The Cancer Journal - Volume 8, Number 2 (March-April 1995)
Aspirin and prevention of colorectal cancers
There is an increasing corpus of experimental and epidemiological data suggesting that aspirin, and some other non-steroidal anti-inflammatory drugs (NSAID), exert a chemopreventive action on colorectal cancers and maybe also on stomach, oesophagus (1), and even bladder (2), cancers.
It is now time to summarize the important facts, outline the prospects, and establish priorities. Four classes of compound contribute toward the major developments in cancer chemoprevention : retinoic acid derivatives, b-carotene, tamoxifen, aspirin and NSAID. A number of convergent epidemiological results have brought aspirin and NSAID into the limelight. The risk of colorectal cancer in subjects who regularly take low doses of aspirin or certain NSAID over long periods is significantly reduced. The correlation between the intake of these drugs and the incidence of colorectal cancer has been observed in a wide variety of contexts leaving little doubt that the association is not one purely due to chance. We are now faced with a decision. How can we best exploit this important finding in order to achieve rapid results, how can we improve the results in the short term ?
The frequency with which men and women fall victim to colorectal cancer is comparable and both sexes benefit from the protection afforded by aspirin and NSAID. The first observations, made in 1988 (3), were quickly confirmed in other human studies and also in experimental work on rats (4,5). In rats and humans, the preventive action relates to colorectal cancers and colon adenomas. However, in one study, aspirin doses large enough to prevent myocardial infarct did not significantly reduce the incidence of colorectal cancer (6). Do the results of this prospective study diminish the relevance of case-controlled studies proving the contrary ? Probably not. The discrepancy might be accounted for by differences in dose.
The mechanisms of action of aspirin and NSAID on the colon remain unelucidated. They do not induce bleeding of the adenomas and cancers and thereby facilitate early detection. Other anticoagulants afford no protection. Aspirin and NSAID would appear to have a direct antineoplasic action. All known active substances act by decreasing cyclooxygenase synthesis - Cox2 rather than Cox1 (7) - but the involvement of this mechanism in the reduction of colon cancer risk is for the moment just a plausible and sketchy hypothesis.
The issue at stake is the reduction of the incidence and mortality associated with one of the most frequent cancers encountered in man. A clear survey of the main questions and possible answers cannot be postponed without seriously prejudicing health.
a) Should campaigns of chemoprevention using aspiring or NSAID be instigated straightaway ?
b) If so, should they be restricted to subjects at risk, i.e., to subjects with a family syndrome of high risk for colon cancer, or with a high-susceptibility gene, or with a positive hemoccult test ?
c) Or, on the other hand, should prevention be extended to all subjects ? If so, to which age categories ?
d) How can iatrogenic risk be reduced so that the benefits expected from chemoprevention are really positive ? Experience tells us that the side-effects of long-term administration of pharmacological doses of aspirin or NSAID are not rare but they should not be a reason for withholding chemopreventive treatment from the many subjects who tolerate these drugs well. Although caution incites us to screen all subjects liable to suffer from side-effects, in the name of progress the others should be informed of the known advantages of the long-term use of these drugs and be encouraged to use them.
e) The choice between aspirin, available NSAID, and NSAID yet to be invented is rather academic. Aspirin is cheap and most subjects know whether they tolerate it well or not. The dice are therefore loaded.
f) The highly prevalent and harmful idea that it is necessary to understand the pharmacological mechanisms of action of chemoprevention before instigating any such prevention should be quashed. Regardless of ruling stereotypes, decisions have to be taken in perfect ignorance of the cause but with perfect certitude of acting in the right direction. Progress in reducing deaths from colorectal cancer has been so slow ....
g) Whatever the mechanism of action of aspirin, one or several endogenous factors, functionnally aspirin-like (endaspirin/s), or stimulated by aspirin, may exist and participate in colic homeostasis.Their deficiency would be a factor of carcinogenesis.These factors should be characterized.
This highly effective and cheap drug - aspirin - continues to incriminate the errant ways of post-modern pharmacologists whose obsession with safety and whose mental rigidity are crushing factors in the stagnation pervading the field of cancer.
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2. Earnest DL, Hixson LJ, Alberts DS. Piroxicam and other cyclooxygenase inhibitors - Potential for cancer chemoprevention. J Cell Biochem Iss. S161, 156-166, 1992.
3. Kune GA, Kune S, Watson LF. Colorectal cancer risk, chronic illnesses, operations and medications: case control results from the Melbourne Colo-rectal Cancer Study. Cancer Res. 48, 4399-4404, 1988.
4. Reddy BS, Rao CV, Rivenson A et al. Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in 1344 rats. Carcinogenesis 14, 1493-1497, 1993.
5. Davis AE, Patterson F. Aspirin reduces the incidence of colonic carcinoma in the dimethylhydrazine rat animal model. Austral N Zealand J Med. 24, 301-303, 1994.
6. Gann PH, Manson JE, Glynn RJ et al. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Nal Cancer Inst. 85, 1220-1224, 1993.
7. Heath CWJr, Thun MJ, GreenbergERet al. Non steroidal antiinflammatory drugs and human cancer: Report of an interdiciplinary research workshop. Cancer 74, 2885-2888, 1994.