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Fig. 1. Effect of ascorbic acid on rectal polyps in primary study group. |
Evidence for dehydrogenation by fecal bacteria in the genesis of colon cancer suggested that an antioxidant might modify these mechanisms. Ascorbic acid, 3 Gm. daily, was given to five patients who had active rectal adenomatous polyp formation long after ileorectal anastomosis for familial polyposis. During a 4 to 13 month study, rectal polyps disappeared in two, regressed partially in two, and increased in one. Among three additional treated patients with rectal polyps, one had a reduction in polyps and two were unaffected.
From the Departments of Surgery and Pathology, Vince Lombardi Colon Clinic, Medical College of Wisconsin, Milwaukee, Wis.
RECENT EVIDENCE has implicated anaerobic bacteria in the genesis of colon cancer. 8 In contrast to low-incidence areas, people from high-incidence areas of colon cancer have a higher proportion of gut anaerobes able to dehydroxylate bile acids, a higher proportion of lecithinase-negative clostridia able to dehydrogenate the steroid nucleus, and greater fecal concentration of degraded neutral and acid steroids. 7 Some steroid metabolites presumably are carcinogenic. 4, 12 If dehydrogenation by anaerobic bacteria in the colon lumen induces neoplasia, the effect might be modified by oral administration of a reducing agent.
A curious fact about familial polyposis, an inheritable premalignant disease, is spontaneous regression of residual rectal adenomatous polyps in some patients after total colectomy and ileorectal anastomosis. 2, 9, 20 Exposure of the rectal mucosa to ileal contents appears to be a prerequisite for spontaneous regression because adenomatous polyps disappear only in the rectum and not in otherwise defunctionalized colon in familial polyposis. 3 This evidence suggested that the rectum of a patient with an ileorectal anastomosis for familial polyposis was a sensitive setting to test the effect of an orally administered reducing agent. Other reasons for selection of patients with ileorectal anastomoses were that a rapid intestinal transit time provided more intensive exposure of rectal mucosa to the reducing agent, the entire remaining target mucosa was accessible to periodic direct surveillance, and a larger number of polyps permitted better quantitation of response.
Five patients were selected for study because they had a diagnosis of familial polyposis, a colectomy and an ileorectal anastomosis done sufficiently remote in time that spontaneous regression could not be incriminated, and active polyp formation at the time the study was initiated. These patients comprise the primary study group. Two additional patients had a colectomy and an ileorectal anastomosis sufficiently close to start of the study (1 and 3 months before) that spontaneous regression could explain decreased polyp formation. One patient had an intact colon with multiple rectal polyps but negligible polypoid disease above the rectosigmoid.
At each patient’s initial visit, detailed information was obtained about previous treatment in order to assess the rate of polyp formation. Patients were provided a thorough explanation about possible risks and informed consent was obtained. Adenomatous polyps were mapped by proctoscopy, measured, and, in some instances, photographed. Representative polyps were removed by biopsy for histologic examination. A specimen of venous blood was obtained for screening studies.
Ascorbic acid (Ascorbicap, ICN Pharmaceuticals, Inc., Irvine, Calif.), 1 Gm. in timed-release capsules, was administered three times each day. The timed-release pellets within the gelatin capsule have an 8 to 10 hour life. Several of the patients noted sporadic appearance of undissolved pallets [pellets] in their feces.
Patients were reassessed at 2 month intervals by historical review, proctoscopy, and repetition of laboratory studies. Invariably, proctoscopy was performed by two professional observers, and occasionally by a third. For comparative purposes, the number of polyps was divided by the centimeters of rectum examined to obtain the polyp density (PD). When many polyps were present, counts must be regarded as best estimates. Patients were studied for possible consequences of long-term ingestion of large amounts of ascorbic acid.
Patient 1. In 1953, a 32-year-old woman (Pedigree III, Number 9 of Schutte 18) had a colectomy and an ileorectal anastomosis. Electrodesiccation of small polyps was performed on six occasions between 1956 and 1963. After a lapse of 7 years, ten small polyps were desiccated in 1970. In October, 1973, 30 polyps were excised or electrocoagulated from the patient, now age 52. In January, 1974, 29 rectal polyps were counted in 17 cm. of remaining rectum (PD = 1.7). Ascorbic acid therapy was initiated. After 6 months, two polyps were found (PD = 0.1); at 7 months, six small polyps were observed (PD = 0.33). One was excised and interpreted as adenomatous. After 10 months, two small polyps (PD = 0.12) were found. At that time ascorbic acid was reduced to 2 Gm. each day. In February, 1975, 13 months after initiation of treatment, no polyps were observed on proctoscopy. The ascorbic acid concentration of a fresh fecal sample was measured 16 and was 125 mg. per gram of dry weight as contrasted with 24.5 mg. per gram of dry weight in a control not receiving ascorbic acid.
