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The Krebiozen Story

James F. Holland, M.D.

My definition of cancer quackery is the deliberate misapplication of a diagnostic or treatment procedure in a patient with cancer. Those who misapply diagnostic or treatment methods unknowingly may be honestly mistaken, inept, or fools. But the culprit who victimizes his fellow man with cancer, impeding the patient's access to available therapies or constructive investigation, all the while greedily enriching himself, is a quack, a criminal, a jackal among men who deserves the scorn and ostracism of society. Because human life is at stake, he must be controlled.

Background History

In about 1944, a Yugoslavian refugee doctor, Dr. Stevan Durovic, with his industrialist brother, Marko, established the Instituto Biologica Duga in Buenos Aires. In 1949, he brought to the United States a substance named kositerin, allegedly isolated from beef blood and supposedly useful in the treatment of high blood pressure. He came to Chicago to Dr. Roscoe Miller of Northwestern University, intending that kositerin be tested in high blood pressure. I have found nothing published on the results of this trial, in animals or in humans, and presumably it was negative.

Later on, Dr. Miller referred Dr. Durovic to Dr. Andrew Ivy, formerly at Northwestern and then the vice-president of the University of Illinois. Having come with kositerin from beef blood for hypertension, and not mentioning any other substance to Dr. Ivy on their first meeting, Dr. Durovic just happened to have available for him 2000 mg of material he stated came from the blood of horses that had been inoculated with Actinomyces bovis. Since later statements of Dr. Durovic indicate that only 1 mg of krebiozen, then called substance X, came from each horse, we are left to conclude that substance X was produced from 2,000 horses. It has been suggested, however, that it was a backup scheme produced by one man if kositerin was not a success. Dr. Durovic met Dr. Ivy and told him after their first meeting, when presumably each man took the measure of the other, that he had a substance X from stimulated horses. Dr. ivy found the idea attractive because it fit with the views he held on chemical substances that must be present in the body to control growth. Indeed, that basic concept -- that there must be internal control of growth in the body -- is not unique with Dr. Ivy, but is shared by many and has been the basis of much commendable research.

Invalid Research

Dr. Durovic told Dr. Ivy his substance was active and -- as Durovic wrote in 1961 in the magazine Today's Japan Orient/West -- that he had treated 12 dogs and cats with spontaneous cancer with krebiozen. Within 6 months, 7 of these animals were "cleared" of cancer and the remaining 5 were improved. He also stated that based on the activity in spontaneous tumors in dogs, the unit dose was established as 10 micrograms (µg). Dr. Ivy studied the protocols of the experiments with only 4 or 5 dogs and cats. At this time, Dr. Durovic had not told him the name of the mold or how he made the extract, since it was a "commercial secret."

Dr. Ivy testified at his recent trial that without repeating the experiments, without previously having heard of Dr. Durovic as a scientist, without having seen analyses or manufacturing records or without knowing what was in the ampules, except for Dr. Durovic's word, he proceeded. He said at the trial, "I will be the first next to Dr. Durovic, the first human being who has taken the medicine." He did so, and then he gave it to his associate Dr. Krasnow in late August or early September, 1949. After injecting himself, Dr. Krasnow, and one dog, and without it occurring to him (he testified) that the alleged substance X might be a hoax, Dr. Ivy injected the first patient on August 20, 1949. The clinical trial was continued by colleagues and physicians in the ensuing months. On March 27, 1951, Dr. Ivy decided to announce his findings, but he did not do this to a scientific audience. A press conference was held in the Drake Hotel to which the science writers of four Chicago papers, the Mayor of Chicago, two United States Senators, and potential financial supporters were invited, in addition to some doctors. Results on 22 patients were presented. Of the 22, 8 were dead, according to the table in a booklet distributed at the meeting, but in not a single instance was cancer listed as the cause of death. In each of the 8 instances, however, as was brought out at the trial, the patient died with and of cancer. Furthermore, 2 more of the 22 patients had died, one 7 days and one 2 days prior to the meeting, both from cancer. Dr. W.F.P. Phillips, a colleague of Dr. Ivy's, attended the meeting. His patient had died two days before, but he didn't mention it at the meeting. The description in the summary still stood as: "dramatical clinical improvement. Now working all day without opiates. Patient had to be carried, couldn't walk."

