Options in the Treatment of...After reading Options in the Treatment of Head and Neck Cancer,...

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Options in the Treatment of Head and Neck Cancer

Edited by

Marshall R. Posner, MD

Medical DirectorHead and Neck Oncology Program

Dana-Farber Cancer InstituteBoston, Massachusetts

Publishers ofONCOLOGY

Oncology News InternationalCancer Management: A Multidisciplinary Approach

www.cancernetwork.com

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Clinical Oncology Advisory BoardCOAB

Note to the reader

The information in this book has been carefully reviewed for accuracy of dosageand indications. Before prescribing any drug, however, the clinician should consultthe manufacturer’s current package labeling for accepted indications, absolute dos-age recommendations, and other information pertinent to the safe and effective useof the product described. This is especially important when drugs are given in combi-nation or as an adjunct to other forms of therapy. Furthermore, some of the medica-tions described herein, as well as some of the indications mentioned, may not havebeen approved by the U.S. Food and Drug administration at the time of publication.This possibility should be borne in mind before prescribing or recommending anydrug or regimen.

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Copyright ©2006 by CMPMedica, The Oncology Group. All rights reserved. Thisbook is protected by copyright. No part of it may be reproduced in any manner or byany means, electronic or mechanical, without the written permission of the publisher.

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Cover image:

X-ray of the skull, side view, showing the upper respiratory tract,including the larynx, pharynx, and nasal passages. (c) Alain Pol. Copyright (c) ISM/Phototake – All rights reserved.

Publishers ofONCOLOGY

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www.cancernetwork.com

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iii

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Preface

When I asked coauthors to contribute chapters for this book, I wantedthem to write a brief, up-to-date review of the options for therapy and thetherapeutic decisions we all face in treating patients with head and neckcancer. This field is rapidly changing, and care for these patients isextremely challenging. The authors of each of the chapters are active inclinical care and clinical research and are leading cutting edge trials in thisfield. They are thinking every day about how to make the care and treat-ment better for our patients, and their chapters individually reflect themost current data and insightful concepts about each topic, the therapy,and the technology available. I think each chapter will surprise the readerby its immediate relevance. What I also found when I read the chapterswas something for both experienced and new care givers.

Each chapter covers an important area of therapy in head and neckcancer and gives background for practitioners and caregivers in differentdisciplines. Dr. Gregory Chronowski and Dr. David Rosenthal give a verythoughtful and logical discussion of the assessment of a patient for chemo-radiotherapy and some of the very tough issues surrounding who shouldbe treated and how much treatment they should recieve. Decision-makingin this population is very hard, and the authors give clarity by identifyingtreatment and patient factors that guide the final choice of therapy. InChapter 2, I give an overview of induction chemotherapy and a review ofthe newest data supporting both induction therapy and sequential treat-ment for patients with advanced disease. This incorporates data from themost recently reported trials in 2006. A reader would understand the prac-tical and biologic rationale and support for a sequential treatmentapproach. In her chapter, Dr. Barbara Murphy defines the issues of toxic-ity, quality-of-life, and management of the sequeallae of increasinglyaggressive and effective therapy. Toxicity has become a major factor in thelives of our patients, and Dr. Murphy is a leader in articulating the biologyand the management of acute and late toxicities of chemoradiotherapy.This chapter promotes thinking about consequences and long-term lifeissues. The chapter by Dr. Ezra Cohen and Dr. Oyewale Abidoye gives agood review and timely discussion of treatment of recurrent disease.Although there are many new agents available, they also review data sup-

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iv Preface

porting an expanded role for re-irradiation and the use of more standardagents, and they address when and how to make decisions concerningpatients with recurrent cancer. Dr. David Adelstein provides a very detaileddiscussion of who is an appropriate organ preservation candidate, deci-sion-making around functional organ preservation, and the data support-ing organ preservation strategies in his chapter. As this field changes andimproves, organ preservation strategies have become increasingly impor-tant in therapy decisions. Finally, Dr. Gregory Russo and Dr. MitchellMachtay write about the basic technology and the common questions sur-rounding the newest important radiation innovation, intensity-modulatedradiotherapy in their chapter. This last chapter lays an important knowl-edge foundation to help practitioners understand both the value and thedeficiencies of IMRT, now a standard practice for head and neck cancer.

As the reader can see, the chapters were selected to represent most ofthe disciplines in head and neck cancer therapy and reflect the importanceof cross-education and multi-disciplinary care so essential to the manage-ment and success of therapy for these difficult patients. We hope readersfind this book and the topics helpful, informative, and interesting.

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Contents

Preface iii

Contributing Authors vi

Continuing Medical Education Pages viii

Introduction xi

Chemoradiation for Head and Neck Cancer 1

Gregory M. Chronowski, MD, and David I. Rosenthal, MD

Evolving Role of Induction Chemotherapy and Sequential Therapy in the Treatment of Locally Advanced Squamous Cell Cancer of the Head and Neck 23


Increasing Cure—Increasing Toxicity: Symptom Management and Chemoradiotherapy 41

Barbara A. Murphy, MD

Management of Recurrent Disease: Current Treatments and New Therapies 61

Ezra E. W. Cohen, MD, and Oyewale Abidoye, MD

Integration of Chemotherapy into Organ Preservation Strategies for Squamous Cell Head and Neck Cancer 77

David J. Adelstein, MD

Intensity-Modulated Radiation Therapy: Promises and Practice 91

Gregory A. Russo, MD, and Mitchell Machtay, MD

Index 115

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3CME

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vi

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Contributing Authors

Oyewale Abidoye, MD

Department of MedicineSection of Hematology/OncologyUniversity of Chicago Pritzker School of MedicineChicago, Illinois


Department of Solid Tumor OncologyTaussig Cancer CenterCleveland Clinic Cleveland, Ohio

Ezra E. W. Cohen, MD

Department of MedicineSection of Hematology/OncologyUniversity of Chicago Pritzker School of MedicineChicago, Illinois

Gregory M. Chronowski, MD

Department of Radiation OncologyThe University of Texas M. D. Anderson Cancer Center Houston, Texas

Mitchell Machtay, MD

Department of Radiation OncologyJefferson Medical College of Thomas Jefferson UniversityPhiladelphia, Pennsylvania


Director, Pain and Symptom Management ProgramDirector, Head and Neck Research TeamVanderbilt Ingram Cancer CenterNashville, Tennessee

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Contributing Authors vii


Medical Director, Head and Neck Oncology ProgramDana-Farber Cancer InstituteBoston, Massachusetts

David I. Rosenthal, MD

Director, Head and Neck Translational Research Department of Radiation OncologyThe University of Texas M. D. Anderson Cancer CenterHouston, Texas

Gregory A. Russo, M.D.

Department of Radiation OncologyThomas Jefferson University HospitalPhiladelphia, Pennsylvania

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Continuing Medical Education

Activity release date: November 1, 2006Activity expiration date: December 1, 2007

About the Activity

This activity is based on the book,

Options in the Treatment of Head andNeck Cancer.

It was developed from an identified educational need forinformation about practical management issues in the practice of medical,surgical, and radiation oncology.

This activity has been developed and approved under the direction ofBeam Institute.

Activity Learning Objectives

After reading

Options in the Treatment of Head and Neck Cancer,

partici-pants should be able to:

• Summarize the history of head and neck cancer therapy, expoundingupon various chemoradiotherapeutic modalities used, timing oftherapy, and selection of patients, drugs, and dosing schedules.

• Review currently available treatment modalities for head and neck can-cer management that may preserve crucial anatomic structures andallow their function.

• Discuss current surgical, chemotherapeutic, and radiotherapeutic meth-ods to treat squamous cell cancer of the head and neck and recurrenceof the disease and new therapies and treatments currently being testedagainst this malignancy.

• Describe the acute and late effects of surgery and/or chemoradio-therapy used for head and neck cancer and how these treatmentsaffect quality of life and need for supportive care.

• Examine current best practice for surgery and administration of che-moradiotherapy for head and neck cancer and the differencesbetween various treatment regimens being investigated.

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Continuing Medical Education ix

Target Audience

This activity targets physicians in the fields of oncology and hematology.

Accreditation

Beam Institute is accredited by the Accreditation Council for ContinuingMedical Education (ACCME) to provide continuing medical education forphysicians.

Continuing Education Credit

Category 1 Credit

Beam Institute designates this educational activity for a maximum of 3American Medical Association (AMA) Physician’s Recognition Award(PRA) Category 1 credit(s)™. Physicians should only claim credit com-mensurate with the extent of their participation in the activity.

Note: This activity complies with all ACCME, U. S. Food and DrugAdministration (FDA), and Pharmaceutical Research and ManufacturersAssociation (PhRMA) guidelines for CME educational activities.

Compliance Statement

This activity is an independent educational activity under the direction ofBeam Institute. The activity was planned and implemented in accordance withthe Essential Areas and policies of the ACCME, the Ethical Opinions/Guide-lines of the AMA, the FDA, the Health and Human Services Office of Inspec-tor General, and the PhRMA Code on Interactions with HealthcareProfessionals, thus assuring the highest degree of independence, fair balance,scientific rigor, and objectivity. However, Beam Institute, the Grantor, andCMPMedica shall in no way be liable for the currency of information or forany errors, omissions, or inaccuracies in the activity. Discussions concerningdrugs, dosages, and procedures may reflect the clinical experience of theauthor(s), or they may be derived from the professional literature or othersources and may suggest uses that are investigational in nature and notapproved labeling or indications. Activity participants are encouraged to referto primary references or full prescribing information resources. The opinionsand recommendations presented herein are those of the author(s) and do notnecessarily reflect the views of the provider or producer.

To earn CME credit, go to www.cancernetwork.com/cme and look for Earn CME section on our site

posFM(i-xii).fm Page ix Wednesday, October 25, 2006 3:53 PM

x Continuing Medical Education

Financial Disclosure

Dr. Posner is a consultant for Amgen, Sanofi-Aventis, Medimmune, GSK,Genentech, NCI, ASCO, and NCCN. Dr. Rosenthal is a consultant and serveson the speaker’s bureau for BMS, Imclone, and Medimmune. The followingcontributors have no significant financial interest or other relationship withthe manufacturers of any products or providers of any service mentioned inthe article: Dr. Abidoye, Dr. Adelstein, Dr. Chronowski, Dr. Cohen, Dr.Machtay, Dr. Murphy, and Dr. Russo.

Copyright

Copyrights owned by Beam Institute, a division of CME LLC. Copyright©2006.

Contact Information

We would like to hear your comments regarding this or other activitiesprovided by Beam Institute. In addition, suggestions for future program-ming are welcome. Contact us at:

Address

: Director of Continuing EducationBeam InstituteCME LLC11 West 19

th

Street, 3

rd

FloorNew York, NY 10011

Phone

: 888-618-5781

Fax

: 212-600-3050

e-mail

: [email protected]

Supported by an educational grant by Sanofi-Aventis

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xi

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Introduction

Chemotherapy, as part of a multi-disciplinary and multi-modalityapproach, has become the standard of care for the treatment of locallyadvanced squamous cell cancer of the head and neck. Until recently, che-motherapy has been delivered as either induction chemotherapy, alsoknown as

neoadjuvant therapy

, or in combination with radiotherapy aschemoradiotherapy (CRT). Although induction chemotherapy with cis-platinum and 5-fluorouracil (PF) is effective in improving survival, patientstreated with induction chemotherapy have a high rate of local-regionalfailure despite a reduced rate of distant failure. CRT has improved survivalby reducing local-regional failure, with no improvement in control of dis-tant disease.

To optimize therapy, sequential therapy approaches, combining induc-tion chemotherapy, CRT, and surgery have been developed. In addition,recent advances in induction chemotherapy, namely the demonstrationthat a three drug induction chemotherapy regimen with docetaxel, cisplat-inum, and 5-fluorouracil (TPF) is significantly more effective than PF, hasincreased interest and optimism regarding the potential gains of inductionchemotherapy, as a sequential therapy approach. Preliminary data supportthe use of sequential therapy in patients with poor-prognosis head andneck, and a phase III trial with this schedule shows highly encouragingimprovements in survival, lessened toxicity, and a significant advantage toTPF in this setting.

The different treatment paradigms of sequential therapy and CRT arebeing compared in phase III studies. TPF has replaced PF as the standardfor induction chemotherapy, and sequential therapy represents an accept-able standard of care for patients with curable, locally advanced head andneck cancer.

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1

CME

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Chemoradiation for Head and Neck Cancer

Gregory M. Chronowski, MD, and David I. Rosenthal, MD

History of Chemoradiation for Head and Neck Cancer

Head and neck cancers affect more than 40,000 patients per year in theUnited States (1). As a result of their location, these tumors can causevarying degrees of functional and cosmetic deficits that are often exacer-bated by cancer treatment. From the 1960s through the 1980s, surgeryand radiation therapy (RT), often postoperative, remained the primarymodalities used to treat these tumors. With the publication of the Depart-ment of Veterans Affairs (VA) larynx preservation trial in 1991 (2), theconcept of non-surgical organ preservation through the use of radiationand chemotherapy entered the mainstream. Since then, the most significantadvances in the treatment of head and neck tumors have been the develop-ment of altered radiation fractionation schedules and concurrent chemo-therapy regimens that have documented improvements in local controland survival, respectively. In addition, the development of intensity-modu-lated RT has allowed for greater conformality of radiation dose, allowingfor relative sparing of adjacent dose-limiting normal tissues, most notablythe brain stem, optic nerves, spinal cord, and parotid salivary glands.

Initial attempts at concurrent chemotherapy with RT were disappoint-ing due to significant mucosal toxicity secondary to the use of bleomycin,5-fluorouracil (5-FU), and methotrexate, whereas the activity of many ofthese agents in squamous cell carcinomas was probably not optimal. With

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2 Chemoradiation for Head and Neck Cancer

the development of highly effective and better tolerated platinum-basedregimens, concurrent chemoradiation regimens moved to the forefront ofinvestigation. The publication of a number of multi-institutional trialsdocumenting both improvements in local control and survival has vali-dated concurrent chemoradiation as the standard of care for locallyadvanced, non-metastatic head and neck cancers (3,4).

Despite these therapeutic gains, there are still several unanswered ques-tions about chemoradiation. What remains somewhat controversial is theappropriate selection of patients for concurrent chemotherapy regimens,as this approach improves survival primarily through improvements inlocal control. In earlier stage cancers or in patients with non-bulky pri-mary tumors and/or small-volume lymphadenopathy, locoregional controlwith RT alone using standard or altered fractionation regimens can beexcellent, and whether there is incremental benefit from the addition ofconcurrent chemotherapy is an area of debate. Despite a general consensusthat platinum-containing regimens are optimal, the actual dose scheduleand types of agents to add to platinum remain open questions, with vari-ous cooperative groups and institutions advocating different drug combi-nations. In particular, the role of neoadjuvant chemotherapy remains anactive area of discussion.

Neoadjuvant or “Induction” Chemoradiation

Neoadjuvant

, or “induction,” chemotherapy is a term commonly used todescribe the administration of chemotherapy followed by RT (or surgery)alone. Advocates for neoadjuvant chemotherapy approaches in head andneck cancers cite the fact that there is better compliance, and thereforegreater potential benefit from induction therapy than for concurrent oradjuvant chemotherapy. Higher doses of chemotherapy drugs can begiven, with fewer unplanned delays and dose reductions, and multipleagents may be used over multiple cycles as compared to concurrentchemoradiation approaches that typically include lower doses of singleagents over 6–7 weeks. The higher doses of chemotherapy given with neo-adjuvant approaches may have greater potential to address subclinical fociof systemic micrometastases that occur in up to 20%–40% of patientsreceiving curative therapy for locoregionally confined disease. Critics ofthis approach cite the potential for tumors to progress during chemother-apy, making it more difficult to obtain local control with curative modali-ties such as RT or surgery. In addition, some have suggested that treatmentof head and neck tumors with neoadjuvant chemotherapy may select formore aggressive clonogens that may be less amenable to treatment with



RT (5). At this time, the weight of the evidence in the medical literaturesupports concurrent chemoradiation over neoadjuvant chemotherapyapproaches. A recent large meta-analysis (6) has confirmed the superiorityof concurrent chemoradiation over neoadjuvant chemotherapy; neverthe-less, there appears to be some greater benefit from platinum-containingneoadjuvant regimens (7). Although most trials have not shown a survivalbenefit for neoadjuvant approaches, two trials have documented a survivaladvantage over RT alone (8,9), but the concept is not universally accepted.

One of the earliest trials of neoadjuvant chemotherapy is the so-called“VA Larynx Preservation Trial” (2). Published in 1991, this trial random-ized patients with stage III or IV larynx cancer to either (a) three cycles ofneoadjuvant chemotherapy with cisplatin and 5-FU followed by definitiveRT or (b) laryngectomy followed by postoperative RT. This trial showedequivalent 2-year survival (68%) between the nonsurgical and surgicalarms. It is important to note that this trial did not appropriately test therole of neoadjuvant chemotherapy, as the study did not include an RT-alone arm. This shortcoming was addressed in the Radiation TherapyOncology Group (RTOG) 91-11 trial (10). This three-arm trial random-ized patients with advanced laryngeal cancer to either RT alone, neoadju-vant cisplatin and 5-FU followed by RT, or concurrent cisplatin and RT.An update of this trial was presented in 2006 (11). At 5 years, both con-current cisplatin/RT and induction chemotherapy followed by RT hadsuperior laryngectomy-free survival (47% and 45%, respectively) com-pared to RT alone (34%). Concurrent cisplatin and RT had superiorlocoregional control (69%) compared to neoadjuvant chemotherapy fol-lowed by RT (55%) or RT alone (51%). Overall survival at 5 years wasstatistically similar between all three arms at approximately 55%.

Concurrent Chemoradiation

The administration of chemotherapy during RT is commonly referred toas

concurrent chemoradiation

or simply

chemoradiation

. This approach isnow the standard of care in most locally advanced cancers of the head andneck based on the results of multiple randomized trials that have docu-mented a survival benefit (Table 1). Chemoradiation appears to confer asurvival benefit over RT alone in both the “unresectable” setting as well asthe postoperative setting.

The first large head and neck cancer trial documenting a survival bene-fit to concurrent chemoradiation was the Intergroup 0099 nasopharynxcancer trial (12). This trial randomized patients to 70 Gy of RT alone withor without three cycles of concurrent cisplatin followed by three cycles of



Table 1.

Selected Randomized Chemoradiation versus Radiation AloneTrials for Head and Neck Squamous Cancer

Trial (Reference) Agents

No. of Patients

Chemo-therapy Schedule Site

Radiation Therapy

Definitive chemoradiation trials

Adelstein et al. (15)

Cisplatin 295 3

×

Multiple qd

Al-Sarraf et al. (12)

Cisplatin 193 3

×

Naso-pharynx

qd

Brizel et al. (20)

Cisplatin + 5-FU

116 2

×

Multiple bid

Denis et al. (14)

Carbopla-tin + 5-FU

226 3

×

Orophar-ynx

qd

Forastiere et al. (RTOG 91-11) (10)

Cisplatin 547 3

×

Larynx qd

Jeremic et al. (27)

Cisplatin or carbo-platin

159 Daily Multiple bid

Postoperative chemoradiation trials

Cooper et al. (17) (RTOG 95-01)

Cisplatin 495 3

×

Postopera-tive

qd

Bachaud et al. (28)

Cisplatin 83 Weekly Multiple qd

Bernier et al. (16) (EORTC 22931)

Cisplatin 334 3

×

Postopera-tive

qd

bid, twice daily; 5-FU, 5-fluorouracil; qd, once daily.



Table 1.

Selected Randomized Chemoradiation versus Radiation AloneTrials for Head and Neck Squamous Cancer (Continued)

ResectableFollow-Up

Local Control

Disease- FreeSurvival

Overall Survival

Distant Metastases

Definitive chemoradiation trials

No 3 y — — 23% vs. 37%;

P

= .014

18% vs. 22%; not signifi-cant

— 3 y — 24% vs. 69%;

P

<.001

47% vs. 78%;

P

<.005

10% vs. 2%;

P

not given

Both 3 y 44% vs. 70%

— 34% vs. 55%;

P

= .07

18% vs. 27%;

P

not given

— 5 y 25% vs.

48%;

P

= .002

15% vs. 27%;

P

= .01

16% vs.

22%;

P

= .05


Yes 2 y 70% vs. 88%;

P

<.001

— No differ-ence

16% vs. 8%;

P

= .03

No 5 y — 27% vs. 51%;

P

= .018

25% vs.

46%;

P

= .007

43% vs. 14%;

P

= .0013

Postoperative chemoradiation trialsYes 3.8 y 72% vs.

82%; P = .01

— No differ-ence


Yes 5 y 59% vs. 77%; P = .08

23% vs. 45%; P <.02

13% vs. 36%; P <.01


Yes 3 y 69% vs. 82%; P = .007

41% vs. 59%; P = .0014

41% vs. 65%; P = .0096




adjuvant cisplatin and 5-FU. The addition of chemotherapy led to signifi-cant improvements in local control, reduction in distant metastases, andimproved 3-year overall survival (78% vs. 47%, P = .005).

In regard to oropharynx cancer, Calais et al. (13) and Denis et al. (14)randomized 226 patients to 70 Gy of RT with or without three cycles ofconcurrent cisplatin and 5-FU. Five-year local control (48% vs. 25%), dis-ease-free survival (27% vs. 15%), and overall survival (22% vs. 16%)were significantly improved with the addition of chemotherapy. Rates ofgrade 3 and 4 mucositis were increased in the chemotherapy arm (71% vs.39%) primarily due to the addition of 5-FU, a potent potentiator of radia-tion mucositis. The publication of this trial in 1999 was particularlyimportant because an accompanying editorial suggested that chemoradia-tion should become an accepted standard of care for patients with locallyadvanced non-metastatic head and neck cancer (3).

Adelstein and colleagues (15) randomized 295 patients in an intergroupstudy with non-nasopharyngeal head and neck squamous cell carcinomas,primarily cancers of the oropharynx, to either 70 Gy continuous daily RTalone, 70 Gy continuous daily RT with three cycles of concurrent cisplatinchemotherapy, or 70 Gy split-course RT with three cycles of concurrent cis-platin. Split-course RT has long been known to be an inferior fractionationschedule for head and neck cancers due to the repopulation of tumor duringthe treatment break, although it does result in less toxicity, primarily muco-sitis. Nevertheless, a hypothesis of this trial was that the loss of efficacy ofsplit-course RT could be overcome with the addition of concurrent chemo-therapy, and the time of break allowed for surgical evaluation of patientswhose tumors were previously considered “unresectable.” At 3 years, over-all survival was significantly improved with continuous once-daily RT andconcurrent cisplatin (37%) compared to RT alone (23%), whereas the over-all survivals between the split-course RT/chemotherapy arm and the RT-alone arm were not statistically different at 27% and 23%, respectively.

The RTOG 91-11 trial (10,11) has already been discussed in the pre-ceding section, but it also documented a local control and larynx preserva-tion benefit to concurrent chemoradiation in larynx cancer. The lack of asignificant survival benefit to concurrent chemotherapy and induction che-motherapy in larynx cancer is noteworthy and may be related to the factthat local failures are more readily salvaged with laryngectomy as opposedto other head and neck sites.

In the postoperative setting, it is important to note that the EuropeanOrganisation for Research and Treatment of Cancer (EORTC) 22931 trial(16) documented significant improvements in local control, disease-freesurvival, and overall survival with chemoradiation over RT alone. TheRTOG 95-01 trial (17) documented improvements in local control and



disease-free survival but was not powered to demonstrate, nor did it show,a significant difference in overall survival. A pooled analysis of EORTC22931 and RTOG 95-01 was performed (18) and found that the additionof cisplatin to postoperative RT improved outcomes for patients withmicroscopically involved resection margins or extracapsular spread oftumor from neck nodes. Concurrent chemoradiation should be consideredthe standard of care in patients with these characteristics in the postopera-tive setting.

Cisplatin-based chemotherapy regimens have been used in all concur-rent chemotherapy protocols to date and have found favor due to cis-platin’s activity, the ability to deliver it as a single agent in full dose withRT, and because it adds relatively little to stomatitis and radiation mucosi-tis compared to other agents (19).

Compared to concurrent chemoradiation, there does not appear to bean effect on overall survival with radiation dose escalation alone in headand neck cancer. Brizel et al. (20) showed no difference in overall survivalwith higher-dose hyperfractionated RT alone to 75 Gy versus similarlyfractionated RT to 70 Gy but with concurrent cisplatin and 5-FU. In fact,local control remained improved with the chemoradiation regimen (70%)versus the radiation dose-escalation regimen (44%). This is similar to theesophageal cancer literature. The RTOG 85-01 trial (21) randomizedpatients with esophageal cancer to 50 Gy of RT with two cycles of concur-rent cisplatin/5-FU versus RT alone to a higher dose of 64 Gy. The 5-yearoverall survival favored the chemotherapy arm at 26% versus 0% for theRT-alone arm.

There remains little consensus regarding the optimal RT fractionationregimen when concurrent chemoradiation is used. To date, most concur-rent chemoradiation protocols have used once-daily fractionation regi-mens using 2 Gy per day to doses of approximately 70 Gy. There havebeen documented improvements in local control with altered fraction-ation regimens using RT alone. The RTOG 90-03 trial (22) showedimproved local control with hyperfractionation (1.2 Gy bid to 81.6 Gy)and accelerated fractionation with concomitant boost (1.8 Gy once daily,with a second daily fraction of 1.5 Gy administered toward the end ofRT as a “boost” to 72 Gy) compared to standard 2-Gy fractions per dayto 70 Gy.

Nevertheless, it is unclear as to whether there is a benefit to alteredfractionation in the setting of concurrent chemoradiation. The RTOG 99-14 trial (23) addressed this question in a phase II trial that used the con-comitant boost fractionation schedule (72 Gy/6 weeks) with two cycles ofconcurrent cisplatin. Outcomes were favorable with acceptable toxicity;local control was 65%, which compares favorably to a local control rate



of 54% found in the concomitant boost RT-alone arm of RTOG 90-03(22). Overall survival in RTOG 99-14 was 71.6%, which also comparesfavorably to the 50.9% overall survival seen in RTOG 90-03 with con-comitant boost RT alone. Obviously, a direct comparison of outcomebetween these two trials is inappropriate from a statistical standpoint;however, the RTOG completed accrual in the summer of 2005 for a phaseIII trial comparing standard fractionation chemoradiation with alteredfractionation (concomitant boost) chemoradiation (RTOG H01-29). Botharms are to receive concurrent cisplatin chemotherapy; two cycles for thealtered fractionation arm due to the shortened treatment time and threecycles for the standard fractionation treatment arm. The goal of this trial isto determine a fractionation standard for all subsequent concurrent chemo-radiation trials.

It is clear that aggressive altered fractionation regimens combined withcertain chemotherapy agents can result in unacceptable toxicity. A trial byStaar and colleagues (24) randomized patients to accelerated concomitantboost RT to 69.9 Gy with or without two cycles of carboplatin and 5-FU.There was no difference between the two groups in regard to local controlor overall survival. However, there was significantly more grade 3 and 4mucositis in the chemoradiation arm (68% vs. 52%) and significantlyhigher rates of gastrostomy tube dependence due to dysphagia (51% vs.25%). RTOG 90-03 documented higher rates of acute and late toxicitywith altered fractionation, and these appear to have been exacerbated bythe administration of concurrent cisplatin and 5-FU.

In general, most trials of concurrent chemoradiation have not docu-mented reductions in the rates of distant metastases with the addition ofconcurrent chemotherapy to RT (see Table 1). As a result, the survival ben-efit imparted by chemotherapy is primarily due to improvements in localcontrol.

Induction Chemotherapy Followed by Chemoradiation

An intriguing approach to the integration of neoadjuvant chemotherapy inthe treatment of head and neck cancer is the use of induction chemother-apy followed by concurrent chemoradiation; an approach that has notbeen tested in prior randomized trials. This approach addresses the risk ofsystemic micrometastases with the neoadjuvant portion of treatment,whereas the issue of local control is addressed directly with the concurrentportion of treatment. A recent study comparing two different inductionregimens (docetaxel plus cisplatin and 5-FU [TPF] vs. PF) followed by sim-



ilar concurrent chemoradiation, did show an improvement in overall sur-vival favoring the TPF arm (25). Although this suggests that more activeinduction regimens can affect survival, the incremental benefit of the use ofinduction chemotherapy before chemoradiation is still unknown andunder investigation. This approach has been piloted in several phase II tri-als, and there are now at least three ongoing phase III trials comparingchemoradiation alone to the addition of induction therapy.

Chemoradiation Regimens

It is clear that chemoradiation imparts an increase in both early and latetoxicities compared with RT alone. In particular, mucositis and long-termgastrostomy tube dependence secondary to dysphagia have emerged asmajor dose-limiting toxicities for chemoradiation (26). It is also clear thatsingle-agent cisplatin (100 mg/m2 every 3 weeks) appears to be relativelywell tolerated and has demonstrated improvements in overall survival dur-ing rigorous testing in multiple phase III trials conducted by various aca-demic and community practices. This regimen has, therefore, been adoptedby the RTOG as their standard reference regimen.

