integrative cancer therapies · 3 editorial: integrative cancer treatment in the 21st century 7...

Integrative Cancer TherapiesEDITOR-IN-CHIEF

Keith I. Block, MDInstitute for Integrative Cancer Careand University of Illinois at Chicago

ASSOCIATE EDITOR

Charlotte Gyllenhaal, PhDInstitute for Integrative Cancer Careand University of Illinois at Chicago

ADVISORY BOARD

Wayne Jonas, MDUniformed Services University

of the Health Sciences

Dennis RothMorristown, NJ

Leslie J. Sandlow, MDUniversity of Illinois at Chicago

Julia Rowland, PhDNational Cancer Institute

William J.M. Hrushesky, MDDorn Veterans Affairs Medical Center

James S. Gordon, MDCenter for Mind-Body Medicine

Norman R. Farnsworth, PhDUniversity of Illinois at Chicago

John Pezzuto, PhDUniversity of Illinois at Chicago

Ralph MossCancer Decisions

Debu Tripathy, MDUniversity of California at San Francisco

Nicholas Vogelzang, MDThe University of Chicago

Robert Oldham, MDCancer Therapeutics, Inc.

Jacob Shoham, MD, PhDBar-Ilan University

Stephen P. Tomasovic, PhDM.D. Anderson Cancer Center

EDITORIAL BOARD

Carole M. Schneider, PhDUniversity of Northern Colorado

Dave Blask, MD, PhDMary Imogene Bassett Hospital

Alfred I. Neugut, MD, PhDColumbia University Presbyterian Hospital

Judith Jacobsen, MDColumbia University Collegeof Physicians and Surgeons

Peter Boasberg, MDJohn Wayne Cancer Institute

Anton Bilchik, MDSanta Monica, CA

Larry ShemenNew York, NY

Lydia Temoshok, PhDMaryland Biotechnology Center

Phyllis Bowen, PhDUniversity of Illinois at Chicago

Lawrence Kushi, ScDColumbia University Teachers College

Lindsey BerksonSanta Fe, NM

Raymond Chang, MDInstitute of East-West Medicine.

Steven Greer, MDSt. Anthony’s Hospital

Robert A. Nagourney, MDRational Therapeutics Inc

Geoffrey Cordell, PhDUniversity of Illinois at Chicago

Jeanne WallaceNutritional Solutions

David M. Gustin, MDUniversity of Illinois at Chicago

Arika Hirsch, MDAssociated Radiologists, Ltd.

Terence Bugno, MDNorthern Illinois Center for Cancer Care

D. Barry Boyd, MDIntegrative Oncology

Stephen M. Sagar, MDHamilton Regional Cancer Centre

Miriam Piven Cotler, PhDCalifornia State University, Northridge

Lorne Feldman, MDCalifornia Hematology Oncology Medical Group

Mark Renneker, MDUniversity of California, San Francisco.

Faith Ottery, MD, PhD, FACNThe Society for Nutritional

Oncology Adjuvant Therapyand Bio-Technology General Corp.

Jeremy Geffen, MDGeffen Cancer Center and Research Institute

Michael J. Hawkins, MDWashington Cancer Institute

Victoria Kut, MDInstitute for Integrative Cancer Care

Michael de la Torre, MDInstitute for Integrative Cancer Care

Leo Stolbach, MDSt. Vincent Hospital

John Knaus, DOSt. Francis Hospital

Richard Fleming, MDThe Fleming Heart & Health Institute

Lorenzo Cohen, MDM.D. Anderson Cancer Center

Louis L. Pisters, MDM.D. Anderson Cancer Center

EDITORIAL CONSULTANTS BOARD

Donny YanceCenter for Natural Healing

Michael Broffman LAcPine Street Clinic

Gar HildenbrandGerson Research Organization

R. Deva Nathan MDOLR Cancer Center

Mark Myers, MSInstitute for Integrative Cancer Care

Penny B. Block, MAInstitute for Integrative Cancer Care

Barry Krost, MACreative Healing Institute

Nischala DeviAbundant Well-Being

Mark BlumenthalAmerican Botanical Council

Timothy C. Birdsall, NDMidwestern Regional Medical Center

Volume 1 � Number 1 � March 2002

Contents

3 Editorial: Integrative Cancer Treatment in the 21st Century

7 Nutritional and Botanical Modulation of the Inflammatory Cascade—Eicosanoids,Cyclooxygenases, and Lipoxygenases—as an Adjunct in Cancer Therapy

Jeanne M. Wallace, PhD, CNC

38 Radioprotective Effects of Vitexina for Breast Cancer Patients Undergoing RadiotherapyWith Cobalt-60

Tran Van Hien, PhD, Nguyen Boi Huong, PhD,Pham Manh Hung, DSc, and Nguyen Ba Duc, MS

44 Integrative Tumor Board: Esophageal Cancer

67 Group Psychological Therapy: An Integral Part of Care for Cancer Patients

Alastair J. Cunningham, PhD, C Psych

76 A Model Program: Exercise Intervention for Cancer Rehabilitation

C. M. Schneider, PhD, Carolyn A. Dennehy, PhD,Michelle Roozeboom, BS, and Susan D. Carter, MD

83 Clinical Corner: Herb-Drug Interactions in Cancer Chemotherapy:Theoretical Concerns Regarding Drug Metabolizing Exzymes

Keith I. Block, MD, and Charlotte Gyllenhaal, PhD

90 Point-Counterpoint: Soy Intake for Breast Cancer Patients

Keith I. Block, MD, Andreas Constantinou, PhD, Leena Hilakivi-Clarke, PhD,Claude Hughes, MD, PhD, Debu Tripathy, MD, and Jeffrey A. Tice, MD

101 Instructions for Submitting Papers

SAGE Publications Thousand Oaks London New Delhi

INTEGRATIVE CANCER THERAPIES (ICT) focuses on a new and growing movement in cancer treatment.The journal emphasizes scientific understanding of alternative medicine and traditional medicine therapies,and their responsible integration with conventional health care. Integrative care includes therapeutic interven-tions in diet, lifestyle, exercise, stress care, and nutritional supplements, as well as experimental vaccines,chrono-chemotherapy, and other advanced treatments. ICT presents scientifically rigorous original research,case studies, current literature reviews, educational roundtables, and commentary on key topics such as: treat-ment strategies, evaluations of current therapies, models for integrating complementary and conventionaltreatment in clinical practice, interventions from alternative and traditional medicine, implementing qual-ity-of-life assessment and counseling in the clinical setting, cancer rehabilitation during and following cancertreatments, potential interactions of cancer chemotherapy drugs with frequently used dietary supplements im-plementing integrative cancer care strategies into oncology practice, relevant molecular mechanisms and biol-ogy behind integrative approaches, impact of timing of chemotherapy administration on toxicity, response, andoutcome by leading oncologists, researchers, and health care professionals.

INTEGRATIVE CANCER THERAPIES (ISSN 1534-7354) is published quarterly in March, June, September,and December by Sage Publications, 2455 Teller Road, Thousand Oaks, CA 91320; telephone (800) 818-SAGE(7243) and (805) 499-9774; fax/order line (805) 375-1700; e-mail [email protected]; http://www.sagepub.com. Copyright © 2002 by Sage Publications. All rights reserved. No portion of the contents may be reproduced inany form without written permission of the publisher.

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BlockEditorial

Editorial: Integrative CancerTreatment in the 21st Century

Every discipline faces historical moments during itsjourney, and the field of integrative cancer care is noexception. For more than 2 decades, a small group ofmedical practitioners, walking a tightrope betweenoverly rigid conventional approaches and overzealousalternative approaches to cancer care, has been work-ing diligently and often independently to help shapeand form an innovative approach to aid the patientconfronted with cancer. While critical sparks flew fromthe extremes of both camps, distorting and diminish-ing each other’s value, a new discipline was beingborn. Early on it was unclear exactly what the disci-pline would look like. Would it focus more on body ormind, supplements or medicines, surgery or medita-tion? But in the last throes of labor when the field wascrowning, a sensible, almost unarguable middle groundemerged. Slowly and methodically, with clinical careand research as the linchpin, this middle groundbegan taking form as the optimal ground. For patientsin search of a broader array of therapies, active engage-ment in their own care, and a life-affirming approachprovided by scientifically rigorous caregivers, hopeand a new wave of cancer care had been born.

For these 20 plus years, since early in the inceptionof this work, I have kept a plaque of Schopenhauer’s 3stages of truth sitting on my desk, summarizing thegenesis of every pioneering discipline: first, it is ignored;second, it is violently opposed; third, it is accepted asself-evident. Although we could debate at what stageintegrative care now finds itself, with the publicationof this, the first issue of Integrative Cancer Therapies, apeer-reviewed academic and professional journal, inte-grative care most certainly has arrived.

Along with a growing cadre of scientific and clinicalexperts, I believe that integrative therapy will rapidlycommand an important position in cancer medicine.But my belief goes a step further. I hold that integra-tive cancer care will be the future standard of all can-cer medicine for the following reasons: integrativecare has a commonsense potential for mitigating tox-icity, it involves a more prominent recognition of thepatient’s needs as a fundamental of care, and it pro-vides for enhanced outcomes due to multidimensionaltreatments with inherent synergisms (i.e., couplingmainstream modalities with selective integrative inter-ventions). Thus, it is logical to position integrative can-cer care as the benchmark against which limited can-cer approaches can be compared.

While all good medicine is patient focused, a basictenet of this new wave of care is committing to andadvocating patients’ needs first. But as essential as thisis to the underlying core, a focus on healing of thespirit and a schema that aims to enhance quality of lifedo not supercede improving health outcomes. I can-not stress this enough. Those of us who have put thegreatest effort in helping to develop the clinical treat-ments and research needed to propel this burgeoningfield forward know that, with time, we will be able todemonstrate its exciting impact on survival of manymalignancies.

By recognizing the inherent value of conventional,experimental, complementary, traditional (non-Western medical practices), and alternative† practices,integrative care eliminates the unnecessary and artifi-cial distinctions between these seemingly independentapproaches to patient care. Integrative treatmentmethods are based on specific evidence and scientificunderstanding of the mechanisms of therapies andthe physiology of disease conditions, while honoringpsychosocial and spiritual needs. Integrative care canalso be thought of as the combination of leading-edgeconventional therapy with scientifically rigorous com-plementary and alternative medicine.

However, I choose the term integrative rather thanintegrated care in order to go an important step further.Whereas integrated care implies simply placing differ-ent practices alongside each other, integrative careimplies an aim to weave practices together into awhole that is greater than the sum of its parts. In addi-tion, integrative care demands a synthesis of relevanttreatments actively brought together with attention tothe patient’s whole being, labs, psyche, soma, andother treatments, and it recognizes and takes advan-tage of their effects on one another. Although a boldundertaking, integrative care aims to treat the patientas a unified whole, promoting integration of body andbiology, mind and spirit, nutrients and drugs.

So why do I believe integrative care is the medicineof the future? First, patients are already tenaciouslypracticing it. In fact, it is so much a part of the wantsand wishes of a growing number of patients that theyare pursuing this kind of cancer care often in the faceof disapproving providers. They are demanding a

Editorial

INTEGRATIVE CANCER THERAPIES 1(1); 2002 pp. 3-6 3

†Alternative in this context means responsible use of reasonablemodalities that contain some logical and scientific undergirding.

comprehensive approach to combating their illness.Cancer patients vote with their feet: they visit integra-tive, complementary, and alternative practitioners; theystudy, self-prescribe, and take supplements; they adhereto various systems from meditation and yoga to qigong and shiatsu—and often combine any and all ofthese. Unfortunately, they do not often inform theironcologists. This in itself poses numerous potentialrisks as medical practitioners and other caregivers mayoperate without knowledge of potential interactiveeffects—some positive, some negative—between a rangeof different modalities. Second, integrative care makessolid scientific sense. A flood of evidence at all levels isaccumulating in support of many integrative interven-tions. These interventions can include lower fat andhigh omega 3 fatty acid diets that retard the inflamma-tory cascade, and exercise systems responsible forimproving quality of life in chemotherapy patients, inaddition to psychological interventions associated withmore favorable prognoses and better responses totreatment. Third, integrative care is the medicine ofthe future because it is an eminently sensible combina-tion of scientific rigor with clinical pragmatism, evenclinical wisdom. There are large databases filled withpragmatic observations of traditional systems of medi-cine. There are also an increasing number of experi-enced alternative and integrative practitioners whohave the intellectual honesty to submit their empiricalsystems to scientific trial.

A good rule in scientific inquiry and clinical medi-cine, when the luxury of time is on one’s side, is to peerback before leaping forward. In looking back at someaspects of my own journey in cancer and integrativemedicine, I find some experiences of value that seemto reflect the evolution of the field itself. In 1980, whilecompleting my training, I received the affectionatenickname “Dr. Sprouts” from my fellow residents.When I was scheduled to lecture, the blackboardwould read, “Dr. Sprouts is presenting today.” I acquiredthis label due to my advocacy of a whole-foods diet. Butwhereas my colleagues questioned the value of mydiet—deeming it a harmless and insignificant aberra-tion—they never questioned the fractured nature ofthe medical system. There were certainly exceptions,but it seemed poignantly obvious to me: the systemreduced patients to their diagnoses and rejected asirrelevant any intervention that was not a direct assaulton the diseased portion of the patient’s body. My per-sonal experiences with illness and my earnest desirefor maximizing my own health convinced me that, asin any complex system, the human organism is a wholeorganism and that it is only by treating the wholeorganism—the whole person—that we can controland overcome illness. This meant that I had to confrontthe disruptions to a patient’s health wherever they

occurred, be it in a specific organ or in the recesses of apatient’s psyche or soul. Thus, my practice evolved as Ievolved. I studied Chinese medicine and acupunc-ture, meditation and yoga, macrobiotic diet and intra-venous nutrition. By addressing seemingly unrelatedaspects of ill health—psychological factors, individualbiochemical alterations, cardiovascular fitness levels,and dietary patterns—I found that patients could achievesignificant improvements in overall well-being and insome cases reverse disease. Yes, it was “anecdotal”observation, but it mattered not. Patients felt betterand their lives were more whole, fulfilled, and con-nected. And it was a start. An important one.

Whereas some early colleagues directed their inte-grative efforts to cardiac medicine or allergies, I foundthat integrative approaches were nowhere more valu-able than in the area of cancer care. The causes of can-cer are multifactorial and still unclear, but it is pre-cisely its puzzling and complex biology that makescancer an unparalleled disease to combat and so chal-lenging to overcome. The treatments of cancer haverelied exclusively on tumor-directed approaches, which,until a recent refocusing toward molecular markers,offered limited advantages in survival and quality oflife. For those of us uncomfortable with what was anobvious dearth of clinical answers for patients con-fronted with metastatic disease, thinking integrativelyprovided options and treatment considerations thathad seemed mostly unavailable. As I and other practi-tioners began exploring and integrating the multi-factored and multidimensional nature of the cancerproblem, I found that viewing the disease through thisvery different prism presented new insights and possi-bilities and more comprehensive treatment strategies.Of equal importance, it provided a means and inspira-tion to deal in greater depth with nearly every aspect ofour patients’ health. It was only a matter of time beforeI began seeing firsthand the clinical fruits of my treat-ing patients using this comprehensive dispensary.

As time passed, a growing number of dedicated anddiverse practitioners joined us in our journey. Therewas a need to dismantle the sacred but imaginary bar-riers and divisions partitioning various medical andcomplementary specialties. To engage in clinical workwith patients desiring survival and healing, first requiredan obliteration of the walls that isolate fields of clinicaloncology, psychology, phytochemistry, anthropology,and other disciplines.

Along the way, a critical hurdle was reached. Vali-dating what was being observed was a new and daunt-ing challenge. Like most fields of medicine, integra-tive practice cannot yet claim to be fully “evidencebased.” The tension between designing randomizedcontrolled trials (RCTs) and providing clinical inter-ventions with reasonable scientific background for

Block

4 INTEGRATIVE CANCER THERAPIES 1(1); 2002

life-threatening disease adds an edge to many profes-sional discussions. This discussion takes on particularproblems when one recognizes the considerable safetyof most integrative modalities and the near impossibil-ity of performing RCTs across the integrative spec-trum. The sheer number of possible interventionsfrom complementary, alternative, and experimentalmedicine, as well as the many decades it could take tocomplete such investigations, virtually guarantees thatthese tense discussions will persist for a very long time.Nonetheless, there are RCTs, and they are growing innumber.

With these sometimes heated discussions comesthe need for a vehicle of communication for the inte-grative cancer care community. With the far-thinkingsupport of Sage Publications and a committed groupof editors, we have brought together a publication thatwill spearhead and focus this new and growing move-ment in cancer treatment. Integrative Cancer Therapieswill provide scientifically based information on thevarious therapeutic interventions—diet, lifestyle change,exercise, stress care, nutritional supplements, enzymetherapies, biofeedback, experimental vaccines, immu-notherapies, chronochemotherapy, and others. Theneed for scientific information on the application ofthese interventions in cancer, even among practitio-ners who consider themselves purely conventional, isbecoming more urgent as patients undertake to inte-grate their own care and as integrative centers appearin hospitals across the country.

Integrative Cancer Therapies is, then, dedicated to fur-thering the rational, scientifically based practice ofintegrative cancer care and to improving the qualityand length of our patients’ lives. The philosophy thatinforms integrative care—seeking a whole that is greaterthan the sum of its parts—will also inform this journal.It will seek to gather in one place the wisdom and workof those who concentrate on researching and imple-menting integrative interventions in the clinical set-ting for the benefit of other clinicians and the patientsthey care for. The journal will recognize, as does a trulyrigorous approach to integrative medicine, that sim-ply gathering a variety of techniques in one place with-out seeking the synergies among them—and evaluat-ing their safety and reliability—is not enough and is nolonger acceptable. Fostering communication betweenscientists and clinicians is another aim of this journal.The scientist, appropriately, maintains a questioning,criticizing, and doubting attitude toward new ideas inmedical care. The clinician, equally appropriately, fos-ters an attitude of hope rather than doubt in his or herpatients. Reconciling the stances of scientist and clini-cian in a single person remains a difficult problem; inthis journal, we plan to provide a specific forum for thescientific approach, but we bear in mind that this is, in

the end, a journal for clinicians and for all integrativecaregivers, a place to seek constructive answers—andhope.

Like most journals, Integrative Cancer Therapies willpublish a variety of peer-reviewed articles. Clinicalstudies are obviously the meat of any medical journal,and this issue features a trial focusing on the radio-protective effects of an antioxidant extract of mungbean in breast cancer patients from Tran Van Hienand colleagues in Vietnam. Integrative providers froma range of practices need systematic education in thescience of the field, and we plan to address this needthrough scientific and educational reviews. This issuefeatures a detailed scientific review by Jeanne Wallaceon the role of the inflammatory cascade in cancer andhow cyclooxygenase-2 inhibitors—both natural andpharmacological—might be used to address it. Educa-tional reviews are also featured. Alastair Cunninghamdiscusses therapeutic and programmatic approachesin the psychological treatment of cancer patients andreflects on the basic directions of research in psycho-oncology. Carole Schneider and colleagues describethe theoretical concerns and practical guidelines of aninstitutionally based exercise program for cancerpatients. Additionally, Charlotte Gyllenhal and I havereviewed the pharmacological interactions of herbsand nutritional compounds with chemotherapiesthrough the cytochrome P450 isoenzyme system.

Any integrative cancer clinic—and conventionalclinics as well—must stress communication betweendifferent practitioners about specific patient cases. Inhospitals, this generally occurs through meetings ofthe facility’s tumor board. In this issue, we are launch-ing the first journal-based Integrative Tumor Board, aunique project in which a variety of practitioners—radiation and medical oncologists, surgeons, nutri-tionists, psychologists, naturopaths, dietitians, bodyworkers, traditional medicine practitioners, and oth-ers—will all respond to case presentations submittedby physicians from integrative clinics. In this feature,we hope to foster knowledge and understanding ofthe treatment goals and strategies of different disci-plines that must all learn to work together to promotefull integrative care of the patient.

Like any scientific approach, integrative care in itsjourney, thus far, has encountered rough waters in theform of controversies that pose treatment dilemmasfor practitioners and raise anxiety among patients.Such controversies include questions of whether soyproducts may be used by breast cancer patients andthe role of antioxidant supplements in chemotherapyand radiation therapy. We will address these in a fea-ture called Point-Counter Point in which differentresearchers will be asked to give their opinions on con-troversial topics. In this issue we address the question

Editorial

INTEGRATIVE CANCER THERAPIES 1(1); 2002 5

of soy and breast cancer. Future issues will also includePatient Perspectives, a series of reviews of the sciencebehind specific herbs, supplements, and techniquesthat are currently in use by patients. Clinical Cornerarticles will address emerging treatments and data thatare important in routine clinical work. ResearchBriefings—short abstracts of research on a variety ofspecific topics—as well as case reports and Letters tothe Editor will also appear. We do encourage you toregard this as your journal as well and alert us to topics,problems, and concerns that you face in your clinicalwork.

Because there was so little known a few decades agoabout cancer and the myriad ways it affected patients,neither practitioners nor patients had much scientifi-cally credible recourse beyond conventional thera-pies. Today, however, even practitioners who prefer tostay within the boundaries of conventional medicinehave no choice but to respond to the torrent of materi-als being unearthed by patients themselves who aredesperately searching for meaningful ways to confronttheir life-threatening diseases. All of us need to exploreand fit into our treatment plans new research in a vari-ety of as-yet neglected areas: the potential impact ofdepression and anxiety on response to chemotherapy,

the power of timing in both breast cancer surgery andin the delivery of chemotherapy, and the use of a widevariety of natural compounds to enhance treatmenteffectiveness and diminish side effects. In the field ofintegrative cancer therapy, our journey—and thisjournal—will lead us to improved care for our patientswhile bringing more scientific credibility to integra-tive treatment. As integrative care actually becomesthe medicine of the future, our patients confrontingcancer can look forward to longer and more fulfillinglives and to ever more humane, compassionate, andscientifically validated treatment. We are embarkingon a journey that addresses the needs of patients atevery level, from the biochemical and molecular to thespiritual. We may even find that these levels are not sofar apart.

Keith I. Block, MDEditor-in-Chief

Block Center for Integrative Cancer CareEvanston, Illinois

University of Illinoisat Chicago College of Medicine

Chicago, Illinois

Block


WallaceNutritional and Botanical Anti-Inflammatory Agents in Cancer

Nutritional and Botanical Modulation ofthe Inflammatory Cascade—Eicosanoids,Cyclooxygenases, and Lipoxygenases—As an Adjunct in Cancer Therapy

Jeanne M. Wallace, PhD, CNC

Emerging on the horizon in cancer therapy is an expansionof the scope of treatment beyond cytotoxic approaches to in-clude molecular management of cancer physiopathology.The goal in these integrative approaches, which extends be-yond eradicating the affected cells, is to control the cancerphenotype. One key new approach appears to be modula-tion of the inflammatory cascade, as research is expandingthat links cancer initiation, promotion, progression,angiogenesis, and metastasis to inflammatory events. Thisarticle presents a literature review of the emerging relation-ship between neoplasia and inflammatory eicosanoids (PGE2and related prostaglandins), with a focus on how inhibitionof their synthesizing oxidases, particularly cyclooxygenase(COX), offers anticancer actions in vitro and in vivo. Al-though a majority of this research emphasizes the pharma-ceutical applications of nonsteroidal anti-inflammatory drugsand selective COX-2 inhibitors, these agents fail to addressalternate pathways available for the synthesis of pro-inflammatory eicosanoids. Evidence is presented that sug-gests the inhibition of lipoxygenase and its by-products—LTB4, 5-HETE, and 12-HETE—represents an overlookedbut crucial component in complementary cancer therapies.Based on the hypothesis that natural agents capable of mod-ulating both lipoxygenase and COX may advance the effi-cacy of cancer therapy, an overview and discussion ispresented of dietary modifications and selected nutritionaland botanical agents (notably, omega-3 fatty acids, antioxi-dants, boswellia, bromelain, curcumin, and quercetin) thatfavorably influence eicosanoid production.

The molecular management of cancer physiopathologyis a promising focus for integrative cancer therapies.In addition to eradicating malignant cells, the expandedgoal in integrative medicine is to control the cancerphenotype, and thereby to improve the quality of lifeand extend the survival of cancer patients. Therapeu-tic approaches employing this paradigm strive to opti-mize host nutritional and metabolic status (whichaffect genetic stability and gene expression), controltumor-promoting messenger molecules (such as growthfactors and hormones), promote differentiation and

apoptosis, curtail angiogenesis, deter invasion andmetastasis, and bolster immune surveillance and tumorimmunoreactivity.1 A key strategy in this model, whichmay affect several of these targets, appears to be themodulation of inflammatory eicosanoids.

Eicosanoids are hormone-like compounds with localactivity, produced both by tissue cells and by tumor-infiltrating leukocytes. They are synthesized from poly-unsaturated fatty acids, predominately arachidonic acid.Collectively, eicosanoids have potent biological activi-ties in cell proliferation and tissue repair, blood clot-ting, blood vessel permeability, inflammation, andimmune cell behavior.2 Prostaglandins are a well-knownclass of eicosanoid, and prostaglandins in the 2 series(e.g., PGE2) have proinflammatory activities.

Prostaglandins are synthesized by the action ofprostaglandin synthase enzymes, also known ascyclooxygenases (COXs). Two distinct isoforms of COXhave been discovered, COX-1 and COX-2. COX-1 isconstitutively expressed and is cytoprotective. It isrequired for normal “housekeeping” functions, suchas protection of gastrointestinal mucosa, maintenanceof renal function, and platelet stabilization and activ-ity.3 A second isoform of COX, COX-2, is inducible andexpressed primarily following inflammatory insult.COX-2 synthesizes series-2 prostaglandins (e.g., PGE2,PGF2-α) that contribute to pain, inflammation, andswelling. COX-2 can be stimulated by inflammatorymediators, cytokines, growth factors, and tumor pro-moters. COX-2 is inhibited by steroids and nonsteroidalanti-inflammatory drugs (NSAIDs). A detailed expla-nation of the biochemical pathways of these and addi-tional eicosanoid compounds is presented later in thisarticle, following a literature review of the role ofCOX-2 and its byproducts in neoplastic diseases.

Nutritional and Botanical Anti-Inflammatory Agents in Cancer


JMW is at Nutritional Solutions, Inc., North Logan, Utah.

Correspondence: Jeanne M. Wallace, Nutritional Solutions, Inc.,2935 North, 1000 East, North Logan, UT 84341, USA. E-mail:[email protected].

COX-2 and PGE2 in Cancer:Review of the LiteratureThere is a large body of literature, dating back to1974,4 exploring the connection between prostaglandinsand cancer. Early research established that humanand experimental tumors have elevated amounts of Eseries prostaglandins and that NSAID blockade ofprostaglandin synthesis inhibits tumor growth in vitroand in vivo.5 The development of selective COX-2 in-hibitors, celecoxib and rofecoxib, and the prospect oftheir therapeutic application in chemoprevention andcancer therapy, has fueled an explosion of research onthe role of inflammatory modulation in cancer. Thefollowing discussion provides a review, for selectedtypes of cancer, of the recent literature on this topic.The studies reviewed here are a small but representa-tive sample of the published scientific literature from1995 through 2001. A summary of this research is pre-sented in Table 1.

Colon CancerThe relationship between COX-2 and cancer was ini-tially discovered, and has been most fully explored, incolon cancer. Research initially focused on chemo-prevention. Ample epidemiologic evidence supportsthe chemopreventive effect of NSAIDs (especially as-pirin) on both polyp formation and the risk of colorectalcancer, with some studies reporting as high as a 40% to50% reduction in cancer mortality.6-11 Chemopreventivestudies on selective COX-2 inhibitors have also demon-strated positive effects.12-14

In vivo studies show similar chemopreventive effects;for example, long-term (40-week) administration of aselective COX-2 inhibitor in rats reduces the inci-dence of azoxymethane-induced colon neoplasms from80% to 85% in the control group and from 45% to50% in the treatment group.15 Some of the strongestevidence implicating COX-2 in colorectal tumorigenesisderives from research on mice with multiple intestinalneoplasia (Min mice), who harbor a mutation in thetumor suppressor gene and are predisposed to multi-ple intestinal adenoma (forming up to 800 polyps)and subsequent colon cancer. Feeding COX-2 inhibi-tors to Min mice dramatically suppresses tumor growth.16

When Min mice are crossbred with COX-2 knockoutmice, their progeny develop markedly reduced num-bers of tumors.16-18

Controlled trials of patients with familial adenoma-tous polyposis (FAP) have achieved 30% reductions inpolyp burden (size and number) with daily adminis-tration of celecoxib.19,20 Because a variety of doses havebeen used in human studies to date, further researchis needed to clarify the dose that safely confers opti-mum chemopreventive effects. Identification of at-

risk individuals who may most benefit from thischemopreventive strategy is yet to be characterized,excepting those with FAP. The Food and Drug Admin-istration (FDA) approved celecoxib for use as anadjunct treatment for FAP in December 1999. Con-sidering the toxicity of chronic NSAID use, and thepotential although as yet not fully documented sideeffects of selective COX-2 inhibitors, the benefit-to-risk ratio needs to be determined. Consequently, blan-ket recommendation of COX inhibitors for colon can-cer prevention is premature. For this reason, muchresearch has turned its focus to the application ofCOX inhibition in cancer treatment beginning withstudies to characterize the up-regulation of COX-2 incancer and its biological effects.

COX-2 protein overexpression is demonstrated inmore than 80% of human colorectal adenoma andcarcinoma biopsy specimens, but it is absent in adja-cent histologically normal tissue.2l,22 Levels of PGE2 arealso significantly elevated in colon cancer samples ascompared to histologically normal mucosa.23

Administration of NSAIDs or selective COX-2 inhib-itors has growth-suppressive effects both in vitro andin vivo. NSAIDs (aspirin, indomethacin, naproxen,and piroxicam) reduce the proliferation of HT-29colon adenocarcinoma cells in vitro via cell cycle arrest—increasing the proportion of cells in G0/G1 phase andreducing the proportion of cells in G2/M and S phases—and programmed cell death.24 Xenografts of HCA-7colon cancer cells (which express high levels of COX-2) in nude mice sustain an 85% to 90% growth sup-pression with daily administration of celecoxib com-pared to no growth inhibition in the placebo group.22

An interesting relationship has been documentedbetween the activities of COX-2 and butyrate, a short-chain fatty acid derived from bacterial fermentation ofdietary fibers. Butyrate is known to induce differentia-tion and apoptosis in colorectal tumor cells in vitro.HT-29 colon carcinoma cells can be sensitized to thegrowth-inhibitory effects of butyrate by a selectiveCOX-2 inhibitor, methanesulfonamide (NS-398).25 Inthis study, treatment of the cell line with NS-398 alonedid not achieve detectable growth inhibition, and celllines not expressing COX-2, as determined by PGE2production, were not sensitized to butyrate. Furtherresearch is indicated to examine the potential interde-pendence of butyrate and COX-2 inhibition. If in vivoresearch confirms the relationship, it could explainthe lack of consistency in research on butyrate andoffer a means to increase the therapeutic efficacy ofstrategies to boost butyrate levels.

Increased COX-2 expression in tumor specimensfrom colorectal carcinoma patients is significantlycorrelated with unfavorable clinicopathological char-acteristics—such as tumor size and Dukes’ staging,

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Table 1. Selected Research Findings for Cyclooxygenase-2 (COX-2) and PGE-2 in Cancer

Brain tumorsShono et al. (2001) COX-2 overexpression in brain tumor tissue is associated with clinically more aggressive gliomas

and is the strongest predictor of outcome for glioma patients, independent of all other variables31

Joki et al. (2000) Although present in all brain specimens sampled, COX-2 protein expression is significantly higherin tumor than normal brain, and considerably higher in high-grade than in low-grade gliomas;NS-398 inhibits growth of 3 human glioma cell lines in vitro in a dose-dependent manner29

Tatsuhiro et al. (2000) Significant positive correlation between COX-2 staining and tumor grade in glioma samples; NS-398 reduces cell proliferation and migration and induces apoptosis in vitro30

Petersen et al. (2000) Selective COX-2 inhibition decreased cell survival, induced apoptosis, and slowed tumor growth invitro and in vivo in human glioma cell line U25132

Breast cancerBlumenthal et al. (2001) Celebrex® has impressive in vitro growth inhibition on breast cancer cell lines38

Kundu et al. (2001) Elevated PGE2 confers increased metastatic potential in a murine model of breast cancer42

Koki et al. (2001) In 25 women with breast cancer, COX-2 overexpressed in 80% of HER-2/neu positive tumors45

Harris et al. (2000) Treatment with selective COX-2 inhibitor reduced the incidence of experimentally induced breastcancers in lab animals in vivo37

Harris et al. (1999) Prospective cohort study shows breast cancer rates declined by about 50% among those with regu-lar ibuprofen intake33

Gilhooly and Rose (1999) Modest breast cancer chemopreventive for selective COX-2 inhibitors35

Fischer et al. (1999) In 341 women with invasive breast carcinoma, regular nonsteroidal anti-inflammatory drug (NSAID)ingestion was inversely associated with size of primary tumor, lymph node status, and numberof involved axillary nodes40

Hwang et al. (1998) Modest chemopreventive role for COX-2 inhibitors in breast cancer36

Harris et al. (1996) Up to 40% reduction in risk of developing breast cancer among women who regularly use NSAIDs,3 to 7 times a week for 1 to 5+ years34

Liu and Rose (1996) Highly invasive MDA-MB-231 breast cancer cell line has high COX-2 expression (and high PGE2production) compared to a less invasive cell line41

Colorectal cancerMasunaga et al. (2000) Increased COX-2 expression correlates with tumor size, differentiation, vascularization, number of

metastatic lymph nodes, and Dukes’ stage; patients with COX-2 positive tumors have signifi-cantly shorter survival times26

Tomozawa et al. (2000) High COX-2 expression significantly correlated with tumor recurrence and metastasis28

Hao et al. (2000) COX-2 overexpression found in more than 80% of adenoma and carcinoma tissue21

Crew et al. (2000) COX-2 inhibitor sensitizes HT-29 colon carcinoma cells to the growth-inhibitory effects of butyrate25

Sheehan et al. (1999) Elevated COX-2 staining in colorectal cancer patients is correlated with advanced disease andpoorer prognosis27

Smalley et al. (1999) Up to 50% decrease in colorectal carcinoma mortality among aspirin or NSAID users8

Kawamori et al. (1998) Celecoxib exerts chemopreventive activity against colon carcinogenesis12

Fukutake et al. (1998) COX-2 inhibitor exerts chemopreventive effect in mice14

Hara et al. (1997) Selective COX-2 inhibitor induces apoptosis in human colorectal cancer cell lines13

Sheng et al. (1997) COX-2 overexpressed in mucosa of colorectal cancer patients but minimally expressed in normalcolonic epithelium22

Sheng et al. (1997) Compared to placebo, celecoxib suppresses growth of tumor xenografts by 85% to 90% in nudemice22

Shiff et al. (1996) NSAIDs reduce proliferation of HT-29 colon cancer cells in vitro via cell cycle arrest and apoptosis24

Thun (1996) Decreased risk of gastrointestinal cancers in NSAID users9

Oshima et al. (1996) COX-2 null mice have significant decrease in number of polyps18

Rigas et al. (1993) Biopsy samples of human colon cancer tissue contain significantly elevated levels of PGE2 com-pared to normal tissue samples from the same patients23

Gastric cancerKang et al. (2001) Overexpression of COX-2 observed in patients’ tumor tissues; aspirin reduces PGE2 production by

50% after 24-hour exposure in vitro; selective COX-2 inhibitors induce apoptosis in gastric can-cer cell line SNU-21649

Ohno et al. (2001) COX-2 indices significantly higher in gastric carcinoma with deep invasion51

Chen et al. (2001) Patients with COX-2-positive gastric adenocarcinoma have poorer prognosis than those with COX-2-negative tumors54

Lim et al. (2000) Up-regulation of COX-2 in gastric cancer tissues (from 104 surgically resected gastricadenocarcinoma patients) compared to normal paired mucosa, but no correlation betweenclinicopathological characteristics of gastric cancer patients and intensity of COX-2 expression52

Uefuji et al. (2000) COX-2 protein overexpressed in 74% of gastric cancers and intensity of COX-2 expression signifi-cantly correlated with lymph node involvement53

Ratnasinghe et al. (1999) COX-2 is overexpressed in gastric adenocarcinoma50

Sawaoka et al. (1998) Selective and nonselective COX inhibitors suppress cell proliferation in gastric cancer cell lines thatexpress COX-2 in vitro48

Gynecological cancerKulkarni et al. (2001) COX-2 detected in 12 of 13 cases of cervical cancer but undetectable in normal cervical tissue56

Sales et al. (2001) COX-2, PGE2 synthesis, and expression of PGE2 receptors are up-regulated in malignant tissue ofthe uterine cervix but not in normal cervix55

Gaffney et al. (2001) Increased COX-2 expression significantly correlates with diminished survival and disease-free sur-vival in patients with invasive carcinoma of the cervix treated with radiotherapy59

(continued)

differentiation, lymph node involvement, vascu-larization, and metastases—and is associated with sig-nificantly shorter survival time compared to patients

with COX-2 negative tumors.26,27 In addition, COX-2overexpression is correlated with recurrence of colo-rectal cancer.28

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Comerci et al. (2001) Staining intensity of COX-2 significantly greater in endometrial hyperplasia and carcinoma com-pared to normal endometrium57

Ryu et al. (2000) COX-2 expression observed in all surgical samples of 36 patients with cervical cancer and was sig-nificantly elevated in those with lymph node or parametrial involvement; COX-2 expression sig-nificantly stronger at the tumor invasion site58

Head and neck cancerGallo et al. (2001) COX-2 higher in tumor samples of squamous cell carcinoma of the head and neck (HNSCC)

patients than in normal mucosa, and COX-2 protein expression correlated with tumorvascularization, vascular endothelial growth factor expression in tumor tissue, and lymph nodemetastasis61

Sumitani et al. (2001) Selective COX-2 inhibition suppressed proliferation of squamous cell oral carcinoma cell line invitro; addition of PGE2 reversed this effect63

Nishimura et al. (1999) COX-2 inhibitor suppresses growth in human head and neck squamous carcinoma xenografts62

Mestre et al. (1999) Nearly 100-fold increase in COX-2 mRNA detected in HNSCC, and COX-2 protein detected in 6 of6 cases of HNSCC but undetectable in normal mucosa60

Lung cancerWilliams et al. (2000) Significantly reduced tumor growth in COX-2 null mice grafted with Lewis lung carcinoma; tumors

grown in COX-2 null mice have decreased vascular density67

Hosomi et al. (2000) COX-2 overexpression detected in more than 80% of precursor lesions of human lungadenocarcinoma64

Ochiai et al. (1999) COX-2 expression in non–small cell lung cancer significantly higher than in normal lung tissue, andsignificantly higher in adenocarcinoma than in squamous cell carcinoma autopsy samples66

Watkins et al. (1999) COX-2 highest in adenocarcinoma cells and lower in large cell and squamous cell carcinoma,respectively; COX-1 undetected65

Achiwa et al. (1999) Presence of COX-2 in human lung associated with poorer prognosis in stage I lung cancerpatients69

Pancreatic cancerKokawa et al. (2001) Inhibitory effect of aspirin on 4 pancreatic cell lines parallels their level of COX-2 expression74

Yip-Schneider et al. (2000) COX-2 expression significantly higher in pancreatic tumor than in matched normal adjacent tissue;COX inhibitors inhibit cell growth in pancreatic tumor cell lines, with greater inhibitory effect forcell lines with stronger COX-2 expression73

Tucker et al. (1999) COX-2 mRNA increased >60-fold in pancreatic cancer tissue compared to adjacent nontumoroustissue70

Koshiba et al. (1999) COX-2 expression identified in all pancreatic cancer tissues tested and in 60% of 5 pancreatic can-cer cell lines; no significant correlation between COX-2 expression and prognosis orclinicopathological factors in this study71

Okami et al. (1999) Moderate to strong overexpression of COX-2 found in 90% of pancreatic carcinomas compared tono or weak expression of COX-2 in benign tumors72

Prostate cancerSubbarayan et al. (2001) Up-regulation of COX-2 and PGE2 is correlated with decreased apoptosis in PC-3, LNCaP, and

DU145 prostate cancer cell lines78

Gupta et al. (2000) 3.4-fold increase in mean levels of COX-2 mRNA in prostate cancer tissue compared to benign tis-sue from same patient80

Fischer et al. (2000) Significant risk reduction for prostate cancer among NSAID users75

Liu et al. (2000) COX-2 inhibition suppresses PC-3 cell tumor growth in vivo79

Irani et al. (1999) Patients with increased peritumoral inflammation have significantly more postoperative biochemicalrecurrence than those with low inflammation81

Tjandrawinata andHughes-Fulford(1997)

Administration of exogenous PGE2 increases cell proliferation of PC-3 cell lines and up-regulatesCOX-2 expression77

Urinary bladder cancerRistimaki et al. (2001) COX-2 highly expressed in bladder carcinomas with highest expression of invasive tumors associ-

ated with invading cells84

Shirahama (2000) COX-2 expression undetected in normal urothelial samples but increased in tumors and signifi-cantly correlated to tumor stage in muscle-invasive tumors83

Khan et al. (2000) No detection of COX-2 in normal urinary bladder epithelium of canines, but increased COX-2expression in neoplastic epithelium in primary tumors and in metastatic lesions82

Komhoff et al. (2000) Elevated expression of COX-2 demonstrated in a high percentage of high-grade bladdercarcinomas362

Kitayama et al. (1999) Dose-dependent reduction in nitrosamine-induced bladder tumors in animals with COX-2 inhibitornimesulide86

Ziegler (1999) Celecoxib chemoprevention of nitrosamine-induced bladder tumors in vivo87

Okajima et al. (1998) Chemoprevention of rat urinary bladder cancer with COX-2 inhibitor85

Table 1. Continued

Brain CancerCOX-2 is constitutively expressed in normal brain tis-sue. Nonetheless, comparative evaluations of COX-2expression in human glioma tumors and normal brainsamples show that COX-2 expression is significantlyhigher in tumor and that COX-2 expression is signifi-cantly higher in high-grade glioma than in low-gradeglioma.29,30 Recent work at the University of Texas,M. D. Anderson Cancer Center confirms that elevatedCOX-2 expression in brain tumors is associated withclinically more aggressive gliomas and is a strong pre-dictor of poor survival, particularly for patients withglioblastoma multiforme.31 Immunohistochemistry eval-uations of tumor specimens from 66 patients foundthat high COX-2 expression (>50% of cells stainingpositive) was the strongest predictor of outcome, inde-pendent of all other variables.

In vitro application of selective COX-2 inhibitorshas been shown to reduce proliferation of humanglioma cell lines, impede tumor cell migration, andincrease the number of apoptotic cells.29,30 COX-2 inhi-bition also slows tumor growth rate in vivo in gliomamurine xenografts.32

Collectively, these findings strongly suggest a poten-tial role for COX-2 inhibitors as an adjunctive therapyfor brain tumors.

Breast CancerThe frontier of COX inhibition in breast cancer pre-vention and treatment is being probed by several linesof evidence. Epidemiologic research demonstrates a40% to 50% decrease in the risk of breast canceramong women who are chronic users of NSAIDs.33,34

The risk reduction is similar to that reported for coloncancer chemoprevention.8 A modest chemopreventiverole for selective COX-2 inhibitors has also been re-ported in breast cancer.35,36 Significant chemopreventionof chemically induced breast cancer in lab rats can beachieved by treatment with ibuprofen or celecoxib.37

In vitro analyses have demonstrated an IC50 forcelecoxib in 12 solid tumor lines ranging from 28 to 58µM, with impressive growth inhibition on breast can-cer cell lines.38 At very high doses, celecoxib (1500mg/kg/day) has significant in vivo antineoplastic activ-ity, achieving tumor regressions in 90% of tumor-bearing animals treated for 6 weeks.39 The excessivedoses employed in this study limit the relevance of itsfinding in clinical practice.

A retrospective analysis of 341 women with invasivebreast carcinoma found regular prior NSAID ingestionwas inversely associated with the size of the primarytumor, lymph node metastasis, and the number ofinvolved axillary nodes,40 suggesting NSAID use mayimpact favorably on factors that determine prognosisand clinical outcome of women with breast cancer.

The supposition that COX-2 is implicated in breastcancer invasion is supported by the observation thatthe highly invasive, metastatic MDA-MB-231 cell lineshows high COX-2 mRNA and protein and elevatedPGE2 production, whereas less invasive cell lines havelower COX-2 expression.41 In a murine model of meta-static breast cancer, PGE2 levels are positively corre-lated with increased tumorigenic and metastaticpotential.42

Provocative observations have been made on theassociation between estrogen and COX-2. The expres-sion and enzymatic activity of COX appears to vary inrelation to hormonal status. Ovariectomized rats hadsignificantly lower COX enzymatic activity than shamoperated animals. However, administration of estradioland progesterone in ovariectomized rats yields signifi-cant up-regulation of COX activity.43 Another compel-ling observation is that PGE2 stimulates the synthesisof estrogen proximal to breast tumor tissue by activat-ing aromatase, a chief enzyme in the biosynthesis ofestrogen.44 Together, these results suggest a reciprocalpromoting effect wherein estradiol increases COX-2activity and the subsequent COX-2 by-product, PGE2,further stimulates increased estrogen biosynthesis. Fur-ther work is needed to confirm these observations,which may ultimately explain the deregulation of estro-gen biosynthesis and metabolism that accompaniesbreast cancer.

Equally provocative is the correlation between COX-2 and HER-2/neu status. A study presented at theMarch 2001 meeting of the American Association forCancer Research reported that COX-2 was over-expressed in 80% of HER-2/neu-positive ductal, lobu-lar, or infiltrating breast cancers evaluated.45 Previousinvestigations into the nature of the relationship betweenCOX and HER-2/neu have employed colorectal can-cer models. Thwarting HER-2 signaling produces anunexpected reduction in COX-2 expression; conversely,activation of the HER-2 pathway up-regulates COX-2mRNA and protein and produces an accumulation ofPGE2 in the culture medium.46 Whereas either celecoxibor Herceptin® inhibit HCA-7 colon cancer cell growthin vitro and in vivo, combination therapy results inadditive effects.47 A trial sponsored by the NationalCancer Institute (NCI) on the combined use of celecoxiband Herceptin® in women with metastatic breast can-cer is currently under way.

Gastric CancerIn vitro research on various gastric cancer cell linesprovides supportive evidence that COX-2 is related totheir cell proliferation. In this research, COX inhibi-tion—via indomethacin or a selective COX-2 inhibitor(NS-398)—suppresses proliferation of gastric cancercells that overexpress COX-2 (MKN45) but has mini-



mal effects on cell lines with lower COX-2 expression(KATOIII and MKN28).48 Exposure of SNU-216 gas-tric cancer cells to selective COX-2 inhibitors showspotent cytotoxicity via apoptosis.49

Examinations of COX-2 expression in patients withgastric cancer reveal a central role for COX-2 in thistype of cancer. COX-2 overexpression is demonstratedin human gastric adenocarcinoma biopsy specimensbut absent in adjacent histologically normal tissue.49-51

Whereas one study reports no correlation betweenCOX-2 expression and the clinicopathological charac-teristics of gastric adenocarcinoma patients,52 other stud-ies have noted a significant relationship. For example,COX-2 mRNA expression is significantly correlatedwith the depth of invasion,51 lymph node involvement,53

and vascular invasion.54 In the latter study, patientswith COX-2 positive gastric adenocarcinoma had sig-nificantly poorer prognosis than those with COX-2negative tumors.54 There was no relationship betweenCOX-1 and prognosis or clinicopathological factors.

Gynecological CancersTissue specimens from patients with adenocarcinomaor squamous cell carcinoma of the uterine cervix showup-regulation of COX-2 mRNA and protein, elevatedsynthesis of PGE2, and increased expression of PGE2receptors.55,56 These findings were absent in specimensof normal cervix. Endometrial carcinoma shows a sim-ilar pattern, with COX-2 expression evident inendometrial carcinoma and hyperplasia but absent innormal endometrium.57

COX-2 appears to correlate with the invasive poten-tial of gynecological cancers, and COX-2 values haveprognostic significance in cervical cancer. COX-2 over-expression is correlated with lymph-vascular spaceinvasion in both endometrial57 and cervical cancer,58

with COX-2 staining particularly strong at the tumorinvasion site. A study of 24 patients with cervical carci-noma treated with radiotherapy evaluated the prog-nostic value of tumor size, stage and grade, radiother-apy dose, pretreatment and posttreatment hemoglobinlevels, and COX-2 distribution staining. Decreased COX-2 staining was the only factor associated with improvedsurvival. Five-year survival rates for patients with low-versus high-tumor COX-2 values were 75% and 35%respectively.59

Considered together, these studies suggest a rolefor COX-2 and PGE2 in cervical and endometrialcancers.

