Antioxidants Chemotherapy Moss 2006

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10.1177/1534735405285882MossAntioxidants With Chemotherapy and Radiotherapy

Should Patients Undergoing Chemotherapy and

Radiotherapy Be Prescribed Antioxidants?

Ralph W. Moss, PhD

In September 2005, CA: A Cancer Journal for Clinicianspub-

lished a warning by Gabriella DAndrea, MD, against the con-

current use of antioxidants with radiotherapy and

chemotherapy. However, several deficiencies of the CAarti-

cle soon became apparent, not least the selective omission of

prominent studies that contradicted the authors conclusions.

While acknowledging that only large-scale, randomized trials

could provide a valid basis fortherapeutic recommendations,

the author sometimes reliedon laboratory rather thanclinical

data to supporther claimthatharm resultedfrom theconcur-

rent use of antioxidants and chemotherapy. She also some-

times extrapolated from chemoprevention studies rather

than those on the concurrent use of antioxidants per se. The

article overstated the degree to which the laboratory data di-

verged in regardto the safety and efficacy of antioxidant ther-

apy: in fact, the preponderance of data suggests a synergistic

or at least harmlesseffect with most high-dose dietary antioxi-

dants and chemotherapy. The practical recommendations

made in the article to avoid thegeneral class of antioxidants

during chemotherapy are inconsistent, in that if antioxi-

dants were truly a threat to the efficacy of standard therapy,

antioxidant-rich foods, especially fruits and vegetables,

ought also be proscribed during treatment. Yet no such rec-

ommendation is made. Furthermore, the wide-scale use by

both medical and radiation oncologists of synthetic antioxi-

dants (eg, amifostine) to control the adverse effects of

cytotoxictreatments is similarly overlooked. In sum,this CAar-

ticle is incomplete: there is far more information available re-

garding antioxidant supplements as an appropriate adjunctive

cancer therapy than is acknowledged. Patients would be well

advised to seek the opinion of physicians who are adequately

trained and experienced in the intersection of 2 complex

fields, that is, chemotherapeutics and nutritional oncology.

Physicians whose goal is comprehensive cancer therapy should

refer their patients to qualified integrative practitioners who

have such training andexpertise to guidepatients. A blanket re-

jection of the concurrent use of antioxidants with chemother-

apy is not justified by the preponderance of evidence at this

time and serves neither the scientific community nor cancer

patients.

Keywords: antioxidants; chemotherapy; radiotherapy;

melatonin; vitamin C; vitamin E; -carotene;

coenzyme Q10; free radicals; neurotoxicity;

ototoxicity; malnutrition; immunosuppression

In September 2005, CA: A Cancer Journal for Clinicianspublished a warning against the concurrent use ofantioxidants with cytotoxic therapies. The article,Use of Antioxidants During Chemotherapy andRadiotherapy Should Be Avoided, by GabriellaDAndrea, MD, is a sharp attack on the use of antioxi-dant supplements by cancer patients.1 CA is distrib-

uted free to many primary care physicians in theUnited States. Furthermore, the article received wide-spread public attention when it was picked up by theWall Street Journaland made the subject of a favorablecommentary that amplified the authors main point:Research suggests the supplements may be doingmore harm than good.2

It is true that much remains unknown concerningthemode of actionof antioxidants. Theoptimum dos-age and timing and the range of possible interactions,both synergistic and potentially detrimental, are stilllargely unexplored, and it is, of course, correct to pro-ceed with caution. However, there is considerabledata

to suggest that certain antioxidants, given under con-trolled circumstances, can significantly alleviate theunpleasant side effects of standard cancer therapiesand, far from impairing the therapeutic efficacy ofthese treatments, may actually enhance it. Certainly,there is scant evidence to suggest thecontrary. TheCAarticle argues from a position of guilty until proveninnocent. The present article is an attempt to redressthe balance by analyzing the CAarticles argumentsand presenting evidence that challenges the basis ofits conclusions.

Points of Agreement

At the start, it is important to acknowledge and rein-force the validity of 3 basic points made (or at least im-plied) by the CAarticle. First, it is true that we do nothave adequate randomized controlled trial (RCT) evi-dence on the interaction of common antioxidantswith radiation and chemotherapy. Oftentimes, the de-

Antioxidants With Chemotherapy and Radiotherapy

INTEGRATIVE CANCER THERAPIES 5(1); 2006 pp. 63-82 63

RWM is at Cancer Communications, Lemont, Pennsylvania.

Correspondence: Ralph W.Moss, PhD, Cancer Communications,Box1076, Lemont, PA16851.E-mail:[email protected]: 10.1177/1534735405285882


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cision as to whether to use particular antioxidantsmust be made without the benefit of adequate scien-tific evidence to factually support such decisions.Whether a patient or clinician chooses to use or avoidantioxidants, he or she runs the risk of falling into er-ror. Therefore, governments and major health chari-

ties should undertake these absolutely necessary,albeit expensive, rigorous clinical studies. (That said,there are formidable economic and political obstaclesto performing such tests, especially those with suffi-cient statistical power to prove that antioxidants donot interfere with standard cancer treatments; seebelow.)

Second, it is true that, ideally, cancer patientsshould not self-medicate with antioxidants. Whilesane and sentient adult patients havean absolute rightto medical autonomy and freedom of choice,3 cancerin essence is not a self-help disease. Treating cancerrequires professional guidance, although of course,

there is much that patients themselves can do toincrease their quality of life and even their chances forlong-term survival.

However, the CAarticle calls fora total avoidance ofsupplemental antioxidants concurrently with radio-therapy and chemotherapy. Many, including thisauthor, would disagree. There is considerable evi-dence to suggest that nutrition, food supplements,and selected phytonutrient antioxidants havemuchtooffer the cancer patient when used wisely and underprofessional guidance. Patients should therefore beunder the care of integrative oncologists who under-

stand not just how to prescribe radiotherapy and che-motherapy but who are also knowledgeable about thecomplex world of clinical nutrition, including foodsupplementation.

Professor Kenneth A. Conklin, MD, PhD, of theJonsson Comprehensive Cancer Center of the Univer-sity of California, Los Angeles (UCLA), expresses thissame position: I always stress that taking nutritionalsupplements during conventional cancer therapiesshould only be done under the guidance of a knowl-edgeable professional (personal communication,September 27, 2005).

The CAarticle isundoubtedlycorrect in stating that

not all antioxidants are likely to be beneficial in theirmode of action or their effect. Certain antioxidantsmay indeed be ineffective or may even interfere withspecific chemotherapeutic agents, and it is essential,therefore, to be selective in their use. This author haspreviously offered a list of several potentially harmfulinteractions between some antioxidants and chemo-therapy.4 However, the key word here is potentially,since in almost all cases, one is relying for evidence oninvitroor animalstudies,rather thanon clinical trials.

In short, although they are sold over the counter,antioxidants are serious medicine. They may havebeneficial effects in ameliorating the notorious toxic-ity of radiotherapy and chemotherapy. But preciselybecause of their power, they may also have some nega-tive effects. Therefore, although the cancer patient

has a critical role to play in directing his or her owncare, the proper use of antioxidants, especially duringconventional treatment, requires the assistance andoversight of a knowledgeable integrative oncologist.

While the clinically well-documented toxicity ofchemotherapy is universally acknowledged withinoncology, it is typicallyconsidered far less of a concernthan theoretical worries over the concurrent use ofantioxidants. But the toxicity of chemotherapy notuncommonly leads to the need for treatment to beinterrupted, which may itself directly threaten out-come (K. Block, personal communication, October11, 2005). Therefore, any measure that reduces

treatment-related morbidity and mortality also helpscompliance.

Concerns About Antioxidant-ChemotherapyInteractionsThe CAarticle offers 3 specific types of evidence to es-tablish the alleged danger of the concurrent usage ofantioxidants and cytotoxic treatments:

theoretical concerns, based primarily on in vitrostudies,

a selective group of clinical trials demonstrating the

interaction of antioxidants with radiotherapy orchemotherapy, and

studies critical of antioxidant use in general but notspecifically addressing the issue of concurrent use.

A Proposed Mechanism of InteractionThe CAarticle states that the mechanism whereby an-tioxidants reduce the adverse effects of radiotherapyand chemotherapy is well understood: radiotherapy,as well as many chemotherapeutic agents, exerts itsanticancer effect by producing free radicals (reactiveoxygen species). Many supplements, on the otherhand, including vitamins C and E, by virtue of being

antioxidants, bind to free radicals, preventing oxida-tive damage.1

There are considerable in vitroand animal datashowing that vitamin C and other antioxidants canprotect cellsagainst radiationand chemotherapy, theauthor adds. Accordingly, It seems likely that they[antioxidants] would therefore reduce treatment-related toxicity and there are promising (but notunequivocal) data that this is indeed the case.

Moss

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This sounds encouraging. However, the articlequickly counters, It also follows that antioxidantsmight protect cancer cells, thereby reducing theoncologic effectiveness of cytotoxic therapy. Withtheuse of the word might, we have slipped from the realmof fact to the realm of conjecture.

This is not what a fair or comprehensive appraisalof the existing literature shows. In general, laboratorywork supports the harmlessness of high-dose dietaryantioxidants added to either radiotherapy or chemo-therapy. This position is summarized by Kedar Prasad,PhD, formerly at the Center for Vitamin and CancerResearch of the University of Colorado. The author ofmore than 45peer-reviewed articles on theinteractionof antioxidants with conventional therapy, Prasad hassummarized his quarter-century experience thus:Experimental data and limited human studies sug-gest that use of these nutritional approaches may

improve oncologic outcomes and decrease toxicity.