Most trials of concurrent chemoradiation have used high-dose cisplatin(100 mg/m2 every 3 weeks). This approach achieves a relatively high sys-temic dose exposure that may address subclinical micrometastases whilestill providing some radiosensitization. Alternatively, some trials have usedlow-dose weekly regimens due to the understanding that survival benefitswith chemoradiation are primarily due to improvements in local control.Low-dose weekly regimens provide more opportunity for tumor radiosen-sitization on this basis. In addition, toxicity may be more easily managedwith weekly regimens through the use of short chemotherapy breaks with-out RT breaks, and weekly regimens may also result in less systemic toxic-ity for some patients. Jeremic et al. (27) used cisplatin at a dose of 6 mg/m2

daily (total, 30 mg/m2/week) and did document a survival benefit and, sur-prisingly, a reduction in distant metastases, leading many to favor a weeklydose of 30 mg/m2. In the postoperative setting, Bauchaud et al. (28) gave afixed dose of 50 mg weekly, which also translates to approximately 30 mg/m2/week and offers further support for this dose as a reasonable choice forweekly cisplatin regimens, though it has not been confirmed in additionalprospective trials. Nonetheless, the RTOG has accepted its use in at leastone postoperative trial currently under way and also when combined withcetuximab (RTOG 0234). Single-agent carboplatin with a weekly areaunder the curve (AUC) dose of 1.5–2.0 was also used by Jeremic et al. (27)and found to be well tolerated with no difference in efficacy compared to



cisplatin at 6 mg/m2/day. A randomized phase II trial from Japan (29)compared daily cisplatin at 4 mg/m2/day and carboplatin at 100 mg/m2

and found that outcomes were improved in the carboplatin arm; however,the authors acknowledged that this may have been due to the low doses ofcisplatin used in the trial.

Concurrent chemoradiation with platinum agents and 5-FU was usedby Calais et al. (13) and Brizel et al. (20) with good results. The dose of 5-FU in both of these trials was 600 mg/m2 every 3 weeks given with eithercarboplatin or cisplatin, respectively. This regimen is highly active whenused in the neoadjuvant and metastatic setting; however, the overlappingtoxicities of stomatitis and mucositis with concurrent RT are substantial(30,31). Based on the preceding efficacy data, the RTOG has selected con-current cisplatin at 100 mg/m2 every 3 weeks as a standard arm becausethis regimen is thought to provide the best balance of efficacy and tolera-bility. It is realized, however, that selected institutions are proficient instewarding patients through the increased toxicity of concurrent cisplatinand 5-FU regimens.

There is increased interest in using taxanes in concurrent chemoradia-tion regimens; however, this approach is still being investigated in thephase III setting. The greatest experience is with paclitaxel. Doses of 30mg/m2/week can be delivered without necessitating unscheduled treatmentinterruptions or dose reductions (32,33). Doses of paclitaxel can be esca-lated further; however, unscheduled treatment interruptions and dosereductions are necessary (34). It also appears that cisplatin at an AUC of 2/week (35) can be added to paclitaxel without significant additional toxic-ity. The combination of concurrent weekly cisplatin (20 mg/m2) andweekly paclitaxel (30 mg/m2) was tested by the RTOG in a randomizedphase II trial (97-03) (36) that compared the preceding regimen to twoother arms consisting of 5-FU/cisplatin and 5-FU/hydroxyurea given onsomewhat nontraditional schedules. The best 2-year disease-free survivaland overall survival rates (51% and 67%, respectively) were found for thecisplatin/paclitaxel arm, although all three arms had superior outcomeswhen compared to historical controls treated with concurrent cisplatinand RT alone. Docetaxel is also highly active in head and neck cancers(37). There are no randomized trials investigating this agent administeredconcurrently with RT, but docetaxel (15 mg/m2/week) and cisplatin (20mg/m2/week) have been combined with accelerated concomitant boost RTin a clinical trial (38). In the neoadjuvant setting, three trials were pre-sented in 2006 documenting a benefit to adding docetaxel to cisplatin and5-FU (Table 2).

Other than the preceding, no other agents or drug schedules have beensufficiently investigated to be considered reasonable options for combination


11

Tab

le 2

.Se

lect

ed R

ando

miz

ed T

rial

s of

Tax

anes

in N

eoad

juva

nt C

hem

othe

rapy

Tri

al

(Ref

eren

ce)

Sche

ma

No.

of

Pat

ient

sSc

hed

ule

Site

RT

Follo

w-

Up

Dis

ease

-Fr

ee

Surv

ival

Ove

rall

Surv

ival

Ver

mok

en

(EO

RTC

24

971)

(6

0)

Doc

etax

el/

cisp

latin

/5-

FU v

s.ci

spla

tin/5

-FU

385

Indu

ctio

n fo

llow

ed

by R

T

alon

e

Mul

tiple

70–7

4 G

y co

n-ve

ntio

nal

or h

yper

-fr

actio

n-at

ed

3 y

Med

ian,

32

mo:

8.2

m

o vs

. 11

mo;

P =

.0

071

Med

ian,

51

mo:

14.

2 m

o vs

. 18

.6 m

o;

P =

.005

2T

ax 3

24

(25)

Doc

etax

el/

cisp

latin

/5-

FU v

s.ci

spla

tin/5

-FU

501

Indu

ctio

n fo

l-lo

wed

by

conc

urre

nt

chem

o-th

erap

y/RT

Mul

tiple

70 G

y co

nven

-tio

nal

3 y

49%

vs.

37

%; P

=

.004

62%

vs.

48%

; P

= .0

058

GO

RTE

C

2000

–01

(61)

Doc

etax

el/

cisp

latin

/5-

FU v

s.ci

spla

tin/5

-FU

220

Indu

ctio

n fo

llow

ed

by R

T

alon

e

Lary

nx a

nd

hypo

-ph

aryn

x

70 G

y co

nven

-tio

nal

3 y

Lary

ngec

-to

my-

free

su

rviv

al:

80%

vs.

58

%

—

5-FU

, 5-f

luor

oura

cil;

RT, r

adia

tion

ther

apy.



with RT in the noninvestigational setting. Gemcitabine is a potent radio-sensitizer but induces significant mucositis, dysphagia, and aspiration (39).

Appropriate Selection of Patients for Chemoradiation in Head and Neck Cancer

Locoregional control of advanced head and neck cancer can exceed 70% withconcurrent chemoradiation approaches (6,10,11,13,16,18,20,28). However,with the reduction in mortality associated with improved control of locore-gional disease above the clavicles, reduction of the competing risk of deathfrom distant metastases becomes increasingly relevant. The overall rate of dis-tant metastases may exceed 40% in patients with N3 lymphadenopathy (40).Vokes and colleagues (41) have referred to this phenomenon of an increase indistant failure in patients who achieve locoregional control of disease as a“reversal of the historical pattern of failure” in which, historically, local failureat the primary tumor site exceeded the incidence of distant metastases.

Therapeutic approaches currently available for patients with locallyadvanced head and neck cancers include the following:

1. Surgical resection followed by postoperative RT with or without chemotherapy, depending on the presence of high risk factors (primarily extracapsular spread of nodal disease or microscopically positive margins) (18)

2. Concurrent chemoradiation with surgical salvage if necessary3. Altered fractionation RT alone with surgical salvage if necessary

With these three options in mind, it is important to remember that thegoal of the multidisciplinary team in assigning patients to appropriatetherapy should be to maximize the projected tumor control probabilitywhile preserving function, structure, and cosmesis.

Patients with locoregionally confined head and neck cancer can be roughlydivided into three groups from least to most aggressive:

Early stage: T1 or favorable T2 primary tumorsN0–N1 lymphadenopathyM0

Intermediate stage: Unfavorable (infiltrative) T2 or favorable (exophytic) T3 primary tumorsN0–N1 lymphadenopathy M0



Advanced stage: Unfavorable (infiltrative) T3 primary tumorsT4 primary tumorsN2 or N3 lymphadenopathyM0

The boundaries between these groups are obviously vague, but neverthelessdo provide some framework for assigning patients to appropriate therapy. Theterms “favorable” and “unfavorable” are traditional terms used to describethe appearance and behavior of primary head and neck tumors. Favorabletumors appear exophytic with lower tumor volume and clearly demarcatedboundaries on physical examination, whereas unfavorable tumors appearinfiltrative and ulcerated with higher tumor volume and vague demarcation onexamination. This distinction has been shown to be relevant to tumorresponse in clinical trials in which exophytic tumors responded more favor-ably to RT than those that were ulcerative or endophytic (42). Patients withearly stage disease have a risk of distant metastases of generally less than 10%,and locoregional control with RT alone (either standard fractionation oraltered fraction) is often in excess of 80%. As a result, the use of chemora-diation in this subset of patients may not be required and is not presently sup-ported by the literature. Patients with advanced stage disease have localcontrol rates of only 40%–60% when treated with RT alone and rates of dis-tant metastases of 30%–40%. Chemoradiation improves overall survival byapproximately 10%–15% or more in this subset of patients, and as a resultshould be considered the standard of care.

The greatest area of controversy in regard to selection of therapy lies, notsurprisingly, with the intermediate stage patients and in patients who are noteasily classified into the above categories. Most chemoradiation protocols inhead and neck cancer that have documented a benefit to concurrent chemora-diation have included patients with American Joint Committee on Cancer(AJCC) stage III or IV disease. However, this is a heterogeneous group ofpatients that includes patients with small T1/T2 N1 tumors, as well as thosewith large T3/ T4 N2/ N3 tumors. Mendenhall and colleagues (43) used thepreceding criteria to describe a favorable subset of patients with AJCC stageIV laryngeal cancer who had excellent outcomes with altered fractionation RTalone. These patients in general had advanced primary tumors but limitednodal disease.

In particular, there is controversy as to whether patients with small (T1/T2) primary tumors but advanced nodal disease derive a benefit from themore toxic chemoradiation approaches, despite being technically classifiedas stage III or IV. A recent retrospective review by Garden et al. (44) ana-lyzed 299 patients with oropharyngeal Tx, T1, or T2 primary disease andN1, N2, or N3 nodal disease (i.e., patients with small primary tumors who



are classified as AJCC stage III or IV due to nodal disease and not due toadvanced primary disease) treated at the University of Texas M.D. Ander-son Cancer Center. All patients received RT alone, either conventionallyfractionated or via altered fractionation regimens, without chemotherapy.This study found that locoregional control with RT alone was 95% forpatients with Tx–T1 tumors, regardless of nodal stage, and 79% forpatients with T2 tumors, regardless of nodal stage. The 5-year rate of dis-tant metastases for patients with N1/2a disease was 11%, compared with28% for patients with N2b/N2c/N3 disease. The 5-year actuarial diseaserecurrence–free survival rate for patients with T1/Tx disease was 80%,compared with 67% for patients with T2 disease. The 5-year overall sur-vival rate for the entire cohort was 64%. These results compare quitefavorably with the results of the numerous phase III trials of chemoradia-tion (see Table 1), and the authors conclude that local treatment intensifi-cation by the addition of concurrent chemotherapy to RT would notsignificantly benefit this subset of patients. Nevertheless, these patients arestill at risk for the development of distant metastatic disease; however, therole of neoadjuvant or adjuvant chemotherapy or biotherapy approachesthat address this risk is still unclear and is being evaluated in clinical trials.

It is important to remember that definitive concurrent chemoradiationin head and neck cancer primarily improves survival through improve-ments in locoregional control. As a result, advanced T stage is a more accu-rate predictor of which patients are at high risk for local failure and willthus benefit most from concurrent chemoradiation approaches. The pres-ence of advanced nodal disease is a more accurate predictor for the risk ofneck failure and distant metastases and should be used in determiningwhich patients should receive therapy directed at reducing such. Also, con-current chemoradiation has been beneficial for postoperative patients withadvanced nodal disease—namely, those with extracapsular spread. Thepreceding discussion highlights the need for treatment decisions to movebeyond simple tumor/node/metastasis stage groupings and evaluate indi-vidual tumor, patient, and treatment factors.

Selection Factors for Chemoradiation

There can be great heterogeneity in prognosis between different tumorsites and subsites in the head and neck that is not adequately reflected bythe present AJCC staging system. Stage for stage, tumors of different sitescan have widely differing prognoses. For example, 5-year overall survivalwith RT alone for T2 cancers of the glottic larynx is in excess of 90% (45),whereas it is only 52% for patients with T1–T2 hypopharyngeal cancers



(46). Even among tumors arising in the same site, there can be significantvariability among tumors of the same stage according to growth pattern.For tumors of the base of the tongue, as noted, Weber and colleagues (47)reported a 2-year rate of local control of 84% for exophytic tumors and58% for ulcerative/infiltrative tumors. Impairment of function also pre-dicted poorer outcome in this report. In general, patients with non-bulkyT1/T2 tumors or T3 tumors with “favorable” growth patterns can be suc-cessfully managed with RT alone, either standard or altered fractionation,as appropriate. Chemoradiation should be considered as standard formore advanced tumors. At the present time, tumor-related selection fac-tors for the treatment of head and neck cancers rely primarily on clinicalevaluation of tumor size, growth pattern, and organ compromise. In thefuture, biologic and molecular tumor markers that predict for outcomewith various therapies will be developed (48).

Although the preceding discussion has concentrated on the use of RT asthe primary modality to achieve local control in head and neck cancers, itis important to acknowledge that in some cases surgical resection may bepreferable to definitive RT. For patients with early stage head and neckcancers, RT or surgery results in similar rates of local control, but with verydifferent functional-, cosmetic-, and treatment-related morbidities. Forexample, many patients with early stage oral cavity cancers are preferen-tially treated with surgery to avoid the morbidity of RT-induced xerosto-mia and the increased risk of soft tissue and bone injury (49). In particular,early (T1/T2) cancers of the oral cavity can achieve excellent local controlwith surgery alone while preserving function if techniques such as hemi-glossectomy are used. Patients with larger oral cavity tumors or patientswith adverse pathologic findings, such as perineural invasion, positivemargins, or more than one involved cervical lymph node, benefit from theaddition of adjuvant RT to improve local control (50,51).

In laryngeal cancer as well, surgical resection may be preferable inselected cases. Adequate baseline organ function is a prerequisite for func-tional organ preservation. For instance, the use of chemoradiation in thecase of a locally advanced T3 or T4 laryngeal tumor in a patient with com-promised swallowing function and significant evidence of aspiration onbaseline examination is probably an exercise in futility, as the patientwould have a high likelihood of requiring toilet laryngectomy for progres-sive aspiration post-therapy (52) as well as a high likelihood of gastros-tomy tube dependence due to progressive dysphagia post-therapy. Thesepatients are better served with laryngectomy, as there is little baseline func-tion to preserve. With the publication of the pooled analysis of RTOG9501 and EORTC 22931 (18), there appears to be a benefit to the additionof concurrent chemotherapy to RT in the postoperative setting for patients



with adverse pathologic features. The blind adherence to organ-preservingapproaches in head and neck cancer without full recognition of the base-line and post-therapy function is not in the patient’s long-term best inter-est. It is important to remember that tumor-related dysfunction andtreatment-imposed dysfunction both contribute equally to long-term func-tional outcome. Adequate baseline organ function is a prerequisite forfunctional organ preservation with chemoradiation.

Patients bring a multitude of preferences and preconceptions to thetable when selecting cancer treatment. These preferences are influenced,among other things, by level of education, socioeconomic status, socialsupport, religious views, and experience with the health care system. It isimportant that all members of the treatment team establish a partnershipwith the patient that takes all of the preceding factors into account whenselecting a mutually agreeable treatment plan. Nevertheless, it is incum-bent on physicians to provide a balanced view during the education ofpatients regarding the benefits of intensive curative therapy and its atten-dant risks and toxicities. Obviously, patient preference after a discussionof the preceding ultimately forms the basis of the mutually agreed on treat-ment plan.

In addition to reliability, social support, and the means to comply withtherapy and follow-up, patients must have adequate performance statusand functional reserve, as well as the psychological make-up to tolerateaggressive cancer therapies. Different chemoradiation regimens have aspectrum of toxicities. A specific regimen may be appropriate for a robust,high-performance status patient with significant physiological reserve, butnot for one more physiologically compromised. It is, therefore, critical thatphysicians are familiar with the acute and chronic treatment-related toxic-ities for specific therapeutic regimens so that informed recommendationsare based on expected patient tolerance.

The experience of individual physicians with the treatment of head andneck cancers is important when selecting patients for chemoradiation.Chemoradiation requires close collaboration and communication amongall members of the multidisciplinary team that should include physiciansfrom head and neck surgery, radiation oncology, medical oncology, radiol-ogy, pathology, and dental oncology. In addition, input from allied healthproviders from nutrition and speech and swallowing therapy is also neces-sary if outcomes are to be optimized in these complex patients. The lack ofany of the above components can significantly hinder the optimal treat-ment of the head and neck cancer patient, and, as a result, facilities with-out the necessary expertise in the preceding disciplines should probablyconsider referral of head and neck cancer patients to a tertiary facility withthe necessary expertise.



The importance of expertise in every component of the multidisci-plinary care team is exemplified in a study conducted at a tertiary careinstitution evaluating the reinterpretation of computed tomography andmagnetic resonance imaging by an expert head and neck radiologist onpatients referred with head and neck cancer. This showed a change ininterpretation in approximately one-half of cases that resulted in changesin treatment recommendation for nearly all patients in this group (53).

Even within disciplines, the collaborative review of patient treatmentplans can improve the quality of care in patients with head and neck can-cer. At the University of Texas M.D. Anderson Cancer Center, the RTtreatment plans are reviewed in a biweekly intradisciplinary conferenceattended by all radiation oncologists who treat head and neck cancers,during which patients are physically present and examined by all physi-cians in attendance. A review of the recommendations of 134 patients pre-sented at this conference found that peer review led to changes intreatment plans for 66% of patients. Most changes were minor, but 11%of changes were major and thought to be of a magnitude that could poten-tially affect therapeutic outcome or normal tissue toxicity. Most changesinvolved target delineation based on physical findings (54).

Conclusion

Chemoradiation for locally advanced head and neck cancer has been exten-sively investigated since the 1980s. The randomized data clearly documentimprovements in both locoregional control and overall survival with concur-rent chemoradiation compared to identical RT regimens given without che-motherapy for appropriately selected patients. However, improvements inoutcome with concurrent chemoradiation are achieved at the expense ofincreased acute and late toxicities, including dysphagia and aspiration (55).Despite hundreds of clinical trials involving thousands of patients on the sub-ject, there remains no definitive standard regarding patient selection forchemoradiation approaches, the appropriate radiation fractionation schedule,which chemotherapy agents to use, or the optimal chemotherapy schedule.

Nevertheless, based on a thorough review of the literature, we proposethe following general guidelines for the use of concurrent chemoradiationin head and neck cancers:

• Patients with T1 and favorable T2 tumors with N0 or N1 lymphad-enopathy achieve excellent local control with once-daily RT alone.

• Patients with unfavorable T2 or exophytic T3 tumors with N0 orN1 lymphadenopathy are well served with altered fractionation



schedules of RT alone based on the consistent finding that locore-gional control is improved without appreciable increase in late tox-icity for this group of patients. Survival in these patients is primarilydependent on achieving locoregional control, as there is minimalrisk for distant micrometastases.

• Although contentious, patients with T1 or T2 tumors with N2 or N3lymphadenopathy achieve excellent control with RT alone, with neckdissection for residual neck disease or consideration for planned neckdissection, especially in non-oropharynx cancer patients (56–59).Given the rather high risk of distant metastases in these patients, thispopulation is ideally suited for testing the efficacy of sequential (adju-vant or neoadjuvant) chemoradiation, with the goal of improvingsurvival.

• Patients with unfavorable T3 and T4 tumors with N2 or N3 lym-phadenopathy are ideally suited for treatment with concurrentchemoradiation.

• Patients with stage III or IV head and neck cancer treated with surgerywho have evidence of extracapsular spread of tumor from lymph nodesor microscopically involved resection margins have improved survivalwith adjuvant concurrent chemoradiation approaches based on theresults of a pooled analysis of two adjuvant chemoradiation trials (18).

In regard to the specifics of chemoradiation schedules, we suggest thefollowing:

• Neoadjuvant, or induction, chemotherapy is no longer consideredstandard treatment for larynx cancer.

• For non-laryngeal, locally advanced primary tumors of the head andneck (primarily oropharynx and nasopharynx), concurrent cisplat-inum (100 mg/m2 every 3 weeks) and conventionally fractionatedRT (70 Gy at 2 Gy per fraction) has been shown to improve overallsurvival in multiple randomized trials and is the most commonlyaccepted, but not exclusive, standard of care.

• In the non-investigational setting, the role of altered fractionationregimens (twice-daily RT or accelerated concomitant boost RT) com-bined with concurrent chemotherapy remains unclear. The results ofthe now closed RTOG H-0129 trial are maturing and should helpanswer this question.

• Lower-dose, weekly concurrent chemotherapy regimens provideradiosensitization and improve locoregional control, but in generalhave less effect in preventing distant metastases. Emerging regimensinclude carboplatin alone (AUC = 1.5–2.0), paclitaxel alone (30 mg/m2/week) or combined paclitaxel (30 mg/m2/week) with either cis-



platin (20 mg/m2/week) or carboplatin (AUC = 1.5–2.0). The pre-ceding regimens have been tested in phase II, but have not beenvalidated in the phase III setting.

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35. Moosmann P, Egli F, Stahel RA, Jost L. Weekly paclitaxel and carboplatincombination chemotherapy in patients with advanced squamous cell carci-noma of the head and neck. Onkologie 2003;26(6):568–572.

36. Garden AS, Harris J, Vokes EE, et al. Preliminary results of Radiation TherapyOncology Group 97-03: a randomized phase II trial of concurrent radiationand chemotherapy for advanced squamous cell carcinomas of the head andneck. J Clin Oncol 2004;22(14):2856–2864.

37. Glisson BS, Murphy BA, Frenette G, et al. Phase II trial of docetaxel and cis-platin combination chemotherapy in patients with squamous cell carcinoma ofthe head and neck. J Clin Oncol 2002;20(6):1593–1599.

38. Glisson BS, Garden AS, Kies MS, et al. Phase I study of docetaxel (D), cisplatin(P), and concomitant boost radiation for patients with locally advanced squa-mous cancer of the head and neck (SCHN). J Clin Oncol 2003;22(500):abstr.

39. Eisbruch A, Shewach DS, Bradford CR, et al. Radiation concurrent with gem-citabine for locally advanced head and neck cancer: a phase I trial and intra-cellular drug incorporation study. J Clin Oncol 2001;19(3):792–799.

40. Brockstein B, Haraf DJ, Kies MS, et al. Distant metastases (DM) after concomitantchemoradiotherapy (CRT) for head and neck cancer (HNC): risk dependant uponpretreatment lymph node (LN) stage. Proc Am Soc Clin Oncol 2000;19:abstr 1635.

41. Vokes EE, Kies MS, Haraf DJ, et al. Concomitant chemoradiotherapy as pri-mary therapy for locoregionally advanced head and neck cancer. J Clin Oncol2000;18(8):1652–1661.

42. Ang KK, Peters LJ, Weber RS, et al. Concomitant boost radiotherapy schedulesin the treatment of carcinoma of the oropharynx and nasopharynx. Int JRadiat Oncol Biol Phys 1990;19(6):1339–1345.

43. Mendenhall WM, Parsons JT, Million RR, et al. A favorable subset of AJCCstage IV squamous cell carcinoma of the head and neck. Int J Radiat OncolBiol Phys 1984;10(10):1841–1843.

44. Garden AS, Asper JA, Morrison WH, et al. Is concurrent chemoradiation thetreatment of choice for all patients with stage III or IV head and neck carci-noma? Cancer 2004;100(6):1171–1178.

45. Mendenhall WM, Parsons JT, Stringer SP, et al. T1–T2 vocal cord carcinoma: abasis for comparing the results of radiotherapy and surgery. Head Neck Surg1988;10(6):373–377.



46. Garden AS, Morrison WH, Clayman GL, et al. Early squamous cell carcinomaof the hypopharynx: outcomes of treatment with radiation alone to the pri-mary disease. Head Neck 1996;18(4):317–322.

47. Weber RS, Gidley P, Morrison WH, et al. Treatment selection for carcinoma ofthe base of the tongue. Am J Surg 1990;160(4):415–419.

48. Lydiatt WM, Schantz SP. Biological staging of head and neck cancer and itsrole in developing effective treatment strategies. Cancer Metastasis Rev1996;15(1):11–25.

49. Fein DA, Mendenhall WM, Parsons JT, et al. Carcinoma of the oral tongue: acomparison of results and complications of treatment with radiotherapy and/or surgery. Head Neck 1994;16(4):358–365.

50. Whitehurst JO, Droulias CA. Surgical treatment of squamous cell carcinoma ofthe oral tongue: factors influencing survival. Arch Otolaryngol 1977;103(4):212–215.

51. Rodgers LW, Jr., Stringer SP, Mendenhall WM, et al. Management of squamouscell carcinoma of the floor of mouth. Head Neck 1993;15(1):16–19.

52. Mancuso AA, Mukherji SK, Schmalfuss I, et al. Preradiotherapy computedtomography as a predictor of local control in supraglottic carcinoma. J ClinOncol 1999;17(2):631–637.

53. Loevner LA, Sonners AI, Schulman BJ, et al. Reinterpretation of cross-sectionalimages in patients with head and neck cancer in the setting of a multidisci-plinary cancer center. AJNR Am J Neuroradiol 2002;23(10):1622–1626.

54. Rosenthal DI, Asper JA, Barker JL, et al. Importance of patient examination toclinical quality assurance in head and neck radiation oncology. Sixth Interna-tional Conference on Head and Neck Cancer, 2004.

55. Rosenthal DI, Lewin JS, Eisbruch A. Prevention and treatment of dysphagiaand aspiration after chemoradiation for head and neck cancer. J Clin Oncol2006;24(17):2636–2643.

56. Clayman GL, Johnson CJ, 2nd, Morrison W, et al. The role of neck dissectionafter chemoradiotherapy for oropharyngeal cancer with advanced nodal dis-ease. Arch Otolaryngol Head Neck Surg 2001;127(2):135–139.

57. Lavertu P, Adelstein DJ, Saxton JP, et al. Management of the neck in a random-ized trial comparing concurrent chemotherapy and radiotherapy with radio-therapy alone in resectable stage III and IV squamous cell head and neckcancer. Head Neck 1997;19(7):559–566.

58. McHam SA, Adelstein DJ, Rybicki LA, et al. Who merits a neck dissectionafter definitive chemoradiotherapy for N2–N3 squamous cell head and neckcancer? Head Neck 2003;25(10):791–798.

59. Peters LJ, Weber RS, Morrison WH, et al. Neck surgery in patients with primaryoropharyngeal cancer treated by radiotherapy. Head Neck 1996;18(6):552–559.

60. Remenar E, Van Herpen C, Germa Lluch J, et al. A randomized phase III multi-center trial of neoadjuvant docetaxel plus cisplatin and 5-fluorouracil (TPF) versusneoadjuvant PF in patients with locally advanced unresectable squamous cell carci-noma of the head and neck (SCCHN). Final analysis of EORTC 24971. 2006ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2006;24(18s):abstr.

61. Calais G, Pointreau Y, Alfonsi M, et al. Randomized phase III trial comparinginduction chemotherapy using cisplatin (P) fluorouracil (F) with or withoutdocetaxel (T) for organ preservation in hypopharynx and larynx cancer. Pre-liminary results of GORTEC 2000-01. 2006 ASCO Annual Meeting Proceed-ings Part I. J Clin Oncol 2006;24(18s):abstr.


23CME

❖Evolving Role of Induction

Chemotherapy and Sequential Therapy in the Treatment of

Locally Advanced Squamous Cell Cancer of the Head and Neck


Treatment Options

The curative treatment of patients with locally advanced squamous cellcarcinoma of the head and neck (HNC) is extremely difficult for the gen-eral oncology clinician and is best met by a multimodality team of physi-cians with specific expertise. HNC patients frequently present to theirphysicians with advanced but still regionally localized disease. The inten-sity of therapy and the prognosis are governed both by the site and the vol-ume of disease. Advanced disease can be defined as either intermediatestage disease of a moderate prognosis with a 50%–75% 3-year survival oras advanced disease with a poor prognosis and an expected 20%–45% 3-year survival. Intermediate disease is usually stage III: T3/N0/M0 or T1–3/N1/M0, although stage II patients with large T2/N0 primary cancers alsofall into this prognostic category. More advanced patients present withstage IV disease: T4/N0–1/M0 or T1–4/N2–3/M0, which may or may notbe surgically resected but frequently are large (1).


24 Evolving Role of Induction Chemotherapy

Even the experienced clinician is faced with significant clinical challenges inmaking decisions regarding therapy. The treatment options are subject to con-siderable debate and differences of opinion. There is site-specific heterogeneityin biology, prognosis, and therapy; functional deficits from therapeutic choicescan be considerable and are part of the therapeutic assessment; and selectionof an appropriate treatment plan that suits the needs and condition of an indi-vidual patient can be difficult. Finally, increasingly aggressive nonsurgicaltherapy results in substantial acute and long-term toxicity that requires con-siderable physician management and experience. Nonetheless, treatment ofHNC is associated with increasing rates of cure, functional organ preserva-tion, and a changing demographic of younger, healthier patients, all of whichhave resulted in substantial improvements in outcome and clinical benefit.

History of Treatment

Therapeutic options have evolved slowly and incrementally since the 1970s.Initial enthusiasm for chemotherapy based on the amazing responsiveness andspectacular regressions of large tumors to induction chemotherapy wasreplaced by disappointment when cure and survival did not meet expecta-tions. Locoregional failure remained high, and research shifted to enhancinglocoregional control through optimizing radiation therapy and experimentingwith chemoradiotherapy. There have been small but important gains in out-comes as a result of these efforts. Improved radiation scheduling and the inte-gration of chemotherapy into radiation therapy have significantly improvedlocoregional control. However, the improvement in locoregional control hasbeen limited, and distant metastases have become an increasing sign of failure.Survival has improved, but gains have been modest.