Head and Neck CancerEvidence to date confirms a role for COX-2 and PGE2in tumor cell proliferation, invasiveness, and metastasis insquamous cell carcinoma of the head and neck

(HNSCC). COX-2 protein is detected in all cases ofpatients with HNSCC but is undetectable in normalmucosa, and a comparison of COX-2 mRNA demon-strates a nearly 100-fold increase in HNSCC comparedto controls.60,61

Selective inhibitors of COX-2 suppress the growthof human HNSCC in a murine xenograft model.62

COX-2 inhibition also impedes the in vitro prolifera-tion of a squamous cell carcinoma cell line (NA),which constitutively expresses COX-2 mRNA.63 Thisinhibitory effect is reversed with the addition of PGE2,suggesting that COX-2 blockage inhibits the prolifera-tion of cancer cells in vitro via suppression of PGE2synthesis.

An evaluation of COX-2 mRNA and protein, andPGE2 levels in 35 patients with HNSCC lends supportto the relationship between COX-2 and tumor pro-gression. In this study, PGE2 levels were higher in thetumor front zone than in tumor core or normal mucosa.Lymph node metastasis was associated with higherCOX-2 protein expression and greater PGE2 levels.61

The researchers also reported a significant correlationbetween COX-2 values and vascular endothelial growthfactor (VEGF) expression in tumor tissue and betweenCOX-2 and tumor vascularization.

Lung CancerCOX-2 expression is detected in 70% to 80% of hu-man adenocarcinoma and its precursor lesions.64 Fur-thermore, there is a differential level of gene expressiondepending on tumor type. COX-2 levels in non–smallcell lung cancer (NSCLC) are greater than COX-2 val-ues in adenocarcinoma, which in turn exceed thosefound in squamous cell carcinoma.65,66

Research on COX-2 null mice lends support to therole of host-derived COX-2 in tumor growth, and pos-sibly angiogenesis, in Lewis lung carcinoma. The growthof implanted Lewis lung carcinoma in vivo is markedlyattenuated in COX-2 null mice but unchanged inCOX-l null or wild-type mice.67 In addition, decreasedvascular density is observed in tumors grown in COX-2(-/-) mice compared to that in wild-type mice.

The COX-2 inhibitor nimesulide inhibits theproliferation—in part via inducing apoptosis—ofNSCLC cell lines in vitro in a dose-dependent manner,even at clinically achievable low concentrations.68 Theinhibitory effect appears to be independent of p53 sta-tus. Notably, responsiveness of NSCLC lines to COX-2inhibitors in this study did not require the presence ofwild-type p53, but may be influenced by the degree ofCOX-2 expression.

A recent clinical study indicates that the presenceof COX-2 is associated with a negative prognosis instage I lung cancer patients.69

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Pancreatic CancerPreliminary investigations offer tentative support forthe association of COX-2 in pancreatic cancer, specifi-cally, but much additional work is needed to character-ize the role of COX-2 and PGE2 in tumor viability,invasion, and metastasis. Levels of COX-2 mRNA areincreased greater than 60-fold in pancreatic cancercompared to adjacent nontumorous tissue, and COX-2protein is present in cases of adenocarcinoma of thepancreas but undetectable in nontumorous pancre-atic tissue and weak or absent in benign tumors.70-73

COX inhibitors (sulindac, indomethacin, andmethanesulfonamide) inhibit cell growth in both COX-2 positive and negative cell lines; however, growth sup-pression is significantly greater in COX-2+ cell lines.73

The growth inhibitory effect of aspirin on 4 pancreaticcancer cell lines parallels their level of COX-2 expres-sion.74 Despite these provocative in vitro and in vivofindings, the only study to date that has examined therelationship between COX-2 expression and progno-sis in pancreatic cancer patients finds no significantcorrelation.71

Prostate CancerNSAID use has a documented chemopreventive effectagainst prostate cancer. Regular daily use of over-the-counter or prescription NSAIDs significantly decreasedthe risk of prostate cancer (odds ratio: 0.35; 95% confi-dence interval: 0.15-0.84) in a case control study.75

These findings represent a risk reduction of NSAIDsagainst prostate cancer surpassing that previously re-ported for colon cancer8 and breast cancer.33

In vitro and in vivo research links both PGE2 andCOX-2 to prostate tumor growth and suggests theirpotential role in prostate cancer progression. TheCOX-2 substrates, linoleic acid and arachidonic acid(AA), as well as the COX-2 by-product PGE2, stimulatecell proliferation and tumor growth in vitro in PC-3human prostate cancer cells.76,77 In PC-3, LNCaP, andDU145 prostate cancer cell lines, up-regulation ofCOX-2 and PGE2 is inversely correlated with apoptosis.78

COX-2 inhibitors suppress PC-3 tumor growth in vivo,achieving this effect via the induction of tumor cellapoptosis, down-regulation of VEGF, and decreasedangiogenesis.79

COX-2 mRNA and protein levels are present in nor-mal prostate epithelial cells, suggesting COX-2 mayplay an important role in healthy prostate function.Nonetheless, COX-2 mRNA levels are 3.4-fold higherin prostate cancer tissue compared to pair-matchedbenign tissue from the same patient.80 Patients withhigh levels of peritumoral inflammation in radicalprostatectomy specimens had significantly more post-operative biochemical recurrence than patents with

low levels of inflammation.81 An NCI-sponsored, phaseI trial of neoadjuvant celecoxib following prostatec-tomy in patients with localized prostate cancer is dueto open shortly at Johns Hopkins Oncology Center inBaltimore, Maryland.

Urinary Bladder CancerFindings similar to those presented thus far in othercancers exist for the association of COX-2 in urinarybladder cancer. COX-2 overexpression is documentedin urinary bladder tumors and metastatic lesions but isundetected in normal bladder epithelium.82,83 Whereasnoninvasive tumors display homogeneous patterns ofCOX-2 staining, tissue examinations of human transi-tional cell carcinoma of the bladder demonstrate COX-2 staining intensity is strongest among the invadingcells of invasive carcinomas.84 This observation sug-gests COX-2 is involved in the invasive process.

Administration of a selective COX-2 inhibitor canachieve chemoprevention of rat urinary bladder can-cer.85 Further animal studies show the addition of vari-ous COX-2 inhibitors to carcinogen-induced bladdertumors results in a dose-dependent reduction in tumorburden.86,87

COX-2 expression appears significantly correlatedwith tumor stage: 93% of human carcinoma in situspecimens expressed COX-2 whereas only 48% ofdysplasia samples expressed COX-2.83 This differentialexpression profile suggests COX-2 may be involved inthe development of transitional cell carcinoma of theurinary bladder.

An NCI-sponsored, phase II/III clinical trial oncelecoxib for prevention of recurrent bladder canceris under way at the University of Texas, M. D. AndersonCancer Center.

What Causes COX to Be Elevated/Up-Regulated in Cancer?Further research is needed on the mechanisms re-sponsible for COX-2 up-regulation in neoplasia. Pre-liminary investigations suggest COX-2 is inducible bycertain oncogenes (e.g., ras and scr), interleukin-1(IL-1), hypoxia, benzo[a]pyrene, ultraviolet light, epi-dermal growth factor, transforming growth factor beta(TGF-β), and tumor necrosis factor alpha (TNF-α).88

Together with the promoting action of various signal-ing molecules in cancer pathophysiology, there ap-pears to be a positive feedback loop wherein increasedaction of COX-2 produces greater concentrations ofPGE2, which in turn further increases the expressionof COX-2. Treatment with epidermal growth factor(EGF) induces COX-2 protein and COX-2 mRNA andstimulates COX-2 promoter activity in cervical cancercell lines.56 Of note, PGE2 has been shown to up-regu-



late gene expression of its synthesizing enzyme, COX-2, in prostate, breast, and colon cancer cell lines.77,89

Physiopathological EventsAssociated with COX-2Thus far, an examination of the impact of COX-2 over-expression in various types of cancer has been pre-sented. But how does COX-2 exert its influence on themalignant phenotype? To date, several mechanismshave been identified by which COX-2, and its by-product PGE2, may contribute to tumor viability andprogression:90

1. Promotion of cell proliferation2. Inhibition of apoptosis3. Increased angiogenesis4. Increased invasiveness (and metastases)5. Immunosuppression.

A review of the relevant literature on these mecha-nisms follows.

Cell Cycle and ProliferationBoth COX-2 and PGE2 appear to have direct effectson cell proliferation. Tumor cells that lack the abilityto express COX-2 proliferate very slowly in vivo.91 Ex-ogenous PGE2 increases cellular proliferation in vari-ous cell lines, including LNCaP (androgen-dependent)and PC-3 prostate cancer cells, breast cancer MDA- MB-134 cells, and human colorectal carcinoma DiFi cells.77,92,93

Cell cycle arrest, or shift in profile of cell cycle parame-ters, has been documented in vitro with NSAIDs.94,95

Some criticism is due portions of the NSAID researchfor the large doses used to achieve growth inhibitoryeffects, which are not achievable clinically and aresupraphysiologic to the small doses required for COXinhibition. However, Eli et al.94 showed low-dose NSAIDswere effective in growth inhibition and cell cycle arrestin vitro, and attenuation of the growth of primary tu-mors and their metastases in vivo.

ApoptosisCOX-2 expression and apoptosis appear to be in-versely correlated. COX-2 inhibitors have been docu-mented to induce apoptosis in vitro in NSCLC,68 gastriccancer,49 and human colon cancer cell lines.7 It is un-known whether the decrease in programmed cell deathcan be attributed to a diminished AA content of cellmembranes, increased PGE2 (or other prostanoid)levels, or via the direct action of COX-2. Decreased cel-lular levels of unesterified AA appear to regulateapoptosis.96 Another study notes COX-2 mediated sup-pression of apoptosis may be controlled by increasedPGE2 levels (which modulate pro-apoptotic and anti-

apoptotic factors such as bcl-2, MAKs/ras, caspase-2,and Par-4).90 Further research is needed to character-ize the nature of the relationship between inflamma-tory events and apoptosis.

AngiogenesisStudies to date suggest a functional role for COX-2and inflammatory eicosanoids in tumor-inducedangiogenesis. This is not surprising given the knowneffect of inflammation in normal angiogenesis, but ap-pears to be excessive and long lasting in tumorangiogenesis.

Under normal physiological conditions, quiescentvasculature expresses only constitutive COX-1 whereasCOX-2 expression is observed in newly formed bloodvessels within and surrounding tumors in both ani-mals and humans.70,97,98 Vascular density is approxi-mately 30% lower in tumors grafted into COX-2 nullmice compared with tumors grown in animals with theactive COX-2 gene.67 COX-2 overexpression in humantumor specimens is directly correlated with microvesseldensity in metastasized HNSCC,61 NSCLC,99 gastriccancer,53 and colorectal carcinoma.26

Treatment with selective inhibitors of COX-2 effec-tively suppresses angiogenesis in in vivo models ofmany types of cancer.100-103 Several mechanisms appearto contribute to the pro-angiogenic effects of COX-2.Increased production of eicosanoid by-products (e.g.,PGE2, TXA2, and PGI2) may potentially reduce endo-thelial cell apoptosis and directly stimulate endothe-lial cell migration.104,105 COX-2 and its prostaglandinby-products increase the expression of pro-angiogenicgrowth factors, such as basic fibroblast growth factor,platelet-derived growth factor, and VEGF.90 In numer-ous studies, the anti-angiogenic effect of COX-2 inhib-itors appears to be mediated through down-regulationof VEGF.79,97,106-109 Fibroblasts from COX-2 null micehave a 94% reduction in the ability to produce VEGF,and the treatment of wild-type mouse fibroblasts witha selective COX-2 inhibitor reduced VEGF productionby 92%.67 Tumors grown in COX-2 null mice have sig-nificant reductions in VEGF expression.110

Invasion and MetastasisCOX-2 (and other inflammatory mediators) have arole in tumor invasiveness and metastasis. NSAIDs andselective COX-2 inhibiting agents reduce invasivenessof human prostate cancer cell lines, PC-3 and DU-145,in vitro, and the effect can be reversed by the additionof PGE2.111

Both in vitro and in vivo research suggest that COX-2 inhibition may be a potent approach to inhibit themetastasis of colorectal cancers. Of 4 colon cancer celllines investigated, the most invasive and metastatic

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variant (HT-29/lnv3) expresses the highest COX-2 val-ues and PGE2 production: etodolac, a COX-2 inhibi-tor, markedly suppresses the invasive property of thiscell line in vitro.112 COX-2 inhibitor treatment of micewith a highly metastatic colon cancer (LM-H3) reducedthe mean number of hepatic metastases in vivo from46.4 ± 18.9 nodules in controls to 3.6 ± 2.9 nodules intreated mice.113 Selective COX-2 inhibition has alsobeen shown to significantly reduce the number oflung metastases from colon cancer in mice.114

In human colorectal cancer patients, high COX-2expression significantly correlates with tumor recur-rence and hematogenous metastases.28 Excessive pro-duction of PGE2 has been linked with both tumormetastasis to bone and poor survival in breast cancerpatients.115 In patients with endometrial carcinoma,those with lymph-vascular space invasion demonstrateincreased COX-2 staining compared to those withoutevidence of invasion.57 In gastric carcinoma speci-mens, COX-2 overexpression in tumors is significantlycorrelated with local tumor invasion and lymph nodemetastasis.116

COX-2 may increase the invasive properties of tumorsby up-regulating metalloproteinases (e.g., MMP-2),thereby resulting in increased tumor cell migration.90,111

COX inhibitors significantly reduce levels of MMPs inculture.111,113

Immune SuppressionA detailed investigation of the complex interactionsbetween inflammatory events and host immune re-sponse is beyond the scope of this article. A brief surveyshows contradictory findings, which perhaps can be ex-plained by this statement: at low levels, inflammationenhances immune response, but when excessive orprolonged, it suppresses immune function.117 This cor-relation may be explained by the difference betweenCOX-1 and COX-2 mediated inflammatory events. Tu-mor-derived PGE2 appears to modify cytokine balanceand impair host immunocompetence.118 Tumor-derivedPGE2 plays a pivotal role in promoting the productionof IL-10 (a potent immunosuppressive cytokine) bylymphocytes and macrophages while simultaneously in-hibiting IL-12 production.119,120 In addition, PGE2 caninhibit the functional activity of lymphokine-activatedkiller cells and natural killer cells.121-123 These findingssuggest that abrogation of excessive inflammatory re-sponse may promote antitumor reactivity by restoringthe balance of IL-10 and IL-12 in vivo and enhancingthe function of natural killer cells.

Complementing Conventional TherapiesA promising area of therapeutic application for anti-inflammatory agents is as adjuncts to conventional

treatments, such as surgery, radiotherapy, and chemo-therapy.

SurgeryBecause surgery provokes an inflammatory response,and because inflammatory events may promote tumorgrowth and angiogenesis, the therapeutic efficacy ofcancer surgery may hypothetically be increased withconcomitant administration of anti-inflammatory agents.Some research supports this hypothesis. Specifically,radical nephrectomy for renal cell carcinoma is con-troversial. When preoperative markers of inflamma-tion are low, median survival of patients is significantlybetter in those who do not elect surgery (80.6 months)compared to those who do (50.2 months). In patientswith elevated inflammatory markers, however, there isno difference in treatment outcome between the 2groups.124 A similar relationship has been demonstratedin hepatocellular carcinoma, wherein up-regulatedCOX-2 expression in nontumorous samples of hepatictissue was associated with increased rates of relapseand shorter disease-free survival.125 The implication ofthese findings is that when inflammation status is nor-mal, tumor progression is slow and surgical treatmentmay actually worsen the prognosis. Conversely, surgi-cal resection may increase its therapeutic efficacy whencombined with steps to effectively control inflamma-tion. In patients with elevated inflammatory markerspreoperatively, it may be prudent to first pursue an ag-gressive anti-inflammatory protocol before proceed-ing with surgery. Investigations to test these hypothesesare an urgent priority.

RadiotherapyCOX-2 inhibition may act as a radiosensitizer. Re-cently published studies employing animal modelshave demonstrated that selective COX-2 inhibitors canaugment tumor response to radiotherapy without in-creasing the radioresponse of normal tissues.32,126,127

For example, administration of a selective COX-2 in-hibitor enhanced radiation-induced cell death in anadditive manner in COX-2 expressing human gliomacell line (U251) both in vitro and in vivo.32 The mecha-nism of action responsible for these effects is unknownand deserves further investigation. One possible ex-planation may be the antiangiogenic effects of COX-2inhibitors, described above. Cotreatment with anangiogenesis inhibitor (e.g., TNP-470) greatly improvestumor radioresponse in mice with human glioblastomaxenografts.128 Glioblastoma multiforme is a particu-larly aggressive and frequently radio- resistant humanbrain tumor. Taken together, these studies suggest alarge potential for improving radioresponse of tumorswith COX-2 inhibitors, which have direct radiosensitizing



properties and may also enhance radioresponse viaangiogenesis inhibition.

ChemotherapyAnti-inflammatory drugs may also have the potentialto increase the cytotoxic effects of chemotherapy. InT98G human malignant glioma cell lines, NSAIDs en-hancethecytotoxic effects of doxorubicin and vincristine,but not carmustine (1,3-bis [2-chloroethyl]-1-nitrosourea), cisplatin, and several other agents.129

This potentiation was achieved independent of free-radical formation or free-radical scavenging effects.The COX-2 inhibitor, nimesulide, potentiates the ef-fects of doxorubicin in human colon carcinoma andlung cancer cell lines by 36% and 61%, respectively.130

At clinically achievable concentrations, nimesulide re-duced IC50 values of various anticancer agents by up to77% in NSCLC cell lines.66

Although further research is needed to elucidatethe mechanisms of action of this potentiation, therecent finding that COX-2 inhibition may offer anti-angiogenesis effects, as well as separate findings thatangiogenesis inhibition appears to provide additivetherapeutic benefit to chemotherapy, suggests a poten-tial mechanism for this finding.104 Of note, NSAIDs shouldnot be given concurrently with methotrexate, due totheir ability to greatly boost blood levels of the drug,leading to serious complications (e.g., diarrhea, fever,ulceration of mouth and gastrointestinal tract, nau-sea, vomiting, kidney failure, blood abnormalities dueto bone marrow damage, and death).131

Cancer-Related PainAnti-inflammatory agents also have a role in the man-agement and control of cancer pain, perhaps delayingthe need for narcotic agents. Tissue damage from tu-mor or treatment is associated with increased prosta-glandin production, which can subsequently sensitizepain receptors, reducing their response threshold forprostaglandin stimulation.132

Broadening the Scopeof Vision: Beyond COX-2An expansive body of research has focused in the past5 years on the relationship between COX-2, its by-product PGE2, and cancer. This focus continues to-day, and is perhaps driven by the pharmaceutical mar-ket for agents that selectively inhibit COX-2 (celecoxiband rofecoxib). In summary, the pathological overex-pression of COX-2 appears to be related to key eventsin tumor promotion, such as cellular hyperprolifera-tion, inhibition of programmed cell death, and tumorangiogenesis. COX-2 expression is up-regulated dur-

ing tumorigenesis and by tumor promoters, and tu-mor number and growth are affected by modulationof COX-2 (as in COX-2 null mice). COX-2 inhibi-tors—and in some cases NSAIDs—reduce tumorgrowth in vitro and in vivo. COX-2 overexpression isdocumented in the malignant tissues of cancer pa-tients and typically correlates with tumor size, tumorstage, tumor metastasis, and patient survival. These ef-fects have been documented in a wide variety of epi-thelial-type tumors: cancers of the breast, colon, headand neck, brain, lung, pancreas, urinary bladder, andothers. Taken as a whole, the research on COX-2 im-plies the conclusion that efficient tumor growth re-quires the presence and action of COX-2 in the tumorhost and that abrogation of COX-2 imparts chemo-preventive effects and potential benefits in cancertreatment. However, is this a complete picture of in-flammatory events and cancer?

Despite the preponderance of research on COX-2and its resulting series-2 prostaglandins, there arenumerous additional eicosanoids and alternate enzy-matic pathways for their metabolism. Eicosanoid by-products of AA, for example, may be produced notonly by COX but also via lipoxygenase (LOX) andcytochrome P450. These eicosanoids are generated bymost cancers and appear to play a significant role inpromoting the induction, proliferation, angiogenesis,and spread of cancers.133 An overview of eicosanoidmetabolism is presented next, followed by a briefreview of the research on leukotrienes and its implica-tion in cancer.

Eicosanoid BiosynthesisEicosanoids are biosynthesized from the fatty acidcomponents of the phospholipid structure of cell mem-branes, the composition of which is directly depend-ent on sources of fatty acids in the diet. Eicosanoids fallinto 3 general groups, prostaglandins, leukotrienes(LTs), and thromboxanes, all arising from 20-carbon(hence their prefix, “eicosa”) fatty acids: AA (20:4w6),eicosapentaenoic acid (EPA, 20:5w3), or dihomo-gammalinolenic acid (DGLA, 20:3w6). The eicosanoidsproduced by these fatty acids have differing actions,ranging from the highly pro-inflammatory action ofAA-derived compounds to the weakly inflammatory,and thereby favorable, actions of EPA-derived com-pounds.

Fatty acids are released from membrane phos-pholipids via the action of phospholipase A2 and thenacted upon by COX and LOX. Figure 1 shows thebiosynthesis of various eicosanoids.

AA is derived from dietary sources, such as meat,dairy products, and eggs, and can also be bio-ssynthesized from omega-6 fatty acids of vegetable

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origin. There are 3 known enzymatic pathways for thesynthesis of eicosanoids from AA. In the first, COXgenerates short-lived endoperoxides (e.g., PGG andPGH) that are immediately converted into series-2prostaglandins (e.g., PGE2, PGF2-α) and thromboxanes(e.g., TXA2, TXB2). The second pathway involves theLOX group of enzymes, which create hydroperoxy-eicosatetraenoic acids (HpETEs). HpETEs are con-verted into series-4 LTs and various hydroxy-eicosatetraenoic acids (e.g., 5-HETE, 12-HETE,15-HETE). The third pathway involves cytochrome P-450, which can directly catalyze the formation of 12-HETE and 16-HETE. AA-derived compounds havepotent pro-inflammatory effects, increase pain,increase vasoconstriction, and promote thrombosis.

DGLA is near nonexistent in the diet and is mostlyderived from vegetable-source omega-6 fatty acids(nuts, seeds, and vegetable oils). DGLA is metabolizedby the action of COX to create series-1 prostaglandins(e.g., PGE1) and thromboxanes (e.g., TXA1). LOXmetabolizes DGLA to create series-3 LTs. Series-1prostanoids function to dilate blood vessels, preventplatelet aggregation, lower arterial pressure, inhibitthrombosis, inhibit cholesterol synthesis, and inhibitinflammation.134

The action of COX upon EPA creates series-3 pros-taglandins (e.g., PGE3) and thromboxanes (e.g.,TXA3). LOX metabolizes EPA to create series-5 LTs(e.g., LTB5). Dietary sources of preformed EPA arecold-water fish. EPA can also be created via enzymebiosynthesis of omega-3 fats, such as linolenic acid(18:3w3) from linseed (flax) oil, and certain otheroils. EPA-derived eicosanoids block the production ofseries-2 compounds and offer anti-inflammatoryeffects.134

Dietary intake of fatty acids is a primary determi-nant of eicosanoid metabolism. The total concentra-tion of fatty acids present in the phospholipid struc-ture of the cell membrane determines which class ofeicosanoid by-products will predominate. Therefore,there is a direct link between the balance of specificfats in the diet and inflammatory responses.135 Reduc-tion of dietary AA intake is paramount. However, thisobservation often leads to an inappropriate recom-mendation: reduction of AA intake, but an additionalemphasis on both omega-6 and omega-3 fatty acids,which are precursors of PGE1 and PGE3, respectively.It is important to note that the omega-6 fatty acidDGLA can be diverted by delta-5 desaturase (∆5D) toproduce AA and the inflammatory series-2 prostanoids(see Figure 1).

Another important consideration governing thera-peutic intake of dietary fats is substrate competition, aspictured in Figure 1. AA and omega-6 and omega-3

polyunsaturated fats must compete for active bindingsites on desaturase, elongase, COX, and LOX. Thus,the predominant dietary fat present in a cell phos-pholipid will determine the direction of eicosanoidproduction.135

The binding affinity of desaturase enzymes increaseswith the number of double bonds present in the sub-strate fatty acid.135 For example, EPA (20:5W3) willbind delta-5 desaturase stronger than DGLA (20:3w6).However, in the absence of adequate EPA, omega-6metabolism is unchecked, favoring the production ofAA and generation of pro-inflammatory compounds.

The activity of desaturase is suppressed by excessiveintake of dietary saturated, monounsaturated, andtrans fats, insulin excess, and magnesium and/or zincdeficiency.134,135

A nonenzyme-mediated pathway for the produc-tion of inflammatory compounds has also been discov-ered. Free-radical catalyzed peroxidation of AA pro-duces isoprostanes, a stable isoform of prostaglandinsthat have much stronger inflammatory effects.134

Adequate control of inflammatory pathways musttake these considerations into the balance. Merelyblocking COX does not address the accumulation ofsubstrate AA, which can alternately be metabolized byLOX. LOX by-products, the LTs and HETEs, are alsoimplicated in tumor growth and progression, andthese effects are reviewed next.

Effects of LOX, LTs, and HETEs in CancerLOX by-products (5-HETE and 12-HETE) have prom-inent roles in the progression of cancer.136 Limited evi-dence to date suggests that, depending on the type ofcancer, LTs may play an even greater role than pros-taglandins in stimulating tumor growth.92,137-144 Unlikeprostaglandins and thromboxanes, which are short livedand synthesized only according to immediate needand then rapidly degraded, LTs are quite stable, with ahalf life approaching 4 hours.145 The impact of LTs onvarious types of cancer is summarized in Table 2.

COX-dependent moieties have been noted todecrease, and LOX by-products, LTB4 and 12-HETE,to increase considerably following tumor implanta-tion in animals.146 Gliomas produce 5-HETE and use itas an autocrine growth factor stimulating their prolif-eration and suppressing apoptosis; consequently,LOX inhibitors have demonstrated significant inhibi-tory effect on in vitro growth rate and cell prolifera-tion in human glioma cell lines.147-149 LOX inhibitorsalso exert growth inhibitory effects and apoptosis-inducing effects in vitro against human leukemia celllines,150-153 MDA-MB-231 human breast cancer cells,154,155

and human colon cancer cell lines (HT-29 and HCT-15).92 In some instances, LOX inhibitors demonstrated



growth inhibitory effects whereas COX inhibitors hadno effect.149,153

While the growth of MCF-7 breast cancer cellsappears to be associated with both prostaglandin andLT production, incubation with a LOX-inhibiting agent(nordihydroguaiaretc acid) was more inhibitory ofcell growth in vitro in the presence of linoleic acidthan a COX inhibitor (indomethacin).156 Tumor growth

of murine adenocarcinomas may be inhibited invivo by LOX inhibitors.157

When the levels of COX and LOX metabolites ofAA were measured in the saliva of patients with HNSCCand compared with controls who had no history ofcancer, LTB4 was significantly increased in cancerpatients, but no significant differences were observedin PGE2 levels.158

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LINOLEIC ACID (LA) [18:2ω6] Most vegetable oils, Nuts and seeds

ALPHA LINOLENICACID (ALA) [18:3ω3]

Flax seed, canola, soybean andhemp oil

GAMMA-LINOLENIC ACID (GLA) [18:3ω6] Evening primrose, borage and black currant seed oils STEARIDONIC ACID

(SDA) [18:4ω3]Black currant seed oil

DIHOMO-GAMMA- LINOLENIC ACID (DGLA) [ 20:3ω6]

EICOSATETRAENOIC ACID [20:4ω3]

PGE1 LBT3and series-3 and series-3eicosanoids leukotrienes ARACHIDONIC EICOSAPENTAENOIC (favorable) ACID (AA) [20:4ω6] ACID (EPA) [20:5ω3]

Animal-source fats: meats, dairy, eggs Cold-water fish

˜15-HPETEà 15-HETE PGG2 PGE3 LTB512-HPETE à 12-HETE and series-3 and series-5

5-HPETE à 5-HETE eicosanoids leukotrienes (favorable)

PGH2 PGE2 PGD2

LTA4 PGF2LTB4LBC4 TXA2LTD4 LTE4 TXB2

Elongase

COX LOX ∆5-Desaturase

LOXcyp450 COX COX LOX

∆5-Desaturase

Elongase

∆6-Desaturase

5-LOX

∆6-Desaturase

˜

Figure 1 Biosynthesis of eicosanoids

The role of 5-HETE has been particularly well inves-tigated in prostate cancer cell lines. Exogenous AAmarkedly increases 5-HETE production by prostatecancer cell lines. When formation of 5-HETE is blocked,both hormone-responsive (LNCaP) and nonresponsive(PC-3) human prostate cancer cells quickly undergoprogrammed cell death in vitro.159-161 Addition of exoge-nous 5-HETE can rescue these cells, suggesting 5-HETE is a potent survival factor for human prostatecancer cells.

12-HETE promotes the proliferation of human coloncarcinoma cell lines,92 pancreatic cell lines,162 andbreast cancer cell lines.163 Elevated 12-LOX mRNA cor-relates with advanced stage and poor differentiationin human prostate cancer.164 12-HETE plays an impor-tant role in cell adhesion and promotion of metasta-sis.165-171 These effects of 12-HETE appear to be medi-ated via the activation of protein kinase C.172 12-HETEappears to play a crucial role in experimental mela-noma invasion and metastasis, and has been suggested



Table 2. Research on Lipoxygenase (LOX) By-Products (LTB4, 5-HETE, and 12-HETE) in Various Cancers

Brain cancerBlomgren and

Kling-Andersson(1992)

LOX inhibitors block DNA synthesis in glioma cell lines more potently than COX inhibitors149

Gati et al. (1990) Potent, dose-dependent inhibition of proliferation of human glioma cell lines by agents that blockLOX147

Gati et al. (1990) 5-LOX inhibitors induce apoptosis in human glioma cell lines148

Breast cancerCunningham et al.

(1997)Incubation of MCF-7 cells with a LOX inhibitor was more inhibitory of cell growth in vitro than a COX

inhibitor (indomethacin)156

Liu et al. (1996) 12-LOX transfected human breast cancer cells have enhanced growth in vitro41

Natarajan and Nadler(1998)

12-HETE promotes proliferation of breast cancer cells in vitro163

Connelly and Rose(1998)

Enhanced growth in 12-LOX transfected human breast cancer cells in vitro171

Earashi et al. (1996) LOX inhibitors suppress growth of MDA-MB-231 cells in vitro154

Tripathi et al. (1996) MDA-MB-231 cell growth in vitro suppressed by LOX or COX inhibition155

LeukemiaAnderson et al. (1994,

1996)Inhibitors of 5-LOX induce apoptosis in vitro150,152

Anderson et al. (1995) Selective inhibitors of 5-LOX reduce blast cell proliferation and induce differentiation in chronicmyelogenous leukemia151

Snyder et al. (1989) LOX inhibitors have growth inhibitory effects against human leukemia cell lines153

Colon cancerBortuzzo et al. (1996) LTB4, 12-HETE stimulate proliferation in 2 human colon cancer cell lines (HT-29 and HCT-15) in

vitro; the effect is reversed with an LTB4 antagonist92

Head and neck cancerScioscia et al. (1997) Treatment with a LOX inhibitor (ketoconazole) resulted in significant inhibition of tumor growth and

reduced tumor weight in a murine model of squamous cell carcinoma of the head and neck363

Ondrey et al. (1996) Leukotriene inhibition (but not prostaglandin inhibition) markedly decreases DNA synthesis and cellproliferation in squamous carcinoma cell line SCC-25137

Malone and Snyderman(1994)

Levels of LTB4, but not PGE2, significantly elevated in squamous cell carcinoma of the head andneck patients compared to patients with no history of cancer158

MelanomaWiner et al. (2001) 12-HETE plays a crucial role in promoting experimental melanoma invasion and metastasis; may

be a marker for cancer progression in melanoma patients173

Prostate cancerMyers and Ghosh (1999) PC3 and LNCaP cells convert arachidonic acid to 5-HETE; when formation of 5-HETE is blocked in

vitro, human prostate cancer cells enter apoptosis in less than 1 hour and are dead within 2hours; exogenous 5-HETE can rescue these cells, suggesting 5-HETE is a potent survival factorfor human prostate cancer cells in vitro161

Ghosh and Myers (1998) Inhibition of 5-LOX, which completely blocks 5-HETE production, induces massive and rapidapoptosis in LNCaP and PC-3 cells in vitro160

Anderson et al. (1998) A 5-LOX inhibitor reduces proliferation in PC-3 cells in vitro364

Liu et al. (1997) 12-HETE increased motility of prostate cancer cells via selective activation of protein kinase Calpha172

Ghosh and Myers (1997) 5-HETE stimulates proliferation of prostate cancer cells in vitro; selective inhibition of COX, 12-LOX,5-LOX, and CP-450 shows 5-LOX to be most growth stimulatory; prostate cancer cells fedarachidonic acid have dramatic increase in 5-HETE production159

Gao et al. (1995) Elevated 12-LOX mRNA correlates with advanced stage and poor differentiation in human prostatecancer164

Pancreatic CancerDing et al. (1999) 12-HETE promotes proliferation of pancreatic cancer cells, and LOX inhibitors abolish the prolifera-

tion of human pancreatic cancer cells in vitro162

as a novel marker for cancer progression of mela-noma.173

LTs may also be involved in regulating angiogenesis.They have been reported to stimulate angiogenesis insome tissues without assistance from growth factors.174,175

For example, 12-LOX appears to stimulate angiogenesisin human prostate carcinoma cells170 and human breastcancer171 in vivo. LTs may induce angiogenesis in partvia inducing NF-kappaB (NFKB). Inhibition of LTactivity may reduce NKFB-induced angiogenesis. Con-versely, NFKB activity may induce angiogenesis in partby promoting LT production (NFKB appears to act asa transcription factor for the genes that control LOXand COX production).176

Because a majority of studies that have examinedthe role of prostaglandins have failed to control forthe effects of LTs, further carefully designed and con-trolled research is needed to elucidate the true impactof LOX-derived compounds.

Rationale for NaturalAnti-Inflammatory StrategiesDespite epidemiologic analyses suggesting chemo-preventive effects of chronic NSAID administration,the risk of toxicity limits the use of these agents in thistherapeutic application. Gastric ulceration, perfora-tion, or obstruction is reported in one third to nearlyone half of chronic NSAID users.177 Reports estimate10,000 to 20,000 NSAID-related deaths and 100,000related hospitalizations in the United States annu-ally.178 Selective COX-2 inhibitors (celecoxib, rofecoxib)have been heralded as much safer drugs. Unlike NSAIDs,they appear to have little or no increased risk of gastro-intestinal bleeding or peptic ulceration. Yet, theirlong-term safety has yet to be documented. COX-2 isconstitutively expressed in kidney, brain, spinal cord,pancreatic islet cells, osteoblasts, and reproductive tis-sues.179 The potential risks of selective COX-2 inhibi-tors appear to be related to kidney, liver, or gastro-intestinal complications. Of note, COX-2 is induced inthe healing of wounds (such as gastric ulcer), so gas-trointestinal side effects may prove problematic in pa-tients with previously asymptomatic gastric lesions, forexample, chronic NSAID users switching to Celebrex®or Vioxx®. Although concerns with regard to poten-tial, as yet undisclosed, side effects of selective COX-2inhibitors may limit their long-term use in chemo-prevention, these concerns are unlikely to deter theirsuccessful application in the treatment of humancancers.

Perhaps a more compelling limitation of pharma-ceutical COX-2 inhibitors is their inability to addressLOX. Moreover, COX inhibitors may actually increasethe production of LOX products via their sparing

action on AA.133,180,181 The administration of COX inhibi-tors alone as an anti-inflammatory strategy is liketrying to fight a fire with a single blast of water whilecontinuing to feed the flames with dry wood and flam-mable liquids.

These concerns underline the need for a nontoxicand comprehensive approach to controlling inflam-matory eicosanoids. The application of natural, non-toxic anti-inflammatory strategies, which modulateboth COX and LOX pathways, may be preferable inboth chemoprevention and cancer therapy. The remain-der of this article outlines such an approach. To date,no clinical investigations have directly tested the influ-ence of natural anti-inflammatory approaches in can-cer patients, and a call for research in that direction isappropriate.

Comprehensive Anti-Inflammatory ProtocolA comprehensive approach to modulate the impact ofinflammatory eicosanoids is multifaceted. Several fac-tors must be addressed, as summarized in Table 3.

In general, the goal of dietary modification is toreduce available substrate (AA) for the production ofseries-2 prostaglandins and series-4 LTs while sub-stantially increasing the substrate for anti-inflamma-tory compounds, such as PGE3. Compared to non-neoplastic cells, cancer cell membranes have greatlyincreased AA content, with up to 40% fatty acid com-position of the cell wall as AA.182 Consumption of ani-mal fats and omega-6 vegetable oils increases the AAcontent of cell membranes, particularly membranesof cancer cells.183 Dietary sources of AA should beactively restricted, emphasizing a low-fat, plant-baseddiet (i.e., near-vegetarian). In addition, plant oils richin omega-6 fatty acids—corn, safflower, peanut, soy-bean, sesame, and other vegetable oils—should beeliminated. Canola oil, soybean oil, black currant oil,and borage oil do contain small amounts of omega-3fatty acids; however, these oils are abundant in omega-6 polyunsaturated fatty acids (PUFAS) and shouldtherefore be avoided. Despite their potential to formthe favorable PGE1, omega-6 PUFAs should be limitedto reduce the risk of inadvertent production of inflam-matory eicosanoids via delta-5 desaturase action onDGLA, particularly in situations of elevated AA and/or deficient EPA. Over the long term, gamma linolenicacid supplementation increases tissue AA levels whiledecreasing tissue levels of EPA.184 As previously noted,the binding affinity of desaturase enzymes increaseswith the number of double bonds present in the sub-strate fatty acid (20:3w6 < 20:4w6 < 20:5w3).

Sources of omega-3 fatty acids should be markedlyincreased, particularly cold-water fish, but also good

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quality flax seed oil. Western diets are overly abundantin sources of omega-6 fats and deficient in sources ofomega-3 fatty acids, often exceeding a ratio of 10:1 to20:1 omega-6 to omega-3 fatty acids.185 Whereas in con-ditions of health a 4:1 ratio is considered ideal,186 thetherapeutic ratio in inflammatory conditions targets a1:1 ratio. Greatly increasing the omega-3 componentof the diet helps prevent enzyme competition byomega-6 fats. Desaturase enzymes favor PUFAs withhigher numbers of double bonds (as indicated by thesecond number in their abbreviation); however, in theabsence of adequate EPA (20:5w3, 5 double bonds),6∆D, and ∆5D will metabolize omega-6 PUFAs, AA(20:4w6), and DGLA (20:3w6), forming pro-inflam-matory compounds.

Dietary fats also appear to modulate cytokine biol-ogy. A review article on the subject notes that (1) fatsrich in w-6 increase the production and tissue respon-siveness to cytokines, (2) w-3 rich fats decrease produc-tion and tissue responsiveness to cytokines, and (3)TNF-induced production of IL-1 and IL-6 correlatespositively with linoleic acid intake.187

Provision of nutrient cofactors is essential to ensureproper function of the enzymes required in the metabo-lism of omega-3 PUFAs. Optimal function of delta-6desaturase requires pyridoxine, magnesium, and zinc.Delta-5 desaturase requires niacin, zinc, and vitaminC.134,188 A high-quality multiple vitamin and mineralproduct can be used to accomplish this goal. Inhibi-tors of desaturase—excess saturated, hydrogenated,and trans fatty acids, alcohol, hyperinsulinemia, andelevated cholesterol levels—must be reduced. Bal-anced blood sugar regulation, with resolution ofhyperinsulinemia, can be very important in control-ling inflammation because excess insulin increases∆5D metabolism of DGLA189 (refer to Figure 1), shifting

eicosanoid production away from the desirable PGE1and PGE3 in favor of inflammatory AA metabolites.

Balanced redox status is paramount to controllingthe inflammatory cascade. The diet should emphasizeample intake of pigment-rich vegetables (5 to 7 servingsdaily) and fruits (1 to 2 servings daily) to reduce free-radical catalyzed synthesis of isoprostanes, stable com-pounds with pro-inflammatory activities exceeding thatof prostaglandins and LTs. Redox status can be evalu-ated via lab assessment, and supplemental antioxi-dants can be taken as needed.

Finally, nutritional and botanical anti-inflamma-tory agents may be employed to further modulate theinflammatory process. The application of multiplenatural agents is recommended to take advantage ofthe synergistic effects offered by combinations of natu-ral agents, which vary in their constituents and gener-ally offer multiple impacts at varying points in theinflammatory cascade. Additionally, botanical selec-tions can be made to offer both COX and LOX inhibi-tion. Detailed information on selected nutritional andbotanical agents that appear particularly promising asanti-inflammatory agents is presented below.

Fish Oils (EPA and Docosahexaenoic Acid)Fish oil supplements derived from cold-water fish,generally herring, mackerel, salmon, bluefish, andtuna, are rich in EPA and docosahexaenoic acid (DHA).Long-chain w-3 fatty acids are rapidly incorporatedinto cell membrane phospholipids, where they influ-ence cell metabolism. In addition to modulatingeicosanoid synthesis, they alter cell membrane fluidityto produce subtle changes in receptor function, alter-ations in cell-signaling mechanisms, and regulation ofgene expression.134 EPA, and to a lesser extent DHA,antagonize AA via several mechanisms: (1) they sup-



Table 3. Checklist for a Comprehensive Anti-Inflammatory Protocol

1. Restrict intake of animal-based foods: meat, dairy, poultry (dietary sources of arachidonic acid, precursor to PGE2, LTB4, 5-HETE, and 12-HETE).

2. Substantially increase dietary sources of omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid anddocosahexaenoic acid: cold-water fish and fish oil supplements (precursors to series-3 eicosanoids, block metabolism ofarachidonic acid).

3. Limit intake of plant-source omega-6 PUFAs, targeting a 1:1 ratio of w3 to w6 PUFAs (prevent enzyme competition and reduceinadvertent shunt to arachidonic acid and inflammatory eicosanoids).

4. Increase dietary antioxidants: 7 to 9 servings a day of deeply pigmented fruits and vegetables (reduce oxidative biosynthesis ofinflammatory eicosanoids and isoprostanes).

5. Eliminate hydrogenated or partially hydrogenated and trans-fatty acids, alcohol, simple sugars, and refined carbohydrates, andreduce elevated cholesterol levels (inhibitors of desaturase).

6. Ensure adequate intake of zinc, magnesium, ascorbate, niacin, and pyridoxine (coenzymes for desaturase metabolism of omega-3 PUFAS).

7. Optimize blood glucose regulation: address hyperinsulinemia (excess insulin shifts dihomogammalinolenic acid toward PGE2synthesis).

8. Provide a combination of several anti-inflammatory botanical agents (modulate inflammatory cascade through multiple and syner-gistic actions, including COX and LOX inhibition).

9. Monitor inflammatory markers (e.g., C-reactive protein, ceruloplasmin) at baseline and interval and adjust protocol as required.10. Consider pharmaceutical COX-2 inhibitors or nonsteroidal anti-inflammatory drugs on prn basis.

plant AA in membrane phospholipids, (2) they inhibitthe synthesis of AA from linoleic acid via their greateraffinity for desaturase enzymes, and (3) they competewith AA for active sites on LOXs and COXs.133 Thiscompetition limits the synthesis of pro-inflammatoryprostanoids and LTs,190 particularly as the LOX andCOX by-products of EPA do not increase cancer cellproliferation.92 Decreased synthesis of PGE2 and/orLTB4 is observed following inclusion of flax or fish oilin the diet.191 Fish oils have been shown to selectivelyinhibit COX-2—without affecting COX-1—in a dose-dependent manner in vitro192 and in vivo.193,194 EPA at 1to 2 µM in culture reduces the production of LTB4195

and 5-HETE.196 In addition, fish oil supplements mark-edly inhibit the synthesis of cytokines TNF-α and IL-1in humans.197 More than 20 human clinical trials havedocumented the anti-inflammatory effects of omega-3fatty acid supplementation, primarily in patients withrheumatic disorders.134 None of these studies have spe-cifically addressed inflammatory events in cancer pa-tients, although some research does support the benefitof fish oil supplements in cancer patients.

With regard to the potential of omega-3 fish oils toinhibit cancer proliferation and progression, a largenumber of in vitro and animal studies have been pub-lished. A majority of cell culture studies report that w-3fatty acids inhibit proliferation or invasion, promptcell cycle arrest or apoptosis, or induce differentiationof cancer cells.141,198-202 Some in vitro and in vivo researchalso suggests that fish oils may have antiangiogenicproperties.203-206

A large number of animal studies also report that w-3 fatty acids, particularly EPA, produce antitumoreffects. In studies of human tumors transplanted tomice, fish oil as 10% to 20% of the diet retards thegrowth of almost every type of cancer studied, includ-ing prostate,207 breast,138,208-211 lung,212,213 and colon carci-nomas.214-216 A fish oil concentrate (providing 51%EPA, 35% DHA, and 7% other fatty acids) completelyblocked the growth of preexisting cancers in rats fol-lowing a 6-week treatment, including a 63% reductionin the size of the largest tumors.217 Fish oil supple-mentation significantly inhibits the develop-ment andseverity of lung metastases in mice implanted withhighly metastatic colon carcinoma218 or MDA-MB-435human breast cancer cells.210 In both studies, linoleicacid stimulated tumor growth and metastasis. Survivaltime is prolonged in mice bearing myeloid leukemiacells fed a diet rich in fish oil.219

A limited number of studies on fish oil have beenconducted in human cancer patients, primarily focus-ing on immunomodulation and anticachectic effects.Advanced pancreatic cancer patients supplementedwith fish oil (2 g EPA, 1 g DHA daily for 4 weeks)achieved a stabilization of acute-phase protein response

markers of inflammation: C-reactive protein (CRP),ceruloplasmin, and fibrinogen.220 Fish oil supplementshave also demonstrated anticachectic effects in patientswith pancreatic cancer.221-223 Supplementation with fish oil(18 g/day over a 40-day period) significantly increased T-helper/T-suppressor cell ratio in cancer patients withsolid tumors.224 A randomized controlled trial of fishoil supplementation (18 g/day) in 60 patients withgeneralized malignancy showed significantly improvedratio of T-helper to T-suppressor cells and prolongedsurvival in patients taking fatty acid supplementationcompared to those on placebo.225

The application of fish oils as an adjunct to conven-tional treatments may also prove useful, as indicatedby preclinical studies. Omega-3 oils increase the cytotoxicefficacy of chemotherapy in vitro226-229 and in vivo.230-233

One mechanism of action underlying this effect isincreased drug delivery across tumor cell membranes.226

EPA and DHA (15 to 45 µM) increase radiation-induced cell kill in a rat astrocytoma cell line,234 sug-gesting the potential to increase the therapeutic effi-cacy of radiation in the treatment of gliomas.

The high doses (e.g., 10% to 20% of diet) of fish oilused in some animal studies would have a humanequivalent of 120 to 240 g per day. At excessive doses,the primary mechanism underlying tumor inhibitionis likely increased lipid peroxidation and not solelyeicosanoid modulation. Although some of these studieshave correlated the antiproliferative effect of fish oilswith increased lipid peroxidation,208,235-237 the applica-tion of this approach may be limited as separate researchlinks increased oxidation with cancer cell prolifera-tion and tumor progression,238 apparently by increas-ing cell mutation and altering cell signaling in waysfavorable to cancer cells. Of note, moderate doses ofEPA/DHA have also been reported to inhibit tumorgrowth and/or reduce metastasis in animals.183,210,239

These studies have employed doses of 1% to 2% of thediet (human equivalent 12 to 24 g per day). A humantrial also showed favorable results with moderate dosesof fish oil. In a retrospective study of 405 patientstreated with stereotactic radiotherapy for metastaticbrain lesions, supplementation with fish oil (3 g/day)and the bioflavonoid silymarin (200 mg/day), begin-ning 2 weeks posttreatment, resulted in a 64% increasein survival duration and significant decrease in radio-necrosis compared to unsupplemented patients.240

Dose recommendations for fish oils among nutri-tion-oriented practitioners vary widely, and furtherresearch is needed to characterize the optimum doseof fish oil in cancer patients. Research on inflamma-tory conditions reports effective oral doses rangingfrom 1.2 to 4.6 g/day of fish oil (600 to 2300 mg/dayEPA + DHA). Moderate doses of omega-3 PUFAs (540mg EPA and 360 mg DHA) favorably alter tissue fatty

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acid profiles in cancer patients,241 and a dose providing2.1 g EPA and 1.9 g DHA reduced PGE2 production inintestinal cells of healthy subjects.242

The tolerable upper limit for a fish oil concentrateoffering 63% EPA + DHA in human cancer patients isreported to be 0.3 g/kg body weight (e.g., for a 70-kgpatient, the tolerable dose is 21 g/day, providing 13 gEPA + DHA).243 Dose-limiting side effects in this studywere gastrointestinal in origin, mainly diarrhea andesophageal or gastric irritation. Taking fish oil supple-ments with meals, as well as coadministration of lipasedigestive enzyme, can limit side effects in some patientstaking high-dose fish oil supplements. In addition, it isessential to ensure high-quality fish oil products whichare stabilized and free of aldehydes and lipid perox-ides. When taking fish oil supplements, increased vita-min E intake is essential to protect against elevatedlipid peroxidation and depletion of antioxidants, par-ticularly tocopherols. Lipid peroxidation can be mon-itored with lab assessment (such as urine malondial-dehyde levels).