This remarkable description, uncorrected by Dr. Phillips or anyone else, described a twenty-week course from the onset of treatment to death. Dr. John Pick, a colleague of Dr. Ivy's, attended the meeting. The second patient was Dr. Pick's own wife, who had died seven days previously from breast cancer, but the description in the summary was allowed to stand "had much pain and mild icterus [jaundice]. Local and abdominal metastases have regressed; much improvement." This was a fifteen-week course from initiation of treatment until death. Dr. Ivy, who certainly knew of Mrs. Pick's death, did not see fit to mention it at the meeting. Dr. Ivy testified that because no one at the Drake Hotel meeting asked whether the patients listed were living or dead, he did not believe there was any obligation upon him as a scientist, doing a scientific investigation, to tell them they were dead. What kind of medical research, critical analysis, scientific reporting and integrity is this?

Immediate attempts to confirm the observations reported by Dr. Ivy were undertaken by cancer research centers and universities throughout the country. In 9 institutions, no evidence of activity was found. In the tenth hospital, preliminary observations suggested some activity, but on continuing the study and reappraising their entire work, the investigators found no evidence of any important effect on cancer and discontinued the study. A compilation of the multi- institutional negative data was made and reported in the Journal of the American Medical Association in 1951. Dr. Ivy had been counseled by a friend that his position was mistaken, that the data he had reported at the Drake Hotel press conference were not supportable, that no confirmation of findings was forthcoming from experts studying the material, and that he should withdraw or correct his erroneous position. But this course wasn't to be followed. Instead, the krebiozen backers howled conspiracy!" They said the American Medical Association and the American Cancer Society were conspiring to keep krebiozen off the market, either to delay the advent of effective cancer treatment or to force the Krebiozen Foundation to cut them in on the windfall which was to be expected.

Dishonest Reporting

Over the ensuing years, while the Foundation and those of like persuasion carried on a propaganda campaign of some persuasiveness to those grasping at a last straw, the number of patients treated with krebiozen mounted. In the report on krebiozen, 1962, published by the Foundation, they indicate that 3,300 physicians treated 4,227 patients. This is a striking finding, since 79.5% of doctors who did try krebiozen must have been discouraged after a single patient: they only treated one. Ninety-two per cent treated no more than two patients. A good and effective drug gets repeatedly used by doctors the country over. Why wasn't krebiozen reused by the doctors who prescribed it once? Cancer is common enough. It surely wasn't for lack of patients.

The Krebiozen Research Foundation, however, could find glowing success in the case records returned to them. They claimed objective improvement with decrease in tumor size in 61% of tumors of the brain and spinal cord, 70% of metastases to the brain, 48% of breast cancers. How then could physicians who saw such striking results be unmoved by their own success? Three cases will suffice to indicate the glaring inadequacy of critical assessment of patient records by the Krebiozen Research Foundation.

Dr. Ivy kept a research record on a Mr. Taietti, although he never saw the patient, who had returned to the Argentine. From time to time, Dr. Ivy received verbal reports from Dr. Durovic which he then entered into the record. In February, 1959 he entered, "The patient has remained well and a recent cystoscopy revealed a normal bladder." In 1961 he wrote, "Patient is well and active." Yet the U.S. Food and Drug Administration (FDA) FDA, in a display of long-distance diligence, showed that the 1959 and 1961 reports were false, because Mr. Taietti died of bladder cancer on July 12, 1955.

In 1962, California physician decided from what he had seen and read that krebiozen research was not a bona fide clinical investigation. He wrote to ask for krebiozen for a patient who had had a bilateral pneumonectomy. Bilateral pneumonectomy (the removal of both lungs) is incompatible with life. No questions were asked, however, and krebiozen was sent with the usual request for $9.50 a vial. When the physician didn't pay, he received rebillings at monthly intervals. When he reported this to the FDA, further investigation followed.

