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In this issue of the British Journal of Cancer , Collett et al (1999) report on an interesting, and until now mostly missing, piece of the jigsaw puzzle concerning the relationship between colorectal cancer risk and the use of non-steroidal anti-inflammatory drugs (NSAIDs). Waddell, in 1983, was the first to report on the results of the treatment of four patients with multiple colorectal polyps with Sulindac, one of the drugs in the class of NSAIDs (Waddell and Loughrey, 1983). All his patients showed a remarkable regression and even disappearance of the polyps when given Sulindac. After the publication of this first case-series, another nine papers reporting on a total of 100 patients were published. It is quite remarkable that overall a 100% response rate was found in these 100 patients. That is to say, in all the patients the polyps in the large intestine either disappeared completely or greatly diminished in size and number. It also has to be noted that these initial patients treated with Sulindac were patients with polyposis related to hereditary conditions, such as GardnerÕs syndrome or familial polyposis coli, who had undergone a subtotal colectomy for their underlying disease. Therefore these patients are not really comparable to the average patient with a sporadic adenomatous polyp. In addition to these early clinical results, a large number of animal-experimental studies was performed evaluating the effect of NSAIDs on colorectal cancer in a variety of animal models. These studies were done using different NSAIDs, under often different circumstances and with a variety of outcome and effect measures. Virtually all of the animal-experimental work confirms the results of the clinical case-series: administration of NSAIDs reduces the risk and the prevalence of indicators for colorectal carcinogenesis. The next question was obviously to evaluate the effect Ð if any Ð of the use of these drugs on colorectal cancer risk in humans. Virtually all descriptive epidemiological studies (Berkel et al, 1996) have shown an inverse relationship between use of NSAIDs and subsequent colon cancer risk, suggesting a protective effect. Among the epidemiological studies were cohort studies, and caseÐcontrol studies performed in different settings and among different populations. In addition, a reduced incidence of colorectal cancer was found in several populations who were often prescribed these drugs for other diseases, i.e. patients with rheumatoid disorders. All these pieces of the puzzle taken together make for an overall picture which is very suggestive of a causeÐeffect relationship. Several pieces of the puzzle were still missing, however, and questions remained in particular with regard to doseÐresponse and duration of use required to have a protective effect; in particular, since in the only reported intervention study, the Physicians Health Study, no beneficial effect of low-dose aspirin (325 mg on alternate days) on colorectal cancer risk was observed after 5 years of follow-up (Gann et al, 1993). In the Nurses Health Study a significant trend in protective effect was found with longer duration of use among women who took 32 aspirins (Giovannucci et al, 1995). The largest risk reduction was found in women who used aspirin consistently for > 20 years (relative risk = 0.56). The question of induction and latent period (Ôhow long does it take before an effect is evident?Õ) was eloquently addressed in the study by Collet, reported in this issue of the journal (Collet et al, 1999). In a non-concurrent cohort linkage study, linking the population-based cancer registry with the database of the provincewide drug prescription plan in the province of Saskatchewan, Canada, the investigators were able to show that it took 310 years for a protective effect of NSAID use to become apparent. Although this result seems to be consistent with the earlier results from the Nurses Health Study, there are some questions about the reliability of their conclusions: because of the fact that the investigators used the Drug Prescription database, there is a distinct possibility for mis-classification bias. On the one hand there is an obvious underestimate of exposure: no data are available about so-called Ôover the counterÕ drug use, and since aspirin is an over the counter drug and is/has been widely available without prescription for a large mixed group of disorders, a differential trend in use over time could seriously impact the results. On the other hand, being given a prescription does not necessarily mean that the drugs are indeed used. In addition, since the investigators choose not to evaluate Ð for a variety of good reasons Ð the effects of individual NSAIDs, but rather use a composite measure of overall use, it is not clear which of the NSAIDs Ð if any Ð is preferable. Despite the potential pitfalls of this study, it contributes significantly to the ever growing body of research which has suggested that NSAIDs have a protective effect on colorectal cancer development in humans. At least three patho-physiological mechanisms have been suggested to explain this beneficial effect. Firstly, it appears that certain prostaglandins, in particular prostaglandin E2, can inhibit cellular immune responses which are important in the host defense against malignant cells. NSAIDs, through their inhibitory effect on the cyclo-oxygenase (COX) enzymes, block the production of prostaglandin E2 and thus may inhibit prostaglandin-dependent immunosuppression, allowing augmentation of the anti-tumour aspects of the cellular immune response. Secondly, through its inhibitory effects on the two COX enzymes, COX-1 and COX-2, the arachidonic acid metabolism is influenced. Marnett (1992) concluded that there was overwhelming support for the notion that influences on arachidonic acid metabolism contribute to the carcinogenetic process in humans and that it is therefore possible to modulate carcinogenesis through, for example, the use of COX-inhibitors. Finally, recently it has been suggested that NSAIDs may exert their protective effect through

Does an ‘aspirin-a-day’ keep the doctor away?