Despite concerns with regard to excessive bloodthinning or interaction with anticoagulant medica-tions, a controlled, randomized, double-blinded humanclinical trial found no interference on the anticoagu-lant status of patients receiving chronic warfarin ther-apy with fish oil supplementation in doses of 3 to 6g/day.244

Green-Lipped Mussel ExtractMarine lipid extracts from Perna canaliculus Martin(Mytilidae), the New Zealand green-lipped mussel,also deserve attention for their potent anti-inflamma-tory effects. In animal models, P. canaliculus extracts(PCEs) are significantly more effective at reducing in-flammation than aspirin, ibuprofen, or indometh-acin.245,246 PCE produces a dose-dependent reductionin LBT4, 5-HETE, and 12-HETE in vitro, with an inhib-itory concentration (IC50) between 20 and 50 µg/ml.247

The concentration is easily achieved clinically.Lipid-rich extracts of stabilized PCE have recently

become commercially available. They are safe andeffective in the management of inflammatory con-ditions and free of significant side effects. UnlikeNSAIDs, they offer a gastroprotective effect. To date,the effects of these extracts have not been studied incancer.

Antioxidant NutrientsThere is a reciprocal relationship between antioxi-dants and inflammation. The magnitude of inflamma-tion plays an important role in regulating circulatingconcentrations of vitamin antioxidants in cancer pa-tients, and antioxidants offer anti-inflammatory ef-fects. High levels of inflammation are known to deplete

host antioxidant stores, and anti-inflammatory agentshave been demonstrated to increase antioxidant re-serves in cancer patients.248 Whereas either a selectiveCOX-2 inhibitor (SC58125) or antioxidant as a singleagent is capable of reducing colorectal tumor growthin vivo, combined treatment demonstrates potent ad-ditive effects, markedly decreasing prostaglandin lev-els and resulting in tumor regression.249 Whereas se-lective COX-2 inhibitors block COX-2 catalytic activity,antioxidants decrease COX-2 expression at the trans-criptional level.249

A large number of substances have antioxidantactivities, including vitamins A, C, and E, selenium,zinc, carotenoids, flavonoids, coenzyme Q10, N-acetylcysteine, lipoic acid, and numerous other compounds.Accordingly, a thorough examination of the role ofthese compounds in the inflammatory events falls out-side the scope of this article. Here, we limit our discus-sion to vitamins A and E.

Vitamin ARetinoids, including all-trans retinoic acid (RA), 9-cis-RA, 13-cis-RA, and retinyl acetate, suppress EGF-medi-ated induction of COX-2 mRNA and protein in vitroand inhibit the synthesis of PGE2.60,250 Treatment ofsquamous carcinoma cells with retinoid (9-cis-retinoicacid) suppressed COX-2 expression and PGE2 bio-synthesis in concentration- dependent fashion andsignificantly inhibited cell growth.251 These findingssuggest that the combination of COX-2 inhibitors withretinoids may offer synergistic effects. Hypothetically,the therapeutic efficacy of 13-cis-retinoic acid (Accutane)in oncology may also be increased with concomitantadministration of COX-2 inhibitors or natural anti-inflammatory protocols. This hypothesis warrantsinvestigation.

Vitamin EVitamin E is the primary antioxidant responsible forthe protection of cell membrane lipids. Alphatocopherol inhibits the activity of phospholipase A2 invitro and in vivo.252 Alpha tocopherol offers anti-inflammatory effects in in vitro and animal studies.253

Macrophages from animals fed vitamin E deficient di-ets secrete significantly higher levels of PGE2, TXB2,LTB4, and 5-HETE.254 Oral administration of tocopheroldecreases production of 5-HETE by rat leukocytes.255

Whereas a 1987 clinical trial of vitamin E supple-mentation failed to demonstrate a reduction in mucosalrelease of PGE2 and LTB4 in patients with ulcerativecolitis,256 a recent study of diabetic patients at risk forcardiovascular disease found that vitamin E supple-mentation reduces inflammatory markers.257 A plausi-ble explanation for the varied findings of these andother studies evaluating antioxidants in humans may



be the failure to measure the functional activity of thenutrient studied. It is inappropriate to derive conclu-sions from studies that standardize the dose, or evenblood level, of an antioxidant nutrient administered.Rather, the baseline oxidative status of the individualsmust be accounted for and individually tailored dosesof antioxidants provided to achieve a standardizedtarget level of oxidative stress, based on laboratorytesting. Furthermore, antioxidant activity cannot beconferred by a single nutrient but only through the co-ordinated activities of a network of vitamins, minerals,and phytochemicals. Recognition of the “antioxidantnetwork” may demand the modification of single-agent research from which conclusions about antioxi-dants have inappropriately been drawn.

The form of tocopherol selected may also be of par-ticular importance. One study reported that gammatocopherol reduces PGE2 synthesis in macrophagesand epithelial cells whereas alpha tocopherol has littleor no effect on PGE2 synthesis.258 Many questionsremain with regard to the impact of vitamin E onarachidonate metabolism and inflammatory events inhumans, and further research is needed.

Botanical Anti-Inflammatory AgentsNumerous botanical agents are capable of modulatingthe inflammatory response in humans. Phytomedicinesare available that offer not only COX-inhibiting butalso LOX-inhibiting activity, and thereby reduce theproduction of PGE2, LTB2, 5-HETE, 12-HETE, andother inflammatory compounds, which have been dem-onstrated to play significant roles in tumor viability,cell proliferation, angiogenesis, invasion, and metas-tasis. Each of the anti-inflammatory botanicals selectedfor review here has some in vitro and in vivo researchon its promise as an anticancer agent. Unfortunately,none of the research to date has investigated theanticancer activities of these herbs in relation to theirCOX- or LOX-inhibiting effects. This observation pro-vides a direction for future research.

The side effect profile of these botanical agents isexceedingly favorable in comparison to NSAIDs andCOX-2 inhibitors. Despite considerable gaps in theresearch, the demonstrated anti-inflammatory actionsand potential anticancer properties of these botanicals—considered together with their safety in human con-sumption—make a compelling case for their use inintegrative cancer therapies. In clinical practice, thecombination of several botanical agents, often at slightlyreduced doses individually, may achieve considerablesynergistic effects.

BoswelliaBoswellia [Boswellia serrata Roxb. Burseraceae] is anAyurvedic remedy (salai guggal) with a long history of

use in rheumatic conditions. The resinous extract isused, with primary efficacy deriving from its boswellicacids, well-tolerated pentacyclic triterpenes. Boswellicacids have been demonstrated to be highly selectiveand potent inhibitors of 5-LOX.259-264

Boswellic acids promote differentiation in variousleukemia cell lines265,266 and, in low micromolar con-centrations, induce apoptosis in glioma cell lines,independent of p53 status.267 Boswellic acids may beparticularly appealing anti-inflammatory agents foradjunct use in human brain tumors. They markedlyinhibit glioma growth in animal experiments andincrease survival time.268,269 Two uncontrolled humantrials of high-dose oral boswellic acids in patients withintracranial tumors showed effective reduction of tumor-associated edema and marked improvement in clini-cal symptoms in as little as 7 days.270,271 No major sideeffects were reported in either study, although a smallpercentage of patients taking boswellia report gastro-intestinal upset (which can often be eliminated byreducing the dose or taking the product with meals).

The recommended dose is based on the concentra-tion of boswellic acids in the extract and is approxi-mately 30 to 50 mg/kg/day. Crude preparations ofboswellia typically contain 43% boswellic acids, withsome commercial sources offering up to 65% boswellicacids.

BromelainBromelain refers to the mixture of sulfur-containingproteases obtained from the stem of the pineappleplant, Ananas comosus (L.) Merr. (Bromeliaceae). Sinceits introduction in 1957, more than 400 scientific pa-pers have been published on its therapeutic applica-tions. A review article272 documents the following ac-tions for bromelain: (1) interference with growth ofmalignant cells, (2) inhibition of platelet aggregation,(3) fibrinolytic activity, and (4) anti-inflammatory ac-tions. Historically, bromelain has been used to reduceinflammation in cases of arthritis, sports injury, trauma,and postsurgical swelling. Bromelain selectively stimu-lates the production of PGE1273 and inhibits the syn-thesis of pro-inflammatory PGE2 in a dose-dependentmanner.274 Bromelain’s inhibition of PGE2 biosynthesisexceeds the anti-inflammatory effects of prednisone,which requires a 10-fold greater dose to achieve thesame effect in rats.274 The anti-inflammatory actions ofbromelain in postsurgically treated patients have beendemonstrated in a double-blind crossover trial.275

Bromelain significantly decreased metastases of Lewislung cancer in mice.276,277 Two uncontrolled trials fromthe 1970s with oral bromelain (doses ranging from600 to 2400 mg/day) reported positive results, includ-ing subjective evidence of tumor regressions of ovar-ian and breast cancers and their metastases.278,279

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Bromelain stimulates immune response in breast can-cer patients,280 which may also in part explain its pro-posed antitumor activity.

Typical oral dose ranges from 250 to 750 mg, TID,on an empty stomach, of product standardized to pro-vide 1800 to 2400 mcu/g (1.5 gdu = 1.0 mcu).Bromelain enhances the absorption of drugs taken con-currently.272 Although bromelain is reported to haveblood-thinning and antithrombotic effects in animalstudies,281 human research has not confirmed this find-ing or substantiated the concern that bromelain mayinteract with oral anticoagulants.280,282

CurcuminCurcumin, diferuloylmethane, is the yellow pigmentand active component of turmeric, Curcuma longa L.(Zingiberaceae). A small molecular weight compound,curcumin constitutes 1% to 5% of the content of tur-meric. It has a long history of safe use in Ayurvedicmedicine, an indigenous system of medicine from In-dia, particularly in the treatment of inflammatory dis-orders. In addition to its anti-inflammatory properties,curcumin is a potent antioxidant, stronger than vita-min E in preventing lipid peroxidation in vitro.283,284

Curcumin inhibits both COX and LOX, reducingthe synthesis of PGE2, LTB4, and 5-HETE in vitro andin vivo.285-292 Numerous studies confirm curcumin’santi-inflammatory effect in vivo. Animals with coloncancer fed curcumin show a 50% decrease in phos-pholipase A2 activity and nearly 40% reduction in thelevels of PGE2 in colonic mucosa and tumor.293 Patientswith colorectal cancer fed an oral preparation ofcurcuminoids (36 to 180 mg curcuminoids per day)exhibited a dose-dependent reduction in COX-2expression and PGE2 production.294 Patients withpostoperative inflammation achieved a similar anti-inflammatory response with oral curcumin (1200 mg/day) compared to NSAID administration.295 In patientswith rheumatoid arthritis, curcumin (1200 mg/day)offers anti-inflammatory effects, without side effects,comparable to phenylbutazone (300 mg/day).296

Interest in the anticancer actions of curcumin isconsiderable, and research efforts are expanding inthis area. Curcumin (3 to 20 µM, occasionally up to 50µM) exhibits antiproliferative effects in vitro in a vari-ety of human cancer cell lines, including estrogen-dependent and estrogen-independent breast,297 pros-tate (both hormone-dependent and hormone-inde-pendent cell lines),298 colon,299,300 oral squamous carci-noma,301 melanoma,302 lymphoma,303 and leukemia304,305

cell lines.Curcumin exerts various influences on the patho-

physiology of malignant cells. In vitro studies on vari-ous cell lines have shown that curcumin promotes cell

cycle arrest299,306 and induces apoptosis.298,304,307,308 Limitedin vitro and in vivo evidence suggests curcumin mayalso have antiangiogenic effects.309-311 In animal studies,curcumin increased the life span of rodents with trans-planted tumors, inhibiting tumor growth and imped-ing metastasis.312,313

Preliminary evidence suggests curcumin may selec-tively enhance the cytotoxicity of chemotherapy whileoffering protective effects against various sideeffects. In animal experiments, very high doses ofcurcumin protect against bleomycin-induced andcyclophosphamide-induced pulmonary fibrosis anddeter chemotherapy-induced increases in biomarkersof the inflammatory response.314-316 In vivo protectionagainst Adriamycin-induced nephrotoxicity has alsobeen demonstrated.317 When given orally withcisplatin, curcumin (28 mg/kg) reduced progressionof fibrosarcoma in rats better than cisplatin alone.318

The human equivalent dose for this latter study isabout 450 mg/day.319

In the only human study to date, topical curcuminointment provided symptomatic relief for patientswith ulcerating oral or cutaneous squamous cell carci-nomas who had previously failed to respond to stan-dard treatments.320

Human studies on curcumin’s anti-inflammatoryeffect have generally used a dose of 750 to 1500 mg/day.Extrapolating from animal studies, the oral dose ofcurcumin that might be expected to offer a benefit incancer is 1500 mg/day or slightly greater, as tolerated.Curcumin is exceedingly safe and nontoxic, even atvery high concentrations. Doses exceeding 2.5 g/kg fedto rats, guinea pigs, and monkeys confer no evidenceof harm or genetic damage.321 Curcumin is contraindi-cated in individuals with biliary duct obstruction.322

QuercetinA ubiquitous flavonoid in plants, quercetin is the ma-jor bioflavonoid in the human diet. Quercetin inter-feres with many steps in eicosanoid metabolism. It inhibitsphospholipase A2 activity323 and blocks both the LOX324

and COX325 pathways of AA metabolism. At micromolarconcentrations (≤15-40 µM), quercetin inhibits COX-2 and LOX-5 activity.325,326 It is also a potent inhibitor ofTGF-α induced COX-2 activity.327

A review article on the anticancer actions of quercetinsuggests that the flavonoid may have significant poten-tial as an anticancer agent.328 The reported in vitro effectsof quercetin include down-regulation of mutant p53protein, cell cycle arrest at G1, tyrosine kinase inhibi-tion, inhibition of heat shock proteins, and suppres-sion of ras protein expression. Documented in vivoactivities reported in this review article include inhibi-tion of tyrosine kinase in cancer patients, inhibition of



tumor growth, and increased life span in tumor-bear-ing animals. In experimental models, quercetin hasdemonstrated significant antitumor activity against awide range of cancers, including brain tumors,329

squamous cell carcinomas,330 non–small cell lung can-cers,331 and cancers of the breast,332 ovary,333 bladder,334

stomach,335 and colon.336,337 In vitro and in vivo studieson various cancer cell lines show quercetin potentiatesthe therapeutic efficacy of cisplatin, adriamycin,busulphan, and cyclophosphamide, and decreases resis-tance to gemcitabine and topotecan.328

For anticancer activity, doses of quercetin report-edly must achieve 10 µM or greater serum concentra-tions, and a suggested oral dose to achieve this concen-tration is 1500 mg/day.328 Quercetin has little toxicitywhen administered orally or intravenously, even inlarge doses, and is well tolerated in humans.

Additional Botanical Agents to ConsiderMany additional herbs have anti-inflammatory effectsand deserve consideration as adjuncts in cancer treat-ment or chemoprevention. These compounds havegrowing bodies of literature investigating their anti-cancer potential. Botanical compounds with docu-mented ability to inhibit COX-2 and/or reduce PGE2synthesis in experimental models are Aloe vera (L.)Burm.f. (Liliaceae)338; epigallocatechin gallate extractsof green tea, Camellia sinensis Kuntze (Theaceae)339;resveratrol340; and licorice, Glycyrrhiza glabra L.(Fabaceae).341 Allium species (e.g., garlic) derived ajoeneinhibits COX-2 enzyme activity in vitro and reducesthe release of PGE2 in a dose-dependent manner.342

Scutellaria baicalensis Georgi (Lamiaceae) containsbaicalein (a trihydroxyflavone), which is a selective in-hibitor of 5-LOX and 12-LOX in micromolar concen-trations.343,344 Herbs with traditional use as anti-inflammatories awaiting research documenting theireicosanoid-modulating effects include bilberry,Vaccinium myrtillus L. (Ericaceae); feverfew, Tanacetumparthenium Sch.-Bip. (Asteraceae); pine bark and grapeseed extracts; devil’s claw, Harpagophytum procumbensDC. (Pedaliaceae); picorrhiza Picrorhiza kurroa Benth.(Scrophulariaceae); hops, Humulus lupulus L.(Cannabaceae); Asian ginseng, Panax ginseng C.A.Meyer (Araliaceae); and milk thistle, Silybum marianumGaertn. (Asteraceae).

Lab Assessments toMonitor InflammationIn using complementary strategies such as dietary, nu-tritional, and botanical support, laboratory assessmentsare imperative to monitor the intervention and toguide individualized tailoring of protocol. Direct mea-surements of COX-2 and LOX activities, and quan-

tifications of PGE2, LTB4, 5-HETE, and 12-HETE,would be ideal but are not readily available. However,the following lab assessments may prove both practicaland worthwhile.

Fatty Acid AnalysisRed blood cell fatty acid analysis can provide valuableinsight into imbalances in eicosanoid substrates andalterations in their metabolism. The results can be par-ticularly helpful in assisting the practitioner to recom-mend appropriate dietary modifications and to monitorcompliance with the diet.

Interleukin-6Serum measurements of IL-6 may be useful, as thiscytokine up-regulates inflammation and also appearsinvolved in cachexia. In patients with colorectal can-cer, those with stage III-IV disease had higher levels ofserum IL-6 levels than those with stage I-II disease. Inaddition, 5-year survival was greater in patients with IL-6 less than 10 pg/mL compared to cases in which IL-6concentration was greater than 10 pg/mL.345 In lungcancer patients, serum IL-6 is frequently elevated, andthe elevation is associated with poorer nutritional sta-tus and shorter survival time.346

Acute Phase ProteinsAcute phase protein response (APPR) markers are aninnovative and invaluable means of monitoring in-flammatory status in cancer patients. During the in-flammatory response, CRP, ceruloplasmin, andfibrinogen concentrations increase whereas levels ofalbumin and transferrin decrease. With disease pro-gression in cancer patients, APPR markers also prog-ress: CRP, ceruloplasmin, and fibrinogen increasewhereas albumin and transferrin decrease.220

CRP appears particularly promising for use in thisapplication. CRP is an acute phase protein formed byhepatic cells via cytokine stimulation, particularly IL-6. CRP levels increase very rapidly in response totrauma, inflammation, and infection; they decreaserapidly with resolution of the condition.

CRP levels have been demonstrated to be elevatedin cancer patients. Compared to healthy controls,serum levels of CRP are significantly increased inpatients with gastrointestinal cancer248 and advancedpancreatic cancer.347

Tumor recurrence following treatment is associ-ated with a statistically significant elevation of CRPconcentration in patients with head-and-neck cancer348

and early stage colorectal cancers.349 Colorectal cancerpatients with elevated preoperative serum CRP hadsignificantly greater incidence of hepatic metastases,peritonitis carcinomatosa, lymph node involvement,

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and intravascular invasion than patients with negativeCRP.350

Moreover, elevated CRP correlates with poorer prog-nosis and decreased survival in cancer patients withunresectable pancreatic cancer,351 multiple myeloma,352

renal cell carcinoma,353 and advanced colorectal can-cer.350,354,355 Two prospective studies have shown a 3-foldincrease in survival duration for cancer patients with-out elevated CRP concentrations compared to those withelevated values. In unresectable pancreatic cancerpatients, median survival of those with acute-phaseprotein response (CRP > 10 mg/L) was 66 days com-pared to 222 days for those with no acute-phase pro-tein response.351 In patients with advanced gastrointes-tinal cancers, those with elevated CRP values had areduced survival duration (median survival: 136 days)compared to patients without CRP elevations (mediansurvival: 466 days).356 This association was independentof significant weight loss (median: 16.6% weight loss).

Treatment with anti-inflammatory agents can reduceCRP levels in cancer patients. For example, ibuprofen(1200 mg/d, po, q 8-11 days) reduces circulating con-centrations of CRP, IL-6, and cortisol, and also lowerselevated platelet counts in patients with gastrointesti-nal cancers.357

Technological advances have yielded a newer ver-sion of the test, the high-sensitivity CRP, which hassuperior sensitivity. CRP is elevated in inflammatorydiseases and bacterial infection (pneumonia, pancre-atitis, pelvic inflammatory disease, urinary tract infec-tion, appendicitis, meningitis, etc.).358 Tissue injury—such as accompanies surgery or radiotherapy—increasesCRP levels.359,360 Liver disease may also influence CRP.Consideration of these confounding variables must bemade in interpreting CRP values in cancer patients.

ConclusionPharmaceutical COX-2 inhibitors hold promise as ad-junctive therapies in the prevention and treatment ofcancer. A handful of NCI-sponsored phase I and II tri-als of Celebrex® in cancer chemoprevention and treat-ment are currently under way. Clinical investigationsneed to determine the dose schedule and duration oftreatment that afford optimum benefit. Inflammationfollows a circadian rhythm, and the timing of daily ad-ministration of COX-2 inhibitors may prove to be animportant variable. For example, administration ofcelecoxib in MCF-7 tumor bearing mice achieved 60%growth inhibition when given 7 hours after light onsetbut only 22% inhibition when administered 3 hoursafter light onset.38 Examinations of circadian effects inhumans taking COX-2 inhibitors may be advantageous.Accurate identification of those cancer patients mostlikely to benefit from COX-2 inhibitors is also needed.

Although in vitro and animal studies completed todate lend substantial credibility to the hypothesis thatnatural COX-2 and 5-LOX inhibitors may enhancecancer therapy, substantial investigations remain to becompleted, culminating in well-designed human tri-als. Today’s cancer patients—many facing dire prog-noses and an urgency that does not afford waiting forthe final results of clinical trials on complementaryapproaches—must evaluate the data currently avail-able and, together with the guidance a qualifiedoncologist and an experienced practitioner of integra-tive medicine, make informed treatment choices. Fromthe available data, it appears that these individualshave much to gain from the incorporation of naturalanti-inflammatory strategies that pose little risk ofadverse effect and offer reasonable promise of benefit.The outcome of these clinical choices needs to becarefully documented. And several directives for futureresearch into natural anti-inflammatory protocols areclear. Natural agents should be screened for LOX- andCOX-inhibiting effects. When natural agents are stud-ied for anticancer properties, the contribution of COXor LOX inhibition should be examined. Optimal doses,as well as characterization of the synergistic effects ofcombinations, must be determined.

A weakness of much research to date is the failure tomeasure and control for the influence of eicosanoidsother than the primary metabolite under investiga-tion. For example, very few studies evaluating COX-2(and PGE2) have accounted for the influence of LTs,thromboxanes, HETEs, and other compounds. Con-tradictory results observed in some of the research,such as studies that have shown that increased inflam-mation induces tumor regressions,361 may ultimatelybe explained by the confounding influence of LTs,HETEs, TXs, isoprostanes, or other as yet undiscov-ered eicosanoids. Further discoveries in eicosanoidresearch are no doubt forthcoming, and followingthese, investigation of their potential roles in tumorphysiopathology. Are there further isoforms of COX(COX-3, perhaps?), and what are their relationshipsto cancer? Beyond PGE2, what are the influences ofother families of prostaglandins (e.g., PGF, PGD, PGI,etc.)? PGF2 alpha has been characterized as a potentpro-inflammatory prostaglandin and deserves evalua-tion. What are the influences on cancer of throm-boxanes? What are the effects of the various isoformsof LOX and their LT metabolites (e.g., LTB5, LTB1)?What is the role of isoprostanes in cancer?

Many questions remain to be explored by futureresearch on eicosanoid modulation in cancer therapy,including the following:

1. Which types of cancer cell growth are mediated pref-erentially by COX- vs LOX-derived eicosanoids?



2. Is there a synergistic inhibitory effect when both COXand LOX pathways are blocked?

3. Can natural anti-inflammatory protocols work as effec-tively as pharmaceutical COX-2 inhibitors (and LOXinhibitors, Zileuton®, soon to enter the market)?

4. What are the best selection criteria for patients mostlikely to benefit from anti-inflammatory protocols?Can lab assessments of inflammation (e.g., elevatedCRP, ceruloplasmin, IL-6) identify these patients?

5. Do natural anti-inflammatory agents synergize withpharmaceuticals? For example, can botanical LOXinhibitors enhance the effects of selective COX-2inhibitors?

6. Which natural anti-inflammatory agents are bestsuited—and which are inappropriate—for combina-tion with conventional treatments, such as surgery,radiation, and chemotherapy? Are immunotherapiespotentiated or hindered by COX or LOX inhibition?

7. What are the interrelationships of eicosanoids andhormones, such as estradiol, progesterone, dehydro-epiandrosterone, cortisol, and melatonin, in cancer?

8. Can other available drugs, perhaps HMGCoAreductase inhibitors, low-dose naltrexone, Accutane®,tamoxifen, butyrate, or cardiac glycosides, potentiatethe anticancer effects of COX-2 inhibitors or naturalanti-inflammatory compounds?

Modern oncology is being challenged to broadenits focus to include molecular management of thepatho- physiological events attending neoplasia. Inflam-matory deregulation represents one of these events,which is particularly amenable to dietary, nutritional,and botanical modulation. The field of eicosanoidresearch in cancer prevention and treatment is in itsadolescent years. Although still struggling through anawkward phase of self-discovery, it is imbued with greatexpectations. If these approaches can fulfill their expec-tations, cancer patients may one day be able to viewtheir disease not as a death sentence but as a chroniccondition requiring ongoing management, which mayultimately allow those afflicted to live out their naturallife span.

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4. Stein-Werblowsky R. Prostaglandins and cancer. Oncology. 1974;30:169-176.

5. Karmali RA. Review: prostaglandins and cancer. ProstaglandinsMed. 1980;5(1):11-28.

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336. Richter M, Eberman R, Marian B. Quercetin-induced apoptosisin colorectal tumor cells: possible role of EGF receptor signal-ling. Nutr Cancer. 1999;34(1):88-99.

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338. Vazquez B, Avila G, Segura D, Escalante B. Anti-inflammatoryactivity of extracts from Aloe vera gel. J Ethnopharmacol. 1996;55:69-75.

339. Haqqi TM, et al. Prevention of collagen-induced arthritis inmice by a polyphenolic fraction from green tea. Proc Natl AcadSci USA. 1999;96:4524-4529.

340. Subbaramaiah K, Chung WJ, Michaluart P, et al. Resveratrolinhibits cyclooxygenase-2 transcription and activity in phorbolester-treated human mammary epithelial cells. J Biol Chem.1998;273:21875-21882.

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342. Dirsch VM, Vollmar AM. Ajoene, a natural product with non-steroidal anti-inflammatory drug (NSAID)-like properties? BiochemPharmacol. 2001;61:587-593.

343. VanLoon IM. The golden root: clinical applications of Scutellariabaicalensis GEORGI flavonoids as modulators of the inflamma-tory response. Alt Med Rev.

344. Butenko IG, et al. Anti-inflammatory properties and inhibitionof leukotriene C4 biosynthesis in vitro by flavonoid baicaleinfrom Scutellaria baicalensis greorgy roots. Agents Actions. 1993:39(C):49-51.

345. Belluco C, Nitti D, Frantz M, et al. Interleukin-6 blood level isassociated with circulating carcinoembryonic antigen andprognosis in patients with colorectal cancer. Ann Surg Oncol.2000;7:133-138.

346. Martin F, Santolaria F, Batista N, et al. Cytokine levels (IL-6 andIFN-gamma), acute phase response and nutritional status asprognostic factors in lung cancer. Cytokine. 1999;11(1):80-86.

347. Barber MD, Fearon KC, Ross JA. Relationship of serum levels ofinterleukin-6, soluble interleukin-6 receptor and tumournecrosis factor receptors to the acute-phase protein responsein advanced pancreatic cancer. Clin Sci. 1999;96(1):83-87.

348. Kolebacz B. Concentrations of selected acute phase proteinsand immunity immunoglobulins in the treatment of head andneck carcinomas [in Polish]. Otalaryngol Pol. 1999;53:743-746.

349. McMillan DC, Wotherspoon HA, Fearon KC, et al. A prospec-tive study of tumor recurrence and the acute-phase responseafter apparently curative colorectal cancer surgery. Am J Surg.1995;170:319-322.

350. Nozoe T, Matsumata T, Kitamura M, Sugimachi K. Significanceof preoperative elevation of serum C-reactive protein as an indi-cator for prognosis in colorectal cancer. Am J Surg. 1998;176:335-338.

351. Falconer JS, Fearon KC, Ross JA, et al. Acute-phase proteinresponse and survival duration of patients with pancreatic can-cer. Cancer. 1995;75:2077-2082.

352. Barlogie B. High-dose therapy and innovative approaches totreatment of multiple myeloma. Semin Hematol. 2001;38(2 suppl 3):21-27.

353. Matsui Y, Fujikawa K, Oka H, et al. Management of renal cellcarcinoma with inferior vena cava tumor thrombus. Urol Int.2001;66(1):4-8.

354. Wigmore SJ, MacMahon AJ, Sturgeon CM, Fearon KC. Acute-phase protein response, survival and tumour recurrence inpatients with colorectal cancer. Br J Surg. 2001;88:255-260.

355. Nielsen HJ, Christensen IJ, Sorensen S, et al. Preoperativeplasma plasminogen activator inhibitor type-1 and serum C-reactive protein levels in patients with colorectal cancer. AnnSurg Oncol. 2000;7:617-623.

356. O’Gorman P, McMillan DC, McArdle CS. Prognostic factors inadvanced gastrointestinal cancer patients with weight loss. NutrCancer. 2000;37(1):36-40.

357. McMillan DC, Leen E, Smith J, et al. Effects of extendedibuprofen administration on the acute phase protein responsein colorectal cancer patients. Eur J Surg Oncol. 1995;21:531-534.

358. Clyne B, Olshaker JS. The C-reactive protein. J Emerg Med.1999;17:1019-1025.

359. Cengiz M, Akbulut S, Atahan IL, Grigsby PW. Acute phaseresponse during radiotherapy. Int J Radiat Oncol Biol Phys.2001;49:1093-1096.

Wallace


360. Hu RJ, Lee PH, Yu SC. Secretion of acute-phase proteins beforeand after hepatocellular carcinoma resection. J Formos MedAssoc. 1999;98(2):85-91.

361. Goddard DH, Bomalaski JS, et al. Phospholipase A2-mediatedinflammation induces regression of malignant glioma. CancerLett. 1996;102(1-2):1-6.

362. Komhoff M, Guan Y, Shappel HW, et al. Enhanced expressionof cyclooxygenase-2 in high grade human transitional cell blad-der carcinomas. Am J Pathol. 2000;157(1):29-35.

363. Scioscia KA, Snyderman CH, et al. Role of arachidonic acidmetabolites in tumor growth inhibition by nonsteroidal anti-inflammatory drugs. Am J Otolaryngol. 1997;18(1):1-8.

364. Anderson KM, Seed T, et al. 5-lipoxygenase inhibitors reducePC-3 cell proliferation and initiate nonnecrotic cell death. Pros-tate. 1998;37:161-173.

Editor’s NoteThis important review by Jeanne M. Wallace of the roleof eicosanoids in stimulation of the growth of tumors,

and the potential for inhibiting their activities by in-hibiting the action of lipoxygenase and cyclooxygenase(COX) enzymes, provides a scientific foundation forone of the most common strategies of integrative nu-tritional programs: the limitation of meat in the dietand its substitution with fish and other sources ofomega-3 fatty acids. Wallace’s exploration of the phar-macology of COX-2 inhibitors in various cancers is de-tailed and convincing, and she has done the integrativemedicine community a real service in reviewing thepotential use of natural COX-2 inhibitors. This phar-macology is truly where mechanism-based biology in-tersects directly with the therapeutic realities of bothconventional and complementary/alternative treat-ment, and this article provides a solid basis for under-standing COX-2 inhibitors for clinicians in both areas.



Hien et al.Radioprotective Effects of Vitexina

Radioprotective Effects of Vitexinafor Breast Cancer Patients UndergoingRadiotherapyWith Cobalt-60

Tran Van Hien, PhD, Nguyen Boi Huong, PhD, Pham Manh Hung, DSc, and Nguyen Ba Duc, MS

Vitexina, a product containing the flavonoid vitexin as themain component, is derived from a plant, Vigna radiata (L.),that has been traditionally used in Vietnam for detoxifica-tion. This remedy is also used to treat the symptoms of con-ditions classified as “hot” in traditional medicine. The presentstudy is a randomized, placebo-controlled comparative clini-cal trial for investigating the radioprotective effects of Vitexinafor breast cancer patients undergoing radiotherapy withcobalt-60. No relevant weight loss, (even weight gain), oc-curred in 70% of patients in the Vitexina group, whereas73% of the placebo group lost 1 to 2 kg of weight after 6weeks of radiation therapy. The administration of Vitexinaproduced a significantly protective effect in peripheral bloodcells in amount and in lymphocyte blast-transformation func-tion. Condition of hot was observed in almost all cancer pa-tients in this study by tongue examination. Hot condition didnot change in the Vitexina group, but the incidence of hotand extreme hot cases were significantly increased in the pla-cebo group after 6 weeks of radiation therapy. The resultssuggest that application of medicinal plants of the “clearingheat and detoxification” classification as an adjuvant wouldbe a potential solution in integrative cancer therapy.

It is well known that exposure to high-energy radiationcan cause damage to biological systems. This effect hasbeen exploited in treating cancer, as cancer cells aredamaged by radiation. However, in the process, adja-cent healthy tissue is also damaged. The protection ofhealthy tissue during radiotherapy for cancer hasbeen one of the strong motivations for continuingresearch on exogenous radioprotectors.1,2

Radiation damage in biological systems is initiatedby the primary toxic, excited and free radical speciesformed during energy deposition events. Radiationdamage is well known to occur with the free radicalburst, leading to oxidative stress in cells and tissue.The application of synthetic antioxidants to protectcells and limit radiation injury might thus benefitpatients during treatment. But use of synthetic antiox-idants has been restricted due to their toxicity. As aresult, interest has grown in development of natural

antioxidants from botanical sources. Flavonoid-containing botanicals are of major interest as plant-based antioxidants.3

The product employed in this study, Vitexina, isderived from a plant, Vigna radiata (L.) Wilczek(Fabaceae) (synonyms Vigna aureus [Roxb.] Hepper,Phaseolus aureus Roxb.), common name dau xanh, thegreen or mung bean, which has been empirically usedin Vietnam for detoxification.4 Vitexina is not yet com-mercially available in Vietnam; it is currently underreview for marketing approval by the Ministry ofHealth. V. aureus has traditionally been used to removefood toxins and alcohol from the body; it is also usedto treat the symptoms of conditions classified as “hot”in traditional Vietnamese medicine, such as dysentery.The product was shown to be a promising antioxidantradioprotective agent in a series of experimental stud-ies conducted by the research team of the VietnamInstitute of Traditional Medicine.5-9 The plant is also acommon foodstuff in Vietnam; the product thus has alarge margin of safety. Acute and subchronic toxicityassays have confirmed this statement.10

The present study examines the use of Vitexina as asupportive therapy for breast cancer patients under-going radiation therapy after initial surgery. Theobjectives of the study are as follows:

1. To assess the effects of Vitexina capsules on generalhealth status during radiation therapy;

2. To assess the radioprotective effects of Vitexina cap-sules for selected peripheral blood cell classes inbreast cancer patients during radiation therapy;

Hien et al.

38 INTEGRATIVE CANCER THERAPIES 1(1); 2002 pp. 38-43

TVH and NBH are at the Vietnam Institute of Traditional Medicine,Hanoi, Vietnam. PMH is at the Military Academy of Medicine, Ha-noi, Vietnam. NBD is at the Cancer Institute, Hanoi, Vietnam.

Correspondence: Tran Van Hien, Vietnam Institute of TraditionalMedicine, Hanoi, Vietnam. E-mail: [email protected].

3. To investigate the possible effects of Vitexina capsuleson the cold-hot status of breast cancer patients duringradiation therapy.

Method

MaterialVitexina is derived from the seeds of V. radiata. Seedsare extracted with 70% alcohol. After removal of sol-vent under vacuum, the residue is extracted with ethylacetate. Residue of the ethyl acetate extract is partiallypurified by washing with petroleum ether (40°C-70°C),water, and finally with acetone. The powder thus ob-tained contains the flavonoids vitexin and isovitexin(9:1 approximate ratio), which have been identifiedby ultraviolet spectrum and by 3H- and 13C-nucleicmagnetic resonance spectrum.

Vitexina capsules (350 mg), containing 100 mgVitexina powder each, are produced by the VietnamInstitute of Traditional Medicine and the Pharmaceu-tical Factory No. 4 in Ho Chi Minh City. Identical pla-cebo capsules contained lactose.

Clinical Trial MethodologyThe present study is a randomized, placebo-controlledcomparative clinical trial. Patients were recruited fromthe Department of Radiation No. 2, Cancer Hospitalin Hanoi; the patient population included patientswith stage II or stage III breast cancer for whom radia-tion treatment was indicated following surgery for pri-mary breast cancer. The study was conducted fromMay to October 1999. Ethical review of the trial wasconducted by the National Center for Cancer in Ha-noi. Trial details were presented on informed consentforms. Patients who consented to participate in thetrial were assigned to treatment with Vitexina (Vitexinagroup) or placebo (placebo group); each group had36 patients. Exclusion criteria for the trial were as fol-lows: patients with distant metastases, infection withtuberculosis, infection with hepatitis, and patients whodid not complete the course of medication or attendthe final physical examination. General health criteriaincluding body weight were assessed by a single physi-cian in the Department of Radiation at the CancerHospital. The observation of hot and cold symptomswas made by a traditional medicine doctor from theVietnamese Institute of Traditional Medicine, who wasblinded to the group assignment of the patients.

Study MedicationsPatients in the Vitexina group received 4 capsules(400 mg active compounds) daily during 6 weeks of ra-diation therapy, whereas patients in the placebo group

received 4 placebo capsules. The capsules were codedby the Department of Pharmacy at the Vietnam Insti-tute of Traditional Medicine.

Radiation ProtocolThe total dose of radiation (Cobalt-60) was 5000 rad.The daily dose was 200 rad, whereas the weekly dosewas 800 to 1200 rad divided in 5 courses per week.

Laboratory AnalysesComplete blood counts were performed at the CancerHospital laboratory. Blast transformation response oflymphocytes was performed by the Immunology Labo-ratory of the Institute of Hygiene and Epidemiology inHanoi. Assessment of hepatic enzyme activities (GOT,GPT) was done at the Vietnamese Institute of Tradi-tional Medicine.

Blast transformation was monitored using the blasttransformation test (LTT). Blood samples were takenfrom patients in the Vitexina and placebo groupsbefore and after 6 weeks of radiation treatment. Bloodfrom healthy people was examined and used as a con-trol. Activation of lymphoblastic transformation wasmeasured by methyl-3H-thymidine incorporation in aliquid scintillation counter. Phytohemagglutinin(PHA) was coincubated together with the lymphocyteculture for 72 hours prior to adding 3H-thymidine.

Radioprotective Effects of Vitexina


Table 1. Weight (kg) Change inCancer PatientsAfter 6Weeksof Radiation Therapy

Before AfterTreatment Treatment P Change

Vitexinagroup 46.8 ± 5.80 47.00 ± 5.90 >.05 +0.193 ± 0.904

Placebogroup 47.62 ± 7.56 46.82 ± 7.66 <.01 –0.800 ± 0.0927

P >.05 >.05

46.8

47.6

47

46.8

46

46.5

47

47.5

48

Before After

Vitexina

Placebo

Figure 1 Weight change in breast cancer patients after 6 weeks ofradiation therapy, plus treatment with Vitexina orplacebo.

ResultsCharacteristics of patients at entry in the study weresimilar between the Vitexina and placebo groups.Mean age of patients in the Vitexina group was 45.77years, whereas mean age for the placebo group was45.63. Weight of patients in the Vitexina group was46.82 kg, and in the placebo group, 47.62 kg.

Clinical SymptomsSide effects frequently found in patients exposed to ra-diation are headache, restlessness, fatigue, poor sleep,and poor appetite. All patients in the Vitexina groupreported to the treating radiation oncologist that sideeffects were not noticeable, that they had good appe-tite, and that they slept well during the course of radia-tion treatment.

Data on weight changes were extracted from medi-cal charts. No relevant weight loss, or even a weight gain,occurred in 70% of patients in the Vitexina group,whereas 73% of the placebo group lost 1 to 2 kg ofweight after 6 weeks of radiation therapy (Table 1, Fig-ure 1).

Peripheral Blood Cell CountsA comparison of the results of hematological exami-nation is presented in Table 2 and summarized in Fig-ure 2. The data indicate an advantage for the Vitexinagroup in erythrocyte, leukocyte, and platelet counts aswell as hemoglobin after 6 weeks of radiation therapy.Erythrocyte counts and hemoglobin improved in theVitexina group but declined in the placebo group.Leukocyte and platelet counts declined to approxi-mately 80% of original values in the Vitexina groupand to approximately 60% of original values in the pla-cebo group. Among the patients in the Vitexina group,67% experienced a reduction in platelet counts of lessthan 20% whereas only 17% of placebo patients expe-rienced a reduction this low (Figure 3).

Effects of Vitexina in LymphocyteBlast TransformationImmune responsiveness in cancer patients is generallydeficient and becomes more seriously so when pa-tients are exposed to radiation. One effect of high-en-ergy radiation is damage to T and B lymphocytes. Blasttransformation activity of lymphocytes was used tomonitor the immune status. The data obtained showthat there was a reduction of the response to PHA incancer patients after surgery in comparison with theresponse in healthy people. The LTT activity mea-sured in lymphocytes from healthy controls after 72hours incubation with PHA is about 6000 to 8000pulses per minute (ppm). No significant difference inthe means of LTT values between the 2 experimentalgroups was observed before radiation treatment; therange of these values was found to be 2000 to 3000ppm. The second measurement showed that there wassome improvement in patients receiving Vitexina incomparison to the controls. In most subjects analyzedin the Vitexina group, lymphocytes still responded toblast transformation initiated by PHA, whereas this re-sponse was almost absent in the placebo group. Thiseffect was not confirmed statistically, as insufficientdata from the 2 groups were obtained for analysis.

Cold-Hot Status Before andAfter Radiation TreatmentAccording to the experience of experts in traditionalmedicine, the syndrome of deficiency-hot as classifiedin Vietnamese traditional medicine is commonly ob-served in cancer patients. Hot symptoms were ob-served in breast cancer patients in this study. Theyseem to be increased by radiation therapy. The Vitexinaused in supportive therapy in this study was evaluatedfor its activity in the improvement of hot symptoms ofradiation-exposed cancer patients. Results of tongueexamination are shown in Figure 4. In the normal con-

Hien et al.


Table 2. Changes in Peripheral Blood Cell Counts and Hemoglobin After 6 Weeks of Radiation Therapy

Before AfterGroup Radiation Therapy Radiation Therapy P Change

Erythrocytes (×106)Vitexina group 3.980 ± 0.225 4.094 ± 0.129 >.05 +0.288 ± 0.430Placebo group 3.980 ± 0.146 3.978 ± 0.236 <.05 –0.147 ± 0.570P >.05 <.01

HemoglobinVitexina group 10.39 ± 2.59 11.85 ± 1.50 <.05 +1.335 ± 2.859Placebo group 11.45 ± 2.05 11.14 ± 1.74 >.05 –0.309 ± 2.757P >.05 >.05

Leukocytes (×103)Vitexina group 7.05 ± 0.46 5.86 ± 0.30 <.05 –1.23 ± 2.64Placebo group 7.05 ± 0.30 4.90 ± 0.28 <.05 –1.80 ± 1.63P >.05 >.05

Platelets (×103)Vitexina group 251.25 ± 15.65 203 ± 10.81 <.05 –45.56 ± 60.22Placebo group 259.77 ± 12.54 158.07 ± 9.24 <.01 –96.03 ± 52.12P >.05 <.05

dition, the tongue has a white coating; the tongue tis-sue is pale pink in color. In patients with hot symptoms,the tongue has a thick white or yellow coating and thetongue tissue is pink. In patients with extreme hotsymptoms, the tongue coating is dry and yellow, orlacking entirely, and the tongue tissue is dark pink.Whereas the incidence of normal, hot, and extremehot symptoms was similar between the Vitexina andplacebo groups at the start of radiation therapy, the in-cidence of hot and extreme hot symptoms was in-creased in the placebo group after 6 weeks of radiation.Degree of tongue coating and color of tongue tissuewere affected in the same pattern.

DiscussionSix weeks of treatment with Vitexina (400 mg per day)appeared to improve the general health of breast can-cer patients during the course of treatment, with resto-



10.39

11.45

11.85

11.14

9.5

10

10.5

11

11.5

12

Before After

Before After

Vitexina

Placebo

7.05 7.05

5.86

4.9

0

2

4

6

8

Vitexina

Placebo

251 260

203

158

0

50

100

150

200

250

300

Before After

Vitexina

Placebo

3.97 3.98

4.09

3.98

3.8

3.9

4

4.1

4.2

Before After

Vitexina

Placebo

Figure 2a Erythrocytes

Figure 2b Hemoglobin

Figure 2c Leukocytes

Figure 2d Platelets

Figure 2 Changes in levels of erythrocytes, hemoglobin, leuko-cytes, and platelets in breast cancer patients following 6weeks of radiation therapy, plus Vitexina or placebo.

35.25

6.66

67.74

16.66

0

20

40

60

80

<10% Reduction <20% Reduction

Vitexina

Placebo

Figure 3 Breast cancer patients treated with radiation therapy andVitexina or placebo: rate of cases in which the reductionof platelet counts is less than 20%.

1415

1

13

16

1

1513

2 2

21

7

0

10

20

30

VitexinaBefore

PlaceboAfter

VitexinaAfter

PlaceboBefore

Normal

Hot

Extreme hot

Figure 4 Results of tongue examination from Vietnamese Tradi-tional Medicine perspective. Normal: white coating, palepink color. Hot: thick white and yellow coating, pink color.Extreme hot: dry yellow coating or no coating, dark pinkcolor.

ration of peripheral blood cells as well as lymphocytefunctions. These effects might result from theantioxidative mechanisms of the active principles inthe product.

Radiation damage in biological systems is initiatedby the oxidative burst of free radicals and then by a cas-cade of free radical reactions. This event influencesfirst the peripheral blood cells. The reduction inerythrocytes, leukocytes, platelets, and hemoglobinhas been reported by others and was confirmed in thisstudy. In the Vitexina group, blood counts were signifi-cantly higher than in the placebo group after radia-tion therapy, as shown in Tables 2 and 3, particularlywith regard to platelets, suggesting a radioprotectiveeffect for Vitexina. Because of the known antioxidantproperties of Vitexina, we suggest that this effect is dueto the inhibition of free radical induced lipidperoxidation.

An effect of Vitexina on the Vietnamese traditionalmedicine concept of deficiency-hot was indicated inthis study based on tongue examination and otherclinical symptoms such as fatigue, restlessness, poorsleep, and constipation. Radiation treatment is typi-cally found to aggravate hot symptoms. However, theclinical assessments of hot symptoms did not changein the Vitexina group, whereas symptoms of extremehot and hot were found in almost all patients in theplacebo group after 6 weeks of radiation therapy.Vitexina is extracted from V. radiata, which belongs tothe “clearing heat and detoxification” classification ofVietnamese traditional medicine. Thus, the applica-tion of a “clearing heat and detoxification” agent toameliorate damage caused by radiation conforms tothe therapeutic principles of traditional medicine.

Radioprotective effects of Vitexina observed fromthe trial suggest that cancer, oxidative stress, and thedeficiency-hot syndrome of cancer patients may berelated, and that a potential solution would be to applythe medicinal plants of the “clearing heat and detoxifi-cation” classification, which are commonly rich inflavonoid compounds with antioxidant activity.

Further studies are necessary to confirm the benefi-cial outcome of Vitexina in combined treatment forcancer patients and to investigate the effects of thisproduct on improvement of nonspecific immunologi-cal response. We are now beginning a study of breastcancer patients treated with surgery, radiation

therapy, and Vitexina in which recurrence, survival,and immune responsiveness will be monitoredprospectively.

References1. Singh A, Single H, Henderson JS. Radioprotection by ascorbic

acid, Desferal and mercaptoethylamin. Methods Enzymol. 1990;186:76.

2. Scott G. Antioxidants, the modern elixir. Chem Br. 1995:879-882.

3. Rice-Evans CA. Flavonoids in Health and Disease. Berkeley, CA:Marcel Dekker; 1998.

4. Tran VH, Ta TP, Nguyen TH, Pham TT. Hepatoprotective effectof flavonoid from Vigna aureus. J Mat Med. 1997;2(4):21-25.

