Chapter 5

Chapter 5

Benefits From High-dose Vitamin C Treatment: Cameron and Others

Ewan Cameron's studies of vitamin C in cancer patients are the most important in this area, and we will begin by discussing these. Cameron gathered most of his data at the Vale of Leven Hospital in Scotland. Publications coming out of this work in the 1970s will be refered to as the Vale of Leven studies. Later work with a separate group of patients, published in 1991, will be referred to as the final Vale of Leven study.

There are a number of other clinical reports that in some way support the findings from Vale of Leven. Most are little known to the critics, or even the supporters of ascorbate therapy. Most are described briefly in relatively obscure sources and all are smaller in scale than the Vale of Leven work. They usually suffer from the same methodological limitations that have kept mainstream doctors from taking Cameron’s work seriously. Nonetheless, taken together, these reports still provide some important evidence. These smaller studies will be described after discussion of Cameron’s work. The negative studies from the Mayo Clinic that were so influential in discrediting ascorbate therapy, are treated separately in the next chapter. That chapter includes a detailed analysis of the evidence for and against anticancer effects of ascorbate in human beings.

In this and the next chapter, where no specific reference is given, information comes from Evelleen Richards' book, Vitamin C: Medicine or Politics (Richards, 1991). This is the only source about many aspects of relations between Cameron and Pauling, about the development of Cameron’s therapy, and the practical problems he encountered in carrying out his work.

The Origin of Cameron's Interest in Vitamin C

Cameron was initially interested in vitamin C because of a suggestion from a reader of Cameron's book Hyaluronidase and Cancer, that it might be an inhibitor of hyaluronidase. At the time, Cameron had been administering a combination of hormones to his terminal cancer patients in the hope of strengthening the ground substance (extracellular matrix) and thereby impeding the growth of their cancers. The results had been discouraging. It was only when he added vitamin C in late 1971, that he seemed to see any benefit. He then dropped the hormones and treated with ascorbate alone.

Soon after this, Cameron communicated his preliminary results to Linus Pauling. Presumably, he did this because of Pauling’s well known interest in vitamin C, and because in November 1971 Pauling had made a speech suggesting that ascorbate might be of value against cancer. Pauling based this suggestion on ascorbate’s antiviral properties and its possible capacity to strengthen the ground substance by stimulating collagen synthesis. Cameron sent a long letter accompanied by a copy of Hyaluronidase and Cancer. Pauling replied with encouragement and the suggestion that about ten grams a day might be an appropriate dose.

Most of Cameron’s work in treating patients with vitamin C (except for the final Vale of Leven study), took place outside of any planned, formal investigation. It seems to have gradually developed from the informal experiments of clinical practice.

The Decision Not to Carry Out a Randomized Double Blind Study

After a certain point, it seemed very clear to Cameron that his patients were benefitting from vitamin C. Because of this conviction he was unwilling to carry out a randomized double blind trial. This would have withheld the treatment from some patients, who would only receive a placebo. He recognized that this would be the most effective way to prove the reality of vitamin C’s benefits to the oncology profession. On the other hand, it would be unethical to withhold treatment that appeared to provide desperately needed benefits.

Cameron also argued that the need for controls was reduced because of the inevitable progression of the disease in the patients he was treating. There would be no need for controls to indicate the level of spontaneous remission, because there was none. His patients could be expected to continuously worsen and die, most within a few months. If some of the treated terminal patients were to show significant improvement, this would be so different from the normal course of the disease that it would be clearly recognizable as an ascorbate effect. This reasoning was to be roundly condemned by Cameron’s critics. However, as we shall see, it was also employed by some of those same critics. In particular, there was a Doctor Moertel, who carried out a similar study of laetril without a randomized double blind methodology ( Moertel et al, 1982).

The decision not to carry out a double blind study was to have grave consequences for the development of vitamin C as a cancer therapy. It would prove terribly difficult to get other oncologists to carry out such a study. The first indications of this came when Pauling tried to involve the cancer specialists at Stanford in vitamin C research, and found them uninterested, or positively hostile. When the randomized double blind study was finally carried out, at the Mayo Clinic, under somewhat different circumstances, none of the striking effects reported by Cameron were seen. If Cameron had carried out such a study with positive results, the oncology profession might have seriously pursued the study of vitamin C.

Unless stated otherwise, the information in this section comes from Cameron and Campbell (1974) which provides the main clinical description of ascorbate effects in advanced cancer patients. It described a consecutive series of 50 terminal cancer patients. Brief descriptions were given in tabular form for all subjects, brief case histories were provided for 17, and some were discussed at greater length.

Those selected to receive ascorbate had all been deemed "untreatable" by any conventional means. Patients of this kind were chosen as subjects so that any dangers the treatment might pose, would be borne by those with the most to gain and the least to lose. This also ensured that the treatment could not interfere with ongoing conventional therapy.

The process which selected patients for ascorbate treatment included the certification by at least two doctors that the patient was untreatable. Ascorbate was only given "...at the time in their disease when in the considered opinion of at least two independent clinicians the continuance of any conventional form of treatment would offer no further benefit.", (Cameron and Pauling, 1976).

After being classified as untreatable the patients would often receive intravenous sodium ascorbate followed by maintenance oral doses. Cameron began by treating with five grams of intravenous ascorbate per day for 5 to 7 days, followed by oral ascorbate at 2 grams per day. When he found that this was well tolerated he increased the intravenous ascorbate to 10 grams a day, and the oral ascorbate to 8 grams and later to 10. The ascorbate dose was never completely standardized and apparently was adjusted for individual patients. Cameron and Campbell describe treatment as usually beginning with "about 10 days" of intravenous treatment, and then 10 grams a day orally.

The oral maintenance dose was in a solution, with a tablespoon taken four times a day. This solution, which was supposed to have been particularly acceptable to patients, included the sweetener, sorbitol (23%). It may be of interest that sorbitol is supposed to have a role in increasing absorption of vitamins (Merck Index, 1983, #8797). Administration of vitamin C in this form was done only in the Vale of Leven studies and not at the Mayo Clinic where subjects received sodium ascorbate capsules. While it does not seem obvious that this modest amount of sorbitol could account for the dramatically different outcomes at Vale of Leven and the Mayo Clinic, this remains a possibility, and is discussed below, particularly in Chapter 6.

Whenever possible, ascorbate was continued as long as the patient lived. Cameron and Pauling believed stopping ascorbate was often associated with death in these patients.

The 10 grams of vitamin C per day used by Cameron, was about 200 times the RDA (Required Daily Amount) recommended by the FDA in the United States. In some patients as much as 45 g/day were given intravenously. These doses must have seemed shockingly large to many doctors. But there is evidence that most people can safely receive much larger intravenous and oral doses, e.g. more than 100 grams in the course of a day (Klenner, 1971; Cathcart, 1981; Riordan et al, 2000).

Cameron and Campbell suggested their results might understate the benefits of ascorbate. This was because the treatment was applied only to the very sickest patients and because those who benefitted enough from ascorbate to be treated by conventional means were excluded from this report.

Palliative Effects

The term "palliative" refers to treatment that provides symptomatic relief without reversing an essential disease process or increasing survival. The clinical studies of ascorbate and cancer don't provide a basis for distinguishing these palliative effects from direct anticancer effects. Rather there seemed to be a continuum of effectiveness from short lived effects which are purely palliative, through stronger and longer term effects, which included slowing or reversal of tumor growth.

Such palliative benefits were an important feature of the Vale of Leven studies. The most important problems common to late stage cancer patients are pain and cachexia (wasting). Pain may not be adequately controlled, or may be controlled, only with very heavy, sedating doses of opiates. Cachexia involves an inexorable loss of muscle mass and body fat, exhaustion, and loss of appetite. It is part of a picture of general debilitation. Cachexia cannot be controlled by increasing intake of calories or by any treatment known when the Vale of Leven study was carried out. Because of the severity of these symptoms, anything vitamin C could do to reduce them would be of great importance, even without effects on survival.

In addition to the common symptoms of pain and cachexia, there are many more specific symptoms which result from the cancer acting at particular sites. Some of these result from compression by the growing tumor and include obstruction of the bowels, of the esophagus, of major blood vessels and of the bile duct. Other important symptoms include the accumulation of fluids in the viscera (ascites), or in other spaces in the body (e.g. around the heart or in the lungs). These accumulations of fluid from cancer are called "malignant effusions". Metastases in bone can produce intense pain and susceptibility to fracture. Anemias and abnormal clotting (thrombosis) are common., and infections may follow immune impairments associated with the cancer or with cancer treatment.

Cameron and Campbell classify some of the palliative effects as subjective. These are effects that would not have been registered through measurement, but would be known only from patient’s or clinician’s statements about mood, appetite, energy level, alertness, pain levels, etc. It was claimed that almost all patients reported some subjective benefits. This even included some of the 17 patients who they classified as showing no recognizable response to ascorbate.

Benefits usually appeared between the fifth and the tenth day of treatment. The authors do not provide a quantitative or summary statement about these subjective responses. However, an examination of the individual case histories shows such changes as dramatic reductions in pain from bone metastases, increased alertness, increased energy, increased interest in their surroundings, and better appetite. In a later summary of experience with ascorbate in cancer, (Cameron and Pauling, 1993, p 131), subjective benefits are said to include feeling better, stronger, and more alert, reduced nausea, and reduction in reported bone pain from metastasises.