5

However, Prasadalso points to some areas of poten-tial harm that might follow administration of antioxi-dants. For example, he counsels against the concur-rent administration of endogenous antioxidants suchas glutathione or its analogs. The use of endogenousantioxidants or antioxidant enzyme-elevating agentsarenotrecommended duringradiotherapyor chemo-therapy, he says, because they may protect cancercells against the cytotoxic effect of standard treat-ments.5

In addition, Prasad has foundexperimentally, atleastthat low doses of antioxidants, used 1 time

shortly before standard therapy, may in fact be harm-ful. Several studies have shown that antioxidants pro-tect cancer cells and normal cells, if dietary antioxi-dants or their derivatives or endogenously madeantioxidants at doses that do not affect the prolifera-tion of these cells are administered only one timeshortly before cancer therapeutic agents (K. Prasad,PhD,personal communication, September26, 2005).

This is disturbing since some oncologists, he says,tell patients to avoid high-dose antioxidants but toinstead take low-dose multivitamin pills. Prasad alsobelieves, based on his laboratory and clinical observa-

tions, that high-dose dietary antioxidants and theirderivatives must be administered several days beforeradiotherapy and continued every day for the entireperiod of treatment (K. Prasad, personal communica-tion, September 26, 2005).

Thepicture is therefore farmore complicated thanthe CA article acknowledges. In several carefullyargued review articles, Professor Conklin has summa-rized extensive literature showing that although someanticancer agents are indeed potent free radical gen-erators, most anticancer drugs haveclearly elucidated

mechanisms of action that do not involve the genera-tion of free radicals.6

In a 2004article, Conklinshows why thegenerationof free radicals, far from being the source of thesedrugs potency, actually can interfere with theiranticancer activity. Their effectiveness depends on

their ability to interrupt cell cycle progression and dis-rupt programmed cell death (apoptosis). Most che-motherapy drugs aremore effective in thepresence ofrapidly dividing cells. Slowing the cell cycle wouldthereforediminishtreatmentresponse.Thus,evenontheoretical grounds, the selective use of antioxidantsduring a course of chemotherapy may actuallyenhance the anticancer activity of many cytotoxicdrugs.7

Multiplicity of Agents

The CA article treats antioxidants generically, as

though they were one monolithic entity with a singlemode of action. This is far from correct. In fact, thereare dozens of different antioxidants that can poten-tially interact in significantly different ways withdozens of cytotoxic agents.

Some of the more widely used antioxidants includea-lipoic acid, proanthocyanidins, vitamin A and b-carotene, lutein, lycopene, melatonin, ascorbic acid,selenium,vitamin E (a-tocopherol) and its analogues,zinc, coenzyme Q10 (Co Ql0), and many more. Eachof these is very complexvitamin E alone comes in 8different forms (4 tocopherols and 4 tocotrienols)andeach of these can havedifferentbiological effects,both alone and in combination. For instance, Profes-sor Bruce Ames of the University of California, Berke-ley, among others, hasshown that certain formsof vita-min Ebut not otherspossess cytotoxic propertiesagainst prostate cancer cells.8 Some forms of a vitaminare powerful antioxidants and others are weak, butthey exert biological effects by different mechanisms.Many medicinal herbs also contain antioxidants,known or yet unknown.9

In addition to this multiplicityof agents, forms,dos-ages, and potentially synergistic interactions, thepotency of antioxidants can vary fundamentally

according to the route by which they are adminis-tered. For example, they can be ingested as a compo-nent of foods, taken as natural or synthetic supple-ments, taken sublingually, given intravenously, and soforth. Failing to specify the particular mode of admin-istration, as the CAarticle does, leads to confusion.Thus, a dose of vitamin C can mean many things: aglass of orange juice, a tablet containing 50 mg ofascorbic acid, or an intravenous injection of 1000times that amount. It is the latter route of administra-tion that is used by many complementary and


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alternative medicine (CAM) practitioners and is pres-ently being tested in a clinical trial at the University ofKansasMedical Center.10 In an article published in theProceedings of the National Academy of Sciences(PNAS),researchers demonstrated that a 10-g dose (10 000mg) of vitamin C given intravenously gives rise to

bloodstream concentrations that are more than 25times higher than concentrations achieved from thesame oral dose.11

It is a fundamental principle of the science ofpharmacokinetics that the nature, dose, and mode ofadministration of a drug can have a profound impacton its physiological effect, including any potentialinteraction with other treatments, such as radiother-apyor chemotherapy, butthis conceptappears tohavebeen overlooked in the CAarticle.

It is also simplistic to label a compound an antioxi-dant and believe that one has thereby exhaustivelydescribed its full range of activity. For example, b-carotene can actas an antioxidant at nutritional dosesbut has the opposite effect at higher doses.12 That isbecause many agents act as antioxidants but also haveother mechanisms of action andother waysof possiblyinfluencing the progression or regression of cancerincluding acting as pro-oxidants under certain cir-cumstances13 (see below).

Radiotherapy and Antioxidants

As to the allegedly harmful interaction of antioxidantswith radiotherapy, the CAarticle cites but does not dis-cuss at length the research carried out by IsabelleBairati and her Universit Laval, Qubec, colleagues,published in the Journal of Clinical Oncology. TheBairati study concluded that supplementation withhigh doses ofa-tocopherol and/or b-carotene signifi-cantly mitigated the side effects of radiation in pa-tientsundergoing treatmentof headand neck cancer.There was a 62%reduction in severe adverse effects tothe larynx and other sites in patients who were ran-domized to receive botha-tocopherolandb-carotene.However, there was also a nonsignificant trend towardsecond primary cancers during the supplementationperiod, which began during radiotherapy and ex-

tended for 3 years afterward.14

This latter findinggenerated a great deal of negative publicity forantioxidants.

The Bairati data was published in 2005 in both theJournal of the National Cancer Institute(JNCI) and theJournal of Clinical Oncology(JCO). The earlier JNCIarti-cle showed that compared to patients receiving pla-cebo, patients receiving supplementation, who had ahigher rate of second primaries while receiving thevi tamins, a lso had a lower rate once thesupplementation was discontinued. In fact, by the

completion of the study (8 years after start of radio-therapy), there were slightly fewer second primariesor recurrences in the supplementation group com-pared to those receiving a placebo (113 and 119 par-ticipants, respectively.)15 Plus, most supplementedpatients were spared the worst side effects of treat-

ment. These mitigating facts were generallydownplayed or ignored in the negative publicity sur-rounding the Bairati trial, especially after publicationof the JCOarticle.

TheQubecauthors havecalled for further trials toexplore the various effects of antioxidants with radio-therapy. Given the current true uncertainty sur-rounding these issues among patients, their treatingphysicians, and in the medical community, RCTsshould be conducted to provide clear scientific evi-dence regarding the efficacy and safety of antioxidantuse as adjuvant therapies for cancer.14

For instance, did these antioxidants actually

quench the free radicals generated by radiotherapy?In an accompanying JCOeditorial, Camphausen et alcas t doubt on the widespread not ion that phytonutrient antioxidants could possibly be presentin sufficient quantity or strength to interfere with theprimary and secondary free radical species producedby radiation therapy.16 They speculate that, instead,antioxidants may suppress continued free radical pro-duction that arises from an inflammatory responsefollowing radiation therapy. This could perhapsimpede antitumor activity, although it is not known ifthis inflammatory response actually occurs in tumor

tissue.

17

Camphausen et al concede that most phyto-chemical antioxidants, far from being simple scaven-gers of free radicals, also trigger complicated signaltransduction pathways, which may ultimately result intumor cell death. A few of these pathways, however,may also lead to tumor cell survival. The authors con-clude that while patients should avoid unnecessarysupplementation during and after radiotherapy,using antioxidants to improve the therapeutic indexof radiotherapy is a reasonable and commendablegoal. Further trials in this area shouldbe conducted incancers in which there is an effective salvage therapy,

in the case that second primaries or recurrences dooccur.16 Unfortunately, for many physicians, thetakeaway message of the Bairati article has been toavoid the concurrent use of all supplementalantioxidants during all forms of radiotherapy andchemotherapy.17

Conklin6 agrees that although radiation kills cellsby generating veryhigh levelsof free radicals,this doesnot necessarily mean that antioxidants are contraindi-cated in all cases. Radiotherapy is most effective inwell-oxygenated tissues, whereas the central portions

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of tumorsareoften hypoxic. So antioxidantsmayactu-ally play a beneficial role in radiation therapy byimproving blood flow within tumors and the sur-rounding tissues, thus rendering tumorsmore suscep-tiblenot less soto radiation. Since free radical gen-eration is proportional to the oxygen tension in the

tissue, antioxidants given in amounts that improveblood flow, but not in amounts that quench the freeradicals,mayalso result in an improved antineoplasticeffect.6

Serious BiasesThefollowingseriousbiasesareevidentintheCAarticle:

It cites ambiguous and/or negative studies butdownplays or fails to mention positive ones.

It correctlystatesthatonlylarge-scale, randomizedtri-als provide a valid basis for therapeutic recommenda-tions but then uses laboratory data to back up the

claim that harm results from the use of antioxidants. It exaggerates thedegreeto which thelaboratorydata

diverge in regard to the safety and efficacy of antioxi-dant therapy, calling such data conflicting and con-fusing, when, in fact, the great preponderance ofdata suggests a synergistic or at least harmless effectwith most high-dose dietary antioxidants.

