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ANTIOXIDANT VITAMINS OR LACTULOSE AS CHEMOPREVENTIVE AGENTS FOR COLORECTAL CANCER
ANTXOXIDANT VITAMINS OR LACTULOSE AS CHEMOPREVENTIVE AGENTS FOR COLORECTAL CANCER
L. Roncucci and M. Ponz de Leon Istituto di Patologia Medica, Policlinico, via Del Pozzo, 71, University of Modena, 41100 Modena, Italy
1
INTRODUCTION
Colorectal adenomas are the natural precursors of most cancers of the large intestine.l.2 Adenomas are usually removed during colonoscopy, but they frequently recur.’ Recently several compounds have been proposed as chemopreventive agents for various human tumours.4 Among them some vitamins and unabsorbable carbohydrates might be suitable for intervention studies in colon cancer prevention. In particular, vitamins A, C and E are wellknown antioxidants and inhibit carcinogenesis in experimental mode1s.4f5 Lactulose lowers the pH of the intestinal environment,6 thus reducing the rate of production of toxic secondary bile acids.’ Thus we evaluated the effect of vitamins A, C and E or lactulose on the recurrence rate of colorectal adenomas after endoscopic polypectomy. 2
METHODS
Patients and Study Desian Two hundred and fifty-five subjects were randomized in 3 endoscopic units into 3 groups after colonoscopic removal of one or more polyps of the large intestine. Group 1 was given vitamin A (30,000 I.U./die), C (1 g/ die) and E (70 mg/die). Group 2 was administered lactulose (20 g /die). Group 3 did not receive any treatment. After enrolment, subsequent endoscopic examinations were planned at 6-8, 12-18 and 24-36 months. Index and subsequent colonoscopies allowed the examination of the entire large intestine in all individuals. Recurred polyps were removed and processed for pathological examination: colonic subsite, hystotype and maximum diameter of adenomas were recorded. Compliance to the treat-
Food and Cancer Prevention: Chemical and Biological Aspects
148
ment was assessed by asking individuals during and at the end of the follow-up whether they continued to take the scheduled treatments. No attempt was made in order to change the dietary habits of the study population. pata Analysis Only subjects with adenomas at index colonoscopy were included in the analysis, according to the "intention to treat" criterion, though 40 individuals did not complete the scheduled treatment. Only adenomas recurred after 1 year since the last colonoscopy were considered not missed by the endoscopist. Kaplan-Meier survival curves were used to estimate the probability of remaining free of adenomas, and the statistical si nificance among groups assessed with the log-rank test Univariate stratified survival analyses were carried out to identify clinical and morphological variables of adenomas at index colonoscopy which could have affected adenoma recurrence. Furthermore a Cox's multivariate regression model was used to adjust for those variables.
.'
3
RESULTS
Of 255 randomized subjects, 46 were excluded from the analysis because their polyps were not adenomas. Two hundred and nine individuals were actually evaluated with an average follow-up time of 18 months. The probability of remaining free of adenomas was significantly different among the 3 groups (log-rank X2 = 17.138, p
Number of subjects with adenoma recurrence, by treatment group
Treatment
Total no. o€ subjects evaluated
No. of subiects with recurrence
70
4 (5.7%)
Lactulose
61
9 (14.7%)
None
78
28 (35.9%)
Vitamins
Total
209
Overall X2 = 22.608 (p
41
Antioxidant Vitamins or Lactulose as Chemopreventive Agents
149
Subsite of recurrence, histotype and diameter of recurred adenomas were similar in the 3 treatment groups. 4
DISCUSSION
The results of the present randomized controlled study show that either antioxidant vitamins or lactulose are effective in reducing the recurrence rate of colonic adenomas after endoscopic polypectomy. Since adenomas are considered precursor lesions of the large majority of colorectal cancers, these findings are consistent with a putative chemopreventive role for these compounds. The anticancer effect of antioxidant vitamins is largely unknown. These vitamins, especially retinoids, are inhibitors of carcinogenesis in several experimental models.' Furthermore, vitamins C and E reduced the recurrence rate of adenomas in some clinical trials.'*'' Finally, antioxidant vitamins can reverse the upward expansion of the proliferative compartment of normal colonic crypts, observed in patients with colorectal tumours." Intracolonic bile acids are promoters of experimental colon carcinogenesis." Lactulose can acidify the intestinal content, because it enhances the production of short chain fatty acids. At pH below 6 the degradation of primary to secondary (more toxic and cancerpromoters) bile acids is reduced because the bacterial 7 alpha-dehydroxylase is inhibited." As we did not assess the dietary habits of the study population, we cannot exclude the influence of other dietary factors on the results of the present study, although they should have had the same weight in the 3 treatment groups. Vitamin A may cause liver damage." However, we observed only one case of toxicity in the vitamins group (pruritus with no skin damage). Moreover, vitamin E seems to be protective against retinol-induced injury to cells." Lactulose may cause diarrhoea, but it is possible to control this side effect adjusting the daily dose. In our study only 3 subjects had to withdraw the intake of lactulose because of diarrhoea. In conclusion the results reported here suggest an effect of antioxidant vitamins or lactulose as chemopreventive agents for colorectal cancer. A large-scale use of these substances is not justified yet. However they can be proposed to subjects at high risk for malignancy of the large intestine, as members of families with hereditary non-polyposis colorectal cancer or familial adenomatous polyposis, or subjects with large, villous, multiple or frequently recurrent colonic adenomas. Larger numbers of subjects and further studies are needed to validate these results, and to test chemopreventive agents in groups of individuals at increased risk for cancer of the large intestine.