Cameron and Campbell cite the following objective benefits. Reductions occurred in the accumulation of fluid in lungs and peritoneum. Hematuria (blood in the urine) and difficulties in urination were reduced in bladder cancer. In six of the 50 cases, there was clear clinical and laboratory evidence of a temporary reversal of liver enlargement and jaundice. Erythrocyte sedimentation rate (ESR) and serum seromucoid concentration, two laboratory indices diagnostic of cancer, did not increase as would have been expected, but instead fell or were unchanged in patients receiving ascorbate. A graph is presented for each of these indices, showing individual responses for ascorbate treated patients, though no summarizing quantitative information accompanies this.

Finally, it is mentioned that the ascorbate content of plasma, lymphocytes and leukocytes, plasma hyaluronidase and PHI content were measured and found to change in a way generally consonant with expectations. This data was supposed to be discussed in a future publication, but as far as I can determine this was never done.

Relief of pain from bone metastases, relief from headache pain and other phenomena are interpreted as strong evidence of reductions of pressure due to reduced tumor growth. However, in most cases in which this was claimed, there was more direct evidence in the form of X-rays, operative or autopsy evidence, or disappearance of palpable masses. Three of their 50 patients were classified as showing long term arrest of tumor growth and 5 as showing regressions.

Side Effects of Ascorbate Administration

The side effects seen with oral ascorbate, (heartburn, nausea, acid reflux, or vomiting) were described as modest and said to chiefly appear in patients who had upper digestive tract symptoms from their cancer. However, these were sufficient to make a number of patients discontinue ascorbate.

Striking differences were claimed in the response of cancer patients and normal volunteers to oral ascorbate. When normal individuals increased their daily oral intake beyond 3 or 4 grams a day, transient bloating, colic, and diarrhea were common. On the other hand, these symptoms almost never appeared in cancer patients. This was interpreted to mean that cancer patients were able to absorb and utilize vitamin C in a different manner than healthy subjects or other kinds of patients, probably reflecting a unique need for ascorbate associated with their disease. This difference between cancer patients and others can be related to numerous reports that cancer patients show very low vitamin C levels relative to normals. When large amounts of vitamin C are administered to advanced cancer patients the vitamin C does not increase plasma levels or overflow into the urine in the same way as normals. This phenomenon is discussed at length in chapter 8.

The failure of the advanced cancer patients to show diarrhea with large intakes of ascorbate, shows their elevation of the "bowel tolerance" described by Cathcart (1981), and discussed in chapter 1. Presumably this represents the same increased ability of these patients to take up ascorbate from their gut that was seen in Cathcart’s patients. However, in an interview with Newbold (1979), Cameron indicated that he had difficulty getting patients to tolerate doses above 10 grams a day, though he does not specify whether this was because of diarrhea or other problems.

Fluid retention and oedema were often seen in patients who were receiving intravenous ascorbate. This was interpreted as a reflection of mild sodium overload, since ascorbate was administered as the sodium salt. This fluid retention and oedema was said to be easily dealt with by routine medical interventions.

In a "significant proportion" of treated patients, after a period of improved well being and slowed or halted tumor growth, there was an "explosive" progression of their cancer, and death. This is described as a "rebound" effect, though more generally, Cameron and his associates used the term "rebound" to describe the effects of discontinuing ascorbate after the body had adapted to a high intake.

This "explosive" progression was regarded as sufficiently unique that it should probably be attributed to the use of ascorbate. This was not seen as a reason to avoid ascorbate. Most of the patients showing this pattern had gone through a period of surprising stasis and relative well being which began with ascorbate administration.

This effect recalls the fact that some studies in the animal and cell culture literature, do describe stimulation of cancer by vitamin C. This subject will be discussed at length in Chapter 7.

A catastrophic syndrome occurring in a small fraction of patients (4 of 50), involved rapid necrotic destruction of tumors, with fever and hemorrhage at the tumor site. In three of the 4 subjects believed to show this syndrome, the existence of tumor necrosis was confirmed either at autopsy or by disintegration of a visible metastasis on the body surface. The susceptible patients seemed to be those with rapidly growing and widely disseminated tumors. Perhaps this phenomenon is related to the observation that in a few other patients, ascorbate gave rise to transient pain at the site of known metastasises. It also is probably related to the observations of Campbell and Jack (1979) described below, in which fever, swelling and pain at tumor sites was a rare but definite side effect of ascorbate therapy.

Because of experience with this tumor necrosis syndrome in the Vale of Leven study, those treating cancer with ascorbate today, usually begin with smaller doses. This may be why I have come across only one other report of this lethal effect, that of Dr. Kalokerinos described later in this chapter.

It is of interest that this "side effect", although the most dangerous to the patient, also seems to represent the most dramatic manifestation of ascorbate’s anticancer effects. There is the suggestion that those patients most susceptible to this effect, would also be most capable of benefitting from ascorbate therapy if it were begun gradually.

As mentioned above, the phrase "rebound effect" was initially used by Cameron and his associates to refer to a sudden acceleration in cancer growth with continued ascorbate administration, after a period of quiescence. However, later, and more generally, the term was used to refer to the supposed stimulus to proliferation provided by the withdrawal of ascorbate after adaption to high intake. Because adaptation would increase the utilization or destruction of a large daily ascorbate dose, sudden discontinuation of ascorbate would reduce ascorbate levels below normal baseline levels. Since an abundance of ascorbate was supposed to be responsible for keeping cancer in check, the low levels which followed sudden withdrawal should leave the cancer uninhibited and free to rebound. Cameron and Pauling attributed deaths in cancer patients to this "rebound" effect with sudden withdrawal of ascorbate.

There doesn’t seem to be any question about the existence some kind of rebound effect (as was described in chapter 1), but it is hardly clear whether it exerted the clinical significance claimed by Cameron and Pauling. In later chapters we will consider evidence for the importance of this effect.

The Benefits of Ascorbate Summarized

Cameron and Campbell (1974) describe the following range of therapeutic responses and the number of patients showing each kind of response:

	Response	Number of Patients
1	No recognizable Response	17
2	Minimal Response	10
3	Growth Retardation	11
4	Cytostasis (or "standstill effect")	3
5	Tumor Regression	5
6	Tumor hemorrhage and necrosis	4

Later, Cameron and Pauling (1993), p. 166), on the basis of many more patient histories, restated the summation of patient outcomes presented above:

1  No response,  about 20 percent, one in five

2  Minimal response,  about 25 percent, one in four

3  Tumor retardation,  about 25 percent, one in four

4  Cytostasis (standstill effect),  about 20 percent, one in five

5  Tumor regression,  about 9 percent, just less than one in ten

6  Tumor death, about 1 percent, one in a hundred

It is important to remember that these numbers are supposed to refer to hopeless, untreatable cases. If these numbers are accurate, this is very impressive. Spontaneous recovery, even temporary improvement, would be extremely rare in such patients. This says that for about 29 percent of the patients the cancer either stopped growing for prolonged periods, or actually regressed.

Placebo Effects

This topic will be considered at length in the next chapter. Here we briefly report what Cameron and Campbell (1974) had to say about the possible role of placebo effects. They state that ascorbate was described to patients as something which might help a little, and never as a possible cancer cure. They suggest that patient expectations about the benefits of treatment were so negative as to "constitute a ‘reverse placebo effect’ in many of these patients".

There is no reason to think that these early patients treated with ascorbate were exposed to any atmosphere of extraordinary enthusiasm about vitamin C. When Cameron was beginning to treat with ascorbate, this kind of treatment was certainly unknown, and the benefits seen in the early trials were equivocal. There is no obvious reason why an atmosphere of excitement should have arisen around ascorbate treatment at the time. This evaluation is in accord with the subdued and cautious character that Cameron and Campbell generally displayed. It seems enormously unlikely that they would have made any extravagant claims for vitamin C to their patients. Cameron et al stress the initially deep skepticism that most of the physicians and support staff felt about ascorbate treatment.

In correspondence between Cameron and Pauling (Richards, 1991, p. 92-3), Cameron noted that the time course of the benefits they observed following ascorbate, seemed to rule out placebo effects. The patients showed no immediate improvement when ascorbate was first administered, indeed, patients might worsen during this period. It was only about a week following initiation of ascorbate therapy, that most patients showed improvement.

There may be a physician’s "expectation" effect corresponding to the placebo effect among patients. We must consider the possible role of these expectations in distorting physician’s perceptions at the Vale of Leven. Certainly the skeptics did so.

However, the role of such expectations seems limited. Most of the changes reported in patients in response to ascorbate therapy were objective facts, not  clinician’s impressions. These objective changes ranged from lab tests and X-ray evidence to the very unexpected survival of patients.

It is easy to imagine these distorting effects changing the judgement of patient’s mood or alertness. But it is very difficult to believe that these expectations could lead doctors to imagine the disappearance of tumor masses, or, imagine a debilitated end-stage cancer patient again becoming ambulatory and returning home when this never happened. This would require something more like hallucination than expectation.

My originally interest in the Vale of Leven studies was inspired by my inability to imagine how such reports could have come to be written, in the absence of real benefits of ascorbate. It seemed to me that ascribing the clinical reports of ascorbate's effects purely to enthusiasm, had no psychological plausibility.

