 | An excerpt from Dr. Golem How to Think about Medicine Harry Collins and Trevor Pinch Alternative Medicine:
The Cases of Vitamin C and Cancer The most scientifically rigorous means we have for assessing the claims for the majority of medical interventions are randomized clinical trials (RCTs); they are legally mandated in many countries. They are rarely applied to alternative medicine. This is a problem which Dr. Stephen Straus, who was appointed director of the National Center for Complementary and Alternative Medicine (NCCAM) in 2000, set out to address. Straus announced his intention to apply “the same designs that are used in definitive studies of conventional medicine” to alternative medicine, including the use of random double-blinded trials. “Since gaining acceptance for alternative medicine is the objective,” he said, “it is important to convince physicians, scientists, and pharmacologists…that studies have been done well and that the answers are as definitive as possible.” In this chapter we shall focus on one example of an alternative cure evaluated in just this painstaking way—the claim that large doses of vitamin C can cure cancer. Linus Pauling and the Vitamin C Cancer Controversy We would probably have never heard of the claim that large doses of vitamin C (ascorbic acid) could cure cancer if the claim had not been associated with the name of Linus Pauling. One of the world’s most famous scientists, Pauling, who died in 1994, won the Nobel Prize in Chemistry in 1954 for his fundamental work on the nature of the chemical bond and the 1962 Nobel Peace Prize for his antiwar crusades. Pauling has many discoveries to his name, but was famously beaten by Watson and Crick in the race to find the structure of DNA. Pauling’s championing of vitamin C in 1970 is often taken to signify the start of his decline as a scientist. But this is to do Pauling a disservice. His work in the area continued to follow the reductionist tenets and experimental methods of molecular biology, and ironically his vitamin C cure smacks of the medical “magic bullet” so decried by holistic medicine. Pauling’s advocacy of vitamin C can be traced to his own earlier acclaimed discovery that the genetic disease sickle-cell anemia is caused by an inherited molecular defect. He reasoned that all humans suffer from another genetic disease, hypoascorbemia, or vitamin C deficiency of the blood. He suggested that at some stage in their evolution humans must have lost the ability to synthesize this essential nutrient through a mutation in their DNA. Pauling generalized this radical approach toward diseases and its causes in 1968 by proposing a new branch of what he called “orthomolecular” (literally “right molecule”) medicine that he defined as “the achievement and preservation of good health and the prevention and treatment of disease by regulating the concentration of molecules that is normally present in the human body. Important orthomolecular substances are the vitamins, especially vitamin C.” There is no doubt that this intrusion by a nonphysician into the realm of medicine caused great furor among the medical profession. Pauling’s ideas came under attack from psychiatrists, physicians, and nutritionists as unscientific and unfounded. Pauling was forced onto the defensive and was unable to interest even his colleagues at the Stanford Medical School in his research plans for this new area of medicine. In 1973 he resigned from Stanford to set up his own independent research institute for orthomolecular research. The sociology of fringe sciences shows how scientists can be pushed further and further toward marginal institutions as they lose their resource base within orthodox science. Pauling soon found himself unable to obtain major research grants from the NSF and NIH—the standard sources—and was forced to turn for funding to the very holists and alternative medicine groups he was loathe to associate with. Unsurprisingly, this was taken to confirm the critics’ suspicions that Pauling indeed was a closet holist and alternative medicine enthusiast. Pauling first advocated vitamin C as a cure for the common cold. In his 1970 book Vitamin C and the Common Cold, he suggested in passing that vitamin C might also prevent or cure cancer (he was given the idea by vitamin C enthusiast and industrial chemist Irwin Stone). The famous “War on Cancer” launched by President Nixon was just getting started, and cancer had become the public health problem in the United States. It was the second leading cause of death (only heart disease killed more Americans), and accounted for approximately one in five deaths with over a million new cases of cancer treated each year. Dr. Ewan Cameron The research on vitamin C and cancer was actually carried out by Pauling’s collaborator, a Scottish surgeon, Dr. Ewan Cameron. In his well-received 1966 book, Hyaluronidase and Cancer, Cameron set out a new approach to cancer based upon controlling its invasiveness rather than destroying cancer cells. Cameron suggested that an enzyme known as hyaluronidase was released by cancer cells and that this modified the “ground substance,” the jelly-like material in which all cells are embedded. The malignant cells could proliferate and penetrate the ground substance and invade surrounding tissues. He proposed that in healthy cells the invasion was kept in check by the existence of a physiological hyaluronidase inhibitor (PHI). Malignant cells and their descendants continuously produced hyaluronidase, and