In March, 1963 another physician wrote deliberately stating his patient had had a bilateral total pneumonectomy, the unambiguous removal of both lungs. This is inconsistent with life and with common sense, but the Krebiozen Research Foundation, whose principal scientific consultant, Dr. Ivy, is a distinguished physiologist, sent 8 ampules of krebiozen and a bill for $76.

The falsification of Mr. Taietti's survival was apparently perpetrated by Dr. Durovic presumably to improve the results from krebiozen. Since Dr. Ivy accepted Dr. Durovic's word, at best he was duped and scientifically uncritical. The conduct of the Krebiozen Research Foundation, which was incorporated in 1951 by Dr. Durovic, his brother, Dr. Ivy and Dr. Pick, is totally discredited scientifically and morally in its merchandising technique of shipping krebiozen to individuals with no lungs with requests for "donations."

But some might say the foregoing are clerical errors; who suffered and from what injury? As an example, Orme Moritz suffered. She had read about krebiozen and thus refused surgery for primary cancer of the breast. She was accepted for study by the Krebiozen Research Foundation and for approximately one year, in 1958, received krebiozen. The records at the Krebiozen Research Foundation show her case at that time as "early operable." The tumor doubled in size while she was on krebiozen. Finally in September, 1958, after nearly a year's delay, Drs. Ivy and Durovic recommended a radical mastectomy. She died 10 months later of metastatic cancer of the lung from adenocarcinoma. of the breast. This is a sad tale of delay and avoidance of what might have been curative treatment because of unfounded hope that krebiozen treatment might make surgery unnecessary. How many similarly lost their chance for effective treatment because of krebiozen is unknown.

"Clamoring for a Test"

I believe the above case reports demonstrate the kind of activity conducted by the Krebiozen Research Foundation. Nonetheless, the most strident characteristic of the last two or three years of the Foundation's activities has been the "quest for a test." The National Cancer Institute has on several occasions indicated to the Foundation the conditions under which a clinical trial would be undertaken, which are the universal requirements, not concocted just for krebiozen.

None of these three prerequisites was ever met by krebiozen or by the Foundation, and in the course of turning up information, much appeared that deterred a test procedure. I shall detail these factors below, but want now to indicate what the Krebiozen Research Foundation means by a fair test. I quote from a letter signed by Drs. Pick, Ivy, and Durovic to a reporter for the New York Post on October 3, 1960:

1. All details of the design and administration and bases of evaluation of the double-blind test shall meet with the approval of Dr. Andrew C. Ivy and the Krebiozen Research Foundation.

2. Such details, noted above to be worked out with the advice and participation of Dr. Andrew C. Ivy or his appointees, must assure that Dr. Ivy or his designated medical representatives, which he can appoint according to his judgment of the situation, will have free and continuing access at all times to observe the patients and their treatment. All records pertaining to their treatment as well as the right to record in the clinical files any disagreements or evaluation of the effect of Krebiozen in the patients or any other omissions or commissions.

3. Within 8 weeks after conclusion of the clinical tests, the results of the evaluating committee shall be published by the Journal of the American Medical Association. If there is not unanimity of opinion then any difference of opinion among members of the evaluating committee shall be published in the same publication simultaneously. It is an explicit condition of our acceptance of the proposal that Dr. Andrew C. Ivy and/or his appointee shall be guaranteed a full publication of the observations and conclusions regarding this test in the same publication simultaneously with that of the evaluating committee members, so that if there is difference of opinion, the scientific community shall have the opportunity to study our views.

4. The New York Post shall be an observer of all negotiations for implementing its proposal and shall at the conclusion of the test report any or all differences of opinion, if any, regarding results. The New York Post also agrees to report at any time during the clinical test, upon the request of any party, any claims of deviation from the agreements made among the parties to the test."

Such stipulations are rarely seen in the course of bona fide medical research. I doubt the National Cancer Institute needs advice from the Krebiozen Research Foundation or its members or partisans, or from a newspaper, on how to conduct fundamental or clinical cancer research properly.