Thus, despite several decades of progress and significant improvements intreatment and supportive care, the prognosis and disease-free survival forpatients with locally advanced HNC has remained poor. Since the 1990s,cisplatin-based combined modality treatment with chemoradiotherapy (CRT)has been the sole accepted standard of care for unresectable, locally advanceddisease and for organ preservation, although induction therapy is still acceptedand used by many physicians in North America and remains a standard inEurope (2,3). At 3 years after standard CRT, only approximately 55% and35% of patients with intermediate and advanced disease, respectively, willbe alive and disease free (2,4,5). Between 30% and 40% of patients willdevelop locoregional recurrences, and 20%–30% will develop distantmetastases. This continues to be a dismal outcome. Failure to control HNCoccurs via two biologically distinct pathways: local recurrence and meta-static spread.


Evolving Role of Induction Chemotherapy 25

Combined Modality Therapy

The debate regarding the optimal delivery of combined modality therapyhas continued unabated with regard to the scheduling and content of ther-apy. Three major approaches have been investigated: (a) primary inductionchemotherapy, or neoadjuvant therapy before definitive surgery and/orradiotherapy; (b) concomitant treatment with chemotherapy and radio-therapy (CRT); and (c) a new synthesis of induction chemotherapy andCRT, sequential chemotherapy (ST), consisting of induction chemotherapyfollowed by CRT (6).

Induction Chemotherapy

Metaanalysis of ResultsA reassessment of results from induction chemotherapy trials has beenprovided by metaanalysis, by recently reported updates and re-analysis ofolder trials with longer follow-up, and by the results of several recentlyreported phase III trials. Metaanalysis allows a broad review of diverseand heterogeneous trials that may not by themselves be sufficiently pow-ered to show an effect or may suffer from defects in performance thatreduce efficacy modestly and obscure significant differences. Metaanalysisreveals that although the general class of induction trials did not improvesurvival in patients with HNC compared to standard therapy, the subset ofinduction chemotherapy trials that used cisplatin/5-fluorouracil (PF) che-motherapy resulted in a 5% improvement in 5-year survival compared tostandard therapy (7). This difference was less substantial than the 8%improvement observed with CRT but was significant at P = .01. The inter-pretation of the results of metaanalysis of induction trials in general is con-founded by combining of non-PF and PF regimens, which are ineffectivecompared to PF, and by the substitution of carboplatin for cisplatin, whichis an inferior agent in the treatment of HNC (8,9).

Platinum/5-Fluorouracil ChemotherapyPF-based induction therapy was developed in the late 1970s and has beenstudied ever since. The notion that induction therapy could enhance curerates and functional organ preservation is rationally based on observationsthat PF chemotherapy resulted in marked shrinkage of tumors in patientswith advanced HNC. In organ preservation trials, PF therapy resulted in asignificant fraction of pathologically negative resections (10–12). Induc-tion chemotherapy is better tolerated than adjuvant therapy given postop-



eratively or to irradiated patients. Hence, higher doses and systemicallyactive treatment can be delivered to the treatment-naïve patient, which canenhance local responses and eradicate micrometastatic disease with lesstoxicity and acute morbidity. Furthermore, drug delivery is better inuntreated, well-vascularized tumors (13). The standard PF regimen com-bined bolus cisplatin and continuous infusion 5-fluorouracil (5-FU) over 5days. This was the most effective induction chemotherapy regimen and hasremained the gold standard in advanced HNC (14). Improved organ pres-ervation, reduced distant metastases, and significant improvements in sur-vival in PF-treated patients compared to control populations treated solelywith surgery and/or radiotherapy have been reported in four randomizedtrials (Table 1) (3,15–17). PF is highly effective in obtaining responses, andreported response rates have averaged 60%–80%, with complete responsesin 20%–30% of patients (3,15–20). Survival advantages, however, werehard to discern in the heterogeneous and complex trials associated withinduction chemotherapy.

Many of the studies with PF-based induction chemotherapy were per-formed in the early 1990s. Many trials also included resectable patients andunresectable patients and interposed surgery between induction therapy andradiotherapy. Although surgery could be avoided in larynx and hypopharynxpatients and a functional larynx preserved, local and regional failure remainedconsiderable, and survival in resectable patients was not enhanced. Thus, PF-based induction therapy has not been widely or formally accepted by thecooperative groups as a standard of care, although many practitioners in thecommunity and in academic centers continued to use PF in patients with veryadvanced cancers and as a means of organ preservation.

As mentioned, many early PF trials included resectable patients. Beforeorgan preservation was established as a standard of care, induction chemo-therapy trials frequently had surgery timed to occur between induction che-motherapy and radiotherapy. Performing definitive surgery or nodal orprimary site “salvage” surgery after induction chemotherapy but beforeradiotherapy negatively impacted on survival and diminished the impact ofinduction chemotherapy on survival in early induction chemotherapy stud-ies (6). After induction chemotherapy, the identification of the marginsbecomes difficult if not impossible. In addition, if the primary site is pre-served and the neck addressed separately, then residual, partially resistanttumor cells can repopulate the site, making subsequent radiotherapy lesseffective. Finally, in the majority of cases the surgical bed also contains resid-ual tumor cells scattered in the lymphatics that are partially resistant to ther-apy and can repopulate the region in an enhanced growth environmentwhile regional treatment with radiotherapy is delayed. This is evident in theStudio Trial in which patients were randomized to standard care or induc-



tion chemotherapy (21,22). Unresectable patients started radiotherapy imme-diately after induction PF, but resectable patients had surgery between PFand radiotherapy. Survival in the resectable patients was slightly worse afterPF and surgery than after surgery alone. On the other hand, PF led to a sig-nificant improvement in the survival of unresectable patients compared toradiotherapy, and the survival advantage was maintained for more than 10years (22). Thus, the proper sequencing of induction chemotherapy in thecombined modality therapy of HNC remains a major issue and obfuscatesthe value of induction chemotherapy. A second large trial by the Grouped’Etudes des Tumeurs de la Tête et du Cou (GETTEC), reported by Domengeet al. (3), confirmed these positive results for PF chemotherapy.

Table 1. Phase III Cisplatin/5-Fluorouracil (PF) Induction Trials

Study Treatment Follow-Up Results

Organ preservationVeterans Affairs

Larynx Trial PF, three cycles;

radiotherapy12 y Larynx preserved in

60% of survivors; no difference in survival; reduced distant metasta-ses with PF

EORTC Hypopharynx

PF, three cycles; radiotherapy

10 y Larynx preserved in 30% of survi-vors; survival equivalent; reduced distant metastases

SurvivalStudio Trial PF, four cycles;

surgery and/or radiotherapy

10 y Significant improvement in survival in unre-sectable patients; reduced distant metastases

GETTEC Oro-pharynx Trial

PF, three cycles; surgery and/or radiotherapy

5 y Significant improvement in survival

EORTC, European Organisation for Research and Treatment of Cancer; GETTEC, Groupe d’Etudes des Tumeurs de la Tête et du Cou.



Induction Chemotherapy in Resectable PatientsInduction chemotherapy does have a role in resectable patients, particularlyfor organ preservation and in patients with poor prognosis. Organ preserva-tion should be considered in the oropharynx, larynx, and hypopharynx topreserve swallowing and speech. In a phase III larynx preservation study, theVeterans Affairs Larynx Cancer Trial, larynx preservation was achieved inapproximately two-thirds of patients treated with PF, and the rate of distantmetastasis was decreased (17) compared to surgery. A study of pyriformsinus cancer performed by the European Organisation for Research andTreatment of Cancer (EORTC) also demonstrated an equivalent survivalbetween the chemotherapy and surgical arms, with organ preservationachieved in one-third of the patients (15). Both studies included primarilypatients with intermediate stage disease, and updates confirmed that theresults were maintained for 10 years or more.

Several studies attempted to replicate these data, but they were unsuccess-ful; most notably, a GETTEC trial that studied laryngeal cancer (23). This trialis difficult to interpret because it included few patients and had significantearly morbidity, which suggests poor patient selection and treatment monitor-ing. The study highlights a problem encountered with many early trials inHNC: the inclusion of patients with significant comorbidities who were inap-propriate for inclusion in clinical trials of aggressive treatments. Inclusion ofthese patients impedes the study of new therapies and impairs the treatment ofhealthier patients who would benefit from more intensive therapies.

Chemoradiotherapy

Comparisons with Induction ChemotherapyMore recently, induction chemotherapy for organ preservation has been com-pared to radiotherapy and to cisplatin-based CRT in the Intergroup 91-11trial (24,25). In the original study, CRT with bolus cisplatin led to greaterlaryngectomy-free survival than radiotherapy alone, without a significant lossof survival, and induction chemotherapy had an intermediate and nonsignifi-cant impact, compared to radiotherapy. Patients were predominantly of anintermediate stage, and advanced patients and hypopharynx sites were notentered. Thus, in this intermediate population in the initial report, CRTappeared to be a more efficient and potentially effective therapy than radio-therapy alone or induction chemotherapy. This study was recently updatedwith a 5-year follow-up (25). Laryngectomy-free survival was identical in thePF and the CRT arms, and both were significantly better than the radiother-apy arm (Table 2). Significantly more patients survived with an intact larynxin the PF and CRT arms than when treated with radiotherapy alone. Further-



more, although as might be expected, CRT resulted in better locoregional con-trol. Disease-free survival was equivalent between the CRT and PF arms. Also,overall survival was 5% better in the PF arm compared to the CRT arm; bothwere better than radiotherapy alone. Although not significant, the overall sur-vival benefit suggests that induction chemotherapy might have had a morepositive impact on this outcome than CRT. This latter result may have becomeevident because patients treated with induction therapy may have a betterfunctional outcome when they begin radiotherapy with reduced tumor sizeand normal speech and swallowing structures than patients treated at the startwith large intact tumors. Thus, the Intergroup 91-11 study demonstrates thatPF-based induction chemotherapy is at least equivalent to CRT for laryngec-tomy-free survival and may have an advantage in overall survival.

Addition of TaxanesMany studies have attempted to improve PF by adding a third agent to thecombination. Taxanes have been shown to have considerable activity inrecurrent disease and have a different spectrum of activity. Combinationregimens of docetaxel or paclitaxel plus PF have been studied extensivelyin phase II trials with good outcomes (26–28). Multiple phase III trialshave been reported that show that three-drug, docetaxel-based PF (TPF)regimens have improved survival or organ preservation compared to theolder two-drug PF standard (Table 3) (29–32). These results document asubstantial improvement in survival or organ preservation and less toxicitythan was observed with PF induction chemotherapy.

In a trial of resectable and unresectable patients, Hitt et al. (30)reported an improvement in response and in overall survival in patients

Table 2. Revised Outcomes for Intergroup 91-11

Outcome Parameter

Treatment

PF (%) CRT (%) XRT (%)

Laryngectomy-free survival 45 47 34a

Locoregional control 55 69 51b

Overall survival 59 55 54Disease-free survival 39 39 27a

Distant metastases 14 13 22

CRT, chemoradiotherapy; PF, cisplatin/5-fluorouracil; XRT, external beam radiation therapy.aP <.01 for both comparisons with XRT.bP <.01 for CRT versus XRT and PF.


30

Tab

le 3

.C

ompl

eted

Pha

se II

I Tri

als

of T

PF v

ersu

s PF

Stud

y (R

efer

ence

)P

atie

nts

TP

F T

reat

men

tR

adia

tion

The

rap

yO

utco

me

TA

X 3

23 (

32)

Unr

esec

tabl

eT

: 75

mg/

m2 ;

P: 7

5 m

g/m

2 ;

F: 7

50 m

g/m

2 IV

CI ×

5

days

; fou

r cy

cles

Stan

dard

rad

ioth

erap

yIm

prov

ed s

urvi

val

for

TPF

TA

X 3

24 (

31)

Unr

esec

tabl

e,

rese

ctab

le w

ith

poor

out

com

e,

orga

n pr

eser

va-

tion

T: 7

5 m

g/m

2 ; P

: 100

mg/

m2 ;

F: 1

,000

mg/

m2 I

V C

I ×

4 da

ys; t

hree

cyc

les

Che

mor

adio

ther

apy:

ca

rbop

latin

are

a un

der

the

curv

e, 1

.5

wee

kly

Impr

oved

sur

viva

l fo

r T

PF

GO

RTE

C 2

000-

01

(29)

Lary

nx a

nd o

ro-

phar

ynx,

org

an

pres

erva

tion

T: 7

5 m

g/m

2 ; P

: 75

mg/

m2 ;

F:

750

mg/

m2 I

V C

I × 5

da

ys; t

hree

cyc

les

Stan

dard

rad

ioth

erap

y fo

r re

spon

ders

Bett

er o

rgan

pre

ser-

vatio

n fo

r T

PF

Hitt

et a

l., 2

005

(30)

Rese

ctab

le a

nd

unre

sect

able

Tp:

175

mg/

m2 ;

P: 1

00 m

g/m

2 ; F

: 500

mg/

m2 I

V C

I ×

days

2–6

; thr

ee c

ycle

s

Chem

orad

ioth

erap

y:

bolu

s cis

plat

in, 1

00 m

g/m

2 eve

ry 3

wee

ks ×

3

Bett

er s

urvi

val i

n un

rese

ctab

le

patie

nts

for

TpP

F

CI,

cont

inuo

us in

fusi

on; F

, 5-f

luor

oura

cil;

P, c

ispl

atin

; T, d

ocet

axel

; Tp,

pac

litax

el.



treated with paclitaxel-based TPF, followed by cisplatin-based CRT. In theHitt trial, which compares TPF as part of an ST regimen, survival was notthe primary end point, and therapy in resectable patients included nodalsurgery for some patients before CRT. TPF significantly improved survivalin the unresectable patients but not in the resectable patients. It could beargued that, by incorporating nodal surgery between induction chemother-apy and CRT, the locoregional control and survival might have beenreduced in the resectable patients. As pointed out regarding the StudioTrial, the failure to see improved survival in the resectable patients mayhave been the result of the delay before radiotherapy, inadequate surgery,or inadequate pretherapy surgical mapping. This was in contrast to theresults achieved in unresectable patients who went immediately frominduction chemotherapy to radiotherapy. Notably, toxicity in the TPF wasless than that observed in the PF arm, and this was mostly due to reducedmucositis.

In a second phase III trial, TAX 323, performed by the EORTC andupdated by Remenar et al. in 2006 (32), patients with unresectable HNCwere treated with either TPF or PF followed by radiotherapy. The Reme-nar et al. study population consisted of patients with advanced disease.More than 70% of patients had T4 cancers, and more than 70% had N2or N3 nodal disease. More than 300 patients were entered on this study.The majority of cancers arose in the oropharynx. Survival was significantlybetter with TPF compared to PF. At 3 years, 37% of the TPF patients werealive compared to 24% of the PF patients. Overall, there was a 29%reduction in mortality with TPF compared to PF in this unresectable popu-lation. Also noteworthy, mucositis in the TPF arm was less than thatobtained in the PF arm, and treatment-related mortality was reduced by50%.

A second phase III trial comparing TPF to PF was presented in 2006, theTAX 324 trial (31). This trial is an ST trial; patients with locally advanceddisease were treated with three cycles of TPF or PF and then received CRTwith carboplatin weekly at a low area under the curve. After CRT, somepatients received nodal surgery if they presented with an N3 neck or had apartial response in the neck after the induction phase. More than 500patients were entered on the trial, which included resectable and unresecta-ble disease. More than one-half of the patients had an oropharyngeal pri-mary, and 80% had stage IV cancers. There was a significant survivaladvantage to TPF. Overall mortality was reduced by 30%, and 3-year sur-vival was 62% and 48% in the TPF and PF arms, respectively. Furthermore,toxicity appeared to be relatively lower in the TPF arm, as dose intensitywas better preserved in patients receiving TPF compared to PF (99% vs.90%), and there was less toxicity-related mortality in the TPF arm.



Recently, Calais et al. (29) presented the results of a phase III organ preser-vation trial performed by the GORTEC in patients with larynx and hypophar-ynx cancer comparing TPF to PF. These patients were treated with three cyclesof TP or PF, and then responders received radiotherapy and nonrespondersunderwent laryngectomy. All patients have finished therapy, and follow-up isongoing. There were significantly more responders in the TPF arm comparedto the PF arm. Patients who received TPF had better laryngectomy-free sur-vival than patients with PF, approximately 80% versus 60%; however, it isstill too early for a complete analysis. Notably, however, toxicity was againless in the TPF arm than in the PF arm.

New Standard of CareThe three-drug TPF regimens have been compared to PF in three completed,randomized trials. Two trials were done for survival, and one for organ pres-ervation. The latter organ preservation trial is still undergoing follow-up, butthe two survival trials are mature, and firm conclusions may be drawn fromthose results, although they have not been formally published. The uniformresult in all three trials is that TPF is substantially superior to PF in terms ofsurvival in patients with locally advanced HNC. In addition, this improve-ment in survival is accompanied by a reduction in treatment-related mortalityand mucositis. Thus, it can be said with confidence that TPF is the standardfor induction chemotherapy. There are differences between the European TPFand the North American TPF. The North American TPF is delivered over 4days compared to 5 days for the Europeans, but the doses of cisplatin and 5-FU are slightly higher (see Table 3). In addition, in the European TAX 323trial, TPF is delivered for four cycles, whereas the North American TPF regi-men is delivered for only three cycles. It is unlikely that these differences willbe resolved in the short term, and they should not obscure the basic andimportant facts, which are that TPF is more effective and less toxic than PFand represents the new standard of care for induction chemotherapy.

Sequential Therapy

An Alternative for Unresectable DiseaseDespite the improvements recently reported in unresectable disease and organpreservation, survival in unresectable disease treated with either TPF-basedinduction chemotherapy followed by radiotherapy or solely with cisplatin-based CRT remains poor at approximately 40%. There are advantages anddisadvantages to both induction chemotherapy and CRT. Induction chemo-therapy provides systemic therapy, treats distant disease, and reduces local andregional disease before the start of radiotherapy (33). The latter effect can lead



to a better functional outcome as may have been shown in the Intergroup 91-11 study. With induction chemotherapy, toxicity is usually transient and issubstantially less than that observed with CRT and aggressive radiotherapy,but induction chemotherapy is associated with prolongation of treatment.After induction chemotherapy, an assessment of response can be used toadjust the intensity of subsequent therapy. Induction therapy results in goodsystemic control, but there are frequent locoregional failures. An analysis offailure among TPF studies performed at the Dana Farber Cancer Institutedemonstrated a 37% locoregional failure rate among patients treated with dif-ferent TPF regimens followed by hyperfractionated radiotherapy (34). Five ofthese patients (6%) had locoregional failure and distant metastases. Therewere no patients with only distant failure.

CRT increases locoregional dose intensity, is ineffective systemic therapy,and is associated with considerable systemic and local toxicity. There is nomethod to assess prognosis and adjust intensity once CRT has started. How-ever, CRT is associated with improved local and regional control and survival.Distant metastases are unaffected, except in larynx cancer. Cisplatin-basedCRT in unresectable patients, oropharynx cancer, and in the postoperative set-ting show no impact on distant metastases. In some studies, distant metastasesoccurred more frequently than locoregional failures.

Combining induction chemotherapy with CRT and surgery as ST makesgood biologic sense (33,35–39). This paradigm may optimize therapy forHNC based on an analysis of the sites of failure of both therapies. In addi-tion to providing a systemic therapy, induction therapy may better preparethe local and regional area by reducing tumor bulk, normalizing vascula-ture, and improving local function. Furthermore, the immediate period aftercompletion of induction chemotherapy is a biologically critical time periodwhen tumor cells in the primary site and region are proliferating rapidly andhave some partial resistance to therapy. In a theoretical modeling of tumorproliferation and growth, tumor cells proliferate more rapidly when tumorvolume is decreased. This model predicts that the addition of a non–cross-resistant therapy with minimal delay (i.e., CRT after induction chemother-apy) should improve locoregional control (40). Tumor cells may well retainincreased sensitivity to radiation therapy and chemotherapy-induced sensiti-zation at this point in treatment.

Therapy ComparisonsSeveral sequential treatment plans have been reported in phase II trials, andthere are several phase III trials comparing TPF-based ST to cisplatin-basedCRT. The University of Pennsylvania (39) reported a sequential programtrial that included two cycles of very high-dose carboplatin and paclitaxelfollowed by single-agent weekly CRT with paclitaxel. Survival was more



than 60% at 3 years. The University of Chicago (38) gave an induction regi-men of six weekly cycles of intensive carboplatin/paclitaxel (CP) chemother-apy followed by aggressive split-course CRT, THFX. The 3-year overallsurvival rate in this phase II study was 70%. The original Chicago inductionregimen of weekly carboplatin and paclitaxel has been modified by the East-ern Cooperative Oncology Group by the addition of weekly cetuximab in aphase II trial for resectable patients. After induction therapy, patients aretreated with CRT with weekly carboplatin, paclitaxel, and cetuximab. Thereis a provision to perform surgery midway through radiotherapy if there ispersistent disease based on an interim positive biopsy. The Minnie PearlCancer Research Network Trial performed a study of high-dose CP for twocycles with 6-week continuous infusion of 5-FU (41). This induction regi-men was followed by CP weekly with radiotherapy. There was a 51%3-year survival in this advanced group of patients. Vanderbilt UniversityMedical Center completed a trial similar to the University of Pennsylvaniatrial (42). Results are early but suggest a 66% 3-year survival, with a medianfollow-up of 31 months.

The University of Michigan has taken a different approach (43). Theyhave used PF-induction chemotherapy to select patients for organ preser-vation or surgery. Patients are assessed after one cycle for response.Responders receive CRT with bolus cisplatin, and two cycles of adjuvantPF are then given to complete responders. Nonresponders to one cycleundergo laryngectomy. Survival is 80% at 3 years, and organ preservationrates are excellent. This population is primarily intermediate stage larynxcancer and is not directly comparable to the more advanced patientstreated in the other sequential studies. Furthermore, with the update of the91-11 trial and the superiority of TPF, this concept should be reexamined.

TAX 324 is a phase III trial; however, both arms were ST based. For thistrial, TPF and PF were followed by CRT with weekly carboplatin, a less-inten-sive CRT regimen than CRT regimens that use bolus cisplatin, or therapy withcisplatin and another drug such as 5-FU or paclitaxel. The TAX 324 trialaccrued more than 500 patients and demonstrated that ST with TPF and car-boplatin-based CRT was a tolerable therapy and that this treatment repre-sented a reasonable standard of care. There are a number of important,ongoing phase III trials comparing CRT with TPF-based ST. The University ofChicago is leading a phase III trial comparing docetaxel/hydoxyurea/5-FU/bidradiation therapy (THFX) CRT to ST with TPF plus THFX (Figure 1A). TheItalian trial compares TPF followed by CRT with cisplatin and 5-FU to CRTalone (Figure 1B). The Spanish trial is comparing three arms: TPF or PF pluscisplatin-based CRT to CRT alone (Figure 1C). The Paradigm trial is compar-ing TPF followed by carboplatin to cisplatin plus aggressive radiotherapy(Figure 1D). The Southwest Oncology Group organ preservation study in



A

BFigure 1. Active phase III trials comparing sequential therapy with docetaxel-based cisplatin/5-fluorouracil (TPF) chemotherapy and chemoradiotherapy(CRT). A: Schema for the University of Chicago sequential trial. B: Schema forthe Italian trial. TPF: docetaxel, 75 mg/m2 day 1 + cisplatin, 80 mg/m2 day 1 +5-fluorouracil (5-FU), 800 mg/m2 continuous infusion (CI) days 1–4 for 3weeks ×3. CRT PF: cisplatin, 20 mg/m2 days 1–4 + 5-FU, 800 mg/m2 CI days 1–4 weeks 1 and 6. (continued)

RANDOMIZE

T

P

F

T

H

F

X

Two cycles of chemotherapy

Six cycles of every other week chemoradiotherapy

T

H

F

X

Six cycles of every other week chemoradiotherapy

RANDOMIZE

T

P

F

PF

PF

CRT

Daily radiotherapy

Daily radiotherapy



C

DFigure 1. (Continued) C: Schema for the Spanish combined modality ther-apy trial. TPF versus PF followed by CRT versus CRT alone. TPF: docetaxel, 75mg/m2 day 1 + cisplatin, 75 mg/m2 day 1 + 5-FU, 750 mg/m2 CI days 1–5 for3 weeks ×3. PF: cisplatin, 100 mg/m2 day 1 + 5-FU, 1,000 mg/m2 CI days 1–5for 3 weeks ×3. CRT: cisplatin, 100 mg/m2 days 1, 22, and 42. D: The NorthAmerican Paradigm trial. *T + accelerated concomittant boost for nonre-sponders. (continued)

RANDOMIZE

T

P

F

P

F

Daily radiotherapy

Cisplatin, 100 mg/m2

Salvagesurgery

RANDOMIZE

T

P

F

PQ 3 weeks

XRT

Daily radiotherapy

ACB radiotherapy

Threecycles ofchemotherapy

Surgery

Surgery

PR, CR

NR

T*ACB

C



resectable oropharynx cancer compares ST with TPF plus CRT to CRT alonefor organ preservation (Figure 1E).

Conclusion

This has been a productive period in the treatment of locally advancedHNC. After three decades of study, major advances in combined modalitytherapy by incorporating three-drug regimens of TPF into treatment arebeing seen. TPF has been shown to improve survival and organ preserva-tion and to result in less acute morbidity than the original standard two-drug PF regimen of induction chemotherapy. In addition, studies of ST as anew treatment paradigm for locally advanced HNC have shown 2- and 3-year survival rates in advanced disease that are unprecedented. There aremore than six phase III studies being performed to compare ST to CRT.Early data from the European trials may be expected in 2007 and 2008.

When the progress in research and the evolution of induction chemother-apy and CRT over the last few years is reviewed, improved chemotherapy,better survival, and potentially better functional outcome for patients may beseen. The concept of ST appears to reflect an increasing understanding of thebiology of HNC. ST makes sound biologic sense and appears to be highlyeffective, but it still remains experimental. Despite the lack of completed phaseIII trials establishing the relative efficacy of this paradigm, the TAX 324 trialshows that ST with TPF induction therapy and carboplatin-based CRT is an

EFigure 1. (Continued) E: The Southwest Oncology Group Oropharynx trial.CR, complete response; H, hydroxyurea; NR, no response; PR, partial response;X, BID radiation therapy; XRT, external-beam radiation therapy.

RANDOMIZE

T

P

F

PQ 3 weeks

PQ 3 weeks

XRT

Daily radiotherapy

Daily radiotherapy

Surgery

Surgery

Surgery>50% ResponseTwo cycles

<50% Response



acceptable treatment and a reasonable alternative for patients with good per-formance status and locally advanced disease. Phase III trials, however, remainthe final determinant as to whether this is truly an improvement over the cur-rent standards of induction chemotherapy or CRT.

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2. Adelstein D, Li Y, Adams G, et al. An Intergroup phase III comparison of standardradiation therapy and two schedules of concurrent chemoradiotherapy in patientswith unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92–98.

3. Domenge C, Hill C, Lefebvre J, et al. Randomized trial of neoadjuvant chemo-therapy in oropharyngeal carcinoma. Br J Cancer 2000;83:1594–1598.

4. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French head andneck oncology and radiotherapy group randomized trial comparing radiother-apy alone with concomitant radiochemotherapy in advanced-stage oropharynxcarcinoma. J Clin Oncol 2004;22:69–76.

5. Semrau R, Mueller RP, Stuetzer H, et al. Efficacy of intensified hyperfractionatedand accelerated radiotherapy and concurrent chemotherapy with carboplatin and5-fluorouracil: updated results of a randomized multicentric trial in advancedhead-and-neck cancer. Int J Radiat Oncol Biol Phys 2006;64:1308–1316.

6. Posner MR, Haddad RI, Wirth L, et al. Induction chemotherapy in locallyadvanced squamous cell cancer of the head and neck: evolution of the sequen-tial treatment approach. Semin Oncol 2004;31:778–785.

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9. Forastiere A, Metch B, Schuller D, et al. Randomized comparison of cisplatinplus fluorouracil and carboplatin plus fluorouracil versus methotrexate inadvanced squamous cell carcinoma of the head and neck: a Southwest Oncol-ogy Group study. J Clin Oncol 1992;10:1245–1251.

10. Jacobs C, Goffinet D, Goffinet L, et al. Chemotherapy as a substitute for sur-gery in the treatment of advanced resectable head and neck cancer. A reportfrom the Northern California Oncology Group. Cancer 1987;60:1178–1183.

11. Ensley J, Jacobs J, Weaver A, et al. Correlation between response to cisplat-inum-combination chemotherapy and subsequent radiotherapy in previouslyuntreated patients with advanced squamous cell cancers of the head and neck.Cancer 1984;54:811–814.

12. Haddad R, Tishler R, Wirth L, et al. Rate of pathologic complete responses todocetaxel, cisplatin, and fluorouracil induction chemotherapy in patients withsquamous cell carcinoma of the head and neck. Arch Otolaryngol Head NeckSurg 2006;132:678–681.

13. Adelstein DJ. Induction chemotherapy in head and neck cancer. HematolOncol Clin North Am 1999;13:689–698, v–vi.



14. Rooney M, Kish J, Jacobs J, et al. Improved complete response rate and sur-vival in advanced head and neck cancer. Cancer 1985;55:1123–1128.

15. Lefebvre J, Chevalier D, Luboinski B, et al. Larynx preservation in pyriformsinus cancer: preliminary results of a European organization for research andtreatment of cancer phase III trial. J Natl Cancer Inst 1996;88:890–898.

16. Paccagnella A, Orlando A, Marchiori C, et al. Phase III trial of initial chemo-therapy in stage III or IV head and neck cancers: a study by the Gruppo di Stu-dio sui Tumori della Testa e del Collo. J Natl Cancer Inst 1994;86:265–272.

17. Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plusradiation compared with surgery plus radiation in patients with advancedlaryngeal cancer. N Engl J Med 1991;324:1685–1689.

18. Munro A. An overview of randomized controlled trials of adjuvant chemother-apy in head and neck cancer. Br J Cancer 1995;71:83–91.

19. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the manage-ment of squamous cell carcinoma of the head and neck region: a meta-analysisof prospective and randomized trials. J Clin Oncol 1996;14:838–847.

20. Pignon J, Bourhis J, Domenge C, et al. Chemotherapy added to locoregionaltreatment for head and neck squamous-cell cancer: three meta-analyses ofupdated individual data. Lancet 2000;355:949–955.

21. Pacagnella A, Buffoli A, Kousis H, et al. Randomized phase II trial of concomitantCT/RT versus TPF followed by concomitant CT/RT in locally advanced squamouscell carcinoma of the head and neck. Proc Am Soc Clin Oncol 2006:5518.

22. Zorat PL, Paccagnella A, Cavaniglia G, et al. Randomized phase III trial ofneoadjuvant chemotherapy in head and neck cancer: 10-year follow-up. J NatlCancer Inst 2004;96:1714–1717.

23. Richard J, Sancho-Garnier H, Pessey J, et al. Randomized trial of inductionchemotherapy in larynx cancer. Oral Oncol 1998;34:224–228.

24. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy andradiotherapy for organ preservation in advanced larynx cancer. N Engl J Med2003;349:2091–2098.

25. Forastiere A, Maor M, Weber R, et al. Long term results of Intergroup RTOG91-11: a phase III trial to preserve the larynx—induction cisplatin/5-FU andradiation therapy versus concurrent cisplatin and radiation therapy versusradiation therapy. Proc Am Soc Clin Oncol 2006:5517.

26. Posner MR, Glisson B, Frenette G, et al. Multicenter phase I–II trial of doce-taxel, cisplatin, and fluorouracil induction chemotherapy for patients withlocally advanced squamous cell cancer of the head and neck. J Clin Oncol2001;19: 1096–1104.

27. Schrijvers D, Van Herpen C, Kerger J, et al. Docetaxel, cisplatin, and 5-fluoro-uracil in patients with locally advanced unresectable head and neck cancer: aphase I–II feasibility study. Ann Oncol 2004;15:638–645.

28. Baselga J, Trigo JM, Bourhis J, et al. Cetuximab (C225) plus cisplatin/carbo-platin is active in patients (pts) with recurrent/metastatic squamous cell carci-noma of the head and neck (SCCHN) progressing on a same dose and scheduleplatinum-based regimen [abstract]. Proc Am Soc Clin Oncol 2002;21:226a.

29. Calais G, Pointreau Y, Alfonsi M, et al. Randomized phase III trial comparinginduction chemotherapy using cisplatinum, fluorouracil with or without doce-taxel for organ preservation in hypopharynx and larynx cancer. Preliminaryresults of GORTEC 2000–01. Proc Am Soc Clin Oncol 2006:5506.

30. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparingcisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction



chemotherapy followed by chemoradiotherapy in locally advanced head andneck cancer. J Clin Oncol 2005;23:8636–8645.

31. Posner M, Hershock D, Le Lann L, et al. A phase III multicenter trial of docetaxelcisplatin and 5-fluorouracil versus cisplatin plus 5-fluorouracil induction chemo-therapy followed by chemoradiotherapy in patients with locally advanced squa-mous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol, SpecialScientific Session, 2006.

32. Remenar E, Van Herpen C, Germa Lluch J, et al. A randomized phase III mul-ticenter trial of neoadjuvant docetaxel plus cisplatin and 5-fluorouracil versusneoadjuvant PF in patients with locally advanced, unresectable squamous cellcarcinoma of the head and neck. Final analysis of EORTC 24971. Proc Am SocClin Oncol 2006:5516.

33. Posner M, Colevas A, Tishler R. The role of induction chemotherapy in thecurative treatment of squamous cell cancer of the head and neck. Sem Oncol2000;27(Suppl G):13–24.

34. Haddad R, Colevas AD, Tishler R, et al. Docetaxel, cisplatin, and 5-fluoroura-cil–based induction chemotherapy in patients with locally advanced squamouscell carcinoma of the head and neck: the Dana Farber Cancer Institute experi-ence. Cancer 2003;97:412–418.

35. Kies MS, Haraf DJ, Athanasiadis I, et al. Induction chemotherapy followed byconcurrent chemoradiation for advanced head and neck cancer: improved dis-ease control and survival. J Clin Oncol 1998;16:2715–2721.

36. Haddad R, Tishler RB, Norris CM, et al. TPF-based induction chemotherapyfor head and neck cancer and the case for sequential, combined modality treat-ment. Oncologist 2003;8:35–44.

37. Haddad R, Wirth L, Posner M. The integration of chemotherapy in the cura-tive treatment of locally advanced head and neck cancer. Expert Rev Antican-cer Ther 2003;3:331–338.

38. Vokes EE, Stenson K, Rosen FR, et al. Weekly carboplatin and paclitaxel fol-lowed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradio-therapy: curative and organ-preserving therapy for advanced head and neckcancer. J Clin Oncol 2003;21:320–326.

39. Machtay M, Rosenthal DI, Hershock D, et al. Organ preservation therapyusing induction plus concurrent chemoradiation for advanced resectable oro-pharyngeal carcinoma: a University of Pennsylvania phase II trial. J Clin Oncol2002;20:3964–3971.

40. Takimoto C, Rowinsky E. Dose-intense paclitaxel: deja vu all over again? JClin Oncol 2003;21:2810–2814.

41. Hainsworth JD, Meluch AA, McClurkan S, et al. Induction paclitaxel, carboplatinand infusional 5-FU followed by concurrent radiation therapy and weekly pacli-taxel/carboplatin in the treatment of locally advanced head and neck cancer: aphase II trial of the Minnie Pearl Cancer Research Network. Cancer J 2002;8(4):298–300.

42. Cmelak A, Murphy BA, Burkey B, et al. Induction chemotherapy (IC) followed byconcurrent chemoradiation (CCR) for organ preservation (OP) in locally advancedsquamous head and neck cancer (SHNC): results of a phase II trial. Proc ASCO2003:22.

43. Urba S, Wolf G, Bradford C, et al. Improved survival and decreased late sal-vage surgery using chemo-selection of patients for organ preservation inadvanced laryngeal cancer. Proc ASCO 2003;22:497.


41CME

❖Increasing Cure—Increasing

Toxicity: Symptom Management and Chemoradiotherapy


History of Management

As recently as the mid-1990s, medical oncologists were peripheral mem-bers of the head and neck cancer (HNC) treatment team, with their rolebeing confined to the administration of chemotherapy for metastatic orrecurrent disease. Now, chemotherapy is being incorporated into the pri-mary treatment plan for the majority of patients with locally advancedHNC. However, the improved treatment outcome resulting from com-bined modality therapy is at the expense of markedly increased acute andlate toxicities. Thus, medical oncologists are faced with making treatmentdecisions as well as managing a complex array of interrelated treatmenttoxicities that are often problematic long after therapy is completed (1). Tocomplicate matters, information to guide physicians in dealing with thetoxicities of therapy has not kept pace with changing practice. Indeed,information regarding the incidence, severity, and management of treat-ment-related toxicities is often weak or lacking. Thus, supportive care inhead and neck oncology has become a critical area of study.

It is important for clinicians to understand the management of acuteand late effects of therapy on both an individual and collective basis. Fromthe standpoint of the individual, assessment of acute and late toxicities isnecessary to minimize the detrimental effects on physical and mental


42 Increasing Cure—Increasing Toxicity

health. Collectively, oncologists need to understand how various treatmentregimens impact a patient’s quality of life (QOL) and supportive care out-comes to design regimens that minimize late effects.

Measuring Effects of Treatment: Quality of Life versus Symptom Control

In evaluating the late effects of therapy, it is important to recognize tworelated, but distinct, outcome measures: the first is QOL. QOL is a global con-struct that attempts to quantify a patient’s sense of general well-being (2). It isinfluenced by numerous factors, including beliefs, life experiences, and expec-tations (3). A number of tools have been developed to measure QOL; the mostcommonly used in the HNC patient population are the Functional Assessmentof Cancer Therapy (4) and the European Organisation of Research and Treat-ment of Cancer systems (5,6). Both systems have well-described generalquestionnaires that address important domains, such as physical, functional,emotional, and social well-being (7), as well as head and neck subscales thatspecifically address issues pertinent to HNC patients. A review of the headand neck QOL literature reveals some important information and insights (8).However, it can be difficult to translate results from QOL studies into practi-cal recommendations for practicing clinicians.

QOL assessments must be distinguished from symptom assessments. Asymptom is a perceived alteration in a sensation or function. Symptoms maycontribute to alterations in QOL; however, it is important to note thatpatients may experience symptoms that fail to significantly impact on QOL.This does not mean that symptoms are unimportant. Patients with HNCmay have a significant symptom burden that does not affect their QOL butthat does have substantial health implications. For example, a patient mayhave moderately impaired swallowing function, which results in maladap-tive dietary changes. The patient may not be “bothered” or “distressed” bythe problem, but the long-term implications of diet alterations may be signif-icant. Unlike QOL outcomes, it is easier to translate symptom and functionoutcomes into clinical practice.

Because it has been recognized that chemoradiotherapy (CRT) is associ-ated with increased toxicity, symptom and functional outcomes have becomean important correlative component of clinical trials. It is, therefore, impor-tant for clinicians to understand the benefits and limitations of differentmeasures to be able to interpret results. Symptoms can be assessed in a vari-ety of ways. Most clinical trials report symptoms based on toxicity-report-ing systems such as the Common Toxicity Criteria. These systems haveinherent limitations, the most important of which is underreporting. Under-


Increasing Cure—Increasing Toxicity 43

reporting is both systematized (trials rarely report grade 1 and 2 toxicities,which may be bothersome or distressing to patients) or inadvertent (failureto assess and document problems). To deal with this issue, self-report mea-sures that address specific symptom control or functional issues can beappended to clinical trials. The advantage of self-report measures is thatefforts can be directed at collecting desired information, the cost is modest,and the patient burden is low. Alternatively, objective measures, such asmodified barium swallow to measure swallow function or pedometers tomeasure activity, may be used. Objective measures have the advantage ofproviding rich, detailed information. However, they tend to be more expen-sive and are often dependent on the expertise of the operator.

Symptom Control Issues

The remainder of this chapter provides a brief review of critical symptomcontrol issues in HNC patients undergoing CRT. The reader is referred toadditional materials for a more comprehensive review (1).

Mucositis

Mucositis secondary to CRT remains one of the major complications oftherapy. Classically, the term mucositis has been used to refer to ulcerativelesions of the mucous membranes. Because the ulcerative lesions of theupper aerodigestive tract were visible on examination, most clinicians thinkof mucositis as confined to the head and neck region. It is often thought ofas a local process with consequences that are confined to the local tissues.Older toxicity grading systems have propagated this limited concept by con-fining mucositis grading to measurement of ulcerative lesions.

As the knowledge base has evolved, the concept of mucositis haschanged. It has become clear that mucositis is associated with complicatedlocal biology and systemic effects. Sonis (9) has developed a model thatexplains the underlying biology of mucositis. The first step in the patho-genesis of mucositis is initiation. During this phase, tissue damage fromchemotherapy and radiation induces the production of reactive oxygenspecies (ROS). During the second phase, ROS activate a number of bio-logic pathways, including nuclear factor κB (NF-κB), sphingomyelinase,and ceramide. NF-κB, a central signaling molecule, upregulates a numberof pathways resulting in, among other things, an increase in proinflamma-tory cytokines such as tumor necrosis factor-α, interleukin-1b (IL-1b), andIL-6. After activation, a series of feedback loops result in amplification of



biologic responses. Although these biologic responses are meant to be pro-tective, prolonged activation of pathways may paradoxically result in tis-sue injury. Ulcers develop in the damaged mucosa, and an inflammatoryinfiltrate may be seen. After the insulting agent is removed, healing maybegin to take place.

Based on this model, it appears that mucositis is best thought of as a com-plex biologic process that results from damage to the tissues by systemic che-motherapy or radiation. Regardless of whether the tissue damage is due tochemotherapy or radiation therapy (RT), there are local and systemic manifes-tations that result from the tissue response to damage. These effects impact ona broad array of organs and function, and may be long lasting. Of note, thereis no doubt that the use of CRT results in a marked increase in mucositis whencompared to radiation alone. The use of radiation alone results in grade 3 and4 mucositis rates of between 20% and 30% (10). Aggressive, concurrent CRTregimens may result in mucositis rates that approach 100%. Thus, it is criticalfor the clinician to have a comprehensive management strategy for the identifi-cation and palliation of mucositis-related symptoms.

Mucositis-Related Symptoms

Mucositis is a clinically important toxicity. First and foremost, increasedrates of mucositis may be associated with breaks in therapy and compro-mised tumor control. In addition to treatment breaks, mucositis is associ-ated with a number of acute and late symptom control and functional issues.The most common symptom associated with mucositis is pain. A recentstudy reported on mucositis-related burden in HNC patients undergoingCRT (11). Seventy-five patients with stage 3 or 4 HNC undergoing radiationor CRT were enrolled in this prospective trial. At the end of week 6, 85% ofpatients were receiving opioid analgesics. Despite the use of opioids, 76% ofpatients complained of “quite a lot” or “extreme” mouth soreness. Pain wasdemonstrated to impact on swallowing, drinking, eating, and talking.

Acutely, mucositis results in tissue edema and inflammation. After RT iscompleted, healing begins. Tissue edema and inflammation may resolve,leaving the patient with few clinically evident side effects. Conversely, somepatients may experience significant fibrosis and scarring of the mucosa andsoft tissues of the neck. The long-term effects of tissue scarring are substan-tial, including lymphedema, decrease in compliance of pharyngeal soft tis-sues, altered swallowing function, and dietary inadequacies.

Dozens of agents in hundreds of trials have been investigated as preven-tive or treatment agents for oral mucositis. To date, there are no pharma-ceutical interventions that have been shown to be effective either in the



treatment or prevention of radiation-induced mucositis. A thoroughreview of the mucositis literature was conducted by the Mucositis Com-mittee of the Multinational Association of Supportive Care in Cancer(MASCC) (12). Based on this review, evidence-based clinical practiceguidelines have been developed. The recently updated version is availableon the MASCC web site (www.mascc.org). The guidelines recommend thefollowing:

• Oral care to attempt the reduction of mucositis• Adequate analgesia• Radiation techniques such as midline blocks and conformal radiation• Benzydamine for prevention of mucositis (not available in the United

States)

Of note, the relative effect of intensity-modulated RT (IMRT) on theseverity and duration of mucositis has yet to be clearly determined andawaits further prospective study.

It is evident that, at this time, care for radiation-induced mucositis issupportive in nature. It is critical that the HNC team assess the patientroutinely for the sequela of mucositis and that aggressive measures be usedto maintain comfort, hydration, and nutritional status.

Despite the disappointing results of prior investigations, pharmaceuti-cal companies continue to attempt to develop new agents for the preven-tion and treatment of oral mucositis. A review of ongoing investigations isbeyond the scope of this text. The reader is referred to the June 2006 issueof Supportive Care in Cancer, which is dedicated exclusively to mucositis.

Data on the systemic effects of mucositis are much more limited. Investi-gators at Vanderbilt University have investigated the physiologic effects ofCRT-induced tissue damage on physical function and muscle mass (13,14).Patients who have completed CRT experience a marked loss of muscle massand a decrease in physical function. This correlates with an increase inproinflammatory cytokines and measures of oxidative stress, and a decreasein antiinflammatory cytokines. Further evaluation of the systemic effects ofmucositis and related tissue damage is urgently needed.

Nutritional Management and Unintentional Weight Loss

At least 50% of HNC patients are malnourished at some point in theirtreatment course. Malnutrition is associated with a decrease in both sur-vival and QOL (15–20). Thus, assessment of nutritional status is a keycomponent in the management of HNC patients throughout the trajectoryof their disease process (21).



At the time of diagnosis, all patients should be assessed to determine ifthey have had any recent weight loss. If so, the severity and rapidity ofweight loss should be determined. Risk classifications have been developedto identify high-risk patients for whom nutritional deficits may significantlyimpact on outcome (Table 1). Of note, patients with extreme weight losshave a decreased healing capacity and may fail to tolerate aggressive com-bined modality treatment regimens. In addition to the severity of weightloss, the etiology of weight loss should be established. For most patients,weight loss at the time of diagnosis is associated with tumor-related pain orobstruction of the alimentary tract. Cancer cachexia, an inflammatory pro-cess due to cancer, may also contribute to weight loss, particularly inpatients with advanced disease (22–24). Once the cause of weight loss isidentified, efforts should be made to ameliorate the identified problem. Ifthis is not possible, patients may require feeding tube placement.

In addition to a weight loss history, it is important to determine whetherpatients are using vitamin supplements. Although the HNC population has alower rate of complementary alternative medicine therapy use when com-pared to other cancer diagnoses, the use of high doses of selected vitamins hasbecome widespread. Antioxidants have been postulated to have a protectiveeffect against the tissue damage from radiation (25). Preliminary data indi-cated that some vitamins, such as vitamin E or vitamin C, may decrease theacute effects of RT (26,27). However, a more recent randomized trial indi-cated that vitamin E and carotenoid supplementation may have a tumor-sparing effect with compromised local control (28). Therefore, patientsshould be warned not to take nonphysiologic vitamin supplements withoutdiscussing them with the medical staff.

Weight loss may also be due to the effects of treatment. Surgery may resultin decreased oral intake in the perioperative period. Generally, if patients areanticipated to have a prolonged period of decreased oral intake postopera-tively, a nasogastric or percutaneous feeding tube is placed at the time of sur-

Table 1. Definition of Critical Weight Loss

Time CourseSignificant Weight Loss (%)

Severe Weight Loss (%)

1 wk ≤ 2 >21 mo ≤ 5 >53 mo ≤ 7.5 >7.56 mo ≤ 10 >10

Information compiled from Blackburn GL, Bistrian BR, Miani BS, et al. Nutritional and metabolic assessment of the hospitalized patient. J Parenter Enteral Nutr 1977;1:11–22.



gery. A more problematic issue is weight loss associated with radiation-basedtherapy (29). Compared to radiation alone, patients who receive CRT have amore profound weight loss, averaging 6%–12% body weight. When usingCRT, clinicians should be prepared to aggressively address nutrition issues.

The most common reason cited for weight loss during CRT is decreasedoral intake due to painful mucositis (11), and mucositis-related pain can berefractory to medical therapy. Patients usually require frequent and rapid esca-lation of opioids along with the use of adjunctive medications such as topicalanesthetics. Because patients have difficulty swallowing, transdermal deliverysystems provide a convenient and effective method for providing analgesia.

Other factors that contribute to decreased oral intake during and immedi-ately after RT include tissue edema and inflammation with resultant decreasein tissue compliance. Noncompliant tissues have decreased mobility thatinhibits normal swallowing function (21,30). There are two major complica-tions of altered swallowing function: (a) nutritional inadequacies and (b) aspi-ration. Due to decrease in oral intake from swallowing abnormalities, a highpercentage of patients with locally advanced HNC undergo feeding tubeplacement. There is considerable debate as to whether a feeding tube shouldbe placed prophylactically. There is little doubt that the prophylactic place-ment of a feeding tube will decrease the amount of weight loss. Recently, how-ever, concern has been expressed that patients with feeding tubes stop usingthe muscles of deglutition, allowing atrophy and wasting. Atrophy and wast-ing are thought to lead to higher rates of feeding tube dependence long term. Ithas also been recently recognized that the need for feeding tube placement andthe rate of long-term feeding dependence is associated with the treatment regi-men. A clear increase in feeding tube placement and long-term feeding tubedependence is noted when CRT is compared to radiation alone (30). It alsoappears that more aggressive regimens may be associated with increased long-term feeding tube dependence (30). Interpretation of these data is complicatedby the heterogeneous patient populations and differences in supportive mea-sures available at institutions. Nonetheless, clinicians must be prepared to dealwith the acute and late swallowing effects of therapy. It is recommended thatpatients continue to attempt to swallow even if they have a feeding tube inplace. Patients should be seen by a speech and language pathologist early intheir course so that they may be provided with exercises that may prevent lossof swallowing function. Early return to swallowing function should be encour-aged as long as it is safe.

Aspiration is one of the unrecognized, but potentially fatal, complicationsof swallowing abnormalities. Aspiration may lead to pneumonia, which isparticularly problematic during therapy with myelosuppressive chemotherapyregimens. Patients who have undergone aggressive CRT are often weak anddebilitated. Thus, if they develop an aspiration pneumonia, they havedecreased reserve. The treating clinician should be aware of several scenarios



that indicate ongoing aspiration. First, patients may complain of coughingwhen eating or after eating. Patients may also present with fever of unclear eti-ology. Chronically, aspiration may present as pulmonary fibrosis and respira-tory compromise. If the clinician is concerned about potential aspiration, amodified barium swallow should be obtained. If patients have significant aspi-ration, the patient may need to have a feeding tube placed and designated toreceive nothing by mouth. However, it is difficult to determine “how muchaspiration is too much aspiration.” Thus, a consultation with speech and lan-guage pathology is helpful.

Xerostomia

Humans produce 1.0–1.5 L of saliva each day. The major components ofsaliva are amylase, mucin, and bicarbonate (31). In addition, saliva contains amixture of proteins, electrolytes, and nonprotein, nonelectrolytes. This com-plex secretion has multiple roles: (a) oral cavity lubrication, (b) maintainingmucous membrane integrity by protecting it from desiccation and environ-mental factors/toxins, (c) antibacterial, antifungal, antiviral effect (lysozyme,lactoferrin, peroxidases), (d) maintaining oral pH, (e) maintaining dentalintegrity, (f) food bolus formation, and (g) aid in taste sensation (31,32).

Xerostomia is the sensation of oral dryness. It results both in a decreasein QOL and marked alteration in critical functions. Xerostomia may becaused by a wide range of processing, including aging, medications, collagenvascular disease, anxiety or depression, and, finally, RT-induced damage tothe salivary glands. When the major salivary glands are within the radiationportal, a >50% reduction in unstimulated flow is noted after 1 week andreaches <10% of basal salivary flow within 2–3 weeks (33). Salivary func-tion may recover partially if the radiation dose is between 30 and 60 Gy;however, damage may be permanent above 30 Gy (34,35).

Patients with xerostomia complain of a variety of symptoms, including:pain or discomfort, painful mucosal ulcers, altered voice (36), increased dentalcaries, difficulty wearing dentures, decreased taste, difficulty with mastication(37), and altered oral intake with nutritional deficits (38). On examination,patients may have fissures and atrophy of the papillae of the tongue; angularcheilitis; dental decay, especially at the roots; erythematous mucosa; dry orpale mucosa due to atrophy; oral ulcers; and candidiasis.

Assessment of salivary function can be made using clinical parameters orby measuring stimulated and unstimulated saliva production. Unstimulatedsalivary flow rates are obtained by asking patients to spit into a plastic con-tainer for 5 minutes. Stimulated salivary measurements may be done by ask-ing a patient to chew on paraffin or sugar-free gum while saliva is collected.



Alternatively, 4% citric acid can be applied every 2 minutes. Normal, unstim-ulated flow is 0.3–0.5 mL/minute, and stimulated flow is 1–2 mL/minute. Var-ious criteria have been developed for rating xerostomia (32) (Tables 2 and 3).The most recent criteria (Common Terminology Criteria for Adverse Events3.0) incorporates the measurement of unstimulated salivary flow.

Once xerostomia has developed, treatment options are limited. If some sal-ivary function is still present, the goal of treatment is to stimulate remainingfunction by mechanical, gustatory, or pharmacologic stimulation. Becausethere is no substitute for the dental protection afforded by saliva, the impor-tance of stimulation of residual salivary function cannot be underestimated.Gustatory stimulants include gum, lozenges, and specific tastes such as sweet,acid, or menthol. Pharmacologic agents include pilocarpine, 5 mg orally (PO)qid (39), or cevimeline, 30 mg PO tid (40). These agents are modestly effectivein improving salivary flow and comfort.

If no function is present, the goal of therapy is to increase oral comfort byusing salivary substitutes. Most salivary substitutes contain carboxymethylcel-lulose. Attempts have been made to add enzymes, such as lysozyme, sialoper-oxidase, and lactoferrin, to add an antimicrobial effect (41). These agents

Table 2. Common Terminology Criteria for Adverse Events 3.0 Standardsfor Xerostomia

Grade Description

1 Symptomatic (dry or thick saliva); no dietary alterations; unstim-ulated flow rate of >0.2 mL /minute

2 Symptomatic and significant dietary intake alterations (requires copious water, lubricants, soft foods, moist foods); unstimu-lated flow rate of 0.1–0.2 mL /minute

3 Symptomatic; significant oral intake alterations leading to inade-quate oral alimentation (requires IV, feeding tube, or total par-enteral nutrition); unstimulated flow rate of <0.1 mL /minute

Table 3. Radiation Therapy Oncology Group Salivary Gland Morbidity Scale

Grade Description

1 Mild dryness, slightly thick saliva, slightly altered or metallic taste

2 Moderate to complete dryness, thick sticky saliva, and marked taste alterations

3 Not defined for xerostomia4 Acute salivary gland necrosis



improve oral comfort, but there are no consistent data to indicate a change inbacterial colonization (41,42).

Because of the devastating effects of xerostomia, investigators haveattempted to identify methods for preventing loss of salivary gland function.Three major methods have been used: salivary gland transfer, pharmacologicagents such as amifostine, and alternative radiation delivery systems such asIMRT. Salivary gland transfer is a surgical procedure that is done before RT.The salivary glands are moved anteriorly and out of the radiation port; thus,the delivery of radiation to the glands is markedly diminished, and functionloss is minimized (43). Preliminary results indicate that this is an effectivestrategy; however, its broad applicability is of concern.

Amifostine is an inorganic thiophosphate that is U.S. Food and DrugAdministration approved for the protection of salivary glands during RT. In arecently published metaanalysis evaluating data on the efficacy of amifostine,Sasse et al. (44) identified 14 randomized trials containing 1,451 patients.Only four studies reported the effects on xerostomia for HNC. Of the fourstudies that looked at acute xerostomia, amifostine reduced the odds of xero-stomia by 76% (odds ratio [OR], 0.24; confidence interval [CI], 0.15–0.36; P<.00001). Only two of the studies looked at late xerostomia. In those studies,amifostine reduced the odds of xerostomia by 67% (OR, 0.33; CI, 0.21–0.51;P <.00001). Despite the positive data, amifostine has not been broadlyaccepted. This is due in part to cost considerations and in part to toxicity. Inan attempt to ameliorate the toxicities of intravenous (IV) amifostine, studieswere done to determine whether amifostine could be used subcutaneously todecrease side effects without decreasing activity. Bardet et al. (45) reported theresults of a randomized trial of 311 HNC patients receiving primary and post-operative CRT who received RT to at least 75% of both glands. Patients wererandomized to amifostine, 500 mg/m2 or 200 mg/m2 IV. Results demonstratedno difference in acute xerostomia, mucositis, or dermatitis between the IV andsubcutaneous administration. The subcutaneous administration was bettertolerated, with fewer episodes of hypotension, nausea, or vomiting.

An alternative method for prevention of xerostomia is to use conformalRT techniques that spare normal tissue. As noted, if the radiation dose to thesalivary gland is limited, salivary function can be spared. Several small studieshave reported a positive effect on salivary function in patients treated withIMRT (46–48). Further evaluation in trials with a larger sample using objec-tive measures of outcome are needed to confirm these results.

Oral Care

Before initiating therapy, patients should undergo a thorough dental evalu-ation. This should include an examination with radiographs, periodontal



care, smoothing of rough dental surfaces, and assessment of dentures andprosthetics. Questionable teeth must be extracted before radiation. Radia-tion should not be started until 10–14 days after dental extraction to allowadequate time for healing (49).

The best recognized and perhaps the most profound ramification ofxerostomia is dental caries. Caries may progress rapidly. Thus, patientsreceiving RT to the head and neck should be advised that an oral care regi-men is critical before, during, and after therapy is completed. The purposeof oral care is to decrease the impact of xerostomia, prevent infections, andcontrol treatment-related symptoms. An oral care regimen should includeroutine brushing (for as long as possible during therapy), flossing, using oralrinses (water, baking soda, saline), and mouth moisturizers for comfort.Patients should use fluoride treatments (either trays or concentrated tooth-paste) throughout treatment until mucositis prohibits its use. Treatmentsshould then be resumed as quickly as possible after mucositis resolves.

Psychological Issues

Patients undergoing stem cell transplant have an extensive pretreatmentworkup that includes a psychological assessment to identify issues that mayimpair their ability to tolerate the aggressive nature of the treatment andrecovery. The use of aggressive CRT regimens for treatment of HNC is no lessrigorous than some transplant protocols. However, psychological assessmentand counseling are not financially viable nor are they acceptable to manypatients with HNC. Psychological care, therefore, becomes a responsibility ofthe HNC treatment team.