the excess of this enzyme overwhelmed the counterbalancing PHI. Cameron could explain many features of the development of cancer with his PHI idea. Furthermore if PHI could be identified, it could be used in treatment to neutralize the malignant capacity of cancer cells. Cameron’s long-term goal was to persuade a large drug company to isolate and define the PHI substance and prepare it in a form suitable for clinical use. With the added impetus of the war on cancer, U.S. researchers became interested in Cameron’s new approach. Cameron himself began treating terminally ill cancer patients with a cocktail of hormones—at the suggestion of a U.S. researcher (not Pauling) he added megadoses of vitamin C. His hope was that the drugs would help render the host ground substance more resistant to malignant invasion and thereby help control cancers. Cameron first wrote to Pauling in 1971 with his initial results. He described them as “very encouraging indeed.” He felt that the vitamin C had made such a difference “that I have omitted the hormonal regime altogether and am trying to devise a suitable therapeutic program using ascorbic acid alone.” Cameron even wondered whether the structure of PHI might actually include ascorbic acid molecules. If this were the case, given sufficient ascorbic acid, the body would be capable of synthesizing its own PHI. Cameron was confident enough in his theory and early results to suggest to Pauling that “we could soon cure cancer.” He knew his approach was controversial because it said, in effect, that the cure for cancer had lain under the noses of specialists for years in corner drugstores and local health food shops. Eventually he planned to publish his findings in the UK medical journal the Lancet, and he asked Pauling to help publicize the theory and put it on a “sound scientific basis.” Pauling, who at this stage of his career was still at Stanford and trying to interest his colleagues in testing vitamin C on cancer patients, was excited by what Cameron had already achieved and impressed by the new therapeutic successes. The Vale of Leven Study Cameron at this point had only seven weeks worth of data on eleven patients. He had administered five grams of vitamin C intravenously for five to seven days, followed by two grams administered orally. Once he saw that patients could tolerate these doses, he had increased them to daily intravenous fusions of ten grams for a week or more followed by daily oral doses of eight grams. What did Cameron expect these massive doses of vitamin C to achieve? He repeatedly stressed that he did not expect to cure cancer, but rather to control it. In other words, the cancer cells would be disarmed and prevented from spreading but would not be killed. Thus, malignant masses would remain even if the treatment was successful, but it was hoped that further growth would be arrested. Preexisting tumors would become benign and isolated, and secondary features of cancer like pain, weight loss, and hemorrhage would be brought under control. His results already indicated that high doses of ascorbic acid could be tolerated with no ill effects and that some of the more distressing symptoms in these terminal patients could be alleviated. In one patient he thought there was some evidence of tumor regression. The results, although inconclusive, showed some promise for the new therapy. Pauling urged Cameron to set up a larger and more systematic study at the Vale of Leven Hospital, where Cameron worked, and suggested that he employ larger doses (as much as fifty grams per day). As Cameron pondered whether to launch the larger study, he encountered a clinical setback—three of his patients from the initial group who had been doing well suddenly died. He felt that despite the setback there were some encouraging signs that the new treatment had helped ease their disease and that he should continue because the theoretical argument in favor of treatment with ascorbate justified its therapeutic evaluation. With the aid of the princely sum of 4,000 pounds from the Scottish Home and Health Department and 1,000 pounds from the Vale of Leven Hospital, Cameron embarked on a larger pilot study at the beginning of 1973. As expected, the Lancet rejected his paper detailing his initial results. Now he urged Pauling to help publicize his work in the United States. Pauling readily agreed. Using his privileged position as a member of the National Academy of Science, he tried to publish a joint paper with Cameron on the theoretical argument for the treatment of cancer with high-dose vitamin C in the Proceedings of the National Academy of Science, where Pauling thought he had guaranteed publication rights. The PNAS rather surprisingly rejected the paper on the grounds that they did not publish speculative therapeutic suggestions in such a highly emotive area as cancer (rejecting the paper broke the Academy’s own publication rules). Pauling protested, and in the face of the ensuing publicity the editor of the international journal of cancer research Oncology (himself an advocate of vitamin C treatment) agreed to publish the paper sight unseen. Meanwhile Cameron and his colleagues continued with their pilot study, settling finally on a dose regimen of ten grams per day intravenously for up to ten days followed by ten grams per day orally indefinitely. Cameron was convinced that this was “a valuable remedy in the great majority of patients with terminal cancer.” He was achieving tumor retardation and prolongation