Patient 2. In 1957, a 17-year-old man had a colectomy and an ileorectal anastomosis (Pedigree II, Number 10 of Schutte 18). Thereafter, proctoscopy was performed periodically with removal of polyps in the rectal segment. In 1973, 25 polyps were electrodesiccated. In August, 1974, when the patient was age 34, 45 polyps ranging up to 8 mm. in diameter were found in a 16 cm. rectal segment (PD = 2.8). Ascorbic acid treatment was initiated. Two months later, 43 polyps were counted on proctoscopy to 19 cm., the level of the ileoproctostomy (PD = 2.26). Four were removed by biopsy; all were adenomatous. After four months of ascorbic acid, 21 polyps were enumerated to 17 cm. (PD = 1.2). One polyp was biopsied and interpreted as adenomatous. After 6 months of ascorbic acid therapy, 17 polyps up to 9 mm. in diameter were counted to 17 cm. (PD = 1.0).
Patient 3. In 1964, a 25-year-old woman had a subtotal colectomy and proctocecostomy. In excess of 100 polyps were found in the excised colon. Proctocecoscopy was performed thereafter at 6 month intervals; several polyps were removed each year. In October, 1974, 12 sessile polyps, ranging from 3 to 5 mm. in diameter, were found in the remaining rectal and cecal segment (PD = 0.6) the patient was age 35. Two polyps were removed; both were adenomatous. Ascorbic acid treatment was initiated. Two months later, two small sessile polyps were observed (PD = 0.1). At 4 months, no polyps could be found.
Patient 4. In 1954, a 22-year-old woman underwent colectomy and ileorectal anastomosis. Familial polyposis was well documented in her family. For the subsequent 9 years, rectal polyps were removed annually. She was not examined from 1963 until 1971, when one polyp was electrodesiccated. In October, 1973, six polyps were removed, and in April, 1974, 12 polyps were removed or electrodesiccated. In November, 1974, when the patient was age 44, nine polyps from 2 to 5 mm. in diameter were mapped in a 20 cm. segment of retained rectum (PD = 0.45). One was excised and interpreted as adenomatous. Ascorbic acid therapy was initiated. Two months later, five polyps were found on proctoscopy to 20 cm. (PD = 0.25). After four months, two small polyps, each 2 mm. in diameter, were found (PD = 0.1).
Patient 5. In 1968, a 50-year-old man had a colectomy and an ileoproctostomy. 10 In excess of 200 polyps as well as a 1.5 x 2 cm. adenocarcinoma were present in the colon specimen. During the ensuing 7 months, nine to 15 rectal polyps were removed at bimonthly intervals. During the following 18 months, no polyps were described. Then polyps were detected with increasing frequency. In January, 1974, four polyps were removed; in March, 1974, 12 polyps were excised or coagulated. In September, 1974, 15 polyps up to 4 mm. in diameter were found on proctoscopy to 20 cm. (PD = 0.75); the patient was age 56. Ascorbic acid therapy was initiated. Two months later, 20 polyps were counted to 22 cm. (PD = 0.91). Two adenomatous polyps were removed as biopsies. After four months of ascorbic acid therapy, proctoscopy to 25 cm. revealed 27 polyps (PD = 1.1). One was removed and interpreted as adenomatous. Six months after initiation of treatment, 28 polyps up to 3 mm. in diameter were counted to 25 cm. (PD = 1.1).
Patient 6. In 1974, a 23-year-old woman had onset of bloody diarrhea. There was an extensive family history of colon cancer and polyps but no prior recognition of familial polyposis. In November, 1974, a colectomy and an ileorectal anastomosis were performed. In excess of 200 polyps up to 1.5 cm. in diameter were found in the resected colon. Forty adenomatous polyps, ranging up to 8 mm. in diameter, remained in the 14 cm. retained rectal segment (PD = 2.9). Ascorbic acid therapy was initiated in December, 1974. Two months later, proctoscopy to the anastomosis at 14 cm. showed 33 polyps (PD = 2.4). One was removed. After 4 months, proctoscopy showed 50 small polyps ranging up to 4 mm. in diameter (PD = 3.6). The ascorbic acid concentration in the feces was in excess of 125 mg. per gram of dry weight.
Patient 7. In May, 1974, a 55-year-old man had a colectomy and an ileorectal anastomosis. The specimen showed in excess of 100 polyps. In August, 1974, 31 polyps, ranging up to 4 mm. in diameter, were counted on proctoscopy to 17 cm. at the site of the ileorectal anastomosis (PD = 1.9). Ascorbic acid therapy was initiated. Two months later, 41 sessile polyps were counted (PD = 2.6). Two were removed; both were adenomatous. Four months after initiation of ascorbic acid, 26 polyps were counted in the rectal segment (PD = 1.6). One was removed. After six months of ascorbic acid, 36 polyps, ranging up to 4 mm. in diameter, were counted (PD = 2.1).
Patient 8. In August, 1974, routine proctoscopy in an asymptomatic 59-year-old woman demonstrated multiple rectal polyps. The family history included a brother who had died of abdominal cancer, but no other evidence of familial polyposis. Barium enema examination and colonoscopy showed that polyps were confined to the rectal mucosa. In November, 1974, proctoscopy to 15 cm. demonstrated eight polyps ranging from 4 to 8 mm. in diameter (PD = 0.53). Two were removed; both were adenomatous. Ascorbic acid treatment was initiated. Two months later, proctoscopy to 15 cm. demonstrated four polyps (PD = 0.27). At 4 months, three polyps, 4, 4, and 7 mm. in diameter, were found (PD = 0.19).
