Pharmacologic and Biologic Treatments

Chapter 5

Pharmacologic andBiologic Treatments

CONTENTSPage

Stanislaw Burzynski: Antineoplastons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91claims .. .. .. .. .. .. .. .. ... ... ....+... +. .. .. .. .., .. .$ .. .,~. +.......+ ... ..*+*.-* 93Published Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93Attempts at Evaluating Antineoplastons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Cellular Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Dimethyl Sulfoxide (DMSO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99Hydrazine Sulfate .;. . . . . . . . . . . . . . . . . . . . .Laetrile . . . . . . . . . . . . . . . ...,$... . . . . . . . . .

Adverse Effects . . . . . . . . . . . . . . . . . . . . . .Attempts at Evaluat.ing Laetrile . . . . . . . .

The Livingston-Wheeler Regimen . . . . . . . .Treatment Regimen . . . . . . . . . . . . . . . . . .Claims of Efficacy . . . . . . . . . . . . . . . ...0

Hans Nieper . . . . . . . . . . . . . . . . . . . . . . . . . . . .Oxygen Treatments . . . . . . . . . . . . . . . . . . . . .Emanuel Revici and “Biologically Guided

Revici’s Cancer Treatment Regimen . . .claims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ●✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎

✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎

✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎

✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎

✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎

✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎

Chemotherapy” . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Attempts at Evaluating the Revici Treatment Regimen . . . . . . . . . . . . . . . . . . . . . . . . . . .Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

claims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ● . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Potential Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Attempts at Evaluating High-Dose Vitamin C in Cancer Treatment . . . . . . . . . . . . . . .

100102103103107109110111113114117118118120121122122

Chapter 5

Pharmacologic and Biologic Treatments

A large and diverse group of unconventionalcancer treatments has as its central component apharmacologic or biologic substance, includingbiochemical agents, vaccines, blood products, andsynthetic chemicals. Some of these pharmacologicand biologic treatments are offered at single sitesunder the direction of a developer or other chiefproponent. Others are more widely available, are notnecessarily associated with particular proponents,and may be used in combination with a variety ofother unconventional and conventional treatments.

Examples of unconventional pharmacologic orbiologic cancer treatments associated with a singlepractitioner include: “Antineoplastons” offered byStanislaw Burzynski, M.D., Ph.D., at his clinic inHouston; an autogenous vaccine developed by thelate Virginia Livingston, M.D., at her clinic in SanDiego; “eumetabolic” treatment offered by HansNieper, M.D., in Hannover, West Germany; and“biologically guided chemotherapy” practiced byEmanuel Revici, M.D., at his office in New York.Each of these treatments is discussed in detail below.Another pharmacologic treatment, “Immuno-Augmentative Therapy” offered by LawrenceBurton, Ph.D., at his clinics in the Bahamas, WestGermany, and Mexico, is discussed in chapter 6.

Examples of pharmacologic approaches offered ata number of places, either singly or in combination,include laetrile, megavitamins, dimethyl sulfoxide(DMSO), cell treatment, digestive enzymes, hydro-gen peroxide, ozone, and a variety of other agents.When used in various combinations and with specialdiets, enemas, and instructions about avoidingsubstances thought to be harmful, these treatmentsbecome part of a general approach often referred toas ‘metabolic therapy,’ a non-specific term used bymany unconventional practitioners to refer to acombination of unconventional approaches aimed atimproving the physical and mental condition ofcancer patients (96). Many of the best known‘‘metabolic clinics’ are located in or near Tijuana,Mexico, not far from the U.S. border, e.g., CentroMedico del Mar, American Biologics, the Mannerclinic, St. Judes International, and Hospital SantaMonica. Practitioners associated with these clinics

include Ernesto Contreras, Robert Bradford, JimmyKeller, and Kurt Donsbach. Some of the majorcomponents of the ‘metabolic’ treatments (vitaminC, laetrile, DMSO, cellular treatment, hydrogenperoxide, and ozone) are also discussed in thischapter. The treatments are presented in alphabeticalorder according to the name of the main practitioneror the substance used.

STANISLAW BURZYNSKI:ANTINEOPLASTONS

In the late 1960s, Stanislaw R. Burzynski, M.D.,proposed that a naturally occurring and continuouslyfunctioning biochemical system in the body, distinctfrom the immune system, could “correct” cancercells by means of ‘special chemicals that reprogrammisdirected cells. He called these chemicals ‘Anti-neoplastons, and defined them as naturally occur-ring peptides1 and amino acid derivatives that inhibitthe growth of malignant cells while leaving normalcells unaffected (124,133). Burzynski developed atreatment regimen for cancer based on the adminis-tration of various types of Antineoplastons, which heoriginally isolated from urine and subsequentlysynthesized in the laboratory. He currently treatspatients with Antineoplastons at his clinic andresearch facility in Texas.

Burzynski received his M.D. in 1967 and hisPh.D. in biochemistry the following year, both fromthe Medical Academy of Lublin in Poland. Hemoved to the United States in 1970, and obtained alicense to practice medicine in Texas in 1973. From1970 until 1977, he held the positions of researchassociate and assistant professor at the BaylorCollege of Medicine in Houston. In 1977, he leftBaylor to establish his own research institute. He isnow president of the Burzynski Research Institute inStafford, Texas, where he and his colleagues con-duct in vitro and animal research on Antineoplas-tons. Burzynski’s clinical practice focuses on treat-ment of cancer patients with Antineoplastons, whichhe administers at his outpatient clinic in Houston.His current regimen for cancer patients includes oraland intravenous use of approximately 10 types of

Ipeptides area broad category of molec~es, including many biologically active proteins, that are made Up of combinations of amino acids.

-91-

92 ● Unconventional Cancer Treatments

Antineoplastons, all of which are manufactured atthe Burzynski Research Institute.

From 1974 to 1976, Burzynski received fundingfrom the National Cancer Institute (NCI) for re-search involving gel filtration techniques to isolatepeptides from urine and for testing their ability toinhibit in vitro growth of several types of culturedhuman cells (142). In 1976, Burzynski appliedunsuccessfully for renewal of this grant, although hedid receive supplemental finding until July 1977(245). In 1983, he applied to the Food and DrugAdministration (FDA) for an Investigational NewDrug exemption (IND), which would allow him touse Antineoplastons in human studies designed todetermin e the efficacy and safety of Antineoplas-tons. That application was put on “clinical hold,”the action taken by the FDA in cases where datasubmitted are insufficient to just@ the investiga-tional use of a substance in cancer patients. In March1989 the clinical hold was removed for one study,allowing a study of the oral form of AntineoplastonA10 in a small number of women with advanced,refractory, breast cancer (125). That study, whichwas planned to be conducted at a U.S. medicalcenter, was later “delayed,” according to a publicnotice from Burzynski’s staff, “due to the highcost’ ‘ of conducting clinical trials in the UnitedStates (858). To date, no form of Antineoplaston hasreceived FDA approval for use on patients outside ofthat specific study.

Burzynski first isolated Antineoplastons fromblood and then the urine of individuals withoutcancer. 2 He reportedly obtained dozens of fractions(128), each containing many different Antineoplas-tons (133). Burzynski and other researchers reportedtesting each fraction for anticancer activity incultured human cells and then for toxicity inanimals. His first fraction, Antineoplaston A, whichhe used to treat 21 cancer patients at a hospital inHouston (143), was later subdivided into fractionsA1, A2, A3, A4, and A5 (132,133). Fraction A2 wasreported to contain an ‘‘active’ ingredient whichwas named Antineoplaston A10; Burzynski identi-fied the chemical structure of A10 as 3-phenyl-acetylarnin o-2,6-piperidinedione (131). In additionto using it to treat patients, Burzynski supplies thisproduct to the Sigma Chemical Co., which offers itfor sale through its catalogue for research purposes.Two degradation products of Antineoplaston A10,

identified as Antineoplastons AS2-1 and AS2-5(130), have also been administered to cancer patients(see discussion below).

Burzynski believes that a variety of Antineoplas-tons are present naturally in the tissue and bodyfluids of healthy people, but that, possibly as aconsequence of cachexia (a metabolic process thatresults in physical wasting), cancer patients excreteexcessive amounts in the urine, leaving them withlow circulating levels. He states that treatment withAntineoplastons reduces the amount of endogenousAntineoplastons excreted, and that excretion ofAntineoplastons decreases with tumor regression(133). Burzynski hypothesizes that Antineoplastonsmay act by interfering with the action of certainenzyme complexes (methylation complex isozymes)that allow malignant cells to gain a growth advan-tage over normal cells (546). He has also suggestedthat Antineoplastons may interact directly withDNA (524).

Burzynski believes that Antineoplastons repre-sent a “completely new class of compounds’ (516).It is unclear whether or how Burzynski’s Antineo-plastons relate to a variety of known growth factorsand inhibitors that are the focus of considerablemainstream research in biochemistry and oncology.Burzynski’s theory of a biochemical antitumorsurveillance system in the body mediated by en-dogenous Antineoplastons has not been recognizedin the broader U.S. scientific community. However,Burzynski has recently supplied some scientists withAntineoplastons which they are testing for biochem-ical and physiologic properties, particularly anti-tumor activity, in cultured tumor cells and in animaltumor models (see discussion below).

Burzynski’s Treatment Regimen

At present, oral and intravenous forms of 10 typesof Antineoplaston are made by the BurzynskiResearch Institute; most patients reportedly take theoral form (124). Treatment starts with small dosesand increases gradually until Burzynski determinesthat an optimal level has been reached. In somecases, Burzynski also prescribes low-dose chemo-therapy (124) and a variety of common prescriptiondrugs (134,136,138). Burzynski claims that follow-ing initial treatment with Antineoplastons, somepatients produce sufficient quantities of endogenousAntineoplastons and no longer need treatment, while

%uzynski developed the laboratory methodology to make at least one type of Antineoplaston (AlO) synthetically.

Chapter 5--Pharmacologic and Biologic Treatments ● 93

others continue taking oral doses of Antineoplastonsto “guard against future recurrence of cancer”(124).

The patient brochure from the Burzynski Re-search Institute states that the treatment is “non-toxic” (124), but that a “small percentage ofpatients had some adverse reaction sometime duringthe course of treatment. ” Side-effects cited include“excessive gas in the stomach, slight skin rash,slightly increased blood pressure, chills and fever”(124).

There are no reports of adverse effects fromBurzynski’s treatment in the published literature.One unpublished report based on a site visit to theBurzynski Research Institute noted two patients whodeveloped sepsis after treatment, one of whom died,although it did not include information confirmingthe association between the patients’ death andBurzynski’s treatment. The authors of that reportnoted that one possible route of infection is throughintravenous injections into an indwelling subclaviancatheter; infections of the indwelling lines would belikely if aseptic technique is not followed; this ismore likely if the patient is not thoroughly instructedin the techniques of aseptic injection (79). Walde,who visited Burzynski’s facilities in 1982, alsonoted this risk of catheter sepsis and air emboliresulting from patients administering their ownintravenous doses through indwelling subclaviancatheters, but concluded that ‘‘the number of com-plications that [Burzynski and his associates] havebeen aware of, or have been notified of, have beenextremely low” (933).

Claims

While treatment success rates are not specificallycited in the Burzynski Research Institute patientbrochure, such rates are widely quoted in the popularliterature. An article in Macleans magazine, forexample, credits Burzynski with a 46 percent rate of“total remission for cancer of the colon” from theuse of one type of Antineoplaston. That article alsoreports that Burzynski has had the most success withcancers of the bladder, breast, prostate, and bone(291). A recent newspaper article quotes a spokes-woman for the Burzynski clinic as saying that“preliminary studies show that 80 percent of tumorpatients respond positively to the treatment” (721).

Burzynski does claim that the ‘majority of cancerpatients treated at [the Burzynski Research] Instituteshowed positive response to treatment” (124). Hispatient brochure states that Antineoplaston treat-ment makes it ‘‘possible to obtain complete remis-sion of certain types of cancer’ and that ‘‘thenumber of patients who are free of cancer over fiveyears as the result of Antineoplaston therapy issteadily increasing” (124). In addition to theirpostulated therapeutic role, Antineoplastons areclaimed to be useful in diagnosing cancer. Burzynskibelieves that measuring the levels of naturallycirculating Antineoplastons in blood and urine“may help to identify individuals who are moresusceptible to the development of cancer or todiagnose the cancer at the early stages” (129,133).

These claims are based on a number of recentclinical studies in which Burzynski reported favora-ble clinical outcomes, including complete remis-sions, partial remissions, and stabilization of dis-ease, in patients with various types of advancedcancer, following injection of Antineoplaston A2(137), A3 (140), A5 (141), A 10 (138), AS2-1 (136),and AS2-5 (134). Burzynski reported that three ofthese Antineoplastons (A3, A5, and A10) will bestudied in phase II trials.

Burzynski occasionally publicizes his treatmentvia press releases. In a recent statement, for example,it was announced that “dramatically improvedresults in the treatment of prostate cancer due to arecent discovery made within the past year’ hadbeen obtained through Burzynski’s administrationof Antineoplastons given orally. It noted that “withthis route of administration, some prostate cancerpatients, even those whose cancer failed to respondto conventional therapy, have experienced a com-plete remission of their cancer in as little time as fivemonths” (126). In that press release and another one(127), it was claimed that Burzynski’s methods‘‘may also be effective in diagnosing and preventingsome types of cancer,” citing results from experi-mental animal studies conducted at the BurzynskiResearch Institute and at the University of Kurume,Japan.

Published Clinical Studies

Burzynski and his colleagues at the BurzynskiResearch Institute have a long list of publishedpapers and presentations at meetings in which theyreport on animal and biochemical studies of Antine-


oplastons, as well as on studies of their use in cancerpatients. Most of Burzynski’s recent clinical papers(studies of the effects of Antineoplastons on cancerpatients, as opposed to laboratory research) appearin supplements to the journal Drugs Under Experi-mental and Clinical Research, one in 1986 and onein 1987. These supplements were devoted entirely toAntineoplastons and all publication and printingcharges for these supplements were borne byBurzynski (840).3

Burzynski’s list of publications (124) includes anumber of “phase I clinical studies,” along withseveral other types of study that also include clinicaloutcome data, such as ‘‘initial clinical studies,” and“toxicology studies.” Many of these studies arelisted as presentations made at conferences outsidethe United States; these reports are not readilyavailable in the open literature. Many of the pub-lished studies appear in the Drugs Under Experi-mental and Clinical Research supplements, oneappears in a journal or a book cited as Advances inExperimental and Clinical Chemotherapy (which isnot listed at the National Library of Medicine), andone appears in a book, which presents the same dataas a paper in one of the supplements.

Despite the fact that these are reported as earlystage studies, which in mainstream research wouldconcentrate on toxicology (i.e., safety more thanefficacy), they also report on clinical outcomes,including partial and complete remissions.Burzynski’s reputation for success rests at least inpart on these reports. OTA’s concern with thesestudies is that, among other problems, Burzynski’sdefinition of a remission, while not stated in any ofthe papers, appears to be discrepant from thegenerally accepted definition,4 making the resultsdifficult if not impossible to understand. Threepapers from the 1987 Drugs Under Experimentaland Clinical Research supplement are representa-tive (’‘Initial clinical study with Antineoplaston A2injections in cancer patients with five years’ follow-up” (139), ‘Phase I clinical studies of Antineoplas-ton A3 injections” (140), and “Phase I clinicalstudies of Antineoplaston A5 injections’ (140)).These are discussed below.

These three papers have similar formats and havea similar level of detail, so some general observa-tions can be made about them. First, the reports raisea question about whether these studies were actuallyplanned prospectively, with protocols includingpatient selection criteria, specific recordkeepingrequirements, etc. (a “clinical trial”), or whetherthey represent groups of patients studied retrospec-tively. Details concerning a protocol, which wouldbe expected in reporting a clinical trial, are generallylacking. In addition, there is little systematic infor-mation about patients’ treatment prior to Antineo-plastons, except in specific cases, some of which arediscussed below. A table with certain informationabout each individual patient (diagnosis, age, sex,length of Antineoplaston treatment, highest dosage,adverse reactions, desirable side-effects, and anti-cancer effect) is included in each of these papers.

A particular difficulty with these papers is thatsome important terms--e.g., “completer regression"and ‘partial regression,’ terms used to describe theeffectiveness of Antineoplastons in these papers—are not used in accordance with their generally-accepted definitions. In the first Burzynski studycited above, six “complete remissions’ were re-ported among 15 patients described as having“advanced neoplastic disease. ” Three of these sixpatients were reported to have non-metastatic transi-tional cell carcinoma of the bladder, grade II, whichwould not be described as ‘‘advanced” by main-stream definitions. These three patients are de-scribed in some detail. Two of them reportedly hadno measurable malignant disease when they beganAntineoplaston treatment. According to the article:

Patient D.D., diagnosed with transitional cellcarcinoma of the bladder, Grade II, had seventransurethral resections of the tumours and sixrecurrences in 16 months preceding the treatmentwith Antineoplaston A2. Her treatment began shortlyafter the last transurethral resection, therefore she didnot have measurable tumour at that time. The patientwas incomplete remission and free from recurrencesfor two years and six weeks as the result of treatmentwith Antineoplaston A2 intravenous injections. Shedeveloped recurrence one year and two months afterdiscontinuation of Antineoplaston A2 injections.

3~ou@ ~o~tme~c~ jow~~ do not c~ge authors for pub~shing papers, it is not unco~on for authors to pay a fee for publication andprinti.ng.d~ conventio~ terminolo~, re~essions may occur in patients who initially have “measurable d-,” which means tbat tumors that can either

be felt during physical examinationor can be seen clearly on some type of diagnostic film or scan, and which can be measured in at least two dimensions.A complete regression is said to occur when the disease measured can no longer be found at all. Partial regression describes the condition where themeasurable tumor is reduced by at least 50 percent in size.

Chapter Pharmacologic and Biologic Treatments ● 95

Patient J.J. . . . underwent transurethral resectionof the tumour shortly before the beginning of thetreatment with Antineoplaston A2 injections. He wasfound to have no recurrence after 56 days oftreatment and decided to discontinue the therapy atthat time. Five months later, he developed recurrenceand underwent transurethral resection of the tumourand instillation of Thiotepa. The patient was disease-free for over five years.