of life in many patients and, perhaps most important of all, he felt he was improving their quality of life. Cameron described for Pauling the “standard response” in his terminally ill patients. They entered into treatment dying from the relentless progress of their tumor, usually heavily sedated and steadily losing weight. On receiving vitamin C they initially showed no improvement and in fact sometimes got worse, which for Cameron was evidence ruling out the placebo effect. About a week after commencement of therapy, patients began to experience a feeling of well-being, recovered their appetites, and began to gain weight. Bone pain from skeletal metastases eased often to the extent that patients could begin to come off their heavy sedation regimes. Other complications of advanced cancer, such as malignant effusions, respiratory diseases, and jaundice were alleviated or arrested. He reported that standard biochemical indices of malignant activity, instead of rising relentlessly, remained stationary and in many patients gradually fell. This “standstill” phase was of variable duration: in some patients it was temporary, while in others it continued for weeks or months before the patient suddenly succumbed to death. The manner of death was also unusual in Cameron’s experience. Instead of the characteristic long, drawn-out decline, the patients went through a “whirlwind” reactivation of their cancer and usually died within a few days. These findings were so encouraging that Cameron started to compile a paper detailing fifty patient histories. Throughout he was concerned with the ethical aspect of the research. Vitamin C was only to be administered to patients who were deemed untreatable in the opinion of at least one other of the attending physicians. Cameron became ever more convinced that vitamin C brought benefits to patients in terms of quality of life, and this, if nothing else, was “good doctoring.” His views were reinforced after visiting the United States for the first time in 1973 (where he also first met Pauling). There he encountered the relentlessly aggressive surgery, irradiation, and chemotherapy regimes that were the standard treatment at the time. He wrote to Pauling, “I do not know what kind of 'results’ they are achieving but they are certainly causing much mutilation and human suffering along the way.” Armed with a draft of Cameron’s paper and a set of x-rays showing tumor regression and bone growth in one fifty-five-year-old man who had received no more treatment than ascorbic acid for six months, Pauling tried to persuade his colleagues at Stanford to initiate trials of vitamin C. After failing to convince them, he turned to the director of the National Cancer Institute (NCI) in the hopes of arranging a double-blind control trial. Again he “failed nearly completely” as the NCI officials responded that there would have to be convincing evidence in animals before any trials were begun with humans. Pauling and Cameron felt the animal trails were unnecessary because they had already shown humans could absorb large doses of vitamin C without ill effect, and in any case results in animals would be misleading, since most animals synthesize their own ascorbic acid. Eventually Cameron and Pauling conceded that if they were going to embark on a big trial treating cancer patients under more favorable circumstances when their cancers were less advanced, they would need to undertake animal trials first. Cameron and Pauling slowly started to interest the wider biomedical community, if not the cancer specialists, in their work. In view of the prevailing hostility, they now played down the theoretical claims for PHI and instead stressed vitamin C as a supportive cancer theory—one that could help with containment. They published several papers (but all in scientific rather than medical journals) and in March 1974 were invited to present their findings to the famous Sloan-Kettering cancer institute that at the time was undertaking trials of the controversial cancer drug laetrile (made from apricot pits). Sloan-Kettering was under increasing public pressure to avail itself of a wider range of cancer therapies, and so agreed to undertake some initial observations of vitamin C. Cameron had one spectacular case in his support: that of a forty-five-year-old truck driver who had been diagnosed at another hospital with a lymph cancer known as reticulum cell sarcoma. Because of an administrative delay this patient had not been given radiotherapy and chemotherapy and had instead been fed intravenous vitamin C almost as a stopgap measure. Much to the amazement of the treating physicians, within two weeks the patient became clinically well and able to return to work. He then stopped taking his vitamin C, as he seemed to be cured. What made the case so convincing was that later the man relapsed and again began treatment with vitamin C alone and again responded well and was cured (and was then continuously taking large daily doses of vitamin C). Of course, cancer cases occasionally undergo spontaneous remissions, but in this case the remissions had corresponded exactly with the vitamin C treatment, and Cameron knew of no other cases in the literature where a patient with this kind of cancer had undergone two spontaneous remissions. He considered this so remarkable that he published a paper on this one case alone. The Sloan-Kettering Study In January 1975 the first report of Sloan-Kettering’s observations on sixteen patients treated with