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ABSTRACT & COMMENTARY
Synopsis: A history of nonsteroidal anti-inflammatory drug use was examined in a large series of cancer patients and controls from the United Kingdom. Long-term use was associated with a decreased risk of colorectal, esophageal, and gastric cancer, but possibly an increased risk of pancreatic and prostatic cancers. No effect was seen on the development of breast or bladder cancer. Perhaps these findings are related to the known increased expression of the COX-2 gene in many of these tumors.
Source: Langman MJ, et al. BMJ 2000;320:1642-1646.
Previously published data has suggested an association of aspirin, or other nonsteroidal anti-inflammatory drug (NSAID) use and a reduced risk of certain malignancies.1-3 The purpose of this study was to use a large database to establish whether this is true for the common malignancies in the United Kingdom. Langman and associates from the University of Birmingham examined data that had been contributed to a large U.K. database managed by the Department of Health. This database includes medical information, contributed by physicians throughout the United Kingdom, on more than 4 million individuals. During a two-year period (1993-1995), there were 12,174 people who first developed either gastrointestinal (esophagus, stomach, colon, rectum, or pancreas) or nongastrointestinal (bladder, breast, lung, or prostate) cancers. Each case was matched for age, sex, and general practice site with three controls. Langman et al went on to determine the relative risk for determining each of the cancers in the context of anti-inflammatory drug use (by prescription). The threshold for anti-inflammatory drug use was considered seven filled prescriptions over the previous three years.
Examining the data as a whole, it did not appear that the overall incidence of cancer was influenced by the use of anti-inflammatories. However, there did appear to be a protective effect against cancer of the esophagus (odds ratio 0.64, 95% confidence interval 0.41-0.98), stomach (0.51, 0.33-0.79), colon (0.76, 0.58-1.00), and rectum (0.75, 0.49-1.14), with dose-related trends. The risk of pancreatic cancer (1.49, 1.02-2.18) and prostatic cancer (1.33, 1.07-1.64) was increased among patients who had received anti-inflammatories but the trend was dose-related for only pancreatic cancer.
Langman et al concluded that anti-inflammatory drugs protected against esophageal, gastric, colon, and rectal cancers. They also have pointed out that these drugs may predispose to pancreatic and/or prostate cancer but they suggested that these observations might reflect undetected biases or chance error.
COMMENT by william b. ershler, md
In the United Kingdom, aspirin and other NSAIDs are available by prescription; thus, quantifying use may be estimated by filled prescriptions. This, and the large database maintained by the Department of Health, made this study feasible. What was found were trends toward reduced incidence of colorectal cancers among people taking these drugs, with the greatest reductions among those receiving more prescriptions. This is, more or less, a confirmation of other epidemiological studies, either cohort or case control.1-3 However, the findings for esophageal and gastric cancer also showed protection and the results of prior surveys were not nearly as positive. This may be because of the size of the current database, which allowed confirmation of a trend that was observed, but not statistically significant in earlier, smaller studies.3,4 In the current study, the protective effect of anti-inflammatory drugs was comparable for gastric and esophageal when compared to colorectal carcinomas. However, the study did not reveal any protection against nongastrointestinal tumors. This runs counter to other published reports in which aspirin, or other nonsteroidals, were shown to protect against breast cancer.5
The finding of an increased risk of pancreatic cancer is curious but must be interpreted with caution. This diagnosis is often difficult to make, and patients might be treated with NSAIDs for their analgesic properties in advance of the diagnosis thereby providing the appearance of an association. The same may also be true for the findings with prostate cancer, as undiagnosed back pain, ultimately proven to be metastatic disease, might initially be treated with NSAIDs.
Certainly, there has been no proven mechanism whereby NSAIDs protect against gastrointestinal malignancies. However, it should be noted that the cyclooxygenase-2 (COX-2) gene is overexpressed in many tumor types, including colon, esophagus, stomach, and breast,6 and perhaps inhibition NSAID exposure inhibits tumorigenesis by inhibition of that enzyme. Future studies of specific COX-2 inhibitors in the context of cancer prevention will be of value.
1. Giovannucci E, et al. Ann Intern Med 1994;121:241-246.
2. Klan R, et al. J Cancer Res Clin Oncol 1993;119:482-485.
3. Thun MJ, et al. Cancer Res 1993;53:1322-1327.
4. Farrow DC, et al. Cancer Epidemiol Biomarkers Prev 1998;7:97-102.
5. Harris RE, et al. Oncol Rep 1999;6:71-73.
6. Prescott SM, et al. Biochim Biophys Acta 2000;1470:69-78.