Neither of these patients had measurable malignantdisease when treatment began and both had recur-rences after treatment. Patient J.J. had curativeconventional surgery and chemotherapy as treat-ment for the recurrence. Burzynski counts both ofthese patients as complete remissions, and J.J. as afive-year survivor, as a result of Antineoplastontreatment. However, the evidence presented does notsubstantiate the claimed benefit to either patientfrom the treatment.

In the second paper, another patientin‘‘completeremission’ is described as having "adenocarcinomaof the colon, status post resection,’ meaning that thetumor had been removed surgically before thepatient started treatment with Antineoplastons:

The patient . . . maintained complete remissionduring the treatment with Antineoplaston A3 . . .After discontinuation of this form of treatment hedeveloped recurrence with liver metastasis, whichresponded to treatment with different formulationsof Antineoplastons and 5-fluorouracil. This patientis alive, well and free from cancer over six years afterhis participation in Phase I studies with Antineoplas-ton A3.

This patient evidently had no measurable diseasewhen Antineoplaston A3 treatment started, butreportedly had a “recurrence,” was treated withconventional chemotherapy plus Antineoplastons,and then was reported free of cancer. There is noevidence that this patient was helped by Antineo-plastons, and the case does not describe a “completeremission’ attributable to that treatment.

Another unusual feature of these studies is thesection describing increases in platelet and whiteblood cell counts as “desirable side-effects.” Ineach case, the post-treatment levels are not justincreased, but are abnormally high. In the case ofplatelet counts, levels are high enough (ranging fromabout 500,000 to 3.4 million) to lead to possibleblood clotting. The authors do not explain why theseeffects should be considered desirable; physicians

would usually consider these levels as indicators ofunderlying disease or as risks for serious medicalcomplications.

Attempts at Evaluating Antineoplastons

In 1983 and 1985, at the request of the CanadianBureau of Human Prescription Drugs, NCI testedthree of Burzynski’s Antineoplastons for antitumoreffects in the mouse P388 Leukemia assay, a test thatNCI used routinely as a prescreen for antitumoractivity until 1985 (2,602) (see ch. 12 for details). Noantitumor activity (as measured by a statisticalincrease in survival) was found for AntineoplastonsA2 and A5. Both showed toxicity at the highest dosegiven, while at lower doses, neither antitumor effectnor toxicity was found. Both Antineoplastons werefound inactive over wide dose ranges (602). Antine-oplaston A 10 was also tested in a range of concentra-tions in this mouse system, and the results indicatedthat there was no increase in survival at anyconcentration and there was toxicity at the higherdose levels (360).

More recently, Antineoplaston A10 has beenstudied in several experimental animal tumor sys-tems. Researchers at the Medical College of Georgiareported on results indicating that oral Antineoplas-ton A10 delayed the development of viral-inducedmammary tumors in C3H+ mice and inhibited thegrowth of carcinogen-induced mammary tumors inSprague-Dawley rats (393). Eriguchi and colleaguesat Kurume University, Japan, presented resultssuggesting antitumor effects of Antineoplaston A10on the development of urethane-induced pulmonaryadenomas in A/WySnJ mice (275). A second groupat Kurume University reported that AntineoplastonA10 reduced the growth of human breast cancer cellsin athymic mice (385). Recent experiments usinghuman and mouse tumor cell lines were summarizedin an abstract written by researchers at the Uni-formed Services University of the Health Sciences,Maryland. It was noted that Antineoplaston AS2-1promoted cell differentiation in human promyelo-cytic leukemia HL-60 cells grown in culture andsuppressed some of the neoplastic properties ofmouse fibrosarcoma V7T cells in culture (775).

A 1981 television news report (“20/20”) onBurzynski’s cancer treatment, followed by numer-ous inquiries from patients about the treatment,reportedly prompted David Walde, a physicianpracticing in Ontario, to visit Burzynski’s facilities


in April 1982. In his written report (933), which hesent unsolicited to Health and Welfare Canada andto NCI, Walde described Burzynski’s clinical andresearch facilities and summarized the treatmentregimen. He reportedly also reviewed about 60patient records, but did not report on them in detail.He concluded that there was sufficient informationabout Burzynski’s treatment to warrant evaluating“then nature and action of [Antineoplastons]. . . evenif these eventually do not result in any majortherapeutic advances” and recommended thatBurzynski apply for investigatory new drug clear-ance in Canada so that Walde could coordinateclinical studies with Canadian health officials. Healso suggested that outside funding sources besought to support clinical studies, and advisedagainst ‘sensationalism through the public media, ’to avoid disruption to ongoing and future clinicalstudies.

In November 1982, consultants to the Ontario(Canada) Ministry of Health visited Burzynski’sclinical and research facilities in Houston for thepurpose of providing information to the Ministry ofHealth about the treatment because some Ontarioresidents had sought reimbursement under the On-tario Health Insurance Plan (79). After reviewingBurzynski’s published papers and viewing the clinicand laboratories, the consultants, Martin Blacksteinand Daniel Bergsagel, asked Burzynski to selectexamples of patients who he believed had had a goodresponse to Antineoplaston treatment. They speci-fied that each case had to satisfy the followingconditions to be considered: 1) proven histologicdiagnosis of cancer; 2) complete record of all cancertreatment before Antineoplastons (some of whichmight be responsible for a delayed response);3) complete record of additional treatment; and4) original X-rays, CT, or isotope scans used todocument a response.

Burzynski presented them with about 12 cases atthe clinic, and sent them additional cases afterward.According to the report, there were original X-raysfor only one case; for two others, selected CT scanswere available. The case with X-ray evidence was apatient with metastatic nodules in the lung from acolon cancer, which, from his history, appeared to bea slowly progressing disease. The consultants con-cluded that the X-rays showed no documentablechange, though there were difficulties in interpreta-tion because the films were reportedly taken ondifferent machines with different magnifications.

They also concluded that the two patients for whomsome CT scans were available showed no definiteresponse to Antineoplaston treatment. In thosecases, they believed that the views on the scans werenot the same, making direct comparison impossible.

In other cases, the consultants reported thatBurzynski’s patients had had effective treatment fortreatable cancers before starting Antineoplastontreatment, and they described two specific examples.The first was a woman who had had radiationtreatment for stage III cervical cancer, and had goneto Burzynski when there was still necrotic tumor inthe cervix; a cytologist was unsure whether anyviable cancer cells remained, but noted extensiveradiation changes. The turner gradually disappeared,which the consultants felt could be attributed to theprior radiation, rather than to Antineoplastons. Theother patient had prostatic cancer with bone metasta-ses who had had an orchiectomy 3 months beforebeginning Antineoplastons. His bone scans im-proved, which the consultants attributed to thedelayed effects of the orchiectomy, which com-monly takes months for full effects to becomeevident.

On the basis of the cases they reviewed, Black-stein and Bersagel reported that they found noexamples of objective response to Antineoplastons.In addition to reviewing the cases, they asked aboutfour patients reported by Burzynski in 1977 to havehad complete remissions with treatment. Accordingto the report, three of those patients had progressedfairly rapidly and died. The fourth patient was stillalive at the time of the review (1982), but theconsultants felt his disease (a solitary bladder tumor)had been removed during the biopsy. In conclusion,Blackstein and Bersagel’s report recommended thatthe Ontario Health Insurance Plan not cover the costof Antineoplaston treatment for Ontario residents.

Burzynski wrote a detailed rebuttal (135) to theirreport, charging that Blackstein and Bersagel "com-pletely distorted the research, production, and clini-cal data presented to them. ” He disagreed with eachindividual assessment, concluding:

Out of the initial nine cases presented in the clinic,six patients obtained complete remission and tworemaining patients were very close to completeremission. Only one patient was treated with radia-tion and chemotherapy and one additional patientreceived a very small dose of palliative radiotherapybefore coming for the treatment with antineoplas-

Chapter 5-Pharmacologic and Biologic Treatments . 97

tons. Two patients died from causes unrelated tocancer like multiple emboli in the lungs and perfora-tion of the stomach ulcer. (135)

Burzynski contested the report’s judgments on thequality and content of the clinical data. He citedclinical records (photocopies of which he included)to show that each case was confirmed by biopsy andthat “the remission of each of them was confinedby at least one other doctor not associated with ourclinic. ‘‘

In 1985, in a separate and more limited effort togather information about Burzynski’s treatment, theCanadian Bureau of Prescription Drugs reportedlycontacted 25 physicians with patients who hadvisited Burzynski’s clinic in Houston for treatmentwith Antineoplastons. According to a memo sum-marizing the effort (829), information on clinicaloutcomes in 36 patients from five provinces report-edly consisted of tumor type and clinical status asreported by telephone from the physicians (actualrecords were apparently not obtained). Of the 36patients noted by the physicians, 32 had died with“no benefit” from the treatment, one had died afterhaving a “slight regression for two months,” onedied after having been stable for a year, followed byprogression of disease, and two were alive at thetime of the survey. Of the two who were alive, onehad metastatic lung cancer and the other had cervicalcancer, and both had received radiotherapy prior toAntineoplaston treatment. The memo does notindicate the existence of more detailed data on theclinical course of these patients (including timebetween treatment and outcome recorded) or thebasis for selecting the 25 physicians for the survey.OTA’s requests to the Canadian Bureau of Prescrip-tion Drugs for further information about this surveyhave been denied. It is not possible to drawconclusions about efficacy or safety of Antineoplas-ton treatment from this limited information, since itwas a retrospective analysis of self-selected patientsand there may have been bias toward reporting pooroutcomes.

Despite a substantial number of preliminaryclinical studies presented by Burzynski and hisassociates describing outcomes among the patientshe treated with Antineoplastons, and an attempt at a“best case” review, there is still a lack of validinformation to judge whether this treatment is likelyto be beneficial to cancer patients. Thus far, prospec-tive, controlled clinical studies of Antineoplastons,

which could yield valid information on efficacy,have not been conducted.

CELLULAR TREATMENTCellular treatment refers to a group of related

procedures that may be referred to as “live celltherapy,’ “cellular therapy,” “cellular suspen-sions, ” ‘‘ glandular therapy,” or “fresh cell ther-apy.” In general, cellular treatment involves injec-tions or ingestion of processed tissue obtained fromanimal embryos or fetuses. It was developed inSwitzerland in the early 1930s by Paul Niehans,M.D., and became widely known when variouspublic figures received the treatment and claimed itrestored their youth or extended their lives (26). Oneof Neihans’ colleagues, Wolfram Kuhnau, M.D.,introduced the treatment in Tijuana in the late 1970s(238,490). Currently, at least 5 Tijuana clinics offercellular treatment as a component of “metabolictherapy” (289,968). To OTA’s knowledge, cellulartreatment is not widely practiced in the UnitedStates, although no Federal or State law prohibitsphysicians from preparing his or her own cellulartreatments for patients. FDA has issued an importalert concerning the detention of shipments offoreign cellular treatment products to the UnitedStates (887).

Cellular treatment uses a variety of materials,including whole fetal animal cells (derived, e.g.,from sheep, cows, and recently also sharks (491))and cell extracts from juvenile or adult animal tissue.The organs and glands used in cell treatment includebrain, pituitary, thyroid, adrenals, thymus, liver,kidney, pancreas, spleen, heart, ovary, testis, andparotid (261). Several different types of cell can begiven simultaneously-some practitioners routinelygive up to 20 or more at once (489).

A number of different processes are used toprepare cells for use. One form of the treatmentinvolves the injection into the buttocks of fleshlyremoved fetal animal tissue, which has been proc-essed and suspended in an isotonic salt solution. Thepreparation of fresh cells then maybe either injectedimmediately into the patient, or preserved by beinglyophilized (freeze-dried) or frozen in liquid nitro-gen before being injected. In the latter process, thepreserved cells can be tested for pathogens, such asbacteria, viruses, or parasites, before use. Fresh cells,in contrast, are used before such testing can beperformed. Other types of cellular treatment may use


dehydrated concentrates in tablet or capsule formtaken orally.

The types of cell given are reported to correspondin some way with the organ or tissue in the patientthat is diseased or malfunctioning (“like cells helplike cells” (261)). Proponents claim that the injectedcells “travel to the similar organ from which theywere taken to revitalize and stimulate that organ’sfunction,” an effect which is said to have been“validated by scientifically controlled laboratoryand clinical experiments’ (322).

Proponents of cellular treatment believe thatembryonic and fetal animal tissue contains activetherapeutic agents distinct from vitamins, minerals,hormones, or enzymes, and “the fact that theseactive agents have not yet been identified seems oflittle consequence” (261). Kuhnau claims thatcellular treatment “stimulate[s] weak organ func-tion and regenerates] its cellular structure” (489).Proponents claim that cellular treatment is acceptedby the body because ‘‘embryonic cells from unbornanimals. . . are immunologically inactive and hencenot recognized as ‘nonself’ by the patient’s immunesystem’ (238). It is stated that the cellular treatmentusing cells from endocrine organs ‘‘harmonizehormones . . . [and] balance the intricate hormone-producing and feedback mechanisms of the endo-crine system” (238). Cellular treatment is alsoclaimed to stimulate the immune system.

Although cancer is not one of the primaryconditions for which cellular treatment is promoted,cellular treatment is included in the array of treat-ments offered to cancer patients at “metabolic”clinics in Tijuana (490). Positive results followingcellular treatment have been claimed for a widevariety of genetic, necrologic, and multifactorialconditions, including Down syndrome, Klinefelter’ssyndrome, Alzheimer’s disease, Parkinson’s dis-ease, epilepsy, multiple sclerosis, lupus, arthritis,muscular dystrophy, and infertility (238). At oneTijuana clinic where cancer patients reportedlymake up 70 percent of the caseload, cellulartreatment, using umbilical cord tissue in particular,is “increasingly being given in cancer therapy” at afrequency per patient of several “rounds” per year(238).

Kuhnau claims that “in the hands of a physiciantrained in this form of therapy, the proper selectionof cells and their appropriate administration pro-vides a well-tolerated treatment which is virtuallyfree of side effects” (489). He claims never to haveseen a fatality or toxic reaction to the material (238).

A number of adverse effects could, however, beassociated with cellular treatment. Allergic reactionsto calf thymus tissue derived from 5-day-old animalswere noted in patients with histiocytosis-X, aheterogeneous group of rare disorders, and cellulartreatment was stopped in these patients (698). Arecent report in the British Medical Journal de-scribed a case of a 79-year-old man who developedantibodies against human skin antigens and signs ofan autoimmune skin disease following injections ofextracts of human placental tissue (778). Cellulartreatment also poses a risk of transmitting bacterialor viral infections, such as brucellosis (a generalizedinfection characterized by fever, sweating, and painin the joints) or encephalomyelitis (a viral infectioncharacterized by inflammation of the brain andspinal cord), from donor animals to recipient pa-tients, as noted in a 1984 FDA “talk paper” (885).

A number of serious immunological reactions tocellular treatment in West Germany were noted in arecent report in Lancet (514). In one example cited,a woman athlete reportedly received several hundredinjections of cellular therapy and subsequently wentinto fatal anaphylactic Shock.5 Other adverse effectswere also noted in that report, including immunevasculitis, encephalitis, and polyradiculitis follow-ing cellular treatment, and a delayed effect ofchronic progressive neurological disease with peri-neural inflammation and demyelination. A 1957survey of 179 West German hospitals reportedlyrevealed 80 cases of serious immunological reac-tions, 30 of them fatal, in cellular treatment recipi-ents. On the basis of these findings, the WestGerman Federal Health Office suspended the prod-uct licenses of a number of commercial cellularpreparations (including lyophilized or freeze-driedwhole-cell preparations and cell extracts), and “stronglyrecommended” that the use of fresh cell prepara-tions, which are made in the clinics themselves anddo not come under pharmaceutical regulations, alsobe stopped.

SAnaphylaxis is an immediate, exaggerated immunologic (allergic) reaction to a foreign protein to which the body has become hypersensitized asa result of past exposure. Anaphylaxis is frequently treatable with appropriate medical care, but in the absena of treatment it can be fatal.


DIMETHYL SULFOXIDE (DMSO)Dimethyl sulfoxide (DMSO) is a commonly

available product with a wide variety of non-medicaluses. In industry, it has been used as a chemicalsolvent. In laboratory research, it is often used as acryopreservative for cultured cells. One of theproperties of DMSO is that it is absorbed veryrapidly through the skin and cell membranes,carrying along almost anything else (particularlylow molecular weight molecules) dissolved in it thatwould not otherwise be able to cross those barriers.Intravenous and oral administration of DMSO allowit to penetrate rapidly into vascular and non-vasculartissues in the body (854). Its popular use amongathletes, people with arthritis, and others havestemmed from claims that topical DMSO reducespain, decreases swelling, and promotes healing ofinjured tissue. The FDA approved the use of bladderinstillations of a 50 percent solution of DMSO (soldunder the trade name “Rimso-50”) to relievesymptoms of interstitial cystitis, a painful chronicbladder disorder (884). At present, “Rimso-50” isstill the only DMSO product approved by FDA foruse in humans. DMSO available in health foodstores or by mail order is an industrial form of thechemical, consisting of about 99 percent DMSO, andis not labeled for human use (45).

DMSO is commonly used in unconventionalcancer treatments, particularly in ‘metabolic’ treat-ments, such as those offered at several clinics inTijuana and in the United States (e.g., at a hospitalin Zion, Illinois and at clinics in Nevada, Pennsylva-nia, and California (289)). DMSO is often combinedwith laetrile and vitamin C, among other substances,and administered to patients intravenously. Forexample, the “Manner Cocktail,” consisting of10CC of DMSO, 25 grams of vitamin C, and 9 gramsof laetrile dissolved in a 250cc bag of a 5 percentdextrose solution (574), is used to treat cancerpatients at the Manner Clinic in Tijuana.

DMSO has been studied in mainstream researchfor a variety of possible therapeutic uses. As apossible cytotoxic agent, DMSO has been studied inhuman tumor cell lines and in human tumor modelsystems in animals, and in each case, DMSOdemonstrated no activity (243). As a possible tumordifferentiating agent (942) (a substance that stimu-lates tumor cells to undergo development to mature,benign cells (827)), DMSO was found to be active inmouse and human leukemic cell cultures and in

human solid tumor cell cultures (243,827), but it didnot improve survival in animals implanted withhuman tumor cells (243); this lack of an effect in vivois the basis for NCI classifying DMSO as a relativelyweak differentiating agent, compared to other avail-able agents (243).