Several key issues should be addressed as part of the initial psychiatricevaluation. First, it is critical to determine whether patients have a history ofsubstance abuse; in particular, a history of alcohol use should be obtained(see Table 4 for Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition, criteria). Although only a small percentage of patients maymeet criteria for alcohol abuse syndrome, a much higher percentage ofpatients may have a history of alcohol dependence. For the small percentageof patients who are unable to refrain from excessive alcohol intake, treat-ment even with radiation as a single modality may be beyond the ability ofthe staff to deliver and the patient to tolerate. In this situation, involvingrehabilitation services before starting therapy is advisable. For patients whodo not exhibit severe maladaptive behaviors, but have a history of heavyalcohol intake, there are several concerns. First, the abrupt discontinuationof alcohol may result in a withdrawal syndrome. In addition, patients mayhave unrecognized nutrient deficiencies and medical sequelae such as com-



Table 4. Pretreatment Evaluation

Symptom assessmentPainVoice or speech alterationsSwallowing difficultyLoss of range of motion in neck or shouldersHearing lossVision changes

Dental careDental evaluation

Examination with radiographsEvaluate for trismus—if present, initiate range of motion exercisesRestoration workPeriodontal therapySmooth, rough, or irregular dental surfacesAssess dental appliances for fitOral surgery for removal of diseased teeth

Dental educationOral hygiene instructionsFluoride treatmentsDiet counseling

Nutritional/swallowing assessmentWeight loss history

Establish degree and rapidity of weight lossNutritional supplements as neededIf patient is at high risk, consider feeding tubeReferral for dietary counseling if needed

Vitamin supplement historyThiamine supplementation if history of alcohol useIron supplementation if indicated (anemia history or chronic bleeding)Speech and language pathology referral if availableProvide swallowing exercises for ongoing use

Psychosocial evaluationDetermine level of social support

(continued)



promised hepatic function or cognitive impairment. Although these factorsare not in and of themselves contraindications to CRT, they must be takeninto account in selecting a patient’s treatment regimen. A simple and realisticapproach to identifying patients with alcohol-related problems is to use abrief questionnaire, such as the CAGE questionnaire, as a routine in allpatients (see Table 4). For treatment recommendations or more informationon alcoholism or alcohol-related illness, visit the American Society of Addic-tion Medicine web site (www.asam.org/publ/detoxification.htm).

The second major psychiatric issue is depression. HNC patients have ahigh rate of premorbid depression. As many as 40% of HNC patientscomplain of depression either before diagnosis or after diagnosis. Patients

Identify current or previous history of mood disorders (anxiety and depression)

Alcohol history (CAGE questionnaire)a

Have you ever felt the need to cut down on drinking? Have you ever felt annoyed by criticism of your drinking?Have you ever had guilty feelings about your drinking?Have you ever taken a morning eye opener?

DSM-IV criteria for alcohol abuseb Failure to fulfill work, school, or social obligations Recurrent substance use in physically hazardous situationsRecurrent legal problems related to substance use Continued use despite alcohol-related social/interpersonal problems

DSM-IV criteria for alcohol dependenceb Tolerance Withdrawal Substance taken in larger quantity than intendedPersistent desire to cut down or control useTime is spent obtaining, using, or recovering from the substance Social, occupational, or recreational tasks are sacrificedUse continues despite physical and psychological problems

aMayfield D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcohol-ism screening instrument. Am J Psychiatry 1974;131:1121.bAmerican Psychiatric Association. Diagnostic and statistical manual of mental disor-ders, fourth edition. Washington, DC: American Psychiatric Association, 1994.

Table 4. Pretreatment Evaluation (Continued)



with advanced stage, a premorbid history of depression, or poor supportnetworks are more likely to develop depression during or after treatment(50,51). Depression has been associated with a decrease in post-treatmentQOL (52). More important, recovery from the effects of CRT requires ahighly motivated and compliant patient. Depressed patients may find itdifficult to get out of bed and participate in rehabilitation activities, mak-ing recovery more prolonged and difficult. A practical method for screen-ing for depression in the office setting is to use a two-question screen thataddresses depressed mood (53). If patients answer either question in theaffirmative, further evaluation and treatment may be indicated.

During the past month, have you been bothered by feeling down, depressed, or hopeless?During the past month, have you been bothered by little interest or pleasure in doing things?

An under-recognized issue in HNC patients is anxiety. In a recent study,Haman (Haman K. Social anxiety in head and neck cancer patients,unpublished data) reported that 20% of patients treated for HNC devel-oped an anxiety disorder during or after treatment. The impact of anxietyon QOL and function was profound. It is interesting to note that mostpatients who developed anxiety during or after therapy do not have aprior history of anxiety. Issues that are often expressed by patients includefear of airway obstruction, fear of being immobilized during radiation,and fear of undergoing magnetic resonance imaging. Patients with severeproblems that impact on function or impact on the patient’s ability tocomplete therapy should be referred for psychiatric evaluation so thatappropriate medical therapy and counseling can be initiated. Patients withsevere claustrophobia may need deconditioning therapy to tolerate RT.

Conclusion

Treatment of head HNC with aggressive CRT regimens is associated withsignificant comorbidities. Careful patient selection is mandatory to ensurethat patients are physically and mentally capable of tolerating and manag-ing complicated treatment regimens and their associated toxicities. To pro-vide optimal outcomes for patients, it is important for the HNC treatmentteam to have a systematic approach for supportive care. Patients should beassessed in an organized fashion before (see Table 4), during (Table 5), andafter therapy (Table 6) for risk factors and areas in which supportive carecan prevent, improve, or treat symptoms. Supportive care protocols andregimens should be agreed on by the team. Individuals should be identified



Table 5. Assessment during Chemoradiotherapy

Symptom assessment (weekly during therapy):MucositisDermatitisTaste changesXerostomiaPhlegmAirway compromiseFatigueDepressionAnxietyCognitive changes

Dental careExamine oral hygieneBland rinses (warm water, bicarbonate, salt rinses) every 3–4 hoursContinue brushing of teeth and flossing until no longer possible due to

mucositisDiscontinue dentures when mucositis beginsFluoride treatment until discomfort from mucositis becomes too severe

MucositisPain medications—opioids are usually needed for moderate to severe

mucositisTopical anesthetics: lidocaine, benzocaine, tetracaineMiracle mouthwashAvoid mucosal irritants: acid, high temperature, spicy foods, alcohol,

or tobaccoMonitor for the development of concurrent infection (Candida, herpes

simplex virus)Nutrition

Weigh weekly Nutritional assessment weekly, with diet adjustments based on degree

of mucosal pain and swallowing abnormalitiesDietary consultation when indicatedSwallowing exercises throughout therapy if at all possibleEncourage continued swallowing if at all possiblePlacement of feeding tube when indicated

(continued)



Mucus productionSuction catheterSleep with head of bed elevated to avoid pooling of secretions in the

throatScopolamine patch (may be too drying for some patients)MucolyticsAntihistamines (may be too drying for some patients)Cough suppressants to avoid irritation of throatClear sodas to help break up mucus Humidification of air

Table 6. Assessment and Treatment after Treatment Is Completed

Symptom assessmentPatients should be assessed weekly in the early recovery phase to assess

toxicities and optimize rehabilitation.Nutrition and oral intake

Continue swallowing exercises while mucositis heals.If patient is tube dependent, initiate swallowing of soft bland foods as

early as possible. Avoid mucosal irritants—mucosal sensitivity may last for a prolonged

period post-treatment.Advance diet as tolerated to encourage tube independence.

Speech and language pathologist referralShould be done early for patients who are unable to swallowShould include instrumental assessment

Modified barium swallow Flexible Endoscopic Evaluation of Swallow

XerostomiaStimulatory measures

Gustatory

(continued)

Table 5. Assessment during Chemoradiotherapy (Continued)



who are willing to take responsibility for the routine assessment and treat-ment of complications and toxicities. With aggressive supportive care mea-sures, patients may tolerate therapy with fewer breaks and will recoverfunction more rapidly.

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PharmacologicPilocarpine, 5 mg PO qidCevimeline, 30 mg PO tid

Comfort measuresHumidified airArtificial saliva

Physical therapyCardiovascular activity—increase as tolerated

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Table 6. Assessment and Treatment after Treatment Is Completed (Continued)



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61CME

❖Management of Recurrent

Disease: Current Treatments and New Therapies

Ezra E. W. Cohen, MD, and Oyewale Abidoye, MD

Current Approach to Recurrent Disease

Head and neck cancers are a select group of uncommon and diverse malig-nancies that can be characterized by their pattern of spread and recurrence.As such, therapeutic approaches to these unique tumors are based not onlyon the tumor histology, but also on the site of disease, surrounding anatomy,as well as regional lymph node involvement. Approximately 95% of thesetumors are squamous cell carcinomas arising primarily from the lip/oral cav-ity, larynx, oropharynx, hypopharynx, and larynx. Other less common can-cers include mucoepidermoid carcinomas, adenoid cystic carcinomas, andadenocarcinomas, originating from the salivary glands (1).

Despite aggressive primary therapeutic approaches, up to 65% of patientsare treated for locally advanced disease relapse after primary therapy with sur-gery and/or radiation. Various studies have implicated locoregional control asa factor in DFS. With improvements in primary therapy, new focus has beendirected toward improving therapy for patients with recurrent disease. Thisincludes surgical resection and radiation or re-irradiation with or without con-comitant chemotherapy for locoregional disease as well as systemic therapywith chemotherapy and novel targeted agents for metastatic disease (1).

This chapter focuses on squamous cell carcinoma of the head andneck (SCCHN) and highlights the current perspectives in treatment for


62 Management of Recurrent Disease

recurrent disease as well as discusses the current investigational conceptsthat are leading to the development of newer therapies and treatmentmodalities.

Locoregional Therapies for Recurrent Head and Neck Cancer

Salvage Surgery

Surgical salvage remains the standard of care for treatment of patients withlocally recurrent disease. However, fewer than 30% of patients who presentwith locally recurrent disease are actually surgically resectable. The ability toobtain tumor-free margins is dependent on tumor location, surroundinganatomy, as well as the surgeon’s expertise. In cases in which extensive resec-tions are required, expected quality of life postoperatively is also a majorconsideration (2).

Overall survival (OS) and disease-free survival (DFS) rates after surgeryare variable and associated with individual patient characteristics, tumorpathology, presence of lymph node involvement, as well as the adequacy ofsurgical margins and use of postoperative radiotherapy (2).

Patients with early stage (T1 or T2) recurrent disease who undergo salvagesurgery alone have been reported to have OS rates and DFS rates of 30%–60%and 44%–88%, respectively (2,3). Ganly et al. (3) investigated the outcome of43 patients with early stage recurrent SCCHN after prior therapy with radia-tion alone for first recurrence. This study also compared outcomes betweenpatients treated with salvage partial laryngectomy (SPL) versus patients treatedwith salvage total laryngectomy (STL). Although the study was able to suggestthe feasibility of SPL in a select group of patients with favorable prognosticindicators, it also reported that up to 50% of patients who received SPL fororgan preservation went on to require an STL after progression of disease, andthis was also associated with poorer survival outcomes.

Gleich et al. (4) conducted a study of 48 patients with locally advanced (T3or T4) SCCHN undergoing salvage surgery. Twenty-four patients had pri-mary site recurrence, 20 patients had local recurrence in the neck, and 4 hadboth local and regional recurrence. Forty-one of these patients were treatedwith salvage surgery with or without radiation; the rest received radiationalone. Of the 48 patients treated, 42 died in less than 2 years. Results fromthis study showed a limited potential for long-term survival and DFS inpatients with recurrent disease treated with salvage surgery after initial ther-apy for advanced primary-site cancer. Careful counseling was recommendedfor patients opting to pursue this course of therapy (4).


Management of Recurrent Disease 63

Complications of salvage surgery are related to extensive surgical resec-tion and manipulation of previously irradiated tissues. These include fis-tula formation and local wound complications (3,4).

Role of Radiation Therapy in Locally Recurrent Disease

Patterns of recurrence have identified locoregional failure to be a commoncause for recurrent SCCHN, both locally and distally. This has led to anemphasis on locoregional control both in the primary setting and also inthe setting of locally recurrent disease. One modality of therapy that hasbeen used to improve locoregional control in recurrent disease after surgi-cal resection is radiation therapy.

Radiation Therapy for Patients Treated with Salvage SurgerySurgically resectable patients with recurrent disease with a high risk forlocoregional failure due to poor prognostic indicators (including multilevellymph node involvement, extranodal tumor extension, or positive surgicalmargins) should undergo adjunct therapy with radiation (5,6). Althoughthere are no absolute contraindications for those groups of patients withrecurrent disease who have not had prior radiotherapy, severe complicationsdo exist, and patients must therefore be closely monitored during and aftercompletion of therapy.

Emerging Concept of Re-Irradiation in Patients with Recurrent Head and Neck Cancer As previously discussed, patterns of recurrence in SCCHN point to locore-gional failure in both locally recurrent and distant metastatic disease (6). Thishas led to the development of the concept of re-irradiation treatment in patientswith locally recurrent SCCHN who have had prior radiation therapy (5,6).

The concept of re-irradiation involves the administration of a secondcourse of radiation therapy for patients with locally recurrent SCCHN whohave had prior therapy with radiation. This course of therapy offers a poten-tial curative option for patients with locally recurrent SCCHN who presentwith unresectable disease (5,6). Re-irradiation is commonly administered indoses of 60–70 Gy with concomitant chemotherapy in radiosensitizing doses.This is done to increase the antitumor activity in the field of recurrence whereradio-resistant tumor clonogens may exist (5,6).

Although several phase I–II studies have demonstrated severe toxicityexists with the administration of radiation to previously radiated tissues, thefeasibility of re-irradiation and its potential for long-term survival and DFS isevident. As such, treatment with re-irradiation for locally recurrent SCCHN



should only be considered by an experienced team ready to meet the problemsand complications and who know the limits of therapy (5,6). Since the 1970s,several studies have been conducted to investigate the feasibility of re-irradia-tion as a treatment modality for patients with locally recurrent disease (6).Table 1 summarizes some of the largest trials to date involving re-irradiation.

Institut Gustave Roussy (IGR) reported a 16-year series that included 169patients with locally recurrent, unresectable head and neck cancer (includingnon-squamous histology) (7). These patients were assigned to three groups. Thefirst group consisted of 27 patients receiving treatment from 1980 to 1996 withradiotherapy alone at a total dose of 65 Gy in 2-Gy fractions as a continuouscourse. The second group consisted of 106 patients who received treatmentwith a split-course re-irradiation and a concomitant chemotherapy regimen of5-fluorouracil (5-FU) at 800 mg/m2 and hydroxyurea at 1.5 g per day adminis-tered daily in a week on–week off fashion. The third group consisted of 36patients receiving hyperfractionated radiation (1.5 Gy twice a day) with a con-comitant chemotherapy regimen of mitomycin, 5-FU, and cisplatin, alsoadministered in a week on–week off fashion. The median cumulative dose afterthe second course of radiation was 120 Gy (6,7). Results of this study showedthat it was feasible to safely administer a second course of radiation with con-comitant chemotherapy. Grade 3 and 4 mucositis was the most common earlytoxicity, occurring in 14%–32% of treated patients. Late toxicities, occurring 6months post-therapy, included cervical fibrosis, trismus, and soft tissue necrosis.Five patients also died from carotid hemorrhage (7). Despite the significant tox-icities observed, the study showed complete response rates in the range of 25%to 41%. The highest rates were seen with the FHX (5-FU, hydroxyurea, dailyradiation) regimen. This was statistically higher than the response rates of 10%seen with palliative chemotherapy. Median survival was 10–11 months for allthree groups, with 13 patients achieving long-term DFS (6,7).

The University of Chicago treated 115 patients on seven different protocolsover 15 years and recently reported a retrospective review of the experience.These studies differed from the IGR study in two key aspects: (a) the strictselection of patients with squamous cell histology and (b) the use of salvagesurgery for complete resection or optimal debulking before re-irradiation in 49patients (6,8). All patients were treated with variants of the FHX regimen,including varying doses of hydroxyurea and 5-FU; the use of daily versustwice-daily radiation; as well as the addition of cisplatin, paclitaxel, irinotecan,or gemcitabine to the FHX regimen at varying doses (8). Nineteen patientsdied of treatment-related toxicity. Six patients had carotid hemorrhage, andonly one of these survived. Thirteen patients also developed osteoradionecrosisrequiring surgical repair (8). The median cumulative radiation dose was 131Gy with 3-year OS, progression-free survival, locoregional control, and free-dom from distant metastases rates of 22%, 33%, 51%, and 61%, respectively,


65

Tab

le 1

. Ph

ase

II–I

II C

linic

al T

rial

s in

Re-

Irra

diat

ion

for

Squa

mou

s C

ell C

arci

nom

a of

the

Hea

d an

d N

eck

Stud

y (R

efer

ence

s)N

o. o

f P

atie

nts

Tre

atm

ent

Med

ian

RT

D

ose

(Gy)

Loco

regi

onal

C

ontr

ol (

%)

Ove

rall

Surv

ival

(%

)

De

Cre

vois

ier e

t al.

(7)

27ST

D fx

RT

65N

A25

(2

y)10

6H

, 5-F

U/S

TD

fx R

T60

24 (

2 y)

36M

MC,

5-F

U, C

DD

P/ H

YP fx

RT

6010

(2

y)Sp

ence

r et

al.

81H

, 5-F

U/H

YP fx

RT

60N

A16

.9 (

2 y)

Sala

ma

et a

l. (8

)11

5ST

D fx

RT

, HYP

fx R

T w

ith

vari

ous

chem

othe

rapy

re

gim

ens

64.8

51 (

3 y)

22 (

3 y)

Hor

witz

et a

l. 10

5C

DD

P, p

aclit

axel

/HYP

fx R

T65

.4N

A25

.9 (

2 y)

Won

g et

al.

(6)

(ong

oing

)24

0 (t

o be

ac

crue

d)C

DD

P, p

aclit

axel

/HYP

fx R

T60

(pl

anne

d)N

AN

AC

T a

lone

CD

DP,

5-F

UC

DD

P, p

aclit

axel

CD

DP,

doc

etax

el

CD

DP,

cis

plat

in; C

T, c

hem

othe

rapy

; 5-F

U, 5

-flu

orou

raci

l; H

; hyd

roxy

urea

; HYP

fx R

T, h

yper

frac

tiona

ted

radi

atio

n; M

MC

, mito

myc

in ;

NA

, not

av

aila

ble;

RT

, rad

ioth

erap

y; S

TD

fx R

T, s

tand

ard

frac

tiona

ted

radi

atio

n.



which were statistically significant when compared to palliative chemotherapyalone (6,8). Multivariate analysis identified surgical resection, re-irradiationdose, and use of triple-agent chemotherapy (i.e., cisplatin, paclitaxel, or irino-tecan with FHX) as independent prognostic indicators for response and sur-vival (6,8).

Common toxicities seen with re-irradiation include xerostomia, mucositis,tissue fibrosis, trismus, osteoradionecrosis, poor healing in soft tissues andbones, dysphagia, and hypothyroidism. Less common severe life-threateningcomplications include vessel rupture (e.g., carotid artery blow-out) (5,6,8).

These two series were followed by three cooperative group trials con-ducted by the Radiation Therapy Oncology Group (RTOG). Two of thesetrials, RTOG 96-10 and RTOG 96-11, have been completed and are sum-marized in Table 1 (6). A third ongoing phase III trial (RTOG 0421) isbeing conducted to compare re-irradiation and concomitant chemotherapyto chemotherapy alone in patients with locally recurrent or second pri-mary SCCHN who are inoperable with a prior history of radiation (6).

Although the role of radiation (with or without concomitant chemo-therapy) in the setting of recurrent SCCHN still remains to be defined, itsrole in the setting of palliative care is definitive (9). Patient selectionincludes those with a relatively good performance status who experiencesignificant impairment in their quality of life due to cancer-related causes(e.g., severe pain and limited mobility due to osseous and spinal metasta-ses). These patients should be referred to a radiation oncologist for consul-tation regarding palliative radiation (9).

Systemic Therapy for Recurrent Head and Neck Cancer

Palliative treatment with systemic therapy includes conventional chemo-therapy and novel targeted therapy. Response rates with these therapiesare variable, with several phase II–III clinical trials showing overallresponse rates to combination chemotherapy in the order of 20%–40%and single-agent therapy, including non-cytotoxics, in the order of 5%–15% (10,11).

Although these response rates are clinically significant, it also impor-tant to remember that systemic therapy has not been adequately demon-strated to improve OS, and its role in therapy continues to be a palliativeone with the goal of controlling symptoms and improving quality of life(10,11). This distinction is important to recognize in the selection of patientsfor treatment, with consideration given to treatment toxicity and tolerabil-ity (10,11).



Evolution of Systemic Chemotherapy

Combination chemotherapy has demonstrated the highest response ratesin systemic therapy for recurrent and metastatic SCCHN, and is currentlythe standard of care. Several phase II–III studies comparing combinationchemotherapy versus single-agent therapy have shown statistically signifi-cant improvement in tumor response with combination chemotherapyover single-agent therapy (10,12). Single-agent therapy is currently recom-mended in cases in which prior combination chemotherapy has failed andtoxicity is of concern (10,13).

Although combination chemotherapy has been shown to have higherresponse rates than single-agent therapy, the incidence of high-grade toxicity issignificantly higher. One exception to this has been the combination regimenof cisplatin and 5-FU. The effective response rates and favorable toxicity pro-file have led to this combination regimen becoming the most widely recom-mended as first-line treatment for recurrent or metastatic SCCHN (10,13).

Other agents currently used in the treatment of SCCHN include the plati-num agents (cisplatin and carboplatin), the taxanes (paclitaxel and docetaxel),5-FU, capecitabine, gemcitabine, pemetrexed, as well as bleomycin andmethotrexate (MTX), which were both the most widely used cytotoxic agentsbefore the advent of the platinum agents (10,13).

Common Chemotherapy Agents Used for Recurrent Head and Neck Cancer

Platinum AgentsThe platinum agents are among the most widely used agents in the treatmentof SCCHN (10,13). These agents act through covalent binding to cell DNA.Cisplatin has been the most widely used and most favored for systemic ther-apy in recurrent SCCHN, in large part due to its statistically higher and rapidresponse rates when compared to other agents. Response rates for cisplatin insingle-agent therapy and combination chemotherapy are 10%–15% and25%–40%, respectively, depending on prior therapy. Its derivative compound,carboplatin, has been tested in phase II–III trials and found to have acceptable,though arguably lower, response rates. Adverse effects of platinum agentsinclude nephrotoxicity, neurotoxicity, nausea, and vomiting (which can bequite severe), as well hypersensitivity reactions (10,13,14).

TaxanesThe taxanes include paclitaxel and docetaxel, which have both found use insingle-agent therapy and as part of combination chemotherapy (10,13,15).



These agents act through inhibition of microtubule assembly in rapidlydividing cells. Single-agent responses range between 20% and 40% inuncontrolled trials (10,15). Both agents are administered on either weekly orevery 21-day schedules, with paclitaxel administered as a 3-hour infusionand docetaxel as a 1-hour infusion (10,15). Premedication is given with pac-litaxel to prevent possible hypersensitivity reaction and with docetaxel toalso prevent edema. Common toxicities include neutropenia, alopecia,fatigue, gastrointestinal symptoms, and peripheral neuropathy (15).

Methotrexate MTX was approved by the U.S. Food and Drug Administration (FDA) forcancer treatment in 1953 (10,14). Before the advent of platinum agents, thisdrug was one of the more widely used cytotoxic agents in the treatment ofSCCHN (10,13,14). MTX is a cell cycle–specific analog that is active in the S-phase of the cell cycle and inhibits the activity of dihydrofolate reductase (13).Single-agent response rates seen in phase II–III studies vary considerably,depending on prior therapy, but typically range between 5% and 10%, withhigher response observed in patients with no prior treatment (10,13).

Other commonly used agents, such as bleomycin and 5-FU, have single-agent response rates of 5%–10% and 15%, respectively (10).

Clinical Trials Using Combination Chemotherapy in Recurrent Head and Neck Cancer

Several clinical trials using combination chemotherapy have shown improve-ment in response rates (10), especially with platinum-containing regimens.However, no regimen has been shown to be better in improving survivalover another (10,14).

Cisplatin and 5-Fluorouracil The cisplatin and 5-FU combination regimen has become a reference regi-men for doublet therapy in part due to its reasonable response rates andfavorable toxicity profile when compared to other regimens (10,12–14).Since the regimen emerged in the early 1990s, several clinical trials havebeen conducted comparing this regimen with other combination regimensand single-agent therapies (10,13). The summation of the trials has beenoverall response rates for recurrent disease in the range of 30% to 40%and median OS of 6–8 months (10,13,14).

Two noteworthy trials were published in 1992, one by Jacobs et al. (16)and another by Forastiere et al. (12). The study by Jacobs et al. involved249 patients who were randomized to three clinical treatment arms (cis-



platin and 5-FU, cisplatin alone, and 5-FU alone). Results from this studyshowed the combination cisplatin and 5-FU regimen was statistically supe-rior in overall response rates (32%) compared to single-agent cisplatin(17%) or 5-FU alone (13%) (10,16). The second study by Forastiere et al.compared cisplatin and 5-FU and carboplatin and 5-FU to single-agentMTX. Results from this randomized control trial of 227 patients also vali-dated the superiority of cisplatin and 5-FU, with response rates to cisplatinand 5-FU, carboplatin and 5-FU, and MTX being 32%, 21%, and 10%,respectively. Neither of the two studies demonstrated improvement in sur-vival between the different regimens, though there appeared to be an asso-ciation between survival and patient performance status (10,12,16).

Taxanes and 5-Fluorouracil After the introduction of platinum-based combination therapy, studieswere also conducted using the taxanes paclitaxel and docetaxel. To date,no major studies have demonstrated superior response rates to the combi-nation of cisplatin and 5-FU. One multicenter phase II study of docetaxeland 5-FU in 63 patients with recurrent and metastatic SCCHN showed anoverall response rate of approximately 20%, with higher response ratesobserved in the cohort arm with a history of prior therapy (10,17,18).

Combination Therapy with Platinum Agents and Taxanes Several promising phase II and phase III trials investigating taxanes incombination with platinum agents have also been conducted. Gibson et al.(19) compared cisplatin/paclitaxel to cisplatin/5-FU in a phase III trial thatenrolled 218 patients. The overall response rates (26% and 27% in thepaclitaxel and 5-FU arms, respectively) and median OS (8.1 months and8.7 months in the paclitaxel and 5-FU arms, respectively) were nearlyidentical. Other phase II trials using platinum and taxane combinationshave demonstrated overall and complete response rates of 41%–70% and27%–52%, respectively (10,19,20).

Triple-Agent Regimens Treatment with triple-agent regimens has yielded higher response rates,both overall and complete, but with increasing toxicity (10,21). Threecommon regimens have included (a) cisplatin with paclitaxel and 5-FU;(b) docetaxel, cisplatin, and 5-FU; and (c) paclitaxel, ifosfamide, and cis-platin. Overall response and complete response rates for these regimensare comparable, 40%–60% and 12%–50% respectively, with the highestresponses and toxicities seen with cisplatin, paclitaxel, and 5-FU; mediansurvival for patients treated with these regimens ranges between 9 monthsand 14 months (10,21).



Despite the improvements seen in response rates, results from phase IIItrials of triple-agent regimens also show increased toxicity, particularlygrade 3–4 myelosuppression. As such, when considering patients for treat-ment with triple-agent regimens, the observation of increased toxicityneeds to be balanced against modest gains seen in survival (10,21).

Novel Targeted Therapy

Despite an increase in the number of available cytotoxic agents and their newuses in combination, median survival for these remains relatively unchangedwhen compared to single-agent therapy and appears to have reached a pla-teau. Toxicity, therefore, becomes a major consideration in therapy that is pal-liative rather than curative. This issue, along with new understanding oftumorigenesis, has led to the development of novel targeted therapy (10,22).

Epidermal Growth Factor ReceptorAs early as the mid-1960s, the epidermal growth factor receptor (EGFR)and its ligands were identified as playing a critical role in tumor cell prolif-eration as well as response to therapy. Most recently, in the 1990s it wasobserved that 80%–100% of SCCHN had an abnormal level of EGFRexpression (10,22,23). This generated interest in therapy through the inhi-bition of EGFR expression via antibodies (e.g., cetuximab) and small mol-ecule inhibitors (e.g., gefitinib and erlotinib) (10,11,22–25).

Cetuximab was approved for use in colorectal cancer in 2004 and in 2006as single-agent therapy for patients with platinum refractory, recurrent, ormetastatic SCCHN. Several phase II clinical trials have been conducted to studythe efficacy of cetuximab in recurrent SCCHN. A European study enrolled 103patients with recurrent or metastatic SCCHN and progression of disease aftertreatment with platinum-based chemotherapy. Subjects were administeredcetuximab at an initial dose of 400 mg/m2 followed by a weekly dose of 250mg/m2 until disease progression. After disease progression, these patients werethen offered the option of salvage therapy with cetuximab and the addition ofthe platinum agent that they previously had been treated with (10,11,22–25).Interim data from this study were first presented in 2004 by Trigo et al. (24)and later by Vermoken et al. (25) in 2005, who demonstrated that cetuximabmonotherapy was well tolerated, with a response rate of 13%, disease controlrate of 46%, and a median survival of 5.9 months, results that were compara-ble to those seen with first-line therapy and that represented a 2.5-monthincrease in median survival compared to platinum-refractory historical controls(10,22–25). Moreover, two phase II studies that each enrolled patients after fail-ure of a platinum-containing doublet regimen to continue platinum in combi-nation with cetuximab revealed an 11% response rate (25–27). In addition, a



phase III trial comparing cisplatin with or without cetuximab in first-line recur-rent or metastatic SCCHN observed a significant improvement in the secon-dary end point of response rate in the experimental arm (26% vs. 10%;P = .03) (28). The data, thus, suggest that cetuximab is an active agent in recur-rent/metastatic SCCHN. Table 2 highlights some of the recent trials involvingcetuximab in the treatment of recurrent or metastatic SCCHN.