Food and Cancer Prevention: Chemical and Biological Aspects
150
REFERENCES 1.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12. 13. 14. 15.
B.C. Morson, Cancer, 1974, 2&, 845. C.M. Fenoglio, et al., pathol. &nu., 1975, U , 87. 1982, l4, 79. J.D. Waye and S. Braunfeld, WOSCODY, 1987, U ,3012. J.S. Bertram, et al., Cancer P.M. Newberne and V. Suphakarn, Cancer, 1977, a, 2553. 608. C. Florent, et al., J. Clin. Invest., 1985, 1987, a, G.P. van Berge Henegouwen, et al., 675. 1. R. Peto, et al., Br. J. Cancey, 1977, H.J.R. Bussey, et al., Gancez, 1982, 5Q, 1434. G. McKeown-Eyssen, et al., Cancer Res., 1988, 48, 4701. G.M. Paganelli, et al., J. Natl. Cancer Inst 1992, 89, 47631. B.I. Rainey, et al., gr. J. Cancey, 1984, J.R. Thornton, m e e t , 1981, 1, 1081. A.P. Geubel, et al., -teroloav, 1991, 1701. J.N. Hathcock, et al., Bg\. J. Clin. N utr., 1990, 183.
m.,
m, a,
x,
.,
u, m,
=,
L. Roncucci and M. Ponz de Leon Istituto di Patologia Medica, Policlinico, via Del Pozzo, 71, University of Modena, 41100 Modena, Italy
1
INTRODUCTION
Colorectal adenomas are the natural precursors of most cancers of the large intestine.l.2 Adenomas are usually removed during colonoscopy, but they frequently recur.’ Recently several compounds have been proposed as chemopreventive agents for various human tumours.4 Among them some vitamins and unabsorbable carbohydrates might be suitable for intervention studies in colon cancer prevention. In particular, vitamins A, C and E are wellknown antioxidants and inhibit carcinogenesis in experimental mode1s.4f5 Lactulose lowers the pH of the intestinal environment,6 thus reducing the rate of production of toxic secondary bile acids.’ Thus we evaluated the effect of vitamins A, C and E or lactulose on the recurrence rate of colorectal adenomas after endoscopic polypectomy. 2
METHODS
Patients and Study Desian Two hundred and fifty-five subjects were randomized in 3 endoscopic units into 3 groups after colonoscopic removal of one or more polyps of the large intestine. Group 1 was given vitamin A (30,000 I.U./die), C (1 g/ die) and E (70 mg/die). Group 2 was administered lactulose (20 g /die). Group 3 did not receive any treatment. After enrolment, subsequent endoscopic examinations were planned at 6-8, 12-18 and 24-36 months. Index and subsequent colonoscopies allowed the examination of the entire large intestine in all individuals. Recurred polyps were removed and processed for pathological examination: colonic subsite, hystotype and maximum diameter of adenomas were recorded. Compliance to the treat-
Food and Cancer Prevention: Chemical and Biological Aspects
148
ment was assessed by asking individuals during and at the end of the follow-up whether they continued to take the scheduled treatments. No attempt was made in order to change the dietary habits of the study population. pata Analysis Only subjects with adenomas at index colonoscopy were included in the analysis, according to the "intention to treat" criterion, though 40 individuals did not complete the scheduled treatment. Only adenomas recurred after 1 year since the last colonoscopy were considered not missed by the endoscopist. Kaplan-Meier survival curves were used to estimate the probability of remaining free of adenomas, and the statistical si nificance among groups assessed with the log-rank test Univariate stratified survival analyses were carried out to identify clinical and morphological variables of adenomas at index colonoscopy which could have affected adenoma recurrence. Furthermore a Cox's multivariate regression model was used to adjust for those variables.
