic myelomacrocytic leukemia; 5-FU = fluorouracil; GFR = glomerular filtration rate; HD = Hodgkin’s disease; MDS = myelodysplastic syndromes; MOPP = mechlorethamine, Oncovin, procarbazine, and prednisone; NHL = non-Hodgkin’s lymphoma; NSCLC

= non–small-cell lung cancer; SIADH = syndrome of inappropriate antidiuretic hormone secretion; WBC = white blood cell

TABLE 6: Antimetabolites and their uses, dosages,

and toxicities

Drug and its uses a Dosages Toxicities b

Folate analog

Methotrexate Numerous dosing Mucositis, GI ulceration

Breast, head and neck, schedules with combin- (may produce hemorrhage

GI, and lung cancers, ation therapy: or perforation), bone

ALL, CNS leukemia Low dose: 2.5-5.0 mg PO marrow depression,

(intrathecal), gestational daily; or 5-25 mg/m2 PO, pulmonary fibrosis

(pre-trophoblastic tumors, IM, IV twice weekly; or viously irradiated area),

NHL (advanced stage), 50 mg/m2 IV every 2-3 wk nerve root irritation andBurkitt’s lymphoma, High dose: 1-12 g/m2 IV convulsion (intrathecal),osteosarcoma, mycosis with leucovorin rescue liver cirrhosis and osteo-

Intrathecal: 5-10 mg/m2 renal damage (high dose),(up to 15 mg) every diarrhea, skin erythema3-7 d

Purine analogs

Fludarabine 25 mg/m2/d IV over Bone marrow depression,

CLL, AML, NHL (low-grade) 30 min for 5 d; repeat nausea and vomiting, fever,

every 28 d malaise, pulmonary infiltrates,

tumor lysis syndrome, CNSeffects (high dose)

Mercaptopurine 1.5-2.5 mg/kg/d PO Bone marrow depression, ALL, CML, AML (100-200 mg in average nausea and vomiting, anorexia,

adult) until response or diarrhea, cholestasistoxic effects are seen;

may increase dose to

5 mg/kg/d; adjust for tenance dose; reduce dose

main-by 50%-75% if given withallopurinol or if renal orhepatic insufficiencyensues

Thioguanine 2 mg/kg/d PO until Bone marrow depression, AML, ALL, CML, advanced response or toxic effects liver damage, stomatitiscolorectal cancer, multiple are seen; may cautiously

Pentostatin 4 mg/m2 IV over 30 min Nephrotoxicity, CNS

Hairy-cell leukemia, every other week or for depression, bone marrow

ALL, CLL, lymphoblastic 3 consecutive weeks; give depression, nausea andlymphoma, mycosis vigorous hydration before vomiting, conjunctivitis

a FDA-approved uses in italics; neoplasms are carcinomas unless otherwise indicated

b Dose-limiting effects in italics

Drug and its uses Dosages Toxicities

Pyrimidine analogs

Capecitabine 1,250 mg/m2 bid PO with Diarrhea, stomatitis,

Breast cancer (relapsed), food (2 weeks on drug, nausea and vomiting, fatigue,

colorectal cancer, and 1 week of rest) hand-foot syndrome, bone

other GI malignancies marrow depression (minimal)

Cytarabine AML induction: 100 mg/m2/d Bone marrow depression, AML, ALL, CML, NHL, by continuous IV infusion on nausea and vomiting, diarrhea,CNS leukemia days 1-7; or 100 mg/m2 IV arachnoiditis (intrathecal),(intrathecal) every 12 h on days 1-7 stomatitis, hepatic dysfunction,

Relapsed ALL: 3 g/m2 IV over fever, conjunctivitis, confusion,1-3 h every 12 h for 4 doses somnolence, cerebellar toxicity

DepoCyt (liposomal Intrathecal: DepoCyt, 50 mg

cytarabine) CNS over 1-5 min every 14 d,

leukemia/lymphoma with dexamethasone, 4 mg

PO bid × 5 d

Floxuridine 0.1-0.6 mg/kg/d over Stomatitis and GI ulcers,

GI adenocarcinomas meta- several days via continuous bone marrow depression,

static to liver, including oral, arterial infusion supplying abdominal pain, nausea andpancreatic, biliary, colon, well-defined tumor; treat- vomiting, diarrhea, liverand hepatic cancers, and ments given over 1-6 wk dysfunction (transient)metastatic breast cancer

