Cruz-Correa et al.88 studied the effects of sulindac in 12 FAP patients with a mean age of 37.1 years with ileorectal anastomosis who received sulindac with a mean dosage of 158mg/day for a mean period of 63.4±31.3 months (range, 14 to 98 months). There was a significant decrease in polyp number in all 12 patients (p=0.039) at a mean of 63.4±31.3 months (p=0.006). Recurrence of high-grade adenomas (tubulovillous, villous adenomas) was also prevented (p=0.004). However, at 35 months of follow-up, a single patient developed Stage III cancer in the rectal stump.

Giardiello et al.89 studied levels of five major prostaglandin metabolites in biopsy specimens of flat rectal mucosa from four patients with FAP before and after sulindac therapy, and from five healthy individuals. They found that the highest concentration of prostaglandin in rectal mucosa from FAP and control subjects was prostaglandin E2. Furthermore, the concentration of thromboxane B2 alone was significantly elevated in FAP patients compared with controls (p=0.016). When FAP patients were treated with sulindac, the prostaglandin metabolite levels were found to be significantly reduced when compared with pretreatment levels (p<0.05), except for prostaglandin D2 (p=0.07). In addition, prostaglandins D2, B2, F2alpha, and 6-keto-Flalpha levels also were significantly reduced in FAP patients on sulindac compared to healthy controls (P<0.05). However, interpatient heterogeneity of response to sulindac was evident, with changes ranging from +19% to -89%, and the patient with the greatest reductions after sulindac developed colorectal cancer after 35 months of therapy. Sulindac treatment, at drug doses shown to regress colorectal adenomas in FAP patients, has heterogeneous effects on the level of major prostaglandins in their rectal mucosa and may not prevent colorectal cancer due to uncoupling of prostaglandin levels and carcinogenesis.

Lynch et al.90 described an FAP patient who developed rectal carcinoma 15 months after beginning chemoprophylaxis with sulindac. There was metastatic adenocarcinoma in 6 of 20 perirectal lymph nodes. In addition to the carcinoma, her rectal mucosa contained two adenomas and multiple foci of adenomatous changes in flat mucosa. It was concluded that, while sulindac may alter the pathogenesis of FAP, those patients undergoing sulindac chemoprevention must be monitored closely by endoscopic examination. This surveillance should include an aggressive biopsy approach, since the absence of polyps does not prove the absence of malignant neoplastic changes.

Along this same vein, Matsuhashi et al.91 described a rapidly growing invasive rectal cancer in 1 of 15 patients treated with sulindac for sporadic adenomatous colorectal polyps 16 months after sulindac treatment. They found that the adenomatous polyp had responded only partially to sulindac, and the rectal cancer developed following sulindac therapy and it showed immunostaining for COX-2. They concluded that while short-term sulindac therapy appears to cause some adenomatous colon polyps to regress, nevertheless it may not reliably prevent CRC in certain patients.

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