While double blind methodology can play an essential role in eliminating the effects of hope and expectation in clinical trials, its absence does not automatically prove that clinical observers were deluded. The mechanically minded opponents of vitamin C found the absence of the double blind methodology sufficient reason to stop thinking about what went on at the Vale of Leven. When controlled studies, carried out under somewhat different circumstances, failed to replicate Cameron’s successes, methodological imperfections were considered the obvious explanation of ascorbate’s reported benefits.

There are also separately published reports (Cameron et al., 1975, 1991), on the particularly interesting patient mentioned in the introduction to this book. This patient recovered with ascorbate administration, relapsed when ascorbate was discontinued, and recovered a second time with intensive ascorbate therapy. No other therapy was given to this patient. The diagnosis was widely disseminated reticulum cell sarcoma, established on the basis of extensive clinical and laboratory data. The evidence included histological confirmation of the cancer and a complete radiographic record through the course of treatment and recovery. All the physicians involved with care of this patient seem to have accepted the diagnosis and the reality of the cure by ascorbate. Before this case history was published, the evidence relating to this patient was reviewed by a number of outside experts. Because of the circumstances of this case, it provided an exceptionally convincing demonstration of ascorbate’s effectiveness. We might call this case history an "existence proof" of ascorbate’s anticancer powers.

In Cameron et al (1990), this subject’s history is extended to about 1990. Two years after his second recovery, he was found to have a small, well-encapsulated tumor in his thyroid. This was successfully removed. In 1986, after having taken 12.5 g of ascorbate continuously for 12 years, he decided to stop because he wanted to know whether he was really cured, and whether the cancer would recur when he stopped. He could not be dissuaded from doing this. The patient abruptly discontinued ascorbate. At the time of publication he had remained cancer free for more than three years after stopping.

Cameron and Pauling's Quantitative Analysis of Ascorbate Effects

Cameron and Pauling had hoped to inspire other researchers to carry out randomized double blind trials of ascorbate. When this failed to happen, the next best thing seemed a comparison of treated patients with matched controls from the Vale of Leven. Methodologically this would be less than ideal. However, if they could demonstrate a substantial effect with reasonably convincing controls, this might still change some minds.

In their analysis (Cameron and Pauling, 1976, 1978), the 50 subjects described in their initial clinical report were included, and an additional 50 were selected at random from their treated patients. Then, ten non-treated controls were found for each treated patient. These controls were matched on sex, age (within 5 years), and site of cancer. In order to ensure objectivity, the selection of the additional 50 cases and the search for matching controls, was handed off to an individual who had not been involved in the treatment with ascorbate, and who worked independently of Cameron and Pauling.

The treated patients had begun receiving ascorbate at the time their physicians decided they were untreatable by any conventional means. It seemed clear that the treated subjects had survived much longer that would have been expected after they had received ascorbate. If survival in untreated patients was to be objectively compared with survival from the time when treated patients began to receive ascorbate, this posed a difficult problem. What was the point in time when an untreated patient was as sick, had progressed as far, as a treated patient beginning to receive ascorbate. The answer seemed to be to look through the medical records of controls, and find a time at which they would have been classified as untreatable if the physicians who had used ascorbate had handled their cases.

Cameron and Pauling say that the person selecting controls, "...established the presentation date of ‘untreatability’ by such conventional standards as the establishment of inoperability at laparotomy, the abandonment of any definitive form of anti-cancer treatment, or the final date of admission for ‘terminal care’." ("Laparotomy" is the opening of the abdomen.) In order to avoid any possible bias in this determination, the individual doing this was blinded with respect to the survival time of each case. Because of large differences in survival times for different types of cancers, subgroups were formed based on cancer site.

In the 1976 report survival from date of untreatability was the only measure analyzed. However, critics suggested that it might be terribly difficult to ensure truly equivalent dates for controls and treated patients. In response to this, the 1978 report also considered survival from the patient’s first cancer related contact with the hospital. This date could be unambiguously determined for most patients. On the other hand, using this date would tend to dilute out any survival enhancing effect of ascorbate. Survival from first date of contact would include a long period prior to ascorbate treatment.

In the second report, (again in response to critics), some of the original treated cases were rejected because their relatively rare kinds of cancer could not be properly matched among the controls. They were replaced by new treated subjects, who had clear matches among the controls.

Of course, in measuring the effects of a treatment, we want to start with treated patients and untreated controls who are as similar as possible before treatment. Most critically, the members of one group should not have been sicker or healthier than members of the other, at the point when they were classified as untreatable. One way of testing that these groups are equivalent, would be to look at their average time from initial diagnosis to date of untreatability. Because cancers tend to progress, the longer the time since diagnosis, the sicker patients would tend to be. If we found that the controls had a greater average time since diagnosis, this would suggest that they were really sicker that the ascorbate treated patients with whom they would be compared. And this would suggest that the supposed effects of ascorbate in prolonging survival were an artifact, reflecting an initial difference between groups.

|It was found that the time between initial hospital contact and date of untreatability was not significantly different between treated patients and controls. This was true both overall, and within each of the cancer type subgroups. The mean number of days between first contact with the hospital and untreatability was 388 for the ascorbate treated subjects and 322 for controls. This would tend to contradict the idea that the treated patients were less sick (were earlier in their illness), at the time that they were classified as untreatable. So to the extent that an initial difference existed between groups, it would have worked against longer survival times for the ascorbate group. Perhaps it could be argued on the other side, that this was evidence that the treated subjects were for some reason progressing more slowly than the controls, and so could have expected a longer survival time after the untreatability date. But because these are non-significant differences, neither of these notions can be taken too seriously.

Results of the Analysis

Overall, and within all cancer subgroups, the ascorbate treated subjects survived longer than controls. All of these survival differences had a high degree of statistical significance. Survival advantages for ascorbate subjects were significant whether survival was measured from the date of untreatability or from date of first cancer related contact with the hospital.

There are various ways of comparing the outcomes for treated patients and controls. One is simply the average length of survival after the classification as untreatable. At the time of the 1976 report, this was 4.2 times longer for ascorbate patients than for controls and 7.7 times in the 1978 report. The ratio should be expected to increase in the two years between these reports because virtually all of the controls had died, while some of the treated patients continued to live. This figure is disproportionately influenced by the long term survival of a small number of patients.

Another comparison is the percentage who lived beyond one year after classification as untreatable. This was 22% for the ascorbate group and .4% for the controls in the 1976 report. At the time of the 1978 report, eight of 100 ascorbate treated patients were still alive, and none of the thousand controls. These are very striking differences and have a very high degree of statistical significance.

Another objection to these reports was that they used "historical controls". This would mean that survival of treated subjects was being compared with the survival of untreated patients, at least some of whom were in the hospital during different time periods. Control patients were selected from the records of the preceding ten years, while treated patients were drawn only from the last 3 or 4 years. Now an additional factor (period in which treatment occurred) would distinguish treated and control groups. This might seem an important weakness in the study. However, when the comparisons were restricted to the subgroup of controls whose period at the hospital overlapped with that of the treated patients, the difference between groups remained significant.

The data below appeared on page 4551 of Cameron and Pauling (1978). A '+' following a survival time indicates that there was still at least one survivor at the time the data was compiled.

			Mean Survival in Days  From First Contact		Mean Survival in Days  From Untreatability
Cancer Site	No. Treated	No. Controls	Treated	Control	Treated	Control
Colon	17	170	458+	316	352+	33
Bronchus	17	170	219+	118	186+	31
Stomach	13	130	286+	159	182+	32
Breast	11	110	1396+	1020	487+	52
Kidney	8	80	774+	492	381+	39
Bladder	7	70	1669+	420	355+	21
Rectum	7	70	634	336	270	43
Ovary	6	60	884	366	183	69
Others	14	140	706+	279	278+	37
All	100	1000	681+	360	293+	38

Hardin Jones Analysis

Another way to compare treated and untreated subjects is to compare the curves of mortality in the two groups over time. Pauling was interested in this approach, which had been introduced by the statistician Hardin Jones. Jones had noted that a fixed proportion of advanced cancer patients tended to die per unit time. This would show itself as a straight line on a graph of the logarithm of survival fraction against time. If the curve changed, (flattened), as patients died, this indicated that the population was not homogenous. A subgroup of shorter lived patients had died off, and another longer lived subgroup with the flatter mortality curve had emerged.

The Hardin Jones approach suggested that ascorbate was exerting different effects in two distinct subpopulations.

In the 1976 report, the results of a Hardin Jones analysis were described in detail. It was stated that more than 98% of the controls showed an average survival time of about 45 days. For most of the remainder, the mean is between 200 and 500 days. On the other hand, among the ascorbate treated subjects approximately 90% had a mean survival time of about 125 days, while the remaining 10% would have a mean survival time beyond 970 days. Only a minimum value could be given for this subgroup because 18 of the ascorbate treated patients were still alive when the analysis was done.

Cameron and Pauling state, "A simple interpretation of these facts is that the administration of ascorbate has two effects. First, it increases the effectiveness of the natural mechanisms of resistance to such an extent as to lead to an increase by a factor of 2.7 in the average survival time for most of the patients.... Second it has another effect on about 10% of the patients, such as to cause them to live a much longer time. This effect might be such as to "cure" them..."