In the course of the legal and political wrangles that have marked the history of krebiozen, the Krebiozen Research Foundation gave to the FDA and the National Cancer Institute records of 504 patients who were supposed to have been among the best in the Foundation's file. The FDA did a thorough job of following up the data on these patients seeking out hospital and doctor's records, pathology reports, death certificates and more complete data than the unsubstantiated records of the Krebiozen Research Foundation. An expert committee applied the usual criteria for evaluation of cancer response. Of the 504 patients, only 288 case records were found adequate for interpretation. Of these, two patients had tumor regression. In 13 other instances, doubtful effects were seen which were either incompletely substantiated, associated with other treatments, or unconvincing in the significance of the effects since early death or simultaneous growth of other tumors occurred. This experience might occur in a large sample of cancer patients, spontaneously. The 24 panel members recommended against clinical trial.

After the full-scale investigation of the Krebiozen Foundation was undertaken by the FDA, the clinical records of the Foundation were photocopied and searched for evidence of objective anti-tumor effects. 4,307 patients with clinical cancer were treated with krebiozen before 1962. Sixty-eight cancer clinicians who convened in small groups over a long period in Washington to review the records found 2,781 records unacceptable for evaluation because of overlapping treatments, lack of proof of diagnosis, inadequate documentation, and similar standard prerequisites for judgment of effect. There were, however, 1,526 patients whose records were considered acceptable for a determination of effect, and of these 1,526, 3 patients were found in whom it is possible, but not certain in each instance, that partial regression of the tumor may have occurred. One remission was of two weeks duration, one remission a reduction in size of a primary breast cancer from which large biopsies were taken during the treatment, and in the third, a 50% decrease in size of a lymph node approximately 3/4 inch in diameter although a co-existent cancer seen in the chest x-ray was not restudied by film.

Laboratory Analysis

Thus, the unusual circumstances existed that a great number of mutually complementary data existed which made the "quest for a test" ring hollow. The misleading data presented at the first occasion of the introduction of krebiozen, the negative results found by the academic institutions and investigators who had studied it in its early days, the failure of 79% of physicians who treated a patient to treat a second patient, and on review of the data of the Krebiozen Research Foundation itself by competent physicians and scientists, the failure to find evidence of reproducible or significant benefit in the 1,526 patients with interpretable records. Any one of these data would be adequate basis for reluctance to undertake a clinical trial. Taken together, they are overwhelming.

Yet, the capstone is still to come. Samples of krebiozen were reluctantly provided on two occasions to the National Cancer Institute, and on one occasion to the FDA in the form of dry powder. In September, 1961, the material was labeled as pure krebiozen, and this identification was confirmed and reiterated as late as March, 1963. All three samples, on analysis by the FDA, consultants from several universities, and by studies at the National Cancer Institute proved to be creatine monohydrate, a normal constituent of muscle and a common laboratory compound purchasable for $.30 a gram, approximately $10 for a 1-ounce bottle.

As you might expect, the Krebiozen Research Foundation had an answer for this set of observations, too. They implied that the FDA had misinterpreted the data and overlooked the important facts --that the creatine monohydrate was just a contaminant in what had previously been labeled pure krebiozen, and that trace quantities of real krebiozen were there.

It may be of some significance at this point to mention that in the course of bona fide considerations of a test on krebiozen, before all this additional information came to light, the National Cancer Institute indicated that ample amounts of the material would be needed for any study. Dr. Durovic stated krebiozen could be provided at a cost of $170,000 a gram, which by calculation is $170,000,000 for the kilogram ordinarily consumed in preliminary study of a drug, unless of course quantity reductions were allowed for a bulk purchaser. This 500,000-fold markup is not the worst of the story, however.