5. Mai VD, Le VD, Vu DQ, Pham MH, Tran VH. Flavonoid fromgreen bean: impact on macrophage function under 7 Gy radia-tion from Cobalt-60 in mice [in Vietnamese]. Med Bull. 1996;2(10):12-15.

6. Pham MH, Mai VK, Tran VH. Antioxidative effects of flavonoidsextracted from some Vietnamese medicinal plants [in Viet-namese]. Paper presented at: First National Conference ofClinical Biochemistry, Vietnamese Association of Clinical Bio-chemistry; 1996; Hanoi, Vietnam.

7. Mai VD, Tran VH, Nguyen XP, Pham MH. Radioprotectiveeffect of flavonoid from Vigna aureus (Vitexina) in mice [inVietnamese]. Paper presented at: Scientific Research Confer-ence, Vietnamese Institute of Traditional Medicine; 1999; Hanoi,Vietnam.

8. Mai VD, Tran VH, Pham MH. Anti-lipid peroxidation activity offlavonoids extracted from green bean (Vitexina) [in Vietnam-ese]. Paper presented at: Scientific Research Conference, Viet-namese Institute of Traditional Medicine; 1995; Hanoi, Vietnam.

9. Mai VD, Ta TP, Tran VH, Pham MH. Lipid peroxidation inhibi-tion by flavonoids from Vigna aureus in liver, spleen, and intes-tine of mice exposed to radiation at 7 Gy [in Vietnamese].Paper presented at: Scientific Research Conference, Vietnam-ese Institute of Traditional Medicine; 1996; Hanoi, Vietnam.

10. Mai VD, Tran VH, Tran LD, Pham TT. Acute toxicity test offlavonoid extracted from green bean [in Vietnamese]. Paperpresented at: Scientific Research Conference, Vietnamese Insti-tute of Traditional Medicine; 1996; Hanoi, Vietnam.

Editor’s NoteReaders from North America and Europe may not befamiliar with the differences between radiation ther-apy using linear accelerators, which is common intheir regions, and therapy using cobalt-60, discussedin the article by Tran Van Hien and colleagues. The ra-diation dosages used in this article are comparable tothose used internationally. However, with cobalt-60,the distribution of the dose is frequently less even thanwith linear accelerators, and there is less ability to de-velop skin-sparing dose regimens, according to Dr.Terry Bugno, whose contribution appears in this is-sue’s Integrative Tumor Board. Skin effects are not dis-cussed in this article, but it would be of interest whetherthis Vietnamese group examined skin effects in futureclinical studies with Vitexina to determine whetherthis antioxidant preparation would be useful for sucheffects. For readers not familiar with the classificationsof “hot” conditions in Vietnamese traditional medi-

Hien et al.


Table 3. Rate of Cases in Which the Reduction of PlateletCounts is Less Than 20%

Group <10% reduction <20% reduction

Vitexina group 35.25% 67.74%Placebo group 6.66% 16.66%

cine, this is a method of evaluating symptoms that is re-lated tosimilarconcepts in traditionalChinesemedicine.

We are quite sensitive to the questions raised bysome workers on the potential of antioxidants to inter-fere with the tumor-inhibitory effects of radiation

therapy and plan to address this specifically in laterissues. We note with approval that Hien and colleaguesplan to proceed with further studies to monitor sur-vival among patients given the Vitexina supplementwith radiotherapy.



Integrative Tumor BoardIntegrative Tumor Board

Integrative Tumor Board: Esophageal Cancer

PrefaceProfessional journals serve as critical avenues to pro-mote communication of new research findings andsyntheses of scientific information throughout themedical community. There can be a delay, however, inthe application of such scientific information to actualclinical practice. In the field of integrative cancer care,this normal delay is complicated by the implementa-tion of many techniques of alternative, complemen-tary, and traditional medicine before scientific valida-tion. Both of these patterns can leave the practitionerscrambling to understand new trends in the field. Tobegin to address the problem of advancing clinicalpractice and understanding in integrative cancer care,this journal will feature an article series called the Inte-grative Tumor Board.

The Integrative Tumor Board is a forum uniqueamong journal-based tumor boards. It is modeled onthe activities of a hospital tumor board but is based onan integrative cancer medicine perspective. In typicaltumor boards, a physician will present standard clini-cal data on a case, and several medical specialists willthen comment on the case from their own perspec-tives. The unique feature of the Integrative TumorBoard is that in addition to comments from medicalspecialists, practitioners of a variety of complemen-tary, alternative, or integrative disciplines will providetheir analyses of each case. Final comments will bemade at the end of the practitioner contributions,pointing out particularly interesting features, or rais-ing issues or concerns; comments are supervised bythe journal’s editor-in-chief in consultation with expertsin several relevant disciplines. The Integrative TumorBoard will be presented in most or all issues of Integra-tive Cancer Therapies; they will be composed of recom-mendations of rotating panels of medical specialistsand other practitioners.

It is important that the reader understand some ofthe basic premises of the Integrative Tumor Board.

1. Suggestions in the Integrative Tumor Board shouldnot be construed as recommendations for medicaltreatment. If a patient reading this material is inter-ested in implementing suggestions made in this fea-ture, he or she should discuss them with a physicianand other experienced health professionals familiarwith his or her medical history. Appearance of varioussuggestions for intervention in Integrative Tumor Boardarticles should not be construed as endorsements of

these interventions by the journal’s editorial staff ormembers of any of its editorial boards. We do notexpect readers to agree with all tumor board recom-mendations. Specific problem areas in tumor boardsuggestions will be noted in the comments, especiallyin areas that might pose potential risks; we will not,however, discuss every area of disagreement.

2. Recommendations in the Integrative Tumor Boardare not presented as an example of how patientsshould be treated from an integrative medicine per-spective. Actual treatment at an integrative clinicrequires regular interaction and exchange betweenthe cooperating practitioners and overall supervisionby a physician who is aware of the potential contribu-tions of the various disciplines represented in theclinic. The Integrative Tumor Board is, rather, a venueto present perspectives of a variety of disciplinesimportant in integrative cancer care in a public forum.Its purpose is to promote knowledge and understand-ing of these perspectives by all health professionalsworking with cancer patients, since a majority of can-cer patients today are taking advantage of one or moreintegrative therapies. We will try to encourage impor-tant areas of synergy and point out potential negativeinteractions (e.g., drug-herb interactions), recogniz-ing that adequate management of both is fundamen-tal to truly integrative care. However, this is not easilyaccomplished when practiced within a single facility,let alone when bringing together many modalitiesfrom several different practitioners. Still, we willattempt to address as best we can the more relevantinterrelationships.

3. Not all of the suggestions made in IntegrativeTumor Board articles will be solidly evidence based,particularly because some aspects of integrative carefall into a category one might call intangibles. Still, weare encouraging integrative practitioners to make anattempt to anchor suggestions in scientific evidence,or at least to submit suggestions that are not unreason-able from a scientific or psychological viewpoint, orfrom a traditional medicine perspective in the articlessubmitted by practitioners from various schools of tra-ditional medicine.

4. We expect that the many evidence-based or scien-tifically reasonable suggestions in Integrative TumorBoard articles will be viewed with seriousness even by

Integrative Tumor Board


readers accustomed to working in a conventional medi-cine perspective. Such readers may be startled, how-ever, by some of the less evidence based suggestions orby the spiritual counseling that will be offered by somepractitioners. Conventionally oriented health profes-sionals should realize that their cancer patients mayindeed be seeing practitioners who work from lessevidence-based perspectives. We strongly feel boththat this is a relevant aspect of integrative care and thatit is important that health professionals understandthe nature of such perspectives, and some of thepotentially healthful (or unhealthful) practices theyprescribe. This is essential information for those elect-ing to work constructively with patients who are usingpractices of alternative, complementary, and tradi-tional medicine in coping with their illnesses.

5. As will become evident in the Case Presentation,the information given to contributing practitioners isthe clinical data obtained before counseling the patienton an integrative intervention. The initial case alsoincludes information on lifestyle and psychosocial issuesof the patient taken from a comprehensive question-naire administered at the clinic of the presenting phy-sician. Many laboratory analyses, and all traditionalmedicine diagnostic techniques, are absent from thepresentation. This limits the ability of practitioners tomake specific recommendations for the patient, asseveral have noted. In response, however, most of thepractitioners have made their own recommendationsfor laboratory analyses and other diagnostic techniques.In these recommendations, one can perceive the typesof clinical analysis used in each discipline included inthe Integrative Tumor Board—information that is surelyas useful as specific clinical suggestions in developingunderstanding of integrative approaches to cancer.

Many readers will find the volume of informationincluded in the Integrative Tumor Board articles over-whelming. This reaction is, in fact, typical of thoseattending hospital tumor boards as well. We also feelthat it is true that integrative care itself can seem over-whelming to both practitioners and patients, particu-larly those just beginning their encounters with thefield. This is not an irrelevant issue when working withpatients already facing circumstances surrounding theirillness and treatments that are burdensome in and ofthemselves. As we have found in patient care, and aswe trust will occur with those of you new to integrativecancer treatment, you will become more familiar withthe various practices that will be included in the Inte-grative Tumor Board, and this sense of being sub-merged in information will diminish. We hope thatthe tumor board series will advance comprehension of

both the conventional medical interventions and thecomplementary, alternative, and traditional medicineinterventions on the part of health professionals andpatients as this new approach to cancer care grows anddevelops.

Esophageal Cancer

IntroductionOur patient in this issue is a classical example of onetype of integrative care patient: someone who has hadthe definitive conventional treatment for her cancerand seeks further counseling as to what she can donext. As will be seen, she has esophageal cancer, forwhich only a limited number of conventional optionspresently exist. Thus, an integrative plan may indeedbe her optimal strategy at this time. Integrative andconventional practitioners approach her with ques-tions: What can she do to prevent a recurrence? Howcan she cope with the side effects of her treatment?What can she do to find meaning in her life, which hasbeen so altered by this unexpected and life-threaten-ing disease?

Case PresentationA 63-year-old woman began experiencing dysphagiaespecially with large mouthfuls in November 2000.The pain became progressively worse; hence, she sawher family doctor who recommended that she see agastroenterologist. The gastrointestinal specialist ar-ranged an esophagogastroduodenoscopy. Endoscopypathology report of December 20, 2000, did not revealany gross tumor or Barrett’s epithelium. The distalesophageal biopsy revealed acute inflammation, andthe gastric biopsy was positive for mild chronic inflam-mation. The pathology report of the distal esophaguswas reread, which revealed hyperplastic squamousmucosa with dysplastic glandular epithelia worrisomefor adenocarcinoma. The staging computed tomogra-phy of the chest/abdomen/pelvis was unremarkable.

In January 2001, the patient experienced chestpains and was admitted to the coronary care unit,where she underwent a complete cardiovascular work-up that did not reveal any evidence of coronary arterydisease. The patient was sent home and started onPrilosec® 40 mg/day. The patient continued to experi-ence dysphagia, and a repeat endoscopy againrevealed gastroesophageal junction inflammation.

On February 22, 2001, an esophageal ultrasoundwas performed that revealed a mass in the distal esoph-agus into the proximal stomach with transmural infil-tration and regional lymphadenopathy; biopsyrevealed invasive grade 2/4 adenocarcinoma of the



distal esophagus. The gastric biopsy was positive foradenocarcinoma in situ.

Computed tomography of the chest showed a massin the region of the esophagus-gastric junction consis-tent with the patient’s known neoplasm. The mass hadan irregular/lobular contour. There were prominentlymph nodes adjacent to the mass, which likely repre-sent tumor extensions/metastases. Computed tomog-raphy of abdomen and pelvis showed no distant metas-tasis. Mammogram and Pap smear were within normallimits.

Past medical history: Unremarkable.

Medications: Zoloft®, Prilosec®, Pepcid AC®, atenolol,estrogen patch, multivitamins, folic acid, calcium, sele-nium, vitamin E. Laxative occasionally. Past use: seda-tives and tranquilizers.

Allergies: Sulfa

Family history: Mother died at 86 of breast cancer.Father died at 72 of coronary artery disease, myocar-dial infarction. Sisters and brothers are alive and well.Three adult children, health satisfactory to good. Ageat first pregnancy: 23.

Social history: Smoked half pack per day for 15 years,quit 1970. Alcohol: occasional for 25 years. No illegaldrug use. Currently retired, office worker for 30 years.Has held positions as nurse and pharmacy technician.No pets.

Physical exam: Well developed, well nourished; alertand oriented to time, place, and person. Not in anyacute distress. Blood pressure: 90/60. Pulse rate: 80.Respiratory rate: 18 bpm. Weight: 135 pounds. Head/eyes/ear/nose/throat: normal. Neck: supple, noadenopathy. Chest and lungs: clear to auscultation.Cardiac: normal sinus rhythm, no murmurs. Abdo-men: flat, soft, no hepatosplenomegaly; well-healedmidline scar. Extremity: no cyanosis/clubbing/edema.Neurologic: alert and oriented; no focal deficit.

The patient was seen by a medical oncologist whorecommended concurrent chemotherapy and radia-tion. She was started on neoadjuvant chemotherapycontinuous infusion of 5-FU and cisplatin. Shereceived her first chemo on March 6, 2001. Thepatient had a J-tube placed because of persistent nau-sea/vomiting and dysphagia. The chemotherapy wasgiven along with radiation, and she subsequentlyreceived 4500 cGy in 25 fractions. The patient had anextraordinarily difficult time with her treatment, withmuch nausea and vomiting, and ultimately a feeding

tube was used. Due to significant toxicity, week 5 of the5-FU was not administered. Patient subsequentlyunderwent surgery on May 8, 2001. An Ivor Lewisesophagogastrectomy procedure was performed, andher postoperative convalescence proceeded alongnicely without major complication or difficulty.

Final pathology revealed invasive grade 3 adeno-carcinoma; predominantly submucosal mass 3 × 2.5 ×2 cm in size. It was located at the gastroesophagealjunction. The tumor infiltrated through the muscularispropria. All margins were free of tumor. Three of 5lesser curvature lymph nodes did show evidence ofmetastatic disease.

Abnormal laboratory results: Hemoglobin low (11),hematocrit low (33), MCV low (79.4), red blood celldist. wid. high (16.8), lymphocytes low (0.67), MPVlow (6.8), albumin low (3.4), total white blood cell low(3300), number of CD3+ (T cells) low (810), percent-age of CD4+ (T helper cells) high (41), oxidized LDLantibodies high (1006), lipid peroxides high (0.99),alpha tocopherol high (65.9), lycopene high (0.91).

Dietary history: Childhood and adult diet: American.Patient consumed a diet that was mostly chicken andfish. She rarely consumed red meat, probably onceevery 3 to 4 months. She had moderate amounts ofrefined sugar and dairy. Her average adult weight was165 pounds prior to cancer diagnosis. Height is 5’5”.Postcancer diagnosis weight is 133 pounds. Currentlyeats almost all meals at home, in dining room. Uses gasfor cooking. Now tries to avoid sugar and fat but willeat almost anything due to lack of appetite after sur-gery. Spicy flavors are favorite. Almost complete disin-terest in food and diminished appetite since surgeryMay 2001, but forces herself to eat to maintain weight.Before surgery had lively interest in food, recipes, andcooking; probably overate.

One-day diet (before integrative nutrition interven-tion): Breakfast: yogurt, banana, toast (peanut butter/jam), orange juice. Lunch: tuna and tomato salad,crackers. Dinner: fish, potatoes, green beans. Snacks:commercial weight maintenance shake. Beverages:apple juice, water. Ninety-nine percent of meals areeaten at home, and 99% of foods are cooked. Mostintense food cravings are for pasta and pizza, butpatient tries to avoid processed foods; least intensecravings are for red meat.

Exercise history: Prior to cancer diagnosis, patientexercised every day, mostly walking or swimming 1 to1.5 hours per day. She would occasionally jog or liftweights using the Nautilus machine in the local uni-versity health club in the past. Postsurgery, the



frequency of exercise decreased to approximately50%. Current exercises: swimming, walking, bicycling,gardening, breath exercise. She also did qi gong—19postures.

Musculoskeletal issues: No problems reported withposture, gait, or coordination.

Supplement history: Patient has always taken supple-ments. Prior to diagnosis, she took a multivitamin withkelp, and cod liver oil.

Emotional/stress factors: Patient characterizes her-self as a fearful person, always worrying. She has a deepfaith in God and the body’s ability to heal itself. Shehas tried to maintain a positive attitude throughoutthe course of her illness.

Marital/home issues: Patient characterizes her mar-riage as very loving and reports that she and her hus-band are supportive of each other. Husband is healthy.

Current symptoms/date started: Dizziness on changeof position (June 2001), difficulty swallowing (Novem-ber 2000), chest pain (January 2001), shortness ofbreath when ascending 1 flight of stairs (since sur-gery), belching (since surgery), getting up 3 times atnight to urinate, avoiding foods (hard crusts) (sincesurgery), trembling in extremities (hands) (since sur-gery), fatigue with no obvious reason (since surgery),change in hair texture (since surgery).

Life patterns: Childhood regarded as happy; middlechild. More recent concern about adult children. Dur-ing working career, had stress due to expectations forjob performance. Wishes to let go of anxiety, concernabout adult children, keep positive attitude about can-cer. Activities for relaxation: exercise, reading, needle-work, and travel. Interested in good diet, exercise, andrelaxation techniques. Currently uses some tapes forimaging relaxation and has made an area at home tomeditate (20 minutes per day). Enjoys being out-doors, adapts well to change.

Sleep patterns: Sleeps 10 hours per night. Sleep habitsare routine. Falls asleep quickly but awakens to void.Awakens slowly but refreshed. Most alert during theday. Does not eat close to bedtime.

Recent stressful life events: Retirement.

Priorities (ordered): Security, relationships, vitality,libido, longevity, appearance, solace, recognition/acknowledgment.

Michael de la Torre, MDBlock Center for Integrative Cancer Care1800 Sherman Avenue, Suite 515Evanston, IL 60201E-mail: [email protected]

Radiation Oncology AnalysisThis presentation highlights many of the tenets ofmultidisciplinary approaches to cancer care that havebeen fostered in recent years to maximize symptommanagement, local control, and overall survival, espe-cially for patients with good performance status. Thiswoman’s symptom presentation for esophageal can-cer is typical: dysphagia progressing over months, yetaccompanied by initial negative diagnostic evaluations.Risk factors including smoking, alcohol, and possiblyreflux (Pepcid AC® use) coupled with chronic lifestressors are noteworthy, and with persistence, pathol-ogy becomes evident. In the United States, esophagealcancers constitute approximately 5% of all diagnoses,usually in a 3:1 male:female ratio, with an increasingpredilection for distal esophageal and gastro-esophageal junction locations, felt to be related toheightened incidences of chronic reflux states and themetaplastic transition from squamous to gastricmucosal surfaces, and the development of Barrett’slining, although not confirmed in this instance. Herdiagnostic evaluation, appropriately comprisingesophagogastroduodenoscopy and subsequent dem-onstration of an adenocarcinoma on pathology re-view, is all too common against a backdrop of a chronicinflammatory state, sometimes found in associationwith chronic gastric infections such as HelicobacterPylori although testing for this is not noted.

Once the diagnosis is established, traditionalclinical staging evaluation is paramount to accuratepretreatment tumor burden assessment and, thus,both staging and sequencing of interventions. Theoriginal computed tomography chest/abdomen/pel-vis being negative in December 2000, and then sugges-tive of anatomic irregularities reflects the likelihoodthat the patient’s local disease volume was relativelyrapidly escalating, with quicker volume-doublingtimes for tumor; one notes the lobulated, irregularfeatures of the gastroesophageal junction, which canbe difficult to interpret relative to adequate oral con-trast distension and accurate imaging, but is consis-tent with locally advanced, likely transmural, disease.In distal esophageal and gastroesophageal junctiontumors, regional nodes include paraesophageal,pericardial, and various regional stomach nodal sites,which are presumptively positive given their evolutionover a few months and size differential. Recentadvances in esophageal ultrasound have enhanced



the documentation of local disease permeation of theesophagus and are aptly correlated with computedtomography findings. Emerging on the scene to fur-ther enhance pretreatment cancer extent is positronemission tomography, which may indicate furthermicrometastatic deposits in normal-sized nodes, andregional to distant spread, especially in conjunctionwith image fusion techniques using computed tomog-raphy or magnetic resonance imaging. Theseadvances can further empower managing physiciansas to true disease extensions beyond the gross exten-sions and assist in both tailoring preoperative radia-tion portals and augmenting the surgeon’s clinicalacumen in planning the required aggressive radicalresections needed to maximize local control.

Finally, in the staging evaluation data, a key con-cern is noted of significant weight loss from 165 to 133pounds, likely multifactorial in nature (disease bur-den, tumor location with heightened symptoms ofreflux and nausea secondary to vagus nerve irritation,obstructive, mechanical factors and global effects includ-ing anorexia, and side effects of chemoradiation treat-ment). Moreover, laboratory data including a loweredlymphocyte count, lowered albumin, and mild anemiasuggest lowered immune state and likely nutritionalcompromise; cancer markers are not stated, but liverfunction tests are presumed normal. In preparationfor a multidisciplinary approach and given the tumor’slocation in the gastroesophageal junction, appropri-ate attention is given to nutritional support via a J-tube, which, although a more invasive procedure thanplacement of a G-tube, is required to eliminate place-ment near potential disease extension into the stom-ach and to reduce potential complications.

The patient’s clinical staging prior to interventionwould likely be cT3 on the basis of transmural exten-sion of disease, but because of extension into the stom-ach cardia, cT4, the nodal regional disease extentwould make her cN1. The computed tomographyreport notes no distant disease (which would includeceliac axis and/or upper mediastinal noncontiguousstations), so the final pretreatment clinical stagingwould be cTNM stage III (cT3-4 cN1 cMX-0 G2) infil-trating adenocarcinoma of the distal esophagus andgastroesophageal junction. Of particular note, subse-quent to neoadjuvant chemoradiation efforts, thetumor was downstaged, which occurs in approxi-mately 50% to 60% of situations, 25% of which areoften pathologic complete responses. The pathologicstate would likely be pTNM stage IIB (pT2 R0 pN1 MXG3), and with the remaining 3 nodes positive, the risksfor both locoregional failure and systemic progressionare somewhat ominous, approaching 50% or better. Itis important to note that often in the clinical setting,

the staging and management of transdiaphragmatictumors is a clinical challenge on virtually all fronts.

In recent years, the multidisciplinary managementfor local ly advanced distal esophageal/gastroesophageal junction tumors has shifted towardpresurgical downstaging, which provides for potentialimmediate symptom management and nutritional sta-bilization. It also diminishes the opportunity for thepatient’s disease to dictate rapid progression to bla-tant metastatic disease that might obviate aggressivelocal resection except for resistant disease, which war-rants a palliative resection such as bypass. Althoughmany protocols have been proferred, the selection ofcisplatinum/5-FU infusion in conjunction with con-ventionally fractionated external beam radiation ther-apy is a standard regimen with overall good toleranceand opportunity for tumor burden clearing. The treat-ment portals are relatively straightforward, includingall measurable gross disease and its contiguous exten-sions into the adjacent nodal regions. Caution is war-ranted as to limiting morbidity profiles to the heart,liver, and, due to the tumor location, left kidney. Thisis now achieved through more refined treatment-plan-ning algorithms including dose-volume histograms,complex 2- and 3-dimensional treatment planning,and multiple high-energy (usually greater than 6-MVphotons) beams appropriately shaped for maximalshielding of noncritical structures. This anatomicalterrain’s location adjacent to symptom-producingstructures (especially the gastroesophageal junctionand vagus nerve/antral associations) makes the eventof significant nausea, vomiting, and dehydration morelikely and further supports the notion of adequatefluid and nutritional support via enteral routes (J-tubefeeding) and antiemetics. The dose of 4500 cGy in 25fractions is a typical dose for addressing microscopicdisease extensions and is enhanced by the radiosensi-tizing effects of both cisplatinum and fluorouracil;recently, the addition of amifostine intravenouslygiven within 15 minutes prior to the daily radiationdose may provide further radioprotection of notewor-thy esophagitis/gastritis incidences and is becomingmore common in the clinical settings. One final noteon radiation oncology technique: intraluminalbrachytherapy, the placement of either low dose rateor, more recently, high dose rate radiation sourcesdirectly into the lumen, has no practical role here,since impending obstruction, bleeding, and so on arenot present, and since there would be limited penetra-tion into the full thickness of the lesion.

It is imperative that an adequate elapse of timefrom the completion of preoperative programs ofchemoradiation to definitive resection be allowed formaximal evolution of downstaging. Then, in theabsence of obvious disease progression, primary



surgical resection of all gross disease and its extensionscan be achieved, with the surgeon marking any areasof obvious residual or unresectable disease and effect-ing appropriate anastomotic connections. Thechemo-radiation treatment regimen is usually not metwith any undue heightened risk for complications inthe hands of experienced surgeons familiar with oper-ations in the radiated field. Studies pioneered by Japa-nese researchers, in which the nodal regions havebeen aggressively resected to effect maximal clearingof tumor burden, have demonstrated apparentimprovements in local control, and in probabilities ofmedian and overall disease control. Assuming thepatient’s performance status allows, aggressive resec-tion should be considered. Her apparent downstagingas noted in the final report is most typical and shouldbe met by additional adjuvant chemotherapy and/orother novel integrative medicine-based interventions.Although a theoretical consideration, routine radia-tion oncology practices are not usually equipped toperform intraoperative radiation therapy proceduresto address local extensions into adjacent tissues, orareas of gross residual disease left during resection.This intervention should, however, be strongly consid-ered if available. Only in restricted, individualized cir-cumstances would the use of additional postsurgicalradiation therapy be employed due to dose-limitingtoxicity to small intestine and other sensitive organswithin the path of radiation therapy, or in the true pal-liative setting.

Efforts to further enhance the nutritional supportfor these cancer patients, including the use of antioxi-dants and digestive enzymes, may be appropriategiven the altered pH state of the gastric mucosa anddigestive surface in conjunction with adverse effectson the microbial flora of the gastrointestinal tract.More novel approaches to address nausea preopera-tively and postoperatively, such as with acupuncture oracupressure techniques, can be considered, alongwith the use of guided imagery and visualization tech-niques in the immediate preoperative/postoperativesetting, as well as in overall management, to reducemorbidity and enhance quality-of-life factors.

Suggested ReadingsLerut T, Coosemans W, et al. Treatment of esophageal carcinoma.

Chest. 1999;116:463-465.DeCamp M, Swanson SJ, Klitsch MTH. Esophagectomy after induc-

tion chemoradiation. Chest. 1999;116:S466-S469.Wang CC, ed. Clinical Radiation Oncology: Indications, Techniques and

Results. 2nd ed. New York, NY: Wiley-Lyss; 2000.

Terrence J. Bugno, MD, FACRNorthern Illinois Center for Cancer Care4305 Medical Center DriveMcHenry, IL 60050

andCenter for Body and Soul12530 South Harlem AvenuePalos Heights, IL 60463E-mail: [email protected]

Medical Oncology Analysis 1Cancer of the esophagus is a malignancy that althoughthought of as a treatable condition is rarely a curableone. Overall survival remains relatively poor, even inpatients who present with nonmetastatic disease ame-nable to surgery, despite recent technical advances indiagnostic methodologies as well as in the delivery oftraditional anticancer treatment modalities. For themost part, the hope for cure depends on diagnosingthe disease at the very early stages, which occurs rarely.The most common symptom at presentation isdysphagia. Unfortunately, once symptoms are pres-ent, patients already harbor a significant cancer bur-den, with bulky tumors and regional nodal metastasesbeing found commonly at presentation. Formerly, themost common cell type was squamous cell cancer, typi-cally located in the proximal or mid-esophagus.Smoking and alcohol use are well-recognized risk fac-tors for this histological form of esophageal cancer. Inrecent decades, there has been a surge of adenocarci-nomas of the esophagus that are usually located in thedistal esophagus and the gastroesophageal junction.The reasons for this increase are yet uncertain, andthe role of smoking and/or alcohol use is also lessclear in adenocarcinoma of the esophagus. The pres-ence of Barrett’s esophagus is the most powerful riskfactor for the subsequent development of esophagealadenocarcinoma and is currently regarded by someexperts as a premalignant lesion. The presence of se-vere dysplasia in a Barrett’s metaplasia is associatedwith a high likelihood of current presence or futuredevelopment of in situ or invasive distal esophagealmalignancies.

Oncology practice dictates that histological confir-mation of the presumed cancer diagnosis be estab-lished through the biopsy of a suspicious primary ormetastatic lesion. This is critical given the implicationsassociated with being diagnosed with cancer of theesophagus and the terribly toxic treatment modalitiesthat are currently in use for the management of thistype of malignancy. In esophageal cancer, a pathologi-cal diagnosis is usually reached through direct biopsyof the primary tumor, under direct endoscopic visual-ization. Less commonly, definitive pathological confir-mation is reached through imaging-guided biopsy of ametastatic lesion. Once a histological diagnosis isestablished, the overall tumor burden is ascertainedthrough a number of staging studies. Computed



tomography scans of the chest and abdomen are usu-ally obtained that provide information with regard tothe primary tumor, the presence of regional nodalmetastasis, or the existence of distant visceral metasta-sis. Endoscopic ultrasonography is used commonly asa staging modality because it seems to complementthe information provided by computed tomography,especially in terms of primary tumor staging accuracyand of regional nodal staging. The current staging sys-tem in use for esophageal malignancies is the TNMclassification designated by the American Joint Com-mittee in Cancer. Tumor stage provides prognosticinformation and helps to determine the treatmentmodalities to be used in a specific case as well as theirintent (curative or palliative). Unfortunately, clinicalstaging remains rather imprecise, thus representing amajor problem when trying to allocate and/or com-pare treatment modalities for patients with esopha-geal malignancies.

The case offered in this report describes a commonpresentation of esophageal cancer. Cancer of theesophagus may occur in both genders, with themedian age of onset in the mid 60s. As was mentionedpreviously, the most common presenting symptom isprogressive dysphagia. Adenocarcinomas of theesophagus may initially develop submucosally andmay on occasion be missed on initial endoscopic eval-uation and imaging studies. The finding on esopha-geal ultrasound of “a mass in the distal esophagus intothe proximal stomach with transmural infiltration andregional lymphadenopathy” is consistent with the con-cept that once symptoms (dysphagia) are present,there is a high likelihood that the disease process is atleast regionally advanced. The pathological diagnosisof an adenocarcinoma is consistent with the currenthistological trend, with adenocarcinoma presentlybeing the most common histological type in the West-ern world. The location of the primary tumor in thegastroesophageal junction is also typical foradenocarcinoma.

Chemotherapy, radiation therapy, and surgicalresection are commonly used singly or in combinationin the management of esophageal tumors. The aggres-siveness of the therapeutic approach that is ultimatelychosen is predicated on the perceived likelihood ofachieving a cure. Patients’ and physicians’ preferencesalso guide treatment choice. Surgical resection con-tinues to play a significant role in the management ofesophageal malignancies and is regarded as a stan-dard therapeutic option for selected patients withstage III tumors, particularly those with T3 lesions.The overall results of surgical resection remain rela-tively poor; in addition, operative morbidity and mor-tality are not insignificant with the most commonlyused surgical techniques (transhiatal resection vs.

abdominal stomach mobilization with transthoracicesophageal resection). Given these results, new thera-peutic modalities have been investigated in recentdecades that have used radiation therapy singly or incombination with chemotherapy. Current evidencesuggests that combined chemoradiotherapy is supe-rior to radiation therapy alone and currently repre-sents the therapeutic standard for the definitive treat-ment of nonresectable regional disease. Althoughlocoregional control is quite reasonable with thesenoninvasive combined approaches, the results interms of overall survival remain poor. The addition ofsurgical resection, when feasible, after neoadjuvanttreatment with chemo-radiotherapy has been studied.Initial phase II reports suggested promise when com-pared to historical surgery-only controls. Given theoverall poor survival results with surgery alone andwith radio-chemotherapy alone in patients withregional disease, many oncologists have advocatedthis more aggressive trimodality approach, with induc-tion chemoradiotherapy followed by surgical resec-tion, as was undertaken in the case under discussion.Although still within the confines of what would cur-rently be considered reasonable care for a patientsuch as the one being discussed here, definitive ran-domized proof of principle is still lacking for this veryaggressive approach. Enrollment in a clinical study, ifavailable, may be the most sensible approach in a casesuch as the one described here. As a final comment,special attention should be devoted to ensuringproper nutritional support when and if indicated inpatients undergoing definitive therapy for an esopha-geal malignancy, which seems to have been properlyaddressed in this case.

David M. Gustin, MDManoj Agarwal, MDDepartment of Hematology/OncologyUniversity of Illinois at Chicago841 Clinical Sciences Building, 840 South Wood StreetChicago, IL 60612E-mail: [email protected]

Bharat Motwani, MDMount Sinai HospitalCalifornia Avenue at 15th StreetChicago, IL 60608

Medical Oncology Analysis 2This patient has been diagnosed with an adenocarci-noma occurring at the gastroesophageal junction, orin the gastric cardia. Esophageal cancer per se is usu-ally a squamous cell carcinoma arising in thesquamous cell lining of the esophagus; however, this



tumor has arisen in the cells lining the stomach and isthus classified as an adenocarcinoma. Tumors occur-ring in the gastroesophageal junction are usually ofthe adenocarcinoma type.

Treatment for esophageal tumors comprises sur-gery, radiation therapy, and chemotherapy. Althoughthe ideal treatment for a fully respectable tumorwould be surgery only, neoadjuvant chemoradiationtherapy is usually given prior to surgery, particularly inpatients with positive lymph nodes. In neoadjuvanttherapy, the chemotherapy acts as a radiosensitizer,and the combination of both treatments usuallydebulks the tumor prior to surgery, making successfulresection more likely. In some cases, surgery is per-formed first and chemoradiation is given postopera-tively, but the choice of chemoradiation prior to sur-gery was made in this case and appears appropriate.

Prognosis for a patient with a tumor of this typedepends, of course, on staging. The presence of posi-tive lymph nodes increases the possibility of recur-rence. A local recurrence is one possibility, but suchtumors often metastasize to the liver or lung. In thecase of metastatic disease in the liver or lung, palliativechemotherapy protocols are available, although theydo not generally result in long-term control. Drugcombinations could be used for palliative treatment:FAM (5-FU, leucovorin, Adriamycin®, and mitomycin)and ELF (etoposide, leucovorin, and 5-FU) are possi-bilities. Treatment with docetaxel or gemcitabine isalso an option in the palliative situation. Bonemetastases are less common than liver or lungmetastases, but they do occur. In the case of painfulbone metastases, radiation therapy can be given forpalliation.

Deva Nathan, MDOLR Cancer Center3800 North CentralChicago, IL 60634

Naturopathic Medicine AnalysisNaturopathic medicine, sometimes called naturopathy,is a distinct system of primary care based on the princi-ples of prevention, removal of the cause of disease,support for the healing power of the body, and treat-ment modalities based on state-of-the-art scientific re-search. Naturopathic physicians who complete 4 yearsof naturopathic medical school receive Doctor ofNaturopathy (ND) degree and are eligible to take na-tional board exams in order to become licensed in var-ious states. Naturopathic practice includes functionalnutrition, botanical medicine, homeopathy, hydro-therapy, and naturopathic manipulation.

Naturopathic recommendations for the care of apatient with cancer either before chemotherapy, radi-ation, or surgery, or after chemotherapy, radiation orsurgery, involve a complementary approach with thepatient’s oncologist. During chemotherapy, varioussupplements have been found to decrease the toxicityand enhance the effectiveness of specific chemo-therapeutic agents. Specifically in this case, thepatient would have benefited with the use ofglutamine,1 milk thistle (silyloum marianum), CoQ10,and vitamins C and E2,3 to help decrease the toxicitybrought on by 5-FU. The possible side effects ofnephrotoxicity brought on by cisplatin can bedecreased through the use of CoQ10 and silymarin,4

whereas ginkgo biloba can help to increase peripheralblood flow and thus decrease possible neurotoxicity.With a decrease in side effects, this patient may havebeen able to finish chemotherapy. In addition, certainsupplements can help support normal tissue repairfrom radiation therapy (i.e., glutamine), provided thepatient does not have excessive nephrotoxicity. Prepa-ration and immediate healing after surgery can becomplemented by homeopathic arnica, bromelain(anti-inflammatory), zinc, gambir (an herb), andother antioxidants.

A naturopathic approach to the patient, who hasalready had chemotherapy, radiation, and an IvorLewis esophagogastrectomy for adenocarcinoma ofthe gastroesophageal junction and adenocarcinomain situ of the stomach, necessitates more extensiveclarification of information. At the beginning of thecase, as a naturopathic practitioner, my approach wouldbe to determine whether she has any gastric functionleft. Assuming that she started on Zoloft®, Prilosec®,Pepcid AC®, and atenolol during chemotherapy andthat all of her symptoms—shortness of breath withexertion, belching, avoiding hard-crust foods, trem-bling in extremities, fatigue, and hair texture—beganafter surgery, one needs to question her ability todigest and absorb nutrients. In addition, further dataare needed on complete blood chemistry values, espe-cially liver and kidney function, both before and afterchemotherapy. As a naturopathic practitioner, I amconcerned with patterns that can be found based onwhere normal chemistry values lie on a continuum.Blood urea nitrogen, serum creatinine, calcium, mag-nesium, and phosphorus, in addition to a thyroidpanel with a serum transferrin and body mass index,would be of benefit. In addition, I would evaluatewhether the patient was truly hyperchlorhydric beforeand after chemotherapy, radiation, and surgery(necessitating her medications of Prilosec® andPepcid AC®). Depending on specifics to her surgery,



does her postsurgery symptoms predispose her tohyper- chlorhydria due to the lack of a lower esopha-geal sphincter? If this were true, the patient would beadvised to stay away from mint and other substancesthat further relax any tissue that serves as her loweresophageal sphincter. Her gastric function woulddetermine the need for specific B vitamins and diges-tive enzymes, the former helpful for anemia and thelatter for nutrient absorption. An amino acid assess-ment can give some indication of absorption of ade-quate amounts of vital nutrients, whereas a urinary ele-mental analysis provides an indication of the lack ofnutritional cofactors.

In addition, a more intense history would need tobe obtained and additional questions answered spe-cific to the patient’s symptoms. Did she experiencegastric reflux prior to her initial dysphagia? What didshe take to treat this? Concerning her nocturia—howlong has this been a problem? Since chemotherapy?Does she drink coffee, alcohol, or water before bed?What volume of urine does she urinate during thenight? Does she have any residual kidney damagefrom chemotherapy? Did she have borderline hyper-tension prior to the surgery, with the surgery pushingher over the edge and necessitating her need forantihypertensive medication? Does her antihyperten-sive medication or anemia contribute to her dizzinessupon changes in posture and her shortness of breath?A careful evaluation would determine the type of ane-mia and whether careful iron supplementation wouldbe of benefit. In addition to changes in hair texture,did she notice any changes in her nails? Does she expe-rience a complete disinterest in food due to adecreased ability to taste? In this case, she might bene-fit from a short period of zinc supplementation. Ordoes she smell intense odors even at a distance fromfood, providing obnoxious stimuli following chemo-therapy? In this case, she may benefit from enhancedliver function and cofactors that support healthyphase I and II of liver detoxification.

With regard to prevention, I would recommendthat optimizing liver function to detoxify carcinogenicsubstances be considered. An evaluation of thepatient’s phase I and II liver detoxification system,although crude at this period of time, would give someindication of her liver’s ability to detoxify substances,especially after chemotherapy. Supplements that sup-port liver function and both phase I and phase II ofliver detoxification could be of benefit to her, such asmilk thistle, curcumin, CoQ10, grape seed extract, var-ious amino acids and B vitamins, molybdenum, andquercetin. If she is interested in old-fashioned treatmentmodalities, she could benefit from a castor oil pack tothe abdomen and liver for 30 to 50 minutes a day.

Besides relaxing, the castor oil pack would help totonify the bowel, prevent constipation, and enhancethe immune system through stimulation of the gut-associated lymphatic tissue (GALT).

With regard to the patient’s nutritional status, herbody mass index, protein, and transferrin levels canhelp to determine the adequacy of her body mass.Most important, the absorption of nutrients both inthe past and after chemotherapy and surgery can giveindications for direction of treatment. Do the changesin the texture of her hair reflect toxicity from the che-motherapy? In this case, a hair analysis can be benefi-cial but may also be questionably reliable. An aminoacid profile might better determine which aminoacids are not being absorbed, contributing to thepatient’s fatigue and malnutrition. A determination ofher gastric pH status may reveal how it influences herability to absorb nutrients and thus determine theneed for further medication or supplementation,depending on whether she has had a completegastrectomy or maintains some gastric function.Before she can be given nutrient recommendations,one must address the reason for her disinterest in foodwith either zinc (taste problems) or liver detoxifica-tion support (overwhelming smell and distaste forfood). In addition, digestive enzymes may help herobtain nutrients from her foods and also help with hercomplaints of belching. Once she is able to eat morefoods, I would recommend fruits (berries), vegetables(cruciferous containing isothiocyanates),5 green tea,6

whole grains and cereal fiber,7 garlic, and onions.8 Inparticular, the use of isothiocyanates may benefit herthrough the suppression of carcinogens activatedthrough the phase I detoxification system and thenthe detoxification of any residual metabolites fromphase I that sneak through to damage cellular DNA.9

Along with the castor oil pack to her abdomen, a table-spoon of ground flax seed added daily over salad,cereal, or in a protein smoothie can help ease heroccasional constipation.

With regard to antioxidant function, an elevatedlipid peroxide level suggests a high amount of oxida-tive stress in the patient’s tissues. Supplementationwith antioxidants such as vitamins C and E, as well asbeta-carotene, selenium, lipoic acid, milk thistle, greentea, quercetin, ginkgo biloba, and grape seed extract,can provide antioxidant protection once she is eatingnormal foods. Avoiding any amount of alcohol wouldbe especially important in reducing the lipid peroxidelevels and decreasing further opportunity for metastasis.

After chemotherapy, radiation therapy, and sur-gery, the patient’s immune function can be especiallycompromised due to chemotherapy and radiation. Iwould recommend rotating various immune-



enhancing herbs/mushrooms in addition to the basicantioxidant vitamins that also provide immunesupport. Rotating different extracts of mushroomsand herbs including maitake, Coriolus versicolor, reishi,shiitake, green tea, arabinogalactans, olive leaf, andberberine-containing herbs every few months wouldbe beneficial in enhancing her immune function. Inaddition, an old naturopathic treatment called “warm-ing socks” may help conserve immune function andcan be done nightly, depending on patientcommitment. This stimulatory treatment, used withpersons who feel an oncoming cold or flu, is donebefore bed. The feet are warmed in a hot water bathand then covered with dampened cotton socks, withwool socks placed over them.

Although homeopathy in the classical sense is spe-cific to the individual, homeopathics recommendedspecifically for symptoms such as nausea, dizziness,and fearfulness during chemotherapy may have beenbeneficial to the patient, that is, provided the cause ofthe symptoms have been thoroughly explored and thespecific homeopathic is matched to a very specific setof symptoms. Currently, the patient can benefit from 1of 2 systems of homeopathic prescribing, the firstbased on a detailed interview with the patient (classi-cal prescribing of 1 homeopathic substance) and theother based on a cellular detoxification process fromEurope called drainage. Drainage involves the use ofhomeopathic substances that are formulated based ona Chinese philosophy that works with the body as a sys-tem. These substances consist of a metal and/or plantthat work together to stimulate cellular release of tox-ins. Many times individuals are not able to release thetoxins on a cellular level or through the various elimi-nation systems in the body that have been overloaded.For example, we use herbs and/or metals in formulato support organs of elimination (i.e., kidney, lungs,intestines, etc.).

Nutrition, botanicals, supplements, homeopathy,and hydrotherapy can all be beneficial approaches tothe patient’s care. The goal of naturopathic care is tohelp stimulate the healing force of the body while pro-viding the least amount of harm. Naturopathic medi-cine through a variety of approaches provides individ-ualized care based on the patient’s needs andinterests, thus allowing the practitioner to choosefrom a wide array of approaches and carefully design amultiple-step approach to care. As mentioned in theabove discussion, 1 food, supplement, or botanicalcan provide assistance in various areas of need, allow-ing the practitioner creativity in building a treatmentplan. From my experience, most patients are seeking amultiple-phase approach to their natural care andbenefit most when support is provided from variousareas such as immune, liver, antioxidant, and so on. In

fact, by closely monitoring the patient’s needs as wellas motivation, the naturopathic practitioner can makerecommendations that allow the patient to adheremore closely to the plan in collaboration with treat-ment plans of other practitioners.

Assessment: Amino acid analysis, detoxification pro-file, and other lab results as above.

Nutrition: Zinc or supplements that support detoxifi-cation depending on patient’s reason for disinterest infood; fresh berries and other fruits, cruciferous vegeta-bles and other vegetables, ground flax seed; whole-grain cereals and fiber, garlic, onions, powderedcurcumin, green tea (not too hot); stir-fry withshiitake, maitake, and reishi mushrooms; proteinshakes; purified or spring water. Avoid corn (myco-toxins) and alcohol (lipid peroxide levels).

Herbs etc.: Silymarin, curcumin, artichoke, quercetin,green tea extract, plant digestive enzymes. Rotatemushroom, larch arabinogalactans, astragalus, andolive leaf extracts every few months.

Supplements: Amino acids based on assessment (espe-cially L-glutamine and L-carnitine), vitamin C, vitaminE, beta-carotene (nonsynthetic), selenium, B vitaminsincluding B12, CoQ10.

Hydrotherapy: Castor oil pack to abdomen and liver,warming socks at night.

References1. Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the pre-

vention of fluorouracil induced intestinal toxicity: a doubleblind, placebo controlled, randomised trial. Gut. 2001;48(1):28-33.

2. Lamson DW, Brignall MS. Antioxidants in cancer therapy: theiractions and interactions with oncologic therapies [review].Alternative Med Rev. 1999;4:304-329.

3. Lamson DW, Brignall MS. Antioxidants and cancer therapy II:quick reference guide. Alternative Med Rev. 2000;5:152-163.

4. Sonnenbichler J, Scalera F, Sonnenbichler I, Weyhenmeyer R.Stimulatory effects of silibinin and silicristin from the milk this-tle Silybum marianum on kidney cells. J Pharmacol Exp Ther.1999;290:1375-1383.

5. Hecht SS. Inhibition of carcinogenesis by isothiocyanates. DrugMetab Rev. 2000;32(3-4):395-411.

6. Gao YT, McLaughlin JK, Blot WJ, Ji BT, Dai Q, Fraumeni JF Jr.Reduced risk of esophageal cancer associated with green teaconsumption. J Natl Cancer Inst. 1994;86:855-858.

7. Terry P, Lagergren J, Ye W, Wolk A, Nyren O. Inverse associationbetween intake of cereal fiber and risk of gastric cardia cancer.Gastroenterology. 2001;120:387-391.

8. Gao CM, Takezaki T, Ding JH, Li MS, Tajima K. Protective effectof allium vegetables against both esophageal and stomach can-cer: a simultaneous case-referent study of a high-epidemic areain Jiangsu province, China. Jpn J Cancer Res. 1999;90:614-621.



9. Zhang Y, Talalay P. Anticarcinogenic activities of organicisothiocyanates: chemistry and mechanisms. Cancer Res.1994;54(suppl 7):S1976-S1981.

Judy A. Fulop, MS, NDCenter for Integrative MedicineNorthwestern Memorial Physicians Group680 North Lake Shore Drive, Suite 815Chicago, IL 60611E-mail: [email protected]

Nutritionist/Dietitian AnalysisImpression: The patient is a 63-year-old woman with ahistory of esophageal cancer, after chemotherapy with5-FU/cisplatin and radiation, followed by esoph-agogastrectomy. She presents within normal limits fordesireable body weight, at upper end range despitehistory of a 19% decrease usual body weight. Nutri-tional risks include rapid significant weight loss (a ma-jor indicator for malnutrition in the elderly),hypoalbuminemia, and microcytic anemia likely sec-ondary to decreased iron absorption due to decreasedintrinsic factor after esophagogastrectomy. Elevatedlipid peroxides and oxidized LDL, indicative of in-creased lipid peroxidation consistent with oxidativedamage due to radiation, were noted. Likely func-tional impairments are gut integrity and hepatic de-toxification. Symptoms contributing to decreased oralintake and weight loss include dysphagia, odynophagia,xerostomia, anorexia, food aversion, eructation, andfatigue.

Recommended Diet TherapyDiet of soft, moist consistency to minimize dysphagia/odynophagia: Congees/porridges (basic recipe 1 cupwhole grain to approx. 6 cups water, add pork, fish,poultry, beef, vegetables, fruit compotes, and season-ings as desired); nut butters; bean purees; tofuspreads; fruit “butters”; fruit compotes; fruit “smooth-ies”; soft, well-cooked vegetables (reserve cooking wa-ter for broth); 8 to 16 oz of fresh vegetable juice daily.