A brief report (Cameron and Pauling, 1979) compared the outcomes for Vale of Leven patients who had a diagnosis of carcinoma of the lung and who received various types of treatments. Some of the subjects had been included in the original Vale of Leven study described above. Again in this comparison the ascorbate treated terminal cancer patients did much better than untreated terminal patients. They also survived more than twice as long as a group treated with chemotherapy and about as long as a group treated with radiation. It was argued that the groups who received chemotherapy and radiation were probably initially in better condition than the ascorbate treated patients. While these findings are suggestive and interesting, they suffer from the usual methodological problems and could not be expected to make any impression on the opponents of ascorbate therapy.

Cameron's Final Publications

The last two papers published on ascorbate therapy by Cameron and his associates appeared in 1991 (Cameron, 1991; Cameron and Campbell, 1991), shortly before Cameron’s death. Much of what they report deals with new data gathered after the 1978 report described above, but they also summarize earlier experience with ascorbate treatment.

Cameron and Campbell (1991) describe the outcome of ascorbate therapy provided at Vale of Leven and two other Glasgow hospitals, in a new group of patients. Data collection using a new automated patient records system began in April of 1978 and continued through 1982. They noted that the population of the area had an exceptionally high level of cancer and low nutritional standards. Supplement use was almost unknown there. These terminal cancer patients differed from those in the United States in that they rarely received cytotoxic chemotherapy.

Ascorbate levels in plasma and leukocytes were regularly monitored in patients receiving ascorbate and in a large number of controls. All of the ascorbate patients received 10 grams of sodium ascorbate a day. A fraction of these patients were started with ten days of intravenous ascorbate. The measurement of plasma levels provided a clear test of subject compliance. Patients were excluded if they met any of the following criteria: had not been classified as untreatable: had received a treatment which was intended to be curative rather than only palliative, follow up from date of first hospital attendance was less than 6 months, had died within 14 days of first hospital attendance, had been treated with chemotherapy, had been prescribed other micronutrients. However, patients were not rejected if they had received prior radiotherapy. Such therapy was usually given early in the course of patient’s illness (post-operatively in the case of  breast cancer patients), and well before incurability. Applying all these criteria left a total of 294 patients who had received ascorbate, and 1532 who had not.

In the three hospitals included in the study, there were a total of 24 consultant led teams. Four of these regularly provided ascorbate and the rest routinely did not. Whether or not a patient was assigned to an ascorbate administering, or non-administering team depended on which team happened to be on duty at the time the patient arrived at the hospital. While this obviously is not a pure randomization, it seems plausible, as suggested by the authors, that it is effectively a good approximation of randomization.

To avoid the possible effects of bias in assigning an "untreatability" date, survival was measured from first hospital attendance to death, or if the patient was still alive, to the end of the study. "Such a policy removes any possibility of clinician bias, but obviously introduces a significant bias against detecting any benefit from supplemental ascorbate administered for only part of that time; this had to be accepted."

To test the comparability of treated patients and controls, these groups were compared on gender, age, score on a simplified staging system, and "delay time" in days. "Delay time" was the number of days prior to first hospital attendance when symptoms were first noticed. According to most of these criteria the two groups were quite similar. However, 58.5% of the ascorbate subjects were in the highest stage ("Cancer with distant metastases") as opposed to only 48.4% of controls.

It was found that the mean survival time of ascorbate treated patients was approximately twice that of the controls, 343 days vs. 180 days. It was also reported that different plasma ascorbate levels were characteristic of individual patients, while all were  receiving the same intake of ascorbate. The authors also noted that "...there seems to be a clear linear relationship between the highest recorded plasma ascorbate concentration and overall survival time, values of >3mg/dl being particularly desirable.".

This relationship can be considered a piece of internal evidence which helps to validate the relationship between ascorbate administration and survival. This suggests a real relationship, in spite of the absence of a randomization procedure. It seems unfortunate that Cameron characteristically fails to provide quantitative information about the relationship between survival and plasma level.

This relationship recalls the opinions expressed much earlier by Cameron and Pauling in interviews (Newbold, 1979) that higher ascorbate intakes would be more helpful. In Cameron’s interview it was mentioned that he had been struggling to get his patients to ingest larger doses of ascorbate.

Cameron (1991) provided a "Protocol for the use of vitamin C in the treatment of cancer". This is Cameron’s final summing up of his clinical experience with ascorbate and cancer. What follows omits information that has already been discussed above.

Cameron suggests that ascorbate therapy should always be used along with standard therapies rather than as a substitute. He cites evidence that ascorbate can act synergistically with conventional cancer therapies.

Intravenous administration is the ideal route for delivering ascorbate, but this will not be practical over the long term. It is suggested that intravenous ascorbate administration begin with gradually increasing doses so as to avoid possible hemorrhagic necrosis of tumors. This complication is said to occur "...only in patients with highly anaplastic [rapidly growing] tumors and a heavy tumor load...".

Oral ascorbate should be in the 10 to 30 g/day range and should be taken in divided doses, every six hours, so as to achieve a stable plasma level. There is reason to believe that plasma level is more useful as an indicator of clinical benefit than leukocyte level. Effective therapy requires plasma concentrations of at least 3 mg per deciliter. Nothing is said here about the form in which oral ascorbate should be taken (the sorbitol solution vs. tablets or capsules).

To deal with malignant effusions, isotonic ascorbate solutions can be instilled into the pleural or peritoneal cavities after drainage. While the effects of this procedure were never definitely established, it appeared to be beneficial, and was painless and safe.

When patients are maintained indefinitely on oral ascorbate, they should be monitored for signs of worsening. When patients respond favorably to ascorbate they often remain on a plateau of improvement for months or years. However, when they relapse, they often do so very rapidly with explosive growth of the cancer and rapid development of metastases. In these cases, a booster course of intravenous ascorbate may be very effective, or may not work at all.

Some cancer patients with osteolytic bone metastases or widespread visceral metastases, may show elevated urinary hydroxyproline as a manifestation of collagen breakdown at growing metastases. If so, within five days of commencing ascorbate, there should be a sharp and sustained decrease in hydroxyproline levels. Radiologically, osteolytic bone metastases may show a gradual conversion to dense osteosclerotic lesions over a period of months.

A discussion about hydroxyproline excretion in cancer and its possible modification by ascorbate administration is found in chapters seven and eight.

The fundamental objection to the Vale of Leven studies was that they failed to employ the randomized double blind methodology. There were however a number of other issues raised by critics. Many of these issues can be understood as a result of Cameron’s primary orientation as a clinician rather than a researcher, of the ad hoc nature of the work with vitamin C, and the lack of resources available to Cameron and his coworkers.

Lack of Planned Collection of Research Data

There seems to have been little collection of specific ascorbate related data about patients and about outcomes. The only exception is the final vale of Leven study which did look at serum and leukocyte ascorbate levels. For the most part such information, beyond that required for normal patient treatment and management, was either not collected or if collected, was never analyzed and published. In Cameron and Campbell (1974), it was implied that levels of plasma and leukocyte ascorbate, and serum hyaluronidase and PHI levels had been measured. However, such data was never published. In the quantitative presentation of treatment outcomes published by Cameron and Pauling in 1976 and 1978, the only numerical data presented and analyzed concerned patient survival. This was data already present in patient records.

Objectively Registering Palliative Effects of Ascorbate

Much of what Cameron and his associates reported about the effects of ascorbate concerned relatively subjective, palliative effects, e.g. improvements in patient’s sense of well being, energy, appetite, mobility, etc. What Cameron et al provided were chiefly statements about their impressions acquired while treating patients. There are however, ways of objectively registering changes in such conditions, e.g. sense of well-being, energy, appetite, mobility, etc. Rating scales filled out by blinded observers can provide meaningful numbers that accurately describe such things. Also, these "subjective" effects can often be objectively registered by counting or measuring some obvious kind of behavior. The amounts eaten from the patients tray could be weighted, time out of bed could be measured, and of course patient’s weight is a pretty obvious measure of appetite and the progress of cachexia. This kind of data would have avoided charges that too much of what Cameron et al reported was subjective and anecdotal.

Failure to Present Data in a Summarizing, Quantitative Form

When quantitative data was available, there was a general failure to present it in a summarizing form which might make it more intelligible. Laboratory findings for individual ascorbate treated patients were presented graphically, without numerical summaries and statistical tests. In all of the reports coming out of the Vale of Leven, almost the only numerical data presented and analyzed concerned patient survival.

There was a failure to provide quantitative information about what permitted a successful response to ascorbate. Was a positive response associated with iv rather than oral administration? Was a positive response associated with higher daily doses and higher plasma ascorbate levels? Was it associated with a particular stage in the disease? Was it associated with particular values on lab tests or with prior receipt of conventional cytotoxic therapies? It would seem that most of this information could have been provided without any enormous investment of time or money. Instead of precise information about the such correlates of treatment success, we are occasionally provided with the author's impressions.

In the main clinical report (Cameron and Campbell, 1974) the opinion was expressed that iv administration did not seem to be any more effective than oral doses. In Cameron’s final publications on the use of ascorbate therapy in cancer, after data had been gathered about plasma levels, plasma levels above 3 mg/dl were associated with better outcomes (Cameron, 1991; Cameron and Campbell, 1991). But characteristically, these expressions of opinions are not accompanied by presentation of the numerical data which would support them.