vitamin C became available. The case histories showed no sign of any benefit. Replication would be a continuing problem. Cameron and Pauling believed Sloan-Kettering had been unable to replicate their results because they had not selected the right group of patients and had not started treatment with ascorbic acid early enough. The cancers in the Sloan-Kettering patients were all extremely advanced and had already been extensively treated with radiation and chemotherapy. Readers familiar with the earlier books in the Golem series will realize that this is a classic instance of a contested experimental outcome, or what we call the “experimenters’ regress.” How do we settle whether vitamin C is a cure for cancer? The answer is we do an experiment. But whether vitamin C works as a cure for cancer depends on the skills of the physicians in administering and evaluating the treatment—in other words, it depends on their skills at “experimenting” with this new cancer therapy. If vitamin C does indeed cure cancer, then Cameron has the requisite skills and Sloan-Kettering does not. If vitamin C does not cure cancer, then Sloan-Kettering are the skilled practitioners. How do we find out who has the requisite skills? The answer is we do an experiment to see whether vitamin C cures cancer, and so on. With no independent measure of skill available, the results are indecisive and we are caught in a regress. Historical Control Matching To try to bolster the credibility of the Vale of Leven results Pauling had been urging Cameron to carry out a double-blind controlled study. Although common in the United States, these studies were seen as more dubious in Britain because it was considered unethical to deny treatment to a group of patients in the control limb of the study (the same issue that later in the United States became a core concern for AIDS activists). Instead Cameron set about searching the Vale of Leven Hospital records for a matched group of control patients—those who had tumors of similar types and similar histories but who had undergone conventional treatment with no use of ascorbic acid. This technique is known as “historical control matching” rather than the prospective control matching used in a full clinical trial. After much technical debate about the adequacy of the randomization procedures used (with a matched control it is still desirable to randomly select the patients to be included in the study, and in this case, since some had been assigned by Cameron, the study was not properly blinded), Cameron was able to publish the paper, again with Pauling’s help, in the October 1976 issue of the PNAS. The paper showed a four-fold enhancement in survival rates over the matched control group. The paper generated much publicity, and New Scientist got wind of its controversial findings. A few days later a BBC broadcast was aired. Soon the British national press picked up the story, followed by favorable stories in the New York Times and Washington Post. Cameron, alarmed by all the publicity, soon found himself overwhelmed by letters from families of desperately ill cancer victims. There was also a personal edge to the story. Pauling’s wife, Ava, had just been diagnosed with stomach cancer and had undergone surgery. She had decided to refuse backup radiotherapy or chemotherapy and was reportedly on the high-dose vitamin C regime of ten grams a day. Cameron and Pauling now felt they had turned a corner. A leading cancer journal, Cancer Research, invited them to submit a review article; slowly other cancer researchers were starting to pay attention. Pauling and Cameron applied to the NCI for a large grant for more randomized control studies, including animal studies. Pauling lobbied assiduously and was helped by a public statement from Dr. Theodore Cooper, assistant secretary for the Department of Health, Education, and Welfare, who said he thought megadoses of vitamin C were valuable in controlling both the common cold and malignant diseases, and that he himself took large doses. But the news was not all good. Sloan-Kettering decided to abandon its trial of vitamin C after treating twenty-three patients with no obvious response. Pauling again pointed to differences between the Sloan-Kettering treatment and that of Vale of Leven. Cameron and Pauling also offered a new interpretation of the negative results. They felt that the patients might have suffered from something they called the “rebound effect.” This was a sudden reactivation of tumor growth produced by curtailing large doses of vitamin C (as had occurred with the truck driver case). Sloan-Kettering in any case was receiving adverse publicity over its studies of laetrile, and decided to withdraw altogether from controversial cancer treatments. The debate with Sloan-Kettering was, however, a taste of the much sharper debate that was to ensue when the prestigious Mayo Clinic entered the fray. Pauling’s application to the NCI was eventually turned down. The reviewers argued that the Vale of Leven study had not been properly randomized (the same as earlier criticisms of the study). But because of Pauling’s continued protests and public criticism, the director of the Division of Cancer Treatment of the NCI, Dr. Vincent DeVita, agreed to approach one of the premier cancer investigators, Dr. Charles Moertel of the Mayo Clinic, to undertake a proper double-blind controlled clinical trail. Moertel, who was a specialist in such trials, agreed. Located outside Rochester, Minnesota, the privately