.'
3
RESULTS
Of 255 randomized subjects, 46 were excluded from the analysis because their polyps were not adenomas. Two hundred and nine individuals were actually evaluated with an average follow-up time of 18 months. The probability of remaining free of adenomas was significantly different among the 3 groups (log-rank X2 = 17.138, p
Number of subjects with adenoma recurrence, by treatment group
Treatment
Total no. o€ subjects evaluated
No. of subiects with recurrence
70
4 (5.7%)
Lactulose
61
9 (14.7%)
None
78
28 (35.9%)
Vitamins
Total
209
Overall X2 = 22.608 (p
41
Antioxidant Vitamins or Lactulose as Chemopreventive Agents
149
Subsite of recurrence, histotype and diameter of recurred adenomas were similar in the 3 treatment groups. 4
DISCUSSION
The results of the present randomized controlled study show that either antioxidant vitamins or lactulose are effective in reducing the recurrence rate of colonic adenomas after endoscopic polypectomy. Since adenomas are considered precursor lesions of the large majority of colorectal cancers, these findings are consistent with a putative chemopreventive role for these compounds. The anticancer effect of antioxidant vitamins is largely unknown. These vitamins, especially retinoids, are inhibitors of carcinogenesis in several experimental models.' Furthermore, vitamins C and E reduced the recurrence rate of adenomas in some clinical trials.'*'' Finally, antioxidant vitamins can reverse the upward expansion of the proliferative compartment of normal colonic crypts, observed in patients with colorectal tumours." Intracolonic bile acids are promoters of experimental colon carcinogenesis." Lactulose can acidify the intestinal content, because it enhances the production of short chain fatty acids. At pH below 6 the degradation of primary to secondary (more toxic and cancerpromoters) bile acids is reduced because the bacterial 7 alpha-dehydroxylase is inhibited." As we did not assess the dietary habits of the study population, we cannot exclude the influence of other dietary factors on the results of the present study, although they should have had the same weight in the 3 treatment groups. Vitamin A may cause liver damage." However, we observed only one case of toxicity in the vitamins group (pruritus with no skin damage). Moreover, vitamin E seems to be protective against retinol-induced injury to cells." Lactulose may cause diarrhoea, but it is possible to control this side effect adjusting the daily dose. In our study only 3 subjects had to withdraw the intake of lactulose because of diarrhoea. In conclusion the results reported here suggest an effect of antioxidant vitamins or lactulose as chemopreventive agents for colorectal cancer. A large-scale use of these substances is not justified yet. However they can be proposed to subjects at high risk for malignancy of the large intestine, as members of families with hereditary non-polyposis colorectal cancer or familial adenomatous polyposis, or subjects with large, villous, multiple or frequently recurrent colonic adenomas. Larger numbers of subjects and further studies are needed to validate these results, and to test chemopreventive agents in groups of individuals at increased risk for cancer of the large intestine.
Food and Cancer Prevention: Chemical and Biological Aspects
150
REFERENCES 1.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12. 13. 14. 15.
B.C. Morson, Cancer, 1974, 2&, 845. C.M. Fenoglio, et al., pathol. &nu., 1975, U , 87. 1982, l4, 79. J.D. Waye and S. Braunfeld, WOSCODY, 1987, U ,3012. J.S. Bertram, et al., Cancer P.M. Newberne and V. Suphakarn, Cancer, 1977, a, 2553. 608. C. Florent, et al., J. Clin. Invest., 1985, 1987, a, G.P. van Berge Henegouwen, et al., 675. 1. R. Peto, et al., Br. J. Cancey, 1977, H.J.R. Bussey, et al., Gancez, 1982, 5Q, 1434. G. McKeown-Eyssen, et al., Cancer Res., 1988, 48, 4701. G.M. Paganelli, et al., J. Natl. Cancer Inst 1992, 89, 47631. B.I. Rainey, et al., gr. J. Cancey, 1984, J.R. Thornton, m e e t , 1981, 1, 1081. A.P. Geubel, et al., -teroloav, 1991, 1701. J.N. Hathcock, et al., Bg\. J. Clin. N utr., 1990, 183.
m.,
m, a,
x,
.,
u, m,
=,