It is inconsistent in its prescriptions since antioxidantsare found naturally in common foods; yet the warn-ing against antioxidants does not extend to includeantioxidant-rich foods,especiallyfruit andvegetables.

It ignores thewide-scale useby both medical andradi-ation oncologists of synthetic antioxidants given byprescriptionto control theadverse effectsofcytotoxictreatments.

It resorts to red herring arguments, citingstudies inthe realm of cancer prevention rather than focusingon the specific issue of concurrent treatment.

This latter bias is particularly misleading. Studies inchemoprevention,while important in their own right,are tangential if not irrelevant to the question of theuse of high-dose antioxidants as adjuncts to chemo-therapy or radiotherapy. For example, the CAarticlestates, Several large prevention trials have reportedclinical data showing no benefit for supplementation.In fact, there are reports that it may be detrimental.1

While it is true that some large-scale prevention trialsdo raise important questions about the use of supple-ments in high-risk populations, they are not germaneto the topic at hand; that is, the concurrent use of anti-oxidants and radiotherapy or chemotherapy and theresults of such studies cannot be extrapolated to theuse of antioxidants in tandem with cytotoxic cancertreatments.

Vitamin CThe CAarticle lays particular emphasis on selectivelynegative data concerning vitamin C (ascorbic acid).The article recounts some of the history of vitamin Cand cancer, mentioning Nobel laureate LinusPauling, PhD, and Ewan Cameron, MD, whose influ-

ential work in the 1970s has often been used to pro-mote the therapeutic use of megadoses of vitamin C.The CAarticle states, quite plausibly, The use of his-torical controls and the methods of patient selectionweaken the level of evidence provided by this study. Itthen relates how 2 RCTs (headed by Charles Moertel,MD, at the Mayo Clinic in the 1980s) arrived at essen-tially theoppositeconclusionsfromthePauling study.

Neither [ofMoertels studies] wasableto show anyobjective improvement in disease progression or sur-vival over placebo, DAndrea writes.1 Indeed, thereseems to be somewhat worse survival in the vitamin Cgroup. But she overlooks the fact that Moertels was astudy of vitamin Cs efficacy as a cancer treatment in itsown right, nota study of its interaction with other con-ventional therapies. Patients in the first trial hadalready completed their chemotherapy. After Paulingand others objected to the inclusion of patients whoseimmune systems were thus compromised, Moertelexplicitly made sure that patients in the second trialreceived no chemotherapy but instead received only10 g per day of orally administered vitamin C or a pla-cebo.18,19 The Moertel trials are thus not valid evidencefor the interaction of vitamin C and chemotherapy.

The well-publicized fact that Moertel exclusively

administered vitamin C by the oral route, whereas DrsPauling and Cameron recommended treatment withboth oral and intravenous doses, is ignored. The dif-ference is not inconsequential. Mark Levine, MD, andcolleagues at theUSNational Institutes of Healthhavesince shown that oral and intravenous vitamin C havedifferent kinetics.

Oral vitamin C produces plasma concentrationsthat are tightly controlled, they wrote in 2004.20 Onlyintravenous administration of vitamin C produceshigh plasma andurine concentrations that might haveanti-tumor activity. Because efficacy of vitamin C treat-ment cannot be judged from clinical trials that use

only oral dosing, the role of vitamin C in cancer treat-ment should be reevaluated.

However, the CAarticle prominently discusses thework of the late David Golde, MD, who showed that avitamin C precursor, oxidized dehydroascorbic acid,enters cells viaglucose transportersand then accumu-lates inside cancer cells in its reduced state (ascorbicacid). Before his untimely death in August 2004,Golde made many negative statements about the




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potential interference of vitamin C with chemother-apy, although his work did not directly touch on thattopic.

Its conceivable . . . that vitamin C mightmake can-cer treatment less effective and, therefore, reasonablethat cancer patients undergoing chemotherapy

should avoid taking large amounts of this vitamin,was one such statement.21 Many things are conceiv-able, but Golde performed no studies on the interac-tion of chemotherapy drugs with vitamin C. Yet start-ing with an American Cancer Society meeting inMarch 2000, his pronouncements spread and havebecome the main justification for avoiding the con-current use of antioxidants to this day.

The CA article takes up where Golde left off. Itstates that Goldes work would suggest that the pro-tective effect of vitamin C might be even greater fortumors than for normal cells.1 But how the authorgets from the avidity of some cancer cells forboth glu-cose and a form of vitamin C to vitamin Cs directinterference with chemotherapy is difficult to fathom.On what basisdoes she conclude that the fact that vita-min C accumulates in cancer cells means that it isfeeding thosecells?The authorcites no evidence forsuch a mechanism. Absent any such evidence, onewould be equally justified in concluding that the pres-ence of vitamin C kills or inhibits the cancer cell.

In fact, the aforementioned research by Levinesgroup revealed just this. They showed that at levelsthat can be achieved only by intravenous administra-tion, vitamin C does indeed selectively kill a variety of

cancer cells in vitro by generating singlet oxygen,notably by acting as a pro-drug to deliver hydrogenperoxide (H

2O

2) to malignant tissues. These find-

ings, they write, give plausibility to intravenous ascor-bic acid in cancer treatment.22

The CA article ignores Levines findings. It alsoignores anyof theclinical data that support theuseful-ness of vitamin C in conjunction with chemotherapy.There are indications that such concurrent use mayindeed be beneficial. The work of some early vitaminC pioneers such as Emanuel Cheraskin, MD, H. L.Newbold, MD, or Hugh Riordan, MD, may under-standably have been left out due to its anecdotal

nature.23-25

An article that should, however, have beencited, at least for balance, in the discussion is the clini-cal trial by Kaarlo Jaakkola, MD, and colleagues at theUniversity of Jyvaskyla, Finland, comparing the treat-ment of patients receiving chemotherapy and radio-therapy for small-cell lung cancer with or without vita-mins and minerals, including vitamin C. They wrote,

Antioxidant treatment, in combination with chemo-therapy and irradiation, prolonged the survival timeof patients with small cell lung cancer compared to

most published combination treatment regimensalone.We also noticed that thepatients receivinganti-oxidantswereableto toleratechemotherapy andradi-ationtreatmentwell. Survivingpatients started antiox-idant treatment in general earlier than those whosuccumbed.26

Lesperance StudyAt one point, the CAarticle acknowledges the theoret-ical nature of its own argument. However, the authorsays, a study that more directly addresses the issue ofantioxidant useconcurrently with cytotoxics is that ofLesperance et al.1

In this study, 90 patients with early-stage breast can-cer were prescribed megadoses of combination vita-mins, minerals, and other antioxidants concurrentwith standard therapy. These patients were then com-pared with a group of well-matched controls. Breastcancerspecific survival and disease-free survival times

for the vitamin/mineraltreated group were shorterthan those for thecontrol group,although overall sur-vival was similar for both groups.27 The CA articleacknowledgesthatin and of itself, this study isnot con-clusive evidence that concurrent treatment with anti-oxidants is deleterious. Although many confoundingfactors may explain these differences in survival, theauthorstates, the data shouldconcern anyoncologistwho has patients considering antioxidant therapy.1

The study in question was headed by Mary L.Lesperance, PhD, a biostatistician at the University ofVictoria, Bri tish Columbia, and concerned the

patients of Abram Hoffer, MD, PhD, a well-knownCAM practitioner and an erstwhile colleague of Pro-fessor Pauling.

While the Lesperance study was well executed andfair-minded in its conclusions, several caveats are nev-ertheless in order. First, rather than arrange an RCT,the authors opted for a less rigorous study design, thatis, a retrospective review involving matched cases.Although they attempted to match the experimentaland the control cases carefully, an observational studycan never offer the kind of even-handedness andimpartiality that an RCT can.

In a standard oncology textbook, biostatistician

Thomas F. Pajak, PhD, warned against using observa-tional studies of this sort as a basis for clinical decisionmaking. These surveys may contain serious potentialbiases, he wrote.28 Epidemiologists generally viewsuch retrospective studies as a springboard for iden-tifying possible future prospective studies, ratherthan the sole evidence on which to base a change ofclinical practice.29

For example, in a retrospective study of this sort, itis impossible to establish whether, and if so how faith-fully, the treated patients actually followed this self-

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administered regimen ofb-carotene, niacin (vitaminB3), vitamin C, selenium, Co Q10, and/or zinc. As thearticle by Lesperance et al correctly notes, Membersof either the vitamin/mineral or the control groupsmay not have followed through on their prescribedsystemic treatment.27 Even for the administration of

postoperative chemotherapy, poor compliance hasbeen reported in most clinical trials in Canada.30 AsHoffer explained in a follow-up article (also not men-tioned in the CAreview), most of his patients saw himfor only 2 visits, a month apart, at the beginning oftheir treatment, after which they were left on theirown.31

The levels of supplements prescribed also varied,sometimes widely. The amount of Co Q10 prescribedor takenwas never even recorded. The amountof sele-nium ranged from 1 to 750 mg, zinc ranged from 0 tomore than 50 mg, and vitamin C from 1 to 24 g/d.Patients were prescribed anywhere from 3 to 6 differ-

ent agents, which they may or may not have actuallytaken consistently. Compliance was thus a major prob-lem in this study. This was simply a retrospective analy-sis of one physicians private practice. One cannotimagine a proper randomized trial conducted in sucha haphazard fashion.

Hoffers patients also differed significantly fromcontrols in terms of what conventional treatment theywere receiving.31 In particular, they were much morelikely to reject radiotherapy than controls. Thus, 16%of Hoffers patients had lumpectomy alone with noradiotherapy compared to only 7% in the matched

controls. According to the authors of the study,lumpectomy alone [without radiotherapy] is associ-ated with modestly higher rates of systemicrecurrence.