endowed and enormously prestigious Mayo Clinic, founded by the Mayo brother surgeons in the 1880s, is synonymous with scientific medicine at its very best. Moertel was a leading cancer researcher, and it was he who had led the NCI-funded team that had officially closed the books on laetrile. His verdict on vitamin C was likely to be similarly definitive. The First Mayo Trial Pauling wrote to Moertel in advance of the trial and stressed the importance of using patients whose immune systems were not compromised by earlier courses of radiotherapy and/or chemotherapy. He also stressed the need to continue with the vitamin C regime for a long period—based on the famous truck driver case where early termination of the vitamin C treatment had meant that the cancer returned. In reply Moertel agreed that every effort should be made to duplicate the conditions that existed in Cameron’s clinical trail. Cameron and Pauling, however, soon became concerned that the difference between treating cancer patients in the United States and Scotland could prejudice the Mayo trial. At the Vale of Leven, patients who needed chemotherapy were referred to another hospital and excluded from the study. Early indications of the protocol for the Mayo study made no mention of chemotherapy in patient selection. Moertel responded to these worries by pointing out that finding patients who had not been exposed to prior chemotherapy was almost impossible in the United States. More tellingly, he did not think the problem was crucial because if vitamin C operated by stimulating the immune system, then those patients whose immune systems had been suppressed by chemotherapy might actually receive greatest benefit. Pauling, however, was unconvinced and started to deny that the Mayo study was a proper replication because the patients had already undergone orthodox treatment. In August 1978 the results of the Mayo study became available. They were negative. Sixty patients who had received ten grams orally of vitamin C a day were compared with sixty-three patients who had received a placebo. There was no statistically significant difference in the two outcomes. The overwhelming majority of these patients, however, had previously received chemotherapy and/or radiotherapy. At first Pauling was not too perturbed by the results—after all he had more or less predicted such an outcome. The subsequent framing of the results, however, as a rebuttal of Pauling and Cameron’s claims led to controversy. Pauling thought that Moertel had acted improperly in not putting greater stress on the fact that, unlike in the Cameron study, all the Mayo patients had already undergone some form of chemotherapy and/or radiotherapy. Furthermore Moertel’s paper, which was to be published in the New England Journal of Medicine under the title “Failure of High-Dose Vitamin C (Ascorbic Acid) Therapy to Benefit Patients with Advanced Cancer,” mistakenly asserted that 50 percent of the Vale of Leven patients had in fact received chemotherapy. The true figure was actually only 4 percent. Pauling and Cameron, having read a preprint, immediately contacted Moertel demanding a correction of the 50 percent figure. Moertel agreed, but when he in turn contacted the New England Journal of Medicine, he found that the paper was too far advanced in the printing process to be changed. He assured Pauling that every effort would be made to publish a correction at the earliest possible time. But the damage had been done. The press was given to believe that the Mayo clinic had decisively refuted Pauling. Even getting the correction published turned out to be difficult. The journal had a policy that such a correction could be made only by Pauling in a letter to the journal. Pauling, now in combative mood, refused categorically, arguing that since Moertel had made the mistake, the onus was on him to correct it. The dispute over how the error was to be corrected was eventually settled with an agreed-upon formula whereby Moertel would publish a letter saying he had received a letter from Pauling correcting the error. Much to Pauling’s fury, however, this gave Moertel the chance to further frame the error as scientifically trivial. For Pauling the error was crucial, as it showed that the study was not a replication of the earlier Cameron study. Cameron himself was very disturbed by the Mayo article and the accompanying negative publicity—for him it meant that patients who read about it might stop taking their vitamin C. The relationship between Moertel and Pauling, which up until then had been courteous and respectful, now broke down completely. Pauling threatened to launch a libel suit against a local Rochester newspaper which ran a story under the headline “Mayo Study: Pauling Wrong on Vitamin C for Cancer.” To avoid the libel suit the newspaper agreed to publish a letter from Pauling where he mentioned that Moertel had sought advice from Pauling as to how to run the Mayo study but had then ignored the advice not to use chemotherapy treated patients. As angry letters were exchanged in the press and scientific journals, both scientists ended up accusing each other of ethical improprieties. What Pauling regarded as Moertel’s continued misrepresentation of the Vale of Leven studies was for him akin to a professional breach of ethics, while for Moertel, Pauling was advocating an unproven cancer treatment. The fight reached a low point when Moertel referred in the Oncology Times to the “non-randomized study conducted in the little