As a potential enhancer of the activity of knowncytotoxic agents, DMSO was found to increase theactivity of some of these agents in tumor-bearingrats (854). DMSO has been tested experimentally forantitumor effects, both in various tissue culture andin animal systems, and was found to be inactive. Ina clinical study using DMSO in combination withthe chemotherapeutic agent cyclophosphamide inpatients with squamous cell carcinoma of the lung,DMSO did not enhance the effect of cyclophospha-mide (319).

One of the most widely available sources ofinformation about the use of DMSO in unconven-tional cancer treatments is the booklet found in manyhealth food stores, Dr. Donsbach Tells You WhatYou Always Wanted to Know About DMS0 (263). Inthis booklet, it is claimed that “while DMSO has notbrought ‘cure’ for health problems, it has been andis now the source of comfort for millions of medicalconsumers.” Donsbach states that DMSO acts bymaking cancer cells “behave more normally bybringing about a mitotic turnabout.” He proposes itsuse as a treatment to relieve pain, to slow the growthof bacteria, viruses, and fungi, to control inflamma-tion and swelling, to relieve burns and sprains, andto relieve the symptoms of arthritis, herpes, tuberculo-sis, sinusitis, and cancer. Another source in thepopular literature discusses the use of DMSO incombination with conventional chemotherapeuticdrugs (593).

Mildred Miller, an advocate of DMSO use incancer treatment (616), claims that intravenousDMSO “dissolves the protein shell surrounding thecancer cells and begins to restore the abnormal cellto normalcy” (615) and that it “stimulate[s] thebody’s own immune system, as well as altering thecancer cell, causing it to become mature or burnout” (617). Miller is associated with a clinic in LasVegas that uses DMSO as one of its main compo-nents of cancer treatment.

Topical application of DMSO has been associatedwith redness, itching, and inflammation of the skinand a garlic-like taste and odor on the breath.Intravenous administration of DMSO has been


reported to cause transient hemolysls (breakdown ofred blood cells), resulting in urinary excretion ofhemoglobin (45,983). Several additional adverseeffects of DMSO are mentioned in the Donsbachbooklet (263), including “possible damaging effectsto the liver, the kidneys, bloodforming organs, andthe central nervous system”; and “headache, dizzi-ness, nausea, and sedation. ”

Toxic effects to the lens of the eye were reportedin studies involving the use of DMSO in dogs,rabbits, and pigs, although no such effects have beennoted in studies with human subjects (45). Thesafety of prolonged use of DMSO in humans has notbeen established.

HYDRAZINE SULFATEIn the mid- 1970s, one of the commonly discussed

unconventional cancer treatments was hydrazinesulfate (646,682), a chemical agent proposed to treatcancer cachexia, the progressive weight loss anddebilitation characteristic of advanced cancer. Onthe basis of animal data and preliminary humanstudies conducted in the United States and the SovietUnion (described below), hydrazine sulfate was alsoclaimed to cause tumor regression and subjectiveimprovement in cancer patients. According to oneobserver (743), hydrazine sulfate was publicized inthe news media as a “dramatic breakthrough—bringing people back from the dead.” The AmericanCancer Society (ACS) published its first ‘UnprovenMethods” statement on hydrazine sulfate in 1976(24). In 1979, however, it was taken off the ACS listof unproven methods, following the initiation ofclinical trials under a new IND exemption (90),although this change was not publicly made until1982, when the next revised list was published.

While hydrazine sulfate has, in the last few years,been studied by some mainstream researchers, it isstill considered an unconventional treatment. Arti-cles in the popular literature continue to highlightcontroversial issues in hydrazine sulfate’s develop-ment (416,549,647). Proponents argue that theprimary emphasis on treating cachexia, rather thanthe tumor itself, resulted in hydrazine sulfate beingnot only ignored but maligned by conventionalmedicine. In a 1988 interview with a WashingtonPost reporter, the former director of NCI, VincentDeVita, Jr., reinforced this view of why hydrazinesulfate was not received more enthusiastically by theoncologic community:

You have to distinguish between good ideas andbad ideas and ho-hum ideas. And hydrazine, I think,is a ho--hum idea. The key thing is not to preventpeople from losing weight while they die; the keything is to get rid of their cancer, and that was alwaysthe issue. The trouble was nobody saw the value ofpumping a lot of resources into a therapy that gaveyou plumper people by the time they died (767).

The initial proponent of hydrazine sulfate wasJoseph Gold, M.D., director of the Syracuse CancerResearch Institute in New York. Gold proposed abiochemical mechanism for primary tumor growthand progression and for the development of cachexia(345). He hypothesized that cancer cachexia resultsfrom a systematic energy-losing cycle involvingglycolysis in tumor cells and gluconeogenesis in theliver and kidney, and proposed that an interruptionin this metabolic circuit could result in clinicalimprovement (347). After considering a number ofpossible agents capable of interfering with theprocess, Gold settled on hydrazine sulfate as a likelyinhibitor of a key enzyme in the process (348,350).

In 1973, Gold reported on results of experimentalanimal tests indicating that hydrazine sulfate inhib-ited the growth of various rodent tumors andpotentiated antitumor action of some chemother-apeutic drugs (346). Several groups, includinginvestigators at Calbiochem (a pharmaceutical com-pany), Memorial Sloan-Kettering Cancer Center,and the Medical College of Virginia, obtained INDexemptions to study the efficacy and safety ofhydrazine sulfate in cancer patients. Positive public-ity about hydrazine sulfate at a 1974 meeting of theNational Health Federation, an advocacy group forunconventional treatment, led the public to requesthydrazine sulfate directly from the company. TheFDA later stopped the company from selling it topatients and withdrew all INDs on the agent.

In 1975, Gold reported results of the descriptivestudy of hydrazine sulfate conducted under Calbio-chem’s IND (349). Using reports from physicianswhose advanced cancer patients were taking hydra-zine sulfate, Gold noted several cases of tumorregression and subjective improvement, and someadverse effects, such as numbness in the extremitiesand transient nausea. An uncontrolled study con-ducted in the Soviet Union also reported tumorregression and subjective improvement among pa-tients taking hydrazine sulfate (794). This latterstudy was followed up with a larger descriptivestudy in the Soviet Union that reported some cases

Chapter 5--Pharmacologic and Biologic Treatments . 101

of partial regression, stabilization, and subjectiveimprovement (324). In contrast, 3 small, uncon-trolled clinical studies found no evidence of tumorregression among advanced cancer patients takinghydrazine sulfate (527,690,828).

More recent clinical studies of hydrazine sulfatehave examined effects other than antitumor re-sponses. Rowan Chlebowski, M. D., Ph. D., and hiscolleagues at the University of California at LosAngeles (UCLA) have examined the effect ofhydrazine sulfate on metabolism and weight loss incancer patients. In 1984 and 1987 papers describingbiochemical studies, Chlebowski reported that hy-drazine sulfate is metabolically active, improvesabnormal glucose tolerance, and reduces the in-creased glucose production rates seen in cancerpatients with weight loss (187,849). These studiesdid not examine clinical outcomes in patients givenhydrazine sulfate.

In a separate study, Chlebowski and colleaguesexamined the effects of a 30-day hydrazine sulfatetreatment regimen on weight, appetite, and caloricintake in cancer patients (185). The study was notdesigned to measure changes in tumor growth, sinceindicators of measurable disease were not requiredof patients entering the study, and concurrentchemotherapy was permitted. Sixty-one of thepatients entered into the study were randomized tohydrazine sulfate or placebo; 40 additional patientswere assigned hydrazine sulfate and included in thestudy results. Approximately half of the patientswere evaluable after 30 days, which greatly reducedthe actual size of the study. Unfortunately, resultsfrom the randomized and nonrandomized groupswere combined, and the report does not state howmany patients from the randomized group were inthe evaluable group included in the results. Report-ing only in percentages, the authors stated that ahigher percentage of the patients on hydrazinesulfate maintained or increased their weight, im-proved their appetite, and increased their caloricintake, suggesting a beneficial effect on theseclinical measures. However, valid judgments aboutsuch differences could be drawn only from therandomized data, which were not presented apartfrom data on the serially treated patients. Neverthe-less, the study did provide suggestive evidence thathydrazine sulfate might improve outcomes in cancerpatients with cachexia, suggesting the need forfurther research.

Stronger evidence of hydrazine sulfate’s effectson cancer patients comes from the most recent studyreported by Chlebowski and colleagues (186). Arandomized, prospective, placebo-controlled clini-cal trial was conducted to assess changes in nutri-tional status and survival time as a result ofhydrazine sulfate taken in addition to cisplatin-containing combination chemotherapy. Sixty-fivepatients with advanced, unrespectable (non-operable)non-small-cell lung cancer were randomized tochemotherapy and hydrazine sulfate (oral doses of60 mg/day) or to chemotherapy and placebo. Thesepatients had had no prior chemotherapy and weredescribed as being partially or fully ambulatory(performance status O to 2). All patients received thesame defined nutritional counseling.

Nutritional status was found to be improved inpatients taking hydrazine sulfate: they had signifi-cantly greater caloric intake and albumin mainte-nance. In previous studies, a low serum albuminlevel inpatients with non-small-cell lung cancer wasfound to be predictive of poor survival time, whilemaintenance of serum albumin level was found to besignificantly predictive of better 2-year survival inpatients with this type of cancer.

Median survival time among patients in the studywas found to be greater among those taking hydra-zine sulfate (292 days) than among those taking theplacebo (197 days), but this difference was notstatistically significant. Differences in survival timedid reach statistical significance when the patientswere separated into two groups-approximately 35patients in relatively better condition (performancestatus O or 1), and approximately 30 patients in moreimpaired condition (performance status 2). Thosepatients in better condition who took hydrazinesulfate lived significantly longer (328 days) thanthose taking placebo (209 days). Forty-two percentof these patients taking hydrazine sulfate were aliveat 1 year, compared to 18 percent of those takingplacebo. There was no similar increase in mediansurvival for patients in relatively worse condition;both treatment groups in this case had a mediansurvival of 132 days. Hydrazine sulfate was notfound to have a direct antitumor effect on patients ineither group. No complete responses were found,and among the partial responses noted, 23 percentwere in patients taking hydrazine, while 29 percentwere found in patients taking the placebo. Thesewere presumably attributable to the chemotherapy.


Based on the results showing that hydrazinesulfate improved nutritional status in patients withnon-small-cell lung cancer and increased survivaltime in the subset of those patients who were morefully ambulatory, the authors suggested that hydra-zine sulfate warrants further evaluation as an adjunctto conventional treatment. As they noted, the modestsize of this trial limits the strength of the conclusionsthat can be drawn from it. The results weresufficiently promising, though, to have recentlyprompted NCI to sponsor one or more phase IIIrandomized studies designed to further evaluate theinfluence of hydrazine sulfate on clinical outcomesin cancer patients (316).

LAETRILELaetrile is perhaps the best known unconventional

cancer treatment of the past two decades. In themid-1970s, an estimated 70,000 people had used itfor cancer treatment, pain control, or cancer preven-tion (274), and by 1979, 21 States had legalized itsuse (722). During the same period, laetrile hadbecome the focus of apolitical and legal controversyabout patients’ access to unapproved drugs (see ch.10) (396,525,578,648,705). Since the early 1980s,laetrile has lost much of its popular appeal, but iscurrently available at many of the unconventionalcancer clinics in Mexico used by U.S. patients.

Amygdalin, laetrile, Laetrile (capitalized), sar-carcinase, and nitriloside are some of the names ofchemically related substances given to patients aslaetrile treatment (903). Proponents have also re-ferred to the treatment as a vitamin (“B-17”) eventhough it has never been recognized as such by thescientific community. One of these names, Laetrile,6

is the trade name for a substance chemically relatedto amygdalin, a substance found naturally in pits ofapricots and other fruits. In this report, the term“laetrile” is used to refer generally to this group ofclosely related substance(s) used in unconventionalcancer treatment.

Laetrile was developed from an extract of amygdalinby Ernst Krebs Sr., M.D., and Ernst Krebs, Jr., andwas frost used to treat cancer patients in California inthe early 1950s. Its use in the United States, Mexico,and Canada gradually expanded in the 1960s, asvarious laboratories were set up to produce and

market the substance (985). The popularity oflaetrile increased dramatically in the early 1970swhen members of the ultraconservative John BirchSociety came to the aid of a physician and fellowmember who had been arrested for illegally treatingpatients with laetrile. Using this case as a startingpoint, several Birch Society members joined to-gether to found the “Committee for the Freedom ofChoice in Cancer Therapy,” pimarily to advocatethe right of cancer patients to use laetrile (722).Other groups, such as the Cancer Control Societyand the National Health Federation, actively pro-moted the use and legalization of laetrile (962). Withthe support of Andrew McNaughton, a Canadianbusinessman, several factories around the worldwere built to manufacture laetrile (101).

Some proponents of laetrile cite a theory of canceretiology known as the ‘‘Unitarian’ or ‘‘trophoblas-tic” theory as the basis for treating cancer withlaetrile. First proposed by John Beard in 1902 andlater expanded on by Ernst Krebs, Jr., in the 1940sand 1950s, that theory draws a connection betweencancer cells and trophoblast cells, which are cellspresent during pregnancy that are thought to protectthe fertilized egg from rejection by the woman’simmune system. Both cancer cells and the tropho-blast cells are described in the trophoblast theory asinvasive, erosive, corrosive, and capable of beingcarried through the bloodstream to other parts of thebody. According to the theory, trophoblast cellscould develop at various places in the body fromprecursor cells distributed throughout the bodyduring embryonic development, and that theseprecursor cells could, under certain circumstances,become cancer cells. Laetrile proponents have alsoproposed that cancer is a deficiency disease causedby a lack of laetrile (“vitamin B-17”) in the diet(362).

When laetrile is subjected to enzymatic break-down in the body, it breaks down into threechemicals: glucose, benzaldehyde, and hydrogencyanide (545). Various preparations of benzalde-hyde have been studied recently, mainly in Japan, forantitumor activity in experimental animals (581) andin preliminary clinical studies (481,482). Cyanidehas well-known toxic effects on human cells, bothnormal and malignant (197).

G~~le WaS nwed in referen~ to its biochemical properties; it was laevorotatory, or left-handed, to pokuized light ~d belonged to themandelonitrile class of chemicak.

Chapter Pharmacologic and Biologic Treatments . 103

Laetrile proponents claim that laetrile kills tumorcells selectively, while leaving normal cells alone. Insupport of this, Ernst Krebs, Jr., hypothesized thatnormal cells produce an enzyme, beta glucosidase,that breaks down laetrile, releasing cyanide, whichis then converted by a second enzyme, rhodanese, tothe less toxic thiocyanate molecule; cancer cells,however, lack the enzyme rhodanese, according toKrebs’ theory, and therefore are killed by the freecyanide (704,903).

In the 1970s, proponents claimed that laetrile haddirect antitumor effects, relieved pain associatedwith advanced cancer, and helped to prevent cancer(903). In recent years, specific claims of antitumoractivity of laetrile have rarely been made. Instead,laetrile is more often discussed in the context of“metabolic” regimens, with claims made for anti-tumor responses and life extension resulting fromthe use of a combination of treatments, includinglaetrile, DMSO, vitamins, minerals, amino acids,enzymes, oxygen treatment, cellular treatment, andother substances (97,239,576).

Adverse Effects

Since laetrile itself is about 6 percent cyanide byweight, cyanide toxicity is possible when laetrile isbroken down in the body. If an excessive amount oflaetrile is ingested, or if something is done toaccelerate or increase the release of cyanide fromlaetrile, then toxic and lethal levels of cyanide can bereached. Beta glucosidase, the enzyme that canmarkedly accelerate the release of cyanide fromlaetrile, is found in common foods as such rawalmonds, other nuts, bean and alfalfa sprouts,peaches, lettuce, celery, and mushrooms (784).When laetrile is simultaneously ingested with asource of the beta glucosidase enzyme, toxic cyanidelevels may result. Cyanide toxicity has been ob-served in patients receiving laetrile, although manypatients have taken it without showing any signifi-cant clinical signs of cyanide toxicity (620,623).Common adverse effects noted in the studies (de-scribed later in this section) by Moertel and col-leagues at the Mayo Clinic were nausea, vomiting,headache, and dizziness. Isolated reports of deathsdue to cyanide poisoning following the ingestion oflaetrile have appeared in the literature(100,585,644,697,768,779,800,8 11). Samples of Mex-ican laetrile were examined at NCI for potency,content, and quality of manufacture (248,249). Itwas found that the measured potency of the samples

differed substantially from the labeled potency. Inaddition, of approximately 1,500 ampules that wereexamined visually, about 400 contained particulatematter, and 20 showed microbial growth (primarilybudding yeast and fungal hyphae), indicating con-tamination of the material. These contaminants poseadditional risks of complications, especially whengiven intravenously to patients who may be im-munosuppressed. Bradford and colleagues at theAmerican Biologics clinic in Tijuana have noted theexistence of “pure” and “decomposed and de-graded” products sold as laetrile or amygdalin (97).

Attempts at Evaluating Laetrile

Since the 1950s, laetrile has been examined forantitumor activity in a variety of experimental testsystems. Its use in cancer patients has also beendescribed by several proponents and it has been thesubject of clinical trials sponsored by NCI. Theseefforts are summarized b e l o w .

Animal Studies

Laetrile has been tested for antitumor activity ina variety of transplanted rodent tumor systems.Experiments were conducted in several differentlaboratories under NCI sponsorship in 1957, 1960,1969 (twice), and 1973, testing the effects of laetrilealone or in combination with beta glucosidase.These experiments used several different sources oflaetrile and a variety of transplanted rodent tumorsystems, and in each case, no antitumor activity wasfound (906). Other investigators have tested laetrilealone (183,404,838) or laetrile with beta glucosidase(519,965) in transplanted rodent tests. No antitumoractivity has been found in any of these experiments.

Laetrile alone and in combination with betaglucosidase has also been tested for antitumoractivity in human tumor xenografts in athymic(nude) mice. Using MX-1 mammary or CX-2 colontumor xenografts in these mice, no antitumor effectsof laetrile with or without the enzyme were found(701).

Spontaneous animal tumor systems have alsobeen used in a variety of tests involving laetrile. Ina study often cited in the proponent literature, HaroldManner and colleagues (575) treated mice that hadspontaneous mammary tumors with the followingthree agents, tested individually and in variouscombinations: laetrile (50 mg/kg body weight perday injected intramuscularly), vitamin A (333,333


IU/kg body weight per day administered via stom-ach tube), and digestive enzymes (10 mg injectedevery other day ‘directly into and around the tumormass’ ‘). The animals were observed for signs oftumor regression during a 30-day period of treat-ment.