This may downplay the potential impact of reject-ing radiation therapy for early-stage breast cancer. Inan often-cited study, Bernard Fisher, MD, and cowork-ers found that after 12 years of follow-up, the cumula-tive incidence of a recurrence of tumor in theipsilateral breast was 35% in the group treated withlumpectomy alone and 10% in the group treated withlumpectomy and breast irradiation.32 In the OntarioClinical Oncology Group study, the numbers were

similar: 35% of the nonirradiated patients versus 11%of the irradiated patients developed recurrent cancerin the ipsilateral breast.33 This difference may help toexplain the disparity in recurrences between these 2populations. After all, one cannot have disease-freesurvival if there is a recurrence of the disease.

According to Lesperance et al,27 however, the great-est limitation of the study wasthat the sample size wasnot large enough to provide adequate power to dis-cern small differences in survival between the twogroups. Bear in mind that there was no meaningful

difference in survival.Thus, thedifference in questionmay have been due to chance, or to extraneous factorssuch as the studys small size, rather than to the inher-ent inferiority of Hoffers program.

However, after publication of the Lesperance et alstudy, with its carefully crafted conclusions, one of the

coauthorsseized theoccasion toattackthe concurrentuse of antioxidants with conventional therapy. Thestudy shows that there may even be a harmful effect,said Ivo Olivotto, MD, chief of radiation oncology atthe BC cancer center. This, as Hoffer justifiablypointed out, was contrary to the conclusions in thepaper itself.31 Olivottos argument received wide-spread publicity, however, with such attention-grabbing headlines as Megavitamins, Cancer Treat-ment Dont Mix, Vitamins Warning: CautionAdvised, and Vitamins May Harm Breast CancerRecovery. Hoffers rebuttal received next to none.The CAarticle repeats this scientifically unwarrantedand highly subjective interpretation, without citingany of the explicit caveats contained in the articleitself.

Co Q10

Another area in which antioxidants may play a criticalrole is in preventing the toxicity of anthracyclines, inparticular doxorubicin (Adriamycin). This class ofdrugs has a major health-impairing as well as dose-limitingeffect: it canlead to irreversibledamageto theheart muscle. This phenomenon was described morethan 3 decades ago.34,35 Even at the present time, de-spite widespread acknowledgment of this effect, somepatientsarestillsuffering andeven dying ofcongestiveheart failure, caused by anthracycline use.36 The solu-tion may lie in theapplication of specific antioxidants.Yet, oddly, the CA article fails to discuss either theproblem or its potential solution. (The CAarticle pro-vides but does not comment on 1 footnote thatreferences the use of vitamin E in this context.)

The mechanism by which anthracyclines damagetheheart is well understood. Moreover, according to asubstantial body of research, recently reviewed in thisjour nal by Conkli n,3 7 An th racycli ne-i nduc ed

cardiotoxicity is easily preventable. Both preclinicaland clinical studies suggest that the antioxidant CoQ10 administered before, during, and afteranthracycline chemotherapy can largely prevent theheart damage for which that drug is notorious(K.Conklin, personal communication, September 27,2005).

This solution was proposed as early as 197638 andwas elaborated on by the late Karl Folkers, PhD, whosaid the following in 1978: Coenzyme Q10 offerspromise of rescue from at least some of the




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cardiotoxicityoccurring in Adriamycin-treatedcancerpatients.39Although that was written many years ago,the message has still not gotten across to manyoncologistswhouseAdriamycin in theirdailypractice.

Conklin is by no means a blind enthusiast for unre-strained antioxidantuseduring chemotherapy. Buthe

believes that Co Q10, far from interfering with stan-dard chemotherapeutic agents, might even enhancetheir anticancer effects. At UCLA, he administers arelatively large dose (200 mg/m2) of this antioxidantto patients receiving Adriamycin, such as those withbreas t cancer . He reports that coenzymeQ10 . . . appears to prevent damage to the mitochon-dria of the heart, thus preventing the development ofanthracycline-induced cardiomyopathy. Conklinbelieves that by preventing this common adverseeffect, oncologists might be able to safely escalate thedose of this powerful drug, which would furtherenhance the anticancer effects (K. Conklin, personalcommunication, September 27, 2005).

Vitamin E

In regard to another popular antioxidant, vitamin E(a-tocopherol), the CAarticle states, In another re-cent study, vitamin E hadno effect on the incidence ofsecond primary head and neck tumors among survi-vors of stage I or II head and neck cancer previouslytreated with radiotherapy. It cites the Bairati JNCIstudy.15 As mentioned previously, this study showedthat while there was a nonsignificantly higher rate ofsecond primaries during the 3-year period ofsupplementation, the rate at the completion of thestudy was identical between the 2 groups. Meanwhile,62% of the supplemented patients had significant re-lief from the adverse effects of treatment.13 The latterfact was ignored by the author of the CAarticle andbyalmost all commentators on the Bairati study.40

These and other results do suggest that there areongoing questions about the actual clinical effect ofantioxidantsupplements during theadministrationofradiotherapy. As mentioned earlier, it would be pru-dent to limit future clinical trials to cancers in whichthere is a high rate of salvage. However, the implica-

tion of this finding for the broad field of radiotherapyand especially chemotherapy is uncertain. In general,the mode of action of chemotherapeutic drugs is lessdependent on oxidation and free radical generationthan is radiotherapy. Furthermore, Camphausen et alhave cast doubt on the notion that phytonutrient anti-oxidants could possibly interfere with the powerfulfree radicals generated by radiotherapy.16 It wouldtherefore not be valid to extend therapeutic caveatsfrom a few ambiguous studies of one modality to theentire class of chemotherapeutic drugs.

Furthermore, the CAarticle here conflates 2 sepa-rate fields of inquiry. The study by Lesperance et al27 isactually a study of chemoprevention, not of the treat-ment of existing cancer by the concurrent use of anti-oxidants alongside chemotherapy or radiotherapy.

While the Lesperance et al study found no benefit

from antioxidants in the prevention of cancer, thereare other studies that conclude the opposite. Forexample, according to scientists from the Yale Com-prehensive Cancer Center (New Haven, Conn), anti-oxidant nutrients such as vitamin E, b-carotene,lycopene, and selenium are regularly found to reducethe risk of lung, prostate, stomach, or total cancers, aswell as oral precancers, in epidemiologic studies.41

There are several clinical studies that also demon-strate the usefulness of specific antioxidants in theprevention of cancer recurrence following treatment.Forexample, a study from theUniversityofTexasM.D.

Anderson Cancer Center, Houston, showed that acombination of 3 agents, including vitamin E, waspromising as adjuvant therapy for locally advancedsquamous cell carcinoma of the head and neck.42

Another trial of the same 3 agents, published in April2005, demonstrated 84% survival among the treatedpatients, compared to a historical 5-year survival of40%. These authors, from the University of Pitts-burgh, concluded, The bioadjuvant combination ishighly effective in preventing recurrence and secondprimary tumors.43

Other articles have demonstrated similar findings.As the CAarticle states, These chemopreventiontrials

are not directly applicable to the question of antioxi-dant use during treatment of active cancer.1Yet thearticle highlights a negative one, while ignoring sev-eral positive trials.

At the same time, the article fails to address thequestion of whether high-dose vitamin E reduces orincreases the toxicity of radiotherapy and/or chemo-therapy or interferes with the effectiveness of thesetoxic treatments. Omissions in this area are notewor-thy since there are in fact half a dozen clinical studiespointing to benefit,without anysign of interference.Abrief summary of some of these studies follows.

The platinum-based drug cisplatin causes peripheralneuropathy in 15%to 20%of patients.44 Certain nutri-ents may offer a protective effect. An RCT was con-ducted to measure the neuroprotective effect ofvitamin E in patients who were being treated withplatinum-based chemotherapy (cisplatin). Forty-seven patients were randomly assigned to either re-ceive vitamin E supplementation during cisplatinchemotherapy or to receive cisplatin chemother-

apy alone. A dose of 300 mg/d of vitamin E (a-tocopherol) was administered orally before cisplatin

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chemotherapy, and daily administration of vitamin Econtinued for 3 months after the end of that treat-ment. The incidence and severity of peripheral nervedamage was significantly lower in the vitamin Etreated group (30.7%) than in the cisplatin group(85.7%). The authors concluded that supplemen-tation of patients receiving cisplatin chemotherapywith vitamin E decreases the incidence and severity ofperipheral neurotoxicity. Furthermore, in the clini-cal work, as well as in preclinical studies, no interfer-ence was seen between vitamin E and cisplatin.

45(The

CAarticle references this study in a footnote, withoutfurther discussion.)