Of the five primary study patients with familial polyposis and a remote colectomy, rectal polyps regressed completely in two, partially in two, and increased in one (Fig. 1). Among the entire group of eight patients under treatment with ascorbic acid, rectal polyps regressed completely in two and partially in three and were not changed or increased in three.
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Fig. 1. Effect of ascorbic acid on rectal polyps in primary study group. |
Of the two patients who experienced complete regression of polyps, one patient had 29 polyps (one was removed as a biopsy) at the beginning of 13 months of treatment, and the other had 12 polyps (two removed) at the initiation of 4 months of therapy.
Of the three patients who had a partial regression of polyps, one regressed from 45 polyps to 17 (five removed) during six months of treatment, one from nine polyps to two (one removed) during 4 months of treatment, and one from eight polyps to three (two removed) during 4 months of treatment. The last patient is the only one with an intact colon.
Among the three patients who were unaffected by ascorbic acid, polyps increased from 15 to 28 (three removed) during 6 months of treatment, from 31 to 36 (three removed) during 6 months of treatment, and from 40 to 50 (one removed) during 4 months of follow-up, respectively. The latter two patients had ascorbic acid started shortly after colectomy and ileorectal anastomosis.
Of the three patients who had partial regression, remaining polyps appeared unchanged or larger in one (Patient 2) and smaller in two (Patients 4 and 8). Of the three patients who had no reduction in number of polyps, remaining polyps appeared unchanged in two (Patients 5 and 7) and possibly smaller in one (Patient 6).
Histologic review confirmed the adenomatous nature of the rectal polyps sampled. Larger polyps were fully adenomatous, although some had villous elements. Smaller polyps often had substantial hyperplastic components. There was no correlation between histological appearance and response to treatment. Nothing was observed that was histologically suggestive of an ascorbic acid effect.
We found no harmful effects of ascorbic acid in the dosage and for the period administered. No symptoms were attributed to ascorbic acid; in particular, there was no urolithiasis. All pretreatment venous blood ascorbic acid levels were normal, and they remained normal during treatment. Because of a report of interference with vitamin B12 absorption by ascorbic acid, 6 serial serum B12 levels were obtained. All were normal. Hematocrit, red blood cell count, platelet count, and erythrocyte sedimentation rate remained normal in all patients. Serum creatinine, calcium, phosphorus, total protein, albumin, alkaline phosphatase, bilirubin, blood urea nitrogen, serum cholesterol, and glucose also were normal or unchanged from pretreatment values.
Ascorbic acid reduced the number of rectal polyps in five of eight patients treated for 4 to 13 months. Four of five responders were patients who had active, and, in some, accelerating rectal polyp formation many years after an ileorectal anastomosis for familial polyposis. One responder with an uncertain history of familial polyposis had an intact colon. In two patients, polyps have disappeared. Maintenance on ascorbic acid has been too brief to assess the likelihood of recurrence.
One caveat must be raised: long-term cyclic variation in polyp formation may occur in patients with familial polyposis. The past histories of Patients 4 and 5 suggest this possibility. Although the natural history of isolated colon polyps is regarded generally as one of slow progressive growth, there is some evidence of occasional regression. Of 213 patients followed for 3 to 5 years with isolated, untreated colorectal adenomatous polyps, two patients developed adenocarcinoma, 17 (8 percent) had a decrease in size of the polyp, and 38 (18 percent) had the polyp disappear. 11
Complete disappearance of polyps in two of our patients and a major reduction of polyps in three others, beyond the temporal limits of spontaneous regression and in excess of any errors of counting, have not been observed previously. We attribute this effect to ascorbic acid. These results suggest that some neoplastic lesions of the colon may be reversible by pharmacologic measures.
The mechanism for action of ascorbic acid is not known. A high concentration of ascorbic acid was measured in the feces of two patients and was likely to have been present in all. A direct effect on intestinal bacteria and fecal steroid metabolism is hypothesized, although other systemic and local pathways are possible. 5, 13, 14, 21
Ascorbic acid has known antitumor effects in experimental animals, presumably from its antioxidant properties. Experimental bladder tumor formation due to 3-hydroxyanthranilic acid 17 is inhibited by ascorbic acid, as are 7,12-dimethylbenzanthracene and croton oil skin carcinogenesis. 19
To the extent that the likelihood of developing rectal cancer is related to the presence and number of polyps in the retained rectum, the important issue from our studies is the possibility of reducing the risk of cancer. The risk of developing rectal cancer in familial polyposis is related to the number of polyps present. 15 Rectal cancer has not been observed in polyposis patients who sustained a spontaneous regression. 22 The rarity of colon cancer in Bantu natives has been associated with the rarity of colon polyps. 1 The duration of follow-up is much too short for any inferences from our patients.
We thank Drs. A. Schutte, W. Boulanger, H. Goldberg, W. Hogan, J. Pinkerton, W. Schulte, and B. Seidel for support.
From Surgery, November, 1975, Vol. 78, No. 5, pp. 608-612
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