Minimize/eliminate the following, which are associ-ated with increased esophageal cancer and/or othercancer risk: Very hot drinks, chilies, alcohol, nitrites,pickled vegetables, “mate”/“Yerba mate” tea, cured/smoked/moldy foods, grilled/broiled foods (or grill/broil 6 inches from direct flame source and/or mari-nate first to minimize hydrocarbons).

Increase the following chemopreventive foods quanti-tatively and qualitatively: Three servings/day of wholegrains (barley, millet, quinoa, amaranth, oats, spelt,kamut, etc.); 4 to 6 servings/day of vegetables

emphasizing carotenoid-rich yellow-orange-red, andleafy green, cruciferous, and sea vegetables; 2 to 4 serv-ings/day of fruits emphasizing carotenoid-rich yellow-orange-red, and flavonoid-rich citrus and red-purple-blue (18 of 22 case control studies have shown a statis-tically significant protective association for fruit andvegetable consumption on esophageal cancer); len-til/bean-containing dish 2 to 3 times per week; 1 oz, 2tablespoons of nuts/seeds 3 to 5 times per week; lib-eral inclusion of mushroom-containing dishes (maitake,reishi, shiitake); liberal use of turmeric, rosemary,alliums, ginger, and fish 4 times per week.

Additional guidelines for food procurement/preparation: Hormone-free and antibiotic-free redmeat, poultry, dairy, eggs, and organic produce. Nofarm-raised fish. Although the American Cancer Soci-ety estimates less than 1% of all cancers are due topesticides/additives and so on, research is accumulat-ing suggesting pesticides act as endocrine disruptersand are deposited in adipose tissues. Given theunknown etiology of many cancers, and likelymultifactorial etiology, avoid substances that contrib-ute to cancer risk. Emphasize monounsaturated fatsfor cooking oils, restrict polyunsaturated fats for use incold food preparation (not heat stable), and decreasesaturated fat and trans fatty acids. Eat small, frequent,calorie/protein dense meals to promote weightmaintenance.

Therapeutic teas: Green tea 32 to 40 oz daily sippedslowly to increase salivary catechin levels and oralmucosa absorption.1 Astragalus tea 1 to 2 cups dailywhile white blood cell count and neutrophils are low.

Recommended SupplementationTo minimize xerostomia, management options per pa-tient preference: Slippery elm bark lozenges, slipperyelm bark tea (2 cups/day), or slippery elm bark extract(1:1 dilution 5 mL TID) as desired (decrease if laxativeeffect occurs); betaine anhydrous (trimethylglycine)toothpaste powder: mix 1/4 to 1/2 teaspoon withenough water to moisten, brush teeth 3 times daily.2

For oral cavity healing and lymphocyte protectionafter radiation therapy, management options perpatient preference: Glutamine powder: 10 g gargle 4times daily, or 4 g swish and swallow every 4 hours ifstomatitis is still acute/unresolved3-6; German chamo-mile oral rinse: 10 to 15 drops German chamomileextract in 100 mL warm water 3 times daily.

For prophylactic prevention of oral cavity infections,management options per patient preference: Tea treeoil: gargle 2 to 3 drops 100% essential oil of tea tree



(Melaleuca alternifolia) in 100 mL of water 3 times dailyfor antimicrobial action.

To minimize eructation, management options perpatient preference: Ginger, fennel seed, or anise seedtea: 1 cup at end of meals (carminative action).

For microcytic anemia pending further workup: Fer-rous SO4: 325 mg orally, 3 times daily, taken with 250mg vitamin C to enhance absorption. Recheck anemiaprofile and labs 6 weeks post-initiation of oral irontherapy. May require parenteral iron infusion if levelsare not normalized on oral iron treatment.

For hypoalbuminemia, weight gain, and immuneenhancement: Discontinue commercial weight gainshake. Hydrolyzed whey protein fortified fruit smoothiewith flax seed (15 g hydrolyzed whey protein concen-trate in 8 oz of organic soy milk with 1/2 cup fruit and1 tablespoon flax seed twice daily). Whey protein con-centrate (WPC) has been shown in animal experi-ments to exhibit anticarcinogenesis and anticanceractivity via the effect on increasing glutathione (GSH)concentration.7 WPC increased weight, albumin, andGSH concentrations in patients with HIV.8 WPC mayenhance the reduced-to-oxidized GSH ratio (GSH/GSSG) in lymphocytes—a marker of oxidative stress inreactive oxygen species mediated disease.

Other: High-potency multivitamin/mineral formulacontaining the following (or individual supplementsto meet recommended doses as needed): folic acid400 mcg daily, vitamin B6 5 mg daily, vitamin B12 100mcg daily, zinc 50 mg daily, selenium 200 mcg daily,manganese 5 mg daily, beta-carotene 15 mg daily, vita-min E 400 IU (natural vitamin E [d-alpha-tocopherol]),magnesium 400 mg daily, molybdenum 250 mcg daily,calcium citrate 1200 mg daily in 2 divided doses, andvitamin C 750 mg daily (taken in divided doses withsupplemental iron). Would further individualizesupplementation regimen with additional antioxi-dants (e.g., CoQ10, alpha lipoic acid, GSH, N-acetylcysteine) and nutrients for cell membrane support(e.g., phosphatidyl choline, taurine, omega-3 fattyacids) to reduce oxidative damage, pending furtherbiochemical workup, as well as nutrients to supportdigestion and replete intestinal flora, pending furtherbiochemical workup.

OtherFurther workup of microcytic anemia: ferritin,transferrin, Fe+, total iron binding capacity, percent-age saturation, B12, folate; stool analysis (digestion/absorption and intestinal flora); detoxification analy-

sis (potential susceptibility to oxidative damage);speech pathology referral to assess dysphagia/aspira-tion risk and/or need for swallowing conditioning ex-ercises; holistic psychology referral for relaxationmodalities (e.g., visualization, meditation, guided im-agery) and/or hypnotic suggestion to minimize foodaversion, nausea/vomiting, dysphagia/odynophagia,and anorexia, and promote weight gain. The patientshould discuss all interventions with her physician be-fore implementation.

References1. Yang CS, Lee MJ, Chen L. Human salivary tea catechin levels

and catechin esterase activities: implication in human cancerprevention studies. Cancer Epidemiol Biomarkers Prev. 1999;8(1):83-89.

2. Soderling E, Le Bell A, Kirstila V, Tenovuo J. Betaine-containingtoothpaste relieves subjective symptoms of dry mouth. ActaOdontol Scand. 1998;56(2):65-69.

3. Huang EY, Leung SW, Wang CJ, et al. Oral glutamine to allevi-ate radiation-induced oral mucositis: a pilot randomized trial.Int J Radiat Oncol Biol Phys. 2000;46:535-539.

4. Anderson PM, Schroeder G, Skubitz KM. Oral glutaminereduces the duration and severity of stomatitis after cytotoxiccancer chemotherapy. Cancer. 1998;83:1433-1439.

5. Anderson PM, Ramsay NK, Shu XO, et al. Effect of low-doseoral glutamine on painful stomatitis during bone marrow trans-plantation. Bone Marrow Transplantation. 1998;22:339-344.

6. Skubitz KM, Anderson PM. Oral glutamine to prevent chemo-therapy induced stomatitis: a pilot study. J Lab Clin Med. 1996;127:223-228.

7. Bounous G. Whey protein concentrate (WPC) and glutathionemodulation in cancer treatment. Anticancer Res. 2000;20(6C):4785-4792.

8. Bounous G, Baruchel S, Falutz J, Gold P. Whey proteins as afood supplement in HIV-seropositive individuals. Clin InvestMed. 1993;16:204-209.

MaryBeth Augustine, RDBeth Israel Center for Health and Healing245 Fifth Avenue at 28th StreetNew York, NY 10016andPrivate PracticeNutritional HealingHartsdale, NY 10530E-mail: [email protected]

Traditional Chinese Medical AnalysisThis patient has a disharmony of the earth phase or el-ement. The earth phase consists of the central meta-bolic unit, which includes the Spleen/Pancreas andthe Stomach. (The names of the organs are capitalizedto differentiate the Chinese interpretation of organfunction from Western biomedical theories.) The Yel-low Emperor’s Classic of Internal Medicine (Neijing Suwenca. 250 BC) states: “The function of the Spleen is totransform and transport the essence of food and fluids



of the Stomach. The symbology of the Earth is to nour-ish all things in nature. The Spleen channel connectswith the Stomach and Spleen organs and circulatesthrough the esophagus. When the Spleen is disor-dered, it cannot effectively transform and transportthe body fluids. The extremities then suffer a lack ofnourishment . . . gradually the muscles and tendons at-rophy and lose function.”1

The patient’s principal symptoms include dysphagia,persistent nausea, emesis, and belching, indicating adisturbance of Stomach Qi flow. With normal Stom-ach physiology, the Qi should flow in a downwarddirection. When the flow of Qi goes in the oppositedirection, it is called Rebellious Stomach Qi. Thesymptoms of loss of appetite and fatigue after her sur-gery are diagnostic of Spleen Qi deficiency becauseSpleen function regulates the appetite and the pro-vides the energy for daily function.

The esophageal cancer is the end stage of the syn-drome of esophageal constriction (Ye Ge).2 Thepathophysiologic factors include (1) disharmony ofSpleen and Liver function from emotional stress, suchas overworrying and repressed anger; (2) smoking,alcohol, and overly rich foods, especially sweet, hot,and spicy foods that create a pattern of Toxic Heat; (3)phlegm nodulation from Spleen dysfunction andinability to process fluids; and (4) blood stasis, which isthe result of chronic Liver Qi stagnation.3

Lifestyle imbalances include a diet high in refinedsugars and carbohydrates, which is characteristic ofSpleen deficiency pattern, and which may contributeto digestive dysfunction and obesity. This pattern ofeating has become the norm in the United States.Also, emotional imbalances such as chronic fear maydeplete Kidney Qi whereas chronic worrying depletesSpleen Qi. This combination weakens the Immunesystem, called deficient Wei Qi, and may lead to ane-mia because the Kidney and Spleen are the 2 principalorgans in blood production.

To further differentiate this case, the appearance ofthe tongue is needed as well as the radial pulse quali-ties of the 12 major organs. Upon differentiation ofthe case, specific recommendations could be made interms of the diet, acupuncture points, and herbalmedicine prescriptions.4

Currently, many Western patients with cancer areseeking complementary and alternative supportivecare such as traditional Chinese medicine. TheNational Institutes of Health Office of Complemen-tary and Alternative Medicine reported that in con-trolled studies, the incidence of postoperative andchemotherapy nausea and emesis could be reducedwith acupuncture therapy.5 Chinese herbal formulasalso offer patients relief from fatigue, anorexia,

diarrhea, neuropathy secondary to chemotherapy,leukopenia, anemia, and thrombocytopenia.

References1. Ni M, ed. The Yellow Emperor’s Classic of Internal Medicine. Boston,

MA: Shambhala Publications; 1995.2. Wu Y. Practical Therapeutics of Traditional Chinese Medicine.

Brookline, MA: Paradigm Publications; 1997.3. Kaptchuk T. The Web That Has No Weaver. New York, NY:

Congdon and Weed; 1983.4. Cheng X. Chinese Acupuncture and Moxibustion. Beijing, China:

Foreign Language Press; 1988.5. NIH Consensus Conference. Acupuncture. JAMA 1998;280:

1518-1524.

Charles H. Lo, MDDr. Lo’s Acupuncture Clinic55 E. Washington Street, Suite 1809Chicago, IL 60602E-mail: [email protected]

Western Herbal-Nutritional AnalysisRecommendations for this patient are as follows:

1. The first objective is to improve her nutritionalstatus. Her low albumin and anemia need to beaddressed. The protocol I recommend will be for 8weeks and then will need reevaluation. Detailed reci-pes and brand suggestions for foods and supplementsdiscussed are available.1

a. I would replace her night time drink with a home-made smoothie: 2 heaping tablespoons organic fer-mented soy powder with probiotics, organic wholegoat’s milk yogurt (6 to 8 oz) (or homemade sesameseed milk), 1 to 2 teaspoons of fish oil, 1 to 2 table-spoons glutamine powder, 8 drops of full-spectrumcarotenoid supplement; add berries and/or freshlymade juice to thin out.

b. Make 12 to 16 oz juice fresh daily using organic pro-duce: use equal parts of carrot/beet/kale/apple andadd 1 to 2 oz of organic cream.

c. Make an immune-enhancing soup from onion, astra-galus, garlic, burdock, ginger, reishi mushrooms, tofu,vegetables, wakame or kombu sea vegetables, water,and miso, and have 1 or 2 bowls daily.

d. Additional dietary suggestions based on a deficientkidney/adrenal system (she has very low blood pres-sure and urinates frequently): (1) use unrefined saltthat has all its natural-occurring minerals includingiodine; (2) cook goitrogenic foods before eating—soy beans, cruciferous vegetables, kale—otherwisethey may suppress thyroid function; (3) eat tyrosine-rich foods and other foods that improve kidney/adre-nal/thyroid function (tyrosine is an amino acid vitallyimportant for healthy thyroid and endocrine func-tion): fish, avocados, sesame seeds, almonds,



apricots, molasses, oats, whole dairy products, eggs,and sea vegetables; (4) foods rich in vitamin E, zinc,and B12 are also important, including cold-pressedoils, whole grains, shellfish, nuts and seeds, eggs, andwhole dairy foods; (5) consume carotenoid-richfoods: winter squash, carrots, mangoes, tomatoes,and sweet potatoes; and (6) consider switching fromtap water, if you have city water, to spring water fordrinking and cooking: artificial fluoride added todrinking water may reduce thyroid function.

e. Eat plenty of bitter greens, including dandelion,which possesses both cholagogic (promotes the flowof bile) and choleretic (stimulates bile secretion inthe liver) properties. Try to eat wild greens such aschickweed, watercress, mustard greens, and nettles.Use romaine lettuce, arugula, escarole, chicory, andwatercress (gallic acid). Also, eat cooked greens suchas kale, collard greens, beet greens, and especiallydandelion. Get used to eating bitter greens, as theydetoxify the liver.

f. Avoid all refined sugar and salt (may use unrefinedsalt in moderation).

g. Snack only on whole fruit and a few whole nuts and/or seeds. Chew all your food very well. Cook vegeta-bles, or cut up into small pieces before eating.

h. Eat foods rich in inulin such as artichokes, sunchokes(Jerusalem artichokes), asparagus, garlic, onions,and burdock root.

i. Until anemia is resolved, I recommend some organicmeat from free-range animals. Best to make soupsand/or stews. Add 2 to 3 pieces of burdock root, 3 to 4slices of astragalus root, and 2 to 3 ginseng roots.

j. Eat fish at least 4 times a week.k. Artichokes: steam and dip into a mustard vinaigrette

dressing (use as a snack). Beets: chop up with fennelroot, quickly steam, and add to salad.

l. Asparagus, sweet potatoes, eggplant, summer squash,black beans, adzuki beans (small red beans), andmung beans are good. Cook and eat, or add to soups.Job’s tears or pearled barley: cook as a breakfastcereal with figs or dates. These may be obtained in anyhealth food store.

m. Drink plenty of water. Flushing your kidneys with lotsof good-quality water (six 8-oz glasses per day) willallow your body’s purification system to do its job andtake some of the workload of detoxification off of theliver.

n. Balance all meals. Get plenty of rest and sunshine.

2. Remove fear and worry. Love and fear cannotcoexist. I would give the patient several suggestionsand some inspirational readings. For example, standstill and lift your hearts and hands to God. “Be still, andknow that I am God” (Ps 46:10).

Stand still, and look into the motivations of life. Arethey such that true foundations of sanctity can be builton them? Within the heart of healing is the infinite, aplace that records no time, a place that understands

that in relation to life’s pilgrimage is the desire to be asaint—a lover of Love.

Agape love. Our faith should be in our creator andabove any system is the utmost importance of creatinga deep loving relationship with all living beings. Whenyou love you heal and when you love, you never fail.Agape love means wholehearted love and service ofour neighbor. You see, all of life is a process, there isnot an end point. When someone gets cancer, it is aprocess too. Very often it is their realization of the can-cer that enables a person to change their path andmake it what it was truly meant to be. With regard tocancer diagnosis, it is not “one day I have cancer, thenext I don’t, and then the next day I have canceragain.” This concept, “I am a survivor,” I think iswrong. It should be “I am alive—filled with life.” Wemust not forget that we are all dying in a sense; death issomething no mortal can escape, and life is not merelyabout survival. We have already survived. If we are infaith, and able to hear Spirit calling us and visualizeGod’s hand reaching out to us, inviting us to be withHim despite all the adversities this world puts beforeus, we shall respond eagerly to that blessed invitationfor “perfect love cast out all fears.” Love never gives upand never fails.

3. Implement a plan of nutritional and herbal sup-plements that can enhance her vitality and/or inhibitcancer growth.

Take 20 to 30 minutes before meals: Cat’s claw; tur-meric (curcumin extract); activated quercetin;ashwagandha/rehmannia/licorice combination;immune mushroom extract; bromelain 2400 GelatinDigesting Units; Chinese herbal formula includingagrimony, cervus, broomrape, corydalis, reishi,Korean ginseng, pollen, licorice, lycoris, patrinia,pyrola, rabdosia, stephania, and prickly ash; reducedglutathione with molybdenum, coenzyme B-2;glutamine powder (taken in smoothie drink).

Take with meals: Fish oil: 1 teaspoon 2 times daily;shark oil: 1000 mg; combination of vitamin B12 andfolic acid: 10 drops 1 time daily; zinc: 30 mg; lipoicacid: 300 mg; selenium and saffron extract (can add tosmoothie): 15 drops; D-limonene and green teaextract: 3 capsules 2 times daily; antioxidant formula:1 capsule 2 times daily; formulation per 2 capsules:carotenoid complex 10,000 IU; vitamin C 500 mg; vita-min E as d-alpha succinate 100 IU; zinc methionine7.5 mg; selenium as selenmethionine 100 mcg;anthocyanins (10% formula); beet root (Beta vulgaris);black current (Ribes nigra); elderberry (Vaccinium



myrtillus); N-acetyl-cysteine 150 mg; alpha lipoic acid50 mg; CoQ10 25 mg; green tea extract (25 mg). Also,a good multivitamin.

Take before bed: Melatonin 1 to 3 mg (to start with);rabdosia 25:1 extract, 1 teaspoon mixed into juice orwater 1 time daily; herbal tonic: 1 teaspoon of the tonicspecified below 3 times daily. The amounts of herbalextracts (made with 35% ethanol) specified will make240 mL of the tonic. This tonic may not be appropriatefor individuals other than the patient for whom it isaddressed, and patients wishing to use a similar for-mula should see an experienced herbalist forguidance.

Thuja occidentalis (thuja): 15 mL extractPolygonum multiflorum (ho shou wu): 15 mLRumex crispus (yellow dock): 15 mLPanax quinquefolius (American ginseng): 15 mLSalvia miltiorrhiza (Chinese salvia): 15 mLWithania somnifera (ashwagandha): 15 mLScutellaria baicalensis (Chinese skullcap): 15 mLGlycyrrhiza glabra (licorice): 15 mLStillingia sylvatica (stillingia): 10 mLEleutherococcus senticosus (Siberian ginseng): 15 mLSchisandra chinensis seed: 15 mLArctium lappa (burdock seed): 10 mLColeus forskohlii: 10 mLCordyceps sinensis: 10 mLEchinacea purpurea (fresh): 15 mLPropolis: 15 mLHypericum perforatum: 15 mLZanthoxylum americanum (prickly ash): 5 mLPotassium iodide: 1 mLEssential oil of clove: 10 dropsOptional: drink a decoction of lapacho/jujube dates/lycium/urtica leaf/plantago leaf.

4. Take a hot Epsom salt bath with lavender oil 3 to 4nights a week before bed.

5. Blood test: Add testing for serum copper and zinc.

6. Tumor test: cyclooxygenase-2 activity

Reference1. Yance DR. Herbal Medicine, Healing and Cancer. Lincolnwood, IL:

Keats; 1999.

Donald R. Yance Jr., CN, MH, AHGCenter for Natural Healing300 North Pioneer StreetAshland, OR 97520E-mail: [email protected]

Ortho-Bionomy AnalysisOrtho-bionomy promotes health and well being by us-ing a number of hands-on and energy techniques tostimulate the body’s own natural ability to heal itself.1

The basic technique involves placing the patient intospecific positions that stimulate self-correction. Muchof the work involves promoting function by restoringstructural alignment and postural balance. Ortho-bionomy uses comfortable and painless methods thathelp the body to remember its natural organization.

The case study presented of esophageal cancershows a patient who could easily benefit from ortho-bionomy treatment. With this patient we would, afteran extensive interview, look at her alignment and hermovement patterns. We would examine tender points,which would allow us to determine appropriate posi-tions to explore.

The first question would be to determine whetherissues related to alignment corresponded to any of herphysical symptoms. Her general feeling of fearfulnessmight create contraction of her psoas muscles, whichcould affect many of her symptoms, including contin-ued difficulty of swallowing, shortness of breath, fre-quent urination, trembling in the hands, and fatigue.Contraction of the psoas can affect the entire spinalalignment, impinge nerves, and compress the abdom-inal space, making normal functioning of organsmore difficult. Surgical procedures and the emotionaldifficulties of radiation and chemotherapy could verywell create trauma in local tissues and throughout thesystem, disturbing function and the ability to reestab-lish balance and well-being.

We would use ortho-bionomy positioning tech-niques to explore ways of reestablishing structuralalignment. In particular, we would look at normalizingthe psoas, abdominal musculature, and spinal align-ment, in particular the mid and upper thoracic verte-bra. We would determine whether the continuednumbness in the hands and difficulty in swallowingcan be relieved by reestablishing spinal alignment. Wework with unwinding and relieving any local or sys-temic trauma by using subtle movements, visualiza-tions, and energy techniques to slowly allow thetrauma to be released and integrated.

Although I have not had direct experience in work-ing with esophageal cancers, I have had success inworking with other esophageal conditions, in particu-lar related to contraction and dysfunction.

Reference1. Kain KL, Berns J. Ortho-bionomy: A Practical Manual. Berkeley,

CA: North Atlantic Books; 1997.

Barry Krost, MACreative Healing Institute



2848 West Gregory StreetChicago, IL 60626E-mail: [email protected]

Yoga AnalysisI would like to suggest a way for the patient to look atthe disease process from a spiritual viewpoint, as it ismanifested from a subtle level. This is the level onwhich disease starts, before there is even the slightestmanifestation on the physical level.

The placement of this tumor is at a very prime junc-tion on both the physical and subtle levels. On a subtlelevel, it is at the junction or meeting place of theenergy that comes to us from a higher level of con-sciousness that can be called God consciousness(referred to hereafter as heaven energy) and theearth’s energy that we need to live on this planet.

This junction on all levels is meant to slow energy asit mixes between heaven and earth. In the case of atumor appearing between the heart chakra (subtlecenter), which is love and compassion, and the solarplexus chakra which is power and will, the energybecomes too restricted and blocked.

When there is not a flow between these 2 energies,there is a feeling of disconnection or isolation fromeven those people close to us, and the love that we feelfor others seems to evaporate as if into a bottomlessvoid. This comes from not just the immediate life’s cir-cumstances but from childhood experiences andexpectation. Even when we seek refuge in God or ourreligious or spiritual teaching, we can be left with afeeling of powerlessness, and this feeling of helpless-ness leads to fear. The fear can be nondescript and canradiate out into all aspects of life.

In our need to make sense out of all this, there is astruggle back to love, but in this case the pathway isblocked by the cancer. There can be a further trigger-ing of helplessness, and the fear can be exacerbated.

The patient describes herself as a perfectionist orhaving perfectionistic tendencies. Having a fixed ideaof what and how things could be goes against the ideaand flow of nature. Nature is always changing, and wecannot hold the heavens or the earth still for even 1second. When we try to keep ourselves or others in aholding pattern of the “perfect way to do or to be,” weare causing ourselves to feel powerless and fearful bynot accepting that life, in order to be life, mustchange.

One of the main suggestions I would have is for thiskind woman to begin to forgive herself and others fornot being perfect and to start to appreciate the sponta-neity and flow of life. As she begins to realize howbenevolently powerful she is, she can then allowenergy to flow between earth and heaven, which then

opens up the way on the physical level (i.e., thetumor). Then, love flows instead of resentment andfear. This could be substantiated by her deep faith andconnection to God.

Other specific advice: spend time in the sun takingin the heat and the direct rays, if possible on the bellyarea, and then imagine they are stored and you canrelease them whenever you need to feel power.

I am going to suggest some simple yoga practices.1

Sun salutation done slowly with a flowing breath. Whendone consciously the body and all its systems are bene-fited by the intentions, stretching, and bending. Also,on an emotional level it gives us the pattern of flow andhow one part of life (pose) affects the next.

Standing poses, especially mountain pose directing thebreath down the legs and into the earth. Then, inhale andbring the earth’s energy up through the feet and intothe solar plexus.

Shoulder stand pose and its complementary fish pose aswell as many of the backward and forward bend poses. Theseposes allow pent-up energy in the solar plexus chakrato move down to earth, which gives us a feeling ofbeing more grounded and steady in our life’s purpose

Deep relaxation for at least 15 minutes twice daily. Whencompletely relaxed, begin imagery. Imagine a softpink glow emanating from the heart chakras, fillingyou with a sense of compassion, and allow that light tomove down into the solar plexus uniting the 2. Allowthe compassion and the power to join and to heal thebody, the mind, all relationships, and the entire life.

Pranayama is the practice of generating and storinggross and subtle energies by varied means mostlyknown as controlled breathing techniques. Start withdeep belly breath. Take in the breath from way deep inthe pelvis. As the inhale increases, bring it up into thesolar plexus. On the exhalation, empty from the solarplexus and down to the pelvis. This is done with asmooth steady breath, not holding in or out. This willallow a sense of connection with the earth and help todissipate fear. After a time, allow the breath on theinhalation to come from the pelvis up to the upperchest and on the exhalation return back to the pelvis.This will help integrate heaven and earth.

Prayer. Choose one that is specifically liked andbegin to repeat it 50 or 100 times a day. Sit quietly afterand listen to any wisdom or feelings that come. Of themany different kinds of prayers, choose one thatallows you to feel a sense of strength and to positionthe Divine as a partner: “I receive divine power directly



from God” rather than “I am nothing and you areeverything.” If the belief is that we are all sinners,begin to soften it into the idea that we are all created inGod’s image and therefore have the potential to begreat and divine.

Reference1. Devi ND. The Healing Path of Yoga. Three Rivers, MI: Three

Rivers Press; 2000.

Nischala Joy DeviAbundant Well-BeingP.O. Box 346Fairfax, CA 94978-0346E-mail: [email protected]

Mind-Body Medicine AnalysisThe goal of mind-body therapy, following surgery foresophageal cancer, is to stimulate the patient’s self-healing capacity. This involves the use of therapeuticinterventions to help elicit in the patient those intrin-sic recuperative resources that are mediated by themind.

The mind (what we believe, expect, cherish) playsan important role in healing, not only by promotingsymptom management and psychosocial adjustmentbut also by modulating immune defense.1-3 Althoughthe full clinical implications of psychoneuroimmunol-ogy are not yet known, a defining feature of psycho-biological approaches to cancer therapy is mind-bodycommunication—the idea that psychological statesaffect the immune system and that the immune sys-tem, in turn, affects brain, behavior, and emotionalstates. At the same time, the spiritual growth of thepatient, the conscious search for wholeness in the faceof illness, is a central focus in integrative cancer care.4,5

Together, therapist and patient create a collabora-tive context that supports the psychological and spiri-tual dimensions of healing work. The therapist pro-vides a safe, holding environment, augmenting, when-ever possible, the interventions of other providers—oncologists, nutritionist, and so on—for synergisticeffects. The patient, in turn, receives guidance andsupport in cultivating her own healing resources. Forthe present patient, we focus on the following compo-nents of treatment: self-inquiry, psychophysiologicalself-regulation, symbolic healing, and spirituality. Self-inquiry enlists the patient’s participation in treatment,a precondition for the psychophysiological learningthat can be applied to managing symptoms associatedwith esophageal cancer. Symbolic healing is a deeperform of inquiry, in which the patient uses personallyrelevant images or metaphors to alleviate distress andstrengthen cell defense. The symbol, a vehicle for

emotional and physical transformation, serves, inturn, as a natural springboard for spiritual pursuit.

Self-InquirySelf-inquiry is a therapeutic process whereby the can-cer patient articulates beliefs and fears about self,body, health, and disease in order to develop insightsand approaches to healing. Equally important in ini-tial assessment as in later treatment, self-inquiryheightens the patient’s awareness of availablepsychosocial resources as well as potential barriers im-peding recovery. It may take the form of a personal in-ventory in which the patient identifies her strengths(e.g., belief in God, a supportive, loving husband) andvulnerabilities (e.g., anxiety, difficulty adjusting to re-tirement). It may take the form of a timeline, or someother biographical methodology, to explore possibleconnections between life events and changes in dis-ease status. Self-inquiry equips the patient to plan acourse of action and commit to self-care. It also pro-vides other health providers with valuable informationto establish rapport, potentiate their own treatments,and reinforce adherence.

An important objective of therapeutic self-inquiryis assessment of the patient’s stress resiliency, which isknown to be related to immune functioning. We know,for example, that she is a chronic worrier, with a pasthistory of sedative and tranquilizer use, currently on aselective serotonin reuptake inhibitor medication: awoman who cares about pleasing others and fretsabout her grown children but is perhaps diffidentabout discussing her own condition. There is evidencethat stress resiliency is associated with emotional dis-closure—how individuals express and handle emo-tions. To better manage her anxiety, the patient learnsto identify links between thoughts and symptoms, toreplace passive worrying with active problem solving.She may also address explicit concerns (includingtrauma or negative emotions associated with past can-cer surgery/treatment) using symbolic drawing orjournaling, such as Pennebaker et al.’s6 narrative dis-closure method, which has been found to enhanceimmunocompetence. To further diminish fearful-ness, we help the patient cultivate an attitude of opti-mism (fighting spirit)7 through a combination of ego-strengthening work and positive affirmations. Addi-tional opportunities for emotional release can befound in a cancer peer support group akin to thosedeveloped by Spiegel and Fawzy.

Focusing is a psychological technique often usedwith cancer patients to identify anxieties and otherfeelings that may be rooted in body experience.8,9 Byinstructing the patient how to “clear a space” andevoke a “felt sense,” this method of inquiry offers abody-based self-exploration to reveal unconscious



barriers to healing—fears about body integrity or pos-sible disease progression. Focusing may help elicitwhether the patient’s worrying about her adult chil-dren reflects a legitimate concern about their well-being or displaced anxiety about her own health sta-tus. It can work well with energy-based and somatictherapies. Used in conjunction with qi gong or yoga,for example, focusing can enhance sensory awareness,decrease sympathetic arousal, and facilitate innatehealing while providing the patient with a psychologi-cal framework for integrating and consolidating physi-cal, emotional, and energetic changes.

Psychophysiological Self-RegulationWe use voluntary self-regulation to help the patientgain control and mastery over chronic stress, distress-ing emotions, and physiological imbalance. The pa-tient faces debilitating medical challenges, dysphagia,and poor appetite, which put her at risk for dehydra-tion, malnutrition, and further weight loss. Usingbreathing, progressive muscle relaxation, hypnosis/imagery techniques, and biofeedback training,psychophysiological self-regulation can result in symp-tom management, decreased stress reactivity, im-proved self-efficacy, and a sense of mental calm.

Surface electrode electromyograph biofeedback fordysphagia. Painful swallowing can engender a frighten-ing sense of helplessness, an emotional state associ-ated with elevated glucocorticoid levels and immuno-suppression. Although biofeedback has been usedextensively to treat gastrointestinal motility, there is lit-tle controlled research on its applicability fordysphagia. A biofeedback therapist skilled in rehabili-tative work could determine whether surface elec-trode electromyograph biofeedback can help thepatient to relax the smooth muscles of the esophagusto facilitate swallowing. In consultation with thepatient’s oncologist, the biofeedback therapist couldfurther investigate whether the Mendelsohn maneu-ver, a treatment strategy to facilitate cricopharyngealsphincter opening, is useful for this patient. The ratio-nale for offering biofeedback-assisted therapy fordysphagia is to help the patient learn how to transforma formerly automatic physiological function (swallow-ing) into a volitionally directed, altered motorresponse,10 thereby alleviating discomfort and distressand promoting a sense of personal competence andcontrol.

Hypnotic suggestion for appetite. The patient’s disinter-est in food since surgery may be a by-product ofdysphagia and/or a residual effect of nausea experi-enced during her chemotherapy treatment. Hypnosishas been used to combat appetite problems and

nausea in cancer patients.11 The therapist workscollaboratively with a holistic nutritionist, using tranceinduction, embedded suggestions, and ideomotor sig-naling to stimulate the patient’s appetite and interestin noncarcinogenic foods. This can promote weightgain and adherence to a new, healthier diet regimen.Indirect suggestions (“healthy appetite” or “zest forlife”) are more effective than direct injunctions to eatmore, which she may resist. Age regression tech-niques, which bring the patient back to a premorbidperiod not associated with dysphagia, compromisedappetite, or nausea, can be another useful hypno-therapeutic intervention.

Breathwork for anxiety and relaxation. Good breathinghabits—particularly diaphragmatic breathing—regulate the physiological correlates of anxiety andpromote sympathetic-parasympathetic balance. It isimportant to assess the patient’s respiratory function-ing because problematic breathing may be related tothe significant (50%) decrease in exercise. Acapnometer reading of end-tidal CO2 levels (the con-centration of carbon dioxide in expired air) can deter-mine whether efficient gas exchange in the lung cellsis taking place (normal CO2 is 40 mm Hg).12 Addi-tionally, a breathing practice is an effective way toteach the patient relaxation skills. Simple exercises,using extended exhalation, are preferable. Somepractices, such as nadi shodhanam, alternate left-rightnostril breathing, are especially helpful in slowingdown the breath and helping calm and center themind.13

Self-regulation for overall relaxation. Biofeedback iseffective for decreasing autonomic arousal and pro-moting general relaxation for the cancer patient.Norris’s14 protocol emphasizes (1) skin temperaturetraining to warm the hands or feet, (2) visualizationsto increase blood circulation to injured or painfulparts of the body, and (3) additional training to regu-late muscle tension, heart rate response, andelectrodermal activity. Self-control of the stressresponse helps manage limbic system arousal anddecrease a number of mutagenic effects, such asleukocytopenia, impaired natural killer cell activity,and decreased phagocytosis,13 associated with a diag-nosis of cancer. Electroencephalographic alpha-thetatraining, although not yet studied with cancerpatients, may reduce anxiety and promote mental qui-etness. Producing a tranquil emotional state can allowthe immune system to function at an optimal level.

Psychophysiological self-control appears to increasethe patient’s confidence in her ability to send effectivehealing instructions (visualizations) to the body.13 Suc-cess in using visualizations during biofeedback



training to intentionally control biological processescan reinforce a belief that visualizations also influenceimmune system activity, even though these responsescannot be directly monitored.13 Future biofeedbackapplications using hematological analysis may evenshow volitional control over antibody or other immu-nological responses.1

Symbolic HealingThe use of image and symbol for therapeutic purposesis intrinsic to psychotherapeutic and healing tradi-tions. Imagery and hypnosis has been shown to influ-ence cellular immunity in healthy subjects14 andcancer patients.15 This may be accomplished by induc-ing a state of deep relaxation during which instruc-tions to the body are received by the subcortical partsof the brain, including the limbic hypothalamic-pitu-itary axis.3 Ericksonian hypnosis, in particular, usestrance induction for therapeutic healing, based on theidea that trance, in tandem with indirect suggestionsand embedded commands, invokes a special mentalstate, which promotes the psychological resynthesis ofexperience.3

In work with the cancer patient, we use, invoke, andelicit images to illuminate and advance therapy work.Our patient knows, in medical terms, that the functionof the esophagus is to carry food and liquids fromthroat to stomach, and that disease has impaired thisfunction. But what does her difficulty taking in nutri-ents (food) signify in a symbolic sense? The notion of ablocked passage (damaged esophagus) impliesobstruction on multiple levels. It can suggest beingimpeded in taking care of (feeding) herself in a mate-rial or physical sense. But it can also mean beingthwarted in the realization of a larger aspiration(unable to nourish herself in spiritual ways). Oneimage that comes to mind is “tied in a knot” or “a kinkin a garden hose.” An image becomes symbolic when itis invested with personal meaning, when the act ofloosening the knot or smoothing out the kinkbecomes a guiding metaphor for releasing a feeling orfor allowing a freer way of life. The power of the sym-bol is that it can encompass complex ideas in a single,emotionally laden representation, and thus provideaccess to a deeper understanding of self and healing.

Typically, hypnosis or imagery work with cancerpatients involves visualizing weak, chaotic, disorga-nized cancer cells being attacked and destroyed in aneffort to enhance immune functioning. For thispatient, a caretaker by nature, aggressive (shark = nat-ural killer cell) types of imagery may be ego-dystonic.She may prefer imagery that is based on the idea ofabsorption (encompassing nonself within self) ratherthan attack:

Perhaps you can see yourself as very small, as small as awater drop . . . you can slip into the mouth and downthe throat . . . a strong white cell that encompasses allof your power, will, and determination . . . a self-cell,now moving slowly and powerfully down into yourblood stream . . . now swimming with clear purpose,now surrounding . . . now dissolving . . . any foreignbody that you encounter.

Of course, it is preferable when the patient sponta-neously develops her own healing images. Standardguided-imagery tapes are helpful but ultimately lessmeaningful than the patient’s own symbology, whichevolves out of sustained self-exploratory work. A self-hypnosis tape, with paced breathing, progressive mus-cle relaxation, and posthypnotic suggestions tailoredto the patient’s own needs and interests can be madeduring a mind-body therapy session and used effec-tively in daily practice. Although the objective is toenvision cellular change, the patient is cautioned thatthe mind’s ability to exert direct physical effects, toprevent tumor growth, is still only a theoreticalpossibility.

SpiritualityFinally, what role can the mind-body therapist play inthis patient’s spiritual life? Spiritual practice is a pri-vate and personal undertaking, and yet integral to in-tegrative cancer therapy. Our patient believes in God,prays, and explores qi gong, a spiritually based prac-tice. And yet, to support her spiritual effort fully, thetherapist must know how, and to what degree, the pa-tient envisions spiritual involvement, both inside andoutside of the psychotherapeutic setting.

The central questions for our patient are 2-fold: (1)What gives my life meaning and purpose? and (2) Howcan I deepen my spiritual practice?

Knowing one’s purpose is an antidote to the suffer-ing associated with serious illness. In his work with can-cer patients, LeShan4 has articulated the importanceof the life fully lived—to “sing one’s song” as a celebra-tion of the patient’s individuality. The therapist helpsspark the patient’s creative imagination, ignites hercuriosity, and spurs her to find strength in her human-ness. For the patient, this may be a time of quiet self-reflection or spontaneous activity, an opportunity tostrengthen friendships, or a chance to pursue forgot-ten passions.

Meditation is one way to help clarify purpose and,at the same time, deepen spiritual work. Our patient isdrawn to contemplation—she has chosen a space inwhich to meditate 20 minutes a day. Awareness ofbreath, which fosters mental tranquility, is a powerfulform of meditation,13 particularly beneficial for apatient prone to worry. The therapist, in helping



meditation become a more integral part of thepatient’s life, can function as guide, witness, or partnerin mutual inquiry, depending on what is needed. Theact of synchronous breathing when practiced in thetherapy session, for example, can bring therapist andpatient into energetic balance and reinforce healingfactors intrinsic to the therapeutic relationship.

Because her faith is rooted in a theistic tradition,the patient might investigate bhakti, a heart-centeredmeditation that calls for compassion and surrender todivine power,17 rather than a practice emphasizingnonduality and detachment. Although meditation isonly one spiritual path, it can support the patient’swish to live her life authentically—by relinquishingfears, granting forgiveness, and expressing love. Dailypractice, in whatever form, is the essence of spiritualdevotion. It enables both patient and therapist to ask,“Do I conduct myself in a way that reflects and honorsmy values?”

Those of us engaged in mind-body-spirit work withcancer patients have yet to discover how best to usemind and consciousness for therapeutic ends. Weknow that belief plays a role in health promotion, weknow that personality, coping style, and emotionalstates are linked to cancer risk, we know that the brainand immune system are in constant mutual dialogue,and yet we lack a language of mental healing shared byall health providers—physicians and nonphysiciansalike. But our success in moving beyond authoritativemedicine to humane, spiritually informed, patient-centered care is contingent largely on creating a lan-guage of consciousness that raises the status of belief,faith, hope, and intentionality in the medicalenterprise.

A spiritually informed therapy invites patient andtherapist to consider possibilities larger than what isknown as mind or self. In psychosynthesis, a humanis-tic psychology, a distinction is made between the “I,”the individual person, and the transpersonal “Self,”which both encompasses and extends beyond thehuman essence or core of that person. The cancerpatient seeking to comprehend the mutiny of cells inher body, the struggle of self versus nonself that char-acterizes neoplastic disease, may derive inspirationand hope in the idea of a transcendent reality that sur-passes personal self or material body. Ultimately, thetranspersonal perspective is a cocreation of patientand therapist. Spiritual seeking is the patient’s desireto find wholeness beyond the self, but the therapistmust be engaged in her own inner growth and devel-opment to fully support and guide the search.

References1. Pelletier KR, Herzing D. Psychoneuroimmunology: toward a

mindbody model. Advances: J Mind-Body Med. 1988;5(1):27-56.

2. Locke S, Colligan D. The Healer Within: The New Science of Mind-Body Medicine. New York, NY: EP Dutton; 1986.

3. Rossi E. The Psychobiology of Mind-Body Healing. New York, NY:WW Norton; 1993.

4. LeShan L. Cancer as a Turning Point. New York, NY: PenguinPress; 1994.

5. Cunningham AJ. Healing through the mind: extending ourtheories, research, and clinical practice. Advances: J Mind-BodyHealth. 2001;17:214-227.

6. Pennebaker JW, Kiecolt-Glaser J, Glaser R. Disclosure of trau-mas and immune function: health implications for psychother-apy. J Consult Clin Psychol. 1988;56:239-245.

7. Greer S. Psychological response to cancer and survival. PsycholMed. 1991;21:43-49.

8. Fawzy I. The benefits of a short-term group intervention forcancer patients. Advance. 1994;10(2):17-9.

9. Katonah DG. Imagery, body and space in focusing. In: SheikhAA, ed. Imagination and Healing. New York, NY: Baywood; 1984.

10. Grendlin ET, Grindler D, McGuire. Imagery body and space infocusing: Clearing a space with someone who has cancer.Focusing-Oriented Psychotherapy New York, NY: Guilford Press;1996; 276-86.

11. Huckabee ML. Oral pharyngeal dysphagia: application of EMGbiofeedback in the treatment of oral pharyngeal dysphagia.Presented at: Annual Meeting of the Biofeedback Foundationof Europe; 1997; Davos, Switzerland.

12. Levitan AA. Oncology. In: Temes R, ed. Medical Hypnosis. Phila-delphia, PA: Churchill Livingstone; 1999:107-111.

13. Fried R. The Psychology and Psychophysiology of Breathing. NewYork, NY: Plenum Press; 1993.

14. Rama S, Ballentine R, Hymes A. Science of Breath. Honesdale, PA:Himalayan Institute Press; 1998.

15. Norris P. Current conceptual trends in biofeedback and self-regulation. In: Sheikh AA, Sheikh KS, eds. Eastern and WesternApproaches to Healing. New York, NY: John Wiley & Sons; 1989.

16. Schneider J, Smith W, Witcher S. The relationship of mentalimagery to white blood cells (neutrophil) function in normalsubjects. Paper presented at the 36th Annual Scientific Meet-ing of the International Society for Clinical and ExperimentalHypnosis, San Antonio, TX. Oct 25, 1984.

17. Hall H, Mumma G, Longo S, Dixon R. Voluntary immuno-modulation: a preliminary study. Int J Clin Hypn. 1992;25(2-3):92-103.

18. Cortright B. Psychotherapy and Spirit. Albany, NY: SUNY Press;1997.

Suzanne Little, PhDBeth Israel Center for Health and Healing245 Fifth Avenue at 28th StreetNew York, NY 10016E-mail: [email protected]

Editorial Notes

Radiation OncologyDr. Terrence J. Bugno is a radiation oncologist whom Ihave known for several years; he is notable among doc-tors in this specialty for his continuing interest in inte-grative cancer medicine. His contribution provides asolid radiation oncology perspective. One role of theradiation oncologist in hospital tumor boards is to dis-cuss the staging of the presented case, which Bugno



does admirably, in addition to his full discussion of thetreatment aspects of the case. Of particular note in hisdiscussion are the therapeutic options includingintraoperative radiotherapy; intraluminal therapy, al-though appropriately not recommended by Bugno inthe current case, is a potential consideration in othercases of esophageal cancer. Bugno also points out thechronic inflammatory state involved in this cancer.The mention of amifostine as a radioprotectant pointsout a significant dimension of integrative care beyondthe use of complementary medicine techniques: inte-grative radiotherapy and chemotherapy treatmentsmay aggressively use conventional drugs to managetreatment side effects, as well as natural techniques orsubstances.

Medical Oncology 1Dr. David M. Gustin’s contribution highlights issues ofpathology and diagnosis in esophageal cancer. Hissummary of the initial diagnostic procedures foresophageal cancer is particularly useful, especially forpractitioners not familiar with this process. Gustin’sconcern for the nutritional status of the patient re-flects the real importance given to nutrition in thiscancer by conventional medicine. He also points outthe puzzling recent decrease in incidence of mid-esophageal squamous cell cancers and increase in in-cidence of adenocarcinomas occurring at thegastroesophageal junction, apparently associated withthe increasing incidence of Barrett’s esophagus.Barrett’s esophagus may be associated with the preva-lence of gastroesophageal reflux disease. Recent dis-cussions of the chemoprevention of esophagealadenocarcinoma have raised the possibility of usingcyclooxygenase inhibitors along with proton pump in-hibitors in patients with Barrett’s esophagus.1 It wouldbe interesting to explore the use of the dietary andherbal anti-inflammatory strategies mentioned in thereview by Jeanne M. Wallace (this issue)2 as a nondrugmeans to inhibit cyclooxygenase for Barrett’s patients.

Medical Oncology 2Dr. Deva Nathan, who has worked as the medicaloncologist with my integrative cancer clinic for severalyears, highlights the reasons this patient may be quiteeager to avoid recurrence. She has received a treat-ment regimen, neoadjuvant chemoradiation therapywith subsequent surgery, that is well grounded in its ef-ficacy. Randomized and nonrandomized trials indi-cate a survival time 3 to 4 times as long for patientstreated with the combined treatment as those treatedwith surgery alone.3,4 Prospects for chemotherapy fol-lowing a recurrence, however, appear to have limitedpossibilities for control of the disease. We plan to notein these comments, from time to time, possible agents

for use in relieving side effects of chemotherapy drugs.Etoposide, a chemotherapy drug in the ELF (etoposide,leucovorin, and 5-FU) regimen mentioned by Dr. Na-than, is associated with a notably elevated risk for sec-ondary acute myelogenous leukemia. This is mediatedby formation of an etoposide phenoxyl radical, cata-lyzed by myeloperoxidase, an enzyme expressed inhigh amounts in bone marrow progenitor cells. Vita-min C reduces production of this radical, as does a vita-min E derivative. Experimentation is under way todetermine whether there is a therapeutic window thatwill allow vitamin C to be used with etoposide at a dosethat reduces leukemia risk but preserves antitumor ef-fect.5

Naturopathic MedicineDr. Judy A. Fulop’s discussion of this case reveals theclose clinical analysis and reliance on systematic assess-ment typical of well-trained practitioners of naturo-pathic medicine—and sometimes overlooked in othermedical approaches. Interestingly, naturopathic prac-titioners are beginning to practice alongside conven-tional physicians in some integrative cancer clinics.Fulop demonstrates a clear sensitivity to the nutri-tional aspects of this patient’s condition, as well as aneffort to ground practice in scientific evidence, andpoints out the areas that have less evidence. Some ofthe basic naturopathic recommendations in this con-tribution are potentially quite applicable to the clini-cal care of this case and are notable for forming aframework from which patient and doctor can selectappropriate interventions to structure a program.

Nutritionist/Dietitian AnalysisMaryBeth Augustine has also consciously providedmanagement options for patient and nutritionist touse in planning a nutritional intervention tailoredaround the patient’s needs and tastes. Her presenta-tion is also quite notable for its effort to use an evi-dence-based approach. There may be some concernin the use of vitamin C plus supplemental iron in a pa-tient with evidence of high levels of oxidative damage,due to the potential for triggering the Fenton reac-tion; careful assessment of the patient’s anemia is thuscalled for. This presentation seems particularly sensi-tive to adapting to the clinical realities of what the pa-tient is willing or able to do.