Indeed, the samples of dry material provided to the FDA and the National Cancer Institute were creatine monohydrate, but creatine monohydrate is insoluble in mineral oil. You will recall that Dr. Durovic had stated that he put 10 micrograms in each milliliter of mineral oil as the krebiozen unit. The FDA analyzed krebiozen of ampules which patients had obtained prior to 1963, during 1963, and in 1964. Ten micrograms in one milliliter of mineral oil would be approximately a 1% solution. No material was found in a concentration of 1%. Indeed, extensive tests were made using methods such as thin layer chromatography, gas chromatography, and other microanalytic and concentrating techniques capable of detecting 100 times lower concentrations than that said to be present by Dr. Durovic. At sensitivities which would have found 1 part in 10 million, not 10 µg per ampule, but 1 µg in 10 ampules, nothing was found in the mineral oil. In 1963, l-methylhydantoin and amyl alcohol were found in the mineral oil. This is easily explained by the necessity of heating creatine monohydrate in amyl alcohol in order to get the compound into solution, and this process of heating changes creatine monohydrate into l-methylhydantoin. FDA found in its investigation that from 1949 to 1959 all ampules of krebiozen analyzed had nothing but mineral oil in them, and in 1964, again all ampules tested had nothing but mineral oil. This leads to the inference that krebiozen, as such, was a fairy tale, a nonexistent fabrication in mineral oil which sold for $9.50 an ampule.
The strengthening of the FDA after the thalidomide tragedy allowed it to require that all investigational drugs be subject to registration. A plan of investigation must be filed, investigators competent by training and professional standing who would conduct the research must be identified and registered, and complete disclosure of manufacturing processes and standards of reproducibility and purity must be provided to obtain FDA clearance for investigational use. All investigational drugs must conform. Immediately prior to the deadline, Dr. Stevan Durovic made the necessary filings with the FDA for krebiozen, but one month later notified he the Secretary of the Health, Education and Welfare that he was withdrawing his request for an investigational new drug application.

Financial Considerations

Now why would all this happen? Cancer quackery is lucrative. Dr. Stevan Durovic is under indictment for evasion of income tax in the amount of $904,907 for the years 1960, 1961, and 1962 alone. Government investigators had shown at his trial that large sums of money were withdrawn from the bank accounts of the Promak Laboratory -- money derived from the sale of krebiozen and sent to Canadian and Swiss banks by Dr. Durovic. There was apparently a leak that a tax claim would be filed against him shortly after the trial, and a watch of international airports was undertaken lest he try to leave the country. But Dr. Durovic did manage to get out. He told a Chicago reporter that he had flown nonstop from Chicago to London and then traveled to Paris. Internal Revenue agents told a Washington correspondent, however, that Durovic had flown from Miami to Bimini in the Bahamas, from Bimini to Nassau, from Nassau to Bermuda, and from Bermuda to London and Paris. This would indeed seem like a serpentine course for a man heading to Paris only because of illness, as Dr. Durovic stated. Currently, he is reported to have moved on to Switzerland amid news reports that he is undergoing treatment for tuberculosis. Dr. Durovic has stated publicly in the newspapers that he does not owe the United States Government a single penny and that he will come back to Chicago to face the charges as soon as his treatment is over. We all know that the rest treatment for tuberculosis sometimes may take many years. It is of interest as an aside that one of Durovic's attorneys has filed a suit seeking $11,787 in unpaid legal fees.

The government has a tax lien against Marko Durovic for more than half a million dollars for taxes which the Internal Revenue Service contends were not paid in 1954-1958.

And what of the finances of Dr. Ivy? He attributed his deposits of $172,722 in a checking account in 1957 to his take-home university pay, cashing in of insurance policies and to in-and-out sales in the stock market, buying and selling stock several times and repeatedly depositing the money made from the sales. The records of his two brokers, however, although reflecting stock purchases in 1957, and a few sales, show that the proceeds of sales were reinvested and not remitted to Dr. Ivy or his wife. This difference in sworn testimony has not yet led to legal actions of which I am aware.

Criminal Prosecution Unsuccessful

Now that is nearly the end of the krebiozen tale, except when Dr. Ivy, Dr. Durovic, and Mr. Marko Durovic were brought to trial for violations of FDA regulations and fraud before a jury of laymen in Chicago, they were acquitted. Despite the evidence of the lack of a component in the mineral oil in the early and recent ampules, and of the presence of l-methylhydantoin in 1963, despite the records on patients with bilateral pneumonectomies, the record of a dead patient reported to be alive and well for 6 extra years, the evidence of inactivity in the 504 patients, and much more data, they were acquitted. The acquittal came after 8 days of deliberation during which time the jury reportedly advised the judge several times that it was hopelessly deadlocked.