According to the published report, no tumorregressions were observed in the animals treatedwith laetrile alone, vitamin A alone, or laetrile andvitamin A in combination. Tumor regressions wereobserved in the four treatment groups receiving thedigestive enzymes (and a few in the control groups);in these animals, ulcerations containing necroticmalignant cells in viscous fluid were found at thetumor sites. Fifty-two percent or more of the tumorsregressed in the groups treated with enzymes alone,enzymes and vitamin A in combination, enzymesand laetrile in combination, or enzymes, vitamin A,and laetrile in combination. The highest percentagewas found in the latter group, in which all threetreatments were given. The authors concluded thatlaetrile given alone is ‘‘not effective in tumorregression” but that when all three are given at thesame time, “76 percent of the tumors do completelyregress.” It appears from the results, however, thatthe main effect observed was the immediate prote-olytic effect of injecting digestive enzymes directlyinto tumor masses.

The largest and most complex set of tests onlaetrile in animals was described by Chester Stockand colleagues at Memorial Sloan-Kettering CancerCenter and Catholic Medical Center of Brooklyn andQueens (837). One of the investigators at Sloan-Kettering, Kanematsu Sugiura, conducted six initialexperiments using CD8FI mice with spontaneousmammary tumors, and found that the mice treatedwith laetrile showed no significant prevention ofgrowth of primary tumors, but did show inhibition inthe development of lung metastasis. In an unusualsequence of events, unauthorized information aboutthese experiments was made public before theresults were confirmed independently, leading toallegations by proponents that “proof” of laetrile’seffectiveness had been obtained and then suppressedby the Sloan-Kettering researchers (240,648,813).

These experiments were followed by a series offive experiments designed to replicate Sugiura’sinitial experiments. In two blinded experiments, theassessment of tumor status was done in such a waythat the observer did not know whether the mice had

had laetrile or the control treatment. This wasintended to address the issue of unintentional bias inobserving the presence of metastasis, since the twomethods that Sugiura used to detect metastases—gross observation and microscopic analysis-werereported to be inherently subjective, while anothermethod he did not use, bioassay, was reported to beless subject to bias. These independent and blindexperiments (including those Sugiura participatedin) did not confirm Sugiura’s initial results. Theauthors concluded that in the spontaneous animaltumor system, ‘‘laetrile was found to possess neitherpreventive, nor tumor-regressant, nor antimetastatic,nor curative anticancer activity. ”

The report summarizing both Sugiura’s work andthe independent experiments (on which Sugiura wasa coauthor) noted that Sugiura believed his initialresults were valid and that laetrile had antimetastaticactivity. In an addendum to the paper, Daniel Martin,Chester Stock, and Robert Good added that thenegative results of the blind experiments suggestedthat Sugiura’s initial experiments were unknowinglybiased, and reiterated their conclusion that laetrilehad “no action against the formation of metastasisin the spontaneous tumor system. ”

Human Studies

From the 1950s until the late 1970s, laetrile wasreported to have been used widely, not only in theUnited States, but also in Europe, Mexico, andelsewhere. Descriptions by practitioners of its use incancer patients appeared in various books andjournals. These include a 1962 book by HowardBeard on the trophoblastic theory of cancer (381), a1962 report in a U.S. medical journal written by aNew Jersey surgeon (643), numerous reports by aphysician in the Philippines (e.g., (662)), an abstractand presentation by practitioners in Italy and Bel-gium (765), papers by Dean Burk and Hans Nieper(e.g., (110)), and a 1977 book describing patientstreated at a California clinic (758). None of thesereports describes controlled, prospective trials fromwhich valid judgments of laetrile’s effects could bemade. They were probably influential in increasingthe popularity of the drug, however, since they allreported good results believed to be specificallyrelated to laetrile.

In the mid-1970s, the National Cancer Institute(NCI) attempted to obtain documented evidence ofobjective responses to laetrile, using an approachdesigned to collect information from the records of

Chapter Pharmacologic and Biologic Treatments . 105

people who themselves claimed, or whose practi-tioners claimed, had been treated successfully. Theintention was not to try to estimate possible rates ofeffectiveness, or to document adverse effects, butsimply to discover any evidence for an antitumoraffect.

Retrospective Review of Cases

NCI sent nearly half a million letters to physi-cians, other health professionals, and pro-laetrilegroups, asking for documented case histories ofpatients who had shown objective responses tolaetrile (274). Consent of the patient or next of kin,confirmatory histologic material, measurable dis-ease, adequately documented history, use of laetrilewith or without metabolic treatment for a period ofat least 30 days, with at least a 30-day periodpreceding during which no conventional cancertreatment was given, and records in English wererequired for cases submitted. Supporting informa-tion for each submitted case was sought fromphysicians, clinics, hospitals, and laboratories.

The solicitation and review of the public recordresulted in identifying 230 patients with claimedobjective responses from laetrile, all of whom (or thenext-of-kin) were asked to authorize release of theirmedical records. Ninety-three gave permission, andafter assembling the records for all cases, 26 werefound to be insufficient for review (many becauserequested records were not sent). The review wasbased on the 67 remaining laetrile-treated cases (oneof whom had two separate courses of laetrile). In anattempt to avoid personal biases against laetrile inthe evaluation, 26 case histories of patients withsimilar types of cancer who received conventionaltreatment, but not laetrile, were pulled from the NCIfiles, and added to the laetrile cases. A summary ofthe clinical course of each of the 93 cases, withoutspecifying whether the patient had or had notreceived laetrile, was presented to a panel of 12expert clinical oncologists from outside NCI fortheir independent review. A group consensus wasthen reached after discussing the results of theindividual reviews.

By consensus, there were two complete remis-sions, four partial remissions, nine cases of stabledisease, and seven cases of progressive disease.Thirty-five cases were non-evaluable, meaning thatthey did not meet original criteria for cases, and 11had insufficient data on which to judge response. Of

the patients from the NCI files who had not hadlaetrile, one, who had not had any treatment, wasjudged to have had a partial response.

Despite attempts to blind the panelists to whetherthe patients had had laetrile, a higher-than-expectedproportion answered correctly when asked to guesswhether patients had had laetrile or other treatment.However, the consensus for the six laetrile-treatedpatients determined to have had partial or completeresponses, and three determined to have had anincreased disease-free survival, was that they hadreceived conventional chemotherapy.

The discussion in the report of that reviewillustrates the difficulty in interpreting results suchas these. The authors make a number of usefulpoints. First, the rather small number of casessubmitted in relation to the solicitation effort, andthe loss of cases due to sources not submittingrequested information, left a relatively small numberof evaluable cases. It is unclear what NCI could havedone differently to increase the number of casessubmitted. The authors also commented that casesrejected from the review as invaluable were notnecessarily examples of poor medical managementor of patients who may not have benefited fromlaetrile. The necessary rigor of NCI’S process alonedetermined their evaluability. A natural tendency isto want to compute a “response rate’ using thesedata, but, in fact, there is no valid means to do so,therefore these data cannot be summarized i n ameaningful statistical sense.

A number of explanations for the six casesdetermined to have benefited after laetrile treatmentare offered in the published report. First, it ispossible that the patients responded to laetrile, but inthis type of study, that explanation cannot beassumed true:

Submission of incorrect clinical interpretations,falsified data, intentional or unintentional omissionof data (for example, concurrent conventional ther-apy), the possibility that we were unaware of somephysicians treating these patients or non-response toour inquiries must all be considered in interpretingthese findings. . . . Spontaneous regressions of tu-mors, although rare, have been documented. . . withfrequency varying according to tumor type. Even inthe absence of true spontaneous regression, the welldocumented variability in the natural history of some


tumors may confuse interpretation (904) and, in fact,the panel judged by consensus that a partial responseoccurred in one patient receiving no treatment duringthe course evaluated. The patients treated withLaetrile were almost always given concomitantmetabolic therapy. . . as well as general supportive-care measures such as improved diet, psychologicsupport and the unmeasurable ingredient of hope.This fact makes it difficult to attribute any tumorresponses to Laetrile alone.

The authors suggested, however, that the data wouldbe used by NCI in determiningg if further study isneeded. A prospective trial, described below, wasconducted following the case review.

Phase I and II Clinical Trials

After the laetrile case review described above,NCI sponsored phase I and II clinical trials, whichwere carried out at the Mayo Clinic. In the phase Istudy (620), information about dosage and toxicitywas gathered in preparation for the phase II study(623), which is described here. One hundred seventy-eight patients with advanced cancers were treatedwith amygdalin, according to a regimen “represen-tative of current Laetrile practice,” and were pre-scribed a diet and vitamin supplements designed bythe investigators to be similar to metabolic regimensoffered by many laetrile practitioners. A subgroup(14 patients with colorectal cancer) was given ahigh-dose regimen of both amygdalin and supple-ments, resembling high-dose regimens used by somelaetrile practitioners.

About a third of the patients had colorectal cancer,the next largest categories being lung, breast, andmelanoma, with rare cancers represented by fewerpatients. All patients had disease for which noconventional treatment was available, though nonewas bedridden and all were able to eat normally.Most of the patients were capable of working at leastpart time. About a third of the patients had had nochemotherapy at all. This is of interest because somemetabolic practitioners claim that laetrile and meta-bolic therapy are more effective in patients whoseimmune systems have not been damaged by chemo-therapy.

The amygdalin was prepared by NCI from apricotpits, corresponding to the laetrile sold by majorsuppliers to U.S. patients. It was administeredintravenously for 21 days, followed by continuedoral dosage, and stopped with progression of thecancer or severe ‘clinical deterioration.’ Amygdalin

was also stopped if an extremely high blood cyanidelevel was reached (3 micrograms per milliliter); thiswas the case for three patients.

Standard criteria were used to assess patientresponse. An “objective response” had to meet thefollowing three conditions: 1) at least a 50 percentdecrease in a particular measurement of the mostclearly measurable tumor area of an originallychosen “indicator lesion” (or if malignant enlargedliver were the measurable disease, a 30 percentdecrease in a particular measurement); 2) no in-crease in the size of other areas of malignant disease;and 3) no new areas of malignant disease. Twocriteria had to be met to be classified as in “stablecondition”: 1) less than 50 percent decrease in themeasurement referred to above in the first criterionfor an objective response; and 2) no new areas ofmalignant disease. Meeting any one of three criteriaconstituted “objective progression’ 1) an increaseof more than 25 percent in any indicator lesion; 2)new areas of malignant disease; or 3) severe clinicaldeterioration precluding further therapy and obser-vation.

The study found that 1 of the 175 evaluablepatients met the criteria for a partial response (atleast 50 percent decrease in size, but not disappear-ance of lesion), and that response was transient.More than half of the patients had measurableprogression at the end of the 3-week intravenousamygdalin course. By the end of 2 months, about 80percent had measurable disease, and by 7 months, allpatients had progressed. The median survival (thepoint after starting treatment at which half thepatients had died) was 4.8 months. The 14 high-dosepatients were similar in these outcomes to the entiregroup.

There was little evidence in this trial population ofsymptomatic relief. Few people gained weight, andimprovements in performance status for those origi-nally impaired were few. Twenty percent of patientsclaimed some symptomatic benefit at some pointduring treatment, but this was generally short-lived.After 10 weeks, 5 percent of patients reported stillreceiving benefit.

Toxicities were generally mild when patientsadhered strictly to the treatment schedules. Typicalsymptoms of cyanide toxicity-nausea, vomiting,headache, and mental dullness-occurred in somecases, particularly when patients took more amyg-dalin during a specified time period than was


prescribed (e.g., when a dose was missed, and thepatient “made it up”).

The authors stated that survival times of patientsin the trial “appear to be consistent with theanticipated survivals in comparable patients receiv-ing inactive treatment or no treatment. ” Whenchallenged on this point in a letter to the editor of theNew England Journal of Medicine (709), the investi-gators compared the survival curve of colorectalcancer patients in the trial to survival of colorectalpatients who had received new chemotherapeuticagents at the Mayo Clinic, and found no difference(619). The study was not designed, however, todetermine if amygdalin causes moderate increases inlifespan (or improvements in well-being or paincontrol), since it did not include a randomizedcontrol group, and thus the author’s comparison isnot entirely valid.

The study was criticized by laetrile supporters,who claimed that the material NCI used was not“Laetrile,” but in fact, a‘‘degradedproduct” (237).However, the NCI product was prepared to corre-spond to one of several popular formulations beingadministered to U.S. patients at the time, and theregimen used in the study did reflect then currentpractices of proponents. If the treatment had theantitumor activity claimed for it, a substantialnumber of patients in this trial should have shownobjective responses. As it turned out, only 1 out of175 patients studied showed a response-a partial,transient tumor response—which was far belowexpectations based on proponents’ claims of lae-trile’s efficacy.

THE LIVINGSTON-WHEELERREGIMEN

More than 40 years ago, the late Virginia (Wuer-thele Caspé) Livingston-Wheeler, M.D.,7 reportedthat she identified a specific microorganism shebelieved was associated with the development andprogression of cancer. During the 1950s, she devel-oped a comprehensive theory of cancer causationbased on this common infective agent and designeda corresponding anti-infective treatment-an auto-

genous vaccine designed to treat and prevent infec-tion with the microbe that she believed causescancer. The current treatment regimen, offered at anoutpatient clinic in San Diego, includes a variety ofcomponents intended to bolster patients’ immuneresponses in general and to counteract effects ofmicrobial infection. These components, which havechanged over time, include antibiotics, vitamin andmineral supplements, and a special diet. The Liv-ingston-Wheeler treatment was added to the ACSlist of unproven methods in 1968 (23). In February1990, Livingston was issued a cease and desist orderby the California Department of Health Services tostop prescribing and administering the autogenousvaccine as part of her treatment regimen (831).8

After receiving her M.D. from New York Univer-sity in 1936, Livingston held a number of academic,clinical, and laboratory positions, including associ-ate professor in the Bureau of Biological Research atRutgers University and associate professor of micro-biology at the University of San Diego (563). In1969, she established the Livingston-Wheeler Clinic,9

where she was director, and began treating cancerpatients on a full-time basis. Livingston was one ofthe most widely known practitioners of unconven-tional cancer treatment in the United States.

Livingston’s hypothesis on the role of infectiousagents in the etiology of cancer originated from herwork in the mid- 1940s on scleroderma, a systemic,autoimmune connective tissue disorder. Comparingtuberculosis, leprosy, scleroderma, and cancer, shenoted that “all four diseases are characterized by asimultaneous process of production and destructionof tissue and by a progressive, systemic involvementof the host” (971). She redirected her research fromthe bacteriology of scleroderma to that of cancer,beginning with tissue from a patient with breastcancer.

In a paper published in 1950 (973), Livingstonreported on a group of microorganisms that sheisolated from tumor tissue. She referred to theseorganisms as a single culture and described thevarious forms in which they appeared: ‘‘minutefilterable granules beyond the limits of visibility of

vofflci~ly, she ~ti the name Virginia C. Livingsto~ M.D. Dr. Livingston died shortly before this OTA Report was finished.8~e Dw~ent fomd tit tie use of tie Vaccfie by the Livingston.wheeler Cwc violated California’s Health and %fety Code, which “prohibits

the sale, providing, or prescribing of any cancer drug, medicine, compound, or device unless it has been scientifically proven to be safe and effectivein the diagnosis, treatmen~ alleviatio~ or cure of cancer and an application therefore has been approved by the Department or the United States Foodand Drug Administration.”

9SiUW her dea@ tie clinic has been renamed the Livingston Medical Center.


the light microscope, “ “larger granules approxi-mately the size of ordinary cocci readily seen withthe light microscope,” “globoidal forms,” “rod-like forms with irregular staining,” and “globoidalforms which appear to undergo polar budding.’ Shereported that she did not find these forms in thetissues of healthy individuals, and suggested thatthis organism might be of primary or secondaryimportance in the etiology of cancer.

Although admittedly not the first to culturemicroorganisms from tumor cells, Livingston be-lieved that she was the first to postulate interrelation-ships among the observed bacteria, viruses, andmycoplasma. To do this, she examined the ‘ ‘devel-opmental cycle of the organism through eachtransitional phase” using specific growth media,differential staining, high power microscopic resolu-tion, and electron microscopy. She concluded thatthese phases represented different developmentalforms of the same microorganism (974), which shecharacterized as “pleomorphic,” a term used inmicrobiology to refer to bacteria that change in sizeand shape during their lifecycle (also called “cellwall deficient” bacteria) (584). She reported thatthese different forms included micrococci, diph-theroids, bacilli, fungi, viruses, and host-cell inclu-sions (977). In 1970, Livingston proposed a formalclassification for this microbe and described hermethod for isolating and culturing it (978). Sheclassified it under the order Actinomycetales, whichincludes the bacteria associated with tuberculosisand leprosy, and named her microbe Progenitorcryptocides (PC), meaning “the ancestral, or pri-mordial, hidden killer” (563).

Livingston believed that P. cryptocides is ubiqui-tous in patients with cancer and, contrary to herearlier observation, that it is also present in someindividuals without apparent disease (560). Shebelieved that in a healthy person, this microbe ismaintained at low levels in the body, but under someconditions, it can multiply in overwhelming num-bers and become invasive and tumor-promoting(978). Special staining methods were developed byLivingston and her colleagues to determine thedegree of latent or overt infection, an indicator thatshe used to determine the progress of the diseaseduring treatment (979).

To examine their potential for causing disease,Livingston inoculated mice and guinea pigs withcultures of P. cryptocides and reported a “widerange of neoplastic tissue changes’ in the inoculatedanimals (972,978). These results were confirmed byIrene Diner at the Institute for Cancer Research inPhiladelphia (255,256). On the basis of these experi-ments, Livingston concluded that P. cryptocides waspathogenic in animals, and extrapolated this patho-genicity to humans. She believed that P. cryptocidesis the “primary etiologic agent in proliferative anddegenerative diseases” (977) and claims that herwork proves it to be the causative agent in allcancers. In the absence of clinical studies examiningthe possible role that P. cryptocides might play in thedevelopment of cancer, however, the pathogenicityof this microbe or group of microbes in humansremains unresolved.