Fluorouracil Numerous dosing schedules Stomatitis and GI

Colon, rectal, stomach, with combination therapy: ulcers (infusion)

pancreas, breast, head Loading dose: 300-500 bone marrow depression

and neck, renal cell, pros- mg/m2; or 12 mg/kg IV (bolus), diarrhea, nausea

tate, and ovarian cancers, daily for 3-5 d, followed and vomiting, esophagitis,squamous cell carcinoma by weekly maintenance angina, cerebellar ataxia,

of esophagus, basal and Maintenance: 10-15 mg/kg radiosensitizer

squamous cell carcinoma IV weekly, as toxicity permits

of skin (topical), hepatic Infusion: 20-25 mg/kg by

con-cancer (intra-arterial) tinuous IV infusion over 24 h

daily for 4-5 d, every 4 wk

Gemcitabine 1,000 mg/m2 IV over 30 min, Bone marrow depression, Pancreatic cancer, lung, once weekly for up to 7 transient fever, flulike

ovarian, breast, and weeks (or until toxicity syndrome, skin rash, mildbladder cancers necessitates reducing or nausea and vomiting

withholding a dose), lowed by 1 week of restSubsequent cycles: Infusionsonce weekly for 3 consecutiveweeks out of every 4 weeks

fol-Substituted urea

Hydroxyurea Intermittent: 80 mg/kg Bone marrow depression, CML, acute leukemia PO every third day mild nausea and vomiting,

(emergent treatment), head Continuous: 20-30 mg/kg skin rashes, radiosensitizer

and neck cancer, ovarian PO daily

cancer, melanoma,

essen-tial thrombocytosis,

TABLE 7: Natural products and their uses, dosages,

and toxicities

Drug and its uses a Dosages Toxicities b

Antitumor antibiotics

Bleomycin 10-20 U/m2 given IV, IM, Pneumonitis and

Testicular cancer, or SC weekly or twice pulmonary fibrosis,

HD, reticulum cell weekly; maximum total fever and allergic

sarcoma, lymphosar- dose, 400 U; a 2-U test dose reactions, anaphylaxis,

coma, squamous cell should be given because of hyperpigmentation,

cancer of the head and a possible anaphylactoid Raynaud’s phenomenon,

neck, skin, cervix, reaction alopecia

vulva, and penis

Dactinomycin 0.010-0.015 mg/kg IV Stomatitis, bone marrow Testicular cancer, ges- daily for 5 d every 3 wk depression, anorexia,

tational trophoblastic (usual adult dose, 0.5 mg), nausea and vomiting,

tumors, Wilms’ tumor, or 2 mg/m2 IV as a single diarrhea, alopecia, skin

rhabdomyosarcoma, dose every 3-4 wk changes, anaphylactoid

Ewing’s sarcoma reaction

Daunorubicin Remission induction: Bone marrow depression, AML, ALL 30-45 mg/m2/d IV for 3 d cardiotoxicity, alopecia,

in combination therapy; nausea and vomiting,total cumulative dose, diarrhea, stomatitis,

550 mg/m2 fever, dermatitis at

previously irradiated sites, redurine, anaphylactoid reaction

DaunoXome Liposomal preparation:

(liposomal daunorubicin) 40 mg/m2 IVevery 2 wk

Kaposi’s sarcoma

Doxorubicin 60-90 mg/m2 single IV Bone marrow depression, ALL, AML, breast, ovarian, injection every 21 d, cardiotoxicity, stomatitis

bladder cancers, HD, 20-30 mg/m2/d IV for 3 d (continuous infusion),

NHL, SCLC, gastric every 3-4 wk, or 20 mg/m2 alopecia, nausea and

cancer, sarcoma, Wilms’ IV weekly; total cumulative vomiting, diarrhea, fever,tumor, neuroblastoma, dose of 550 mg/m2; reduce dermatitis at previouslythyroid cancer dose for liver dysfunction irradiated sites, red urine,

and platinum-based regimens),

Kaposi’s sarcoma 20 mg/m2 IV every 3 wk Bone marrow depression,

hand-foot syndrome

Epirubicin 100 mg/m2 IV on day 1, or Bone marow depression, Breast cancer 60 mg/m2 IV on days 1 and cardiotoxicity, stomatitis,

8 in combination therapy alopecia

Idarubicin 12 mg/m2/d IV for 3 d Bone marrow depression, AML, CML (blast every 3 wk in combination nausea and vomiting,

cardiotoxicity

a FDA-approved uses in italics; neoplasms are carcinomas unless otherwise indicated

b Dose-limiting effects in italics