Cameron as a Clinician Rather Than Researcher

Perhaps Cameron’s primary orientation as a clinician rather than a research scientist explains the conduct of the Vale of Leven studies. A physician who was primarily a researcher would have given more thought to objectively measuring patient’s state before, and after commencing ascorbate, rather than simply recording impressions. While Cameron had published some clinical research papers he had never participated in any methodologically sophisticated research and probably had not been exposed to such research in his medical training in the 1930s. In Cameron and Campbell (1974) doubt was expressed that the new randomized double blind methodologies were really of much value.

Cameron's Lack of Resources

When plans were made to gather additional information for research purposes, this proved difficult because of a lack of resources. Cameron seems to have been very busy with his ongoing duties as Senior Consulting Surgeon and there was no money to hire staff to carry out a research program.

There were times when Cameron did have ambitions for a larger research effort to study vitamin C’s effects, both in his patients and in experimental animals. It appears that limited attempts were made to provide more complete documentation in terms of clinical records, imaging and laboratory tests. Richards (1991, p. 87) mentions that some of the more advanced imaging and clinical laboratory procedures would have been available through the University of Glasgow. Cameron intended to systematically assay patient’s plasma, leukocyte, and urine ascorbate levels and serum PHI and hyaluronidase concentrations. He was also thinking about the possibility of doing animal experiments with guinea pigs. Cameron (1986) described plans to examine the effects of ascorbate on carnitine levels in cancer patients and in normal controls. Apparently none of this data was ever published or perhaps even collected, and again this was probably due to a lack of resources.

Even the clerical work involved in analyzing patient records was almost too expensive for Cameron. At the beginning of 1973 he was able to hire a clinical research assistant, but soon had to scramble for funds to retain that person. The proposed guinea pig experiments were delayed for lack of funds and eventually abandoned. Cameron did succeed in getting some small grants, but nothing proportionate to his needs. In the late 1970's Cameron was able to get funds to computerize patient record processing from 1978 through 1982. This seems to have made possible his final report about work at the Vale of Leven (Cameron and Campbell, 1991).

Cameron and Pauling's Difficulties in Publishing Their Work

One of the major problems facing Cameron and Pauling was how to communicate their findings to the biomedical community. They found that the normal channels for medical publication were largely closed to them. That vitamin C had significant benefits against cancer was emphatically not what journal editors and reviewers expected or wanted to hear. If Cameron and Pauling had wished to report that some new pharmaceutical had some modest benefits against cancer, there would have been no problem. After all, editors and reviewers had no a priori conviction that some new pharmaceutical could not provide benefits in terminal cancer patients. Apparently they did have such a conviction about vitamin C.

Cameron submitted the first reports of this work to The Lancet in 1972, soon after he had first administered ascorbate to cancer patients at the end of 1971. One item which was accepted without difficulties (Cameron and Rotman, 1972), was a letter briefly setting out their hypothesis about ascorbate and PHI (the Physiological Hyaluronidase Inhibitor present in the serum). They noted the similarity between ascorbate and glucuronic acid, one of the units composing the hyaluronic acid polymer. They suggested that the incorporation of ascorbic acid into PHI, might enhance its ability to inhibit the hyaluronidase enzymes. They also said they had gathered some preliminary evidence that ascorbate was producing the anticipated benefits in cancer patients.

On the other hand, their other submission to the Lancet, which set out the rationale for ascorbate use at some length, was "flatly rejected" (Richards, 1991, p. 83). Cameron had submitted this to the Lancet’s hypothesis section, but the evidence was still considered too insubstantial for publication.

The next possibility was to publish Cameron’s paper in the PNAS USA (Proceedings of the National Academy of Sciences, USA). Pauling was a member of the academy, and according to the academy’s rules, if Pauling’s name appeared on the paper, the academy was obliged to publish it. However, the editor of the PNAS as well as the editorial board as a whole, were unwilling to allow this. Because the paper was concerned with a therapeutic procedure, it was said to be outside the purview of the academy. It belonged instead in a medical journal where it could be appropriately peer reviewed. Next, the paper, bearing both Cameron and Pauling’s names was submitted to the British Medical Journal. There too it was rejected. Pauling tried a second time to get the paper accepted by PNAS by removing some of the references to the therapeutic use of ascorbate and making it a more theoretical paper. Again it was rejected.

Pauling’s jousting with the PNAS did finally have some effect. The violation by the PNAS of its normal acceptance policy, the controversial nature of the article’s content, and Pauling’s fame, eventually led to media attention which the PNAS’s editor and board found uncomfortable. This led to a clarification and formalization of the acceptance policy. It also led to an invitation to resubmit the paper.

This offer came too late. In the meantime, the journal Oncology (Basel), committed to publication, sight unseen. This offer resulted from the media attention which had made Oncology’s editor aware of the paper. It was published (Cameron and Pauling, 1973) the following year. In this paper they explained the increased utilization of vitamin C in cancer, wound repair and inflamation as due to its incorporation into the hyaluronidase inhibitor, PHI.

Also in 1973, Cameron and Baird published a brief account of the striking analgesic effects of ascorbate in patients with bone metastases (Cameron and Baird, 1973). This was published in the IRCS (International Research Communication Systems), apparently a journal intended for rapid publication and therefore with relatively lenient acceptance policies. (Because no American University library subscribed to this journal before 1974, it has been impossible to consult this citation).

In early 1974 Cameron submitted two papers to the journal Cancer, one of the most important oncology journals. Both were promptly rejected with the comment that they were "not of sufficiently high priority to warrant publication space" (Richards, 1991, p. 99). After some revisions, and with Pauling now a coauthor on the theoretical paper, they were submitted to the non-medical journal Chemico-biological Interactions.

In 1979 Cameron and Pauling published two articles in the Journal of the International Academy of Preventive Medicine, an obscure journal devoted to nutritional medicine. A venue which would be considered entirely beyond the pale by mainstream doctors. However, in that same year they also were able to publish a review article (Cameron et al, 1979) in the very mainstream journal Cancer Research.

Cameron’s report on the final Vale of Leven study (Cameron and Campbell, 1991), remained unpublished for years. It was repeatedly submitted to various prestigious journals where it was endlessly reviewed and endlessly rejected. By this time the negative and methodologically correct, Mayo Clinic studies had been published, and a therapeutic role for ascorbate in cancer was widely regarded as having been discredited. By this time, Pauling’s acrimonious battles with the Mayo Clinic researchers and with the editors of the New England Journal of Medicine (NEJM) had further alienated the medical profession. While sympathetic observers might feel that Cameron's work was rather convincing in spite of its methodological lapses, NEJM's reviewers found this report completely uninteresting. It was finally published in Medical Hypotheses, a journal whose function is to provide a venue for the expression of unconventional ideas. Despite its relatively radical agenda and content, this journal seems to be present in many medical school libraries. This journal also published Cameron's (1991), final summation of his clinical experience with ascorbate.

Other Reports of Ascorbate Effects in Cancer Patients

Perhaps the first attempt to replicate the work at Vale of Leven, was carried out by Dr. Charles Young at Sloan-Kettering Memorial hospital in 1974. This research was never published and is only known from its discussion in correspondence between Cameron and Pauling (Richards, 1991, page 102). The results in an initial series of 16 patients were entirely negative. These patients were said to have had "extremely far advanced disease" and unlike the Vale of Leven patients, had received extensive prior cytotoxic therapy. The final news from Doctor Young in 1976 was that he had worked with a total of 23 patients and still had found no benefit.

Cameron and Pauling suggested that the results were negative because treatment had been discontinued when patients had been treated with ascorbate at some time between 5 and 64 days. It was also suggested that the patients might have suffered from a rebound effect when ascorbate was discontinued. The problem with these suggestions is that in the reports of Cameron et al, and  in reports of others who had positive results treating advanced cancer patients, very distinct benefits were seen within a week, and sometimes sooner. While the rebound effect might explain a failure to show prolonged survival, it doesn't at all explain why striking palliative benefits were not seen at any point during treatment. No information is available about the form in which this researcher administered ascorbate or any other details.

A study (Morishige and Murata, 1979; Murata, Morishige, and Yamaguchi, 1982) was carried out at two hospitals in Fukuoka, Japan. I have only been able to consult the second of these two references.

Ninety nine terminal cancer cases were treated with high dose ascorbate at the Torikai hospital and 33 at Kamioka Kozan hospital. Variable amounts of ascorbate were administered to these patients. At the Torikai hospital, it was found that the 44 patients who received 4 grams/day or less had a death rate about three times higher than the remaining 55 patients who received 5 or more grams/day. The average survival time of the high ascorbate group was 5.6 times as long as that of the low ascorbate group. At the time these data were reported, there were still three patients alive in the high ascorbate group and none in the low ascorbate group. The increased survival time in days was considerably higher for cancer of the uterus (642), than for stomach cancer (103), lung and bronchus (71), and remaining cases (286). No statistical tests were applied to these differences.

Survival times were also compared for the group that received 5-9 grams per day and for the group which received 10-29 grams/day. There was little difference between these groups. A group which received 30-60 grams/day had somewhat poorer survival times, but the authors thought that this might be because this group had the poorest prognosis to begin with. The same kinds of palliative effects were seen, as had been reported by Cameron et al; in particular better pain control.

Generally similar results were reported in the smaller group of patients at the second hospital.

