sulindac and Rectal-Neoplasms

The justification of colectomy and ileorectal anastomosis as the primary treatment for familial adenomatous polyposis (FAP) remains questionable because of the rectal cancer risk. We estimated both the cancer risk and the need of rectal excision for benign polyposis in 100 FAP patients. We also evaluated the effects of sulindac therapy and the complications of polyp fulgurations during the follow-up time of the median of 10.6 years (2 to 29 years) after ileorectal anastomosis. There were 46 women and 54 men with a mean age of 32 years (17-67 years) at the operation. Forty-two patients were propositi and 15 had colon cancer primarily. Cumulative risk of rectal cancer and combined risk of cancer and rectal excision for other causes were estimated (Kaplan-Meier analysis) both from the date of surgery and from birth. Nine patients developed rectal cancer, while 12 others has the rectum excised for benign conditions. The cumulative rectal cancer risk was 4%, 5.6%, 7.9% and 25% at 5, 10, 15 and 20 years after the operation, respectively. Rectal excision rates were 7.3%, 13.7%, 23.6%, and 36.6%, correspondingly and finally 73.8%. Age-dependent rectal cancer risks were 3.9%, 12.8% and 25.7% at 40, 50 and 60 years, and the rectal excision rates 9.5%, 26.3% and 44%, respectively. Sulindac caused at least partial regression of rectal adenomas in 71% of patients without major adverse effects, but the long term effects of sulindac and impact on malignant transformation of rectal adenomas are not known. Our results favour proctocolectomy and ileonal anastomosis as the primary operation for FAP instead of colectomy and ileorectal anastomosis.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Age Distribution; Aged; Anastomosis, Surgical; Anti-Inflammatory Agents, Non-Steroidal; Colectomy; Female; Finland; Follow-Up Studies; Humans; Ileum; Incidence; Male; Middle Aged; Rectal Neoplasms; Rectum; Registries; Risk Factors; Sulindac

This nonrandomized, controlled Phase II pilot study aims at the lowest effective dose of rectally applied sulindac to achieve and maintain adenoma reversion in colectomized patients with familial adenomatous polyposis (FAP).. The study group (n = 15) underwent proctoscopic and laboratory follow-up for polyp reversion every 6 to 12 weeks. Polyp reversion was followed by dose reduction in predefined steps. Proliferating cell nuclear antigen/cyclin (PCNA) and KI-67 proliferation indices (PI) were performed by point counting. Prostaglandin (PG)E2 and PGF2 alpha were quantified by time-resolved competitive fluorescence immunoassay.. All patients responded to therapy within 6 to 24 weeks. Sixty and 87 percent of patients achieved complete adenoma reversion after 48 weeks at 53 and 67 mg of sulindac per day per patient on average, respectively. Reversion was evident compared with the control group. Dose reduction by one-sixth to one-eighth of the usual oral dose was significant (Mann's trend test, P < 0.05). PCNA and KI-67 PIs of adenomatous and flat mucosa were significantly reduced (Wilcoxon's test, P < 0.05). Correlation of PCNA and KI-67 PIs indicate similar reaction of different tissue structures (Spearman's rank correlation test, P < 0.01). Nonsteroidal anti-inflammatory drug-induced redifferentiation from high-grade to low-grade dysplasia occurred in all but two patients. Tissue-PGE2 levels were greatly reduced. Unwanted, curable side effects were rare (gastritis, n = 2), and laboratory controls are within detection limits.. Low-dose rectal sulindac maintenance therapy is highly effective in achieving complete adenoma reversion without relapse in 87 percent of patients after 33 months. Rectal FAP phenotype should be crucial for the surgical decision. Colectomy with ileorectal anastomosis and regular chemoprevention might proceed to be a promising alternative to pouch procedures. Chemoprevention with lower incidence of FAP-related tumors via dysplasia reversion may be possible in the future.

Topics: Adenomatous Polyposis Coli; Administration, Rectal; Adolescent; Adult; Anastomosis, Surgical; Colectomy; Cyclins; Dinoprost; Dinoprostone; Female; Follow-Up Studies; Humans; Ki-67 Antigen; Male; Middle Aged; Neoplasm Proteins; Nuclear Proteins; Pilot Projects; Proctoscopy; Proliferating Cell Nuclear Antigen; Rectal Neoplasms; Remission Induction; Sulindac

Topics: Adenomatous Polyposis Coli; Duodenal Neoplasms; Humans; Intestinal Polyps; Rectal Neoplasms; Sulindac