There is little support, outside of a few researchers(see, e.g., (106)), for Livingston’s belief that thedifferent microbes observed in tissues and blood ofcancer patients are actually different forms of thesame organism. At present, no independent evidenceexists to corroborate her contention that the micro-bial forms are related to each other as different formsof a single, pleomorphic organism. Evidence doesshow that the bacterial culture Livingston isolated isnot a new and unique species as claimed: P.cryptocides cultures supplied by Livingston wereidentified as different species of the genus Staphylo-coccus and Streptococcus (3,4,258). The issue ofisolating bacteria of any kind from tumor tissue andurine of cancer patients, however, is generally notdisputed, since many groups of researchers havereported isolating various species and strains ofbacteria from such sources (see, e.g., (3,62,209)).Some of these bacteria have also been shown toundergo morphologic alterations characteristic ofcell wall deficient (or pleomorphic) bacteria (4).Acevedo and others have looked into the effect thatthese organisms might have on the body’s immuneresponse to malignant cells (4).

During the course of her research into theproperties of P. cryptocides, Livingston discoveredthat this microbial culture produces a substance invitro that is closely related to the human hormonechorionic gonadotropin (hCG) (980).10 Her reportwas the first to document the production of a

lwuman chorionic gonadotropin is a hormone secreted in pregnancy by the trophoblast cells that form the outer part of the -o ~d allowimplantation. In early pregnancy, this hormone plays a role in main- the lining of the uterus and in preventing spontaneous abortion of the fetus.

Chapter S-Pharmacologic and Biologic Treatments ● 109

mammalian hormone-like substance by microorgan-isms, and this has been confirmed by other investiga-tors (209,580). Others have observed a proteinsimilar to hCG produced in vivo by a variety ofmicroorganisms (5). The hormone has been found intumor tissue isolated from cancer patients, thoughnot from every species of bacteria isolated fromcancer patients; it has also been found in bacterialisolates from individuals without clinical manifesta-tions of cancer (3). These findings suggest that theproduction of a chorionic gonadotropin-like sub-stance by human tissues or microorganisms is notuniquely associated with cancer, although they donot rule out a possible role for the hormone in thedevelopment of some cancers. Researchers havesuggested the possibility that chorionic gonadotropin,whether produced by human cells (691) or bybacterially infected human tumor tissue, may sup-press certain immune responses (517), and thatsubstances acting against hCG may inhibit thegrowth of malignant cells (471).

Livingston believed that P. cryptocides is “anessential but dormant part of all cells, ” and isnormally kept in check by a fully functional immunesystem. She believed that ‘‘when immunity issuppressed or weakened, P. cryptocides proliferateand allow cancer to gain a foothold, secreting thesame (chorionic gonadotropin) hormone found inabundance in all tumors. ’ She viewed cancer as an“immune deficiency disease” caused by specificinadequacies in the diet and by toxic chemicals in theenvironment. She stated in her 1984 book, “themodern diet is simply deficient in providing thenutrition essentials that maintain a healthy, vitalimmunity to cancer . . . what we put in our mouthseither causes or directly contributes to the onset ofcancer through the depression of our immunity”(563).

Possible treatment approaches for cancer based onher theory of cancer causation were discussed for thefirst time in a paper Livingston published in 1965(977). In that paper, she reported treating 40 patientswith a regimen that included an autogenous vaccine-one made from each patient’s culture of P. cryp-tocides. The vaccine was designed to promote theproduction of immunologic cells, to suppress theinvading microorganism, and to promote host resis-tance. Other components of the treatment includelaxatives, cleansing enemas, and a special diet lowin carbohydrates and high in well-cooked proteins,fresh fruits, raw vegetables, and vitamin and mineral

supplements. That paper described how the vaccinewas made and administered to cancer patients,although clinical details about the patients, such astumor type, previous treatment, or outcome, werenot provided; it was noted only that, followingvaccine treatment, “a number of these patientsappear to be improving. Livingston did not publishany other papers in the medical literature presentingdata on tumor regression or life extension in cancerpatients treated with her regimen. At present, otherinformation about the treatment consists of thematerials available from the Livingston-WheelerClinic (a patient brochure, a physician handbook,and a compendium of published research papers byLivingston and some of her colleagues), and twobooks written for a general audience (Cancer: A NewBreakthrough (975) and The Conquest of Cancer(563)). The Conquest of Cancer contains casehistory Summaries of patients treated at the clinic(see discussion below).

Livingston stated in a deposition (559) that hertreatment does not interfere with conventionaltreatment and can be used adjunctively (559). Shestated in her book, however, that she preferred thatpatients avoid conventional treatment before start-ing her regimen, since, as she explained it, “oftenthey come to us after having been so heavily treatedthat their immune systems are all but destroyed, andtheir turners are far advanced” (563).

Treatment Regimen

The treatment regimen (as of July 1990, beforeDr. Livingston’s death) used at the clinic included anumber of different immunologic, pharmacologic,and nutritional components.

Before the 1990 “cease and desist” order wasissued (see above), the autogenous vaccine wasadministered to all patients. The vaccine was in-tended to eliminate P. cryptocides from the body andwas made from each patient’s own culture ofmicroorganisms, which were isolated from urine. Inthe initial treatment period, each patient was sup-plied with enough vaccine for 9 to 12 months.Thereafter, new cultures were obtained periodicallyfor the production of new vaccines, so that thetreatment continued to correspond to any changes inthe patient’s P. cryptocides levels as treatmentprogressed (559). Gradually, the frequency of auto-genous vaccine administration was decreased andeventually, only occasional booster shots were


given. Livingston also gave a “purified antigen”vaccine made at the clinic, consisting of a cell wallextract of a general P. cryptocides culture (562).

Other immunologic treatments included in theregimen are mixed bacterial vaccines, antibiotics,and various commercially prepared nonspecificimmune stimulators, such as levamisole (a conven-tional antiparasitic agent also used as an immunestimulant and recently shown effective in treatingpatients with colon cancer), and tuftsin (an experi-mental agent noted for various immune stimulatingproperties). The bacillus Calmette-Guérin (BCG)vaccine, a vaccine that immunizes against tuberculo-sis and used as a general immunologic stimulant insome conventional cancer treatment, is also used inmany cases. Other treatments are offered on acase-by-case basis.

Progress in reducing infection with P. cryptocidesis monitored by examining smears of a patient’sblood under a darkfield microscope, an uncommontype of microscope that Livingston believed a key toidentifying P. cryptocides microbes. A decrease orincrease in the number of visible P. cryptocidesmicrobes in the blood smear is used to indicateincreasing or decreasing immune response as a resultof treatment. Other tests are also used to assessimmune response and progress of treatment (563).

Another component of the regimen is the provi-sion of fresh, whole-blood transfusions from ayoung, healthy person (preferably a family mem-ber), and injections of gamma globulin to increasethe number of circulating antibodies. Livingstonalso used a “custom formula,” consisting of anextract of sheep liver and spleen, to “increase thewhite blood count [and] enhance immunogenicsystems.” Other immunologic agents that may beused include T-cells, thymosin (a hormone-likefactor extracted from calf thymus), interferon, andtumor necrosis factor.

Livingston recommended that patients followspecific nutritional guidelines. The recommendeddiet emphasizes ‘living food’ ’-whole grains, freshvegetables, and fruits. She strongly encouragedpatients to stop smoking and to eliminate meat andpoultry products, alcohol, coffee, refined sugars, andprocessed foods from their diets. Also included is anutritional supplementation program, consisting ofhigh doses of vitamins (especially vitamins A, B6,B12, and C), minerals, digestive enzymes, and bilesalts.

Another component of the regimen is bowelhygiene and detoxification. Livingston stated thatfrequent enemas, and sometimes high colonies, arenecessary to cleanse the intestinal tract of patho-genic bacteria and toxic materials. She stated alsothat they help relieve pain and improve appetite anddigestion. Daily coffee enemas may be recom-mended.

In this regimen, emphasis is placed on the use ofabscisic acid, a plant hormone and vitamin A analogthat Livingston believed neutralizes chorionic gona-dotropin in the blood and urine. She stated thatabscisic acid is normally produced in the humanliver, unless its function is impaired (561,976). Thisclaim has apparently not been examined independ-ently by researchers unaffiliated with Livingston.

There have been no reports in the literature ofdirect adverse effects from the Livingston regimen.There are some potential risks, however. As with anyinjection into the body of a foreign substance, theinjection of the autogenous vaccine carries theassociated risk of sepsis or anaphylaxis. Some riskof contamination in the preparation of the material isalso possible, depending on the processes andprocedures used to make and assure the sterility ofthe vaccines manufactured at the clinic. In addition,in any setting, the use of whole blood transfusion,even with directed donors’ blood, carries a small riskof transmitting various infectious agents. Living-ston’s ‘custom formula,’ consisting of an extract ofsheep liver and spleen, carries certain risks associ-ated with all types of cellular treatment. (Seediscussion of cellular treatment earlier in thischapter.)

Claims of Efficacy

Livingston claimed that her treatment regimen iscapable of curing cancer by stimulating the immunesystem. In support of this claim, she presented in herbook, The Conquest of Cancer, a summary ofclinical outcomes of patients treated at her clinic.According to Livingston, “someone not employedby our clinic drew 100 charts from our files totallyat random,” which Livingston then evaluated.Sixty-two of these were considered evaluable byLivingston’s criteria: she excluded patients whoserecords lacked confirmed pathology reports, whodiscontinued the Livingston-Wheeler treatment, whowere ‘‘too weak and ill to carry out the program,’and “who had only recently checked into the clinic,


or whose cases were so recent that even thedramatically fast reversals could only be labeledinconclusive. Patients who received previous orconcurrent conventional treatment were not ex-cluded.

Livingston concluded from her review that “oursuccess rate has been 82 percent” and “consideringthe patients we called inconclusive but for whom wewere able to be of some help, it is over 90 percent,’although there was no discussion of which caseswere included in these percentages and for whatreasons. She did not define what she meant by“success” or being of “some help. ” Regarding the18 percent that she did not consider successful, shestated that she “probably could have helped thesepatients had they not come to us with enormouslydebilitated immune systems resulting from havingalready undergone massive chemotherapy and radia-tion."

The conditions of some of the patients in thisreview may or may not have improved as a result ofLivingston’s treatment, but the data presented in herbook on this group of self-selected patients do notsupport calculation of an overall “success rate. ”Insufficient information is presented on the clinicalcourse of these patients for readers to arrive atindependent judgments about the treatment’s useful-ness and the complete, original patient data have notbeen examined by outside researchers.

At present, there is insufficient information toindicate whether this regimen is or is not effective intreating cancer. However, Livingston’s ideas havestimulated other researchers to study some aspectsof her cancer treatment regimen. For example,Anthony Strelkauskas, M.D., at the University ofSouth Carolina, is reportedly studying the immuneresponses of breast cancer patients to the autogenousvaccine, but results have not yet been published(559).

A prospective clinical trial of the use of anautogenous vaccine in the treatment of cancer iscurrently underway in Virginia under the directionof Vincent Speckhart, M.D., and Alva Johnson,Ph.D. (819). The aim of the evaluation is to observetumor responses following vaccine administrationamong 33 patients described as having advancedforms of cancer and as either failing previoustreatment or having recurrences following conven-

tional treatment. For a 6-month period, patients weregiven regular doses of an autogenous vaccineprepared from cultures of chorionic gonadotropin-producing bacteria isolated from the patients’ urine(820). According to a summary of preliminaryresults (a full description is not yet available), thestudy found several cases of tumor regression, somecomplete and some partial, in this group of patients.No adverse reactions, except localized redness andan occasional rash that were resolved by changingthe vaccine dose, were noted. Speckhart andJohnson’s full results may contribute information tothe further evaluation of the efficacy of suchvaccines in cancer treatment.

HANS NIEPERAnother widely known practitioner of unconven-

tional cancer treatment is Hans Nieper, M.D., a WestGerman physician. Patients from many countries,including the United States, reportedly have soughthis treatment. Nieper specializes in the treatment ofcancer, multiple sclerosis, and heart disease (77).For cancer, Nieper prescribes a combination ofconventional and unconventional agents (includingpharmaceutical drugs, vitamins, minerals, and ani-mal and plant extracts), and recommends thatpatients follow a special diet and avoid particularphysical agents, foods, and physical locations (“ge-opathogenic zones’ that he believes are damaging.

Since 1964, Nieper has been affiliated with theParacelsus Silbersee Hospital in Hannover, WestGermany. He received his M.D. from the Universityof Hamburg in 1953 (77). In addition to his medicalpractice and clinical research, Nieper hypothesizesabout some aspects of theoretical physics. Hiswritings cover subjects such as the “shieldingtheory of gravity” and the potential for harnessinguseful energy from space, which he refers to as the‘‘tachyon field. Some of his ideas about problemsin medicine, including some aspects of canceretiology and treatment, are based on his theories ofenergy fields (677).

Nieper has published a large number of papers andbooks on medical subjects, in several languages,according to information from a private library inWisconsin 11 that collects and distributes some ofNieper’s papers in the United States. These papers,some of which are translated from German, are

ll~e Admir~ Ruge Archives, A. Keith Brewer Science Libr~, Richland Center, WiSCO~in.


distributed by that library as mimeographed type-scripts, with a title, Nieper’s name as author, and adate; although in all but a few papers, no source orcitation is given to indicate whether they correspondto published articles. Using indexes to the openmedical literature accessible in the United States(e.g., Index Medicus and Science Citation Index),OTA found citations to a small number of articles byNieper, only a few in English (675).

In 1985, an English translation of his bookRevolution in Technology, Medicine and Societywas published (677). This book contains discussions(often difficult to follow) of his theories and researchinterests (titled, e.g., “On the Subject of Medicineand the Tachyon Era,” ‘‘ The Symposium on EnergyTechnology in Hannover,” “Congress on GravityField Energy in Toronto, “ “Epilog for the Hannoverand Toronto Energy Conferences,’ and ‘Encourag-ing Signs in Politics, Economy, and IntellectualLeadership”). Within the context of these subjects,Nieper discusses approaches to the treatment ofcancer, multiple sclerosis, thrombosis, arterioscler-osis, lupus, asthma, heart disease, and a variety ofother conditions.

Nieper’s book and mimeographed papers cover arange of issues in cancer prevention and treatmentand also discuss particular treatments that he be-lieves are important. Although he states that hisideas are based on clinical and laboratory data, hedoes not explain them in the context of otheravailable medical literature. Rather, he discusses hisapproaches to treatment in the context of theoriesand conclusions derived from his general knowledgeof medical research. The lack of straightforwarddescriptions of his treatment approaches and ofcitations to existing medical literature make itdifficult, at best, to determine the components of histreatment regimens and the specific information(including his data and others’) on which they arebased.

Nieper offers additional information about histreatments in the course of occasional seminars andworkshops in the United States, which are sponsoredby the Hans Nieper Foundation, an information andsupport group based in California and directed by aformer patient. At a 1987 full-day seminar formedical professionals, held in New York, Nieperdiscussed his protocols for the treatment of cancerand multiple sclerosis (453). There is virtually noother available information intended for a U.S.

audience on Nieper’s treatment regimens fromNieper or his supporters.

Thus far, government and private organizations inthe United States have not provided synopses ofNieper’s treatment, as has been done for a variety ofother unconventional cancer treatments that U.S.cancer patients use. No written statements aboutNieper are available from the Cancer InformationService (CIS) at NCI or the Committee on UnprovenMethods (ACS). One aspect of Nieper’s treatmentwas addressed in a 1986 FDA ‘talk paper’ (890) onthe issue of importation of Nieper’s treatmentmaterials. In 1987, FDA issued an import alert (891),announcing that shipments of drugs prescribed byNieper would be detained by U.S. Customs agents.FDA considers the shipment of these drugs into theUnited States to be in violation of the Food, Drug,and Cosmetic Act, since they lack U.S. approval foruse and are not labeled according to standards setforth in that law.

Based on the book and mimeographed papersreferred to above, some aspects of Nieper’s treat-ment for cancer can be described. Nieper describeshis approach to treatment as “eumetabolic,’ a termhe coined to refer to the use of substances derivedfrom plants or animals that he considers not to be“foreign” in the human body. The regimen forcancer includes “subtoxic doses of chemotherapy,’“hormone therapy,” and “gene-repair therapy;”the components and rationale for them are onlyindirectly and partially described. The overall aim ofthe cancer treatment regimen is to activate the‘‘internal defense system,’ which Nieper believes isthe body’s own mechanism for fighting cancer. Heuses low-dose chemotherapy, radiation, and surgeryto kill or remove tumor cells directly, but cautionsthat chemotherapy ‘‘must never be so extensive thatvaluable mechanisms of the body’s own defenses arethoughtlessly damaged” (677). Nieper believes thatinternal mechanisms control the healing process incancer; “exogenous factors and procedures have,therefore, little effect on. . . the incidence. . . and thecuring rate” (676). Nieper believes that cancer iscaused by suppression of natural host defenses, byovereating the wrong types of food, and by exposureto certain environmental factors. He refers to partic-ular environmental factors that he believes lead to“gene instabilities” and to the activation of onco-genes: X-rays, ultraviolet radiation, alternating cur-rent electrical fields, and the “tachyon field turbu-lence of the geopathic zone. ”


In Nieper’s view, geopathic zones “play a deci-sive role in the development of cancer cells andcancerous tumors” (677), in that he believes there isa higher incidence of cancer in areas of high levelsof earth radiation and in areas situated over subterra-nean water veins. He believes that geopathic zonescause disturbances in the magnetic or electrostaticproperties of tissues in the body, which disrupt thegenetic material. Nieper claims that 92 percent ofcancer cases he has examined are associated withlong-term occupancy (particularly where the indi-viduals sleep) of geopathic zones. He believes that‘‘removal of cancer-stricken patients from geopathiczones absolutely belongs to the conscientious dutiesof an oncologist” (677).

Nieper states that his treatment regimen is “moreor less the same in all conditions of malignancywhatever the finding” (673). A wide range ofsubstances used to treat cancer patients is discussedin his writings, including dehydroepiandrosterone,magnesium, selenium, beta carotene, bromelaine(papain), cod liver oil capsules, vitamin C, photons,BCG, gamma globulin, magnesium orotate, tumos-terone, mistletoe, amygdalin and mandelonitriles(laetrile), benzaldehyde, urea, glutathione, Didrouval-trate, carnivora (an extract of the Dioneaea muscip-ula plant), pau d’arco, ‘‘adrenal whole extract,’ andsqualene (derived from shark’s liver oil) (676).