Overall, this report supports the observations of Cameron and associates. However, this study suffers from the same kind of methodological problems as the Vale of Leven studies. This was an open (not double blind) trial with no formal control group. We don’t know how the decision was made to administer a particular dose to a particular patient and we can’t know that no bias entered into the selection of patients for high or low dose ascorbate. The critics who find the methodology of the Vale of Leven trials unacceptable would certainly also reject the evidence from this study.

Few details were provided about how ascorbate was administered in this study. The authors state that in some cases iv infusion was used, and that doses up to 30 grams a day were taken orally. This suggests that the ascorbate was administered as a solution rather than in the form of pills, because such large oral doses may be more manageable in a liquid form. It also seems natural that the authors would have chosen to use the same ascorbate solution as Cameron and his associates, but this remains specualtion.

In a later report (Morishige et al., 1986), evidence was presented for immune stimulation in cancer patients who received at least 10 grams of ascorbic acid iv along with chemotherapy. The inclusion of ascorbate was said to maintain natural killer cell function and pokeweed mitogen induced multiplication of B cells. These responses are ordinarily impaired by chemotherapy. In some patients the tuberculin skin test was also given. When ascorbate by itself was not able to maintain immune function as indicated by these measures, a million units of interferon (type unspecified) was added. Unfortunately, many details are missing from this presentation. Their data is presented graphically by plotting individual patient values, without averages or measures of statistical significance.

These authors also found that the level of Colony Forming Units (CFU) in the patients blood (an indication of hematopoietic function) declined with the course of chemotherapy. This effect could be reversed by administering an iv mixture of ascorbate and nucleic acids.

This group had earlier shown both in vitro and in vivo, (Kimoto et al., 1983) that the cytotoxic action of ascorbate could be enhanced by combining it with copper bound to a tripeptide, glycylglycylhistidine (GGH). Here they report on the use of GGH in a number of cancer patients. In one case, described in detail, iv ascorbate was supplemented by continuous close arterial infusion of GGH to the patient’s osteosarcoma. At other times, the patient took 20 mg/day of copper sulfate in combination with the ascorbate. With this treatment the bone lesion stopped taking up the radioactive tracer gadolinium and recalcified. Eventually the patient appeared to be fully recovered.

Accounts of A. Hanck's work with ascorbate are provided below. These are gathered from the fragmentary reports scattered through a number of Hanck’s papers. Descriptions of this work are provided incidentally in the course of general reviews of other topics relating to ascorbate. The papers by Hanck cited below are generally symposium presentations rather than peer reviewed journal articles.

Hanck (1982) indicates that his patients received between 10 and 15 gm/day of ascorbic acid. These patients, "...were not treated with cytostatics (‘cytotoxic’ chemotherapy') nor by radiation. Some of them had undergone operations which were only palliative." He says that because most of his patients had received treatment for less than a year it was impossible to be sure about the long term effects. However, he describes three patients who had been treated for at least a year and a half, and who showed "an extremely remarkable amelioration".

One patient with local recurrence of a head and neck tumor, (histologically demonstrated), became free from symptoms during daily treatment with 14g ascorbic acid. This treatment had lasted two and a half years when his report was written. Another patient was seen with an inoperable carcinoma of the bronchus. His general condition was initially very poor. During therapy with 15 g of ascorbic acid per day he gained body-weight and regained his full working capacity. The third patient suffered from a local recurrence of a breast carcinoma. This tumor regressed during combined treatment with interferon and high doses of ascorbic acid.

Hanck noted that all patients receiving high doses of ascorbic acid showed indications of immunostimulation, but significant biochemical changes could not be identified that accompanied ascorbate administration. Excreted ascorbate in high dose patients was 10 to 15% of the administered dose.

Hanck (1986) described research with rats in which clear anti-inflammatory and analgesic effects of ascorbate were demonstrated using standard tests. (This work is described at length in chapter eight.) He briefly refers to similar findings in patients: "This effect was demonstrable also in patients with pain caused by bone metastases in breast cancer and in osteosarcoma." These effects were seen with iv administration and elevation of plasma levels to one hundred times normal ascorbate levels. No side effects were seen with this treatment.

Hanck (1988) describes the results of an unpublished study which was the subject of a dissertation by S. Gupta. This study randomized cancer patients to either a radiation + placebo or to a radiation + ascorbate group. On each day of radiation therapy, the subjects received placebo or five grams of ascorbate (in five divided doses). All these patients had histologically confirmed and previously untreated cancers.

The pre-treatment plasma ascorbate levels in the treated and control groups were respectively, .45 and .46 mg/dl. By the end of treatment, the corresponding values were .65 and .33.

One month after the end of therapy, 87% of the ascorbate group had a complete remission versus 55% of controls, at four months the corresponding values were 63 and 45. At six months 67% of treated subjects were disease free vs 45% of controls. The treated group did better with respect to the side effects of radiation: anemia, pain, loss of appetite, and loss of weight. Unfortunately, this study is not described in much detail, and no statistical significance is given for group differences.

Hoffer and Pauling (1990), compared survival in a group of ascorbate treated cancer patients seen by Dr. Hoffer with some non-treated patients. Hoffer is a Canadian psychiatrist interested in nutritional medicine. He had become a well known and controversial figure in the 1960's when he began treating psychiatric patients with very large amounts of niacin. As was mentioned in chapter Four, Hoffer’s work (in collaboration with Humphry Osmond) had led Pauling to his original conception of "orthomolecular" psychiatry.

Hoffer’s vitamin C data were not the product of a formal study, but simply the accumulated records of psychiatric patients who had cancer, and for whom Dr. Hoffer had recommended nutritional cancer therapy. Of the 134 patients to whom Dr. Hoffer recommended this regimen, 33 chose not to follow it. Most of these patients were at an untreatable stage, but were still ambulatory which implies a less advanced stage than Dr. Cameron’s hospitalized patients. The data were analyzed using the Hardin-Jones statistic described above. Patients were grouped into relatively homogenous subsets, 33 non-compliant patients, 40 compliant female patients (all gynacological cancers), and a group of 61 compliant patients with other cancer types.

It was found that within each of these groups there was a relatively homogenous group of patients who could be identified and assigned a predicted survival time. There were 31 of these patients in the control group, and a total of 81 in the two treated groups. The predicted mean survival time was 5.7 months and 92 months respectively for the controls and experimental subjects. At the time the study was reported, only two of the 33 controls were still alive, while 47 had survived in the treated group.

Treatment described in this paper differed from that given at the Vale of Leven in that the dosing with vitamin C was different and there were major nutritional components in addition to ascorbate. Subjects were generally started on 12 grams per day of oral vitamin C, with the dosage increased to bowel tolerance. If patients could not take more than 12 grams per day orally, they might be started on iv administration. Subjects also generally received 1.5 or 3 grams/day of niacin or niacinamide (vitamin B3), 250 mg/day of pyridoxine (a form of vitamin B6), sometimes other B vitamins, 800 IU/day of vitamin E, 30,000 IU/day of Beta-carotene, 200 to 500 micrograms/day of selenium, and often additional dietary changes.

The usual methodological problems are present. This study cannot provide compelling evidence of anything because we can’t know for certain that there were no large prior differences between the groups which receiving the treatment and the group which did not. For instance, it might have been the case that the patients who refused to participate were consistently sicker than those who did choose to do so.

I believe this report still provides at least some suggestive evidence. While there could have been a strong bias of sicker patients to reject the nutritional therapy, it seem unlikely that this would be sufficient to produce the extremely large survival differences between treated and untreated patients. It is known that the treatment histories and mean ages of controls and treated groups were similar. The survival times are surprisingly long for the treated patients given that they were advanced cancer patients. With all its imperfections, this study still adds a little evidence for vitamin C’s anticancer effects.

An interesting feature of this study is the statement that 85% of both treated and control patients had previous exposure to conventional cancer therapy. Cameron and Pauling criticized the first attempt to replicate Cameron’s work at the Mayo Clinic because the patients in that study had almost all received prior cytotoxic therapy. But perhaps the range of agents used in addition to vitamin C makes such a comparison questionable. Of course we cannot separate out the effects of ascorbate from all the other agents used.

Hoffer and Pauling (1993) produced a similar analysis using a new group of psychiatric cancer patients treated by Dr. Hoffer. The results were very similar to those of the 1990 paper.

Hoffer (1995), provided an overview of treatment results to that date. He was now able to include a total of 600 patients in his analysis. Because of the longer follow ups available by 1995, he describes some of these patients as probably cured. He describes Q10 as an important addition to the treatment and discusses the improved quality of life of his treated patients .

Vitamin B3 seems to be an important part of this therapy. Unfortunately the value of a vitamin C/B3 combination has apparently never been tested in animal studies or in vitro.

Hoffer also provides anecdotal accounts (Hoffer, 1995), of patients with advanced cancer, whose probability of spontaneous recovery would seem to have closely approached zero. When these patients recovered with Hoffer’s treatment and in the absence of conventional treatment, it was difficult to imagine, that anything other than this treatment could have been responsible.

One of the most interesting and important attempts to develop an ascorbate cancer therapy has been carried out at the Bio-Communications Research Institute in Wichita, Kansas. This is an organization affiliated with an alternative medicine treatment center. Here a small group of researchers, has systematically attempted both to develop the clinical use of ascorbate as a cancer therapy, and to provide a scientific understanding of ascorbate’s cytotoxic effects. While this group has published most of their papers in alternative, or "fringe" venues (e.g. Medical Hypotheses and The Journal of Orthomolecular Medicine), recently they also published a paper in the mainstream, British Journal of Cancer (Casciari et al, 2001).