Traditional Chinese Medicine AnalysisDr. Charles H. Lo received an MD training in conven-tional Western medicine in the United States, andthen went on to receive full training in traditionalmedicine in China. His analysis of the case from thetraditional Chinese medicine (TCM) perspective issolid and thorough, although limited due to his inabil-



ity to conduct a diagnostic workup using assessmentstypical of TCM, which include modes of taking thepulse different from those of Western medicine andevaluation of the appearance of the tongue. We hopeto be able to include this basic clinical data in some ofthe tumor boards appearing in later issues. Readerswho are not familiar with the concepts of the bodily or-gans such as the Spleen in TCM should note that theseconcepts do not exactly correspond to the physical or-gans with the same names in the West; they are actuallymore functional concepts.

Western Herbal-Nutritional AnalysisDonald R. Yance Jr. is an herbalist whose clinical rootsare in the eclectic and physiomedical traditions ofmedicine, both schools of thought that began in theUnited States in the 19th century and concentrated onherbal remedies and other natural interventions. Weappreciate the large set of possible interventions for anutritionally compromised patient. It is important topoint out that in some situations there may be clinicalconcerns about the use of very large fluid volumes as isapparently recommended. Some have observed thatpatients with suppressed appetites may feel too full af-ter drinking large amounts of water or juices and beunable to take in sufficient calories to achieve or main-tain a healthy weight. Use of the herbal tonic recom-mended by Yance should be undertaken with thesupervision of an experienced herbal practitionerwho can manage the tailoring of the formula to a pa-tient’s condition, as well as guide the appropriate useof herbs with possibilities for toxicity, such as thuja.The wide variety of herbs used in the formula, many ofwhich have at least some mechanistic or clinical trialbackground, indicates the depth of the potential use-fulness latent in herbal medicines.

Ortho-Bionomy AnalysisBarry Krost, an ortho-bionomy instructor in the Chi-cago area, presents the approach of this relativelyyoung discipline in the field of body work. Ortho-bionomy, along with TCM, suffers from the inability toassess the patient properly through a written case pre-sentation: it relies heavily on actual manipulation ofthe body to diagnose and address painful areas. I havehad the opportunity to work with different individualstrained in ortho-bionomy in our integrative oncologyclinic and have found the work to be of considerablevalue to cancer patients, particularly those sufferingfrom disease-related pain.

Yoga AnalysisSome yoga practitioners approach the field from aphysically based perspective only, using yoga asanas

and breathing techniques as a source of flexibility andstress management exercises. Some practitioners ad-ditionally see yoga as a spiritual discipline; NischalaJoy Devi is obviously one of the latter. She addressesthe heart of the patient as well as recommending spe-cific yoga postures. Yoga practitioners have a variety ofideas about the source of disease, and not all wouldagree that every disease begins on a spiritual level, aconcept that may be disturbing to many patients.Frawley,6 for instance, points out that according toayurvedic thought (ayurveda is the traditional medi-cine system of India, of which yoga is an importantpart), disease can have both physical causes and psy-chospiritual causes.

Spiritual counseling is an important means of cop-ing with cancer for many patients, and the perspec-tives of yoga may be of value to them. The advice in thiscontribution on the importance of flexibility andaccepting the changing nature of life, versus thepatient’s expressed perfectionism, seems particularlyapt and is an example of useful insights gained fromthis type of counseling. Spiritual counselors must alsobe aware of a patient’s religious faith, if one is speci-fied; some Christian denominations, for instance, mayfind that a recommendation to say the same prayerrepeatedly is not in accord with their doctrinal posi-tions. We plan to continue to present the insights of avariety of spiritual and pastoral counselors in the Inte-grative Tumor Board. Although it is not an evidence-based discipline, spiritual counseling addresses needsof patients on a level that medical management mayoverlook or find difficult to address—but that mattersdeeply to patients and their families as they face life-threatening diseases.

Mind-Body Therapy AnalysisDr. Suzanne Little presents a thorough and well-thought-out multidimensional approach to assistingthis patient in managing her difficult health and lifeproblems, even without being able to interview her inmore detail. The interventions she describes are pa-tient centered rather than theory centered and are,appropriately, not wedded to a single methodology.Although much discussion in psycho-oncology cen-ters on mental influence on the immune system, itshould be pointed out that the actual ability of im-mune cells to affect the progression of many of themost common cancers is still in question. Little’s rec-ommendations, however, in the area of psychophysio-logical self-regulation are creative and well targeted.Her analysis of the symbolic implications of the dam-aged esophagus is very interesting and potentially use-ful for the patient, and her suggestions for ways todiscuss spiritual issues are insightful and tactful.



References1. Fennerty MB, Triadafilopoulos G. Barrett’s-related esophageal

adenocarcinoma: is chemoprevention a potential option? AmJ Gastroenterol. 2001;96:2302-2305.

2. Wallace JM. Nutritional and botanical modulation of theinflammatory cascade—eicosanoids, cyclooxygenases, andlipoxygenases—as an adjunct in cancer therapy. Integrative Can-cer Ther. 2002;1:7-37.

3. Bedard EL, Inculet RI, Malthaner RA, Brecevic E, Vincent M,Dar R. The role of surgery and postoperative chemoradiationtherapy in patients with lymph node positive esophageal carci-noma. Cancer. 2001;91:2423-2430.

4. Heitmiller RF, Foastiere AA, Kleinberg L, Zahurak M. Neo-adjuvant chemoradiation followed by surgery for respectableesophageal cancer. Recent Results Cancer Res. 2000;155:97-104.

5. Kagan VE, Yalowich JC, Borisenko GG, et al. Mechanism-based chemopreventive strategies against etoposide-inducedacute myeloid leukemia: free radical/antioxidant approach.Mol Pharmacol. 1999;56:494-506.

6. Frawley D. Ayurvedic Healing. Salt Lake City, UT: Passage Press;1989.

Keith I. Block, MDBlock Center for Integrative Cancer Care1800 Sherman Avenue, Suite 515Evanston, IL 60201E-mail: [email protected]



CunninghamGroup Psychological Therapy

Group Psychological Therapy:An IntegralPart of Care for Cancer Patients

Alastair J. Cunningham, PhD, C Psych

Adjuvant psychological therapy can help cancer patients in 2main ways. It has, first, a well-documented capacity to allevi-ate distress and thus improve quality of life. However, if thiskind of assistance is to be made available to the majority ofcancer patients, a number of problems need to be solved: ad-ministrators need to become aware of the evidence for effi-cacy of psychosocial care for cancer patients; the treatmentneeds to be advocated in a manner that would benefit pa-tients rather than being left to the patient to request it; and,for reasons of economy, large, classroom-style, psycho-educational classes may need to be offered in place of smallsupport groups. Furthermore, to allow for individual differ-ences in preferences and abilities, a variety of modes of helpshould ideally be made available. The author discusses howthe provision of coping strategies can be organized in a pro-gressive way to encourage development of greater copingskills. An example of such a stepwise program is given, all as-pects of which have been researched and made available inmanuals over some 20 years. The possibility of prolonginglife with this kind of therapy is still controversial. While ran-domized controlled trials have become the method of choiceto investigate this question, reasons are given for stronglypreferring more exploratory modes of research at the pres-ent early stage of knowledge. The central task is seen as un-derstanding the states of mind that promote healing orlonger life, something that cross-sectional, psychometric re-search has not been able to accomplish. As an alternative,prospective, longitudinal designs are needed, with detailedinterview-style analyses of patients’ mental attributes. An ex-ample is given of one such study. Furthermore, it is sug-gested that we consider much more intensive therapies ofthis kind, since the impact of mind on body will logically berelated to the extent of psychological change experienced.

Psychological therapy for cancer patients has the poten-tial to help them in 2 main ways. The first is relativelyobvious and no longer questioned: it can improvequality of life, usually through relief of emotional dis-tress. The second is controversial at present: possibleslowing of progression of disease in some cases. Thepurpose of this article is to discuss how these potentialsmay be realized. For the first, because efficacy is not indoubt, I want to offer some ideas on how the therapyneeds to be presented if it is to be integrated into rou-tine care, in order to reach a majority of cancer patients.

For the second, the discussion will focus on researchissues: how to gain information about this most intrigu-ing possibility and how to increase the likelihood thatpsychological therapy may prolong life for at leastsome patients.

Adjuvant Psychological Therapyto Improve Quality of Life

IndicationsThe term “adjuvant” is adopted from Greer et al.1; itemphasizes that psychological help can be considereda regular adjunct to medical care in the same way as,for example, adjuvant chemotherapy. “Psychologicaltherapy” is preferred to “psychotherapy,” since the lat-ter has a more restricted meaning, and I intend hereto include any kind of treatment that acts through themind of the patient, including emotional support,teaching coping strategies, fostering stronger spiritualconnection, and psychotherapy proper that aims atfundamental change through exploration of defensesand retrieval of unconscious affect and ideas.

While psychoactive medication and traditional modesof therapy (usually individual counseling) are neededfor some psychiatrically impaired patients, the greatmajority of people with cancer are psychologically“normal” but suffer from a severe stressor, the threatthat their lives may end prematurely. Adjuvant psycho-logical therapy (APT) tends, at present, to be suppliedonly to individuals who are obviously distressed, or tothose who specifically request it. I have argued elsewhere2

that a more appropriate criterion would be the onegenerally used in medicine: APT would be advocatedwhen it appears likely, to the attending professional,that such an intervention would benefit the patient.Instead of bypassing psychosocial help for those who

Group Psychological Therapy


AJC is in the Department of Epidemiology, Statistics and Behav-ioral Science, Ontario Cancer Institute/Princess Margaret Hospital,Toronto, Ontario, Canada.

Correspondence: Alastair J. Cunningham, Department of Epide-miology, Statistics and Behavioral Science, Ontario Cancer Insti-tute/Princess Margaret Hospital, 610 University Avenue, Toronto,Ontario, Canada M5G-2M9. E-mail: [email protected].

are “coping well” or have “adequate resources,” thequestion would become: “Could this patient be helped(to cope even better) with some form of psychologicaltherapy?” In practice, adopting such a philosophywould probably mean that most individuals wouldreceive this kind of help as a routine part of theirtreatment.

If the value of psychological help is accepted, thelogical next questions concern the kind of help andhow best to provide it. As will be seen, economics con-strain the choices.

EfficacyThere is abundant evidence that brief psychologicalinterventions can diminish distress (improve qualityof life) for most cancer patients.3-9 Thus, the fact thatsuch interventions are not routinely offered to mostpatients in many settings indicates that their effects onquality of life are not yet valued by policy makers. Be-cause most patients do not seek psychosocial care oftheir own volition, and may even view it unfavorably atfirst,10 it needs to evolve from being an optional extrato becoming an integral part of the management ofcancer. In practical terms, this means that unequivocaladvocacy by physicians is needed. Stronger evidencefor effects on length of life (discussed below) seemsmore likely to persuade physicians of the value of psy-chological help than further data on quality of life.

The predominant form of help offered to cancerpatients, in either health care facilities or communitycenters, is group support—discussing problems andexpression of emotion.11 Useful though this is, there isevidence that people benefit more if coping skills aretaught in addition to providing them with emotionalsupport.3,7,10,12-15 Thus, logic would suggest that this kindof psychoeducation be adopted in addition to sup-port. As with making use of psychosocial interventionsin the first place, the learning of new skills may meetresistance, since it requires more effort, on the part ofboth the group leaders and the patients themselves.Again, however, a principle guiding general medicaltreatment seems to apply; that efficacy, rather thanease of application, should be the main determinantof treatment choice.

EconomyIf APT were to be supplied to all patients likely to bene-fit from it, it would involve thousands of individualsper year in any large cancer center. Thus, group thera-pies are much more feasible than individual counsel-ing, and present indications are that they provide amore effective format, although evidence is sparse.16-18

The great advantage of a group setting is that peoplewith similar problems can support, inform, and in-spire one another.

A moment’s reflection, however, shows that theproblem of reaching large numbers is unlikely to besolved by reliance on the traditional small-group for-mat. In a setting treating 10,000 new patients per year,if one half were referred to an APT involving, say, 8weekly sessions with groups of 10 patients, 500 suchgroups per year would be needed. Assuming each hada single professional leader, and that each leader con-ducted 10 groups per year, a staff of 50 would berequired. Parallel groups for family members coulddouble this number. It is not inconceivable that thiscould be done, but until the psychosocial dimensionof care becomes much more highly valued than it is atpresent, sufficient counseling staff to treat patients insmall groups are unlikely to be hired.

One solution is to use large, classroom-style formatsin which an almost unlimited number of people canbe exposed to some discussion of the problems ofbeing, or supporting, a cancer patient, and where self-regulation strategies such as relaxation or mentalimaging can be taught and practiced. With a psycho-educational approach in a classroom or auditorium, asingle therapist/teacher can readily minister to 100 ormore patients at a time. The disadvantage is that, withsuch numbers, few of those participating get a chanceto express their feelings. To offset this, the classroomsetting allows some people, who might not come to asmall group, to preserve their anonymity while learn-ing useful skills. We have used such a format for manyyears and have found, in nonrandomized compari-sons, that the relief of dysphoric mood from 4 class-room sessions compares well with that obtained in 6 to7 sessions in small groups.19 The Internet offersanother possible way of reaching large numberscheaply (through public chat groups or videocon-ferencing). Telephone counseling can be used to con-tact patients in distant locations, although even con-ference calling would likely involve only a few peopleat any one time. All of these modes need much moreresearch.

AccessibilityTime is short and levels of stress are high for many can-cer patients; it is extremely frustrating and potentiallydamaging to those wishing to attend an APT to be puton a waiting list for months. Thus, it becomes impor-tant to design a program in which new classes orgroups begin frequently and regularly. This in turnmeans that interventions need to be brief, somethingthat economics also dictates. Long-term therapies areunlikely to be made available to more than a tiny pro-portion of patients.

To increase the accessibility of APT to patients, ATPneeds to be presented in a nonthreatening way (e.g.,“stress management” rather than “group therapy”).

Cunningham


The learning of coping skills can be assisted by provid-ing audiotapes or other technical aids and by fosteringa group culture in which home practice is the norm.Methods used to promote adherence in behavioralmedicine generally can be applied in this specificfield; for example, we have found that motivation isimproved and efficacy increased when patients writeabout their self-help practices at home and receivefeedback on this work. To assume that because peopleare seriously ill or have distressing symptoms theyshould not be expected to help themselves is todisempower them.

Helping Patients Makethe Most of Their AbilitiesThe process of assisting psychologically normal peo-ple to help themselves cope with a serious stressorsuch as cancer differs from psychotherapy for the psy-chologically impaired. The assumption here is thatthe individual has freedom to choose strategies and toact toward adapting more effectively. The therapist’stask becomes mainly to educate and motivate. A vari-ety of techniques needs to be offered to match the in-terests and abilities of different people. In the absenceof empirical data on the relative value of differenttechniques, the array offered will depend on the ex-pertise and interest of the therapists and might in-clude supportive discussion and ventilation as a basicor “bedrock” technique; relaxation training; medita-tion; thought monitoring and changing (i.e., cogni-tive behavioral methods); goal definition; mental imag-ing and drawing; consulting an “inner healer”;journaling, writing, and presenting a life story; read-ing and discussing a variety of spiritual traditions;working on blocks to spiritual connection, such asjudgment, resentment, and guilt; prayer; and bodyawareness techniques such as yoga, tai chi, and qigong. All of these techniques have the potential tohelp patients; we have used most of them for years our-selves, as have many other therapists, but few if anyform part of regular conventional care of most cancerpatients. The lack of interest in and research supportfor these adjunctive mind-body methods in the treat-ment of serious chronic physical illness will come to beseen, I believe, as a serious failure in modern medi-cine.

In addition to providing a variety of approaches,there is a second and very important principle to beobserved in designing a program of this kind for can-cer patients. The self-help methods taught need to beorganized in a way that promotes progressive develop-ment of the individual toward greater understandingand control, that is, from simpler to more sophisti-cated modes. Furthermore, because of the very obvi-ous and large differences in the interests and ability of

participants, it is extremely helpful, to both patientsand staff, to organize the teaching in “steps” or mod-ules. This allows participants to choose how much ofthe program they wish to attend, and to then leave theprogram without the awkwardness that accompaniesdropping out in the middle of a course. Table 1 showsone arrangement that we have used for many years;after an introductory course of 4 weekly sessions, thereare longer (8-session) courses leading to greater self-awareness (level II), to involvement in spiritual aspectsof healing (level III), and to longer-term (up to 1 year)therapy or to unstructured follow-up meetings forgraduates. The numbers decrease, quite sharply, asthis path is ascended (about half leave between levels Iand II, and again between II and III). While this way oforganizing therapy has not yet been widely used in psy-cho-oncology, “stepped” therapy is offered in othercontexts such as addiction treatment.20,21

Figure 1 illustrates the arrangement of differentself-control and self-awareness strategies as a pyramid,a figure chosen to represent the declining number ofpatients interested as a therapy becomes more demand-ing. Each level includes those below it, and as oneascends the hierarchy, more active participation isrequired by the patient. The evolutionary process ofascending this pyramid starts with support at the baseand progresses through training in active coping strat-egies. Some are relatively simple, such as relaxation,thought management, and using mental imaging forhealing. Others are more advanced or demanding



Table 1. Main Elements of the “Healing Journey” Program

CoreLevel I (4 sessions): Taking Control:

Coping With Cancer StressCommunicating feelingsDeep relaxationThought monitoring (introduction)Mental imagery (introduction)Setting goals (introduction)

Level II (8 sessions): Getting Connected: Skills for HealingFurther development of the skills of level IJournaling (self-examination)Consulting “inner wisdom”: the “inner healer” techniqueMeditationDropping resentments

Level III (8 sessions): Finding Meaning:Steps to Spiritual Healing

Understanding spiritualityIdentifying and dropping the obstacles to spiritual

connection (e.g., judgment, guilt, projection,self-importance)

Spiritual practices (e.g., meditation, prayer, chanting,reading, meeting with others)

Additional modulesOngoing (fortnightly) group for graduates of core programGroup psychotherapy (9 to 12 months) for metastatic

patientsLife story (8 sessions); (any time after level II)

(regular psychological reflection, keeping a psycholog-ical journal, consulting sources of inner or intuitive wis-dom with techniques such as the “inner healer,” prac-ticing “forgiveness,” meditation, and other aspects ofthe spiritual search). “Psychotherapy proper” involvesa further order of personal difficulty when conscien-tiously pursued, namely, confronting and changingone’s habitual patterns of thought and behavior. Dedi-cated spiritual practice, such as meditation for rela-tively long periods (hours) each day, may also belongin this category of difficulty. And finally, at the top ofthe hierarchy, we place an integrated use of psycho-therapeutic and traditional spiritual techniques. Asthe pyramid is ascended, the aim of the work may

gradually shift from better coping and quality of life toslowing progression of disease (or diminishing likeli-hood of recurrence). The ultimate outcome can be atransformation of sense of self and relationship to theworld, with a greater acceptance of one’s mortalitycombined with a hope that disease progression will bedelayed or arrested in order to allow the pursuit of anewly defined sense of purpose in life (generally cen-tered on helping others).

More detailed descriptions of this process weregiven by Cunningham and Edmonds.10 The elementsof therapy can be organized in different ways; forexample, meditative techniques may be given promi-nence from the start.22 However, it is to the advantage

Cunningham


Psychospiritual

(Integrated

and spiritual work).

Aim:Psychological Psychotherapy properand spiritual Spiritual practicedevelopment

Coping skills trainingAdvanced: meditation; inner

"wisdom"; reflection & journaling

Aim: Coping skills trainingCoping Basic: stress management; CBT

Aim: SupportComfort (Caring, expression of emotion, problem solving)

psychological

therapy

Figure 1 A pyramid of types of adjuvant psychological therapy, arranged in order of increasing demands made on the patient (CBT = cog-nitive behavioral therapy).

of patients if programs are structured so that theymove from the bottom of the pyramid toward the top,that is, from easier to more demanding techniques.There is also obviously a great deal of variation in theamount of assistance that different individuals requireto move up this path, and many, given the present gen-eral lack of understanding of mind-body techniques,have difficulty making much progress. The fact thatfew people currently make full use of sophisticatedprograms should not be taken to mean that it is notworth offering them; rather, it indicates that individu-als need to be supported and helped in any way thatallows them to benefit as much as is possible for them.For example, immersion courses lasting weeks or evenmonths could be instituted at retreat centers for thosewhose lives were under serious threat. This sounds for-eign in the context of cancer: it is relatively routine forthe treatment of addictions, however.

Outstanding Organizational,Clinical and Research IssuesThe evolution of APT to enhance quality of life dependson coordinated clinical and research efforts. Some ofthe areas needing study have been suggested already.To summarize, I view the most immediate issues asfollows:

• We need to determine why most patients do not usethese modes and why most professionals do not advo-cate them strongly (this requires detailed, interview-style analysis, not superficial surveys).

• Studies are needed on the efficacy, cost, and effective-ness in practice of various therapies. We need to knowwhat kind of therapy helps which patients, and in whatways. The relative efficacy of classroom-style teachingversus more traditional small-group modes and indi-vidual therapy needs further exploration. We needdata on the effects of meditation training for cancerpatients and at what stage of a program it is best ap-plied. Similar questions apply to spiritual instructiongenerally.

• Studies are also needed on the long-term effects of thevarious modes, in particular, the extent to which pa-tients continue to use coping strategies.

• Standards need to be set and technicalities discussedfor all APT modes. A good start has been made for sup-portive-expressive therapy by the Spiegel group.9,23

Adjuvant Psychological Therapyto Prolong Life or PreventRecurrence of CancerCan psychological interventions prolong life? Thispossibility, in one form or another, has been widelyaired in the popular press, although professionalstend to be skeptical. Quite apart from its great theoret-ical interest and potential practical significance, the

question is important because a clear positive answerwould influence medical professionals to take APTmuch more seriously.

Limitations of Clinical TrialsThere is a temptation to treat psychological therapylike a drug, and to believe that the appropriate re-search strategy is to test its efficacy by means of clinicaltrials. There are, at present, 10 published studies, mostof them randomized controlled trials (RCTs), of theimpact of various psychological interventions on thelife span of cancer patients. Five reported positiveresults24-28 (i.e., the therapy prolonged life, usually to asmall extent), and 6 failed to show an effect.29-34 Thelargest of the negative studies34 was a replication of theinitial Spiegel study, but with 235 women with meta-static breast cancer. No effect on life span was foundwith a year of supportive-expressive therapy. More suchstudies are in progress, but it seems unlikely that a con-sensus will soon be reached with this design. Further-more, the existing trial results give us no guide as towhat therapies might be most helpful, or for which in-dividuals, since the interventions tested varied sowidely: they included a year of supportive-expressivetherapy,24 6 weeks of basic training in problem solv-ing,26 training in self-hypnosis,27 education to increasecompliance with medication,25 and in-hospital coun-seling preoperatively and postoperatively.28 The con-flicting results leave no sense of certainty about thepossibility that APT can affect life span and are un-likely to have much influence on the general practiceof oncology.

Pincus35 provided an excellent, practical discussionof the limitations of RCTs and has outlined alterna-tives. Randomized trials are concerned with a group ofsubjects as a whole, not with the individual, and ask asimple question: “Is the mean/median survival of theintervention group greater than that of the controls?”They are used to test efficacy of a treatment at a latestage of investigation, following much preliminaryresearch on the properties of the treatment. Theapplication of this specialized design to questions ofhealing the body through mental change obscures theenormous variability between patients in their psycho-logical characteristics, particularly in their adherenceto treatment. Thus, if a minority of patients receivingan APT were keenly involved in or strongly adherentto the intervention, and the majority were not, anyimpact on life span might be lost in a comparison ofthe means of test and control subjects. RCTs are alsonot designed to explore what state of mind promoteslongevity. “Secondary analyses” are possible (relatingconcurrent psychological measures to survival) buthave not provided useful information in the 10 trialspublished to date.



The Value of Correlative StudiesUnderstanding of what might be called “healingthrough the mind” is at a very early stage. We need ex-ploratory research and protocols flexible enough toallow us to identify associations between mental fac-tors and physical outcomes that were unanticipated inthe planning phases. Clinical trials are designed onlyto verify, not to discover new relationships. To take ac-count of individual variability, a correlative design isneeded, in this instance, relating outcome (e.g., lifeextension) to psychological adaptation within each in-dividual subject. This point has been made by manyworkers in general psychotherapy outcome re-search.36-39 Elsewhere, I contrasted the negative resultsour group obtained using a randomized trial testingthe impact of psychological therapy on life span33 withthe highly significant relationship we found betweenpsychological attributes and survival in a separate,small, correlative study.40 This latter study used qualita-tive analysis to define patients’ psychology and wasprospective and longitudinal, allowing us to track thechanging behavioral repertoire used by patients asthey fought for survival.41,42 Such observational ap-proaches are the way knowledge is usually acquired,both in clinical learning and in real life, with the dif-ference that in research, systematic recording andcontrol for possible confounding variables is under-taken. Using a qualitative analysis, the observer is ableto define relatively complex meaning structures as thework unfolds; in our case, “involvement in self-help,” acomposite measure of dedication, application to self-help, and expectancy, was shown to be a strong predic-tor of survival.

Why then have many decades of correlative studiesattempting to relate personality variables to onset orprogression of cancer43 failed to reach a consensus?Part of the problem is that the psychometric tests thathave been almost universally employed, while undoubt-edly convenient, do not provide reliable or in-depthunderstanding of the mental processes of individualsubjects. Responses to self-report questionnaires canbe superficial and affected by issues of social desirabil-ity or by unconscious defenses. The positive correlationseen between fighting spirit and survival by Greer andcolleagues was derived by a combination of psychometrictesting and interviewing, whereas a much larger studyby Watson et al.,44 relying entirely on a superficialpsychometric test for fighting spirit, failed to showsuch a relationship. In our own small, correlativestudy, cited above, scores on 4 standard psychometrictests did not show a significant relationship to survival,whereas qualitatively derived psychological attributeswere strongly related.

An even more important limitation of the usualdesign for testing a “personality-cancer” link may be

that conditions have not been set up to detect change;the studies have almost all been cross-sectional andhave almost never used patients receiving an interven-tion. It is crucial to look for psychological changerather than at static qualities. This point seems suffi-ciently important, both for therapy and research, torequire a separate section.

The Need for Change toPromote Longer SurvivalIt is part of the accepted lore of research into the cellu-lar biology of cancer that a tumor, by the time of its de-tection, has typically been growing for months or evenyears in its host. During this time, the evolving popula-tion of neoplastic cells has had ample opportunity toadapt to the prevailing micro- environment. Thus, thecells will continue to proliferate unless conditionschange. If this happens, if a physical condition/dis-ease is to be ameliorated by the mind, it follows logi-cally that there must first be some change in theexisting patterns of psychological functioning. Suchchanges will then induce corresponding shifts in neu-rological and endocrine function, which act ulti-mately on regulators (such as the immune system,cytokines, and growth factors) in and around diseasedtissue. To promote alterations in patterns of behavior,affect, and cognition, we need therapies capable of in-ducing such change—hence, the emphasis on a step-wise progression toward more potent modes in Figure1. And to detect change, we need longitudinal studies,a point that seems to have been largely overlooked inthe personality/cancer literature.

Understanding States of MindThat Relate to Living LongerThe first need, then, is not for more RCTs but for abetter understanding of the states of mind that pre-cede and accompany different physical outcomes. Whilesome understanding of this relationship might begained by population studies, much better definitionof the relevant psychological qualities can be achievedby idiographic, case-by-case documentation of patients’behaviors, affect, and cognition. Psychometric tests mayprove useful in this endeavor, although historicallythey have not done so. An alternative is to use qualita-tive analyses of verbal data obtained from patients’statements (or written homework) and/or therapists’observations (observer rating). Analyses of patients’psychology should be prospective; that is, they shouldprecede knowledge of the physical endpoint (whichmight be recurrence of disease, in a patient with pri-mary cancer, or death if the cancer was advanced). Thecharacterization needs to extend over time (months) toallow recognition of change. It should be noted thatall patients in such a study contribute to the growing

Cunningham


knowledge base; whether or not they live longer thanexpected, the contrast will be informative. Also, totake account of differing seriousness of disease and toidentify the degree of physical benefit subjects have at-tained (e.g., extent to which they outlive prognoses),we need the best possible indication of the expectedoutcome for each person against which the observedoutcome can be compared. For survival, this might bedone using a large historical database containing in-formation on subjects matched to those in the study,or better, predictions from an expert panel who couldtake into account the unique features of each patient.Studies such as this will necessarily be small because ofthe work involved in the psychological characteriza-tion, but if they are undertaken by a number of re-search groups, a picture of properties favoring longev-ity should emerge fairly quickly.

Optimizing TherapyUnderstanding the qualities that accompany livinglonger will allow us to craft better therapies. It will nodoubt be found that different people benefit mostfrom different kinds and amounts of help, and we willtherefore need to devise research strategies that test,not a single favored therapy, but programs that areflexible enough to be adapted to these varying needs.The principle of supplying a graded series of thera-peutic and educational interventions will likely be rel-evant for most. An understanding of the mentalcorrelates of physical healing will allow us to assess theimpact of therapies on individuals and to use mentalstatus as a covariate in eventual randomized trials ofthese interventions.

Clinically, we must seek APTs best suited to produc-ing relevant changes in psychological adaptation. Itwould appear, a priori, that purely supportive thera-pies are less likely to change the subject than thoseoffering training in coping strategies in addition tosupport, and that these in turn are likely to be lesseffective than interventions aimed at more profoundpersonal development in psychological and spiritualdomains. This reasoning underlies the hierarchicalprogression of APTs in Figure 1. All such predictionsstand open to refutation by experiment, however.While we might expect that the more intense the ther-apy the greater the potential to prolong life, we willneed to take careful note of patient traits that allow orprevent expression of such benefits. In-depth psy-chotherapies, spiritual practices, and integratedpsychospiritual approaches need to be investigated.Many variants of these types of APT exist, of course.The more comprehensive therapies are likely toinclude an explicit spiritual (not religious) compo-nent. A stepwise program format not only allows inter-ested people to progress to more intensive modalities

but also provides, for research purposes, a grading ofthe degree of dedication demonstrated by eachsubject.

Psychological therapies with the explicit aim of pro-longing life must, of course, be presented responsiblyand sensitively to patients. The first thing to beacknowledged is that there are no guarantees ofeffects on disease progression. Second, there is no rea-son for self-reproach if the cancer does not appear torespond to self-help efforts: all cancers are unique,and many are sufficiently aggressive that they will notrespond to any intervention, medical or psychologi-cal. We use the metaphor of a balance beam to illus-trate this point, with a “weight” corresponding to thecancer on one side and “the body’s own defenses” and“medical treatment” on the other side, to which onecan add a further weight, one’s personal efforts, to tryto tip the balance. Third, some patients will deducethat if it is said their minds can affect cancer progres-sion, logically their premorbid mental state must haveencouraged development of the disease. This is besthandled, in our experience, by acknowledging thatsome such influences are conceivable, although evi-dence is lacking, but that no blame is implied if it hap-pened outside of awareness. Then, we advocate focus-ing on the present situation and on the potential ofmind to change the internal environment in a usefulway. This philosophy, overall, is described as “falsehope” by those who do not consider it possible thatmind can affect a disease such as cancer. We feel, bycontrast, that this objection is a disempowering “falsepessimism,” and that the only reasonable attitude atpresent is open-mindedness to the possibility ofsome mind- mediated healing. At the very least, qualityof life can be enhanced.

Finally, it needs to be said that we have barelyscratched the surface of possible therapies to be usedas APTs in the treatment of cancer patients. Assumingthat the degree and duration of the change in themilieu interieur is likely to be related to change in theregulation of cancer growth, we should rationally aimat helping people achieve mental change that laststhroughout the week (rather than mainly during thetherapy period). Various models are conceivable.Bolletino and LeShan45 described a 1-week intensive.The possibility of periods of immersion in a therapeu-tic program, analogous to residential treatments foraddiction, was mentioned in relation to helping peo-ple cope better. When the aim is to affect the disease,this makes even more sense. At a retreat center, incompany of others with similar disease, away fromone’s normal environment and assisted by caring pro-fessional staff, greater changes could be made thanare usually seen with the traditional weekly contact.



Such a program may sound expensive but would costless than a much shorter time spent in the hospital.

Elsewhere, I discussed in detail some of the clinicaland research requirements if we wish to study healingthrough the mind.40 As many writers have noted, pay-ing serious attention to this potential in patients wouldmark something of a revolution in the current philoso-phy of medicine. Within psycho-oncology and healthpsychology generally, this would entail exploring newand more comprehensive psychological therapies,using research designs that are not highly regarded atpresent. The release of significant funds for this pur-pose obviously depends on support from the clinicaland research community.

References1. Greer S, Moorey S, Baruch J. Evaluation of adjuvant psychologi-

cal therapy for clinically referred cancer patients. Br J Cancer.1991;63:257-260.

2. Cunningham AJ. Adjuvant psychological therapy for cancerpatients: putting it on the same footing as adjunctive medicaltherapies. J Psycho-Oncol. 2000;9:367-371.

3. Trijsburg RW, Van Knippenberg FCE, Rijpma SE. Effects of psy-chological treatment on cancer patients: a critical review. PsychosomMed. 1992;54:489-517.

4. Meyer TJ, Mark MM. Effects of psychosocial intervention withadult cancer patients: a meta-analysis of randomized experi-ments. Health Psychol. 1995;14:101-108.

5. Devine EC, Westlake SK. The effect of psychoeducational careprovided to adults with cancer: meta-analysis of 116 studies.Oncol Nurs Forum. 1995;22:1369-1381.

6. Bottomley A. Where are we now? Evaluating two decades ofgroup interventions with adult cancer patients. J Psychiatr Men-tal Health Nurs. 1997;4:251-265.

7. Cwikel JG, Behar LC. Social work with adult cancer patients: avote-count review of intervention research. Soc Work Heal Care.1999;29:39-67.

8. Fawzy FI. Psychosocial interventions for patients with cancer:what works and what doesn’t. Eur J Cancer. 1999;35:1559-1564.

9. Blake-Mortimer J, Gore-Felton C, Kimerling R, Turner-CobbJM, Spiegel D. Improving the quality and quantity of life amongpatients with cancer: a review of the effectiveness of group psy-chotherapy. Eur J Cancer. 1999;35:1581-1586.

10. Cunningham AJ, Edmonds CVI. Group psychological therapyfor cancer patients: a point of view and discussion of the hierar-chy of options. Int J Psychiatr Med. 1996;26:51-82.

11. Presberg BA, Levenson JLA. Survey of cancer support groupsprovided by National Cancer Institute (NCI) clinical and com-prehensive centers. J Psycho-Oncol. 1993;2:215-217.

12. Telch CF, Telch MJ. Psychological approaches for enhancingcoping among cancer patients: a review. Clin Psychol Rev. 1985;5:325-344.

13. Cunningham AJ, Tocco EK. A randomized trial of grouppsychoeducational therapy for cancer patients. Patient EducCounseling. 1989;14:101-114.

14. Fawzy FI, Fawzy NW, Arndt LA, Pasnau RO. Critical review ofpsychosocial interventions in cancer care. Arch Gen Psychiatry.1995;52:100-113.

15. Helgeson VS, Cohen S. Social support and adjustment to can-cer: reconciling descriptive, correlational, and interventionresearch. Health Psychol. 1996;15:135-148.

16. Krupnick JL, Rowland JH, Goldberg RL, Daniel UV. Profes-sionally-led support groups for cancer patients: an interventionin search of a model. Int J Psychiatr Med. 1993;23:275-294.

17. Fawzy FI, Fawzy NW, Wheeler JG. A post-hoc comparison of theefficiency of a psychoeducational intervention for melanomapatients delivered in group versus individual formats: an analy-sis of data from two studies. J Psycho-Oncol. 1996;5:81-89.

18. Sheard T, McGuire P. The effects of psychological interventionson anxiety and depression in cancer patients: results of twometa-analyses. Br J Cancer. 1999;80:1770-1780.

19. Cunningham AJ, Edmonds CVI, Williams D. Delivering a verybrief psycho-educational program to cancer patients and fam-ily members in a large group format. J Psycho-Oncol. 1999;8:177-182.

20. Sobell MB, Sobell LC. Stepped care as a heuristic approach tothe treatment of alcohol problems. J Consult Clin Psychol. 2000;68:573-579.

21. Howard KI, Lueger RJ, Maling MS, Martinovich Z. A phasemodel of psychotherapy outcome: causal mediation of change.J Consult Clin Psychol. 1993;61:678-685.

22. Speca M, Carlson L, Goodey E, Angen M. A randomized wait-list controlled clinical trial: the effect of a mindfulness medita-tion based stress reduction program on mood and symptoms ofstress in cancer outpatients. Psychosom Med. 2000;62:613-622.

23. Spiegel D, Classen C. Group Therapy for Cancer Patients: AResearch-Based Handbook of Psychosocial Care. New York, NY: BasicBooks; 2000.

24. Spiegel D, Bloom JR, Kraemer HC, Gottleib E. Effect ofpsychosocial treatment on survival of patients with metastaticbreast cancer. Lancet. October 14, 1989:888-891.

25. Richardson JL, Shelton DR, Krailo M, Levine AM. The effects ofcompliance with treatment on survival among patients withhematologic malignancies. J Clin Oncol. 1990;8:356-364.

26. Fawzy FI, Fawzy NW, Hyun CS, et al. Malignant melanoma:effects of an early structured psychiatric intervention, copingand affective state on recurrence and survival 6 years later. ArchGen Psychiatry. 1993;50:681-689.

27. Ratcliffe MA, Dawson AA, Walker LG. Eysenck PersonalityInventory L-scores in patients with Hodgkin’s disease and non-Hodgkin’s lymphoma. J Psycho-Oncol. 1995;4:39-45.

28. Kuchler T, Henne-Bruns D, Rappat S, et al. Impact of psycho-therapeutic support on gastrointestinal cancer patients under-going surgery: survival results of a trial. Hepato-Gastroenterol.1999;46:322-335.

29. Linn MW, Linn BS, Harris R. Effects of counseling for late stagecancer patients. Cancer. 1982;49:1048-1055.

30. Morganstern H, Gellert GA, Walter SD, Ostfeld AM, Siegel BS.The impact of a psychosocial support program on survival withbreast cancer: the importance of selection bias in program eval-uation. J Chron Dis. 1984;37:273-282.

31. Ilnyckyj A, Farber J, Cheang MC, Weinerman BH. A random-ized controlled trial of psychotherapeutic intervention in can-cer patients. Ann Roy Coll Physicians Surg Canada. 1994;27:93-96.

32. Edelman S, Lemon J, Bel DR, Kidman AD. Effects of group CBTon the survival time of patients with metastatic breast cancer.Psycho-Oncol. 1999;8:474-481.

33. Cunningham AJ, Edmonds CVI, Jenkins G, et al. A randomizedcontrolled trial of the effects on survival of group psychologicaltherapy for women with metastatic breast cancer. J Psycho-Oncol.1998;7:508-517.

34. Goodwin PJ, Leszcz M, Ennis M, et al. The effect of grouppsychosocial support on survival in metastatic breast cancer. NEngl J Med. 2001;342:1719-1726.

35. Pincus T. Analyzing long-term outcomes of clinical care with-out randomized clinical trials: the consecutive patient ques-tionnaire database. Adv: J Mind Body Health. 1997;13:3-32.

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36. Beutler LE, Crago M. Psychotherapy Research: An InternationalReview of Programmatic Studies. Washington, DC: American Psy-chological Association; 1991.

37. Seligman MEP. The effectiveness of psychotherapy: the Con-sumer Reports study. Am Psychol. 1995;50:964-974.

38. Howard KI, Moras K, Brill PI, Martinovich Z, Lutz W. Evalua-tions of psychotherapy: efficacy, effectiveness, and patient prog-ress. Am Psychol. 1996;51:1059-1064.

39. Tennen H, Affleck G, Armeli S, Carney MA. A daily processapproach to coping: linking therapy, research, and practice.Am Psychol. 2000;55:626-636.

40. Cunningham AJ. Healing through the mind: extending ourtheories, research and clinical practice. Adv Mind Body Med.2001;17:214-227.

41. Cunningham AJ, Edmonds CVI, Phillips C, Soots KI, Hedley D,Lockwood GA. A prospective, longitudinal study of the rela-tionship of psychological work to duration of survival in patientswith metastatic cancer. J Psycho-Oncol. 2000;9:323-39.

42. Cunningham AJ, Phillips C, Lockwood GA, Hedley D, EdmondsCVI. Association of involvement in psychological self help withlonger survival in patients with metastatic cancer: an explor-atory study. Adv Mind Body Med. 2000;16:239-316.

43. Garssen B, Goodkin K. On the role of immunological factors asmediators between psychosocial factors and cancer progres-sion. Psychiatr Res. 1999;85:51-61.

44. Watson M, Haviland JS, Greer S, Davidson J, Bliss JM. Influenceof psychological response on survival in breast cancer: a popu-lation-based cohort study. Lancet. 1999;354:1331-1336.

45. Bolletino RC, LeShan L. Cancer patients and marathon ther-apy: a new model. Advances. 1995;11:19-35.

Editor’s NoteAlastair J. Cunningham raises a critical question for allof us who are concerned with the impact of psycho-oncology interventions on survival in cancer: have weproceeded too quickly into the use of randomizedcontrolled trials (RCTs) for survival-oriented interven-tions in psycho-oncology? The lure of conforming tothe highest standards of “evidence-based medicine”may have pulled this field into RCTs before any con-cepts of what psychological factors are actually associ-ated with increased survival were systematically devel-

oped or explored. Thus, the interventions studied inRCTs—and Cunningham points out that these inter-ventions have been so varied as to be nearly non-com-parable—may not have been interventions that haveany impact on survival. This would help to explain theconfusing results of RCTs that have been reported todate. Cunningham counsels that it may be time to goback to basics in psycho-oncology, before spendingmore money on RCTs of interventions that may bewithout proper theoretical foundations, or may befrankly impractical in the clinical situation. He alsoidentifies the specific value of alternative research de-signs. His long experience and sophistication in thisfield challenges workers in this area to consider hissuggestions seriously.

Some specific points deserve mention. In the UnitedStates, it is possible that economics of care in small-group or individualized interventions may not yet beas challenging as the article asserts. Many insurancecompanies do cover charges for psychological care incases of life-threatening illness. It may thus be risky toadvocate only large-group formats, which some patientsmay find uncomfortable and thus avoid. Cunninghampoints out the disempowering nature of the expecta-tion that seriously ill persons would not be able to helpthemselves, an idea well worth remembering. He alsocontributes an especially valuable insight with hisrelabeling of the critique that therapeutic alternativesare simply “false hope” as a “disempowering ‘false pes-simism.’” The “false hope” critique has dogged inte-grative cancer medicine for years. As this issue shows,the biological and psychological evidence for the effi-cacy of integrative techniques, although far from com-plete, is beginning to find its place in genuine scien-tific and clinical discourse.



Schneider et al.Exercise for Cancer Rehabilitation

AModel Program:Exercise Interventionfor Cancer Rehabilitation

C. M. Schneider, PhD, Carolyn A. Dennehy, PhD, Michelle Roozeboom, BS, and Susan D. Carter, MD

Recent advances in cancer detection and treatment have re-sulted in an increase in the survival rate of individuals diag-nosed with cancer. The increased survival rate brings newchallenges for increasing the quality of life for cancer survi-vors. Debilitating side effects can result from the cancer it-self and the cancer treatment. The negative effects lead todecreased functional (work) capacity, increased fatigue, anddebilitating muscular weakness. There have been very posi-tive benefits seen from the use of individualized prescriptiveexercise intervention in alleviating these cancer treatment re-lated symptoms. The role of exercise intervention as a com-plementary therapy is just emerging. Studies have shownthat exercise decreases the amount of fatigue, improvesfunctional capacity, increases immune function, and leads toimproved quality of life. The effects of cancer and cancertreatments require that an exercise intervention program bewell based in sound scientific principles. The exercise inter-vention needs to be carefully structured and controlled. Allpatients should be assessed and reassessed to evaluate prog-ress. A cancer exercise specialist should closely monitor theexercise regime. Exercise should involve a whole-body ap-proach that emphasizes all areas of fitness. Exercise therapyfor cancer patients is a new and exciting area that will con-tinue to grow as medical professionals realize the necessityfor post-cancer treatment intervention to improve quality oflife.

The American Cancer Society predicts that 1,268,000new cancer cases will be reported in 2001.1 The excit-ing news is that many will survive the disease. Presently,there are 8.9 million cancer survivors.2 Recent advancesin cancer detection and treatment have resulted in anincrease in the survival rate of individuals diagnosedwith cancer. The increased survival rate brings newchallenges for increasing the quality of life for survi-vors. Cancer treatments, although effective in elimi-nating cancer, lead to debilitating side effects in 72%to 96% of cancer patients who undergo treatment.3

Cancer treatments such as chemotherapy, radiation,and surgery destroy or eliminate cancer cells, but inthe process they destroy normal healthy tissue andalter normal tissue function. As a result of this addedburden on the physiological systems, debilitating sideeffects occur.

ToxicitiesCancer patients experience a vast array of externalsymptoms and many potential internal alterations.Toxicities can occur in the cardiovascular, immune,pulmonary, gastrointestinal, musculoskeletal, neuro-endocrine, and hepatic systems. These physiologicalchanges that occur within the body can manifest exter-nally as decreased functional (energy) capacity, debili-tating fatigue, and severe muscular weakness.

Cardiovascular ToxicityRadiation has significant acute and chronic effects onthe cardiovascular system. Most acute effects of radia-tion are found in the basal cells of the epidermis, themucosal epithelia, and the hematopoietic cells of thebone marrow. However, the injury to cells in these ar-eas leads to the release of substances (i.e., histamine)that cause inflammatory responses to the vasculature.Inflammation leads to vascular dilatation, increasedcapillary permeability, and interstitial edema. Long-term effects on the vascular system occur with progres-sively reduced capillarization in the irradiated tissue,resulting in a decrease in blood perfusion.4,5

Centrally, the pericardium, the myocardium, andthe coronary arteries can be affected. With mediastinalradiotherapy, pericarditis (inflammation of the mem-branous sac enclosing the heart) is the most commonside effect, lasting approximately 2 to 5 months.Radiation-induced pericarditis is fatal in about 6% ofpatients. Another cardiovascular abnormality appearsin the electrocardiogram (EKG), where the T waveinverts or becomes flattened. The EKG reverts to nor-mal within 4 months to 1 year following treatment.There have been reports of severe cardiac conduction

Schneider et al.


CMS, CAD, and MR are in the Department of Kinesiology, RockyMountain Cancer Rehabilitation Institute, University of NorthernColorado, Greeley, Colorado.SDC is at the Regional Breast Centerof Northern Colorado, Greeley, Colorado.

Correspondence: C. M. Schneider, Department of Kinesiology,Rocky Mountain Cancer Rehabilitation Institute, University ofNorthern Colorado, 2590 Gunter Hall, Greeley, CO 80639. E-mail:[email protected].

problems developing 6 to 23 years following radiation.Reduced ventricular function has been found 5 to 15years after radiation. Five years or more after mediastinalradiation, investigators found narrowing of the coro-nary arteries resulting in myocardial infarctions.

Vascular tissue alterations occur during treatmentand are important because the tissue response to thesealterations often produces chronic toxicity. Acutechanges in the vascular tissue include edema, inflam-mation, and vascular spasms.