Tyrosine kinase inhibitors directed against the EGFR also appear to beactive single agents, with both gefitinib and erlotinib demonstrating objectiveresponses (11% and 4%, respectively) (11). A phase II study of gefitinib dos-ing at 250 mg in recurrent or metastatic SCCHN was recently conducted atthe University of Chicago, and results demonstrated gefitinib to be well toler-ated at 250 mg, with modest benefit and without significant deterioration inoverall quality of life (29).

Randomized trials testing the role of gefitinib in SCCHN are under way.Almost every trial administering an EGFR inhibitor in SCCHN has also notedan association between development of skin toxicity related to the agents andimproved outcome. Whether this association reflects a true biologic phenome-non and the possible mechanisms underlying it remain to be elucidated (11).

Abidoye et al. (30) recently completed a phase II study of lapatinib, a dualinhibitor of EGFR and erbB2 tyrosine kinases, in patients with recurrent ormetastatic SCCHN. Preliminary data from this study did not indicate a statis-tically significant survival benefit when compared to best supportive care;however, further studies are ongoing (11,30).

Other AgentsOther agents under investigation in trials for recurrent or metastatic SCCHNinclude sorafenib, an inhibitor of Raf kinase and the vascular endothelialgrowth factor (VEGF) receptor, which recently gained FDA approval in thetreatment of renal cell carcinoma. Two phase II trials of sorafenib as single-agent therapy in recurrent or metastatic SCCHN have demonstrated a responserate of approximately 5% (31,32). Bevacizumab, an anti-VEGF monoclonalantibody, has been combined with erlotinib in recurrent/metastatic SCCHN,with a 14% response rate reported, suggesting the possibility of enhancementof EGFR-inhibitor activity. In addition, a phase I study of gefitinib with cele-coxib, a cyclooxygenase-2 inhibitor, demonstrated tolerability of the combina-tion and a promising response rate of 22% (33).

Conclusion

Even though the majority of patients with SCCHN present with local diseaseand there have been vast improvements in therapy of locally advanced disease,the majority of patients will eventually experience recurrent or metastaticmanifestations. The treatment of recurrent or metastatic disease can involve


72

Tab

le 2

.C

linic

al T

rial

s of

Cet

uxim

ab in

Rec

urre

nt o

r M

etas

tatic

Squ

amou

s C

ell C

arci

nom

a of

the

Hea

d an

d N

eck

Stud

y (R

efer

ence

s)N

o. o

f P

atie

nts

Cet

uxim

ab D

ose/

Sche

dul

eP

rior

T

hera

py

aR

esp

onse

R

ate

(%)

Pro

gres

sion

-Fre

e Su

rviv

al (

mo)

Ove

rall

Surv

ival

(m

o)

Base

lga

et a

l. (2

6)96

400

mg/

m2 l

oadi

ng;

250

mg/

m2 w

eekl

y1

prio

r pla

tinum

-co

ntai

ning

do

uble

t

102.

25.

2

Her

bst e

t al.

(27)

7640

0 m

g/m

2 loa

ding

; 25

0 m

g/m

2 wee

kly

1 pr

ior p

latin

um-

cont

aini

ng

doub

let

102.

86.

1

Burt

ness

et

al. (

28)

117

200

mg/

m2 l

oadi

ng;

125

mg/

m2 w

eekl

y;

cisp

latin

, 100

mg/

m2 q

4wk

No

prio

r che

mo-

ther

apy

26b

4.2

9.2

Ver

mok

en e

t al

. (25

)10

340

0 m

g/m

2 loa

ding

; 25

0 m

g/m

2 wee

kly

1 pr

ior p

latin

um-

cont

aini

ng

regi

men

132.

35.

9

a Pri

or th

erap

y re

pres

ents

pat

ient

elig

ibili

ty r

estr

ictio

ns in

thes

e tr

ials

.b R

espo

nse

rate

of c

ispl

atin

plu

s ce

tuxi

mab

.



surgery or re-irradiation if the disease is confined to locoregional recurrence,whereas systemic therapy is used with palliative intent in most patients. Cyto-toxic doublet therapy is active but has reached an efficacy plateau. Novel tar-geted agents are being intensely studied as monotherapy and in combinationwith conventional chemotherapeutic agents in recurrent or metastatic SCCHNin an effort to improve outcome, with inhibitors of EGFR already approved byregulatory authorities. Figure 1 displays a recommended treatment approachto the patient with recurrent or metastatic SCCHN.

References

1. Gibson MK, Forastiere A. Multidisciplinary approaches in the management ofadvanced head and neck tumors: state of the art. Curr Opin Oncol 2004;16:220–224.

Figure 1. Treatment approach to patients with recurrent or metastaticsquamous cell carcinoma of the head and neck. EGFR, epidermal growth fac-tor inhibitor.

Locally recurrent or distal recurrence/metastatic disease

Locally recurrent Distal recurrenceMetastatic disease

Is patient surgically resectable or operable?

Consider salvage surgery with or without adjuvant radiation

Consider treatment with radiation alone (if no prior) or with re-irradiation with concurrent chemotherapy

Consider clinical trial or systemic therapy with chemotherapy OREGFR inhibitor

Progression of disease

Consider clinical trial OR therapy with single-agent chemotherapy OR EGFR inhibitor

Consider clinical trial OR single-agent chemotherapy Discuss goal of care, consider hospice if progression continues

Further progression of disease

OR

YES NO



2. Wong LY, Wei WI, Lam LK, et al. Salvage of recurrent head and neck squamouscell carcinoma after primary curative surgery. Head Neck 2003;25:953–959.

3. Ganly I, Patel SG, Matsuo J, et al. Results of surgical salvage after failure ofdefinitive radiation therapy for early stage squamous cell carcinoma of theglottic larynx. Arch Otolaryngol Head Neck Surg 2006;132:59–66.

4. Gleich LL, Ryzenman J, Gluckman JL, et al. Recurrent advanced (T3 or T4)head and neck squamous cell carcinoma. Is salvage possible? Arch OtolaryngolHead Neck Surg 2004;130:35–38.

5. Sadeghi A, McLaren J, Grist WL, et al. Value of radiation therapy in addition tosurgery for cancer of the head and neck. Otolaryngol Head Neck Surg 1986;94:601–604.

6. Wong SJ, Machtay M, Yi L. Locally recurrent, previously irradiated head andneck cancer: concurrent re-irradiation and chemotherapy, or chemotherapyalone? J Clin Oncol 2006;24:2653–2658.

7. De Crevoisier R, Bourhis J, Domenge C, et al. Full dose reirradiation for unre-sectable head and neck carcinoma: experience at the Gustave-Roussy Institutein a series of 169 patients. J Clin Oncol 1998;16:3556–3562.

8. Salama JK, Vokes EE, Chmura SJ, et al. Long-term outcome of concurrent che-motherapy and reirradiation for recurrent and second primary head and necksquamous cell carcinoma. Int J Radiat Oncol Biol Phys 2006;64:382–391.

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10. Covelas AD. Chemotherapy options for patients with metastatic or recurrent squa-mous cell carcinoma of the head and neck. J Clin Oncol 2006;24:2644–2652.

11. Cohen EE. Role of epidermal growth factor receptor pathway-targeted therapyin patients with recurrent and/or metastatic squamous cell carcinoma of thehead and neck. J Clin Oncol 2006;24:2659–2556.

12. Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cis-platin plus fluorouracil and carboplatin plus fluorouracil versus methotrexatein squamous cell carcinoma of the head and neck. A Southwest OncologyGroup Study. J Clin Oncol 1992;10:1245–1251.

13. Fanucchi M, Khuri FR. Chemotherapy for recurrent or metastatic squamouscell carcinoma of the head and neck. Semin Oncol 2004;31:809–815.

14. Browman GP, Cronin L. Standard chemotherapy in squamous cell head andneck cancer: what we have learned from randomized clinical trials. SeminOncol 1994;21:311–319.

15. Schrijvers D, Vermoken JB. Taxanes in the treatment of head and neck cancer.Curr Opin Oncol 2005;17:218–224.

16. Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized study comparingcisplatin and fluorouracil as single agents and in combination for advanced squa-mous cell carcinoma of the head and neck. J Clin Oncol 1992;10:257–263.

17. Colevas AD, Adak S, Amrein PC, et al. A phase II trial of palliative docetaxelplus 5-fluorouracil for squamous cell cancer of the head and neck. Ann Oncol2000;11:535–539.

18. Genet D, Cupissol D, Calais G, et al. Docetaxel plus 5-fluorouracil in locallyrecurrent and/or metastatic squamous cell carcinoma of the head and neck. Aphase II multicenter study. Am J Clin Oncol 2004;27:472–476.

19. Adamo V, Ferraro G, Pergolizzi S, et al. Paclitaxel and cisplatin in patients withrecurrent and metastatic head and neck squamous cell carcinoma. Oral Oncol2004;40:525–531.

20. Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cis-platin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and



neck cancer (E1395): an intergroup trial of the Eastern Cooperative OncologyGroup. J Clin Oncol 2005;23:3562–3567.

21. Glisson BS, Murphy BA, Frenette G, et al. Phase II study of docetaxel and cis-platin combination chemotherapy in patients with squamous cell carcinoma ofthe head and neck. J Clin Oncol 2002;20:1593–1599.

22. Hitt R, Jimeno A, Millan J, et al. Phase II trial of dose-dense paclitaxel, cis-platin, 5-fluorouracil, and leucovorin with filgrastim support in patients withsquamous cell carcinoma of the head and neck. Cancer 2004;101:768–775.

23. Cohen EE. Novel therapeutic targets in squamous cell carcinoma of the headand neck. Semin Oncol 2004;31:755–768.

24. Trigo J, Hitt R, Koralewski E, et al. Cetuximab monotherapy is active inpatients with platinum-refractory recurrent/metastatic squamous cell carci-noma of the head and neck (SCCHN). Results of a phase II study. Proc Am SocClin Oncol 2004;22(14S):5502.

25. Vermoken J, Bourhis J, Trigo J, et al. Cetuximab (Erbitux ®) in recurrent/metastatic(R&M) squamous cell carcinoma of the head and neck (SCCHN) refractory to firstline platinum based therapies. Proc Am Soc Clin Oncol 2005;23(16S):5505.

26. Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepi-dermal growth factor receptor monoclonal antibody cetuximab in combinationwith platinum-based chemotherapy in patients with platinum-refractory meta-static and/or recurrent squamous cell carcinoma of the head and neck. J ClinOncol 2005;23:5568–5577.

27. Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epi-dermal growth factor receptor antibody cetuximab and cisplatin for recurrentand refractory squamous cell carcinoma of the head and neck. J Clin Oncol2005;23:5578–5587.

28. Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cis-platin plus cetuximab in metastatic/recurrent head and neck cancer: an EasternCooperative Oncology Group study. J Clin Oncol 2005;23(34):8646–8654.

29. Kane MA, Cohen EE, List M, et al. Phase II study of 250-mg gefitinib inadvanced squamous cell carcinoma of the head and neck (SCCHN). Proc AmSoc Clin Oncol 2004;22(14S):5586.

30. Abidoye OO, Cohen EE, Wong SJ, et al. A phase II study of lapatinib(GW572016) in recurrent/metastatic (R/M) squamous cell carcinoma of thehead and neck (SCCHN). Proc Am Soc Clin Oncol 2006;24(18S):5568.

31. Williamson SK, Moon J, Huang CH, et al. A phase II trial of BAY 43-9006 inpatients with recurrent and/or metastatic head and neck squamous cell carci-noma (HNSCC): a Southwest Oncology Group (SWOG) trial. Proc Am SocClin Oncol 2006;24(18S Part I):5550.

32. Siu LL, Winquist M, Agulnik SF, et al. A phase II study of BAY 43-9006 inpatients with recurrent and/or metastatic head and neck cancer squamous cellcarcinoma (HNSCC) and nasopharyngeal cancer (NPC). Proc Am Soc ClinOncol 2005;23(16S):5566.

33. Wirth LJ, Haddad RI, Lindeman NI, et al. Phase I study of gefitinib plus cele-coxib in recurrent or metastatic squamous cell carcinoma of the head and neck.J Clin Oncol 2005;23:6976–6981.


77CME

❖Integration of Chemotherapy

into Organ Preservation Strategies for Squamous Cell

Head and Neck Cancer


Treatment Goals

The appropriate identification of a treatment goal is critical in the manage-ment of any malignancy. Cure, when possible, is clearly the end point of great-est importance. However, for patients with cancers of the head and neck,achievement of that cure often comes with a significant cost. Surgical resec-tion, the historical standard of care, can result in the loss or compromise ofcrucial anatomic structures involved in important human functions, includingspeech, swallowing, and non-stomal breathing. As such, the concept of organpreservation has emerged as another important end point in head and neckcancer management.

It is important, however, that organ preservation be distinguished fromorgan function conservation. Although it may seem obvious that preservationof the organ is a necessary prelude to preservation of its function, this is anoversimplification. Current reconstruction and rehabilitation techniques oftenallow for successful preservation and/or restoration of organ function evenafter surgical resection. Conversely, nonoperative management, such as radia-tion with or without chemotherapy, may obviate primary site resection yet stillresult in significant functional disability. Furthermore, aggressive attempts topreserve one organ function may significantly and adversely affect another, as


78 Integration of Chemotherapy into Organ Preservation

in the patient who retains his or her larynx at the expense of significant inter-ference in swallowing. Attempts to preserve an organ that is destroyed by theinitial tumor extent are, as such, ill advised.

In patients with advanced laryngeal and hypopharyngeal cancers, theorgan at risk is the larynx. Although partial laryngeal surgery is possible inmany patients, larger primary site tumors often mandate a total laryngectomyfor optimal oncologic care. Stomal breathing and loss of normal vocalizationresult. For patients with oropharyngeal cancer, the definition of the organ atrisk is less clear. Little functional impairment is expected after resection of anearly tonsil or tongue lesion. Surgery for larger tumors, however, particularlyof the base of tongue or pharyngeal wall, may require significantly morbidprocedures, including total glossectomy and/or laryngectomy, and may pro-duce marked interference with normal speech and swallowing. Efforts to min-imize the resultant functional impairments are critical.

It is also critical that we, as oncologists, remember our patients’ charge.List et al. (1) reported the results of a study examining the relative valueassigned by patients to specific outcomes after treatment of head and neckcancer. The most important patient-defined treatment goal was cure, with sur-vival prolongation in second place. Symptomatic and functional concerns,such as freedom from pain, ability to swallow, and retention of a naturalvoice, proved less important. Maximizing a patient’s chance for cure, even atthe cost of functional impairment, remains the top priority. Although individ-ual patients may choose to sacrifice curative potential or survival benefit forfunctional preservation, this is not the rule, and these issues require carefulexploration when treatment options are reviewed.

Thus, although organ preservation and, more specifically, organ functionconservation are desirable treatment goals, they are secondary end points. Thesurvival equivalence of a nonoperative organ-preserving intervention and con-ventional surgical treatment must be established before such an organ-preser-vation strategy can be considered acceptable. Furthermore, better assessmentsof long-term organ function and measurements of overall patient satisfactionmust be designed and implemented. In the absence of these tools, however, thepotential for organ preservation often provides the best measure of organfunction conservation.

Organ-Preservation Strategies

Radiation Therapy and Surgery

Radiation therapy is the original organ-preserving treatment strategy insquamous cell head and neck cancer, and these malignancies are generally


Integration of Chemotherapy into Organ Preservation 79

considered to be very radiosensitive. However, organ function–preservingsurgical procedures are now welldefined for many head and neck primarysites and may be equally, if not more, successful in achieving primary sitecontrol and preserving primary site function (2). Thus, small primary sitetumors (T1–T2) may be approached with either single-modality radiationtherapy or surgery with, in many cases, relatively similar results. In theabsence of definitive studies comparing these two treatment approaches,the choice is often based on institutional expertise and patient preference.

Treatment of the primary site must also be considered separately fromtreatment of the neck. Organ preservation and organ function conserva-tion reflect an approach to the primary site tumor. The presence of clinicalneck node involvement or the possibility of spread to neck nodes must alsobe considered in all patients. A neck dissection can be accomplished irre-spective of the approach taken for the primary site and is often indicatedeven when definitive radiation therapy is chosen as the primary manage-ment. Although there can be functional deficits resulting from a neck dis-section, these rarely interfere with speech or swallowing.

For patients with larger (T3–T4) primary site tumors, the relative successof surgical resection and postoperative radiotherapy, compared to definitiveradiation therapy alone (with subsequent surgical salvage if necessary), isunknown. It is in this group of patients that the addition of systemic chemo-therapy to definitive locoregional management has had the greatest impact.

Integration of Systemic Chemotherapy

Systemic chemotherapy, as a single-treatment modality, can produce signif-icant tumor shrinkage in previously untreated patients with squamous cellhead and neck cancer. Response rates of 70%–90% (complete in 30%–50%) have been reported and led to considerable enthusiasm about thepotential impact of this treatment modality (3). It was disappointing whenthe phase III studies that tested chemotherapy given either before definitivemanagement or as an adjuvant after locoregional treatment were unable todemonstrate a reproducible survival benefit (3–5). When chemotherapyand radiation were given concurrently, however, whether as the definitivenonoperative treatment or in the postoperative adjuvant setting, a clearimprovement in overall survival was demonstrated. As such, concurrentradiation and systemic chemotherapy became an integral part of the stan-dard care for many patients with locoregionally advanced squamous cellhead and neck cancer (3,4).

Whether systemic chemotherapy can also improve the possibility of organpreservation can be evaluated in several ways. Optimally, a phase III trial



should be performed comparing a nonsurgical, chemotherapy-based, organ-preserving approach with a primary operative intervention. The objective ofsuch a study would be to demonstrate an improvement in organ preservation(and by inference, organ function conservation) without a reduction in sur-vival. Alternatively, and less definitively, comparative clinical trials of definitivenonoperative approaches (e.g., radiotherapy versus concurrent chemoradio-therapy) can report the likelihood of local disease control—a reasonable meas-ure of organ preservation in the absence of planned surgical resection.Although the likelihood of organ preservation in surviving patients has oftenbeen cited as an end point of interest, it reflects a measure of limited impor-tance if significant numbers of patients do not survive. A more meaningful endpoint is the likelihood of survival with an intact organ.

The potential for chemotherapy to favorably impact the likelihood oforgan preservation in patients with squamous cell head and neck cancer wasfirst reported by Jacobs et al. in 1987 (6). Twelve head and neck cancerpatients who had experienced a pathologic complete response at the primarysite after induction chemotherapy with 5-fluorouracil and cisplatin weretreated with definitive radiation therapy alone, rather than the originallyplanned laryngectomy, glossectomy, or composite resection. When this experi-ence was reported, 8 of the 12 patients so treated were free of disease, with asurvival rate equivalent to patients who had undergone definitive surgery.Other investigators repeated this experience, often focusing on larynx cancer(7–10). Avoidance of a laryngectomy was thought to be a sufficiently compel-ling reason to justify an organ-preservation strategy, particularly as salvagelaryngectomy, even after failure of definitive radiation, was a well-establishedand successful procedure.

This phase II experience led to the design and performance of the largeDepartment of Veterans Affairs (VA) Laryngeal Cancer Study Group larynxpreservation trial, first reported in 1991 (11). Three-hundred thirty-twopatients with advanced larynx cancer were randomized to receive either induc-tion chemotherapy with cisplatin and 5-fluorouracil followed by radiationtherapy in responders or to a laryngectomy followed by radiation. Chemother-apy nonresponders underwent laryngectomy and postoperative radiation.Patients on the nonsurgical arm with residual or recurrent disease after defini-tive radiation were also offered salvage laryngectomy.

The response to induction 5-fluorouracil and cisplatin was equivalent to thebest of the induction chemotherapy regimens previously reported, with anoverall response rate of 85% and a complete response rate of 31%. Similar toother induction trials being completed at this time, no survival benefit wasidentified for those patients who received the induction chemotherapy. How-ever, there was also no loss of survival potential on this treatment arm. Further-more, for the chemotherapy-treated patients, larynx preservation was possiblein approximately 2/3 of the survivors, and survival with an intact larynx at 3



years was 31%. The results of this study supported the contention that chemo-therapy might substitute for surgical resection in responsive patients, perhapsby enhancing the benefit achieved from the radiation therapy. Alternatively, itwas suggested that a response to induction chemotherapy might have onlyserved to identify those patients likely to experience a good response afterdefinitive radiation therapy. Chemotherapy (and therefore radiotherapy) non-responders were thus identified early and better served by an immediate surgi-cal resection. Regardless, the absence of a clear survival difference betweenthese two treatment arms justified a nonoperative, organ-preserving approachfor patients with advanced resectable larynx cancer and legitimized the conceptof organ preservation as an appropriate end point in the management of thisdisease.

The potential for organ preservation has been supplemented by long-termfunctional assessments that have been reported from this study (12,13). Mostpatients undergoing laryngectomy were able to re-establish some kind of vocalcommunication, whether by esophageal speech, a tracheoesophageal puncture,or an artificial larynx. Objective evaluation, however, demonstrated signifi-cantly better speech intelligibility in patients randomized to the nonoperativetreatment. Swallowing assessments, as reported by the patient, were equivalentbetween the two treatment arms, but overall quality of life was better in thelarynx-preservation arm.

A similar study was reported by the European Organisation for Researchand Treatment of Cancer (EORTC) in patients with primary hypopharyn-geal tumors using a nearly identical study design (14). Survival again provedstatistically equivalent between the two treatment arms, and the 3-year sur-vival with a functional larynx was 28% in the patients treated with chemo-therapy. A third, smaller trial, reported in 1998 by the French Grouped’Etudes des Tumeurs de la Tête et du Cou also used the same study designin previously untreated patients with T3 disease, all presenting with a fixedvocal cord (15). This study was terminated prematurely because of patientrefusal to be randomized to the surgical arm. Despite this early closure, sur-vival and disease-free survival proved significantly worse in the group giveninduction chemotherapy, a result discordant with the other two, larger stud-ies (Table 1). A metaanalysis of updated individual patient data from thesethree randomized trials noted a nonsignificant trend suggesting a survival ben-efit in those patients randomized to laryngectomy despite the clear improve-ment in organ preservation on the chemotherapy arm (Table 2) (16).

A closer look at this study design, however, leads one to conclude that theimpact of the chemotherapy is not clear. Indeed, the survival equivalencebetween the two treatment arms seen in the VA and EORTC trials may onlyreflect the equivalence of a primary surgical and a primary radiotherapeuticapproach in patients with advanced laryngeal and hypopharyngeal cancers.This observation led to the development and performance of a second-


82

Tab

le 1

.Ra

ndom

ized

Org

an P

rese

rvat

ion

Tri

als

of In

duct

ion

Che

mot

hera

py a

nd R

adia

tion

vers

us S

urgi

cal R

esec

tion

and

Radi

atio

n

Gro

up

(Ref

eren

ce)

Year

Pri

mar

y Si

teN

o. o

f P

atie

nts

Che

mot

hera

py

Surv

ival

A

live/

Org

an

Pre

serv

ed

Dep

artm

ent o

f Vet

eran

s A

ffai

rs L

aryn

geal

Can

-ce

r St

udy

Gro

up (

11)

1991

Lary

nx33

2PF

No

diff

eren

ce31

% (

3 y)

Eur

opea

n O

rgan

isat

ion

for

Rese

arch

and

Tre

at-

men

t of C

ance

r (1

4)

1996

Hyp

opha

r-yn

x20

2PF

No

diff

eren

ce28

% (

3 y)

Gro

upe

d’E

tude

s de

s T

umeu

rs d

e la

Têt

e et

du

Cou

(15

)

1998

Lary

nx68

PFA

dvan

tage

: su

rger

y—

F, 5

-flu

orou

raci

l; P,

cis

plat

in.



generation Head and Neck Intergroup larynx preservation trial (RadiationTherapy Oncology Group 91-11) (17,18). In this trial, the successful experimen-tal arm from the VA laryngeal cancer study (induction chemotherapy followedby radiation in responders) was compared to radiation therapy alone and to athird arm of radiation therapy with concurrent single-agent, high-dose cisplatinin patients with resectable stage III and IV larynx cancer. A laryngectomy armwas not included in this study, and laryngectomy was reserved for persistent orrelapsed disease or for nonresponders to induction chemotherapy. A neck dis-section was planned for all patients with N2 or N3 disease at the time of diag-nosis. The results of this study demonstrated no significant difference in larynxpreservation or in locoregional control when the induction chemotherapy armwas compared to the radiation therapy–alone arm. The concurrent radiationand single-agent cisplatin treatment arm, however, proved superior for both endpoints. It should be noted, however, that in the most recent update of this study,reported at the 2006 meeting of the American Society of Clinical Oncology, thecombined end point of laryngectomy-free survival was equivalent for the induc-tion and the concurrent arms and was superior to radiation therapy alone (18).Survival remained the same between all three treatment arms, an observationattributed at least in part to the success of salvage laryngectomy.

A similar observation was made in a smaller trial reported from the Cleve-land Clinic (19). This study randomized non–site-specific patients with resect-able stage III and IV head and neck cancer to either definitive radiationtherapy or definitive radiation and concurrent chemotherapy. The concurrentchemoradiotherapy regimen consisted of radiation, cisplatin, and 5-fluoroura-cil. Provisions for salvage surgery were incorporated into the study forpatients with no clinical response after 50–55 Gy of radiation, with persistent

Table 2. Metaanalysis: Larynx Preservation Trials of Neoadjuvant Chemotherapy

Response Rate (95% Confidence Interval)

Chemotherapy (%)

No Chemotherapy (%)

Overall survival

1.19 (0.97–1.46) 39 45; P = .1

Disease-free survival

1.18 (0.97–1.44) 34 40; P = .1

Note: Survivors with functional larynx at 5 years = 58%.Information compiled from Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. Lancet 2000;355:949–955.



disease after the completion of a full course of radiation, or with a subsequentlocoregional recurrence. Recurrence-free interval, local control without surgi-cal resection, and overall survival with primary site preservation proved statis-tically superior in the concurrent chemoradiotherapy arm. An unplannedsubset analysis demonstrated an improvement in overall survival with primarysite preservation for both the patients with laryngeal cancer and hypopharyn-geal cancer when treated with concurrent chemoradiotherapy. When required,salvage surgery proved successful in between 63% and 73% of patients, and,as a result, there was no difference in overall survival between the two treat-ment arms.

The results from these two studies in patients with resectable head andneck cancer are, therefore, consistent (Table 3). The addition of concurrentchemotherapy to definitive radiation therapy can improve the potential fororgan preservation. Appropriate integration of surgical salvage appears toblur any overall survival differences between these two treatment approaches,although a survival benefit has been observed from concurrent chemoradio-therapy (compared to radiotherapy alone) in unresectable patients (20) and inthe postoperative setting (21,22).

It should again be noted, however, that the results after concurrent chemo-radiotherapy in these two trials were not compared to definitive surgery-basedapproaches. The survival equivalence (or superiority) of concurrent chemora-diotherapy and conventional surgery has not been established. There has beenonly one reported study that has compared these two treatment approaches.This study, from Singapore, compared concurrent 5-fluorouracil, cisplatin,and radiation therapy with surgery and postoperative radiation in 119 ran-domized patients (23). Although there was significant difficulty in patientcompliance with both treatment regimens, no overall survival difference wasidentified between the two treatment arms. Organ preservation was possiblein 42% of the entire patient cohort treated with chemoradiotherapy and in62% of those patients with larynx or hypopharyngeal primaries.

The data for oropharynx cancer is considerably less clear. Phase II trials ofboth induction and concurrent chemoradiotherapy programs have beenreported, and the possibility of avoiding surgical resection has been described(24,25). Phase III trials of concurrent chemotherapy and radiation therapyhave suggested both a survival benefit and an improvement in locoregionalcontrol when concurrent chemoradiotherapy is compared to radiation ther-apy alone (26,27). Once again, however, in the absence of conclusive random-ized data, the survival equivalence of primary surgery and these nonoperativeapproaches has not been proven. Furthermore, equivalence in long-termorgan function conservation can also not be assumed, and assessments of bothobjective measurements of speech and swallowing as well as subjective mea-sures of overall quality of life are required.


85

Tab

le 3

.Ph

ase

III T

rial

s of

Con

curr

ent C

hem

orad

ioth

erap

y fo

r O

rgan

Pre

serv

atio

n

Stud

y (R

efer

ence

)E

nd P

oint

aR

adia

tion

(%)

Che

mor

adia

tion

(%)

Ind

uctio

n (%

)P

roba

bilit

y

Inte

rgro

up

(R

adia

tion

Th

erap

y O

nco

logy

Gro

up

91-

11)

(18)

Lary

ngea

l pre

serv

a-tio

n66

8471

<.0

1

Lary

ngec

tom

y-fr

ee

surv

ival

3447

45.0

11

Loco

regi

onal

con

trol

5169

55<

.01

Ove

rall

surv

ival

5455

59N

.S.

Cle

vela

nd

Clin

ic (

19)

Surv

ival

with

org

an

pres

erva

tion

3442

—.0

04

Loca

l con

trol

with

-ou

t sur

gery

4577

—<

.001

Ove

rall

surv

ival

4850

—N

.S.

a Fiv

e-ye

ar e

stim

ates

.N

.S.,

not s

tatis

tical

ly s

igni

fican

t.