In a Brazilian RCT, 54 patients with cancer of the oralcavity and oropharynx were randomly assigned torinsetheir mouths with a solutioncontainingeithervi-tamin E or a placebo mouthwash before every dose ofradiationand again 8 to 12hours later throughout the5 to 7 weeks of radiotherapy. Among the patientsgiven vitamin E, there was a 21.6% incidence of

radiation-induced mucositis (ie, inflammation of thelining of the mouth and gastrointestinal tract) versus33.5% among the placebo group. Vitamin E was thusassociated with a 36%reduced risk of mucositis. It wasalso associated with reduced World Health Organiza-tion grades 2 and 3 pain during radiation treatment(53.8%in theplacebogroup to10.7%inthevitaminEgroup, a 5-fold reduction in incidence). No signifi-cant influence was detected in survival, the authors

reported.Theyconcludedthata-tocopherol(vitaminE) decreased the incidence of symptomatic oralradio[therapy]-induced mucositis in patients withcancer of the oropharynx and oral cavity.46

Another RCT on the use of vitamin E for the preven-

tion of chemotherapy-induced neuropathy foundthat such nerve damage occurred in 73.3% of thosewho received chemotherapy alone verus just 25% ofthose whoalso received vitamin Ea3-fold reductionin incidence.47

Yet another RCT showed that vitamin E plus the drugpentoxifylline caused a significant reduction inradiation-induced fibrosis (RIF), an adverse effect ofradiotherapy for cancer. The authors report that themean RIF regression was 60%for the combined treat-ment versus 43% in the placebo control group.48

From the same research group, there was a more re-cent clinical trial of pentoxifylline, vitamin E, andclodronate to treat osteoradionecrosis (ORN). This

study also found that this 3-agent regimen, includingvitamin E, is an effective treatment of mandibularORN, which induces mucosal andbone healing in amedian period of six months.49

An Indian RCT, published in an American journal,studied high-dose multiple antioxidants (vitamin C,

E,andb-carotene) as an adjunct to thestandarddrugspaclitaxel and carboplatin in non-small-cell lung can-cer (NSCLC). One hundred thirty-six patients withstages IIIB andIV NSCLCwere randomized to receivechemotherapy alone orchemotherapy plusthese anti-

oxidants. In the chemotherapy-alone arm, the re-sponse rate was 33%, with no complete responses. Inthe antioxidant-added arm, the response rate was37%, and2 patients hada complete response. Mediansurvival was9 months in thechemotherapy armversus11months intheantioxidantarm.Overall survival at1year was 32.9% for chemotherapy versus 39.1% in theantioxidants-addedarm.At2 years,it was11.1%in thechemotherapy arm and 15.6% in the combinationarm. Toxicity was similar in both groups. In every pa-rameter, includingoverall survival, theseadvancedpa-tients fared better when they received antioxidants inaddition to chemotherapy. The authors concludedthat theseresults do notsupport theconcern that an-tioxidants might protect cancer cells from the freeradical damage induced by chemotherapy.

50

Vitamin E (400 IU) and vitamin C (500 mg) have alsobeen shown to offer protection against proctitis, apainful chronic injury that affects 5% to 20% of pa-tients receiving radiation therapy for cervical and

prostate cancer.

51

To repeat, noneof these clinical trials is mentionedin the CAarticles discussion of vitamin E. Yet that arti-cle does expand on a single negative and ultimatelyirrelevant article on chemoprevention.

MelatoninMelatonin is a hormone naturally secreted by the pi-neal gland in the brain in response to darkness. It hasbeen linked to the regulation of circadian rhythms,and for that reason,many people employ it, in supple-

mental form, as a hypnotic agent to overcome insom-nia and jet lag. Melatonin is the subject of ~12 000PubMed-listed articles.

Melatonin is an antioxidantbut hasother modes ofaction as well. It is an immune-modulating substancethat has been shown experimentally to haveantitumor, anticytokine, and anticachectic effects.52 Italso counters apoptosis in normal brain cells and hastherefore been proposed as a potential treatment ofAlzheimer disease.53 Different doses may have varyingbiological effects. Thus, while many people take 1 or 3mgas a hypnotic agent, Italian clinical trials forcancercall for nighttime doses of 20 mg or more.

Melatonin has an effect on chemotherapy andradiotherapy. In 2003, Paolo Lissoni, MD, chief ofoncology at a large public hospital in northern Italy,andcolleagues, showedthatmelatonin canmodulatethe effects of cancer chemotherapy, by enhancing itstherapeutic efficacy and reducing its toxicity.54 It wasonly the latestin a long line of positive clinical trialsonthis topic.

Lissoni postulated a complicated relationshipbetween melatonin and chemotherapy: The increasein chemotherapeutic efficacy by melatonin may




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depend on two main mechanisms, namely preventionof chemotherapy-induced lymphocyte damage and itsantioxidant effect, which has been proved to amplifycytotoxic actions of the chemotherapeutic agentsagainst cancer cells.54

In2003, Lissoni andcolleagues lookedat 5-yearsur-

vival rates from metastatic NSCLC. One hundredpatients received the standard drugs cisplatin andetoposide, with or without the concomitant adminis-tration of melatonin (20 mg/d orally in the evening).According to the authors, Both the overall tumorregression rate and the 5-year survival results were sig-nificantly higher in patients concomitantly treatedwith melatonin.54 In particular, no patient treatedwith chemotherapy alone was alive after 2 years,whereas a 5-year survival was achieved in 3 of 49 (6%)patients treated with chemotherapy and melatonin.Moreover, they state, chemotherapy was better toler-ated in patients who were treated with melatonin.

This study confirms, they wrote, in a consider-able number of patients and for a long follow-upperiod, the possibility to improve the efficacy of che-motherapy for both survival and quality of life by aconcomitant administration of melatonin.54 Lissoniand colleagues have demonstrated similar effects inRCTs of colorectal55 and metastatic lung cancer,56 aswell as thrombocytopenia.57

The CA article entirely fails to mention Lissoniet als54work on melatonin. The omission is odd sinceLissoni is the author of 111 PubMed-listed articles onmelatonin, 48 of which describe clinical trials. In Feb-

ruary 2003, he was a guest speaker at the US NationalCancer Institute, and his work is well known aroundthe world.58

Cisplatin and the Problem of Ototoxicity

One of the major problems with certain anticancerdrugs is their potential to cause nerve damage. Theplatinum-containing drugs, such as cisplatin, are par-ticularly liableto produce peripheral neuropathy, oneform of which, ototoxicity, or damage to the auditorynerve, can result in auditory changes that range in se-verity from annoying tinnitus to profound, irrevers-

ible hearing loss.59

Various antioxidants have been tested as ways ofpreventing platinum-related ototoxicity. The mostpromising is glutathione, one of the thiol-containingsubstances manufactured endogenously. However,the use of thiol-containing antioxidants together withthe drug cisplatin remains somewhat controversial.There are those even within the CAM field who feel itis an inadvisable to mix thiol-containing antioxidantswith platinum-based products (K. Conklin, personalcommunication, September 27, 2005). There is

indeed a laboratory study suggesting that 1 thiol-con-taining antioxidant, N-acetylcysteine, blunts thecytotoxic effect of cisplatin in bladder cancer cells.60

Some authors feel thatif glutathione were to bind withcisplatin, carboplatin, or oxaliplatin, before cancercells took up those drugs, thiswould inhibit the drugs

antineoplastic activity.While recognizing this theoretical concern, the

preponderance of clinical data does support the con-current use of glutathione with platinum-containingdrugs.For example, in 1993, physicians in Milan, Italy,treated 20 patients with advanced ovarian carcinomausing a combination of cisplatin and glutathione.They achieved a complete response in 11 of 20patients, half of whom had bulky disease. The medianoverall survival was 26.5 months, and 5 such patientswere still alive and disease free at 35 months. Toxicitywas limited. The authors concluded that glutathionehad no negative interference with cisplatin and in

fact might improve the therapeutic index.61 Therehave been several other phase 2 trials showing thesame positive result.62-64

Although the latter were nonrandomized phase 2trials, there have also been randomized trials of thesame concept. In one study, 151 patients receivedcisplatin for ovarian cancer. But 58% of patients whoalso received glutathione were able to complete thefull 6 courses of cisplatin compared to just 39% in thecontrol group. The patients quality of life was alsoimproved.Theauthors wrote,There wasa statisticallysignificant improvement in depression, emesis,

peripheralneurotoxicity,hair loss,shortnessof breathand difficulty concentrating.65

Despite fears to the contrary, glutathione did notresult in either a reduced number of responses ordiminished survival. There were better outcomes intheglutathione-added group (73% vs62%, notstatisti-cally significant). The authors concluded that addingglutathione to cisplatin allowed more cycles of treat-ment to be administered because less toxicity isobserved and the patients quali ty of l i fe isimproved.65

JCOpublished a study of 50 patients with advancedgastric carcinoma, 42 of whom were assessable. After

15 weeks of treatment, 4 of 24 (16.7%) patients receiv-ing both cisplatin and glutathione experienced nervedamage compared to 16 of 18 (88.9%) in the placebogroup. These results were highly significant.Glutathione reduced by half the need for blood trans-fusions (32 vs 62 incidents), and the response rateswere also higher: 76% (with 20% complete response)in the glutathione group versus 52% (with 12 com-plete response) in the placebo arm. The authors con-clude that glutathione is a promising and effectivenew drug for the prevention of cisplatin-induced

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neuropathy and that it does not reduce the clinicalactivity of chemotherapeutic drugs.66 They laterachieved similar results with the related drugoxaliplatin.67

In 2000, Austrian physicians showed comparableresults in a randomized trial of glutathione for head

and neck cancer. They compared glutathione supple-ments to intensive hydration alone in patients under-going chemotherapy with a cisplatin-based regimen.Six patients with advanced NSCLC and 14 withadvanced head and neck cancer were enrolled in thestudy. All received cisplatin along with etoposide or 5-fluorouracil every 4 weeks. Half were randomized toreceive 5 g glutathione immediately before applica-tion of cisplatin. Blood toxicity was significantly lesspronounced in patients treated with glutathione thanin the control group. Hemoglobin, white blood cellcount, and platelets all improved.68

In regard to the idea thatantioxidantsdiminish the

response rate of chemotherapy, these authorsobserved an objective remission in 6 of 11 patients inthe glutathione group (55%, including 9% completeremission) versus 4 of 8 evaluable patients in the con-trol group (50% partial remission). The increase inoverall survival time, although trending in favor of theglutathione group (13.5 months vs 10.5 months), wasnot statistically significant, probably due to small sam-ple size. The authors concluded that the addition toglutathione to cisplatin seems to be safe and feasibleand the anti-tumoral efficacy of cisplatin is apparentlynot impaired by theconcomitant useof glutathione in

patients with solid tumors.