Since the trial had no bearing on the scientific issues, as distinct from the legal, and no compliance with regulations for new drug investigation has been accomplished, the FDA does not permit the interstate distribution of krebiozen, however.

Government Vigilance Still Needed

One might make suggestions for trials of this kind for the future, since cancer quackery regrettably is not dead and repetition -- particularly on an intrastate basis -- is virtually assured from time to time. The Government should pick a single or at most a few charges rather than the multiple citations that were handled in the krebiozen trial. It seems unnecessary that the entire history of a quackery promotion be put on trial. One or two glaring instances which prove that the accused was deliberately misapplying diagnostic or treatment procedures to patients with a specific disease or diseases would suffice. Justice could then be served and the quackery deterred. Thus the trials would not last for months, and if we are obliged to use lay juries, their attention could be focused on major topics and concepts. I am not sure that lay juries are the best way to handle actions which involve matters of cancer research or other controversies of similar scientific complexity. Perhaps a blue-ribbon jury or a panel of judges such as sit in Appeals Courts and Supreme Courts would better be able to sift the facts. As our society becomes scientifically more complex, it may not be realistic to expect an average peer jury adequately to comprehend scientific data relevant to each proceeding.

Secondly, what is sought in a trial of this kind is justice. A change of venue from the home town of an indicted individual where newspaper coverage has been extensive might remove him from prejudice of his fellow townsmen, which just as often as not, might be adverse. Certainly, a jury in some other city in Illinois or the United States might have had less prior association with the news and doings of the defendants in the krebiozen trial and thus have less subconscious basis for any bias.

The FDA, with its added support, and the competence which this support will allow, should become a powerful guardian of the public health. Since it is composed of humans like the rest of us, it can make mistakes. But surely the FDA has been unjustly accused of the most venal activities while performing a fine public service in its conduct of the krebiozen investigation.

The FDA should deal in science and science deals in facts. The interpretation of these facts are opinions. The FDA, like other governmental science agencies, therefore, should thus have periodic review by nongovernmental expert consultants.

But by and large the facilities of the FDA and its skills, and mission are such that it will be the major factor in the United States in determining drug safety and efficacy. With alert and professional direction, the FDA should be able to eliminate the hazard of cancer quackery in interstate commerce.

And what about the states? Since the states, with possibly few exceptions, can hardly afford the extensive laboratory and professional staff of the FDA, it might be well that they routinely subscribe for intrastate use to FDA regulations for interstate use. I believe no state will wisely relinquish all prerogatives for exceptions, however, should a State Health Department find itself, based on fact, in substantial disagreement with FDA policy. But this is a retreat position, a legal safeguard for the states, and it is likely that most State Health Departments would welcome the enabling legislation which allowed them to adopt FDA regulations on an ad hoc basis for intrastate regulation of drug manufacture and use.

We must remember that the great tragedy of the krebiozen myth is that it is a myth. Cancer still maims and kills. Its control will require the best of science. There are too few people in the world qualified and able to pursue cancer research to dissipate their energies on negative leads. Society asks for progress and results against cancer and it will gain them through the evolving discoveries of science and medicine. The cancer cell is deaf to oratory and lawsuits. Our concerns must be to continue a cancer research program of wide scope, imaginative creativity and unquestioned integrity. Important advances in understanding the treatment of cancer with chemicals have been recorded, but they are largely unknown to society because of the clamor surrounding krebiozen. The challenge of cancer is too important and pervasive for society and the scientific community to squander any more time on false lures or mineral oil.

___________________

Dr. Holland is Distinguished Professor of Neoplastic Diseases and Director Emeritus of the Derald H. Ruttenberg Cancer Center, Mount Sinai Medical Center in New York City. He is also senior editor of Cancer Medicine -- a massive medical textbook now in its 4th edition. This article is adapted from his presentation to the Third National Congress on Medical Quackery in Chicago on October 7, 1966.

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This article was posted on February 29, 2000.