The clinical side of their work began with the treatment of a small number of cancer patients in their own practice. As early as 1980, they began using relatively modest intravenous vitamin C doses (like those used by Cameron). They gradually shifted to the use of much larger iv doses (e.g. more than 100 grams), supplemented with continuing oral ascorbate. More recently, beginning in 1998, they have carried out phase I and Phase II FDA approved trials with renal adenoma patients at the University of Nebraska Medical Center. This work was discribed briefly in Life Extension Foundation (2003, pp, 252-5) and Riordan (2003). Riordan et al (2003) provide practical guidelines for the use of high dose intravenous ascorbate. A more recent paper by this group (Riordan et al, 2005) is apparently an account of the Phase I study mentioned above. To date I have not been able to consult this article, but only the abstract available on PubMed.The Life Extension article tells us that the methods being used by Riordan et al in the FDA approved trials have been patented.

In their own practice, they treated patients who either had refused conventional therapy, had specifically requested to be treated with ascorbate, or whose oncologist had said that more conventional therapy would be useless. It appears that as of 2000, (Riordan et al., 2000), they had treated a total of ten such cases. In most they saw the patient’s condition stabilize or actual tumor regression.

These authors have done a good deal of work with prostate cancer. They have concluded that high dose iv ascorbate cannot directly kill prostate cancer cells, but can still produce major benefits. With ascorbate treatment the disease does not progress in the expected way. They suggest that this may be due to increased collagen synthesis which helps to immobilize prostate cancer cells and prevent invasion and metastasis.

It is also mentioned that they are combining ascorbate with vitamin B12, evidently in response to the reports of Poydock et al (described in Chapter 7), which showed that the effects of ascorbate or dehydroascorbate could be greatly enhanced when these compounds were complexed with the cobalt present in vitamin B12. Riordan et al also believe that ascorbate’s effects can be potentiated by lipoic acid, vitamin K, selenium, quercetin, niacinamide, biotin, and grape fruit seed extract.

It is of interest that this program investigating ascorbate therapy, known by the acronym REGNAC, has been largely supported by a single philanthropist for about a decade. In the whole history of vitamin C as a possible cancer therapy, this may be the only long term and adequately funded program of research and development.

In basic research supporting the clinical work, this group looked at the effects of progressively higher doses of intravenous ascorbate, testing the safety and the resulting plasma ascorbate levels. They ended up giving doses above 100 grams They studied the pharmacokinetics of ascorbate and developed a mathematical model of how plasma levels change as a function of infusion rate and duration .

They also measured the toxicity of ascorbate to cultured cancer cell lines (Casciari et al., 2001;Riordan et al., 1995, 2000). Cancer cell killing was studied in standard cell cultures and in a hollow fiber model that was supposed to provide a more realistic model of the situation of cancer cells in vivo. They systematically examined the effects of ascorbate in combination with other compounds. In some cases they were able to demonstrate additive (vitamin K3) or synergistic effects (alpha lipoic acid). In some experiments they tied this cytotoxicity assessment back to their clinical work by culturing cancer cell lines in plasma which had been sampled from their patients during treatment. These investigations told them that higher plasma ascorbate levels were required for cytotoxicity than could be obtained through oral doses or through the dosages which were typical in earlier use of intravenous ascorbate against cancer. All-in-all, this work represents a major advance toward a scientifically sound cytotoxic therapy based on ascorbate.

Using levels of ascorbate attainable with orally administered ascorbate (2 to 4 mg/dl), they showed that cultured tumor cells increased their collagen production (Riordan (2003). This corresponds to the observation by this group of hardening and lack of progression of ascorbate treated prostate cancers.

The in vitro studies of this group are discussed in more detail in chapter Seven.

Another publication in which this research group participated (Gonzalez et al, 2002), presents evidence that the production of hydrogen peroxide is the main process responsible for the anticancer effects of high dose ascorbate. This is a theme which is examined at length in Chapter Seven.

Another study in which members of this group participated (Kim et al, 2003), looked at the effect of alternative high vitamin C dosing and vitamin C restriction in nine patients who had been unsuccessfully treated for acute myeloid leukemia (AML). This was in response to the finding that in vitro, both very high and very low ascorbate levels reduced growth of leukemic cells. A response to the therapy was seen in five of the nine patients. It is interesting that this treatment combines in a unique way the previously reported anticancer effects of both ascorbate deprivation and ascorbate supplementation. The effects of ascorbate deprivation in cancer are discused later in this chapter, and in Chapter 7.

How does the work of this group relate to the Vale of Leven trials? These authors note that the cytotoxic concentrations for most cancer cell lines are well above the plasma concentrations that are produced by oral ascorbate. They take this as an indication that the therapeutic effects observed in the Vale of Leven trials must not be due to a direct cytotoxic effect. The suggested alternative is some form of immunostimulation or increased collagen synthesis, which would reduce cancer cell invasiveness. On the other hand, (as discussed in chapter 7) there is a great variability in the sensitivity of different cell lines to ascorbate and it does not seem impossible that some of the regressions and the hemorrhagic destruction of tumors reported by Cameron et al could represent direct cytotoxic effects against cancers which were exceptionally sensitive to vitamin C.

Riordan was one of the authors of a paper (Padayatty et al, 2004), which examined the plasma and urinary concentrations produced by various amounts of ascorbate administered either orally or intravenously. The subjects were volunteers who had been maintained for long periods on a vitamin C deficient diet. The authors conclude that intravenous doses can produce plasma levels 30 to 70 times higher than the maximum produced by an oral dose in this study. This article takes a very conservative stance on the use of oral vitamin C supplements which seems strangely at variance with Dr. Riordan’s position on vitamin C use in his other papers.

It is also stated in this article that what distinguished the successful Vale of Levin trials from the unsuccessful Mayo Clinic trials, was iv rather than oral administration. From this it is argued that the negative evidence of the Mayo Clinic studies cannot negate the findings of Cameron et al because of the procedural differences at the Mayo Clinic and at Vale of Leven. Similar views of these issues are presented in Padayatty and Levine (2001).

However, as was pointed out in the discussion of Cameron’s work, and will be discussed at length in the next chapter, it is not true that Cameron’s subjects all received iv ascorbate. A significant fraction of his patients received only oral ascorbate and some of this subgroup showed the same dramatic effects as patients who received iv ascorbate.

Padayatty et al (2004) also argue that ascorbyl radical has only been detected in animals intravenously receiving the equivalent of 10 grams in a human being. They argue that the ascorbyl radical is responsible for the direct cytotoxic effects directed against cancer cells. Therefore, the lower concentrations ingested orally, cannot have meaningful effects against cancer. As we will see in chapters 7 and 8, there are quite a number of possible anticancer mechanisms of ascorbate besides direct cytotoxic effects and these might be invoked to explain anticancer effects that appeared with oral administration. In some animal studies (reviewed in Chapter 7), anti-cancer effects are certainly seen with orally administered ascorbate.

Meyer and Orgel (1950) described their treatment of advanced cancer patients with vitamin C and a product extracted from trees affected by plant cancers. The results they describe in advanced cancer patients are intriguing and curiously reminiscent of the benefits which Cameron reported. Their references to ascorbate complexed with metallic ions recall reports of effective combinations of ascorbate and transition metal ions against cancers in experimental animals. (These are described in Chapter 7). The treatment was administered im or iv. Unfortunately, the report of this work suffers from an astonishing vagueness about the dosages and the nature of the preparations used in this therapy. There are other publications by these authors which I have not yet been able to consult. Perhaps this information can be found there (Meyer and Orgel, 1949; Meyer and Exner, 1953).

But in any case, some of the claims made for this treatment are as follows. The ascorbate treatment was said to reduce oedema, and thereby reduce "...spasm, obstruction, and irritative symptoms, etc." Tumors sometimes showed substantial shrinkage. In some cases there was histological evidence that with treatment tumors showed "...marked fibrosis associated with patchy areas of degeneration and necrosis often making identification of the original tumour impossible." "There is an extremely wide margin between the therapeutic and the toxic dose. There are no unpleasant side effects..." "In Hodgkins and leukaemias it was found to have a remarkable effect on the neoplastic cell while at the same time improving the blood picture."

When both ascorbate and the tree derived agent were used together, the following effects were reported. Note that increased radio-sensitivity of tumors with treatment (item six) is supported by some reports from the literature on ascorbate effects in animals (Chapter 7).

1 Immediate freedom from pain.

2 Improved sense of well-being and increased activity.

3 Increase in appetite and improved blood picture.

4 Disappearance of toxic symptoms such as vomiting and diarrhoea.

5 In some cases tumor shrinkage

6 Increased radio-sensitivity.

In judging which of the above effects are being attributed to ascorbate, we might want to subtract the effect attributed to the other agent administered. The substance derived from trees was said to dramatically reduce pain without dulling consciousness, reduce temperature when elevated, reduce the cancer marker ESR (Erythrocyte Sedimentation Rate), and reduce symptoms due to irritation or obstruction. On the other hand, these benefits have also been attributed to ascorbate in the reports reviewed earlier in this chapter.