68

Yet the CA article does not discuss the issue ofcisplatin toxicity, including its notorious ototoxicity,nor does it mention the simple solution of givingpatients undergoing cisplatin treatment supplemen-tal glutathione, which has now been shown in a num-berof randomized trialsto be an effectivetechnique.

Correcting MalnutritionThere is another good reason for administering anti-oxidants during radiotherapy or chemotherapy,which the CAarticle does noteven consider. Manycan-cer patientsas a result of their disease, its treatment,

or bothbecome deficient in selected nutrients.Some even become clinically malnourished orcachectic. Here is a description of the process fromthe US National Cancer Institute (NCI) Web site:

For many patients . . . some side effects of cancer andcancer treatments make it difficult to eat well. Symp-toms that interfere with eating include anorexia,nau-sea, vomiting, diarrhea, constipation, mouth sores,trouble with swallowing, and pain. Appetite, taste,smell, andthe ability to eatenoughfoodor absorb the

nutrients from food may be affected. Malnutrition(lack of key nutrients) can result, causing the patientto be weak, tired, and unable to resist infections orwithstand cancer therapies.69

Radiotherapy and chemotherapy are often the direct

cause of this malnutrition. These cytotoxic treatmentsattack normal as well as malignant cells and as a resultcan cause nausea, vomiting, infection, fever, and ageneralized state of anxiety and malaise. All of theseconditions can obviously result in weight loss andeven organ damage. Although protein and caloriedeprivation are the more obvious forms of mal-nutrition, severe hypovitaminosis is also frequentlyencountered.

The decline in vitamin status and intrinsic antioxi-dant levels after irradiation can be subtle but long last-ing. Many oncologists assume that antioxidant levelsspring back quickly after irradiation. However, this is

not necessarily the case. At Leiden University MedicalCenter, Holland, scientists found that the levels of theintrinsic antioxidants bilirubin, albumin, and uricacid all remained low for quite a while after irradia-tion, as did the ratio of vitamin E to cholesterol andtriglycerides. Dutch physicians called this a failureof the antioxidant defense mechanism againstoxidative damage, caused by commonly used toxictreatments.70

CAM clinicians tend to believe that it is very impor-tant to restore the bodys antioxidant levels to normalas quickly as possible. For instance, albumin alone is abellwether of how long a patient will live, a significant

independent predictor of survival.71

Scientists in Tbingen, Germany, have looked atthe levels of vitamins C, a-tocopherol, b-carotene,and so forth before, during, and after high-dosechemotherapy. The drug etoposide significantlyincreased free radical damage to fats. b-Carotene lev-els fell by 50% and vitamin E (a-tocopherol) levels by20%.72,73

It has long been known that both chemotherapyand radiotherapy causemalnutrition and vitamin defi-ciencies.74 It seems entirely unnecessary that in the21st century, cancer patients should still be suffering

from such deprivation. Under these circumstances,however, many clinical nutritionists believe that foodsrich in antioxidants area way of restoringbiochemicalsufficiency. Phytonutrients absorbed from dietarysources can bolster the bodys overall antioxidant lev-els. However, enhanced food intake alone is often notenough. Because of damage to the gastrointestinaltractandother healthproblems,many cancerpatientssimply cannot eat properly nor absorb nutrients nor-mally. Therefore, antioxidants, in the form of eitheroral or intravenous supplementation, may be neces-




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sary to remedy the patients depleted nutritionalstatus.75

It should be emphasized that antioxidants, given inthis context, area wayof precisely restoringto patientswhat treatment and disease have taken from them. It isnota matterof ingestingunspecified amounts of puta-

tivelyanticancer vitaminsbutof returningpatients toanormal state of metabolic activity, before, during, orafter cytotoxic therapy.

By way of illustration, let us take the case of headand neck cancer, where treatment often causes dam-age to the mouth and throat and therefore interfereswith proper food intake. Scientists at Yale University(New Haven, Conn) have found that in addition toweight lost prior to the diagnosis of head and neckcancer, the patient may lose an additional 10% of pre-therapy body weight during radiotherapy orcombined-modality treatment. In fact, a reduction

of greater than 20% of total body weightsadly, notan uncommon occurrenceresults in an increase intoxicity and mortality.76

In fact, almost every vitamin, from A to K, has beenfound to be lacking in some cancer patients after theyreceive chemotherapy. These findings would suggest,then, that such nutrients (including various antioxi-dants)should be expeditiously restored to reverse andprevent the ravages of vitamin deficiency. Yet the CAarticle does not mention this legitimate use of antioxi-dants or even the existence of nutritional deficienciesfollowing cytotoxic therapy.

Immunosuppression

Similarly, chemotherapy can cause a profound, evenpotentially fatal, suppression of the immune system.In the postWorld War I era, 2 Chicago scientistsshowed that mustard gas inhibited the formation ofantibodies in theblood.77 This dreaded form of chemi-cal warfare profoundly modified the leukocyte countof the blood in experimental animals.78

The a lkyl a t ing agent s , and par ti cular ly cyclophosphamide (Cytoxan), which were initiallydeveloped in the 1940s from research into mustardgas, were found to be among the most immuno-

suppressive substances ever discovered. In fact,cyclophosphamide, as well as another such agent,chlorambucil, is still used in the treatment of autoim-mune disease precisely for that reason.79,80 Because ofits immunosuppressive qualities, cyclophosphamidehas also been used to intentionally destroy the bonemarrow in preparation for stem cell transplants.81 Inaddition to cyclophosphamide, many other drugs,including carboplatin, methotrexate, ara-C, andgemcitabine, are myelosuppressive. As is well known,

myelosuppression is one of the most common dose-limiting complications of chemotherapy.

Little has been done clinically to explore the possi-ble use of supplements, including antioxidants, tocounteract this adverse effectof cytotoxic therapy. Butthere are some hints in the medical literature.

In a clinical trial, scientists at Memorial Sloan-Kettering Cancer Center showed that far from inter-fering with the therapeutic action of the standarddrug irinotecan, its efficacy could be significantly en-hanced by concurrent administrationof a vitamin-likeflavonoid compound called flavopiridol.

82

Theaforementioned Paolo Lissoni, MD, of Monza, It-aly, has repeatedly demonstrated a reduced degree ofmyelosuppression in patients treated with cisplatinand etoposide who also received melatonin for ad-vanced NSCLC.

83

Astragalus mongholicus is an herb that contains

isoflavonoids with antioxidant properties.

84

TheCochrane Collaborative reviewed Chinese clinical tri-als and found a decrease in the rate of leucopenia,as well as a significant reduction in . . . nausea andvomiting, following the use ofAstragalus-containingmixtures. Such compounds may stimulate immuno-competent cells and decrease side effects in patientstreated with chemotherapy. . . . We found no evidenceof harm arising from the use of Chinese herbs, theywrote. They have called for randomized trials.85

Of course, there are patented, expensive pharma-ceutical-grade agents that are used to protect theblood-forming system from the ravages of radiother-

apy and chemotherapy. These include granulocytecolonystimulating factor, marketed as filgrastim(Neupogen) and pegfilgrastim (Neulasta), as well asepoetin (Epogen, Procrit),a man-made form of a hor-mone thatstimulatesperipheral stem cells in thebonemarrow to produce red blood cells. However, syn-theticagents such as epoetin may haveserious adverseeffects, including possibly diminished survival.86

It is difficult not to be struck by the tremendous dif-ference in cost between these prescription drugs andover-the-counter antioxidants. The retail cost of a sin-gle 6 mg/0.6 mL syringeof Neulasta is $3384,with therecommended dose being 1 injection per chemother-apy cycle. Amgens worldwide sales of Neupogen andNeulasta were US $795 million for the first quarter of2005, which works out to $3.18 billion, if prorated forthe entire yearand sales were up 20% over the com-parable period in 2004. Epogen andProcrit were evenmore profitable. In 2004, worldwide sales of these 2forms of epoetin were ~$6 billion per year. Andalthough the patent on these products ran out inOctober 2004, the price did not drop. That is becauseAmgen won as many as 12 extra years of protection

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beyondthat first patent, which will keep thepricehighuntil 2016, according to an informed newspaperaccount.87

The patented agents Neupogen, Neulasta, andProcrit cost patients thousands of dollars and earnnearly US $10 billion per year for Amgen alone. By

comparison, a 20-mg dose of melatonin costs approxi-mately25cents.One could take thatdoseevery day fora year and still not exceed $100 in costs.

Onemight think that oncologists would be eager tofind nontoxic nutritional factors thatmight be used toprotect or restore the immune system and allow for aless toxic chemotherapy experience. But the writingsof many oncologists, including the CAarticlesauthor,evince no interest in exploring the use of inexpensiveantioxidants in preserving and restoring immunefunction, which is a crucial factor in cytotoxic cancertherapy.