In addition to prescribing some or all of theseagents, Nieper cautions patients to avoid alternatingcurrent fields, such as electric blankets and heatingpads, and to avoid all cigarette smoke. He recom-mends that they follow a special diet—a low-salt,low-carbohydrate, ‘Kirlian-positive vegetarian diet,”including whole grain cereals and breads, carrotjuice with heavy cream, vegetable and fruit juices,low-fat milk, all types of vegetables and fruits,moderate amounts of coffee, tea, eggs, and butter,and limited amounts of fish. Patients are cautionedto avoid most types of meat, sausage, chicken, veal,shellfish, sugar, alcohol (except “sour” wine),white bread, cheese, vitamin B12, and iron (167).

The information available about Nieper’s treat-ment regimen contains very little clinical data onoutcomes in cancer patients following treatment. Amimeographed paper dated 1977 and a 1980 paperwith the same information show a table listing 23general tumor types found in 214 patients, alongwith the number of patients with each tumor typeand the number of “positive responses’ to his

treatment. A “positive response” was defined as“18-month survival with considerably improvedhealth.” Nieper claims that “the percentage ofpatients whose disease gets under control within an18-month period of observation is close to 40percent” but he restricts this to “mobile, so-calldincurable patients, ’ because “the results with hos-pitalized patients are less than half as good sincehospitalization indicates that the disease has pro-gressed too far” (674,675). Since no data are givenon tumor stage, prior treatment, specific treatmentsgiven to patients under his regimen, or how theseparticular patients were chosen for inclusion in theanalysis, the information provided is insufficient todraw any conclusions about efficacy.

OXYGEN TREATMENTSVarious types of oxidizing agents are discussed in

the popular literature on unconventional cancertreatments and at meetings sponsored by advocacyand information groups such as the Cancer ControlSociety (162). Although not apparently widespreadin the United States, the use of oxidizing agents hasbeen reported at clinics in Mexico and WestGermany where U.S. cancer patients are treated(289,588). The most commonly mentioned treat-ments of this type are ozone (a gas), hydrogenperoxide (a liquid), antioxidant enzymes, and relatedproducts (853). Oxidizing agents such as ozone andhydrogen peroxide are commonly available andhave a variety of mainstream uses: as antiseptic,disinfectant, and cleansing agents, as laboratorychemical reagents, and in the food packagingindustry. In addition to their use in unconventionalcancer treatments, oxidizing agents are also pro-posed as components of unconventional treatmentsfor AIDS, cardiovascular disease, multiple sclerosis,arthritis, and a variety of other conditions (96,297).

The late Otto Warburg, a German chemist twiceawarded the Nobel Prize, was one of the first todiscuss an association between oxygen levels in thebody and the etiology of cancer, and to suggest thatthe growth of cancer cells is favored by an intracellu-lar environment low in oxygen (936). Many othershave since expanded on Warburg’s ideas, and muchhas been written about oxygen treatments in general.Not only is there no accepted rationale for theproposed effects of oxidizing agents in cancertreatment among current proponents, but disputesamong oxygen proponents are found in descriptionsof these treatments in the unconventional literature


(80,217). The role of oxygen compounds in theinitiation and progression of cancer has long been asubject of mainstream scientific study. In general,active oxygen is thought to contribute in a variety ofways to the development of malignant cells (180).

Ozone can be administered by direct infusion ofthe gaseous mixture into the rectum or into muscle,but it is usually given by unconventional practition-ers in blood infusion, a process whereby blood isremoved, treated with oxygen, and returned to thebody, as explained in a recent review by anunconventional medicine advocate:

The ozone is produced by forcing oxygen througha metal tube carrying a 300-volt charge. A pint ofblood is drawn from the patient and placed in aninfusion bottle. The ozone is then forced into thebottle and mixed in by shaking gently, whereuponthe blood turns bright cardinal red. As the ozonemolecules dissolve into the blood they give up theirthird oxygen atom, releasing considerable energywhich destroys all lipid-envelope virus, and appar-ently most other disease organisms as well, whileleaving blood cells unharmed (297).

Medizone International, a company that manufac-tures a device used to deliver ozone by infusion inthe blood system, has filed an investigational newdrug application with FDA to study the possible useof ozone as an antiviral agent. Before phase I studiesin humans can proceed under the IND, however, thecompany is required to submit data, probablyinvolving tests in animals using a range of doses,showing that ozone can be administered safely.Little information in the published, peer-reviewedliterature is available on the use of ozone in generalin the treatment of cancer, or on the recommendeddoses and regimen for treatment. Claims for theefficacy of ozone are based on a number of papersand case reports of its use on cancer patients(926,929), in animal studies (52,586), and in cellculture (940). One paper by Sweet and colleagues,published in Science, presents indirect evidence thatatmospheric ozone selectively inhibits the growth ofhuman tumor cells in cell culture (in vitro) (846).

Hydrogen peroxide is given in dilute form byvarious routes--oral, rectal, intravenous, vaginal,and in bathing. Proponents state that hydrogenperoxide oxidizes toxins, kills bacteria and viruses,and stimulates immunity (364). One unconventionalpractitioner, Kurt Donsbach, who treats cancerpatients in Tijuana, formulated a line of products

using hydrogen peroxide, including ear drops, nasalspray, and tooth gel. Donsbach states that everycancer patient at his clinic in Tijuana receives dilute“infusions of the 35% food grade hydrogen perox-ide throughout their entire stay” (262). In 1988, theU.S. Postal Service issued Donsbach a cease anddesist order to stop him from claiming that thehydrogen peroxide used orally or intravenously iseffective against cancer or arthritis, or that it is fit forhuman consumption (69). Another clinic, the Gersonclinic in Tijuana, has recently added ozone therapyto their regimen, partly on the basis of the laboratorystudy by Sweet and colleagues referred to above(401). Patients at the Gerson clinic are commonlygiven ozone enemas, consisting of 500 to 1,000 cc ofozone given rectally in less than 1 minute (318).

Another form of oxygen treatment, superoxidedismutase, is an antioxidant enzyme believed to playa role in aerobic metabolism (689), Several uncon-ventional treatment facilities in Tijuana (e.g., theManner Clinic and American Biologics Hospital andMedical Center), reported using this enzyme in theirregimens for cancer patients (22,574).

Oxidizing agents, such as ozone and hydrogenperoxide, can destroy cells, including those of theblood-forming organs, and at some doses, can beseriously damaging or even lethal (860). The dosesat which these agents can be administered safelyhave not yet been determined. Although advocatesof ozone and hydrogen peroxide maintain that thesesubstances can be used safely, other unconventionalpractitioners have noted possible adverse effects(98).

EMANUEL REVICI AND“BIOLOGICALLY GUIDED

CHEMOTHERAPY”Emanuel Revici, M.D., is a physician in his

nineties who currently practices in New York City.During a career spanning seven decades and fourcountries, Revici has developed an apparently uniqueapproach to the treatment of cancer and a wide rangeof other disorders, including AIDS, Alzheimer’sdisease, arthritis, chronic pain, radiation injury,Sshizophrenia drug addiction and others (597,747,748).Revici proposes that the clinical manifestations ofcancer are associated with an imbalance of twogeneral classes of lipids (fatty acids and sterols) inthe body and in some cases also with the presence ofparticular lipid constituents (conjugated fatty acids).

Chapter S-Pharmacologic and Biologic Treatments ● 115

Using a test system he developed to measure certainphysiologic changes that he believes reflect theselipid imbalances, Revici treats patients he identifiesas having a predominance of one or the other classof lipid with one or more lipid-based pharmacologicagents intended to counteract the imbalance (741).Revici characterizes his regimen as a “dualistic”approach to cancer chemotherapy (747), referring tohis proposal that different and opposing groups ofagents, rather than a single type operating by onemode of action, may be required to treat cancer.

Revici received his medical degree in 1920 fromthe University of Bucharest, Romania, where helater worked as assistant professor in internalmedicine. He practiced medicine and conductedclinical research in Paris (1936-41) and in MexicoCity (1941-46) before settling in New York, wherein 1946 he established the Institute of AppliedBiology. Since 1947, Revici has maintained aprivate practice in New York. He also served as chiefof oncology (1955-65) and as consultant (1965-78)at Trafalgar Hospital, formerly the Beth DavidHospital, a New York facility purchased by Revici’sfundraising organization (212,213). A recent reviewof Revici’s career characterized that hospital as ageneral care facility employing over 200 residentand visiting physicians, and noted that it containedanimal research laboratories staffed by 35 scientistsand technicians, “all involved in projects inspiredby or related to Revici’s theories and therapeuticmethod” (212). Trafalgar Hospital closed in 1978,reportedly because of financial difficulties (21 1).

In 1949, the AMA Council on Pharmacy andChemistry published an article in the Journal of theAmerican Medical Association (J.AM.A.) warningagainst Revici’s treatment, among other unconven-tional treatments (39). In a letter to the editor, theAMA article was criticized for disparaging Reviciwith unwarranted accusations about his work (738).The J.A.M.A. article was reportedly reprinted anddistributed by the ACS’s Brooklyn Cancer Commit-tee, which Revici later sued for libel. The case waseventually settled out of court through mediation bythe Medical Society of the State of New York (740).The ACS Committee on Unproven Methods ofCancer Management published its first statement onRevici’s treatment in 1961 (22a). Since 1984, Revicihas faced legal challenge regarding his license topractice medicine in New York State; he is currentlyon probation for a 5-year period that began inOctober 1988. Two malpractice suits charging

medical negligence have also been filed against himin Federal court since 1983 (see ch. 11 for details).

The main source of information available aboutRevici’s treatment is his book, published in 1%1,entitled Research in Physiopathology as a Basis ofGuided Chemotherapy With Special Application toCancer (747), which focuses on the theoretical basisfor his approach. In it, he argues that “cancer-aswell as other conditions-can be integrated into ahierarchic concept of organization which appliesthroughout nature.” According to his theory, thatorganization is determined by certain laws, amongthem the law of dualism, or opposing forces, at everylevel. He discusses his views of the activity oforganic and inorganic substances in relation to: thelevel of organization in the body at which they act(nuclear, cellular, organ, etc.); their “dualistic na-ture’ other substances in the body (particularlylipids); and how they affect the body’s defensemechanism (747). Revici believes that this dualismaffects one’s physiologic state and is key to under-standing how disease may develop and how it maybe treated.

Revici deseribes his treatment for cancer-whichhe refers to as “biologically guided chemotherapy” —as nontoxic, individually guided chemotherapy usinglipid and lipid-based substances (210). He believesthat tumor cells, as well as other types of abnorma1cells, share a common biochemical characteristic—an imbalance in the normal distribution of lipids-which he views not as the primary cause of cancer,but as the direct cause of its impact on the body’smetabolism. He categorizes two general patterns oflocal and systemic effects of lipid imbalancesreportedly found by him in patients with cancer, onepattern resulting from an excess of fatty acids and theother pattern resulting from an excess of sterols.

According to Revici’s analysis, a relative predom-inance of fatty acids leads to an electrolyte imbal-ance, specifically an increase in sodium in theextracellular fluids, and an alkaline environment intumor tissues; Revici refers to this as a “catabolic”condition. In the opposite case, a predominance ofsterols reportedly leads to a reduction in cellmembrane permeability and an inhibition of thecells’ oxidative processes, which in turn reduces theavailability of intracellular oxygen, interferes withthe breakdown of carbohydrates, and results inexcess lactic acid in the extracellular fluids; Revici


refers to this outcome as an ‘anabolic’ condition.12

Patients determined by Revici to have a predomi-nance of fatty acids are treated with sterols and otheragents with positive electrical charges that cancounteract the negatively charged fatty acids. Thosedetermined to have a predominance of sterols aretreated with fatty acids and other agents that increasethe metabolic activity of fatty acids (513,741,749).

A physician who worked closely with Revici from1946 until 1957 noted in a summary of Revici’sapproach that “since the lipid imbalances appear toplay an important role in determiningg the metabolic,local and systemic features of the disease,” thetreatment regimen is intended to modify thosefeatures by administering substances that influencethe lipid imbalance. Some of Revici’s researchefforts focused on developing chemical agentscapable of modifying lipid imbalances and ondeveloping tests to identify and measure the balanceof lipid in individual patients (741).

Revici has some support for various aspects of histheoretical approach among a small group of re-searchers. In a recently published paper, HaroldLadas reviewed Revici’s work with selenium com-pounds in the treatment of cancer (513). In a recentunpublished manuscript, Leonard Kunst, HaroldLadas, and Frederick van Kampen reviewed someaspects of Revici’s theory in the context of currentknowledge about the role of lipids in the cancerprocess, and suggested that lipid substances such asthose Revici uses may act by targeting and potenti-ating the action of antitumor agents at the tumor site(494). In another unpublished manuscript, Kunst andLadas reviewed Revici’s proposal regarding bio-chemical changes in lipids associated with radiationexposure and the use of n-butanol to treat radiationinjury (492). A third unpublished paper by Kunstand Ladas examined Revici’s ideas concerningcorrelations between the molecular charge andbiological activity of certain types of molecules(493). In a 1985 Institute of Applied Biologypublication, one of Revici’s medical associates,Dwight McKee, described many aspects of Revici’scurrent theoretical approach to treating a widevariety of conditions (597). There has been nocomprehensive review in the mainstream medicalliterature of Revici’s theory and its application tocancer treatment, however.

Revici’s treatment regimen has apparently notbeen adopted or continued by other practitionersoutside of his institute, either in the context ofconventional clinical studies or unconventionalpractice, so at present, Revici’s New York office isthe only site where the treatment is used. For severalyears in the 1960s, however, some of Revici’streatment agents were reportedly used in Belgium bythe late Joseph Maisin, who at that time was Directorof the Cancer Institute of the University of Louvainand President of the International Union AgainstCancer. According to several letters written toRevici between 1965 and 1970 (573), Maisinobtained a number of compounds from Revici(including fluoroheptanol, selenium diethyl-thiocarbamate, and others referred to as “PCA,”“CMS,” “MHS,” "MHSe5,’ and “anti-MHSe”)and treated patients generally described as thosewith advanced metastatic cancer who had failedprevious treatment. Some patients were treated witha combination of Revici’s agents and radiotherapy,while others were given Revici’s agents alone.These letters do not describe the conditions underwhich the patients were treated (e.g., as part of aformal evaluation or on an informal basis), or howparticular agents were chosen for particular patients.The letters were apparently written to inform Reviciof Maisin’s clinical observations, and included briefsummaries of some cases considered to have re-sponded well to the treatment. Maisin noted thatsome patients experienced tumor regressions, disap-pearance of metastasis, and improved fictionalstatus following treatment. Maisin died in 1970 andno further information about Maisin’s experiencewith Revici’s treatment is available.

Earlier in his career, Revici published papers inSouth American and European scientific journals(31). Since the 1950s (751,961), however, Revicihas not published updated descriptions or studies ofhis cancer treatment in the peer-reviewed scientificliterature (although attempts were reportedly madeto do so (739,836)). The most recent openly avail-able description of his cancer treatment regimenwritten by Revici is his 1961 book, referred to above,which provides some information from laboratoryexperiments and clinical experience (including casehistories of patients treated with his method) sup-porting his theoretical approach. The book does not,

lz~ofic~dca~bolic we terms referr@ to the body’s metabolism. In usual usage, anabolic metabolism corresponds to the cons~ctive Synthesisof macromolecules, whereas catabolic refers to the breakdown of complex materials in the body and the release of energy.

Chapter 5-Pharmacologic and Biologic Treatments ● 117

however, provide details of the empirical basis forclassifying cancer patients’ metabolic conditions orfor choosing specific treatment agents according tothat system of classification. At present, Revici andhis associates appear to be the only ones who knowhow to interpret and apply his diagnostic andtreatment protocols, since the protocols are, at leastto some extent, proprietary and cannot be deducedfrom his book. In the absence of up-to-date descrip-tions of the rationale and process of his treatmentregimen, it maybe impossible for Revici’s treatmentto be continued in the future without his personalinvolvement.

In

Revici’s Cancer Treatment Regimen

order to determine whether a patient’s condi-tion is anabolic or catabolic, Revici-tests for certaincharacteristics (specific gravity, pH, and surfacetension) of the patient’s urine before treatment isinitiated. Revici believes that these indices, whilenot diagnostic of cancer, reflect systemic changes inthe body produced by lipid imbalances (513,741).As treatment progresses, the urine is reexaminedperiodically to determine whether and by how muchthese indices change. A sterol predominant oranabolic condition is considered to be indicated byurine that is alkaline (pH greater than 6.0 to 6.2), hasa high surface tension (above 68 dynes/cm2), and hasa low specific gravity. Patients whose urine meas-ures below 6.0 to 6.2 in pH and below 68 dynes/cm2

in surface tension are considered to be catabolic, orfatty acid predominant (741).

Revici reportedly believes that, in healthy indi-viduals, these urine indices tend to fluctuate up anddown over a narrow range around median values—pH of 6.0 to 6.2 and surface tension of 68 dynes/cm2—while cancer patients tend to show values fixed ateither higher or lower levels (741). Progress oftreatment is measured by the degree to which it altersthese urine indices toward normal values. Reviciasks his patients to monitor these changes at homeusing a colorimeter to indicate urine pH. Urinarysurface tension is measured using a glass “uroten-siometer” (747), a device designed for Revici’s use.Other urine indices reportedly used in Revici’sclassification method include specific gravity and achloride index (the ratio between specific gravityand chloride concentration) (748).

The urine indices that Revici uses as diagnosticand treatment tools are not used in this way inmainstream medicine; they are not diagnostic of thepresence of cancer or its systemic effects and havewide natural variations depending, for example, onfluid intake and ingestion of acid or alkaline foodsor other substances. Revici’s 1961 book and some ofhis articles discuss the use of these urine indices, butdo not offer evidence validating their reliable use inidentifying metabolic abnormalities, or confirmingthat such metabolic abnormalities actually existamong patients. In support of his conclusions aboutthese tests and their clinical significance, Revicirefers to laboratory experiments and clinical studiesconducted under his direction at the Institute ofApplied Biology over many years, the bulk of whichhave apparently not been reported, critiqued, orconfirmed externally.

Revici uses the Periodic Table of Elements as oneof several guides to deciding on treatment regimensfor his patients. Based on his study of the organiza-tion of elements in the Periodic Table, he believesthat the periods (horizontal rows) indicate at whichlevel of biological organization in the body aparticular element acts—at the level of subnuclearparticles, the nucleus, the cell, the tissue, or thewhole body. He also believes that the placement ofelements in particular series (columns) determineswhether they act anabolically or catabolically in thebody (749). For example, he considers elements ingroup VIA-oxygen, sulfur, selenium, and tellurium-active against a chronically anabolic state (513).