hospital, Vale of Leven in Scotland.” Pauling in response pointed out that the Vale of Leven Hospital is a “large hospital with 440 beds” and accepts 500 new cancer patients each year and that Stanford University Hospital, considered to be one of the leading hospitals in the United States, has only 420 beds! Pauling warned Moertel that he considered his description of the Vale of Leven Hospital as having been used “for the purpose of derogation.” The Second Mayo Clinical Trial Even before the Mayo results were announced, Pauling was pressing the NCI for a second study which would exactly replicate the conditions obtaining at the Vale of Leven. As a famous scientist, Pauling had powerful allies in Congress and the support of no less a person than President Carter. At this stage the NCI was under some pressure from a Senate subcommittee on nutrition to initiate research on the links between diet and cancer and was therefore vulnerable to political criticism. In March 1980 it was announced that Moertel and the Mayo clinic would undertake another NCI-funded trial of vitamin C. Cameron was less than enthusiastic about this second trial, having become convinced that Moertel was not a “reliable independent investigator” but was a protector of the “established cancer industry.” Cameron also foresaw a serious methodological problem with the Mayo studies—patient compliance. He argued that dying patients in the control group would take ascorbic acid without supervision and thus muddy the comparison between the two limbs of the trial. Moertel had tested for compliance in the first study by randomly monitoring ascorbic acid levels in the patients’ urine, but Cameron thought that blood tests were a more accurate measure. Cameron offered to help set up the protocols for the second Mayo study, but he was studiously ignored by the Mayo team. Pauling’s wife, Ava, who had continued to take the vitamin C megadose and remained in reasonably good health, eventually died of her cancer at age seventy seven on December 5, 1981. This was five years after being diagnosed. According to NCI statistics, her five-year survival chance was 13 percent. Pauling was devastated by her death, but what he regarded as her successful response to the cancer using only vitamin C hardened his determination to fight on. The results of the second Mayo trial were published in the New England Journal of Medicine in January 1985. They were again negative and in effect killed off this particular alternative means of treating cancer. The Mayo team had elected to study patients with advanced colon cancer because this was the most frequent tumor type in the Cameron Vale of Leven studies. Since there was no known effective chemotherapy for this cancer, the Mayo team felt ethically justified in not using chemotherapy first. Patients’ urine was randomly checked to ensure compliance with the trial protocols. The results were that “vitamin C performed no better than a dummy medication. No patient had measurable tumor shrinkage, the malignant disease in patients taking vitamin C progressed just as rapidly as in those taking placebo, and patients lived just as long on sugar pills as those on high-dose vitamin C. Surprisingly, and perhaps by chance, there were more long-term survivors receiving placebo than vitamin C.” Accompanying the results of the study was a guest editorial written by Dr. Robert Wittes, associate director of the Cancer Evaluation Program of the NCI (such guest editorials were standard practice in the case of contentious or important findings). Wittes hailed the trial as definitive and claimed, “It is difficult to find fault with the design or execution of this study. Ascorbic acid was given in the same daily doses and by the same route advocated by Cameron and Pauling.” Wittes rubbed salt in the wounds by adding that the apparent earlier positive findings from the Vale of Leven had probably resulted from case selection bias. Although Pauling had requested of Moertel the standard courtesy of seeing the paper before it was published, he was able to see the paper only after Moertel had done the round of all the major TV studios denouncing vitamin C as worthless as a cancer treatment and the Pauling-Cameron studies as “biased.” Scrambling for a response, Pauling was put on the defensive by Moertel’s media coup. Perhaps sensing that the stakes had now been raised, he issued public statements charging the Mayo clinic with making “false and misleading claims” and went on to accuse the New England Journal of Medicine and the NCI of condoning a “fraudulent” study. Pauling was said to be considering lawsuits against all three bodies. The nub of Cameron and Pauling’s criticisms of the second Mayo study was to reiterate points they had made earlier in criticizing the Sloan-Kettering pilot trial and the first Mayo trial. They argued that the controls were inadequate (this was Cameron’s main criticism). Of the one hundred patients in the trial only eleven had had their urine randomly checked. Of these only six were taking the placebo and one of these according to the Mayo report was found to be excreting over 550 mg of vitamin C per twenty-four hours while the remaining five were found to be excreting “negligible” amounts of 550 mg or less. Cameron immediately latched onto this figure of 550 mg; since cancer patients normally excrete 0-10 mg (normal healthy patients excrete 30 mg). Thus at least two out of six controls excreted vitamin C at two orders of magnitude above normal. For