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An important determinant in interpreting the results of colorectal polyp chemoprevention trials is the rate of polyps missed during colonscopic examination. We prospectively examined 90 patients by tandem colonoscopy performed by two alternating examiners. In 69 (76.7%) patients, 221 neoplastic lesions were documented histologically. Of a total of 58 lesions detected in 31 patients, no neoplastic lesion greater than or equal to 10 mm in size was missed; 16% of diminutive (less than or equal to 5 mm) neoplastic polyps and 12.3% of medium-sized (6-9 mm) neoplastic polyps were missed by the first examiner. We conclude that an experienced colonoscopist will miss about 15% of colorectal neoplastic polyps less than 10 mm in size in the setting of adequate bowel preparation. Large (greater than or equal to 10 mm) polyps were rarely missed, however, with the "miss" rate in our study equal to 0, with a 95% confidence limit of 4.64%.

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Nonsteroidal antiinflammatory drugs (NSAIDs) have considerable potential as chemopreventive agents for colorectal cancer. Recent case-control drug surveillance and large cohort studies found that patients with regular aspirin use had a reduced incidence of colorectal cancer and/or decreased death rate from this disease. Several different NSAIDs reduce formation of both colon adenomatous polyps (the precursor lesion of colon cancer) and cancers in experimental animals given known carcinogens. Perhaps most convincing are reports that the NSAID sulindac promotes regression and inhibits recurrence of adenomatous colon polyps in patients with adenomatous polyposis coli. The best characterized pharmacologic effect of the NSAIDs is their reduction of prostaglandin synthesis by inhibiting prostaglandin synthetase PGE,, which catalyzes the formation of prostaglandin precursors from arachidonic acid. Several lines of evidence are contrary to the concept that inhibition of prostaglandin synthesis is central to the NSAIDs' chemopreventive effects. Relatively high levels of prostaglandins have been reported to inhibit tumor cell growth both in viva and in nitro, and to inhibit differentiation in some tumor cell lines. We evaluated comparative chemopreventive effects on colon tumor formation in an azoxymethane ( A0M)-induced colon carcinogenesis rat model using the NSAIDs piroxicam, sulindac, and sulindac sulfone, a metabolite of sulindac which lacks the anti-prostaglandin synthetase activity typically associated with NSAID-induced gastrointestinal toxicities. The results demonstrate that sulindac sulfone, a compound lacking anti-prostaglandin synthetase activity, inhibits AOM-induced colon cancer in rats. Substantial dose-dependent reductions in both tumor burden and tumor multiplicity were observed in the sulindac sulfone-treated animals. Although both piroxicam and sulindac significantly reduced rat colonic mucosal PGE, levels to less than 50% of their AOM control value, even the highest dietary concentration of sulindac sulfone had no statistically significant effect on mucosal PGE, concentrations. These results suggest that NSAIDs do not exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase. Non-steroidal antiinflammatory drugs (NSAIDs) are the most promising chemopreventive agents for colorectal cancer. Three case-control drug surveillance studies and one large cohort study found that patients with regular aspirin use had a reduced incidence or decreased death rate from colorectal cancer 11-41. Furthermore, recently published case-control [5] and cohort [61 studies show a significantly lower incidence of colorectal adenomas in subjects reporting regular aspirin intake. Among patients enrolled in a randomized trial of antioxidant vitamins, those who took aspirin regularly had an appreciably lower probability of having an adenoma detected at their one year follow-up colonoscopy [71; however, in the Physicians' Health Study [a], regular aspirin use, at a dos...

Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) widely used for treatment of inflammatory arthritis. Recent experimental and clinical studies suggest that piroxicam, as well as other NSAIDs, may be useful for chemoprevention of colon cancer. While there is less information regarding NSAlDs for chemoprevention of urinary bladder malignancy, there are compelling data which suggest that this should be evaluated.A major effect of NSAlDs is inhibition of cyclooxygenase, the rate-limiting enzyme for conversion of arachidonic acid to important signal molecules, including prostaglandins, which profoundly affect cellular functions in many tissues. The initial enzyme reaction leading to formation of prostaglandin H can be accompanied by cooxidation of xenobiotics resulting in extrahepatic and local tissue production of reactive products which are carcinogenic. The end product prostaglandins, especially prostaglandin E2 (PGEz), are biological modifiers which can significantly affect cell proliferation and tumor growth. High levels of PGE2 stimulate growth of certain tumor cell lines while inhibition of prostaglandin synthesis with indomethacin or piroxicam can cause suppression. The mechanisms for this effect are unclear. Studies in cultured cells exposed to indomethacin show inhibition of GI-to-S phase progression of the cell cycle and a reduction in overall DNA synthesis. It is unclear whether this effect on cell growth results from some direct action of the NSAID or a reduction in prostaglandins or indirectly from modulation of important control signals, such as calcium flux. In addition to cyclooxygenase, NSAlDs can inhibit activity of other enzymes, including phosphodiesterases and cyclic GMP-AMP protein kinases, which may be central to cancer initiation and promotion. NSAlDs can also interfere with transmernbrane ion fluxes and with cell-to-cell binding.Prostaglandins can modulate a variety of immunological responses and thereby play an important role in host antitumor immunity. For example, high levels of tissue PGE2 are frequently associated with suppression of immune surveillance and killing of malignant cells. Conversely, immune responses are generally enhanced by drugs that inhibit prostaglandin synthesis. PGE2 can act as a feedback inhibitor for cellular immune processes, such as T-cell proliferation, lymphokine production, and cytotoxicity. This effect is also seen for rnacrophage activity and natural killer cell toxicity. In general, either increased production of PGE2 or increased sensitivity to normal amounts of PGE2 results in depressed cellular immunity. Cyclooxygenase inhibitors (NSAIDs) such as piroxicam which decrease PGE2 production can stimulate cellular immune function both in vifro and in viva.A variety of tumor cell lines and human malignancies produce large quantities of prostaglandins. O f interest, the concentration of PGE2 is increased in certain prernalignant lesions, such as benign adenomatous colon polyps, and further increased incancerouscolontissue. Thisobservation, take...