ASCORBIC ACID DOES NOT CURE CANCER

A prospective, double-blind randomized trial of 10 g ascorbic acid given daily to patients with advanced adenocarcinoma of the colon and rectum, not previously

treated by Chemotherapy, showed no increased survival.

Key Words: vitamin C, ascorbic acid, adenocarcino- ma, colorectal cancer, cancer, chemotherapy, blad- der cancer, N-butyl-N-(4-hydroxybutyl)nitrosamine, tumor initiation, tumor promotion, ascorbate, dehy- droascorbate

For more than ten years, ascorbic acid (vitamin C) has had a reputation as an agent that can inhibit or even cause regressions of malignant tumors when taken in large doses. This view was derived principally from three publications, beginning with one by Cameron and Camp- bell,’ followed by two from Cameron and Pau- ling.*f3 In their studies, comparisons were made between a selected group of 50 patients with terminal cancer receiving 10 g ascorbate per day and a control group of 1000 cancer patients selected from past records of the hos- pital in which the treatment took place. Survival time was a mean of 293 days or more in the ascorbate-treated patients, compared to 38 days in control patients. This spectacular re- sult, which included five objective tumor re- gressions, led to a prospective randomized double-blind study by Creagan et al.4 of the Mayo Clinic. In this experiment, the survival rates of ascorbic acid-treated (10 g daily) and placebo-treated patients were identical.

Pauling5 objected to these results, on the grounds that most patients in the Mayo Clinic study had been subjected to chemotherapy pri- or to ascorbic acid treatment. Because Paul- ing’s hypothesis was that ascorbate may function by enhancing host resistance to the tumor, or generally by potentiating the body’s own protective mechanism, cytotoxic agents such as those used in chemotherapy may have prevented the ascorbic acid from exerting its action. The Mayo Clinic group6 then carried out a new study that duplicated the experimental conditions of Cameron and Pauling, except that the investigation was a prospective, ran- domized, double-blind study restricted to 100 patients with metastatic colorectal carcinoma who had not received chemotherapy. More-

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over, this treatment is generally ineffective for that type of cancer. Because the study was double-blind and randomized, the control group was current and not historical.

Patients were entered into the study at the time the unresectable disease was diagnosed. Sites of metastases and measurable areas of malignancy were determined. After breaking the treatment code, the balance of prognostic factors in the treated (n=51) and control (n = 49) groups was found to be adequate. Pa- tients were in good condition, ambulatory, with minimal symptoms and working full- or part- time. Ascorbic acid therapy was well-tolerated. Nearly 90 percent consumed at least 75 per- cent of the dose. Compliance was checked by daily patient records as well as by urinalysis of 11 patients: five of these, who were later found to belong to the ascorbic acid group, had at least 2 g ascorbic acid per 24-hour urine sam- ple. Five of the placebo group had negligible ascorbic acid excretion. One placebo-treated patient had an intermediate value, possibly re- lated to his diabetic condition, which may have caused the presence of interfering substances in the urine.

Two criteria were used to evaluate treatment efficacy, the time until “tumor progression” was detectable and the time of survival from entry into the study. Time of “tumor progression” was arbitrarily fixed as the time when 1) there was an increase of more than 50 percent in the product of the perpendicular diameters of any measurable area of known malignant disease, 2) new areas of malignant disease appeared, 3) there was a substantial worsening of symp- toms or performance status or 4) there was a loss of body weight of ten percent or more. The curves of the ascorbic acid and the placebo (lactose) groups with time from initiation of treatment to “tumor progression” plotted against percent not “progressed” were prac- tically superimposable. (Statistical analysis showed that the likelihood that ascorbic acid produced even a 25 percent increase in time

between treatment initiation and “tumor pro- gression” was extremely low, p- 0.01 .) Surviv- al time curves for ascorbic acid and placebo groups were also very similar, with 49 and 47 percent, respectively, surviving the first year. Again, there was no likelihood that ascorbic acid produced even a 25 percent increase in survival time over placebo (p = 0.01 7). In fact, survival was somewhat greater in the placebo group. No measurable tumor shrinkage oc- curred in any patient.