Cameron and Pauling this meant that the controls were clearly ingesting possibly as much as one or more grams of vitamin C per day, and this invalidated the study. Pauling’s own immediate criticism of the study was that the patients had not been given vitamin C for an “indefinite time.” Rather, what had happened was that vitamin C was halted once tumor progressions were noted and the patients were then given a highly toxic chemotherapy treatment. Vitamin C was administered only for a median time of two and a half months, whereas in the Vale of Leven studies vitamin C had been administered from the onset of the experiment until death (or for the few long-term survivors until the present). The lifespan data given by Mayo were thus suspect. All they had measured was the effect of vitamin C on tumor growth for the initial interval and hence only this contribution to the lifespan of the patients. Pauling and Cameron’s third and final critique of the new Mayo data was perhaps their weakest, as it depended upon the “rebound effect”—something which the Mayo researchers did not think existed. This was the effect first pointed to by Cameron back in 1973; if large doses of vitamin C were suddenly withdrawn, the patient’s circulating ascorbate would fall to well below normal levels and might induce acceleration in tumor growth. It was the same argument they had made earlier against the Sloan-Kettering study. Cameron and Pauling believed that it was quite possible that the sudden withdrawal of vitamin C followed by highly toxic chemotherapy may even have shortened the life of the patients in the second Mayo study. As the minutiae of the second Mayo study were put under Pauling’s microscope, he found more differences. For one thing, Cameron had carried out his work in a hospital and hence had been able to make detailed observations of the initial positive response to vitamin C treatment. The Mayo patients were ambulatory and were not examined during the first month of vitamin C treatment, so the initial improvements documented so assiduously by Cameron went unnoticed. The underlying gist of Pauling and Cameron’s criticism was that the Mayo researchers had failed to grasp that their own approach was about cancer control and that they never claimed, except for a very few fortunate patients, that they could stop tumor progression. Rather the claim was that they could slow tumor progressions, improve quality of life, and slightly but significantly expand survival times. The Mayo oncologists had tested vitamin C as if it were a cytotoxic drug to be administered for a short period of time, and whose therapeutic impact is measured primarily in terms of tumor shrinkage. Pauling was particularly goaded by the second Mayo trial and what he considered to be the underhand way that Moertel had denied him access to the paper until the day of publication. But as far as most reputable cancer researchers, the press, and the wider public were concerned, the game was over. Pauling tried in vain to pressure the NCI and the National Cancer Advisory Board and the editor of the New England Journal of Medicine for retractions, but made little progress. His bullying tactics and threats of lawsuits seemed counterproductive. He could see that his funding, which had always been precarious, was being threatened by the negative publicity. Pauling still believed in his personal ability to win over his fellow scientists. He even mischievously offered to visit the Mayo clinic and give a talk on vitamin C and cancer. The offer was politely turned down by a Mayo administrator on the grounds that it would be impossible to arrange a suitable audience for him. Moertel, who had publicly been accused of fraud by Pauling, retreated into silence apart from the occasional public pronouncement that the study had been properly conducted and that it would have been ethically repugnant to keep patients on a treatment under which they were regressing. Wittes, who had published the supportive editorial, and Pauling maintained a correspondence. Wittes found it totally implausible that vitamin C could have any effect past the point of demonstrable tumor enlargement, and to support this he went back over Cameron’s cases to show that even in the Vale of Leven trials there had been no such regression after tumor enlargement. Nor could Wittes accept Pauling’s claims about the rebound effect. The debate was inconclusive and Wittes did not change his mind. With Pauling and Cameron struggling to get papers published in the mainstream cancer journals and failing to obtain retractions from their critics, it was apparent to most people that the issue was dead. Two negative trials had been conducted by the most renowned cancer institute with the backing of all the leading cancer researchers. The Mayo had also given the appearance of bending over backward to respond to Pauling and Cameron’s criticisms of the first trial (criticisms which the Mayo scientists themselves found to be “obscure”). The controversy was closed, with defeat for Pauling and Cameron. As in many such controversies, the originators refused to bow out gracefully. Pauling’s death in 1994, however, in effect ended the sustained effort to promote vitamin C as a cancer cure. Conclusion What then are we to make of this episode—one of the few cases where a nonstandard approach to cancer has been checked by the best instruments of orthodox medicine? One point that is worth bearing in mind is that, as we document in the chapter on AIDS (chapter 