Identification of Optimal Treatment

An important question arises from these nonoperative, organ-preservingtreatment strategies. Can patients likely to do well with nonoperative interven-tion be identified early in their treatment course? If so, such patients couldmore confidently be given definitive nonoperative therapy with the goal oforgan preservation. Patients not deemed likely to benefit from this approachcould undergo initial surgical resection. There are currently several clinical dis-ease features that can identify patients less likely to do well with radiation ther-apy and more appropriate for surgical resection. Certainly, those patientspresenting with a destroyed organ will not experience any benefit from anattempt to preserve this organ. Similarly, patients with advanced larynx orhypopharynx cancer with subglottic extension or tumor directly invading intoneck, thyroid, or cricoid cartilage do not do well with primary radiation ther-apy–based approaches. In addition, comorbid illness or limited social supportsmay actually mandate surgical resection as the less morbid of treatmentapproaches, given the considerable toxicity associated with chemotherapy andradiation.

In recognition of the observation that a response to induction chemother-apy is predictive of a subsequent response to radiation therapy (28), it hasbeen suggested that chemotherapy responsiveness may be useful in prospec-tively identifying those likely to benefit from nonoperative approaches. Inves-tigators in Michigan have reported their results from a trial in stage III and IVlarynx cancer using this approach (29). After an initial course of chemother-apy, nonresponders proceeded to immediate laryngectomy while those achiev-ing a response were treated with definitive concurrent chemoradiotherapy.Larynx preservation proved possible in 70% of the patients in this series, witha 3-year projected overall survival of 85%.

A similar approach has been incorporated into the current Intergroupphase III trial for resectable oropharynx cancer (Figure 1). Patients entered onthis trial are randomized between definitive concurrent chemoradiotherapyalone and induction chemotherapy followed by concurrent chemoradiother-apy in responders. Patients not responding to induction chemotherapyundergo early surgical salvage. This study will hopefully shed light on both thepotential improvement in survival to be gained from adding induction chemo-therapy to concurrent treatment, as well as the possibility that a failure torespond to chemotherapy can identify those patients who will benefit fromearly surgical salvage. Critical in the evaluation of results from this study willbe a careful assessment of both late toxicities and quality of life.

It must be pointed out that the use of induction chemotherapy should stillbe considered an experimental intervention. This is important when interpret-ing the recent reports of randomized trials comparing the well-tested cisplatinand fluorouracil induction regimen with the three-drug combination of cis-



platin, fluorouracil, and a taxane (3,30). Although the three-drug inductionregimens have consistently produced a superior response rate, the impact ofthese induction regimens on the results achieved after optimal concurrent che-moradiotherapy is unknown and is the question being asked by several ongo-ing phase III trials such as the Intergroup study previously discussed (seeFigure 1). Indeed, Calais and colleagues (31) have recently reported theirresults comparing induction cisplatin and fluorouracil with or without doce-taxel followed by radiation therapy for larynx preservation. Although radia-tion therapy alone, as definitive management, must be considered a suboptimalchoice, both the response rate and the laryngeal preservation rate were supe-rior in the docetaxel arm. These results are intriguing and certainly confirmgreater activity for this three-drug chemotherapy combination. Although suchan induction regimen may ultimately prove of benefit in conjunction withoptimal concurrent treatment, induction chemotherapy is currently onlyappropriate within the context of a clinical trial.

Recent results from a large phase III trial comparing radiation therapy withradiation therapy and cetuximab have been reported (32). An improvement inboth overall survival and locoregional control was found in those patientstreated with cetuximab, although this benefit appeared to be confined topatients with oropharynx cancer treated with the concomitant boost radio-therapy schedule. No impact on distant metastases was seen from the additionof cetuximab. Incorporation of this kind of targeted intervention into current

Figure 1. Treatment schema for the current Intergroup phase III trial of con-current chemoradiotherapy, with or without induction chemotherapy forresectable squamous cell carcinoma of the oropharynx. *Unresectable patientsor those refusing surgery proceed to concurrent chemoradiotherapy. 5-FU,5-fluorouracil; RT, radiation therapy.

RANDOMIZE

Induction:Docetaxel (T), 75 mg/m2

Cisplatin (P), 75 mg/m2

5 FU (F), 1,000 mg/m2/d × 4– one course –

Concurrent:RT: 70 Gy at 2 Gy/dCisplatin, 100 mg/m2

q21d × 3

Concurrent:RT: 70 Gy at 2 Gy/dCisplatin, 100 mg/m2

q21d × 3

Nonresponders: Surgery*

Responders: TPF × 2 (3 total)



chemotherapy and radiation therapy schedules is being intensively exploredwith the hope that an improvement in both organ preservation and survivalwill result.

Conclusion

An agenda for clinical investigation has emerged. Although it is unlikely thatany additional true organ-preservation trials with a surgery-based controlarm will be conducted in the future, investigation will continue to focus onthe optimal integration of chemotherapy, radiation therapy, and the newertargeted agents. An improvement in survival remains the most importanttreatment goal, but attention to not just organ preservation but to a carefulassessment of organ function and quality of life is mandatory. These answerswill only come through continued close cooperation between all profession-als involved in the care of these patients and continued entry of thesepatients onto well-designed and carefully conducted clinical trials.

References

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2. Weinstein GS. Surgical approach to organ preservation in the treatment of can-cer of the larynx. Oncology 2001;15:785–796.

3. Adelstein DJ, LeBlanc M. Does induction chemotherapy have a role in themanagement of locoregionally advanced squamous cell head and neck cancer?J Clin Oncol 2006;24:2624–2628.

4. Cohen EEW, Lingen MW, Vokes EE. The expanding role of systemic therapy inhead and neck cancer. J Clin Oncol 2004;22:1743–1752.

5. Laramore GE, Scott CB, Al-Sarraf M, et al. Adjuvant chemotherapy for resect-able squamous cell carcinomas of the head and neck: report on IntergroupStudy 0034. Int J Radiat Oncol Biol Phys 1992;23:705–713.

6. Jacobs C, Goffinet DR, Goffinet L, et al. Chemotherapy as a substitute for sur-gery in the treatment of advanced resectable head and neck cancer. A reportfrom the Northern California Oncology Group. Cancer 1987;60:1178–1183.

7. Demard F, Chauvel P, Santini J, et al. Response to chemotherapy as justifica-tion for modification of the therapeutic strategy for pharyngolaryngeal carci-nomas. Head and Neck 1990;12:225–231.

8. Pfister DG, Strong E, Harrison L, et al. Larynx preservation with combinedchemotherapy and radiation therapy in advanced but resectable head and neckcancer. J Clin Oncol 1991;9:850–859.

9. Karp DD, Vaughan CW, Carter R, et al. Larynx preservation using inductionchemotherapy plus radiation therapy as an alternative to laryngectomy inadvanced head and neck cancer. Am J Clin Oncol 1991;14:273–279.

10. Price LA, Shaw HJ, Hill BT. Larynx preservation after initial non-cisplatin con-taining combination chemotherapy plus radiotherapy, as opposed to surgicalintervention with or without radiotherapy in previously untreated advanced



head and neck cancer: final analysis after 12 years follow-up. J Laryngol Otol1993;107:211–216.

11. Wolf GT, Hong WK, Fisher SG, et al. Induction chemotherapy plus radiationcompared with surgery plus radiation in patients with advanced laryngeal can-cer. N Engl J Med 1991;324:1685–1690.

12. Terrell JE, Fisher SG, Wolf GT, et al. Long term quality of life after treatmentfor laryngeal cancer. Arch Otol Head Neck Surg 1998;124:964–974.

13. Hillman RE, Walsh M, Wolf GT, et al. Functional outcomes following treat-ment for advanced laryngeal cancer. Ann Otol Rhinol Laryngol 1998;107(Suppl 172):1–27.

14. Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriformsinus cancer: preliminary results of a European Organization for Research andTreatment of Cancer phase III trial. J Natl Cancer Inst 1996;88:890–899.

15. Richard JM, Sancho-Garnier H, Pessey JJ, et al. Randomized trial of inductionchemotherapy in larynx carcinoma. Oral Oncology 1998;34:224–228.

16. Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregionaltreatment for head and neck squamous-cell carcinoma: three meta-analyses ofupdated individual data. Lancet 2000;355:949–955.

17. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy andradiotherapy for organ preservation in advanced laryngeal cancer. N Engl JMed 2003;349:2091–2098.

18. Forastiere AA, Maor M, Weber RS, et al. Long-term results of IntergroupRTOG 91-11: a phase III trial to preserve the larynx—induction cisplatin/5-FUand radiation therapy versus concurrent cisplatin and radiation therapy versusradiation therapy. 2006 ASCO Annual Meeting Proceedings Part I. J ClinOncol 2006;24(abstract):284s.

19. Adelstein DJ, Lavertu P, Saxton JP, et al. Mature results of a phase III random-ized trial comparing concurrent chemoradiotherapy with radiation therapyalone in patients with stage III and IV squamous cell carcinoma of the headand neck. Cancer 2000;88:876–883.

20. Adelstein DJ, Li Y, Adams GL, et al. An Intergroup phase III comparison ofstandard radiation therapy and two schedules of concurrent chemoradiother-apy in patients with unresectable squamous cell head and neck cancer. J ClinOncol 2003;21:92–98.

21. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with orwithout concomitant chemotherapy for locally advanced head and neck cancer.N Engl J Med 2004;350:1945–1952.

22. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiother-apy and chemotherapy for high-risk squamous-cell carcinoma of the head andneck. N Engl J Med 2004;350:1937–1944.

23. Soo KC, Tan EH, Wee J, et al. Surgery and adjuvant radiotherapy vs. concur-rent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head andneck cancer: a randomised comparison. Brit J Cancer 2005;93:279–286.

24. Pfister DG, Harrison LB, Strong EW, et al. Organ-function preservation inadvanced oropharynx cancer: results with induction chemotherapy and radia-tion. J Clin Oncol 1995;13:671–680.

25. Urba SG, Moon J, Shankar Giri PG, et al. Organ preservation for advancedresectable cancer of the base of tongue and hypopharynx: a Southwest Oncol-ogy Group trial. J Clin Oncol 2005;23:88–95.

26. Staar S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated acceleratedradiotherapy limits the additional benefit of simultaneous chemotherapy-results of a multicentric randomized German trial in advanced head and neckcancer. Int J Radiat Oncol Biol Phys 2001;50:1161–1171.



27. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head andNeck Oncology and Radiotherapy Group randomized trial comparing radio-therapy alone with concomitant radiochemotherapy in advanced-stage oro-pharynx carcinoma. J Clin Oncol 2004;22:69–76.

28. Ensley JF, Jacobs JR, Weaver A, et al. Correlation between response to cisplat-inum-combination chemotherapy and subsequent radiotherapy in previouslyuntreated patients with advanced squamous cell cancers of the head and neck.Cancer 1984;54:811–814.

29. Urba S, Wolf G, Eisbruch A, et al. Single-cycle induction chemotherapy selectspatients with advanced laryngeal cancer for combined chemoradiation: a newtreatment paradigm. J Clin Oncol 2006;24:593–598.

30. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparingcisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil inductionchemotherapy followed by chemoradiotherapy in locally advanced head andneck cancer. J Clin Oncol 2005;23:8636–8645.

31. Calais G, Pointreau Y, Alfonsi M, et al. Randomized phase III trial comparinginduction chemotherapy using cisplatin (P) fluorouracil (F) with or withoutdocetaxel (T) for organ preservation in hypopharynx and larynx cancer. Pre-liminary results of GORTEC 2000-01. 2006 Annual Meeting Proceedings Part1. J Clin Oncol 2006;24(abstract):281s.

32. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab forsquamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–578.


91CME

❖Intensity-Modulated Radiation Therapy:

Promises and Practice

Gregory Russo, MD, and Mitchell Machtay, MD

Introduction of a New Treatment Approach

Intensity-modulated radiation therapy (IMRT) is a relatively new way ofdelivering three-dimensional conformal radiation therapy (3D CRT). Ideally,IMRT allows for delivery of high doses of highly conformal radiation therapyto clinical target volumes while preserving critical normal structures. Since itsintroduction into clinical use in the late 1990s, it has resulted in a flurry ofactivity in research and clinical practice to identify the ideal clinical situationsto which it should be applied, how to safely and effectively implement a treat-ment program, and how to develop the necessary complementary technolo-gies to take full advantage of its capabilities.

Since the 1990s, IMRT has become standard practice in the treatment ofselected types of head and neck cancers at many academic and private centers.Recently, preliminary reports of the first prospective randomized trial ofIMRT versus traditional radiation therapy were presented at the annual meet-ing of the American Society of Clinical Oncology (ASCO) in 2005 thatshowed the benefits in the preservation of salivary gland function (1).

As with any new technology, there is a learning curve associated withIMRT that appears to be very large. As institutional experiences are reviewed,the benefits of IMRT in the preservation of normal critical structures andimprovement of target coverage come at a cost of increased resources and, insome cases, increased treatment-related toxicity. In this chapter, we provide an


92 Intensity-Modulated Radiation Therapy

overview of the differences between IMRT and traditional radiation therapy,the potential benefits and stumbling blocks associated with this technology,and the selection of patients for whom IMRT is an appropriate treatment.

Intensity-Modulated Radiation Therapy—Definition and Historical Perspective

Before the introduction of IMRT into clinical practice, most head and neckcancers were treated with a combination of large opposed lateral (right and leftlaterally directed) radiation fields to encompass the primary tumor andregional lymphatics in the upper and mid-neck, plus an anteriorly directed radi-ation field to encompass the lower neck and supraclavicular fossa (Figure 1).Through the use of custom blocking, some critical structures peripherally orcentrally located can be partly or wholly shielded from radiation exposure todecrease acute and/or long-term toxicity. Within the entire treatment field, thedose of radiation measured in centigrays was homogeneous. This providedgood assurance that the target(s) was/were being irradiated appropriately, butit also meant that large volumes of normal tissues were receiving very highdoses of radiation. For example, in the treatment of pharyngeal carcinomas(especially nasopharynx cancer), the dose received by almost the entirety ofboth parotid glands was equal to the dose received by the tumor. Consequently,the rate of late grade ≥2 xerostomia in large prospective clinical trials was atleast 35%–50% with standard radiation therapy alone. The introduction theradioprotectant drug amifostine has shown some improvement in rates ofxerostomia with radiation treatment (2,3). However, amifostine protection isincomplete, and the drug is often poorly tolerated due to its side effects.

Figure 1. Three-field plan for radiation treatment of patient with locallyadvanced larynx cancer status-post total laryngectomy—right and left lateralportals to treat the primary tumor and regional lymphatics in the upper andmid-cervical region (A and B) and anterior portal to treat lower cervical andsupraclavicular lymph nodes (C).


Intensity-Modulated Radiation Therapy 93

In contrast to conventional 3D CRT, IMRT allows the delivery of highdoses of radiation to the same targets and differentially decreased doses ofradiation to critical normal structures even when they are relatively close toone another. This is accomplished by delivering radiation from multiple anglesand with multiple beam segments of variable intensity (Figure 2) (hence theuse of the term intensity-modulated); the summation of these beams results ina highly variable, heterogeneous dose distribution within the patient. Thisbecomes obvious when reviewing the set of slices from the radiation therapytreatment planning computed tomography (CT) scan (Figures 3–5). It isimportant to note that the radiation being delivered is physically the same aswith conventional radiation therapy; it is simply delivered in a different way.Most modern linear accelerators can be used for either conventional radiationtherapy or IMRT.

The user (radiation oncologist) dictates the complexity of any IMRT planwith regard to number of beams and beam segments, size of beam segments,and a set of dose constraints for targets and normal tissues. Increasing thenumber of allowed beams and beam segments, decreasing the size of beamsegments, and demanding more highly conformal dose constraints can pro-duce a plan with better conformality and steeper dose gradients. This is done

Figure 2. A–F: Radiation treatment portals for six-field intensity-modulatedradiation therapy plan to treat a patient with locally advanced oropharynx cancer.Within each portal, the varying degrees of red color indicate increasing (white =low dose, red = high dose) intensity of radiation delivered at that location.



at the expense of a longer treatment planning time (potentially delaying thepatient from starting radiation therapy), longer actual patient treatment time(potentially 20–40 minutes per day), and increased exposure of the patient tomoderate levels of background radiation (4). There has been much focus ondeveloping treatment-planning algorithms that reach an acceptable balancebetween quality of treatment plan and increased treatment time. However,there are currently no universally accepted standards of care for IMRT plan-ning and delivery; the closest such series of guidelines are those set forth inseveral actively accruing Radiation Therapy Oncology Group (RTOG) clinicaltrials (e.g., RTOG 0522).

There are essentially two ways of planning IMRT: forward planning andinverse planning. In both situations, the treating radiation oncologist definestargets and normal structures. Dose constraints are then assigned for each

Figure 3. Axial (A and B) and coronal (C and D) images from intensity-modulated radiation therapy treatment plan. Red color indicates high-doseregions, and blue indicates low-dose regions. White marks indicate locationof the parotid glands. The left parotid gland is receiving a lower radiationdose in an attempt to spare parotid function, whereas a higher dose is beinggiven to the gross tumor volume and clinical target volume.



individual structure. For forward-planned IMRT (FP-IMRT), the gantryangles and beam segments are defined by the radiation oncologist; a series ofmanual iterations to optimize the intensity of each segment is then performeduntil a satisfactory plan is achieved (5). In contrast, for inverse-planned IMRT(IP-IMRT), the gantry angles are defined by the treatment team, but the treat-ment planning software determines the exact number and shape of segmentsas well as the dose intensity to be delivered through each segment within pre-defined constraints. This process is done automatically, based on a pre-programmed series of treatment planning algorithms plus the dose constraintsprescribed by the radiation oncologist.

Treatment times tend to be shorter with FP-IMRT, although treatmentplanning time can be substantial due to the need for manual “trial byerror” technique. Plan quality is probably comparable between the two

Figure 4. Axial (A and B) and coronal (C and D) images from intensity-mod-ulated radiation therapy treatment plan showing coverage of the parapharyn-geal tissues and posterior cervical lymph nodes while delivering a differentiallylower dose of radiation to the spinal cord and posterior neck tissues.



types of IMRT planning, although IP-IMRT potentially offers improvedability to achieve extremely sharp radiation dose gradients adjacent to orwrapping around critical structures (e.g., spinal cord).

Volume Definition for Intensity-Modulated Radiation Therapy Treatment Planning

One of the most critical steps in formulating an effective IMRT treatment planfor patients with head and neck cancer is the accurate definition of the targetvolumes and normal tissue structure volumes. These volumes include (a) thegross tumor volume (GTV), representing a region(s) with proven cancer;(b) the clinical target volume(s) (CTVs), one or more identifiable regions atrisk for microscopic spread of disease; (c) the critical normal structures,referred to as organs at risk (OAR); and (d) planning volumes, which repre-sent the other types of volume plus a “safety margin” to account for variousuncertainties such as changes in target volume size and shape over time. Errorsin target and/or OAR delineation cannot be easily rectified through the courseof the patient’s treatment and can have a large impact on the actual adminis-tered doses to the tumor and OAR. These errors can potentially affect theprobability of tumor control and/or normal tissue complications.

Gross Tumor Volume

The GTV is defined by using information from physical examinations, ana-tomic imaging, invasive staging (e.g., panendoscopy) and, more recently, func-

Figure 5. Axial (A), coronal (B), and sagittal (C) images of intensity-modulatedradiation therapy treatment plan for a patient with diffuse squamous cell carci-noma of the paranasal sinuses. High-dose region ends abruptly with sharp dosegradient to spare the optic chiasm, indicated by the white arrow (A and C); doseis bent around the eyes to deliver high-dose radiation to the sinuses (C).



tional imaging. The radiation treatment planning CT scan provides the criticalinformation for the IMRT treatment plan, including the geometry of thepatient with respect to the incident radiation beams, the relative positions oftargets and critical structures, and the relative density of tissues within theregion of interest. CT scans have also proved to be superior to other imagingmodalities in evaluating for bony invasion that can be present, particularlywith tumors of the nasopharynx and oral cavity (6). Through the use of imagefusion software, magnetic resonance imaging (MRI) and positron emissiontomography (PET) scans can be fused to the treatment planning CT scan andused as adjuncts to CT image information.

Several groups have shown that MRI can provide critical informationwith regard to invasion of soft tissues, particularly in the parapharyngealspaces and retropharyngeal lymph nodes (7). In addition, PET has beeninvestigated for radiation treatment planning and has been shown toincrease or decrease the size of the GTV by up to 49% in selected patients(8). Other groups have shown that PET fusion has proved instrumental indefining the extent of the primary tumor and regional nodal metastases inpatients thought to have N0 cancer by other means of evaluation (9,10).

Organs at Risk

OARs include those structures that can be irreparably damaged by expo-sure to high doses of radiation and cause permanent morbidity or mortal-ity. In the region of the head and neck, OARs can include the spinal cord,brain stem, optic apparatus (chiasm, optic nerves, retina, cornea, lens),parotid glands, organs of speech and swallowing, temporal lobes, and thecerebellum. These structures should be defined anatomically using infor-mation from the treatment planning CT scan.

Clinical Target Volume(s)

The definition of the CTV(s) for patients receiving IMRT for head andneck cancer has proved to be a difficult task. There are two importantcomponents of the CTV as it applies to IMRT planning: (a) areas at riskfor direct invasion by tumor and (b) lymph nodes at risk for micrometasta-ses. The former is defined with knowledge of the pathologic features of thetumor, its location, and the natural history of the disease entity beingtreated. The latter has required a fair amount of adaptation from previoustechniques and is based on knowledge of the natural history of the diseaseentity, including studies dating back more than 30 years (11).



Whereas bony landmarks previously served to separate different lymphnodal levels at risk, an exact anatomic delineation is now necessary. Severalgroups have published atlases of cross-sectional anatomy to define the dif-ferent nodal stations in the head and neck (12–15). A consensus conferencewas convened for the purpose of developing an atlas of neck lymph nodesand is available on the RTOG’s web site (www.rtog.org) (16). Once defined,different doses of radiation therapy can be assigned to different nodal levelsbased on knowledge of patterns of metastatic spread.

The task of CTV definition can be further complicated in patients who havehad either the primary tumor or regional lymphatics removed before radiationtherapy. Surgical manipulation distorts the boundaries of natural tissue planesand introduces more uncertainty into the process of target definition (Figure 6).

Planning Volumes

For several reasons, before starting IMRT planning, it is necessary to add a“safety margin” around the GTV, CTV, and at least the most critical OARs.The volume defined by a target volume plus this safety margin is called a plan-ning target volume (PTV). The volume defined by a critical OAR plus thissafety margin is called a planning at-risk volume (PRV). The reason for addingthese safety margins and thus creating PTV/PRVs is to account for variousuncertainties (errors) in treatment planning and delivery. These potential

Figure 6. Axial computed tomography images (A–C) of a patient withlocally advanced larynx cancer status post-laryngectomy and bilateral neckdissections. Clinical target volume 58 (CTV58) and planning target volume 58(PTV58) in right side of neck indicated by inner and outer lines, respectively.CTV66, CTV60, and PTV60 in left side of neck. CTV66 is boost to the operativebed innermost green contour, CTV63 inner purple is the region of removedcervical lymph nodes containing metastatic cancer, and PTV63 is the outer-most purple contour. Note the distortion of the anatomic planes.



errors may include uncertainties in volume definitions (as discussed in the sec-tion “Volume Definition for Intensity-Modulated Radiation Therapy Treat-ment Planning”), changes in volume size/shape during a course of radiationtherapy or even during an individual radiation treatment (organ motion and/or deformation), and systematic and/or random setup errors that may occuron a day-to-day basis.

Determining the size of the safety margin (CTV-to-PTV margin) is com-plex, controversial, and may require a great deal of individualization. Fac-tors that influence the size of this margin include reproducibility of setupand availability of adequate patient immobilization. Several groups havedone dosimetric analyses to simulate random setup errors, evaluate theirinfluence on target coverage, and identify the appropriate CTV-to-PTVmargin to minimize target under-dosing (17–20).

Ultimately, the size of the PTV margin should be customized to each indi-vidual clinic and be based on an analysis of daily setup reproducibility. Mostclinics have adopted a CTV-to-PTV margin size of between 3 mm and 8 mm. Alarge margin will result in extensive overlap between the target volume(s) andone or more OARs; this situation can result in the IMRT computer planningsystem “failing” to achieve a satisfactory treatment plan. Similarly, the use of aPRV margin has been shown to decrease the likelihood of delivering unaccept-ably high doses of radiation to critical normal structures, but can cause furtheroverlap with adjacent PTVs. Overlapping structures ultimately complicates thetreatment planning process and the ability to interpret treatment plans. In con-trast, a small margin affords the potential for an improved computer-generatedIMRT plan but, theoretically, a greater risk of tumor recurrence/progression ifthere are clinically relevant errors/uncertainties in treatment planning.

To combat these issues, proper patient immobilization and positioningverification that eliminates setup variability can help to minimize possibleerrors while allowing a modest-sized PTV margin. Consequently, the dosesto surrounding normal structures and resultant probabilities for long-termmorbidity can be reduced (21). To accomplish this, some centers have imple-mented daily positioning verification protocols with two-dimensional orthog-onal portal imaging or three-dimensional imaging with accelerator-mountedcone beam CT scanners. This is referred to as daily image-guided IMRT (IG-IMRT) and is quickly gaining popularity.

Intensity-Modulated Radiation Therapy Treatment Planning and Evaluation

Once the targets and OARs are defined, specific dose constraints must beapplied to each structure. Typically a goal, maximum, and minimum dose as



well as the volumetric percentage of each structure allowed to receive doseabove and below the goal are defined; this process attempts to dictate thedegree of allowable heterogeneity to minimize hot and cold areas within thetreatment field. For standard fractionated radiation therapy, the typical dosefor gross disease is 66–72 Gy; for resected disease with a positive surgical mar-gin or for lymph nodes with extracapsular extension, the goal is 63–66 Gy; forcompletely resected disease with negative surgical margins, the goal is approxi-mately 60 Gy; and for electively irradiated nodal regions for microscopic dis-ease, the goal is 50–55 Gy. The classic values used for normal tissue toxicitylimits were defined by Emami et al. in 1991 (22) and have been adapted for thepurposes of IMRT (Table 1). After completing the process of defining targets,OARs, and dose specifications, the radiation oncologist works closely with ateam of radiation physicists and dosimetrists to achieve an optimized com-puter-generated IMRT plan. This process can require a variable amount oftime—from several hours to several weeks. Once treatment planning is com-pleted, the actual doses to each target and critical normal structure needs to becompared to the predefined constraints. There are few instances where everysingle dose constraint can be met with perfection, and the radiation oncologistand physics/dosimetry team strive to optimize the plan as best as possible.

A detailed discussion of the processes involved in IMRT planning isbeyond the scope of this chapter, and the reader is referred to a consensus

Table 1. Typical Intensity-Modulated Radiation Therapy Dose ConstraintsUsed for Organs at Risk in the Head and Neck Region

Organ Maximum Dose Whole Organ Dose

Spinal cord 1% of PTV not to exceed 50 Gy 45 GyBrain stem 1% of PTV not to exceed 60 Gy 54 GyOptic nerves 1% of PTV not to exceed 60 Gy 54 GyOptic chiasm 1% of PTV not to exceed 60 Gy 54 GyParotid/subman-

dibular glandsAt least 50% of organ <30 Gy Mean dose, 26 Gy

Temporal lobes <1% PTV to receive >65 Gy 60 GyMandible/temporo-

mandibular joint1 cc of PTV not to exceed 75 Gy 70 Gy

Oral cavity/lips As low as possible (typically 20–30 Gy)

—

Tongue 1% not to exceed 65 Gy 55 GyLarynx/pharynx — Mean dose, 45 Gy

PTV, planning target volume.



report from the American Society of Therapeutic Radiology/Oncology and theAmerican Association of Physicists in Medicine (23). In general, during theprocess of IMRT planning and evaluation of plans, compromises are made,and this is part of both the art and science of medicine. The highest prioritiesare given to achieving adequate coverage of the GTV and strict avoidance ofexceeding maximum tolerated dose limits on the spinal cord and optic appa-ratus. A somewhat lower level of prioritization is assigned to the CTVs, andthe lowest (albeit still significant) priority is given to normal structures that areimportant but not life sustaining (e.g., the parotid glands).

The reliability of any IMRT plan to accomplish its preset goals of deliver-ing highly conformal radiation to target tissues and the sparing of OARs isdependent on maintaining setup reproducibility, both internally in and exter-nally. External patient setup reproducibility can be accomplished with stan-dard treatment aids and image guidance (for details, see section “PlanningVolumes”). Internal reproducibility can be affected by rapidly respondingtumors and/or patient weight loss, resulting in changes in the patient’s externalcontour or relative positions of targets and OARs within the patient. Becauseof certain physical properties of ionizing radiation, these changes can alter thefinal location of high- and low-dose regions of radiation within the patient,potentially undertreating portions of the target(s) and delivering higher thanintended doses to critical structures. Mid-treatment repeat CT scanning andreplanning in select patients has shown significant deviations in the intendeddoses to the target and critical structures, suggesting that this may need to beconsidered routine for similar patients (24).

Intensity-Modulated Radiation Therapy in Clinical Use—Potential Advantages

The leading rationale for head/neck IMRT has been to achieve excellent radia-tion therapy coverage of all relevant target volumes while minimizing radia-tion therapy dose to the parotid glands. In addition, IMRT has proved usefulin other areas that previously presented significant challenges in radiationtreatment planning. These included elimination of uncertainty at match lines,coverage of deep and midline structures, sparing of optic nerves/chiasm intreating tumors of the nasal cavity and paranasal sinuses, and sparing of otherstructures, such as those responsible for swallowing, to decrease long-termmorbidity related to dysphagia and aspiration.