According to Revici and several others writingabout Revici’s treatment, a wide variety of chemicalagents has been used in his regimen. Revici recentlystated that most of the substances he uses astreatments for cancer are either “twin formations”(reportedly defined as two adjacent carbon atomshaving the same induced electrical charge (493)) orinorganic elements (e.g., iron, magnesium, copper,or selenium) incorporated in or bound to lipids(749), but he did not say which specific substancesare in current use in his practice.

Since the 1940s, one of the agents Revici hasfrequently used to treat patients classified as havinga sterol predominance is lipid-bound selenium.Revici reportedly has used many different prepma-tions of selenium, such as “T Sel’ (selenium boundto “eleostearic acid,” “Rel” (“a mixture of a7-carbon diselenide and 3-heptanone”) (513), and


hexyldiselenide (741). Other substances used to treatthis classification of patients include: fatty acids(including some isolated from human and animalsources), sulfur compounds (e.g., colloidal sulfur,sodium thiosulfate), hydrines (e.g., epichlorohy-drin), aldehydes, male hormones (testosterone), andmustard compounds (513).

Substances Revici has reported using to treatpatients classified as catabolic or fatty acid predomi-nant include: sterols (e.g., cholesterol), alcohols(e.g., butanol, glycerol, heptanol, octanol), femalehormones (estrogens), amines (e.g., aminobutanol),nicotinic acid derivatives, metals (mercury, iron,bismuth), and halogens (e.g., iodine) (747).

The treatment agents are given orally or byinjection (210). Revici’s technicians prepare thetreatment agents according to Revici’s formulas andinstructions (213). To OTA’s knowledge, thesetreatment agents have not been analyzed independ-ently. According to a 1989 statement on Revici bythe American Cancer Society, Revici was issued 17U.S. patents between 1981 and 1988 for chemicalformulations described for use against cancer, viraldiseases, and substance abuse, and for termination ofpregnancy (31).

While selenium compounds can generally betoxic (197), Revici reportedly believes that he hasidentified a form of selenium that is nontoxic topatients (the “negative bivalent form”) (213). Hebelieves that treatment can cause inflammationaround the area of the tumor, causing it to becomemore painful and to become larger and softer, beforecausing it to shrink and disappear (513). No adverseeffects from Revici’s treatmentin the medical literature.

Claims

have been reported

Revici states in his book that his treatment ‘whencorrectly applied. . . can, in many cases, bring undercontrol even far-advanced malignancies” (747). Insupport of this, he presents many case histories ofcancer patients with partial or complete remissionsfollowing his treatment. The recent transcripts of acongressional hearing held in New York alsocontain numerous presentations by and on behalf ofRevici’s cancer patients claiming remissions as aresult of his treatment (749). Revici concludes his1961 book by noting:

The results obtained and especially their highproportion, even in far advanced cases, permits a fairjudgment of the place of the present form ofapplication of this method in the fight against cancer.Based on these results, we are fully entitled toconsider it, not only a highly beneficial treatmentwhich can be offered now for this disease, but evena major step nearer to the solution of the problem ofthe therapy of cancer (747).

Attempts at Evaluating the ReviciTreatment Regimen

In 1978, two compounds containing selenium thatRevici has used—amyl selenide and selenium dieth-yldithiocarbamate (“Secar’’)-were submitted onRevici’s behalf to the Drug Therapeutics Program,NCI, for testing of antitumor activity in an animaltumor screening test (l). One of the compounds,amyl selenide, showed antitumor activity in themouse P388 Leukemia test system (905). The othercompound, selenium diethyldithiocarbamate,showed no antitumor activity in this test (905).Although agents that test positive in prescreen areusually tested further in NCI’S tumor panel, amylselenide was not submitted for further testing.Another compound, trithioformaldehyde, was saidby Revici supporters to have been tested in experi-mental animals at Roswell Park Memorial Institutein the late 1970s (212,652), but the Institute has norecords to confirm such tests or their results (754).

More recently, another selenium compound thatRevici reportedly uses was tested in several otheranimal tumor systems. According to a letter from aBritish company (Advisory Services, Ltd., London),the diheptyl diselenide was reportedly tested at theImperial Cancer Research Fund and WestminsterHospital, London, on a variety of tumor systems, andwas found to be active in four of them (L1210leukemia, Lewis lung metastasis, M5076 livermetastasis, and early S 180 tumor growth). Acuteand chronic toxicity of the compound was alsostudied, and it was found that the dose at whichantitumor activity was found was ‘fairly close to thetoxic dose” (484). Further studies on the compoundwere recommended ‘‘to determine more preciselythe nature of the activity and to see if we can obtainsignificant anti-tumor activity without, at the sametime, inducing undue toxic reactions” (484).

As a means of presenting Revici’s overall clinicalexperience in cancer treatment, a descriptive studyof clinical outcomes in all the cancer patients treated


with the Revici regimen between 1946 and 1955 wassummarized in an unpublished paper (741). Thepaper was written by Robert Ravich, M. D., whoworked closely with Revici at the Institute ofApplied Biology and who, with Revici, treated thepatients described in the report. Most of the patientswere reported as “far advanced” or “terminal” andhad had previous treatment (e.g., surgery, radiation,hormones, and nitrogen mustard). Cases included inthe report were limited to those whose diagnosis ofcancer was ‘clearly established by the best availablemeans, by qualified physicians, surgeons and pa-thologists not connected with the Institute of Ap-plied Biology” but otherwise were not selectivelyincluded or excluded, since the report was intendedto describe the entire population of patients treatedby Revici during that time.

The 1,047 patients were classified as either fattyacid or sterol predominant, according to Revici’sdiagnostic testing (based mainly on urine analyses ofpH and surface tension, as described above). Of thepatients found to have a sterol predominance, 152were treated with sodium thiosulfate and sulfurizedoil; 95 with sulfhydryl containing compounds (e.g.,ethyl, hexyl, heptyl and dodecyl mercaptan, meth-ylthioglycholate, and dimercaprol); 78 with fattyacid mixtures extracted from various natural sourcesincluding human placenta, and animal and fishorgans; 64 with conjugated or alpha-hydroxy fattyacids; and 53 with hexyldiselenide. Of the patientsfound to have a fatty acid predominance, 106 weretreated with n-butanol; 77 with glycerin, 51 withcholesterol or other non-saponifiable lipids ex-tracted from unspecified organs; and 10 with oc-tanol. Treatment agents given to the remaining 361patients were not specified. Individual determi-nations of dose were made on the basis of eachpatient’s urine analyses and it was noted that notoxic reactions were observed. Treatments weregiven orally and by injection.

Both objective and subjective outcomes wererecorded. A favorable objective response was de-fined as measurable “reductions in size and extentof the disease as visualized either directly by the eyeor by X-ray, or by palpation” that were ‘‘sustainedfor a significant period of time and in the directionof improvement over several successive observationintervals.’ However, in some cases, stabilization ofdisease “over long intervals” was also consideredan objective response. A favorable subjective re-sponse was defined as ‘‘satisfactory improvement

for a sustained period as reported by the patient,”usually referring to relief from pain, a sense ofwell-being, and increased energy, strength, andappetite.

Of the 1,047 cases reviewed, 100 were judged tohave had favorable objective and subjective re-sponses; 11 had objective responses only; and 95had subjective responses only. These cases included23 different types of primary cancers. Two hundredninety-six patients were judged to have had noresponse, subjective or objective, and 545 patientshad equivocal or undetermined responses (380 ofthis latter group were treated less than 3 months).Details of the individual cases were not given in thereport.

To date, the only published clinical study ofRevici’s treatment for cancer is a paper that appearedin J.A.MA. in 1965 written by the ‘‘ClinicalAppraisal Group” (CAG), a group of nine NewYork physicians assembled specifically for thatstudy (571). According to the report, the study wasdone at the request of the Board of Trustees ofRevici’s Trafalgar Hospital. It evaluated the clinicalcourse and outcomes of selected cancer patients whowere referred to Revici for treatment. The authorsreported that they did not influence or modify thetreatment Revici offered to these patients during thestudy. All of these patients were considered refrac-tory to conventional treatment. Other criteria werethat only hormone-independent (571), solid tumors,certified by tissue diagnosis, were included. Ex-cluded from the study were tumor types that were notexpected to progress in a short period of time andpatients who had recently undergone conventionaltherapy. Thirty-three cancer patients were ultimatelyincluded in the study.

The authors reported that 22 of the 33 patientsdied of cancer or its complications while on theRevici treatment. Eight other patients left the studygroup “in unimproved condition” after some timeon the regimen. Four of these eight patients later diedof cancer, two of them went elsewhere for palliativetreatment, and two were lost to followup. The threeremaining patients were under Revici’s care at theclose of the study period and all of these werereported to have shown signs of tumor progression.The study group concluded that none of these 33patients Revici treated showed signs of objectivetumor regression. The group concluded that “the


Revici method of treatment of cancer is withoutvalue” (571).

Apparently responding to a full version of thereport (a two-page summary of which became thepublished J.A.M.A. version), Revici wrote a detailedstatement sharply criticizing the CAG’S methods,conduct, and interpretations (750). He also presentedsummaries of patient records that he claimed showedobjective responses to treatment, contradicting theCAG’s interpretation of the same data. He noted,among other things, that several patients in the studyhad tumor remissions that the study group allegedlyfailed to recognize. Revici also noted that it was he,rather than the Board of Directors of the TrafalgarHospital, who requested the study in the ‘‘hope thatthe demonstration of positive results in even a few ofthese advanced cases would excite sufficient interestto lead to a large scale study of our approach. ’ Heparticularly criticized the overall conclusion statedin the full version of the report (that “the Revicimethod of treatment of cancer . . . should beabandoned.”), he wrote:

In the event that this method should have provenineffective in the types of cancer accepted (in theanalysis), and not a single reduction in the size of anytumor noted, these should have been the onlyconclusions that could have been rightfully drawn.To conclude from a limited study, such as this, thatthe method should be discontinued, in all cancers, isto say that since surgery and radiation have failed inthese same terminal patients, these “recognized”methods should also be discontinued, not only inthese types of cancer but in all cancers in general.(emphasis in original)

Recently, Seymour Brenner, M.D., a radiologistin private practice in New York, took initial stepstoward documenting and verifying the medicalrecords of 10 patients treated by Revici. In present-ing summaries of these cases at the March 1990meeting of the Advisory Panel for the present OTAstudy, Brenner stated that he believed these 10patients to be examples of successful treatment withRevici’s method, citing evidence of tumor regres-sion, improved quality of life, and enhanced sur-vival. These case histories have not yet beensubjected to critical review. No prospective con-trolled clinical trial to evaluate the safety andefficacy of Revici’s treatment has been conducted.

VITAMIN CVitamin C (ascorbic acid or ascorbate) may be

discussed more frequently in connection with thecommon cold, but its use in the treatment andpalliation of cancer has also been promoted andwidely adopted; thousands of U.S. cancer patientsare believed to take large doses of vitamin C (756).The proponents most closely associated with thestudy and use of vitamin C for cancer treatment arethe Nobel laureate Linus Pauling, Ph.D., whoseadvocacy, expressed in books, articles, and personalappearances publicized by the media, has beenprimarily responsible for popularizing vitamin C forcancer, and his colleague Ewan Cameron, M. B.,Ch.B., a Scottish surgeon. Treatment with vitamin Cis generally promoted as an adjunct to conventionalcancer treatment, with the aim, according to Cameronand Pauling, of supporting the patient’s naturaldefenses against the disease--e.g., to support encap-sulation of the tumor, to resist the formation ofmetastasis, to enhance immunologic competence, toreduce cachexia, and to improve general healthStatus (158).

Although it is an essential nutrient, vitamin Ccannot be synthesized by the human body and mustbe derived from the diet or from supplements, whichcan be prepared synthetically or extracted from fruitsand vegetables. Relatively small amounts of vitaminC in the diet are needed to avoid overt deficiencydiseases such as scurvy. The recommended dailyallowance (RDA) for vitamin C is 45 milligrams(0.045 grams) per day (661a). Its use in unconven-tional cancer treatment usually involves megadoses(usually 10 grams per day or more) of vitamin C,administered intravenously or orally (dissolved inwater or juice or as capsules). Dosages are adjustedto each patient, but in general, they usually beginwith 1 to 2 grams daily and increase gradually to 10grams or more per day. The tolerance level isreached when the patient experiences the vitamin’slaxative effects (when taken orally), and dosage isthen reduced and maintained at a slightly lower level(557). Proponents state that they do not know thebest dose in cancer patients, but generally assume itto be about 10 grams per day, which is “as muchascorbate as the patient can tolerate without gastro-intestinal side effects” (158).

The idea of using vitamin C in cancer treatmentwas first proposed in the early 1970s by Cameron.Cameron examined the process of uncontrolled


invasiveness in tumor growth, and looked for waysto inhibit cancer cells from infiltrating and damagingsurrounding normal tissue and from metastasizing todistant organs. He focused on the possible role of anenzyme, hyaluronidase, in supporting tumor inva-siveness, and suggested that manipulation of aninhibitor of this enzyme, which existed in the blood,could be used to control the process (151). In theearly 1970s, Cameron and his colleague DouglasRotman noted that the inhibitor molecule they wereexamining contained an ascorbate component. Theyhypothesized that increasing the supply of ascorbatein the blood might increase the production or actionof the hyaluronidase inhibitor, and thereby restrainthe invasion of tumor cells into normal tissue (160).

Linus Pauling, working in California, considereda possible role for vitamin C in cancer treatment. Hefocused on the role of collagen in the process oftumor invasiveness, and noted that vitamin C wasrequired for the synthesis of collagen ( 158). Cameronand Pauling, collaborating in their research, sug-gested that increasing the intake of vitamin C wouldstimulate the synthesis of more collagen fibrils andthereby strengthen it, which in turn would helprestrain malignant cells from invading surroundingtissue and increase the body’s natural resistance tocancer (155). They later reported that a deficiency ofvitamin C was associated with a weaker intercellularmatrix, and suggested that malignant cells couldmore easily infiltrate local tissue and metastasize todistant sites as a result (159).

Cameron began administering high-dose vitaminC intravenously to some of his most advancedcancer patients at the Vale of Leven Hospital, LochLomonside, Scotland, in 1971. He reported that “themajority had gained a respite period of relativewell-being, comfort, and dignity” despite eventu-ally succumbing to their disease (153). In 1974,Cameron and a colleague reported tumorregressionsand subjective benefits in cancer patients treatedwith high-dose vitamin C (154). He and Paulingreported enhanced survival and improved well-being (improved appetite, increased mental alert-ness, decreased need for pain relievers, etc.) amongpatients who took high-dose vitamin C (156,157)(see discussion below for details of these studies).

Cameron and Pauling’s advocacy of the use ofvitamin C in cancer patients sets them apart frommainstream medicine, but they are by no means

alone in research into the biochemical and physio-logic effects of ascorbate in experimental systems.During the 1980s in particular, a wide range ofexperimental studies supporting a biological ration-ale for considering the role of ascorbate in cancerprocesses was conducted and reported in the litera-ture. Many of the studies focus on the role of vitaminC in preventing the development of cancer (e.g.,epidemiologic studies examining associations be-tween consumption of foods containing vitamin Cwith cancer incidence), reviewed and summarized inthe recent National Research Council (NRC) docu-ment Diet and Health (661). That document alsoreviewed experimental evidence concerning the roleof ascorbic acid in preventing the formation ofcertain carcinogens in the body and in enhancingcellular immunity. In addition, studies have exam-ined the effect of ascorbate in animal tumor models,which have produced positive, though somewhatvariable, results (342).

Claims

Cameron and Pauling state that high doses ofvitamin C are ‘‘helpful to virtually every cancerpatient and can be dramatically beneficial to afortunate few” (558). They claim that vitamin C‘‘not only increases the time of survival of thepatient but also leads to improvement in generalhealth and the feeling of well-being” (158). Theynote in their 1979 book that:

Giving vitamin C in large dosage to patients withadvanced cancer produces subjective benefit inalmost every patient by about the fifth day. Thepatient will claim to feel better, stronger, andmentally more alert. Distressing symptoms such asbone pain from skeletal metastasis diminish andmay even disappear completely . . . the patientbecomes more lively and shows more interest andalso eats more food, indicating that he has a betterappetite and is no longer feeling nauseated andmiserable. (158)

Vitamin C is generally advocated as a supportivemeasure, not a replacement for mainstream treat-ment. “With the possible exception of duringintense chemotherapy,’ Cameron and Pauling write,“we strongly advocate the use of supplementalascorbate in the management of all cancer patientsfrom as early in the illness as possible . . .“ (158) tomake patients more resistant to their illness and toreduce toxic side-effects of mainstream treatment.

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Cameron and Pauling’s 1979 book, Cancer andVitamin C (158), contains brief case histories ofpatients who had reportedly exhausted all main-stream treatment options. Responses to vitamin Ctreatment are categorized as: no response (20 percentof patients), minimal response (25 percent), retarda-tion of tumor growth (25 percent), cytostasis (the“standstill effect”) (20 percent), tumor regression(9 percent), and tumor hemorrhage and necrosis (1percent). The authors speculate that better resultswould be seen with earlier adjunctive use of vitaminC with surgery, radiotherapy, or hormonal treatment,although possibly not with chemotherapy (eventhough vitamin C is stated to protect againstunpleasant side-effects of the chemotherapy).

Pauling states that “a large body of scientificwork clearly shows that vitamin C plays a centraland most important role in developing and maintain-ing the immune system’ and that it is ‘‘a keymaterial necessary to this defense system’ (556). Hebelieves it acts by “strengthening the natural protec-tive mechanisms of the body and making them moreeffective” (158).

Potential Adverse Effects

Pauling states that large doses of vitamin C can begiven over long periods of time without seriousside-effects. No large case series or placebo con-trolled studies have revealed any adverse effects ofmegadoses of vitamin C other than looseness of thebowels. In the two studies conducted by the MayoClinic (discussed later in this chapter), vitamin Cmegadoses were found to be relatively nontoxic(236,622). Mild nausea and vomiting, the mostfrequent toxic reactions, which affected 40 percentof patients in the earlier study (236), were seen inidentical proportions of treatment and placebogroups.