To summarize both ascorbic acid trials of the Mayo Clinic group (with and without prior chemotherapy), the authors state that: “Well over 200 patients have failed to demonstrate any perceptible antineoplastic effect of high- dose vitamin C for advanced cancer.”‘ How, then, can one explain the spectacular success in treatment by Cameron and P a ~ l i n g ? ~ , ~ It was probably a question of selection bias in choosing the control group. The Mayo Clinic authors6 point out that in their first study5 they selected, as Cameron and Pauling did, patients for whom chemotherapy and other treatments had failed. The resulting survival times for both ascorbic acid and control groups were found to be comparable to those of the selected, un- treated control patients of Cameron and Pauling. In the present study,‘ the Mayo Clinic group selected patients who had not had che- motherapy, but who had a better prognosis on the basis of showing no symptoms and leading almost normal lives. This time the ascorbic acid and control groups both resembled the ascor- bic acid-treated patients of Cameron and Pau- ling. Thus, the historical survival times of untreated patients with a disease as complex as cancer are of no value in assessing a subse- quent therapeutic study.

This study lays to rest the ghost of the theory that megadoses of ascorbic acid will cure ad- vanced cancer. As an editorial by Wittes7 points out, however, the entire case is not yet closed. In vitro, ascorbate has inhibited the growth of nonlymphoblastic leukemia cellsa

and potentiated the cytotoxicity of various drugs or hormone^.^ On the other hand, a re- cent report“ showed that a very high dietary level of sodium ascorbate (5.0 percent of the diet), which led to high levels of urinary sodium ascorbate and dehydroascorbate, could pro- mote tumor formation in the urinary bladder of rats. Rats were given a single dose of the blad- der carcinogen N-butyl-N-(4-hydroxybutyl)ni- trosamine, sufficient to initiate the process of bladder carcinogenesis, but not sufficient to cause actual tumors. When the high-dose (5.0 percent of the diet) sodium ascorbate was fed, hyperplasia, papillomas and tumors resulted. The authors suggested that this effect may not depend on a direct promoting action of ascor- bate, but rather, may be a result of a high level of an anion (ascorbate and dehydroascorbate) in urine, similar to the bladder tumor-promoting action of high doses of saccharin in male rats. 0

1. E. Cameron and A. Campbell, Chem. Biol. Inter- act. 9: 285-315, 1974

2. E. Cameron and L. Pauling, f roc. Natl. Acad.

3. E. Cameron and L. Pauling, Proc. Natl. Acad.

4. E.T. Creagan, C.G. Moertel, J.R. O’Fallon, A.J. Schutt, M.J. O’Connell, J. Rubin and S. Frytak, New Engl. J . Med. 301 : 687-690, 1979

5. L. Pauling, New Engl. J. Med. 302: 694, 1980 6. C.G. Moertel, T.R. Fleming, E.T. Creagan, J.

Rubin, M.J. O’Connell and M.M. Ames, New Engl. J . Med. 312: 137-141, 1985

7. R.E. Wittes, New Engl. J. Med. 312: 178-179, 1985

8. C.H. Park, M. Amare, M.A. Savin and B. Hoog- straten, Cancer Res. 40: 1062-1 065, 1980

9. K.N. Prasad, P.K. Sinha, M. Ramanujam and A. Sakamoto, Proc. Natl. Acad. Sci. USA 76: 829- 832, 1979

10. S. Fukushima, K. Imaida, T. Sakata, T. Oka- mura, M. Shibata and N. Ito, Cancer Res. 43:

Sci. USA 73: 3685-3689, 1976

Sci. USA 75: 4538-4542, 1978

4454-4457, 1983

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