Brief case reports are provided for 15 treated individuals.

A nutritionally oriented medical doctor published a popular book about vitamin C and cancer (Newbold, 1979). He described his first experiences treating a cancer patient with ascorbate. He was able to report a dramatic improvement of the patients’s symptoms, when after a course of chemotherapy and radiation, she was switched to high dose vitamin C and additional nutrients. Her cancer (oat cell lung cancer) failed to progress in the expected way. At the time of publication this patient had been treated for less than a year. Newbold also had success treating skin cancers with a combination of ascorbate ointment and oral ascorbate.

In addition to talking with Pauling, Cameron, and Cameron’s coworker Alan Campbell, Newbold interviewed three additional doctors who were treating cancer patients with high dose vitamin C. These three had experience with a total of about 150 patients, most of them terminal. All were in agreement that in these patients vitamin C had a primarily palliative role. The most dramatic effects were relief of pain and an improved sense of well being. In some cases, their debilitated terminal patients were able to resume normal activities. Tumor progression was temporarily stopped, but would eventually resume. In some cases, tumor shrinkages were seen, though these were always temporary. One of the doctors spoke of a delay of about six months in disease progression. Except in skin cancer cases cures were exceptional. One of these doctors had also treated skin cancers with a combination of ascorbate ointment and oral ascorbate, and like Dr. Newbold, had reported "Very, very good" results.

One of the doctors interviewed, (Dr. Kalokerinos) reported hemorrhage at tumor sites in several patients following ascorbate. This was associated with tumor shrinkage. In one case the patient ‘s death was attributed to this hemorrhagic reaction.

One of the interesting features of these treatments is the size of the doses and how much ascorbate these patients were able to handle orally. All these doctors regarded iv administration as unnecessary if patients tolerated oral ascorbate well. Patients would often be started on iv ascorbate with 30 to 60 grams a day, then switched over to divided oral doses which might total over 70 grams per day.

These doctors generally felt that vitamin C worked well in combination with conventional cytotoxic therapies, reducing side effects without impairing treatment effectiveness. However, one of them, Dr. Saccoman, thought that ascorbate was conspicuously less effective in some patients who had received extensive prior chemotherapy.

Finally, Newbold cites the work of a physician who had asked not to be named, who did claim to cure cancers. This doctor used much higher doses of ascorbate, taken orally to bowel tolerance, and supplemented with 60 grams intravenously on most days. This doctor also initially combined ascorbate with 200,000 unit of vitamin A per day. This would be maintained until the patients hair started to fall out. At this point, vitamin A would be reduced to 150,000 units per day. This treatment was supposed to regularly shrink tumors and produce real cures. It is likely that this doctor who wished to remain nameless worked in California, a state which had especially draconian laws restricting unconventional cancer treatments.

The two Australian doctors interviewed by Newbold later published a collection of testimonials attesting to the remarkable results of ascorbate in a variety of conditions (Kalokerinos et al, 1982). Many of these refer to striking improvements in cancer patients given ascorbate. The relief of pain in both cancer and non-cancer patients was emphasized. One of their unidentified correspondents had worked with a large group of terminal cancer patients (106 of them) and generally saw benefits, including in almost all cases, relief of pain. They even have a report from a veterinarian whose report of benefits in animals is said to help exclude the role of placebo effects. This report has a radical and exuberant tone which is likely to irritate conservative readers. Such readers of course, are free to dismiss this evidence as merely "anecdotal".

Cheraskin et al. (1968), reported that cervical cancer patients had a dramatically improved response to radiation when they received 750 mg/day of ascorbate together with a fairly elaborate nutritional regime. Of course the relatively small dose of vitamin C and the unknown role of the other nutritional changes make it harder to relate this to Cameron’s work.

Frederick Klenner, a doctor who has described his 30 years of experience using high doses of ascorbate in a variety of conditions, mentions in passing a few cases in which ascorbate was used against cancer (Klenner, 1971). He notes that he was able to remove several skin cancers (small basal cell epitheliomas) with 30% ascorbate in an ointment.

Waddell and Gerner (1980) reported on the combined effect of indomethacin (a non-steroidal anti-inflamatory) and ascorbate, on desmoid tumors in two patients. (Desmoid tumors are relatively rare, scar-like cancers of connective tissue.) In one of these patients, an initial tumor regression was induced by indomethacin. When four months later, rapid growth resumed, five grams of ascorbate per day was added. This resulted in a prompt and rapid reduction in tumor size. This regression continued more slowly thereafter. In the second patient, ascorbate (initially 3 and then 5 gm/day) and indomethacin produced a gradual reduction in tumor size over about two years. Thereafter, tumor growth resumed and it was necessary to control this with X-ray treatment.

Allan Campbell coauthored the 1974 paper which provided the main clinical description of ascorbate effects at the Vale of Leven (Cameron and Campbell, 1974). He seems to have continued on his own to use ascorbate in treating cancer patients. There is a report by Campbell and Jack (1979) of three cases in which high dose ascorbate produced fever, pain and swelling at the site of the tumor. These patients experienced severe problems atributed to compression of the tumor’s surroundings. In one case there was an obstruction of the airways. Two of these patients were given conventional chemotherapy to quickly reduce tumor size. In the other case, after ascorbate administration was stopped, it was gradually resumed and was believed to have produced benefits. Later, when conventional therapy was begun, the subject continued on ascorbate.

Campbell and Jack believed what they saw in these patients was the same "tumor necrosis" phenomenon reported by Cameron and Campbell (1974). Here there was no direct observation of necrosis, and in only one of the patients was there a close temporal connection (response within 36 hours) with the onset of ascorbate therapy. The authors are primarily concerned with pointing out the very serious problems associated with this necrotic response if ascorbate therapy is not begun gradually.

Van der Merwe (1984), administered a combination of gamma linolenic acid and ascorbate to 11 advanced liver cancer patients and increased the mean survival time to 90 days (versus 42 days for historical controls). One of the 11 treated patients was still alive after 314 days of treatment and showed tumor regression. These results of course can only be considered suggestive.

Luhrs and Bacigalupo (1959), building on work done in vitro and in experimental animals (described in Chapter Seven), treated cancer patients with DHA (dehydroascorbate) the oxidized form of ascorbate. This is of interest because of the possibility that breakdown products of ascorbate might be responsible for some of ascorbate’s reported anticancer effects. Evidence supporting this possibility is presented in chapters 7 and 8. In particular, there is the experience of Poydock et al, who worked with ascorbate, which, upon analysis, was found to contain large amounts of DHA.

Luhrs and Bacigalupo administered daily intravenous doses of approximately 2 mg/kg to their patients. They state that "...dehydroascorbic acid alone cannot impede a fully developed tumor with additional metastasis." However, they discuss two cases in which lung metastases were successfully treated with DHA after removal of the primary tumor. In one case, treatment was continued for one month, and in the second case for two. In this brief report no information is given about the total number of patients treated, or long term survival in the patients successfully treated for lung metastases.

The doses used seem surprisingly small. With an average male weighing something like 70 Kg, this would be a dose of only 140 mg. It is also true, that the DHA might be fairly quickly reduced back to vitamin C in the body.

Lamm et al (1994) compared the effects of daily megadose vitamins (40,000 units vitamin A, 100 mg B6, 1 gram vitamin C, 400 units of vitamin E, and 90 mg zinc) vs RDA amounts of these vitamins in groups of bladder cancer patients. These patients were also receiving therapy with one of two levels of treatment with BCG (Bacillus Calmette-Guerin), either administered into the bladder alone, or into the bladder and percutaneously. This was a randomized double blind study.

No significant differences in recurrence were seen during the first 10 months. The authors point out that this would be expected of a chemoprevention trial with slowly acting nutrients. Recurrences after the first year were 37% in the RDA group and 9% in the megadose group (p=.008). The estimated 5 year recurrence rates for the RDA group were 91% and 41% in the megadose group (p=.0014). Overall long term survival rates were very similar for both groups, (74% RDA and 76% megadose), but the megadose group showed much longer interval to recurrence (mean survival time of 33 months for the megadose group vs 18 months for the RDA group).

This study has the usual problem of not distinguishing the effects of vitamin C from those of the other nutrients which accompanied it. It is also true that the ascorbate dose was rather small, and the reported differences between groups might have been reduced because this was a comparison between "megadoses" vs RDAs rather than a comparison between "megadoses" and no supplementation.

The Early German Language Literature on Ascorbate and Cancer

We will now consider some very early evidence for benefits of vitamin C in cancer patients. These effects were generally seen with intravenous administration of ascorbate, and with amounts no more than four grams per day. These studies appeared in German language medical journals from the late 1930s through the 1950s. This work seems to have been very much part of the mainstream medicine of its time, but later would be almost completely forgotten. Although a few of these papers were cited by Cameron and Pauling, this work does not seem to have made much of an impression either on them or on the enemies of ascorbate therapy.

It is true that most of these early reports provide only clinical impressions and case histories, rather than the results of formal experiments. Perhaps the fact that only palliative effects were reported with vitamin C also discouraged interest. The only reports of tumor regressions occurred when vitamin C was used in combination with vitamin A and even these were very rare. Nonetheless, it seems to me that the consistency of those reports makes a convincing case for the reality of ascorbate's palliative effects in cancer. These early reports show striking agreement with those of Cameron and his