Since 2000, there have been a number of clinical, retrospective series report-ing outcomes with IMRT-based radiation therapy for head and neck cancer.Although these studies compare current patients to retrospective or concurrentnonrandomized patient groups and, hence, lack the power and rigor of phase



III randomized trials, the studies do strongly suggest that locoregional controlis not compromised by IMRT, at least when given at an experienced academiccenter that treats a substantial number of head and neck cancer patients withIMRT (25–28). It is hypothesized that IMRT might actually improve locore-gional control over standard radiation therapy because IMRT can yield ahigher mean target volume dose (even if the prescription dose at the edge of thetarget volume is numerically the same as that with standard x-ray therapy).

In contrast, there has been a well-documented locoregional controladvantage to altered (hyper- and/or accelerated) fractionation radiation ther-apy (29,30), at least for stage III–IV nonoperative head and neck cancer.Altered fractionation radiation therapy has become less commonly used inthe era of concurrent chemoradiation therapy but is still highly relevant. Theuse of altered fractionation with IMRT is the subject of ongoing investiga-tion. The currently accruing major RTOG trial (RTOG 0522) allows investi-gators to use altered fractionation IMRT (6 fractions per week) togetherwith systemic therapy.

Several investigators are exploring the use of a new type of altered fraction-ation based on IMRT; specifically, accelerated hypofractionation. Acceleratedhypofractionation refers to the use of one fraction per day at a larger thannormal daily dose (2.2–3.0 Gy), significantly increasing the biologic intensityof the radiation therapy course. With standard radiation therapy, acceleratedhypofractionation is feasible but requires an attenuation of the cumulativeradiation therapy dose and/or the deletion of concurrent chemotherapy. It ishypothesized that IMRT can overcome these obstacles by strictly limiting thevolume of tissue irradiated to an ultra-high-dose intensity. This technique hasbeen labeled the “SMART” (simultaneous modulated accelerated radiother-apy) technique as piloted at Baylor University (31). Phase I–II studies of thisapproach appear to show acceptable toxicity for IMRT-based acceleratedhypofractionation alone (32,33), but rigorous data combining this techniquewith concurrent chemotherapy are scant (34). As of this writing, patientsreceiving IMRT with concurrent chemotherapy are generally prescribed con-ventional daily dose/fractionation schedules.

Parotid Sparing

One of the most significant long-term toxicities in patients treated with radia-tion therapy for head and neck cancer is xerostomia caused by excessive dosesdelivered to the major salivary glands (see Figure 6). Rates of grade 2 orhigher xerostomia following head and neck irradiation range up to 68% inlarge randomized studies (30). Maintenance of good salivary flow is essentialfor good oral health (35); grade 2 xerostomia indicates moderately severe dry-



ness with significant functional impact. The potential for IMRT to spare theparotid glands and decrease late xerostomia has been extensively investigated.

Initial work by investigators at the University of Michigan identified thethreshold dose of radiation to the parotid gland—approximately 26 Gy—above which permanently decreased salivary flow resulted. In patients treatedwith IMRT with limited doses to a single parotid gland (36), improvement inquality of life with regard to eating, communication, pain, and emotion wasnoted (25,37). Subsequently, other studies have been published, illustrating theability of IMRT to decrease treatment-related xerostomia when treating headand neck cancer, particularly nasopharyngeal and oropharyngeal tumors.

There has been one randomized trial comparing IMRT to standard radia-tion therapy, specifically in early stage nasopharyngeal carcinoma (NPC). Thisstudy has only been reported in abstract form (ASCO 2005), and long-termresults are pending. However, preliminary results showed that patients ran-domized to IMRT had significantly less xerostomia 1 year after treatment,with dramatically better parotid function and whole saliva flow comparedwith standard radiation therapy. However, quality of life as assessed by ques-tionnaires was not significantly different between the two arms.

In addition to parotid gland sparing, there have been attempts to limit doseto the submandibular glands. Significant decreases in salivary flow were notedamong patients who did not have submandibular gland sparing versus thosewho did. Patients with submandibular gland sparing IMRT reported lessxerostomia and decreased need for saliva substitutes (38).

Of course, salivary gland sparing should not be attempted if there is ahigh risk of cancer recurrence in the nodal region directly adjacent to theparotid gland. In general, parotid sparing is attempted for the contralateralparotid gland in patients with well-lateralized cancers with clinically orpathologically cancer-free contralateral neck lymph nodes. Patterns of fail-ure studies in patients receiving parotid-sparing IMRT have shown that thepreponderance of locoregional failures are not in the region adjacent to thespared parotid gland and are, instead, within the regions that were con-firmed to have received high doses of radiation. The failures seem to be morelikely in patients who have clinicopathologic features of their tumors thatare predictive of failure, such as positive surgical margins, extracapsularextension, multiple positive nodes, and postoperative patients, possibly indi-cating hypoxic regions portending relative radioresistance (39,40).

Match Line Dosimetry

IMRT also offers other benefits in addition to parotid gland sparing whentreating cancers of the head and neck. As noted in the section “Definition



and Historical Perspective,” the traditional means of treating the entireneck, from skull base to supraclavicular fossa, was with lateral fields treat-ing the upper neck matched to a lower neck field (see Figure 1). In patientswith extensive neck nodal disease and/or low-lying primary tumors (lar-ynx/pharynx), where the match line would have to be through very high-risk regions, this can cause an area of underdosing (or overdosing) due touncertainty at the match line (41). IMRT allows for the treatment of theentire neck in one uninterrupted field (see Figures 3C, 3D, 4C, and 4D).This eliminates the uncertainty at the match line (42) and reduces the pos-sibility of neck failures in selected patients. Treatment of the entire neck ina single field does increase treatment time and may not be appropriate forpatients with limited neck disease that does not cross the match line. Insuch cases, treatment of the primary tumor/surgical bed and the upperneck lymphatics can be treated with IMRT and a matching anterior low-neck field. Because IMRT treatment plans do not produce sharp dose gra-dients at the field edge similar to a half-beam blocked static field, there isalso uncertainty inherent in this process. Strategies have been formulatedto eliminate the uncertainty of matching IMRT fields with static fields(43,44).

Coverage of Nasopharynx/Parapharyngeal Tissues

For cancers of the nasopharynx in which coverage of the parapharyngealspaces and retropharyngeal lymph nodes is crucial in achieving local con-trol, IMRT has proved superior to traditional techniques of matchingphoton and electron fields where significant cold regions can exist at thematch line (see Figure 4) (45). A study at Princess Margaret Hospitalshowed that conventional planning/treatment of NPC resulted in poordose coverage of the tumor volume and a relatively high rate of localrecurrence (46). Several modern series of IMRT-based treatment for NPCsuggest that local control rates in excess of 90% are achievable (47).This compares favorably to the U.S. Intergroup standard experience withconventional chemoradiotherapy that showed approximately 75% localcontrol (Table 2) (48).

Several groups have reviewed their experience treating nasopharyngealcancer with IMRT. Outcomes indicate excellent locoregional control ratesand survivals at least equivalent to traditional radiation therapy techniqueswith decreased rates of toxicity (see Table 2). A recently completed RTOGphase II (RT 02–25) trial of IMRT for nasopharyngeal cancer will be thefirst multi-institutional data showing the utility of IMRT in the treatment ofnasopharyngeal cancer.


105

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Laryngopharyngeal Sparing

IMRT can also be used to decrease the radiation dose to the pharyngealconstrictor muscles and the glottic/supraglottic larynx. These structuresare centrally located and often receive large doses of radiation when treat-ing lymph nodes in the neck. When large volumes of these structuresreceive radiation doses in excess of 50 Gy (V50) there is a substantial riskof developing long-term dysphagia and/or aspiration. Contouring thelaryngopharynx, defining it as an OAR, and setting dose constraints tolimit the V50 may theoretically decrease the risk of developing dysphagiaand/or aspiration (49).

Sparing of Optic Structures

IMRT is also used to treat cancers of the nasal cavity and paranasal sinuses(see Figure 5). Traditional radiation treatment fields resulted in large doses tothe optic apparatus, which puts patients at risk for the development of radia-tion-induced optic neuritis, a catastrophic side effect of radiation therapy thatcan cause complete blindness. Dosimetric analyses have shown good cover-age of the CTV with less dose delivered to the optic structures with IMRTcompared to 3D CRT (50), and IMRT to be especially useful when the uppercervical lymph nodes are included in the treatment volume (51). In one studyof 39 patients treated with postoperative IMRT for T2–T4b ethmoid sinuscancer, 2-year overall survival and local control rates were 68% and 73%,respectively; these are comparable to historic controls with decreased rates ofvision impairment and no radiation-induced blindness (52).

Coverage of Midline Structures

IMRT can also produce superior dose profiles and coverage of target volumesthat cross the midline and wrap around central structures such as the spinalcord. One such organ is the thyroid gland. In the past, treatment of substantialvolumes of the thyroid gland to doses ≥45 Gy was limited by the spinal cordtolerance. The ability of IMRT treatment plans to wrap dose around centralstructures in a horseshoe pattern has made treatment of the much larger vol-umes of the thyroid with substantially higher doses of external beam radiationtherapy possible (53,54). This has correlated to good clinical outcomes in thepublished experience of the Memorial Sloan-Kettering Cancer Center, treating20 patients with nonanaplastic thyroid carcinoma, showing 85% locoregionalcontrol rates and no increase in toxicity (55).



Re-Irradiation of Head and Neck Cancer

IMRT has also made re-irradiation of head and neck cancers more feasible,particularly for patients with local or regionally recurrent nasopharynx cancer.A Chinese group reported on their initial experience re-irradiating 49 patientswith recurrent nasopharynx cancer. They showed that the treatment was feasi-ble with acceptable toxicity and encouraging response rates and local control(56). Others have evaluated IMRT for re-irradiation in other subsites of thehead and neck and have shown encouraging response rates, with 50% ofpatients showing partial or complete response with acceptable toxicity (57).

Potential Disadvantages of Intensity-Modulated Radiation Therapy

Risk of Marginal Miss

As the reader can probably discern from the section on IMRT volume defini-tion and treatment planning, IMRT is a technically demanding exercise. Thereis little room for error at every stage in this planning process. Theoretically, theuse of small margins around target volumes and irradiation plans with sharpdose gradients between these target volumes and normal structures couldresult in a higher rate of local recurrence. There have been reports of recur-rences in areas adjacent to a “spared” parotid gland after IMRT.

Risk of Secondary Malignancy

The increased complexity of IMRT treatment plans requires an increasedamount of time to deliver any single fraction of radiation therapy. Increasedtreatment time can create problems with patients being unable to tolerate lyingstill in the treatment position for extended periods of time; this may be over-come with the use of sedatives, nursing, and psychosocial support. However,another theoretical concern is that increased radiation therapy beam-on timeand the use of numerous beam angles and segments exposes patients’ totalbody to a low-dose of radiation. This amount of irradiation is difficult to meas-ure and well below the threshold for causing typical radiation therapy-inducedorgan damage but may be relevant for radiation carcinogenesis. In vivo mea-surements show that together these factors result in an increase in total bodyradiation dose of from 242 mSv for conventional treatment to 1,969 mSv forIMRT (58). It has been estimated that the risk for development of secondary



malignancies could be two- to eightfold higher with IMRT than that forpatients treated with conventional radiation therapy (58,59). In the case ofhead and neck cancer in which 6 MeV photons are predominantly used, therelative risk of fatal second malignancy is 3.0–3.7 (60,61).

To date, there have not been any clinical reports to support or refutethis concern, but because IMRT is an exceptionally new technology andbecause clinical studies of radiation carcinogenesis require many years andlarge numbers of evaluable patients, these data may not be available untilthe mid-2010s. Clinicians should be cognizant of this potential risk whentreating patients in their 50s and 60s and balance this against the potentialrisks of conventional radiation therapy that contribute to late morbidityand mortality: radionecrosis, aspiration, and dental complications.

Increased and/or “New” Toxicity(ies)

Due to the high degree of dose heterogeneity in IMRT plans, there is thepotential for unplanned “hot spots” receiving over 120% of the prescribeddose. With an ideally optimized IMRT plan, these hot spots are within theGTV; however, they may also occur in normal tissues. This can causeincreased acute and chronic side effects such as severe mucositis, osteora-dionecrosis, trismus, and/or tissue necrosis. Strategies to control hot spotformation have been used in the planning process and have proved effec-tive, but it is important to note the location and possible consequences ofthese hot regions when evaluating treatment plans.

Another drawback of IMRT is the potential to have an increased radiationdose to the skin, resulting in increased rates of grade 3 and 4 radiation derma-titis, necessitating treatment breaks and resulting in poor compliance withtreatment. Multiple factors have been implicated in this process, including thebolus effect from immobilization devices (i.e., Aquaplast mask), contouring ofCTV and PTV near to the skin surface, and the use of multiple tangential radi-ation beams. Strategies to reduce skin toxicity have been suggested, includinguse of virtual bolus during treatment planning to allow for adequate build-upso that the optimizer does not favor tangential beams, assigning dose limits tothe skin as an OAR, or editing PTV contours to be at least 5 mm inside theskin when it is not a part of the CTV (62,63).

Cost/Resources

To treat a patient with IMRT, there is a significant increase in the necessaryresources, and, hence, the monetary cost of the treatment. The hardware andsoftware for IMRT planning and delivery are considerably more expensive



than that for conventional radiation therapy. There is an increase in physician,dosimetrist, therapist, and physicist time over conventional radiation therapy.Increased beam on-time translates to a need for more regular maintenance oflinear accelerators and a busier treatment schedule, which can create a needfor increased clinic hours and the subsequent costs of overhead and staffing.

Conclusion

IMRT has come far since its introduction in the clinic. There exists anexpanding wealth of knowledge regarding the potential benefits and pitfallsof this new technology. It is significantly more labor intensive from planningto delivery, requiring many more resources. IMRT is likely not appropriatefor all patients. It remains uncertain as to which patients will benefit mostclearly from IMRT. The most likely beneficiaries from IMRT are patientswho would otherwise receive extremely high doses to their parotid glandsand/or unacceptably high irradiation dose to the optic apparatus. This sug-gests that IMRT may be more useful in cancers of the nasopharynx, oro-pharynx, and paranasal sinuses than for cancers located in the lower neck.However, from a technical standpoint, IMRT might decrease some of thedosimetric problems associated with comprehensive head and neck irradia-tion for a multitude of types of head and neck cancer, ranging from cancersof the tongue to the larynx/hypopharynx and cancer to the thyroid.

Taken together, the reports in the peer-reviewed literature convey a tone ofcautious optimism. Longer follow-up and extensive quality control reviews arenecessary to determine if the risk of second malignancies is clinically relevant,and to determine if “marginal misses” are occurring near structures that havebeen intentionally underdosed via IMRT. Larger, multicenter studies of IMRTare currently lacking; at this time it is unclear if the promising results withIMRT achieved at several centers of excellence can be duplicated in the generalradiation oncology community. Efforts at standardization and quality assur-ance across multiple centers have lagged behind the enthusiasm about the use ofIMRT in the community. New technologies in head and neck radiation therapy,such as IG-IMRT, are constantly evolving, and this or any review on IMRT willlikely be very different in 1, 2, or 5 years. Each investigator using IMRT mustpay close attention to new developments and determine if, when, and how toadapt his or her treatment algorithms based on the current state of the art.

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115

❖Index

Note: Page numbers followed by f refer to figures; page numbers followed by t refer to tables.

Accelerated hypofractionation, defined, 102

American Association of Physicists in Medicine, 101

American Joint Committee on Cancer (AJCC) stage III or IV disease, 13–14

AJCC stage III or IV laryngeal disease, 13–14

AJCC stage IV laryngeal cancer, 13–14

AJCC staging system, 14American Society of Addiction

Medicine web site, 53 American Society of Clinical

Oncology (ASCO), 91

American Society of Therapeutic Radiology/Oncology, 101

ASCO, 91Aspiration, swallowing abnormali-

ties and, 47–48

Baylor University, 102

Bevacizumab, for recurrent SCCHN, 71

Cancer(s)head and neck. See specific

types, sites, and Head and neck cancer

laryngeal, AJCC stage IV, 13–14

Carboplatin, for head and neck cancer, 10

Carboplatin/5-FU, for head and neck cancer, 4t

Cetuximabfor head and neck cancer, 9for recurrent SCCHN, 70–71,

72tChemoradiation

assessment after, 54, 56t–57t, 57assessment during, 54, 55t–56t,

57concurrent, 3–8, 4t–5tdocetaxel-based cisplatin/5-FU

chemotherapy vs., phase III trials compar-ing, 33–37, 35f–37f


116 Index

for head and neck cancer, 1–22concurrent chemoradiation,

3–8, 4t–5thistory of, 1–2induction chemotherapy fol-

lowed by chemoradia-tion, 8–9

neoadjuvant or “induc-tion” chemoradia-tion, 2–3

patient selection for, 12–14regimens, 9–12, 11tselection factors for, 14–17therapeutic approaches, 12–

13unanswered questions

related to, 2“induction,” 2–3in locally advanced SCCHN,

28–32, 29t, 30tas new standard of care,

32taxanes with, 29–32, 30tvs. induction chemotherapy,

28–29, 29tneoadjuvant, 2–3radiation alone trials vs., for

SCCHN, 4t–5tsymptom management and,

41–60history of, 41–42measuring effects of, 42–43symptom control issues, 43–

54, 46t, 49t, 52t–53tChemoradiotherapy. See Chemo-

radiationChemotherapy

combination, for recurrent SCCHN, clinical trials using, 68–70

induction. See Induction che-motherapy

in organ preservation for SCCHN, 77–90. See also Squamous cell carcinoma of head and neck (SCCHN), organ preservation strategies for

systemicevolution of, 67in organ preservation for

SCCHN, 79–84, 82t, 83t, 85t

Cisplatin, for head and neck can-cer, 3–10, 4t–5t

Cisplatin/5-FUin locally advanced SCCHN,

25–27, 27tfor recurrent SCCHN, clinical

trials using, 68–69Clinical target volumes (CTVs), in

IMRT treatment plan, 97–98, 98f

Combined modality therapy, for locally advanced SCCHN, 25–37, 27t, 29t, 30t, 35f–37f. See also specific modality, e.g., Induction chemo-therapy

Common Terminology Criteria for Adverse Events, 49, 49t

Common Toxicity Criteria, 42–43Concurrent chemoradiation, 3–8,

4t–5tCost(s), IMRT-related, 108–109CTVs, in IMRT treatment plan,

97–98, 98f

Daily image–guided IMRT (IG-IMRT), 99

Dana-Farber Cancer Institute, 33


Index 117

Department of Veterans Affairs (VA) Laryngeal Can-cer Study Group lar-ynx preservation trial, 1, 3, 28, 80

Docetaxel, for head and neck can-cer, 10

Docetaxel-based cisplatin/5-FU, chemoradiation vs., phase III trials compar-ing, 33–37, 35f–37f

Docetaxel/cisplatin/5-FU, vs. cis-platin/5-FU, for head and neck cancer, 11t

Dosimetry, match line, IMRT in, 103–104

Eastern Cooperative Oncology Group, 34

EGFR, for recurrent SCCHN, 70–71

EORTC, 28, 31EORTC 22931 trial, 6, 7, 15–16Epidermal growth factor receptor

(EGFR), for recurrent SCCHN, 70–71

European Organisation for Research and Treat-ment of Cancer (EORTC), 28, 31

22931 trial of, 6, 7European Organisation for

Research and Treat-ment of Cancer (EORTC) systems, 42

FDA, 50, 685-Fluorouracil (5-FU), for head

and neck cancer, 105-Fluorouracil (5-FU)/carbopla-

tin, for head and neck cancer, 4t

5-Fluorouracil (5-FU)/cisplatinfor head and neck cancer, 10for recurrent SCCHN, clinical

trials using, 68–695-Fluorouracil (5-FU)/hydrox-

yurea, for head and neck cancer, 10

5-Fluorouracil (5-FU)/platinum, in locally advanced SCCHN, 25–27, 27t

5-Fluorouracil (5-FU)/taxanes, for recurrent SCCHN, clinical trials using, 69

Food and Drug Administration (FDA), 50, 68

Forward-planned IMRT, 95–96Functional Assessment of Cancer

Therapy, 42

Gefitinib, for recurrent SCCHN, 71

GETTEC, 27, 28, 81GORTEC 2000–01 trial, 30t, 32Gross tumor volume (GTV)

defined, 96–97in IMRT treatment plan, 96–97

Groupement d’Etudes des Tumeurs d la Tête et du Cou (GETTEC), 27, 28, 81

Head and neck cancer. See also specific types

chemoradiation for, 1–22. See also Chemoradiation, for head and neck cancer

prevalence of, 1recurrent, management of, 61–

75. See also Recurrent disease, management of


118 Index

re-irradiation of, IMRT in, 107squamous cell carcinoma. See

Squamous cell carci-noma of head and neck (SCCHN)

Hypofractionation, accelerated, defined, 102

IG-IMRT, 99“Induction” chemoradiation, 2–3Induction chemotherapy

chemoradiation after, 8–9in locally advanced SCCHN,

25–28, 27tmetaanalysis of results, 25platinum/5-FU chemother-

apy, 25–27, 27tin resectable patients, 28vs. chemoradiation, 28–29,

29tInstitut Gustave Roussy, 64Intensity-modulated radiation

therapy (IMRT), 91–114

advantages of, 101–102in coverage of midline struc-

tures, 106in coverage of nasopharynx/

parapharyngeal tis-sues, 104, 105t

defined, 92disadvantages of, 107–109

cost/resources, 108–109increased toxicity, 108new toxicity, 108risk of marginal miss, 107risk of secondary malig-

nancy, 107–108forward-planned, 95–96historical perspective of, 92–

96, 92f–96fintroduction of, 91–92

inverse-planned, 95–96in laryngopharyngeal sparing,

106in match line dosimetry, 103–

104in parotid sparing, 102–103planning of, 94–95in re-irradiation of head and

neck cancer, 107in sparing of optic structures,

106Intensity-modulated radiation

therapy (IMRT) treat-ment plan

evaluation of, 99–101, 100tvolume definition for, 96–99,

98f. See also Volume definition, for IMRT treatment plan

Intergroup 0099 nasopharynx cancer trial, 3

Inverse-planned IMRT, 95–96

Lapatinib, for recurrent SCCHN, 71

Laryngeal cancer, AJCC stage IV, 13–14

Laryngopharyngeal sparing, IMRT in, 106

Locoregional therapiesfor recurrent head and neck

cancer, 62–66, 65tsalvage surgery, 62–63

for recurrent SCCHN, radia-tion therapy, 63–66, 65t

Malignancy, secondary, IMRT and, 107–108

Marginal miss, IMRT and, 107

MASCC, 45


Index 119

Match line dosimetry, IMRT in, 103–104

Methotrexate, for recurrent SCCHN, 68

Midline structures, coverage of, IMRT in, 106

Minnie Pearl Cancer Research Network Trial, 34

Mucositis, in head and neck can-cer patients under-going chemoradiation, 43–44

Mucositis Committee, of MASCC, 45

Mucositis-related symptoms, in head and neck cancer patients undergoing chemoradiation, 44–45

Multinational Association of Sup-portive Care in Can-cer (MASCC), Mucositis Committee of, 45

Nasopharynx/parapharyngeal tis-sues, coverage of, IMRT in, 104, 105t

Neck, cancer of. See Head and neck cancer

Neoadjuvant chemoradiation, 2–3Nutritional management, in head

and neck cancer patients undergoing chemoradiation, 45–48

OARs, in IMRT treatment plan, 97

Optic structures, sparing of, IMRT in, 106

Oral care, in head and neck cancer patients undergoing chemoradiation, 50–51

Organ preservation, in SCCHN, strategies for, chemo-therapy integration in, 77–90. See also Squa-mous cell carcinoma of head and neck (SCCHN), organ pres-ervation strategies for

Organs at risk (OARs), in IMRT treatment plan, 97

Paclitaxel, for head and neck can-cer, 10

Parotid sparing, IMRT in, 102–103

Planning at-risk volume (PRV), for IMRT treatment plan, 98

Planning target volume (PTV), for IMRT treatment plan, 98–99

Planning volumes, in IMRT treat-ment plan, 98–99

Platinum agentsfor head and neck cancer, 10for recurrent SCCHN, 67

Platinum agents/taxanes, for recur-rent SCCHN, clinical trials using, 69

Platinum/5-FU, in locally advanced SCCHN, 25–27, 27t

PRV, for IMRT treatment plan, 98Psychological issues, in head and

neck cancer patients undergoing chemora-diation, 51–54, 52t–53t


120 Index

PTV, for IMRT treatment plan, 98–99

Quality of life (QOL), symptom control vs., 42–43

Radiation therapy (RT)chemotherapy during, 3–8, 4t–

5tchemotherapy with. See

Chemoradiationintensity-modulated, 91–114.

See also Intensity-modulated radiation therapy (IMRT)

for locally recurrent SCCHN, 63–66, 65t

for patients treated with sal-vage surgery for SCCHN, 63

surgical resection with, in organ preservation for SCCHN, 78–79

Radiation Therapy Oncology Group (RTOG), 3, 9, 66, 94. See also spe-cific RTOG trials

Radiation Therapy Oncology Group (RTOG) Sali-vary Gland Morbid-ity Scale, 49t

Reactive oxygen species (ROS), 43

Recurrent disease, management of, 61–75

approaches to, 61–62, 73flocoregional therapies in, 62–

66, 65tsystemic therapy in, 66–71,

72t, 73fchemotherapeutic agents,

67–68

combination chemotherapy, clinical trials using, 68–70

EGFR, 70–71evolution of, 67methotrexate, 68novel targeted therapy, 70–

71, 72tplatinum agents, 67taxanes, 67–68triple-agent regimens, 69–70

Re-irradiationof head and neck cancer, IMRT

in, 107for patients with recurrent head

and neck cancer, 63–66, 65t

Resource(s), IMRT-related, 108–109

ROS, 43RTOG, 3, 9, 66, 94

RTOG 85-01 trial, 7RTOG 90-03 trial, 7, 8RTOG 91-11 trial, 3, 6RTOG 95-01 trial, 6–7, 15RTOG 99-14 trial, 7–8RTOG H-0129 trial, 18

Salvage surgery, for recurrent SCCHN, 62–63

radiation therapy with, 63Sequential therapy, in locally

advanced SCCHN, 32–37, 35f–37f

compared with other therapies, 33–37, 35f–37f

docetaxel-based cisplatin/5-FU chemotherapy and chemoradiation, phase III trials comparing, 33–37, 35f–37f

for unresectable disease, 32–33


Index 121

“SMART” technique, 102Sorafenib, for recurrent SCCHN,

71Southwest Oncology Group Oro-

pharynx trial, 34, 37, 37f

Squamous cell carcinoma of head and neck (SCCHN)

chemoradiation vs. radiation alone trials for, 4t–5t

locally advanceddefined, 23treatment of, 23–40

chemoradiation in, 28–32, 29t, 30t

combined modality therapy in, 25–37, 27t, 29t, 30t, 35f–37f

history of, 24induction chemotherapy

in, 25–28. See also Induction chemotherapy, in locally advanced SCCHN

options in, 23–24sequential therapy in,

32–37, 35f–37fmanagement of

approach to, 73fgoals in, 77–78options in, 77–78

organ preservation strategies for

best treatment options, early identification of, 86–88, 87f

chemotherapy integration in, 77–90

radiation therapy and sur-gery, 78–79

systemic chemotherapy, 79–84, 82t, 83t, 85t

recurrentmanagement of, 61–75. See

also Recurrent dis-ease, management of

systemic therapy in, 66–71, 72t, 73f

re-irradiation for patients with, 63–66, 65t

Supportive Care in Cancer, 45Surgical resection, radiation ther-

apy with, in organ preservation for SCCHN, 78–79

Swallowing abnormalities, aspira-tion due to, 47–48

Symptom control, quality of life vs., 42–43

Symptom control issues, in head and neck cancer patients undergoing chemoradiation, 43–54, 46t, 49t, 52t–53t

mucositis, 43–44mucositis-related symptoms,

44–45nutritional management, 45–

48oral care, 50–51pretreatment evaluation, 52t–

53tpsychological issues, 51–54,

52t–53tunintentional weight loss, 45–

48, 46txerostomia, 48–50, 49t

Systemic chemotherapyevolution of, 6–7in organ preservation for

SCCHN, 79–84, 82t, 83t, 85t


122 Index

Systemic therapy, for recurrent SCCHN, 66–71, 72t, 73f. See also Recur-rent disease, manage-ment of, systemic therapy in

TAX 323 trial, 30t, 31, 32TAX 324 trial, 30t, 31, 34, 37Taxane(s)

chemoradiation and, in locally advanced SCCHN, 29–32, 30t

for recurrent SCCHN, 67–68Taxane(s)/5-FU, for recurrent

SCCHN, clinical trials using, 69

Taxane(s)/platinum agents, for recurrent SCCHN, clinical trials using, 69

Toxicity(ies), increased or “new,” IMRT and, 108

Tyrosine kinase inhibitors, for recurrent SCCHN, 71

University of Chicago, 34, 35f, 64

University of Michigan, 34, 103University of Pennsylvania, 33

University of Texas M.D. Ander-son Cancer Center, 14, 17

U.S. Food and Drug Administra-tion (FDA), 50, 68

“VA Larynx Preservation Trial,” 1, 3

Vanderbilt University, 45Vanderbilt University Medical

Center, 34Volume definition, for IMRT

treatment plan, 96–99, 98f

CTVs, 97–98, 98fGTV, 96–97OARs, 97planning volumes, 98–99

Weight loss, unintentional, in head and neck cancer patients undergoing chemoradiation, 45–48, 46t

Xerostomiaadverse events associated with,

48–49, 49tin head and neck cancer patients

undergoing chemoradi-ation, 48–50, 49t


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