The medical literature contains a few case reportsof toxicities that might have been associated withtaking large doses of vitamin C. One report sug-gested a risk of kidney failure in patients withpreexisting renal insufficiency (587,696). Vitamin Cingestion may also increase the risk of kidney stones(812), although no cases have been reported. It hasalso been argued that vitamin C may increase therisk of other types of kidney stone (e.g., matestones), and Stein and colleagues (833) noted that asingle 4 gram dose of vitamin C could increaseurinary excretion of uric acid, which might increase

the risk of developing urate stones. No cases of uratestones have been reported in the literature, however.

Several additional side-effects noted in a smallnumber of patients have been attributed to highdoses of vitamin C, although the clinical signifi-cance of these problems is unclear. These side-effects include “rebound scurvy” (a scurvy-likesyndrome) resulting from sudden cessation of high-dose vitamin C intake (8 18), gastritis (inflammationof the lining of the stomach due to the acidity ofvitamin C) (821), hemolysis (breakdown of redblood cells) (161), reduction of serum ceruloplasminactivity (which suggests interference with coppermetabolism) (290), and iron overload.

Attempts at Evaluating High-Dosein Cancer Treatment

Vitamin C

The first major study reporting clinical results ofvitamin C treatment in patients with advancedcancer was published in 1974 by Cameron andCampbell (154). They studied a series of 50 consecu-tive patients with advanced cancer who were underCameron’s care at the Vale of Leven Hospital inScotland and who, at the time, had no viablemainstream treatment options. Most patients weretreated with 10 g/day of oral ascorbic acid (a liquidformulation), and some began with intravenousascorbic acid for up to 10 days, at a usual dose of 10g/day (some received higher doses), then switchingto the liquid oral formulation.

The authors categorized the responses of patients’tumors into the following categories: no response,17 patients; minimal response, 10 patients; growthretardation, 11 patients; cytostasis (stopping ofgrowth), 3 patients; tumor regression, 5 patients; andtumor hemorrhage and necrosis, 4 patients. Inaddition, the majority of patients reported improve-ments in well-being. Other benefits included: reliefof pain from bone metastasis; in one patient, reliefof headache from a cranial tumor; reduction inmalignant ascites and pleural effusions; reduction inhematuria (blood in the urine) in patients withurinary tract cancers; reduced malignant hepato-megaly (liver enlargement) and reduced malignantjaundice in some patients; and halting or reversal ofrising erythrocyte sedimentation rates. The authorsalso claimed that these patients lived longer thanexpected, an outcome that cannot be reliably meas-ured in this type of study, which lacked a comparablecontrol group.


In a 1976 study (156), Cameron collaborated withLinus Pauling, reporting on the 50 patients from theCameron and Campbell study described above plus50 additional ascorbate-treated patients. The pa-tients were matched for certain characteristics (age,sex, and site and histologic features of the primarytumor) in a 1 to I0 ratio with patients not treated withvitamin C whose records were pulled from the filesof the Vale of Leven Hospital. All patients in bothgroups had been labeled as “untreatable” withmainstream treatment. A follow-up to this study waspublished in 1978 (157) in which 10 of the original100 ascorbate-treated patients who had rare cancerswere replaced with 10 patients with more commoncancers, for whom 10 good control “matches”could be made. A new control group was chosenfrom the same pool of hospital cases as for the earlierstudy (about half of the earlier control group wasalso in this group). In the 1976 and 1978 papers,comparisons of survival from: 1) frost “hospitalattendance,’ and 2) “date of untreatability” werepresented. In the later results, which were somewhatmore extreme than the earlier ones, a survival timefrom date of untreatability for vitamin C patients of293 days was reported, compared with 38 days forthe control patients. The survival times from firsthospital attendance were 681 days for treated and360 for control patients. Cameron knew that thesestudies were “less than perfect” methodologically,but he hoped that they would stimulate interestamong investigators with experience in clinical trialdesign to carry out randomized trials (153).

The experience of 99 Japanese cancer patients,classified as “terminal,” who received vitamin Cduring the period 1973 through 1977 has beenreported by Morishige and Murata (640), researchersaffiliated with the Linus Pauling Institute. The mostprevalent cancers were of the stomach, lung, anduterus, accounting for more than half the total.Patients were divided into two groups for analysis:‘‘low-ascorbate,’ defined as zero to four g ofvitamin C per day (44 patients), and “high-ascorbate,” defined as 4 or more g/day (14 patientshad 5 to 9 g/day, 13 had 10 to 29 g/day, and 28 had30 to 60 g/day). The practice in the hospital wherethey were treated had evolved toward larger doses,over the time period of this retrospective review, sothe low-ascorbate group was treated generally in theearlier years and the high-ascorbate group in lateryears.

Patients in the low- and high-ascorbate groupswere compared according to “survival times afterbeing pronounced terminal.” The low-ascorbategroup survived an average of 43 days and thehigh-ascorbate group, 201+ days (some patientswere still alive at the time the paper was written).The authors concluded that this report “may beconsidered to substantiate the observations reportedby Cameron and Pauling.” They further concludedthat “vitamin C seems to improve the state of wellbeing, as indicated by better appetite, increasedmental alertness, and desire to return to ordinarylife.” No information is given on how thesecharacteristics were assessed.

This study has similar drawbacks to Cameron andPauling’s, mainly that the groups compared were notcomparable on factors other than vitamin C. In thisstudy, the two groups were treated at different(though overlapping) time periods, making thecomparison more tenuous. The suggestive results ofthis study, however, reinforced the need for random-ized studies.

The First Mayo Clinic Study

Cameron and Pauling’s clinical studies, whichgenerated widespread interest among cancer pa-tients, prompted a series of three NCI-fundedrandomized trials of vitamin C. The first trial,conducted at the Mayo Clinic, enrolled 150 ad-vanced cancer patients; most (93 percent) hadprogressive disease after prior radiotherapy or che-motherapy and the rest were considered too ill toundergo mainstream treatment (236). About 40percent of the patients had colorectal cancer, whichwas also a prevalent type in Cameron’s studies.About 20 percent had pancreatic cancer, 10 percenthad lung cancer, and the rest had various other types.

Of the 150 patients randomized to receive vitaminC or placebo, 27 chose not to participate immedi-ately following randomization, before they hadtaken any of their assigned medication. The 63patients in the control group were given a‘ ‘compar-ably flavored lactose placebo. ’ The vitamin C dosewas 10 g/day, as recommended by Cameron andPauling, taken as 20 500-milligram capsules; thosetaking the placebo were also given 20 capsules perday. Treatment was continued until death or until thepatient was no longer able to take the oral treatment.Median survival for all patients in the study wasabout 7 weeks.


The survival curves for the vitamin C-treated andplacebo-treated groups were nearly identical. In theentire study population, there was one long-termsurvivor, a patient with metastatic pancreatic cancer,who had a massively enlarged liver, and jaundice.He had not responded to “many previous attemptsat chemotherapy,’ but had symptomatic improve-ment and some reduction of the jaundice, and wasalive 63 weeks after entering the study. This patientwas in the placebo group.

The two groups of patients taking vitamin C orplacebo were found to be similar in the percentagesof patients experiencing symptomatic relief andside-effects. About a quarter in each group reportedimproved appetite, and about 40 percent, improvedactivity levels. Improvements in strength and paincontrol were slightly greater in the vitamin C group(63 percent of patients) compared to controls (58percent), but this difference was not statisticallysignificant. More than 40 percent of both vitamin Cand placebo groups reported nausea and leg swel-ling, and between 20 and 40 percent reportedvomiting, heartburn, and diarrhea.

The authors concluded that vitamin C conferredno significant survival or symptomatic benefit on thepatients in the study. Noting that the patients in thisstudy differed, however, from those in Cameron andPauling’s studies in at least one respect-priortreatment with immunosuppressive chemotherapy--Creagan stated that it was impossible to draw anyconclusions about the possible effectiveness ofvitamin C in previously untreated patients. Theimmune systems of the patients in Creagan’s studymay have been more compromised (though notconsidered entirely unable of mounting an immuneresponse) than Cameron’s patients, few of whomhad received prior cytotoxic chemotherapy. Creaganand colleagues noted that their patients’ “earlierimmunosuppressive treatment might have obscuredany benefit” resulting from vitamin C.

The Second Mayo Clinic Study

The postulated interference of previous chemo-therapy on the action of vitamin C prompted theMayo Clinic investigators to undertake anotherrandomized trial, this time including only patientswith no previous chemotherapy (622). All patientshad advanced colorectal cancer, a type claimed byCameron and Pauling to respond well to vitamin C,and one for which no chemotherapy was recom-mended at the time of the study. These patients were

not considered eligible for surgery or radiation. Thedoses of vitamin C and placebo were the same as forthe first Mayo Clinic trial and were administeredorally in the form of 20 tablets per day. Nointravenous or oral liquid doses were used.

The endpoints in this trial were: survival afterrandomization, time to disease progression, objec-tive regression, toxicity, and changes in pre-trialsymptoms. One hundred and one patients wererandomized, one dropping out before taking any ofthe capsules, so the analysis is based on the 100patients who participated. Eight patients stoppedtaking the capsules or reduced their dosage for avariety of reasons. Three of these cases were knownto be related to adverse effects of treatment: onetaking placebo stopped because of intolerable side-effects, and the other two, who were taking vitaminC, reduced dosages because of gastrointestinalupset. All treatment was stopped at progression ofdisease, worsening of symptoms or performancestatus, or loss of body weight. As in the first MayoClinic study, side-effects were similar among thetwo groups, and not generally severe.

The study found no difference in time to progres-sion of disease and no increase in survival time inpatients treated with vitamin C; through the frost yearof followup, 49 percent of patients taking vitamin Cand 47 percent of patients taking placebo were alive,and there was a substantially larger proportion oflong-term survivors in the placebo group. Nopatients in the study had measurable tumor regres-sion. Eleven vitamin C-treated and 17 placebo-treated patients had some cancer symptoms at thebeginning of the trial; 7 and 11, respectively (aboutequal proportions), reported symptomatic reliefduring the trial.

The Third Mayo Clinic Study

According to one of the investigators in the firsttwo studies, a third, multi-center randomized trial,with similar treatment regimens to the first twotrials, was undertaken to address criticism that theearlier trials may have been inherently biasedbecause they were single-center trials (234). Theonly published report of this trial gives preliminaryresults in abstract form (859). The authors report nosurvival benefit, but “a possible but not significanttrend of improved appetite, strength and pain controlin the vitamin C group but no change in disability.’The median survival of all patients in the study was6.5 weeks. Little other information is given.

Chapter S-Pharmacologic and Biologic Treatments . 125

According to one of the investigators (235),analysis of this study was never completed becausethe early results were unpromising, consistent withthe results of the two previous studies. He believedthat the vitamin C question had been laid to rest anddid not consider it important to complete and publishfull details of this study.

Australian Study

A clinical trial of the effect of megadoses ofvitamin C on survival in cancer patients was begunin 1982 at the Royal North Shore Hospital inSydney, Australia (152,540). The results of the studyhave not yet been published, so only the design canbe described here (541). Using a double-blind,randomized prospective format, the study focusedon survival time among 99 patients with Dukes Dcolorectal cancer who had not undergone majorsurgery, radiotherapy, or chemotherapy for at least 4weeks prior to entry in the trial. Asymptomaticpatients were randomized to receive either vitaminC (10 g in liquid oral doses) or placebo (liquid oralcitric acid), while symptomatic patients were ran-domized to receive mainstream chemotherapy plusvitamin C or chemotherapy plus placebo. Thevitamin C or placebo mixtures were to be continuedin each patient regardless of changes in their clinicalstatus. The study protocol did not indicate whetherpatients were tested for compliance to the regimenby performing urine or blood analyses for ascorbate.According to one researcher who interviewed theprincipal investigator of the study, no survivalbenefit of vitamin C over placebo was found in thestudy (757). OTA was unable to obtain furtherdetails about the results of this study.

Methodologic Issues in Evaluations of Vitamin C

The explicit aim of the frost two Mayo Clinicstudies was to confirm or refute Cameron andPauling’s assertion that patients treated with mega-doses of vitamin C would live longer than expectedand would benefit from an improved quality of lifeduring their illness. The Mayo Clinic studies at-tempted to test Cameron’s treatment regimen inprospective, randomized, placebo-controlled studiesdesigned to generate unbiased conclusions abouteffects of the treatment. As discussed above, Moerteland colleagues found that patients who were ran-domly assigned to vitamin C had no survivaladvantage over patients assigned to placebo. Amajor consideration in interpreting Cameron andPauling’s positive results is the possibility that

“selection bias,’ a problem often encountered inretrospective, uncontrolled studies, was responsiblefor the apparent success of the treatment.

Cameron does not deny the existence of inherentflaws in his studies, but he argues that the MayoClinic trials did not adequately test his premise orreproduce his procedure, and therefore do not refutehis conclusions. Several important methodologicissues raised by the Mayo Clinic studies, some ofwhich have been debated in a number of publishedletters and articles (621,708,710,755,756), are sum-marized below.

Types of Patient Enrolled-In Cameron’s study,few patients were previously treated with chemo-therapy, whereas in the first Mayo Clinic study, themajority had previous chemotherapy or radiother-apy. Pauling argued that vitamin C acted by strength-ening patients’ immune systems and that those whowere previously exposed to cytotoxic chemotherapywere less capable of responding to the immune-enhancing effects of vitamin C than were patientswho had not had chemotherapy. Creagan andcolleagues argued that, although the patients wereirnmunosuppressed, they were not totally incapableof generating an immune response. They noted,however, that their results in pretreated patients didnot allow them to draw conclusions about thepossible effectiveness of vitamin C in previouslyuntreated patients. The second Mayo Clinic studyaddressed this issue by enrolling patients who moreclosely resembled Cameron’s patients-patients withadvanced cancer of the large bowel who werepreviously unexposed to cytotoxic drugs.

Method of Administration of Ascorbate—Cameron administered ascorbic acid either by intra-venous solution or by oral liquid doses. In Moertel’sstudies, patients were instructed to take 20 tabletsorally per day. It has been argued that higher bloodlevels of ascorbate could have been achieved usingintravenous administration compared with eitheroral form, but this was not measured in any of thestudies reported here. Also, since oral doses given inliquid form are generally easier to take than are 20pills a day, patient compliance with the oral tabletregimen could have been lower than with an oralliquid regimen.

Testing for Compliance to the Regimen—It ispossible that some patients in the Mayo Clinic trialsmay have taken fewer than the assigned 20 pills aday (which could result in lower vitamin C doses in


the treatment group) and that some patients mayhave self-medicated with commonly available vita-min C supplements outside of the trial (which couldresult in higher vitamin C levels in the placebogroup). One or both of these possibilities couldreduce the difference observed between treatmentand control groups and thereby make the detectionof treatment effects more unlikely.

Ascorbate concentrations in the body can bemeasured in samples of urine or blood. Such testingby urinalysis was not conducted in the frost MayoClinic trial, but was done to a limited extent in thesecond trial, where 11 patients were tested at onepoint: 5 patients assigned to the vitamin C groupshowed high urine ascorbate levels, and 5 patientsassigned to the placebo group had “negligible”levels within the range of normal controls for theassay. The other patient assigned to the placebogroup had an intermediate level, but the result wasattributed to problems with the assay in that case.

Cameron and Pauling argued that the levels ofascorbate measured in patients assigned to theplacebo group were higher than would be expectedfor cancer patients and that the testing was incom-plete and inadequate to verify compliance with theregimen, since only about 10 percent of the patientswere tested and then only once during the study.Moertel argued that their data, based on patientcompliance records’ and urinalyses, indicated thatpatient compliance with the regimen was very highand that self-medication among the patients as-signed to the placebo group did not occur. Testingfor ascorbate in blood, rather than urine, may haveprovided more meaningful data, particularly if suchtesting were done periodically during the study.

Duration of Treatment-It is common in clinicaltrials of cytotoxic agents for treatment to be with-drawn when patients show signs of tumor progres-sion. In Cameron’s studies, vitamin C was adminis-tered to patients in most cases until the time of death,since it was believed that vitamin C acts not by directcytotoxic action, but by strengthening patients’resistance to the disease, slowing the rate of tumorprogression, or increasing the patient’s ability toforestall death even in the presence of the disease. Inthe second Mayo Clinic trial, vitamin C or placebowas withdrawn when patients showed signs ofsignificant tumor progression or deterioration ingeneral or symptomatic status, since such signs were

taken to indicate treatment failure. Cameron andPauling argue that normal procedures for dealingwith cytotoxic drugs in clinical trials should nothave been applied to vitamin C.

In addition, Pauling believes that patients couldhave been harmed by the sudden cessation of highdoses of vitamin C, and that gradual reduction indose is a safer approach to stopping treatment.Pauling states that high blood levels of vitamin Ccan drop to below normal levels when intake isstopped abruptly (described as the ‘‘rebound ef-fect”) and that for a period of a week or two, verylow ascorbate levels can cause greater susceptibilityto infection, decreased resistance to the disease, orworsening of an existing condition (158,555). Ex-perimental evidence exists for a biochemical effectin the body of sudden cessation of high doses ofvitamin C, but it has not yet been shown that thesebiochemical changes lead to overt changes inphysical condition among cancer patients. InMoertel’s study, patients treated with and thenwithdrawn from vitamin C showed similar survivaltimes compared to patients in the placebo group, butother possible adverse effects of ascorbate with-drawal were not specifically reported.

Although the Mayo Clinic trials addressed someof the relevant questions pertaining to the effects ofvitamin C, they do not appear to have settled thecontroversy surrounding its efficacy in cancer treat-ment. In addition to the issues discussed above, theMayo Clinic trials did not fully address Cameronand Pauling’s claims that vitamin C improves thequality of life of advanced cancer patients in helpingto control pain and improving general well-being.Cameron and Pauling found easing of pain particu-larly in patients with bone metastasis; few patientsin the Mayo Clinic trials had bone metastasis.Among the issues noted above, only the issue oftesting patients not previously treated with chemo-therapy was addressed in subsequent evaluations.The other issues remain unresolved and lead todifficulties in interpreting the results of the twoMayo Clinic studies.

Cameron reported that he and Pauling submitteda collection of ‘‘best cases” to NCI for review inDecember 1989. According to Cameron, NCI issponsoring a symposium at NIH in September 1990,on experimental research concerning biologicalfunctions of ascorbate in relation to cancer (153).

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Pharmacologic and Biologic Treatments