One might also think that the low cost of antioxi-

dants would encourage hospitals, government agen-cies, and health insurance companies to advocate anincreased use ofor at least experimentation withantioxidants in this context. However, the campaignagainstantioxidantshasbeen so relentless and, by andlarge, so successful that few influential voices havebeen raised in their defense. In any case, the impact ofthe medical insurance industry on large therapeuticdecisions is relatively small compared to that of thepharmaceutical industry, which derives much of itsprofits from the legal monopoly provided by the pat-ent system.88

The low price of nutritional antioxidants, and thefact that they are generally unpatentable, makes themunlikely to attract the favorable attention of the phar-maceutical industry.89 In fact, one could argue thatthey represent an implicit threat to the continuedsaleof incrementally more expensive pharmaceuticals.The antagonism of the pharmaceutical industrytoward readily available and inexpensive therapeuticagentseventually translates into a widespread indiffer-ence or even hostility on the part of the mainstreammedical profession, resulting in a paucity of rigorousstudies of these potentially useful and cost-savingagents.

The Columbia Example

There are some notable exceptions. Specialists in theDivision of PediatricOncology of theCollege of Physi-cians and Surgeons of Columbia University, New York,have been investigating the relationship between theuse of chemotherapy and antioxidant status in theiryoung patients. They have shown that in those patientswho had higher than average plasma concentrationsof antioxidants, there was a beneficial association

wi th fewer dose reduct ions , fewer in fect io ns ,improved quality of life, less delay in chemotherapytreatment schedule, reduced toxicity, and fewer daysspent in the hospital.90,91 In other words, ampleamounts of antioxidants were found to translate intohealthierpatients and betterclinical outcomes. These

oncologists have therefore begun to administer anti-oxidants to pediatric patients to overcome patentnutritionaldeficiencies. Theresults areencouraging.

Greater vitamin C intakes at six months, KaraKelly, MD, and her Columbia colleagues wrote, wereassociated with fewer therapy delays, less toxicity, andfewer days spent in the hospital. Greater vitamin Eintakes at three months were associated with a lowerincidence of infection. Greater beta-carotene intakesat six months were associated with a decreased risk oftoxicity.92 In addition, there has been no sign of thenegative interaction between antioxidants and che-motherapy that the CAarticles author fears.

Inconsistency: Foods Contain Antioxidants

There is also an inconsistency in the CAarticles argu-ment against the concurrent use of antioxidants andcytotoxic therapy. The author never specifies whatquantities of antioxidants are allegedly dangerous.Antioxidants are naturally found in many foods, in-cluding most fruits and vegetables. As Professor DavisLamson, ND, of Bastyr University has pointed out,Without antioxidants, life itself is impossible (Seat-tle, Wash; personal communication, September 26,2005).

Yet obviously, some fruits and vegetables containabundant quantities of antioxidants. If antioxidantstruly interfered with radiotherapy and chemotherapy,one would think that patients should be counseled toreduce their intake of berries, red peppers, pome-granates,and so forth,which are amongthe foods thathave high oxygen radical absorption capacity values.Thiswould seemto be a necessarycorollary tothe pro-posed restriction of supplemental antioxidant useduring conventional t reatment : a b l and ,phytonutrient-deprived diet would be preferable,according to this theory, to an antioxidant-rich feast of

colorful produce.The reader may think that this is nothing morethan a reductio ad absurdum. But in fact, there is a sci-entist who advocates precisely this course of action.Rudolph I. Salganik, MD, PhD, of the University ofNorth Carolina, Chapel Hill, believes that even smallquantities of dietary antioxidants could interfere withchemotherapy. To err on the side of caution, he hasproposed that cancer patients be put (experimentallyat least) on a regimen depleted of such nutrients. Hefeels that even the amount of antioxidants




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encountered during normal fresh food consumptioncould undermine the therapeutic effect of treatment-induced free radicals.93 Cancer patients, especiallythoseundergoingchemotherapy or radiationtherapy,maydo betteron an antioxidant-depleteddiet,he hasopined.94

While few clinicians have adopted the draconianregimen proposed by Salganik, one can see the logicof his position and even admire the consistency of hisargument. One is left wondering why the CAarticledoes not extend the prohibition of antioxidant sup-plements to encompass antioxidant-rich foods thatpatients are likely to ingest as part of normal, well-balanced meals. If antioxidants are so deleterious topatients undergoing cancer therapy, shouldoncologists counsel patients to avoid fresh orange orpomegranate juice, bowls of blueberries, or plates ofbrussels sprouts? Or is the ideal diet during chemo-therapy hamburgers and French fries (without, ofcourse, any lycopene-containing ketchup)?

The Issue of Synthetic Antioxidants

The CAarticles proposed avoidance of supplementalantioxidants during radiotherapy and chemotherapyis inconsistent in yet another way. There are severalagents that are widely used in conventional oncologywhose principal mode of action is antioxidative. Theseradioprotectants and chemoprotectants includemesna (Mesnex) , amifos t ine (Ethyol) , anddexrazoxane (Zinecard).

Mesna (Mesnex) was the first synthetic antioxidantapproved by theFood andDrug Administration (FDA;in 1988). It is primarily used to counteract hemor-rhagic cystitis, which is one of the most common sideeffects of the drugs cyclophosphamide andifosfamide. As the FDA stated, in granting approval tomesna, Two prospective controlled trials show statisti-cally significant reduction in hemorrhagic cystitis bymesna without interference with tumor response.95

Yet mesna is an antioxidant.96 In fact, its own limitedantioxidant activity seems to be powerfully increasedby the addition of over-the-counter antioxidants suchas melatonin and a-tocopherol97 or quercetin and

epigallocatechin-3 gallate (derived fromgreentea),atleast in experimental studies.98

Dexrazoxane (Zinecard) was approved by the FDAin 1996 for the prevention of cardiomyopathy associ-ated with doxorubicin administration. The FDAdescribed it as a chelating agent that interferes withiron-mediated free radical generation thought to beresponsible, in part, for anthracycline-inducedcardiomyopathy.99 In other words, it is also a powerfulantioxidant. The ability of dexrazoxane to prevent orreduce the incidence and severity of Adriamycin-

induced heart damage has been demonstrated in 3prospectively randomized placebo-controlled studies.In no instance did the drug shorten the survival ofpatients receiving Adriamycin. The FDAspecified thatthe drug was to be used for reducing the incidenceand severity of cardiomyopathy associated with

doxorubicin administration in women with metastaticbreast cancer . . . and who will continue to receivedoxorubicin therapy to maintain tumor control.100

However, in fairness, it shouldbe noted that theAmer-ican Society of Clinical Oncology (ASCO) ClinicalPractice Guidelines for the Use of Chemotherapy and Radio-

therapy Protectants recommends that dexrazoxaneshould be used with caution alongside doxorubicin insituations in which that drug has been shown toimprove survival because of concerns about thetumorprotectant effect of dexrazoxane.101

Amifostine is particularly powerful since it scav-enges 3 types of free radicals: superoxide, hydroxyl,

and lipoperoxyl.102 It protects against both cisplatin-and radiation-induced damage. In an RCT of 242patients with advanced ovarian cancer, amifostine sig-nificantly reduced the cumulative kidney damageassociated with cisplatin, without any signs of under-mining that drugs anticancer effects.103 If anything,response rates and survival were somewhat better inthe amifostine group. While 24% of the cisplatin-onlygroup had to discontinue treatment because of toxic-ity, only 9% of the amifostine-added patients did so.103

The FDA based its approval on the fact that objectiveresponse rates, time to progression, and survival dura-

tion were similar in the amifostine and control studygroups.104

In addition, a phase 2 trial of amifostine andcisplatin was conducted in patients with NSCLC.Although there was no randomized comparisongroup in this study, the response and survival statisticswere well within the reference range. The FDA con-cluded, These results indicate that Ethyol[amifostine] may not adversely affect the efficacy ofthis chemotherapy for non-small cell lung cancer.105

As with dexrazoxane, the ASCO Clinical PracticeGuidelines for the Use of Chemotherapy and Radiotherapy

Protectantsdoes endorse the use of amifostine for the

reduction of nephrotoxicity in patients receivingcisplatin. But it stops short of endorsing the routineuse of amifostine to prevent cisplatin-associated neu-ropathy and ototoxicity. However, the ASCO guide-lines do explicitly state that there is no evidence fromthe available clinical data that amifostine leads to pro-tection of tumor cells.101

Amifostine was also tested in the radiotherapy ofhead and neck cancer. In a randomized trial, it wasfound to have a significant effect against treatment-induced xerostomia. Amifostinesignificantly reduced

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acute xerostomia from 78% to 51% and chronicxerostomia from 57% to 34%. One year after treat-ment, saliva production was 2.6 times greater in theamifostine group than in the radiotherapy-only con-trols.106

As the Duke University Medical Center, Durham,

authors properly stated, Tumor protection is thegreatest potential risk associated with the use of anytoxicity modifier. An agentthatameliorated treatmenttoxicity butthatalso reduced antitumorefficacywouldbe unsuitable for clinical use. However, the authorsnote, local-regional control and disease-free survivaland overall survival were equivalent among patientswho did or did not receive amifostine and argueagainst any such protection.106

Based on these results, and others, the FDAapproved amifostine for thereductionof cisplatintox-icity in advanced ovarian cancer (1995), NSCLC(1996), and postirradiation xerostomia (1999). Thegeneral consensus is that such agents prevent orreduce toxicity without compromising the anticancerefficacy of standard treatments.107

To summarize, if dietary antioxidants or over-the-counter supplements really did interfere in practicewith conventional treatments, would not this also bereflected in clinical trials involving such powerful syn-thetic antioxidants?

Who Is Responsible?