7), cancer clinical trial methodologies have undergone evolution precisely because of the sorts of criticism made by Cameron of the Mayo studies. In the AIDS case it became difficult to carry out clinical trials double-blinded, because desperately ill patients did not want to be in the placebo limb of the trial and were sharing drugs with friends and fellow AIDS sufferers. In the AIDS case exactly the sort of matched historical control that Cameron used became accepted. (Though they are still open to criticism and the RCT is still the gold standard). This does not mean that the criticism of Cameron’s randomization techniques might not still be made. Also important in shaping the debate and in particular the issue of replication were the differing cancer treatment regimes in operation in the United States and Britain. The administration of cytotoxic chemotherapy as applied in the United States was not standard practice in Scotland. And Cameron’s own choice of pursuing a historically controlled trial rather than an RCT was affected by the prevailing norms in the UK, where RCTs were less common. Are the Mayo studies definitive, then? As we have seen, this is a case of experimenters’ regress. But the argument has in effect been closed in favor of orthodoxy. Experiments alone did not settle matters, but given the implausibility of Pauling and Cameron’s claims within the orthodox framework of cancer theory and practice, the experimental evidence offered a credible source of rebuttal. Cameron’s own experimental evidence was said to be methodologically flawed. The publishing difficulties which Cameron and Pauling experienced meant that at no stage were they able to get their clinical results published in an orthodox medical journal. On the other hand, their Mayo clinic opponents twice published their results in the prestigious and powerful New England Journal of Medicine. On offer are two versions of the impact of vitamin C on cancer and how it should be assessed. The dominant professional view of the leading cancer researchers is to assess vitamin C according to their standard methodologies. Within their framework and view of medical expertise, vitamin C is not effective. Cameron and Pauling’s claim, however, that vitamin C is a control rather than a cure for cancer, does not seem to have been refuted. Nevertheless, given that interest in Pauling and Cameron’s work was in effect killed off by the Mayo studies, neither is there a mass of evidence supporting the use of vitamin C as a cancer control; their claims continue to live on in the twilight world of alternative medicine. Pauling and Cameron failed to get the medical establishment to change their way of evaluating cancer drugs, and their own particular claims for vitamin C remain unproven. The messy fight between Pauling and his critics seems to be typical of these sorts of cases. It was never conclusively shown, in a quasi-logical sense, that the vitamin C treatment would not alleviate the symptoms of cancer and would not enrich, and perhaps extend, the lives of sufferers. Assuming that the results of the experiments were meaningful, what was shown was that those who had already been treated with chemo- or radiotherapy would not benefit, nor would those who were given vitamin C for a relatively short time. So if vitamin C worked at all, and this was never decisively demonstrated either, it worked only on a subset of cases. It is tempting to reach too quick a conclusion from this typical case of divided expertise, namely, “more research is needed.” Perhaps in this case it would be the right conclusion, perhaps not. The trouble is that what we already know about science (e.g., see The Golem and The Golem at Large) shows us that any piece of scientific research which is examined closely enough will reveal the same deficiencies when compared with quasi-logical standards. Therefore, the liberal-minded approach is a prescription for more research on everything, and that is no kind of advice at all in a world of scarcity. Every choice to do more research has an opportunity cost for some other project. Evelleen Richards, the author of the study from which we have taken most of our description of the vitamin C debate, recommends a change in the way alternative medicine is assessed to something like the approach followed in the Netherlands. The Dutch have instituted a system which gives a far greater weight to consumer preference in the distribution of medical resources. Given the huge consumer demand for alternative medicine, this means more money for such cures. In turn, this means that treatments are supported by the state even when there is no scientific evidence that they work or even an unwillingness to expose them to standard scientific tests. Richards too believes consumers have a right to express their preferences for unproven remedies and influence the distribution of state resources accordingly. We believe this conclusion confounds what is reasonable for medicine as succor with what is reasonable for medicine as science. Medicine as science and as a collective responsibility must not be driven by popular opinion, even though individuals may be right to seek out any unproven alternative for themselves when the ultimate questions are asked. To say “leave it to the people” is to risk the abrogation of our long-term collective responsibility to scientific medicine, even if sick and dying individuals might still be wise to try the cure. |
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