Chemotherapy agents (i.e., doxorubicin) can alsodirectly damage the heart. There appears to be a grad-ual increase in heart damage with increased doses.The cardiomyopathy that occurs with chemotherapyappears in about 4 weeks following chemotherapy andhas a higher incidence (50%) of fatality compared toradiation. There are abnormal occurrences seen onEKG. For example, QRS complexes have lower ampli-tudes, nonspecific ST and T wave changes, sinus tachy-cardia, prolongation of the QT interval, prematureatrial and ventricular beats, and supraventriculararrhythmias. Chemotherapy has a profound affecton the bone marrow stem cell, causing myelo-suppression throughout the vascular system.4-6

Hematopoietic ToxicityHematopoietic tissues (tissues that produce bloodcells, i.e., bone marrow) are vulnerable to cancer ther-apy. Damage to the hematopoietic tissue results inleukopenia (low levels of white blood cells) andgranulocytopenia (deficiency of neutrophils, whichare the first line of defense against infection, basophils,and eosinophils). Thrombocytopenia (decreased num-bers of circulating mature platelets causing bleeding)and anemia (low levels of red blood cells resulting inlow concentrations of hemoglobin and decreasedhematocrit levels) can also be caused by hematopoietictissue damage.7,8

Pulmonary ToxicityPulmonary toxicity may be acute or chronic, develop-ing within days, months, or years following radiother-apy and chemotherapy. Long-term treatment may causeintra-alveolar pulmonary fibrosis (formation of scartissue) and abnormal development of pulmonary tis-sue, especially the endothelial and epithelial cells. Pa-tients may experience coughing, dyspnea, and a low-grade fever as a result of pulmonary toxicity. Addi-tionally, patients will have a diminished diffusion ca-pacity and decreased pulmonary compliance within 8months to 10 years after therapy. Pulmonary toxicitypresents symptoms of fatigue, low exercise tolerance,restlessness, and tachypnea.7

Gastrointestinal System ToxicityRadiotherapy causes acute changes in the intestinalmucosa, probably due to the damage to the cell repro-ductive cycle. The chronic intestinal changes includethickening of some of the bowel segments, stenosis (nar-rowing), ulceration, intestinal fibrosis, vascular edemaand wall thickening, muscle hypertrophy, distortion ofthe arteries, and increased intestinal motility leadingto diarrhea. Additionally, there are metabolic insuffi-ciencies. There is a reduction of disaccharidases andaminopeptidases, the digestive enzymes involved inthe catabolism of carbohydrates and proteins. The ab-sorption capacity of the intestine is reduced, whichcan lead to protein deficiency, fat absorption abnor-malities, and carbohydrate, vitamin, and electrolyteabsorption impairments. Abdominal radiation can pro-duce vomiting, nausea, and loss of appetite. The lossof the digestive and absorptive capacity of the nutri-ents in conjunction with loss of appetite can lead tomalnutrition. This reduction in the capacity to pro-duce energy leads to extreme fatigue, muscular wast-ing, and extreme muscular weakness.5,8

Chemotherapy-induced nausea and vomiting canlead to increased energy requirements, nutritionalabnormalities, dehydration, and electrolyte imbalances.Depending on the type of chemotherapeutic agent,the patient can experience extensive morphologicaldamage to the intestinal mucosa, leading to diarrhea,abdominal pain, and intestinal disease. In patientsreceiving certain antineoplastic drugs, constipation,distension, and abdominal pain are often reported.7

Musculoskeletal AlterationsAs mentioned earlier, radiotherapy and chemother-apy alter bone marrow, which affects the vascularizationof the bone and muscle as well as other tissues. It hasbeen reported that muscle integrity is disturbed withradiation. Radiotherapy may alter the sarcolemma,sarcoplasmic reticulum (SR), and mitochondrial mem-branes, which lead to disturbances in the generationof muscle force. The loss of muscle force (muscleweakness) may be a result of the abnormalities in therecycling of Ca2+ by the SR and abnormalities in theCa2+-ATPase system. Abnormalities in these mecha-nisms can lead to failure in the excitation-contractioncoupling process, thus limiting muscle contraction.There is also some evidence that damage and disorga-nization occurs to the muscle myofibrils and myofila-ments within the muscle. Patients may develop musclewasting and cachexia. Cachexia is characterized byweight loss, anorexia, and weakness due to tissue ne-crosis resulting in decrements in muscle mass andbody fat mass.5,9

Exercise for Cancer Rehabilitation


Connective tissue alterations can occur during treat-ment. These alterations often produce chronic toxic-ity. Acute changes in the connective tissue, musculartissue, and serous membrane include edema, hemor-rhage, and inflammation.

Hepatic ToxicityAcute hepatic (liver) radiation toxicity usually pres-ents within 2 to 6 weeks after completion of radiation,although manifestation of the toxicity may not occurfor 6 months or longer. Symptoms of hepatic toxicityinclude rapid weight gain, increase in abdominal girth,fatigue, and anorexia. Liver enzymes are elevated inthe blood serum.

Some chemotherapy agents such as 5-fluorouracilare hepatotoxic. However, to establish a direct effecton the liver is difficult. There appears to be liver injurycausing hepatocyte necrosis, steatosis (fatty degenera-tion), and cholestasis (arrest of bile excretions). Chronicalterations to the liver include cytotoxic lesions, hepaticfibrosis (development of scar tissue), cirrhosis (dis-ease of the liver), and chronic cholestasis (loss of bileexcretion). Liver disease is usually temporary and canbe controlled with careful therapeutic planning.5,7,9

Neuroendocrine ToxicityRadiotherapy of high doses can affect thyroid tissue,leading to cell necrosis and atrophy. Radiation-in-duced DNA damage and a continuous stimulation bythyroid stimulating hormone cause the major thyroidmalfunction. Radiotherapy can also affect the hypo-thalamus and pituitary, causing abnormalities in growthand abnormalities in the release of growth hormone.

Chemotherapy-induced neurotoxicity includes awide range of central nervous system symptoms suchas confusion, memory loss, hearing loss, drop foot,and so on. The incidences of neurologic side effectsare low to moderate and are dependent on factorssuch as dose and age of the patient. Symptoms maypersist up to several years following treatment.8

Dermatological ToxicityChemotherapy drugs usually cannot differentiate be-tween actively reproducing cancer cells and normalcells. Drugs such as Cytoxan®, Adriamycin®, andvincristine act on DNA synthesis and mitosis and de-stroy rapidly growing hair cells, and the result is hairloss. The chances of having hair loss increase duringcombination chemotherapy.8

Exercise InterventionRecently, exercise has been investigated as a possibleintervention for alleviating cancer treatment relatedsymptoms. Investigators have found that excessive rest

and sleep do not alleviate chronic cancer fatigue butactually augment fatigue.10 Reduced activity secondaryto cancer diagnosis and treatment may affect every or-gan system and cause irreversible loss in energy effi-ciency.11 This finding lends credibility to the use ofactivity/exercise as an intervention for cancer fatigueand muscular weakness. Exercise has many benefitsfor healthy individuals. Such benefits include increasedcardiovascular performance, increased immune func-tion, increased muscular function, improved balance,increased metabolic rate, and a decrease in musclemass loss. Such improved physical functioning wouldimprove energy levels in cancer patients, leading todecreased fatigue, increased muscular strength, andan enhanced quality of life.12 There have been limitedinvestigations in this area. Current exercise programsfor cancer patients are home based and require thepatient to keep a journal of frequency, intensity, andduration of exercise.11 Self-monitored exercise pro-grams do not control the consistency of exercise andthe intensity. A well-structured program would pro-vide better understanding of the relationship betweencertain amounts of exercise and the symptoms of can-cer treatment. The program should provide specificitywith regard to frequency, intensity, and duration dur-ing and following cancer treatment.13 Prescribing ex-ercise for cancer patients should limit exercise intensityto moderate, since vigorous exercise may suppress theimmune system. Exercise may affect bone metastasisand bone integrity and may increase fatigue. Struc-tured programs monitor the patient’s ability to toler-ate exercise while receiving treatment and followingtreatment.14

Rocky Mountain CancerRehabilitation InstituteThe Rocky Mountain Cancer Rehabilitation Institutewas founded in 1996 to advance the quality of life ofcancer patients during and following treatment throughprescriptive exercise rehabilitation. The goals of theinstitute are to provide scientifically based individual-ized prescriptive exercise intervention for cancer pa-tients, ongoing basic and clinical research for thepurpose of alleviating cancer treatment related symp-toms, and advanced educational preparation and pro-fessional development to promote high standards incancer rehabilitation. Thus far, a model cancer reha-bilitation program that has shown significant benefitsto cancer patients has been established. Clinical inves-tigations on prescriptive exercise intervention for can-cer treatment relatedsymptomshavebeencompleted.15-22

Improvement in functional capacity, muscular strength,muscular endurance, and pulmonary function with aconcomitant decrease in the perception of fatigue and

Schneider et al.


feelings of depression has been consistently shown.Cancer exercise specialist workshops have been de-signed and implemented for individuals in all areas ofthe health profession and within our college curricu-lum. The institute sees the need to enhance the qualityof life of cancer patients as a very real and criticalconcern.

Cancer rehabilitation programs should be compre-hensive and address the multidimensional needs ofthe cancer patient during treatment and recovery.Staff for such a program should use health profession-als, exercise physiologists, exercise and dietary special-ists, and health management personnel. These individu-als provide a mix of medical and scientific communitiesand lead to an integrative team approach to the treat-ment of cancer-related symptoms.

Essential Components ofCancer RehabilitationThe goal of cancer rehabilitation should be to provideappropriate assessment, prescription, and programguidelines for cancer patients during and followingcancer treatment. Thus far, it has been determinedthat the essential components of cancer rehabilitationshould include a physician referral and preassessment,physical examination, screening, a thorough fitnessassessment, an individualized exercise prescriptionthat outlines specific goals for a 6-month interventionprogram, and reassessment to determine the effective-ness of the intervention.

Physician referral is essential to the cancer rehabili-tation program. In many instances, cancer patientsappear to be “apparently healthy” because many of thesymptoms associated with cancer and cancer treat-ments are not obvious, and yet can be serious and lifethreatening.

In addition to a physician referral, it is essential toget meticulous information from the patient prior tothe assessment. From the information collected,appropriate assessment techniques and protocols canbe determined. Screening should be comprehensive.Because the effects of cancer treatments are multidi-mensional, screening should include physiologicalscreening (i.e., physical examination, medical history,etc.) and psychological screening (i.e., quality of lifeindices, etc.).

Effective assessment should include relevant mea-surable parameters that are valid and reliable. Theassessment procedures should be rigidly controlled sothat exact procedures can be repeated during the reas-sessment. The patient’s rights and privacy should beprotected during all procedures. Accurate interpreta-tion of the assessment data is critical for the develop-ment of an appropriate individualized exercise

prescription. A thorough assessment prior to the exer-cise intervention will help determine appropriate orcontraindicated activities during the exercise inter-vention. The assessment provides baseline informa-tion that can be used to monitor physiological alter-ations that occur during or following cancer treatment.

The individualized exercise prescription is devel-oped after careful analysis of the patient’s type of can-cer, cancer treatment, and length of time out of treat-ment. In addition, data from the assessment are factoredinto the prescription goals, recommendations, andprecautions.

Trained cancer exercise specialists should be respon-sible for carefully designing the 6-month exercise inter-vention program from the exercise prescription. The3-day-per-week program should accomplish the intendedgoals and improve the patient’s functional capacity.The activities completed each session are recorded inthe patient’s logbook. Prior to each session, a briefhealth and fatigue status report is obtained from thepatient. Modifications of the exercise intervention aremade based on changes in treatment regimens, alter-ations in drug therapy, or as a result of any new devel-opments in health status. The rate of progression dur-ing the exercise intervention is based on themodifications made in the patient’s exercise prescrip-tion due to the above considerations. The exerciseintervention will be significantly different betweenpatients during treatment and posttreatment. Thespecialist outlines an exercise program that uses awhole-body approach toward exercise. All areas ofphysical fitness are emphasized during each exercisesession. The activities that are prescribed should beboth aerobic (endurance) and anaerobic (strength)in nature.

Following the 6-month exercise intervention pro-gram, the cancer patient again completes all the assess-ment procedures that were used before exercise inter-vention. The differences between the preassessmentvalues and the reassessment values help determine theeffectiveness of the exercise intervention. The reas-sessment also helps determine modifications in theexercise prescription for the next 6-month exerciseintervention.

Ancillary services should be provided to meet thespecial needs of the patients. Possible services mayinclude psychological counseling, physical therapy,massage therapy, occupational therapy, and informa-tion on other applicable services throughout thecommunity.

Exercise Program GuidelinesAn exercise intervention is designed from the exerciseprescription, which is developed from the screening,



physical examination, and assessment data. The exer-cise intervention guidelines for patients during treat-ment and following treatment encompass a sequentialrehabilitation model integrating whole bodywork andprogressing to specific affected tissues and systems.The sequential model for patients during treatmentencompasses a slow progression with continuous mon-itoring and adjustments if the health status of the pa-tient changes. The exercise intervention for patientsfollowing treatment also follows a rehabilitation modelrather than a model strictly for the development of fit-ness. Usually, the exercise intervention following treat-ment will not have the severe patient fluctuations thatare seen with patients during treatment.

The first 4 months of the exercise program forpatients during treatment focus on the whole body,since total body fatigue seems to be prevalent amongcancer patients. The goal of the exercise interventionis to keep the patient active while undergoing cancertreatment. The intervention will fluctuate dependingon the patient’s tolerance for the treatment regimen.During weeks 4 through 6, the intervention containsmostly whole bodywork for the purpose of minimizingtreatment fatigue. However, the intervention can alsoinclude rehabilitation of a specific area that was affectedby cancer, such as working on range of motion in a sur-gical breast cancer patient who is undergoing a regimeof chemotherapy.

The exercise intervention for patients followingtreatment is also a sequential rehabilitation model.Patients in this model can progress somewhat faster;however, this is dependent on the progress reportsand status of the patient. The first 3 months of theexercise program for patients following treatment againfocus on the whole body. The exercise interventionincludes whole bodywork; however, rehabilitationbecomes more specific to the muscle groups and sys-tems affected by the type of cancer and cancer treat-ment within the next month. Finally, the exerciseworkouts contain a whole-body component and becomevery specific to the physiological components (i.e.,range of motion work for a surgical breast cancerpatient) that need to be rehabilitated for the patientto gain even more advances toward improved qualityof life (4 to 6 months).

Special Considerationsfor Cancer RehabilitationPatients will present for cancer rehabilitation with nu-merous complications due to their cancer and/or can-cer treatments. Surgical patients will present with recentincisions and sutures, with the possibility of develop-ing infection. Therefore, it is important to monitorfactors within your facility that will reduce the possibil-

ity of infection. These factors include cleanliness offloors, equipment, locker rooms, pools, spas, and theair filtration system. Another complication that needsto be addressed with surgical patients is the pain theyexperience with movement. The exercise programneeds to be designed to minimize the patient’s painand maximize the patient’s comfort. A possible strat-egy is to exercise the nonsurgical side until the patientcan tolerate exercise movement on the affected side.Additionally, the surgical patient experiences changesin body image (mastectomy). These changes may bedifficult for the patient to perceive positively. Actual orperceived body changes usually cause severe anxiety.The reactions of the staff will influence the patient’sability to adapt to changes in body image. With a surgi-cal patient, there is always the possibility of edema(swelling). This is a symptom that must be monitored.

Patients who have received radiation therapy willpresent with similar and yet very different complica-tions compared to surgery patients. Radiation causesacute and chronic skin reactions. Skin reactions aredescribed in degrees: (1) first-degree skin reaction ischaracterized by loss of hair in the radiated area; (2)second-degree skin reaction shows skin redness in theradiated area, with inhibition or loss of sweat glands;(3) third-degree skin reaction shows deep redness inthe skin, blisters, destruction of the sweat glands, andpermanent hair loss; and (4) fourth-degree skin reac-tion shows deep blisters and ulcerations and signifi-cant pain.6 If leukopenia (low levels of circulatingmature white blood cells) occurs, the patient is suscep-tible to infection. Care must be given during the exer-cise intervention to reduce infection, eliminate skinirritation, and prevent an excessive rise in body tem-perature. Additionally, the patient may experienceother physiological symptoms (e.g., nausea, diarrhea,anemia, thrombocytopenia) that can require a modifi-cation in the exercise prescription. Dehydration is alsoa side effect of radiation; therefore, the exercisingpatient must have plenty of fluids available. Edema inthe affected area needs to be monitored and precau-tions taken to eliminate any causes of swelling.

Chemotherapy patients have complications thatalso must be addressed by professionals during exer-cise intervention. Leukopenia, which increases thepatient’s chance of infection, must be monitored.Many chemotherapy patients experience thrombo-cytopenia (decreased numbers of circulating matureplatelets); therefore, precautions need to be takenduring activities that may produce bleeding, such asblood collection. The chemotherapy patient is suscep-tible to bruising; therefore, be careful with patientsusing free weights, dumbbells, and so on. The patientcan also experience negative symptoms during treat-ment (e.g., nausea, diarrhea, vomiting) that will alter

Schneider et al.


the exercise prescription. Ensure adequate hydrationduring exercise to prevent further complications. Addi-tionally, it is essential to understand the effects of thevarious chemotherapy drugs on the parameters thatare used to assess exercise intensity such as heart rateand blood pressure.

Patients with bone marrow transplantation havealtered immune status, leaving them vulnerable toinfection. There are also bleeding tendencies and ane-mia, which must be taken into consideration whenexercising patients following bone marrow transplan-tation. Blood values in a bone marrow transplantpatient, especially total leukocyte count, platelet count,and hemoglobin concentration, must be followed closelyby the cancer rehabilitation facility physician and bythe cancer exercise specialist.

SummaryAcute and chronic exercise can enhance the cardio-vascular system both centrally and peripherally. Thephysiological changes that occur reduce the stress onthe heart and blood vessels, thus enhancing an indi-vidual’s functional aerobic capacity or ability of theheart and lungs to more efficiently deliver oxygen tothe working tissues. The evidence obtained at theRocky Mountain Cancer Rehabilitation Institute15-22

has shown significant improvements in functional ca-pacity, resting heart rate, time on treadmill, forced vi-tal capacity, and range of motion with concomitantreductions in perception of fatigue and depressionfollowing 6-month exercise interventions in cancerpatients compared to nonexercise cancer patient con-trols. Additionally, muscular alterations such as dis-ruption of the sarcolemma, disruption of the sarco-plasmic reticulum, and damage to the myofibrils andmyofilaments can lead to muscle weakness and loss offorce production. Evidence by the aforementioned in-vestigators showed that muscular strength and endur-ance significantly improved in cancer patients. In fact,the muscular weakness that was observed in the cancerpatients appeared to be more highly correlated withthe debilitating fatigue experienced by patients thanwith cardiovascular endurance.

The careful attention directed to the special consid-erations for cancer rehabilitation, the implementa-tion of each of the essential components, and the useof the exercise prescription guidelines thus far devel-oped by the Rocky Mountain Cancer RehabilitationInstitute have shown positive improvements in thephysiological and psychological health of cancer patients,with no concomitant adverse effects. Thus, the followingimportant points for the development of the exerciseprescription and exercise intervention for cancerpatients should be noted:

• Be keenly aware of the special considerations thatshould be accounted for during cancer rehabilitation.

• Provide comprehensive physiological and psychologi-cal assessments to develop appropriate exercise pre-scriptions and exercise interventions.

• The individualized exercise prescription and inter-vention program is based on the type of cancer, stageof cancer, severity of treatment, and time out of treat-ment.

• The exercise intervention is continuously monitoredand changed if the health status of the patient changes.

• The variability in the exercise prescriptions and exer-cise interventions emphasize the importance of hav-ing trained cancer exercise specialists.

• The exercise prescription and exercise interventionprogram should be based on appropriate modes, fre-quency, intensity, duration, and progression of exer-cises. Manipulation of these parameters determinesthe exercise dose. Exercise dose has been reported ashaving an influence on the immune system. It appearsas if a moderate exercise dose has a positive effect onthe immune system, whereas being sedentary and ex-ercising intensely has a negative effect on the immunesystem.23 Be sure to maintain a logbook of the exerciseworkout to maintain continuity for the patient.

References1. American Cancer Society. Mid-Atlantic Division: Cancer Facts and

Figures 2001. New Castle, DE: American Cancer Society, Mid-Atlantic Division Inc; 2001.

2. Ries LAG, Eisner MIP, Kosary CL, et al. SEER Cancer StatisticsReview, 1973-199 7. Bethesda, MD: National Cancer Institute;2000.

3. National Cancer Institute. Information From PDQ for Patients.Available at: httn://www.gravlab.ac.uk/cancernet/504461.html.Accessed October 12, 2001.

4. DeVita VT, Hellman S, Rosenberg SA. Cancer Principles and Prac-tice of Oncology. Vols 1, 2. 5th ed. Philadelphia, PA: Lippincott-Raven Publishers; 1997.

5. DeVita VT, Hellman S, Rosenberg SA. Cancer Principles and Prac-tice of Oncology. Vols 1, 2. 6th ed. Philadelphia, PA: Lippincott-Raven Publishers; 2001.

6. Snyder CC. Oncology Nursing. Boston, MA: Little, Brown andCompany; 1986.

7. Fischer DS, Knobf MT, Durivage HJ. The Cancer ChemotherapyHandbook. 4th ed. St Louis, MO: Mosby; 1993.

8. Dollinger M, Rosenbaum EH, Cable U. Eveyone’s Guide to CancerTherapy. 3rd ed. Kansas City, MO: Andrews McMeel Publishing;1997.

9. Chabner BA, Longo DL. Cancer Chemotherapy and Biotherapy. 3rded. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.

10. Johnson D. Coping with fatigue. Lifelines. 1998;6:1-2.11. Winningham ML. Walking program for people with cancer:

getting started. Cancer Nurs. 1991;14:270-276.12. Smith SL. Physical exercise as an oncology nursing interven-

tion to enhance quality of life. Oncol Nurs Forum. 1996;23:771-778.

13. Winningham ML, MacVicar MG, Burke CA. Exercise for cancerpatients: guidelines and precautions. Phys Sports Med. 1986;14:128-134.

14. Courneya KS, Mackey JR, Jones LW. Coping with cancer. PhysSports Med. 2000;28(5):49-73.



15. Bentz A, Dennehy CA, Busing K, Carter SD, Schneider CM.Physiological alterations with adjuvant cancer therapy. Med SciSports Exerc. 1999;3l:S104.

16. Dennehy CA, Carter SD, Schneider CM. Physiological manifes-tations of prescriptive exercise on cancer treatment-relatedfatigue. The Physiologist. 2000;43:357.

17. Dennehy CA, Carter SD, Schneider CM. Prescriptive exerciseintervention for cancer treatment-related fatigue. Phys ActivityCancer: Cooper Aerobics Inst. 2000;4:22.

18. Dennehy CA, Schneider CM, Carter SD, Bentz A, Stephens K,Quick K. Exercise intervention for cancer-related fatigue. Res QExerc Sport. 2000;71(suppl 1):A27.

19. Dennehy CA, Bentz A, Stephens K, Carter SD, Schneider CM.The effect of cancer treatment on fatigue indices. Med Sci SportsExerc. 2000;32:S234.

20. Dennehy CA, Bentz A, Fox K, Carter SD, Schneider CM. Breastcancer risk profile of sedentary, active, and highly trainedwomen. Med Sci Sports Exerc. 1998;30:S63.

21. Schneider CM, Stephens K, Bentz A, Quick K, Carter SD,Dennehy CA. Prescriptive exercise rehabilitation adaptationsin cancer patients. Med Sci Sports Exerc. 2000;32:S234.

22. Stephens K, Schneider CM, Bentz A, et al. The influence oftime from cancer treatment on selected fatigue indicators. MedSci Sports Exerc. 2000;32:S233.

23. Nieman DC, Johansen LM, Lee SW, Arabatzis K. Infectious epi-sodes in runners before and after the Los Angeles marathon.J Sports Med Phys Fitness. 1990;30:316-28.

Editor’s NoteThe Rocky Mountain Cancer Rehabilitation Instituteis one of several programs offering exercise interven-tions for cancer patients. C. M. Schneider and col-leagues have outlined the medical background andorganization of this comprehensive, institutionally basedexercise program for cancer patients, which is attunedto the many potential physical complications of cancer

and its treatments. These complications highlight theneed for physical assessment and prescriptive exerciseprograms for cancer patients. Benefits of such inter-ventions are clear; however, some are noted in otherpublications of this group. A reviewer suggested, addi-tionally, that the exercise program may have positiveimpacts on depression, which is noted frequently amongcancer patients, and that this could contribute to fa-vorable outcomes of exercise treatment. The benefi-cial effect of exercise on major depressive disorder1

and on depression in breast cancer patients2 has beennoted in recent clinical studies.

We note that this article mentions the monitoringof bone marrow transplant patients by physicians andother staff of rehabilitation-oriented institutions. Bonemarrow transplant patients are likely to be monitoredquite intensively by their oncology specialists, whoshould be specifically informed about any exerciseprograms their patients undertake. Where the staff ofrehabilitation institutions might be of considerableassistance is in the monitoring of patients who havecompleted standard-dose chemotherapeutic regimens,who tend to be monitored less closely than bone mar-row transplant patients.

References1. Babyak M, Blumenthal JA, Herman S, et al. Exercise treatment

for major depression: maintenance of therapeutic benefit at 10months. Psychosom Med. 2000;62:633-638.

2. Segar ML, Katch VL, Roth RS, et al. The effect of aerobic exer-cise on self-esteem and depressive and anxiety symptoms amongbreast cancer survivors. Oncol Nurs Forum. 1998;25:107-113.

Schneider et al.


Block, GyllenhaalClinical Corner Review

Clinical Corner: Herb-Drug Interactions inCancer Chemotherapy: Theoretical ConcernsRegarding DrugMetabolizing Enzymes

Keith I. Block, MD, and Charlotte Gyllenhaal, PhD

Interactions between herbal medicines and conventionaldrugs have recently been reported; the most significant herbwith such drug interactions is Saint John’s wort, an inducerof cytochrome P450 3A3/4, an enzyme responsible forclearance of many clinically important drugs from the body.Foods (especially grapefruit) and habits or lifestyle factorssuch as smoking or alcohol consumption may also alter themetabolism of drugs through effects on the cytochromeP450 system. The authors review here the functioning of thedrug-metabolizing enzymes and discuss their particular sig-nificance in cancer chemotherapy treatment. They thenpresent the herbal medicines, foods, and lifestyle factorsthat induce or inhibit drug-metabolizing enzymes that areimportant for both cancer chemotherapy drugs and drugsused adjunctively in cancer treatment. It is notable that noactual herb-drug interactions have been reported clinicallyin cancer treatment, and their potential for interaction stillmust be regarded as theoretical. Although some chemother-apy patients may be interested in taking herbal medicinesthat could potentially interact with cancer chemotherapyagents, it may be wise to counsel them to use other means ofaddressing the problems for which they use specific herbsduring the time they receive chemotherapy.

Early in 2000, the medical community was confrontedby the news that a popular herbal medicine, SaintJohn’s wort (SJW; Hypericum perforatum L., Hyperi-caceae), had been shown to have clinically significantinteractions with some widely used drugs. Discussionsof case reports of interactions with theophylline1 andcyclosporine2 and reports of interactions with digoxin3

and indinavir4 appeared in national news magazines aswell as in medical journals. Although these publica-tions triggered a number of overly alarmist specula-tions about the dangers of all herbal medicines, theyalso focused attention on dimensions of the biologicalactivities of herbs and plant-derived dietary supple-ments that had been substantially neglected in thepast. One of the most important of these was the roleof inducers and inhibitors of the cytochrome P450family of drug-metabolizing enzymes. Because inte-grative cancer therapies may employ drugs meta-

bolized by these enzymes, and foods or herbs that altertheir function, it is important that health professionalsin this field understand the mechanisms and conse-quences of potential interactions. The interactions wewill discuss in this article are all so far theoretical. Nocase reports exist of natural agents interacting withdrugs used in cancer treatments, to the best of ourknowledge. Because of the life-threatening nature ofcancer, however, caution with potentially interactingagents is warranted.

Functions of Phase I (Cytochrome P450)and Phase II Enzymes

Metabolism Through EnzymesMetabolism of drugs and other xenobiotics (or chemi-cal substances that enter the body from without) is ac-complished in part through a series of enzymes referredto as phase I and phase II enzymes.5 These occur pri-marily in the liver and are also found in some other tis-sues. The phase I enzymes frequently accomplish thebiotransformation of drugs by structurally changingthe functional groups that are responsible for their ac-tivity. These transformations are achieved through avariety of chemical reactions including hydrolysis,hydroxylation, oxidation, and reduction. The effecton the drug’s activity depends on the nature of thedrug. Some important chemotherapy drugs (e.g.,cyclophosphamide, ifosfamide) are introduced intothe body as prodrugs, whose structure must be alteredby phase I enzymes to become active against cancercells. Drugs that are introduced into the body in theiractive forms, on the other hand, are de-activated byphase I enzymes as a part of the process of their clear-

Clinical Corner


KIB and CG are at the Program for Collaborative Research in thePharmaceutical Sciences, University of Illinois at Chicago, Collegeof Pharmacy, Chicago, IL, and at the Block Center for IntegrativeCancer Care, Evanston, IL. KIB is also at the University of Illinois atChicago College of Medicine.

Correspondence: Keith I. Block, Block Center for Integrative CancerCare, 1800 Sherman, Suite 515, Evanston, IL 60201. E-mail:[email protected].

ance or removal from the body. Phase I enzymes havealso been of interest in the study of carcinogenesis be-cause they can activate certain carcinogens; substancesthat increase their activity, such as charcoal-grilledmeats, are suspected of being co-carcinogens. Sub-stances that inhibit these enzymes are considered tobe anticarcinogenic.6

Phase II enzymes accomplish a different chemicalprocess, referred to as conjugation. In conjugation, anew chemical entity is attached to a drug’s functionalgroup to make the drug more polar, facilitating itsremoval from the body. Among the chemical entitiesthat are conjugated to drugs are some sulfur-contain-ing compounds and glucuronic acid. Phase II enzymesare considered to have a significant role in disablingand exporting chemical carcinogens. Natural substancesfound in broccoli and other cruciferous vegetables(e.g., cabbage family, including Brussels sprouts, kale,mustard greens, cauliflower, etc.) increase the activityof phase II enzymes; they are thus important as anti-carcinogenic agents.7

From the viewpoint of drug pharmacokinetics, phaseII enzymes are usually regarded as not being rate-limiting in the breakdown of drugs. Phase II enzymes,however, may be of interest in other contexts for inte-grative cancer medicine, particularly in the area ofefficient removal of chemotherapy drug metabolitesthat have been de-activated after their cytotoxic effect,a topic that will not be addressed in this article. It isimportant to note that not all drugs go through thephase II metabolizing enzymes; many are removedafter metabolism by phase I cytochrome P450 enzymes.The activities of phase I and phase II enzymes on activedrugs and prodrugs are summarized in Table 1.

The Cytochrome P450 Drug-Metabolizing EnzymesThere are many types of cytochrome P450 (CYP450)enzymes that metabolize drugs; they are grouped intoclasses or families. Most drugs that are metabolized bythese enzymes are substrates of the families CYP1,CYP2, and CYP3, the largest number being metabo-lized by the CYP3 group.5

Individual enzymes in these families are given alpha-numeric names. Thus, the phase I enzyme most involvedin drug metabolism is CYP3A4, which metabolizesmore than 50% of the drugs that are substrates of theCYP enzymes. The next most active enzyme is CYP2D6.

The activity of CYP450 enzymes can be affected by anumber of factors. Genetic deficiencies of certainenzymes (such as CYP2D6) are known.8 Persons withliverdiseasemayhave insufficient levelsof someenzymes.Age, gender, stress, pregnancy, and intake of sub-stances that stimulate or suppress the activity of theseenzymes can affect drug metabolism.9 The CYP450

system is quite complicated, though, and we do notknow the clinical significance of all these factors.LeMarchand et al., for instance, surveyed CYP1A2activity in 90 Hawaiians of different ethnic back-ground.10 Using as variables plasma lutein, lycopene,and alpha-tocopherol, as well as intake of alcohol, caf-feine, aceta-minophen, hormonal replacement ther-apy, and a variety of other nutritional characteristics,these investigators were able to explain only 27% ofthe variance in CYP1A2 activity; 73% of varianceremained unexplained. The authors suggested thatacetaminophen and coffee enhanced CYP1A2 activity,whereas estrogen, alcohol, and foods containinglutein and alpha-tocopherol inhibited it. But due tothe large number of other factors, including unknownfactors that inhibit or enhance CYP450 activity, it wasfelt difficult to be certain that these effects are of greatclinical relevance.

Mechanistic studies of drug metabolism have revealedmore specific details of how activities of CYP450 enzymesare stimulated and opposed. Certain substances inducethese enzymes, or stimulate their production, some-times through activation of a genetic sequence knownas the xenobiotic response element, as was found forthe SJW interaction with theophylline.1 Other sub-stances directly inhibit the activity of certain CYP450enzymes, as is found for the well-known interaction ofgrapefruit juice (modulated by its content of naringeninand bergamotin) and CYP3A4. Another way in whichthe activity of an enzyme may be inhibited is throughsubstrate competition. In this instance, 2 substancesare both substrates for the same CYP450 enzyme. Ifboth are in the body in sufficient amounts at the sametime, the amount of enzyme normally available may beinsufficient to metabolize the amount of substrateavailable, so that neither substance will be effectivelymetabolized, or the substance with the higher affinityfor the enzyme in question will be metabolized prefer-entially to the other substrate. The effect will be simi-lar to inhibiting the activity of the CYP450 enzyme.

What are the consequences of CYP450 enzyme induc-tion or inhibition (including direct inhibition or sub-strate competition)? Consequences depend on thetype of drug being metabolized. For a prodrug that

Block, Gyllenhaal


Table 1. Functions of Phase I and Phase II Enzymes onProdrugs and Drugs Administered in Active Form

Phase I Phase IIDrug Type Enzymes Enzymes

Active drugs Activation, Conjugation,clearance clearance

Prodrugs Deactivation, Conjugation,clearance clearance

needs to be activated by a CYP450 enzyme, an excess ofthe enzyme, brought about by induction, might resultin higher levels of toxicity as the prodrug would beactivated more quickly than anticipated, although thishas not been shown clinically. More important forprodrugs, if the activity of the metabolizing enzymehas been inhibited, the anticipated drug level may below as the prodrug may not become fully activated,resulting in treatment failure. Higher or unexpectedtoxicity could result, also, if the prodrug itself is toxic.

For a drug administered in the active form, whichthe CYP450 enzyme deactivates, the consequences ofenzyme induction and inhibition will be the oppositeto those for prodrugs. If a metabolizing enzyme hasbeen induced, the drug will deactivate it more quickly,and a suboptimal dose and treatment failure couldresult. If the enzyme has been inhibited, on the otherhand, the drug may not be deactivated and clearednormally, blood levels of the drug may remain high fortoo long a time, and toxicity may result. This was seenin a study by Hirth et al., in which the levels of CYP450activity were measured by the erythromycin breath testin 22 cancer patients receiving docetaxel.11 Patientswith low CYP3A4 activity (corresponding to an inhib-ited status) had higher levels of grade 3 or 4 leukopenia,and grade 4 stomatitis, than patients with higher levelsof CYP3A4. The 2 patients with the lowest levels ofCYP3A4 activity were hospitalized for toxicity. On theother hand, the 4 patients in the study who met the cri-teria for partial remission also had lower CYP3A4 activ-ity, and thus, presumably, higher docetaxel levels.

Optimization of treatment with chemotherapeuticdrugs depends on setting drug dosage levels at a pointin relation to enzyme activities that balances the needfor sufficient blood levels of drug with the need toavoid toxicity. Intake of substances that induce orinhibit CYP450 enzymes beyond what is expected inpatient populations on which drug dosages may havebeen calibrated might upset this balance, resulting infailure of treatment or toxicity.

Recognized Inducers andInhibitors of CYP450 Enzymes

PhytomedicinesThe phytomedicine that sparked recent interest inherb-drug interactions, SJW, was found to be an in-ducer of the important drug-metabolizing enzymesCYP3A4 and CYP1A2.1 As is true with most other rec-ognized inducers and inhibitors, SJW induces onlyspecific CYP450 enzymes. It will thus have the poten-tial to affect only drugs metabolized by that enzyme.What are some of the other recognized inducers andinhibitors? As mentioned above, grapefruit juice is a

well-known inhibitor of CYP3A4 and of CYP2E1, andwarnings about food-drug interactions involving grape-fruit juice are commonly given to patients taking af-fected drugs. Charcoal-grilling of meat and cigarettesmoking both induce CYP1A1 and CYP1A2.12,13 The lat-ter is involved in carcinogenesis, but also in the metab-olism of tamoxifen. Some flavonoids induce, whereassome inhibit CYP1A2.14 Cruciferous vegetables andtheir indole compounds induce CYP1A1, CYP1A2,CYP2B1, and CYP2E1 (the last is also involved in themetabolism of tamoxifen).15,16 Watercress, with its ac-tive compound phenylisothiocyanate (PEITC), is astrong inhibitor of CYP2E1,17 as are garlic oil and somegarlic compounds.18 Chronic alcohol intake also in-duces CYP2E1, whereas acute intake inhibits it.19

In addition to inducers and inhibitors, some com-monly used (or abused) natural compounds can act assubstrate competitors for certain CYP450 enzymes.These include caffeine (a substrate of CYP1A2 andCYP2E1), alcohols (substrate of CYP2E1), and nico-tine (substrate of CYP2A6).20,21 It is worth noting herethat some commonly used no-prescription drugs aresubstrates of CYP450 enzymes: acetaminophen (CYP1A2,CYP3A4) and dextromethorphan (CYP2D6).22

Other recent studies uncovering some potentialdrug-herb interactions must be viewed as preliminary.In vitro screening tests are available that examine thecapacity of different substances to induce or inhibitCYP450 enzymes, and some of these have been appliedto herbal medicines. Rosemary has been shown toinhibit CYP1A2 and CYP3A4 activities.23 Different com-pounds in Korean ginseng and other members of thegenus Panax, known as ginsenosides, induce CYP3A4and CYP2C9, or inhibit CYP3A4 in vitro; however, therelevance of these activities to the human situation wasunclear and consequently they are not presented inthe tables in this article.24 A recent in vitro studyreported inhibition of CYP3A4 by several commonlyused herbs (Saint John’s wort, echinacea, goldenseal,cat’s claw, licorice, chamomile, and red clover), againwithout any further investigation of the potential clini-cal significance.25 Other natural substances have alsobeen tested in vitro for interactions with cytochromeenzymes. Capsaicin, the “hot” constituent of chili pep-pers, and ellagic acid, a constituent of berry fruits,both inhibited CYP450 enzymes, including 2A2, 3A1,2B2, and 2C6.6 In vitro data, however, cannot be usedreliably as a guide to activity in humans; Obach observedinhibition of CYP3A4 in vitro by SJW26 whereas Durret al. and Roby et al. recorded induction of 3A4 inhumans.27,28 Yohimbine, a natural phytochemical derivedfrom the African herbal medicine Pausinystalia johimbePierre ex Beille (Rubiaceae), is used as an aphrodi-siac.29 The herbal medicine is used in potency enhancersand in various weight loss products and has been

Clinical Corner


found to inhibit CYP2D6.30 The clinical effects of SJWon cyclosporin are also consistent with an inductionmechanism. Other than SJW, no clinical reports ofdrug interactions have been located for any of thesenatural substances, and their potential for significantinteractions must be regarded as strictly theoretical.

Data on Cancer TreatmentDrugs Metabolized by CYP450Bearing in mind the different levels of evidence forthe biological effects of the various herbal medicinesdiscussed, we have compiled in Tables 2 and 3 the liter-ature on botanicals, foods, and lifestyle factors thatmay potentially affect drugs used in cancer treatment.Table 2 presents information on the drugs used fortheir anticancer effects (cytotoxic or hormonal), whereasTable 3 presents data on some ancillary drugs used inthe supportive care of cancer patients. Each tableshows the drugs; whether they are administered asprodrugs or active drugs; the enzymes for which theyare substrates; the substances that are inducers, inhibi-tors, or substrate competitors for each enzyme; andthe potential effects of induction, inhibition, and sub-strate competition.

Inducers, inhibitors, and competitors that are knownto affect drug metabolism in humans are shown inboldface; SJW and grapefruit are the 2 so designated.Cruciferous vegetables and charcoal-grilled meats areshown in italics, as they are strongly suspected tometabolize xenobiotics on the basis of their epidemio-logical links to carcinogenesis. Watercress is in italicsbecause of the noted strong activity of PEITC.17 Nospecific reports of effects on drug metabolism havebeen noted for these, however. Inducers, inhibitors,and competitors that have only experimental evidenceare shown in regular type. It is notable in the table thatthe largest number of potential interactions is shownwith CYP3A4, consistent with its role as a metabolizerof many important drugs.

For the 1 prodrug in Table 2, ifosfamide, ingestionof a strong inducer could potentially activate more ofthe prodrug, or activate it more quickly, than usuallyanticipated, resulting in toxicity. In fact, tumor cellsthat overexpress CYP2B1 for local injection are nowbeing investigated as potential treatments for cancersthat are otherwise resistant to the effects of ifosfamide.31

Ifosfamide is metabolized to a neurotoxic inactivecompound as well as an active form, also by the CYP450enzymes, and induction of the enzymes would resultin higher levels of the neurotoxic compound.32 Inhibi-tors, however, would result in failure of activation andthus insufficient blood levels of active drug. Cyclo-phosphamide, a drug well known to be activated by theCytochrome P450 system, is activated by the CYP2B

system, for which no natural product inhibitors orinducers have been noted.5 For the drugs in the tableadministered in the active form, the CYP3A4 inhibitorscould, by deactivating the drug too rapidly, result intreatment failure.

Tamoxifen is the drug with the largest number ofpotential inhibitors and inducers that might affecttherapeutic outcome. Among major inducers, whichwould result in treatment failure if their interactionswere clinically significant, are charcoal-grilled meats,alcohol, high-fat diets, protein, nicotine, and cruciferousvegetables. Among inhibitors are watercress, grape-fruit, and garlic, whereas caffeine, alcohol, and nico-tine could act as competitors. The clinical significanceof the variety of actors in the metabolism of patientstreated with tamoxifen has yet to be explored. Fromthe perspective of integrative care, patients on cancer-oriented vegetarian-type diets would be likely to increasetheir consumption of cruciferous vegetables and gar-lic. However, they would also be likely to decrease theirconsumption of meats, alcohol, fat, nicotine, and caf-feine. One could speculate that the overall result,therefore, might be similar to the populations onwhom initial tamoxifen dosage recommendations weredeveloped, although no specific data on this questionexist.

Clinical SignificanceThe first point to be made about the tables is that theonly natural substances that have been observed to af-fect metabolism of drugs in humans are SJW andgrapefruit, and, of these, SJW has not been actually ob-served to affect any drugs used in cancer treatment.The other interactions we list are either theoretical,based on in vitro testing, or based on preliminarypharmacological research. Thus, it is unreasonable toconclude that, for instance, the several common herbsreferred to in the table will all interfere with thesedrugs. It is even questionable to conclude that SJW willalways have clinically relevant effects. For instance,Burstein et al.33 found no effect of SJW on the metabo-lism of carbamazepine, a CYP3A4 substrate, in healthyvolunteers, whereas Markowitz et al.34 found no effectson the drugs dextromethorphan, a CYP2D6 substrate,or alprazolam, a 3A4 substrate. Petersen et al.35 re-viewed research on the effects of omeprazole, a con-ventional drug for gastro-esophageal reflux that inhib-its the CVYP2C subfamily and induces the CYP1Asubfamily. The CYP1A induction of omeprazole wouldbe expected to increase the liver toxicity of aceta-minophen, although this is not reported clinically.However, the much stronger inducers, cigarette smokeand charcoal-grilled beef, are actually unable to alteracetaminophen metabolism.35 The effect of SJW on

Block, Gyllenhaal


cancer drugs may depend on the pharmacologicalcharacteristics of each drug: cyclosporin, for instance,has a small therapeutic window and is known to be sen-sitive to medications that modulate CYP3A4. It is alsosensitive to the modulation of P-glycoprotein expres-sion—another system affected by SJW.27,9,36 The clinicalimpact of the inducers and inhibitors on these lists isthus difficult to predict at this time. Since docetaxel,one of the drugs known to be a substrate for CYP3A4,

has been found to have outcomes that vary by patients’CYP3A4 levels, this might be a drug that might be clini-cally affected by an SJW interaction.11 An additionalcomplication is that other antidepressants also havepotential drug interactions: fluoxetine, for instance,inhibits CPY2D6 and CYP2C19.19

An interesting possibility, yet to be explored inexperimental or clinical settings, is the use of CYP450inducers or inhibitors to positively alter drug meta-

Clinical Corner


Table 2. Interactions of Cancer Chemotherapy Drugs With Natural Inhibitors and Inducers of CYP450 Enzymes

Theoretical TheoreticalDrug Activity Substrate of Inducers Result Inhibitors Result Competitors

Anastrozole Antiestrogen 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophencommon herbs?1

Busulfan Alkylating 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophenagent common herbs?

Docetaxel Microtubule 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminopheninhibitor common herbs?

Doxorubicin DNA 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophenintercalation common herbs?

Estradiol Estrogen 1A2 Charcoal-grilled Failure Rosemary, Toxicity Caffeinemeats, SJW, grapefruitcigarette smokecrucifers, caffeine

3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophencommon herbs?

Ethynyl Estrogen 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophenestradiol common herbs?

Etoposide Microtubule 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminopheninhibitor common herbs?

Finasteride Antiandrogen 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophencommon herbs?

Flutamide Antiandrogen 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophencommon herbs?

Ifosfamide Alkylating 3A3/4 SJW Toxicity Grapefruit, Failure Acetaminophenagent, prodrug common herbs?

2B1 Crucifers ToxicityPaclitaxel Antimicrotubule 2C8 Quercetin Failure


Tamoxifen Antiestrogen 1A2 Charcoal-grilled Failure Rosemary, Toxicity Caffeinemeats, SJW, grapefruitcigarette smoke,crucifers

2A6 Grapefruit Failure Nicotine2E1 Alcohol (chronic), Failure Grapefruit, Toxicity Alcohol,

corn oil, high-fat watercress, caffeine,diets, crucifers, garlic acetaminophencigarette smoke


Teniposide Microtubule 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminopheninhibitor common herbs?

Tretinoin Retinoic acid 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophencommon herbs

Vinblastine Vinca alkaloid 3A3/4 SJW Failure Grapefuit, Toxicity Acetaminophencommon herbs?

Vincristine Vinca alkaloid 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophencommon herbs?

Grapefruit and SJW in bold type have reports of clinically significant interactions with some drugs, not necessarily in this table.SJW = SaintJohn’s wort.1. Common herbs reported to be CYP3A3/4 inhibitors in vitro: echinacea (Echinacea spp., Astraceae), goldenseal (Hydrastis canadensisL [Ranunculaceae]), cat’s claw (Uncaria tomentosa DC. [Rubiaceae]), licorice (Glycyrrhiza glabra L [Fabaceae]), chamomile (Matricariarecutita L [Asteraceae]), red clover (Trifolium pratense L. [Fabaceae]). No in vivo reports of drug interaction have been located for theseherbs.

bolism. For instance, a patient in whom docetaxelappeared to be ineffective, or whose CYP3A4 activitywas known to be high, could be given grapefruit as aninhibitor to raise blood levels and potentially increaseeffectiveness—bearing in mind, of course, the risk ofincreased toxicity.

For now, however, use of inducers and inhibitors inadjusting the balance between treatment efficacy andtoxicity must await further research. We are not able,either, to predict with certainly which of the potentialinteractions listed in these tables will prove to be ofclinical relevance. However, it does seem reasonableto take into account clinically the inducers and inhibi-tors that are known to affect the metabolism of cancerdrugs in making decisions about the use of food andherbal medicines during chemotherapy, because ofthe critical nature of cancer treatment. The physiciancaring for a depressed cancer chemotherapy patientwho wishes to take SJW may need to weigh the poten-tial drawbacks of temporarily changing the patient’santidepressant prescription to another drug againstthe potential, however uncertain, effect of causingincreased toxicity or treatment failure, with poten-tially grave consequences.

AcknowledgmentsThe assistance of fourth-year pharmacy interns from the Univer-

sity of Illinois at Chicago College of Pharmacy, especially Kyung-HeeLee and Peter Kim, is gratefully acknowledged.

References1. Nebel A, Schneider BJ, Baker RK, Kroll DJ. Potential interac-

tions between St. John’s wort and theophylline. Ann Pharmacother.1999;33:502.

2. Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G. Acuteheart transplant rejection due to Saint John’s wort. Lancet.2000;355:548-549.

3. Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M,Roots I. Pharmacokinetic interaction of digoxin with an herbalextract from St. John’s wort (Hypericum perforatum). Clin PharmacolTher. 1999;66:338-345.

4. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J.Indinavir concentrations and St. John’s wort. Lancet. 2000;355:547-548.

5. Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, GilmanAG. Goodman & Gilman’s The Pharmacological Basis of Therapeu-tics. 9th ed. New York: McGraw Hill; 1996.

6. Zhang Z, Hamilton SM, Stewart C, Strother A, Teel RW. Inhibi-tion of liver microsomal cytochrome P450 activity and metabo-lism of the tobacco-specific nitrosamine NNK by capsaicin andellagic acid. Anticancer Res. 1993;13:2341-2346.

7. Kensler TW, Curphey TJ, Maxiutenko Y, Roebuck BD. Chemo-protection by organosulfur inducers of phase 2 enzymes:dithiolethiones and dithiins. Drug Metabol Drug Interact.2000;17:3-22.

Block, Gyllenhaal


Table 3. Interactions of Drugs Used in Supportive Care of Cancer Patients, With Natural Inhibitors and Inducers of CYP450Enzymes

Theoretical TheoreticalDrug Activity Substrate of Inducers Result Inhibitors Result Competitors

Dexamethasone Steroid 3A4 SJW Failure Grapefruit, Toxicity Acetaminophencommon herbs?

Diphenhydramine Antihistamine 2D6 Yohimbine FailureDolasetron Antinausea 2D6 Yohimbine Failure

3A4 SJW Failure Grapefruit, Toxicity Acetaminophencommon herbs?