The CAarticle warns that one cannot make recom-mendations to cancer patients based on laboratorystudies but that one requires data from human clini-cal trials and that these need to be large. Yet the au-thor acknowledges that there has been no attemptto mount the kind of trial needed to guide clinicalpractice.1

This is basically correct. There have been someRCTs of melatonin and a few other antioxidants, asmentioned above. But by and large, these have beenmodestly sized, single-center studies. We need betterand more vigorous multicenter research. Yet a searchof the US governments clinical trials database yieldsfew studies currently under way on this crucial topic.

For example, a search of the terms radiotherapyandantioxidantsyields no current trials. Using the termschemotherapyand antioxidantsyields just the single clini-cal trial on the use of antioxidants in ovarian cancer,mentioned previously.10

Overall, there is little rigorous clinical researchunder way and, therefore, no chance of resolving thisissue any time soon through normal scientific chan-nels. Thus, theCAarticles statement that contrastingevidence from extensive human studies is neededbeforepatientsareadvised totakeantioxidants during

cytotoxic therapy is beside the point. Given the longlag time between the inception and publication of aclinical trial, the authors proposed moratoriumwould effectively preclude the use of all antioxidantsduring radiotherapy or chemotherapy for theforeseeable future.

One must recognize a fundamental economic fact.There is little incentive, under the current system, forvitamin and supplement manufacturers to carry outexpensive anddifficult research. Nor do most of themhave the network of connections in the clinical trialfield to arrange such trials. The fundamental eco-nomic fact about dietary supplements is that(with fewexceptions) they exist in the public domain and aretherefore unpatentable. Proponents therefore lackthe economic motivation that drives pharmaceuticalcompanies to do expensive research, that is, attain-ment of a legal 20-year monopoly on the sale of anapproved new drug. Exclusive rights to such an agent

are among the most valuable commodities in the mar-ketplace. They sometimes generate billions of dollarsper year in sales, which provides a strong economicincentive for pharmaceutical development.

In theabsence of this compelling profitmotivation,who then will take up the task of exploring the healtheffects of antioxidants in relation to cancer and itstherapy? Logically, this task falls to the governmentand large nonprofit entities in the field. In the UnitedStates, that means primarily the governments NCI,particularly its Office of Cancer Complementary andAlternative Medicine, the National Center for Com-

plementary and Alternative Medicine, health chari-ties, such as the American Cancer Society, and thelarge well-funded cancer centers. This cancer estab-lishment has both a scientific and moral responsibil-ity to patients, tax-paying citizens, and financial bene-factors to leave no stone unturned in the search foreffective cancer treatments. It is deplorable that lead-ers of these organizations have so far mainly criticizedthe concurrent use of antioxidants and radiotherapyor chemotherapy, without investing their awesomeresources to objectively evaluate those effects throughRCTs.

Furthermore, in the present intellectual climate, it

is questionable whether antioxidants would receive afair trial in the hands of conventional oncologists.Small but deleterious changes to study design canhave a huge impact on outcome. For instance, if agroup were to study the impact of high doses of a sin-gle antioxidant (particularly a synthetic one, as hap-pened in theCARETstudy108) and thenwere toattain anegative result, this might be a crushing blow toantioxidant use in general.

A more fruitful approach would be to start withpatient groups that are at high risk of failing to




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complete therapy altogether or of having disablingside effects, such as peripheral neuropathy or oto-toxicity, and then test a combination of antioxidants,rather than starting one big trial, which has in factbeen suggested. It might be more productive at thispoint to have a number of different medical centers

carry out a variety of different phase 2 studies andapproaches and then to pursue those agents that per-formed the best in these smaller trials. This will avoidthe pitfall of an all or nothing approach to antioxi-dant trials, whichjudging by experienceis morelikely to fail than to succeed.

Comparison to Pharmaceuticals

It is disingenuous to insist on rigorous, large-scale,phase 3 RCTs before antioxidants can be used clini-cally, when some prominent chemotherapeuticagents have been approved based on small ,

nonrandomized trials. For example, the FDA ap-proved the drug gefitinib (Iressa) for treating lungcancer based on scanty data demonstrating thatabout10% of patients may have gained short-term benefitfrom the drug. Iressas sales subsequently skyrocketedto $389 million in 2004.

Then, in June 2005, the FDA issued a warning thatnew patients should not be given Iressa because in alarge study Iressa did not improve overall survival.109

Butthis fact waswell known throughrandomized trialsbefore the drug was approved. Meanwhile, Iressa hasremained on the market and continues to generate agreat deal of incomeforits manufacturer. Onecanjus-tifiably ask why advocates of nonpatentable over-the-counter antioxidants should be required to conformto a higher standard of proof than AstraZeneca, the$21.4 billion corporation, that manufactures thisblockbuster drug.110

Meanwhile, inexpensive antioxidants could possi-bly substitute for some of these same indications. Fore xam pl e , N e up o ge n i s u se d t o t re a t t hethrombocytopenia that is often associated with radio-therapy or chemotherapy.111 However, readily avail-able natural agents such as melatonin may have com-parable effects. In 1995, Lissoni et al112 showed that

melatonin administeredwith standardtherapy ledto anormalization of platelet counts in 10 of 14 (71%)tested patients. Lissoni et al suggested that melatoninwas able not only to overcome interleukin-2-inducedthrombocytopenia but also to increase platelet num-bers in thrombocytopenic cancer patients.112 Whengi ven wi th the s t andard drug ep irubic in(Pharmorubicin) for advanced breast cancer,melatonin normalized the platelet count in 9 of 12evaluable patients (75%), and no further plateletdecline occurred in chemotherapy.113

Lissoni et al subsequently showed that anotherpineal gland hormone, indole 5-methoxytryptamine,augments theseeffectsof thebetter-known melatonin.Thirty patients were randomized to receive eithermelatonin alone (20 mg/d orally in the evening) ormelatonin plus 5-methoxytryptamine (1 mg/d orally

in the early afternoon). A normalization of plateletcount was achieved in 5 of 14 (36%) patients treatedwith melatonin plus 5-methoxytryptamine and innoneof thepatients treated with melatoninalone.56,57

Helicobacter pyloriParallelsOne can see similarities between the hostility toward,or neglect of, antioxidants and that encountered byBarry J. Marshall, MD, and J. Robin Warren, MD, whoshared the 2005 Nobel Prize for their discovery of therole ofH. pyloriin the development of stomach ulcers.It is noteworthy that Marshall and Warren made their

epochal discovery in WesternAustralia in 1982. At thattime, peptic ulcers were generally blamed on stressor even on poor parenting practices, as in this 1967textbook: Thus, the mothers of ulcer patients tendedto have psychogenic symptoms, and to be striving, ob-sessional, and dominant in the home; fathers tendedto be steady, unassertive, and passive.114 It took a de-cade and a half before Marshall and Warrens revolu-tionary thesis was accepted and made part of routineclinical practice.

The opposition we got from the drug industry wasbasicallyinertia, said Marshall,and because themak-ers of H2 blockers funded much of the ulcer research

at the time, all they had to do was ignore theHelicobacterdiscovery. If thedrug companies were trulyinto discovery, they would have gone straightafter theHelicobacter, Marshall continued. But they did notbecause of the success with H2 blockers.115 Had thesedrugs not existed, the drug companies would havejumped on our findings, he added. The fact that thebig drug companies who were supporting the journalarticles ignored H. pyloriwas far more effective thanactually saying that a bacterial cause was not truebecause if they had said it was false, or not important,they would have created a controversy and maybemedia interest.115

All the factors created a type of rigidity that manydoctors saystillexists forbetter or worse, accordingtoLawrence K. Altman, MD, senior medical correspon-dent of the New York Times.115

ConclusionsIn an analysis of common scientific fallacies, JohnP. A.Ioannidis, PhD, showed that misleading results oftenoccur when researchers are wedded to a particularoutcome of their study.116 Bias can entail manipula-

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tion in theanalysisor reportingof findings, theTuftsNew England Medical Center biostatistician wrote.Selective or distorted reporting is a typical form ofsuch bias.116

What is more, research can sometimes be noth-ing more than the predetermined enshrining of the

dominant medical prejudices. Claimed researchfindings may often be simply accurate measures of theprevailing bias, adds this veteran research analyst.

And, indeed, this seems to be the primary source oferrors in the CAarticle. The author is careful in citingsources, and some of her concerns, such as the dan-gers of self-medication with high-dose antioxidants,are legitimate. But overall, the article seems to bebased on an a priori judgment that antioxidants as aclass interfere with radiotherapy and chemotherapy,and then a scanty selection of data are stretched to fitthis Procrustean framework. In other words, the arti-cle seems more intent on making a tendentious case

against the concurrent use of antioxidants andcytotoxic treatments than in dispassionately examin-ing both sides of this complex issue.

There is far more information regarding antioxi-dant supplements as an appropriate adjunctivecancertherapy than is addressed in CAs incomplete review ofthis critically important subject. Patients would there-fore be well advised to seek the opinion of physicianswho are adequately trained and experienced in bothclinical nutrition and oncology. Physicians whose goalis comprehensive cancer therapy should refer theirpatients to qualified integrative practitioners, who

have the training and expertise to guide patients. Ablanket rejection of the concurrent use of antioxi-dants at this time serves neither the scientific commu-nity nor the burgeoning population of cancerpatients.

AcknowledgmentMy thanks to the following individuals for commentsand suggestions: Keith I. Block, MD; D. Barry Boyd,MD; Kenneth A. Conklin, MD, PhD; Jeanne Drisko,MD; Davis Lamson, ND; Kedar Prasad, PhD, andLeanna Standish, PhD,

Documents

Antioxidants Chemotherapy Moss 2006