Granisetron Antinausea 3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophencommon herbs?

Hydrocortisone Anti-inflammatory 2D6 Yohimbine Failure3A3/4 SJW Failure Grapefruit, Toxicity Acetaminophen

common herbs?Meperidine Analgesic/narcotic 2D6 Yohimbine FailureMetoclopramide Antinausea 2D6 Yohimbine Failure

1A2 Charcoal-grilled Failure Rosemary, Toxicity Caffeinemeats, SJW, grapefruitcigarette smoke,crucifers, caffeine

Morphine Pain 2D6 Yohimbine FailureOndansetron Antinausea 1A2 Charcoal-grilled Failure Rosemary, Toxicity Caffeine

meats, SJW, grapefruitcigarette smoke,crucifers, caffeine

2D6 Yohimbine Failure2E1 Alcohol (chronic), Failure Grapefruit, Toxicity Alcohol, caffeine,

corn oil, high-fat watercress, garlic acetaminophendiets, crucifers


Grapefruit and SJW in bold type have reports of clinically significant interactions with some drugs, not necessarily in this table.SJW = SaintJohn’s wort.

8. Britzi M, Bialer M, Arcavi L, Shachbari A, Kapitulnik T, SobackS. Genetic polymorphism of CYP2D6 and CYP2C19 metabo-lism determined by phenotyping Israeli ethnic groups. TherDrug Monit. 2000;22(5):510-516.

9. Wilkinson GR. The effects of diet, aging and disease-states onpresystemic elimination and oral drug bioavailability in humans.Adv Drug Deliv Rev. 1997;27:129-159.

10. LeMarchand L, Franke AA, Custer L, Wilkens LR, Cooney RV.Lifestyle and nutritional correlates to cytochrome CYP1A2activity: inverse associations with plasma lutein and alpha-tocopherol. Pharmacogenetics. 1997;7:9-11.

11. Hirth J, Watkins PB, Strawderman M, Schott A, Bruno R, BakerLH. The effect of an individuals cytochrome CYP3A4 activity ondocetaxel clearance. Clin Cancer Res. 2000;6:1255-1258.

12. Kall MA, Clausen J. Dietary effect on mixed function P450 1A2activity assayed by estimation of caffeine metabolism in man.Hum Exp Toxicol. 1995;14:801-807.

13. Heudorf U, Angerer J. Urinary monohydroxylated phenan-threnes and hydroxypyrene—the effects of smoking habits andchanges induced by smoking on monooxygenase-mediatedmetabolism. Int Arch Occup Environ Health. 2001;74(3):177-183.

14. Li Y, Wang E, Patten CJ, Chen L, Yang CS. Effects of flavonoidson cytochrome P450-dependent acetaminophen metabolismin rats and human liver microsomes. Drug Metab Dispos. 1994;22:566-571.

15. Lampe JW, King IB, Li S, Grate MT, Barale KV, Chen C, et al.Brassica vegetables increase and apiaceous vegetables decreasecytochrome P450 1A2 activity in humans: changes in caffeinemetabolite ratios in response to controlled vegetable diets.Carcinogenesis. 2000;21:1157-1162.

16. Smith TJ, Guo Z, Li C, Ning SM, Thomas PE, Yang CS. Mecha-nisms of inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone bioactivation in mouse by dietary phenethyl isothio-cyanate. Cancer Res. 1993;53:3276-3282.

17. Leclerq I, Desager JP, Horsmans Y. Inhibition of chlorzoxazone,a clinical probe for CYP2E1, by a single ingestion of watercress.Clin Pharmacol Ther. 1998;64:144-149.

18. Sheen LY, Chen HW, Kung YL, Liu CT, Lii CK. Effects of garlicoil and its organisulfur compounds on the activities of hepaticdrug-metabolizing and antioxidant enzymes in rats fed high-and low-fat diets. Nutr Cancer. 1999;35:160-166.

19. van Schalwyck J. Cryptochrome P450: Alphabetical Drug List.The Worldwide Anaesthetist.Available at: www.anaesthetist.com/physiol/basics/metabol.

20. Rasmussen BB, Brosen K. Determination of urinary metabo-lites of caffeine for the assessment of cytochrome P4501A2,xanthine oxidase, and N-acetyltransferase activity in humans.Ther. Drug Monit. 1996;18(3):254-62.

21. Nakajima M, Kwon JT, Tanaka N, Zenta T, Yamamoto Y,Yamamoto H, et al. Relationship between interindividual dif-ferences in nicotine metabolism and CYP2A6 genetic polymor-phism in humans. Clin Pharmacol Ther. 2001;69:72-78.

22. Xenotech LLC. Reference Guide to Substrates, Inhibitors and Inducersof the Major Human Liver Cytochrome P450 Enzymes Involved inXenobiotic Transformation. Kansas City, KS: Author; n.d.

23. Offord EA, Mace K, Ruffieux C, Malnoe A, Pfeifer AM. Mecha-nisms involved in the chemoprotective effects of rosemaryextract studied in human liver and bronchial cells. Cancer Lett.1997;114:275-281.

24. Henderson GL, Harkey MR, Gershwin ME, Hackman RM,Stern JS, Stresser DM. Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic activity. LifeSci. 1999;65:PL209-PL214.

25. Budzinski JW, Forster BC, Vandnhoek S, Arnason JT. An in vitroevaluation of human cytochrome P450 3A4 inhibition by selectedcommercial herbal extracts and tinctures. Phytomedicine. 2000;7:273-282.

26. Obach RS. Inhibition of human cytochrome P450 enzymes byconstituents of St. John’s wort, an herbal preparation used inthe treatment of depression. J Pharmacol Exp Ther. 2000;294:88-95.

27. Durr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC,Meier PJ, et al. St. John’s wort induces intestinal P-glycoproteinMDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther.2000;68:598-604.

28. Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AH. St.John’s wort: effect on CYP3A4 activity. Clin Pharmacol Ther.2000;67:451-457.

29. Mansoor GA. Herbs and alternative therapies in the hyperten-sion clinic. Am J Hypertens. 2001;19:971-975.

30. McCarty MF. Modulation of adipocyte lipoprotein lipase expres-sion as a strategy for preventing or treating visceral obesity. MedHypotheses. 2001;57:192-200.

31. Lohr M, Muller P, Karle P, Stange J, Mitzner S, Jewnowski, et al.Targeted chemotherapy by intratumor injection of encapsu-lated cells engineered to produce CYP2B1, an ifosfamide acti-vating cytochrome P450. Gene Ther. 1998;5:1070-1078.

32. Brain EG, Yu LJ, Gustafsson K, Drewes P, Waxman DJ. Modula-tion of P450-dependent ifosfamide pharmacokinetics: a betterunderstanding of drug activation in vivo. Br J Cancer. 1998;77:1768-1776.

33. Burstein AH, Horton RL, Dunn T, Alfaro RM, Piscitelli SC, The-odore W. Lack of effect of St. John’s wort on carbamazepinepharmacokinetics in healthy volunteers. Clin Pharmacol Ther.2000;68:605-612.

34. Markowitz JS, DeVane CL, Boulton DW, Carson SW, Nahas Z,Risch SC. Effect of St. John’s wort (Hypericum perforatum) oncytochrome P-450 2D6 and 3A4 activity in healthy volunteers.Life Sci. 2000;21:PL133-PL139.

35. Petersen KU. Review article: omeprazole and the cytochromeP450 system. Pharmacol Ther. 1995;9:1-9.

36. Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR.Drug interaction between St. John’s wort and cyclosporine.Ann Pharmacother. 2000;34:1013-1016.

Clinical Corner


Block et al.Point-Counterpoint Point-Counterpoint

Point-Counterpoint: Soy Intakefor Breast Cancer Patients

Keith I. Block, MD, Andreas Constantinou, PhD, Leena Hilakivi-Clarke, PhD, Claude Hughes, MD,PhD, Debu Tripathy, MD, and Jeffrey A. Tice, MD

Should breast cancer patients consume soy, either assoy foods or soy supplements? Postmenopausal patients,as well as patients experiencing early menopauseinduced by adjuvant chemotherapy, may be inclinedto use soy products as a “natural” alternative to hor-mone replacement therapy (HRT). Others may bemotivated to consume soy products based on thebelief that they may improve their prognosis or pre-vent a recurrence. Such beliefs lack the support ofclinical data, as relatively few studies of soy have yieldedinformation relevant to individuals diagnosed withbreast cancer. Moreover, concern has arisen over apotential adverse impact of soy intake by breast cancerpatients because of the estrogen-like effects of theisoflavones, notably genistein and daidzein, containedin soy. Estrogens have been linked to breast cancerpromotion and progression, and some preclinical stud-ies suggest that soy or its isoflavones may indeed increaseproliferation of breast cancer cells. Other laboratoryresearch indicates, however, that genistein and daidzeinexert a wide range of anticancer activities as well.

The estrogenic effects of soy have led to controversyamong both researchers and health professionals overthe use of soy (and particularly soy-derived supple-ments) by breast cancer patients. Dr. William Helferich,an associate professor of nutrition at the University ofIllinois, has publicly expressed concern that post-menopausal women with estrogen-dependent breastcancer may be harmed by soy supplements. Dr. Greg-ory Burke, chairman of the public health sciencesdepartment at Wake Forest University School of Medi-cine in Winston-Salem, North Carolina, is worried thatwomen may overdose on isoflavone pills, which mayprovide doses up to 10 times as much as women con-sume in Japan. Dr. Daniel Sheehan, a research biolo-gist at the Food and Drug Administration’s NationalCenter for Toxicological Research in Jefferson, Arkan-sas, contends that there are different degrees of sus-ceptibility in different organs, depending on age, andthat consequently the same individual may show bothbeneficial and adverse outcomes. Such intense debatehas caused considerable perplexity and consternation

among breast cancer patients currently undergoingtreatment, as well as among postmenopausal survivors.

Unfortunately, human studies of soy and cancerhave focused primarily on prevention, not treatment.Soy is thought to play a role in the low rates of breastcancer seen in Asian populations, in which soy con-sumption is an order of magnitude higher than inWestern populations.1 One meta-analysis of observa-tional studies in Asia and the United States concludedthat increased soy consumption is associated with a20% reduction in the risk of breast cancer in pre-menopausal women, while having no effect in post-menopausal women.2 In the 2 U.S. studies to date,median soy intake levels were so low that they may onlyhave been a marker for healthier eating patterns ingeneral. The remaining studies were conducted inAsia, where soy is consumed from early childhood.Asian women living in their native country are exposedto soy’s effects in the critical adolescent years of breastdevelopment. In animal studies, neonatal and early-life exposures to soy genistein prevented the develop-ment of dimethylbenz[a]anthracene (DMBA)-inducedmammary adenocarcinomas, whereas exposure in adult-hood had little or no effect.3,4 During the 1990s, CoralLamartiniere of the University of Alabama and LeenaHilakivi-Clarke of Georgetown University independ-ently postulated that during this early-life period, theestrogenic effects of soy may stimulate breast cells todifferentiate in a manner that protects them againstcarcinogenic agents.5,6

Block et al.


KIB is at the Block Center for Integrative Cancer Care, Evanston, Il-linois and the College of Medicine, University of Illinois at Chicago.AC is at the College of Medicine, University of Illinois at Chicagoand the College of Medicine, University of Illinois at Chicago.LHC isin the Department of Oncology, Georgetown University, Washing-ton, D.C. CH is in the Department of Obstetrics and Gynecology,Duke University Medical Center, Durham, North Carolina. DT is inthe Department of Medicine, Division of Hematology and Oncol-ogy, University of California, San Francisco. JAT is in the Depart-ment of Medicine, University of California, San Francisco.

Correspondence:Keith I. Block, Block Center for Integrative Can-cer Care, 1800 Sherman Avenue, Suite 515, Evanston, IL 60201.Tel: 847-492-3040. E-mail: [email protected].

The arguments of Lamartiniere and Hilakivi-Clarkesuggest that soy may be helpful if consumed in earlylife, but confer no benefit if consumed later in life.This line of argument, however, does not rule out apossible therapeutic effect of soy after tumors havealready developed; nor does it rule out the possibilitythat soy could help prevent the recurrence of tumorsfollowing cytoreduction. In this latter regard, animalstudies have indicated that soy may magnify the chemo-preventive effects of tamoxifen.7,8 Andreas Constantinouand colleagues9 recently reported that the incidenceof DMBA-induced mammary tumors was reduced 29%with tamoxifen, 37% with soy protein isolate, and 62%by the combination; tumor latency increased only inthe combination group. In contrast, the evidence fromin vitro studies has been mixed, with some studies sug-gesting synergism10,11 and others indicating antago-nism between soy and tamoxifen.12

Several mechanisms have been proposed for thecancer-inhibiting effects of soy, including inhibition oftyrosine kinase, inhibition of DNA topoisomerase,inhibition of cell cycle progression and angiogenesis,and antiestrogenic effects (competition with estrogenfor binding to receptors).13 Soy genistein may preventmetastasis by down-regulating the production of matrixmetalloproteinases (MMPs) or up-regulating MMPinhibitors.14 The precise dosage of soy needed to mod-ulate these different mechanisms remains unknown,although many researchers believe that very high,supraphysiologic doses are needed for maximal effects.The question of soy’s interaction with other estrogen-modulating components of the diet (e.g., fat, fiber,indole-3-carbinol) merits attention as well.

Given the range of potential therapeutic effects, doconcerns with regard to the estrogenic effects of thesoy isoflavones have merit? Should breast cancer patientsbe consuming soy? How do soy researchers reconcilethe well-substantiated chemopreventive properties ofsoy foods with the apparent ability of soy isoflavones tostimulate the growth of breast cancer cells?

Scientists concerned about soy use also concludefrom the data on stimulation of breast cancer cells,animal tumor growth and weak estrogenic effects ofsoy in humans that cancer patients have reason to beconcerned about soy use.15 Recommendations by thesescientists include such cautions as avoiding consump-tion of soy isoflavone supplements and avoidance ofsoy by women who do not have cancer but are at highrisk for estrogen receptor positive (ER+) cancer. Accord-ing to these recommendations, cancer patients whohave not previously consumed soy would not increasesoy intake as part of a cancer treatment program.Although women who already consumed soy beforebreast cancer diagnosis may continue to include it intheir diets.1

The question of whether to consume soy continuesto plague women with breast cancer and to baffle phy-sicians who would like to support their patients’ self-care choices in a way that promotes, than impedes,recovery from cancer. In our Point-Counterpoint fea-ture this issue, we explore several dimensions of thecontroversy based on opinions from researchers whohave investigated the potential effects of soy and con-sidered its impact on women with breast cancer. Wewill consider data indicating that soy consumptionmay affect the course of malignant disease and thusthe survival of breast cancer patients. We provideresponses of several soy researchers and 2 clinicians tospecific questions with regard to the possible impact ofsoy after a diagnosis of breast cancer. Some of the pan-elists provided a written response to the questions thatincluded citations. Others elected to respond eitherverbally or in writing without citing the medical litera-ture. The resulting roundtable discussion provides adiverse range of perspectives. An integrative clinicalperspective follows the individual responses.

—Keith Block

Question 1:

What is your (brief) assessment of the state of research onthe estrogenic effects of soy at this time?

Constantinou: We are only beginning to understand thediverse estrogen-modulating effects of soy and its com-ponents in a variety of tissues. We’ve identified a sur-prisingly large number of biological responses thatcan be modulated by soy and its main components.The main components of soy are the soy isoflavonesgenistein and daidzein, saponins, Bowman-Birk pro-tease inhibitor, and phytic acid. Processes that aremodulated at the cellular level are cell growth and dif-ferentiation, cell cycle progression, and expression ofestrogen responsive genes. In rodents, soy preventscarcinogen-induced mammary tumors, prostate can-cer, and colon cancer. At the human level, soy isknown to alter hormonal levels and change the men-strual cycle in women. Apparently, studies suggest thatsoy may reduce the frequency and severity of symp-toms associated with menopause including osteopo-rosis and hot flashes. Soy clearly provides cardiovascu-lar benefits in both men and women, and it may alsoreduce the risk of breast cancer in women and pros-tate cancer in men. Despite all these effects of soyfoods such as soy protein isolate, soy milk, and tofu, itis presently not clear whether these benefits are due tospecific components of soy (i.e., isoflavones).

In a recent set of studies I submitted to Nutritionand Cancer, there were significant effects of dietary soyin the form of soy protein isolate (SPI), with or with-out isoflavones, for preventing mammary tumors. This

Point-Counterpoint


suggests that, rather than the isoflavones, other com-ponents contained within soy may be responsible forthe antitumor effects. Alternatively, a combination ofisoflavones and other dietary components (either fromsoy or nonsoy sources) may be needed. We should notunderestimate the effects of isoflavones, particularlydaidzein, which seems to have a stronger effect thangenistein. At the present time, I’m carrying out in vivostudies as well to evaluate the effects of either genisteinor soy protein, to see whether the growth of mammarytumors can be suppressed. So far, however, we’ve seenonly marginal effects on the prevention of mammarytumors. Effects on existing tumors are even less clear.

Hilakivi-Clarke: Soy contains an estrogenic componentgenistein. At physiological concentrations, genisteinhas been shown to actively bind to estrogen receptors.The implications of this activity are unclear, however,because soy foods also contain many other compo-nents that might interfere with genistein’s estrogenicproperties. Thus, we do not yet know how soy prod-ucts, as food, might affect women with breast cancer.That is to say, we don’t know whether it will have anestrogenic impact or not.

Hughes: The estrogenic actions of the isoflavones in soyare reasonably well understood. These compoundsare weak agonists at the ER-α and moderate agonistsat the ER-β. The key to understanding the target tis-sues of actions of isoflavones will be to discern theintracellular signaling pathways mediated by these 2estrogen receptors and potentially other nuclear ornonnuclear receptors in people who have breast can-cer. Isoflavones should be expected to be weak estro-genic agonists.

Tice: Soybeans contain isoflavones, phenolic compoundsthat are structurally similar to estradiol, bind to estro-gen receptors (ERs), and have higher relative bindingaffinities for ER-β than for ER-α.16 Thus, soy has thepotential to have either estrogenic or antiestrogeniceffects. However, there are few data documentingestrogenic effects of soy on humans at this time. Moststudies have found no effect of soy protein or isolatedisoflavones on the vaginal maturation index, a mea-sure of estrogenic effect on vaginal mucosa.17-22 Otherstudies have found no effect of soy on the endo-metrium.19,21-23 However, there is evidence that soy affectsboth menstrual cycle length24,25 and hormone levels inmenstruating women.26 Furthermore, 3 studies havesuggested modest estrogenic effects of soy on thebreast.27-29 The data on relief of hot flashes is mixed,with some studies reporting a modest beneficialeffect30-32 and others reporting no benefit comparedwith placebo.33

Tripathy: It’s always difficult to extrapolate from labora-tory or epidemiologic research to clinical practice.The epidemiologic studies indicate that younger womenare at lower risk of developing breast cancer if they eatmore soy. The question is whether that research hasany clinical relevance, and specifically whether soywould modify the risk of breast cancer recurrence in awoman who already has cancer. Consider the case of

estrogen. We know that estrogen replacement therapyor oral contraceptives for 10 years or more is associ-ated with a higher risk of getting breast cancer. But ifyou’ve already been diagnosed with breast cancer, wedon’t know whether either estrogen replacement ther-apy or oral contraceptives increase your risk of recur-rence. The small studies that have been done so farsuggest this is not the case. The first point, then, is it’sdifficult to extrapolate epidemiologic studies of pri-mary prevention onto the clinical goal of secondaryprevention. We need clinical trials to actually demon-strate that effect.

The second general area is this whole question ofhow to interpret laboratory data in terms of the estro-genic potential of some of the compounds in soy—theisoflavones genistein and daidzein—and again trans-late this into something of clinical relevance. The con-servative view is that we simply don’t know the impactof soy, either at normal or very high doses. We don’tknow whether moderate or high doses of soy proteinare helping or possibly harming the patient with breastcancer. In the absence of prospective randomized tri-als, it’s difficult to make any clinical recommenda-tions for breast cancer patients.

In some cell culture studies, high doses of soy pro-tein have shown stronger anticancer effects than lowdoses, which appear to be either ineffective or growth-stimulatory. One also sees this bimodal effect withserum estradiol. That is, with very low concentrationsyou have growth, whereas high concentrations giveyou growth inhibition. Because phytoestrogens arebound by proteins, however, it’s unlikely that evenvery high doses will have a substantial effect. (Estradioland other estrogens are bound to proteins as well.)The effects that you see with phytoestrogens in vitroappear to be greatly attenuated in vivo.

Question 2:

Are soy foods safe for postmenopausal breast cancer patientsinmoderate amounts? How about for premenopausal patients?What can we say about safety with regard to estrogen-receptor status (ER+ vs. ER–) in these 2 groups of patients?Are there doses that you feel are safe/unsafe?

Constantinou: The epidemiological data suggest thatconsumption of soy products is safe. Asians regularlyconsuming soy products have substantially lower ratesof breast and prostate cancer than people from theWest consuming diets that are devoid of soy. The riskassociated with high soy intake is probably about 25%less for breast cancer and possibly the same for pros-tate cancer. Only a few studies evaluated the effects ofsoy diets in non-Asians. With respect to human inter-vention studies, unfortunately, the data are not verystrong. There is definitely an effect of soy diet on hor-monal levels, and you will see what appear to beestrogen-modulating effects. Patients’ estrogen lev-els, menstrual cycle patterns, and excretion of harmful

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estrogen metabolites will change in a favorable direc-tion in terms of lowering breast cancer risk. The datahave been focused mainly on evaluating tumor mark-ers and hormonal levels. Although intervention dataindicate that soy diets alter hormonal levels in bothmen and women, studies of tumor markers are incon-clusive and conflicting. In a pilot study by Petrakis andcolleagues,27 Western women eating soy showed ahigher proliferative index as measured by nipple aspi-rate. Other studies indicate that proliferative markersactually decrease, which of course would be protec-tive. We are currently studying the effects of soy onnipple aspirate in a more controlled way. The Petrakisstudy had several design problems that seriously limitour interpretation because they compromise the reli-ability and validity of the findings.

With respect to ER status and safety, there are nodata at present in human populations, at least to myknowledge. The general thinking at this time is that ifyou’re an ER+ breast cancer patient, you shouldn’ttake soy products because genistein in soy acts as anestrogen and is going to increase the proliferation oftumor cells. Frankly, I think the premise that ER+ can-cer patients may be placed at a higher risk by eatingsoy products is narrow minded. This thinking is basedrather simplistically on the estrogenic effects of soygenistein. However, we have to consider the 2 maintypes of estrogen receptors as well, namely, ERα andERβ. Genistein binds to the ERβ with a much higheraffinity compared to ERα, and the greater bindingactivity of ERβ may lead to biological responses thatare not well understood. For instance, the genistein-ERβ complex may result in an antiproliferative (andantiestrogenic) response in tumor cells that are ERβ+.More studies are needed, because at this point we areattempting to answer the question almost entirely at atheoretical level.

Hilakivi-Clarke: We do not know whether soy foods aresafe for postmenopausal breast cancer patients (orpostmenopausal women not diagnosed with breastcancer). Animal data would suggest that they are notsafe, but human studies have not indicated that soyintake would increase breast cancer risk. Findingsobtained in animals with intact ovaries (premeno-pausal) suggest that soy is either protective or has noeffect. Human data clearly indicate that premeno-pausal breast cancer risk is reduced in women con-suming soy.

Genistein binds preferentially to ERβ, and we donot know what the function of this receptor is. It mightreduce breast cancer risk, but it might also be linkedto poor prognosis. Women with ER– tumors are ERα–but may be ERβ+. Thus, at this point it cannot be con-cluded whether soy is “safer” in ER– compared to ER+women.

Hughes: If a moderate amount is on the order of a serv-ing per day or less, then I think so. When you get tomultiple servings per day, it is hard to say whether itwould be safe. In terms of the safety with regard toestrogen-receptor status (ER+ vs. ER–) in these 2

groups of patients, we can say virtually nothing spe-cific. If there is concern about use of small amounts ofa potent estrogen agonist (such as a small transdermalskin patch) in a patient, then the concern about thedietary intake of a moderate to large amount of a weakestrogen agonist should be comparable. If there is noconcern about the former, then there is logically noconcern about the latter. The dosage issue is alsounclear. Nonetheless, a general interpretation can bemade based on epidemiological studies of soy intake.These studies have used estimates of dietary intakefrom traditional diets from Asia, India, and the Mid-dle East, and it is logical to assume that those intakelevels are safe.

Tice: Our first duty to our patients is to do no harm.There are too few data to make strong recommenda-tions. The epidemiologic data consistently suggestthat women who eat large amounts of soy are at lowerrisk for breast cancer, but the relationship is by nomeans proven to be causal.34-36 Women in Asia wheresoy is consumed daily have a substantially lower life-time risk of breast cancer compared to women inWestern countries. However, most of the animal datasuggest that exposure early in life (during the periodof breast tissue maturation) appears to be critical forthe protective effects of soy.37-39 As indicated above,there are data in women suggesting that phyto-estrogens act like estrogens in breast tissue and increasebreast epithelial proliferation, potentially increasinga woman’s risk for recurrent or new disease.27-29 Fur-thermore, studies in nude mice with engrafted tumorsreported that genistein, the major isoflavone in soy,stimulated tumor growth.40,41 Thus, I would not recom-mend that women with breast cancer start consumingsoy either as foods or as supplements.

The evidence to date does not suggest that womenreceiving estrogen replacement therapy after treat-ment for breast cancer are at increased risk for recur-rence or a second primary.42-46 However, these studiesare small, with relatively short follow-up time. Soyisoflavones may be estrogenic in the breast, but onlyweakly, and thus are probably safe given that estrogensat worst minimally increase a woman’s risk for tumorrecurrence or a second primary tumor. Therefore, Idon’t counsel women who consume soy as part of theirregular diet to stop after a diagnosis of breast cancer.Dietary consumption of soy in Asia averages 20 to 80mg of isoflavones per day (1 to 3 servings of soy food),and this level of intake is probably safe.

There are no data to support different recommen-dations for premenopausal versus postmenopausalwomen nor women with ER+ versus ER– tumors. Invitro studies using both ER+ and ER– breast cancercell lines show that isoflavones stimulate cell growth atlow to moderate concentrations and inhibit growth athigher concentrations.

Tripathy: Soy foods would probably be safe for bothpremenopausal and postmenopausal patients, whetheror not the tumors in question are ER+. I’ve heardmainly theoretical soft opinions against soy.

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Nonetheless, I do not know of any scientist or soyresearcher out there who is clamoring to get rid of soy.I don’t think you’ll find any strong arguments againstit. As a food, it’s hard to argue that there would be astrong effect.

Question 3:

Are soy isoflavone supplements safe for postmenopausal orpremenopausal breast cancer patients? Do you feel there ismuch of a difference in soy versus isoflavones in terms ofpossible benefits versus risks?

Constantinou: While we can say that soy isoflavone sup-plements have not been proven safe, we cannot inferthat they are unsafe, because at the present time noepidemiological studies have been designed to answerthis question. There are risks of overdosing with sup-plements, but clearly we do not have that informationwith soy protein or concentrates. When you provide asoy concentrate, my guess is that there would be noadverse effects. When you extract certain key compo-nents from the soy, they are more likely to exert nega-tive effects as well as positive effects. The negativeeffects become more prominent when the soy proteinisolate is not there to provide a buffer or some mea-sure of protection.

All the components in soy that may have anti-cancer effects seem to be safe for human ingestion.They are not toxic, they do not make people sterile orfeminized, and they do not cause reproductive failure(sterilization or infertility). Currently, there are nodata on the safety of isoflavone supplements inhumans. There may be risks, especially with high-doseintakes, but it’s only speculation at this point.

In terms of inducing differentiation and apoptosis,it’s generally true that a more moderate dose inducesdifferentiation whereas a higher dose induces apoptosis.My lab demonstrated this about 4 years ago. Higherdoses induce apoptosis. Differentiation is induced atbetween 15 and 30 micromolar, whereas apoptosisrequires doses of between 50 to 150 micromolar, apharmacological dose. We do, however, see biologicaleffects at lower levels, related to estrogenic effects.We’re talking about tumor cell lines specifically. Thereare few exceptions to the dosage issue, but not thatmany. I would say that about 80% of the tumor celllines have responded to induction of differentiationof genistein.

I would like to point out that higher doses of soy, asprovided by supplements, may certainly be desirablein order to achieve the higher doses needed forapoptosis. This appears to be only of theoretical inter-est, however, because you may never be able to attainthe high levels you need in order to induce apoptosisin tumor cells. The maximum we seem to be able toattain in vivo, following oral intake, is 15 to 20 micro-molar, but this is substantially lower than one needs toattain the levels needed for apoptosis. Evidently, the

soy isoflavones are rapidly metabolized and brokendown, so a threshold is reached fairly quickly. A potentialconcern here is that the 15 to 20 micromolar range mayactually induce estrogenic effects, which of coursewould be undesirable. In other words, instead of anti-cancer effects, you may get cancer-promoting effectsat these low levels. For this reason, taking supplemen-tal soy may not necessarily be a good thing unlessyou’re receiving chemotherapy at the same time. Thisis because genistein shows synergies with some che-motherapy drugs. One possibility is that certain che-motherapy agents may tend to induce apoptosis morereadily with adjunctive use of genistein.

Thus, the anticancer effects are only attainable atvery high levels, which are unattainable unless youmake certain modifications in genistein itself. Someresearch indicates that if you conjugate genistein tosurface receptors that recognize tumor antigens, youcan introduce genistein at high levels into the tumorcell, and at these high levels you can induce apoptosis.Therefore, you have to do pharmacological modifica-tion in order to introduce genistein into tumor cells atthese very high levels. So of course at this point itbecomes a drug issue.

Hilakivi-Clarke: If estrogenic effect is the goal (bone,etc.), then isoflavones may be more effective than soy.However, if an estrogenic effect needs to be avoided,soy is a better alternative. Most likely, postmenopausalwomen should not consume isoflavone supplements.In general, it is advisable to use “normal” dietary expo-sures rather than be exposed to a specific componentisolated from a food product (carrot vs. β-carotene),and this may also apply to genistein versus soy.

Hughes: If the supplement in question actually containswhat it claims, and if anything is known about thepharmacokinetics of that product, then it makes nosense to think that it matters how a molecule of a par-ticular isoflavone was delivered to the bloodstream. Idoubt there is any difference between soy foods versussoy isoflavones in terms of possible benefits versusrisks for breast cancer patients.

Tice: We just don’t know. Soy isoflavone supplements mayact differently from soy foods. They are riskier becausewomen may be tempted to think that “more is better”and consume levels of isoflavones several times higherthan those consumed in traditional soy-rich diets. Fur-thermore, if soy does prove to be effective for breastcancer prevention, it may be due to components otherthan those included in supplements. Soy containsmany potentially bioactive compounds includingphytosterols, calcium, fiber, protein, and fatty acids.

Tripathy: When it comes to effects of isoflavones or soysupplements, this is where you might get a bit moredivision. There are concerns that soy supplementscould be problematic for postmenopausal women. Ihave one colleague [Petrakis] who found that soyincreased the secretion of nipple aspirate fluid, whichis a risk factor for breast cancer. He was concernedabout this. But I think that dietary amounts are okay.

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Although I have no strong opinion either wayabout ER+ or ER–, I would be more concerned withhigh-dose soy supplements in ER+ women. Whenwe’re talking about soy supplements, we just have tobe conservative. As physicians, we have to keep inmind that above all, we don’t want to do any harm.

I generally counsel my patients that, in the absenceof clear data, it makes sense to avoid unphysiologicconcentrations of anything—whether it’s vitamins orother dietary components. I think as a rule we have toassume that there could be harm when soy or soyisoflavones are taken in concentrations that you would-n’t get in the diet. That’s when I get concerned; eventhough I recognize very well that the high dose mighthelp, we can’t rule out the possibility that high dosesmay hurt. Dietary amounts are okay, but megadose orsupraphysiologic amounts of soy don’t make sense. Itwould be important to do a study of high-dose soy con-centrate, soy protein, or soy isoflavones in breast can-cer patients before recommending these supplements.

Question 4:

Would soy foods with low isoflavone contents be safe forthese patients?

Constantinou: I would have to say yes. Low isoflavoneintake in general should be safe. Now, I cannot saywhether people would be better off consuming lowamounts of dietary isoflavones versus high amounts,or whether people would get more protection fromone than the other. The epidemiological data are onlysuggestive in terms of safety and efficacy because thereare too many confounders in the existing studies.

Hilakivi-Clarke: This is not known.Hughes: If a patient consumes a broad-based diversified

diet and thus eats only one serving of soy per day orevery other day or every third day, then isoflavone con-tent is rather irrelevant.

Tice: In general, a diet with 1 to 3 servings of soy each dayis probably safe for women with breast cancer, irre-spective of the isoflavone content. Soy in modestamounts, as part of a low-fat diet rich in fresh fruitsand vegetables, is likely to be safe and healthful.

Tripathy: Yes.

Question 5:

What would you advise about soy consumption for patientstaking tamoxifen?

Constantinou: Fortunately, we just received 2 grants tostudy this issue. We will be looking at soy protein prep-arations with and without isoflavones to study theireffects in combination with tamoxifen. We hope to beable to evaluate how the tamoxifen receptors may beaffected by soy and to determine whether we caninhibit tamoxifen resistance in tumors. We obtained

some preliminary animal data last year based on exper-iments in which we combined SPI with tamoxifen andcompared them to data based on experiments withtamoxifen alone. We observed a significant reductionin tumor numbers in the combination group. Spe-cifically, we saw a 65% reduction in tumor burden withthe combination versus 35% with SPI and 29% withtamoxifen alone. So, clearly, there is an additive effectof SPI and tamoxifen. I’m not a statistician, so I can’tsay whether this effect is synergistic. To obtain theseeffects in patients, I calculate that 70 g of soy protein(as SPI) would be sufficient to provide the benefit withtamoxifen. People in Southeast Asia are consumingsomewhere between 50 and 75 g at the highest level ofdietary intake.

At this point, we don’t know the number of yearsthat might be needed to see a protective effect oftamoxifen. It’s assumed that 5 years is the optimalamount of time, but we don’t know for sure. What wedo know is that, in animals, if you give them tamoxifen,they eventually develop tamoxifen-resistant tumors.We’d like to know whether soy protein or soy genisteincould in some way reduce the rate of tamoxifen-resistant tumors. Unfortunately, the mechanism behindtamoxifen resistance is poorly understood. We doknow that tamoxifen resistance occurs more often inER–tumors. After 1 to 2 years of tamoxifen, you beginto see tamoxifen-resistant tumors. A number of ques-tions may be asked. Could soy combined with tamoxifenfurther augment the chemopreventive effects oftamoxifen? Could soy possibly reduce the requireddose of tamoxifen, so that we might only need to usethe lowest possible dose of tamoxifen? Some animalstudies suggest that this might be the case. That wouldbe good news for cancer patients but perhaps not allthat great for the drug companies.

One final note about SPI. It may not translate intodietary consumption. SPI is an isolate of soy, but itdoes contain most of the original soy. It is about 90%protein. Normally, soy is about 40% protein, so thisraises the protein concentration substantially. SPI is apowder that can be easily placed in beverages orturned into a bar, as some companies have alreadydone. Finally, I’m not recommending 70 g of soy pro-tein per day. I’m only saying that this is what can bededuced by extrapolating from the experimental andepidemiological data.

Hilakivi-Clarke: Tamoxifen might interact with genistein.Some studies suggest that there is a positive interac-tion—that is, that genistein increases tamoxifen’s abil-ity to inhibit cell proliferation. Other studies suggestthat genistein may inhibit tamoxifen’s action.

Hughes: It hardly matters. Drugs like tamoxifen are suchpotent antiestrogens that their actions surely abrogateany weak estrogenic actions of isoflavones.

Tice: Again, there are few data. One study in animalsfound that soy enhanced the beneficial effects oftamoxifen.9 In vitro data demonstrate that the bind-ing affinity of tamoxifen for estrogen receptors is

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much higher than that of soy isoflavones, suggestingthat soy should have no significant effects in the set-ting of tamoxifen therapy (assuming that the soy actsthrough isoflavones interacting with the estrogen recep-tor). I would not encourage a woman already consum-ing soy to change her diet, nor would I recommendthat women on tamoxifen add soy to their diet. Todate, the evidence suggests no harm, but we needcareful studies to look for interactions betweentamoxifen and the constituents of soy.

Tripathy: In terms of tamoxifen, again, dietary amountsare probably okay and may even support the effects oftamoxifen. I recognize that soy in some women mayhelp reduce hot flashes, although a recent study byCharles Loprinzi of the Mayo Clinic did not show anybenefit in reducing hot flashes. In a subset of women,however, there may be an effect. Right now, it’s all trialand error. So if people want to take it for symptoms,they should take dietary amounts. If they want toinclude it in their diet, there should be no problem.

Question 6:

Do you have any suggestions for physicians who would liketo begin incorporating soy into the clinical decision-makingprocess?

Constantinou: I firmly believe we have an obligation topresent our research to the general public, especiallyin situations such as this that have a direct impact onlifestyle and health. The data may never be conclusive.We have to present our knowledge even if much of theinformation has limited rigor, because it lacks thebacking of randomized clinical trials. We have to gowith the best available evidence and make some edu-cated guesses. If you are a physician counseling awoman with breast cancer, and she wants to do some-thing more than just chemotherapy and wants to dosomething to possibly reduce her risk of recurrence,you can go 1 of 2 ways. You may say to her simply, “Ihave no answer for you.” Or you may say that soy maybe an option for you, it may help prevent the risk ofrecurrence. The possibility that it does prevent recur-rences is worth trying now, in the clinical setting, inorder to save lives.

Hughes: There is still no reason to think that there is anydietary advice superior to that of advising patients toeat a broad-based diversified diet that is not domi-nated by some tiny number of food items. There aremany different healthful compounds in foods that arenot isoflavones and do not occur in soybeans.

Hilakivi-Clarke: We do not know whether starting soyintake after being diagnosed with breast cancer is safe.No recommendations can be made at this time.

Tripathy: I do think that practical recommendations forsoy can be made. One can look at theoretical data andsay that, as much as we can tell, low doses of soy are notgoing to have a detrimental impact, and may evenhave a helpful impact. The effects of high doses of soy

protein, in contrast, are completely unknown. Wedon’t know to what extent these high doses wouldinfluence estrogen receptor biology.

At this point in time, then, I would recommendagainst soy supplements across the board, as a group,because the effect could go either way—it could behelpful or it could be harmful. So whether or not thewoman is premenopausal or postmenopausal, whetheror not her breast tumor is ER+ or ER–, I feel sheshould avoid soy supplements unless she’s part of aclinical trial. In that case, I think the interventionshould include a high-dose component in order to seewhich way the effect goes, and I believe it’s likely thatthere would be an effect. We just don’t know the direc-tion of that effect. Without doing the study, we’reoperating in the dark here. My approach is to becautious.

Finally, we do know that there’s reasonably strongevidence that higher circulating estrogen in post-menopausal women increases the risk not only of get-ting cancer but of having a recurrence of cancer fol-lowing initial efforts at cytoreduction. If you gainweight after getting cancer, this is counterproductivebecause your estrogen and insulin levels will tend torise. If a patient is obese, she may want to work on los-ing weight. So I do strongly encourage women tomaintain an ideal weight. If you’re using diet to loweror manage weight, then a low-fat diet makes sense.The exact dietary composition in terms of fat, how-ever, is still a bit controversial because of the problemof cachexia in advanced-stage cancer. With advancedmetastatic breast cancer, the caloric intake has to bewatched carefully, and that usually means more liberalintake of dietary fat. But at this point, the main focusshould be on maintaining normal weight with exer-cise and a low-fat diet in women who are not experi-encing cachexia.

Integrative Clinical PerspectiveExamining the responses to our questions by the panelof experienced researchers and clinicians who haveauthored this article is a valuable—and challenging—exercise in the assessment of controversy and consen-sus in the area of soy and breast cancer. Soy is a foodthat is of great interest, and potential value, for pa-tients in integrative cancer care. Most integrative prac-titioners counsel vegetarian or semivegetarian diets,or at least some reduction in intake of specific meats.Soy has to be regarded as an important component ofvegetarian diets: soy foods in general are easy to cook,soy is a good protein source, and the versatility of soyallows it to take the form of everything from sandwich“meats” to powders for incorporation into smoothiesand shakes. Soy may contribute to the management ofhot flashes that are problematic for women undergo-ing natural or treatment-induced menopause, althoughthis effect is not completely supported in the litera-

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ture; the apparently beneficial impact on bone makesit an attractive option for patients who are concernedabout osteoporosis. Thus, for a variety of reasons, soyfoods could play a productive role in the diets ofwomen with breast cancer.

The Estrogenicity of SoyEven with all these potential benefits, soy would, infact, be the wrong choice for breast cancer patients if itpromotes cancer recurrence, as those concerned aboutthe estrogenic effects of soy have warned. Our panel ofresearchers points out both the reality of the estro-genic effect and the clinical context of that effect. Thesoy isoflavones genistein and daidzein are known tobind to estrogen receptors. Genistein is a weak agonistof ERα and a moderate agonist of ERβ. Genistein in-creases the proliferation of estrogen-sensitive breastcancer cell lines in the laboratory; several in vitro stud-ies have also reported biphasic effects in which growthis stimulated at low doses but suppressed at high doses.These data surely do give pause to women with estrogen-receptor positive cancers, especially postmenopausalwomen whose endogenous estrogen levels are low.

Our panelists point out, however, that the relevanceof these in vitro studies is less clear in the context ofhumans, where soy might play either estrogenic orantiestrogenic roles. Soy has been shown to increasemenstrual cycle length, to reduce circulating estrogenlevels, and to reduce excretion of potentially tumor-promoting estrogen metabolites. Soy protein isolatecontributes to tumor prevention in animal studies. Soydoes not affect the vaginal mucosa or endometrium,indicating lack of estrogenicity in these tissues. But 3studies have shown evidence of some weak estrogeniceffect on the breast. Two of these, by Petrakis et al.27

and McMichael-Phillips et al.28 found evidence ofincreased breast cell hyperplasia and increased DNAsynthesis in breast cells in studies where women werefed genistein-containing products, but the third, byHargreaves et al.29 found no effect on cell prolifera-tion. Because of questions about the experimentaldesign of these studies, the estrogenic effect of soy onbreast cells must still be regarded as not having beenfully validated.

Our panelists also point out that soy contains othersubstances besides genistein that may have anticancereffects. In fact, genistein itself has other activities thatmay play an important role in inhibiting the growth ofbreast tumors. Genistein may inhibit the activity ofestrogen-metabolizing enzymes necessary for estradiolsecretion from the ovaries in premenopausal women.This may account for the estradiol-lowering effects of asoy-supplemented diet.24 It may also inhibit enzymesthat participate in the reduction of estrone to estradiol

in adipose and other tissues. Genistein may also sup-press growth of breast cancer cells stimulated byestrogen and other growth factors associated withbreast cancer.47 Finally, it should be noted that even ifsoy or genistein have clinically significant estrogeniceffects, it is not certain that giving estrogen to breastcancer patients, such as would be done in hormonaltherapy, increases theriskofcancerrecurrence,althoughmore studies in this area need to be done.

What can we conclude from the variety of some-times conflicting data our panel has reviewed? We cer-tainly must admit that much remains to be done indetermining the health benefits and risk of soy phyto-estrogens. However, our panel members generally pointout that harmful estrogenic effects of soy foods inhumans are still not established; the many phyto-chemicals and other components of soy may contrib-ute to an overall attenuation of the in vitro estrogenicactivities of genistein and daidzein.

Safety of Soy Foods forBreast Cancer PatientsOur panelists agree that soy foods can be eaten as partof an overall healthful diet. Although the reports ofbinding of soy isoflavones to estrogen receptors raiseconcern mainly among ER+ patients, there are insuffi-cient data to support distinguishing dietary recom-mendations depending on receptor status at this time.Premenopausal women actually seem to be at lowerrisk of breast cancer if they consume soy, so the level ofconcerns for them might be quite low. Potential con-cerns even for postmenopausal women consuming soyfoods were not thought to be large by most panelists. Areasonable level of soy food for patients would bearound 1 serving per day. An exception to this generalview was expressed by one panelist who affirmed theidea that if a woman is already consuming soy as part ofher diet when her cancer is diagnosed, she may con-tinue to do so, but that patients should not be encour-aged to add soy to their diets after diagnosis.Nonetheless, a majority of panelists felt that consump-tion of soy foods did not raise serious clinical concerns.

Safety of Soy Isoflavone SupplementsOur respondents generally felt that soy isoflavone sup-plements are less advisable for breast cancer patients,although one pointed out that it does not matterwhere isoflavones come from since they are, in fact,the same substance whether they are found in soy-beans or in capsules. No epidemiological or clinicalstudies have been conducted on the safety or efficacyof such supplements in breast cancer patients, and ourpanel felt that such studies would be necessary beforerecommending supraphysiologic levels of these, or

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other, natural dietary components. This is especiallytrue of soy, in which activities other than the isoflavone-based estrogenicity might be important in anticancereffects.

Safety of Low-Isoflavone Soy FoodsMany processed soy foods, which may appeal to pa-tients as convenience items, are actually low in isofla-vones. A database of isoflavone contents of various soyfoods can be found on the Internet at the followingWeb site: http://www.nal.usda.gov/fnic/foodcomp/Data/isoflav/isoflav.html. Most of our panel felt low-isoflavone foods would be safe in reasonable quanti-ties, although some pointed out that not much isknown about such foods, and that they may lack someof the potential beneficial elements of natural soyfoods. It should be pointed out that at this time, we arenot certain whether the effects of soy isoflavoneswould be harmful or beneficial in different popula-tions of breast cancer patients. It is conceivable thatthey may eventually be found to be beneficial to someor all breast cancer patients. For now, however, wemust exercise caution in our recommendations of soyisoflavone preparations because it is still not clearwhether isoflavones stimulate the growth of breast tu-mors.

Safety of Soy Use During Tamoxifen IntakeConstantinou has recently published work indicatingthat soy protein isolate given with tamoxifen reducedtumors in animals compared to tamoxifen alone, andhas recently received funding to study this issue fur-ther. Other animal studies also suggest positive effects.Panelists also pointed out that because tamoxifen issuch a potent drug, and because it binds to estrogenreceptors more strongly than isoflavones, it wouldlikely overwhelm any effects of isoflavone intake.Whether benefits of soy intake with tamoxifen will beestablished experimentally is obviously not clear yet,but there does not appear to be any directly harmfuleffect.

Advice for Physicians Counseling PatientsThere are a number of investigators who express con-cerns about the use of soy. Margo Woods, PhD, an asso-ciate professor at Tufts University School of Medicine,suggests that “we can only make an educated estima-tion of what should be recommended to breast cancerpatients at this time.” Woods is particularly concernedabout the biphasic response to soy, and specifically thepossibility that low doses may be harmful. She con-tends that no one seems to know with certainty howmuch soy is necessary to attain the higher levels that

may be required to override the potential estrogeniceffects. This will need to be studied in breast cancerpatients exposed to different doses and forms of soy,with careful monitoring. Until we have such research,Woods recommends that breast cancer patients con-sume soy foods as part of a well-designed dietary plan;isoflavone tablets and soy protein concentrates, on theother hand, should be strictly avoided.

Although one of our panelists feels that no recom-mendations about soy consumption can be made atthis time, some other members agree with Woods’sadvice that soy foods can be taken as part of an overallhealthy diet, although isoflavone supplements shouldbe avoided, as they have a potential for abuse not pres-ent with soy foods. In discussing this possibility withpatients, physicians need to discuss the available datawith them even if it is inconclusive; soy is certainly notthe only area of contemporary cancer treatment thatlacks clear evidence at this time, and few physiciansshrink from discussions of other controversial areaswith their patients. Trials on soy foods and constitu-ents certainly need to be done in patients who areactively combating breast cancer, and these trials mayeventually help clarify this situation. In view of theoverall context of both the estrogenic and the anti-cancer effects of soy, it does not appear necessary toprohibit soy use to interested patients.

Soy may contribute in a useful way to helping patientsnormalize their weight as part of a healthy, low-fat,generally vegetarian diet. Although soy is higher in fatthan many other legumes and thus should be taken inlimited quantities, it is lower in fat than many of themeats and other foods that it might replace in the diet.The availability of soy protein powders may also behelpful for patients with advanced disease to aid insupporting protein intake. Although the use of isoflavonesupplements by breast cancer patients is generally notsupported by the panel, and although there is as yet nospecific evidence that soy consumption will lower therisk of disease recurrence, our panel feels that, basedon current research findings, breast cancer patientswho wish to include soy in healthful eating plans maydo so.

—Keith Block

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7. Constantinou AI, Mehta RG, Vaughan A. Inhibition of N-methyl-N-nitrosourea-induced mammary tumors in rats by thesoybean isoflavones. Anticancer Res. 1996;16:3293-3298.

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Point-Counterpoint


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Block et al.


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Instructions for Authors


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