Twenty-four patients with familial adenomatous polyposis who had previously undergone prophylactic colectomy and had advanced duodenal polyposis were entered into a randomized trial to assess the effect of the non-steroidal anti-inflammatory drug sulindac on duodenal and rectal polyps. Polyp size and number were assessed by videotaped duodenoscopy (and rectoscopy in 14 patients) at entry and after 6 months of treatment; the tapes were compared by two assessors who were unaware of the randomization and the shuffled chronological order of the recordings. Mucosal cell proliferation was measured by in vitro incorporation of 5-bromo-2'-deoxyuridine. Sulindac therapy was associated with a reduction in epithelial cell proliferation in the duodenum (median labelling index (LI) 15.8 versus 14.4 per cent, P = 0.003) and a trend towards duodenal polyp regression (P = 0.12). In the rectum, cell proliferation showed a marked reduction (median LI 8.5 versus 7.4 per cent, P = 0.018), and significant (P = 0.01) polyp regression was seen. Rectal polyposis was less severe than that in the duodenum and responded more dramatically. Sulindac is a possible treatment for patients in whom rectal polyps have failed to show significant regression after ileorectal anastomosis and who are unsuitable for pouch surgery; it may be useful in early duodenal polyposis or as an adjunct after duodenal clearance.

Topics: Adenomatous Polyposis Coli; Adult; Aged; Cell Division; Double-Blind Method; Duodenal Neoplasms; Duodenum; Female; Humans; Intestinal Mucosa; Intestinal Polyps; Male; Middle Aged; Rectal Neoplasms; Rectum; Sulindac

Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported.. We conducted a randomized, double-blind, placebo-controlled study of 22 patients with familial adenomatous polyposis, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every three months for one year.. A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac, as compared with those given placebo. When treatment was stopped at nine months, the number of polyps had decreased to 44 percent of base-line values and the diameter of the polyps to 35 percent of base-line values (P = 0.014 and P < 0.001, respectively, for the comparison with the changes in the group given placebo). No patient had complete resolution of polyps. Three months after treatment with sulindac was stopped, both the number and the size of the polyps increased in sulindac-treated patients but remained significantly lower than the values at base line. No side effects from sulindac were noted.. Sulindac reduces the number and size of colorectal adenomas in patients with familial adenomatous polyposis, but its effect is incomplete, and it is unlikely to replace colectomy as primary therapy.

Topics: Adenomatous Polyposis Coli; Adult; Double-Blind Method; Female; Humans; Intestinal Polyps; Male; Rectal Neoplasms; Sulindac

In familial adenomatous polyposis, sulindac-induced polyp regression has been reported by several authors. In this study, the goal was to confirm these results by a randomized, placebo-controlled, double-blind crossover study in 10 patients with rectal polyps that had been previously treated by colectomy and ileorectal anastomosis. Patients received sulindac, 300 mg/day, or placebo during two 4-month periods separated by a 1-month wash-out phase. One patient was not compliant and was excluded. With sulindac, the authors observed a complete (6 patients) or almost complete (3 patients) regression of the polyps. With placebo, the authors observed an increase (5 patients), no change (2 patients), and a relative decrease (2 patients) in the number of polyps. The difference between sulindac and placebo was statistically significant (P less than 0.01). In biopsy specimens of polyps and normal rectal mucosa of 6 patients, the authors conducted an immunohistochemical study of the cellular proliferation index using the Ki 67 monoclonal antibody (Ki 67 index), at the beginning and at the end of each treatment period. They were not able to show a sulindac-induced modification of the Ki 67 index. The authors conclude that sulindac is effective in inducing the regression of rectal polyps in familial adenomatous polyposis.

Topics: Adenomatous Polyposis Coli; Adult; Double-Blind Method; Female; Humans; Male; Rectal Neoplasms; Remission Induction; Sulindac

To probe the risk of colorectal polyp, colon and rectal carcinoma and the intake of NSAIDs.. Case-control study participants were from patients who underwent colonoscopy at different hospitals, the persons with the above disease was as cases, and those without the above diseases was as controls. Use of NSAIDs was assessed by interviewing the participants with a questionnaire which include a list of NSAIDs and related dietary and life style factors and family history.. There are 37 cases of colorectal polyp, 105 cases of colon carcinoma and 142 cases of rectal carcinoma and 66 controls. Adjusted for potential confounders, the risk of colorectal polyposis, colon carcinoma and rectal carcinoma were markedly reduced by NSAIDs. The OR values were 0.21 (95% CI 0.07-0.65, P = 0.007), 0.13 (95% CI 0.05-0.35, P < 0.001), 0.15 (95% CI 0.11-0.58, P < 0.001) respectively. The risk of the above diseases were also reduced markedly by aspirin, the OR values were 0.265 (95% CI 0.07-0.96, P = 0.044), 0.10 (95% CI 0.03-0.35, P < 0.001), 0.15 (95% CI 0.04-0.49, P = 0.002) respectively. The risk of colon carcinoma was also reduced by profen, with the OR being 0.11 (95% CI 0.02-0.64, P = 0.014).. Aspirin and other NSAIDs could reduced the risk of colorectal polyp, colon carcinoma and rectal carcinoma markedly. Aspirin was the most prospective chemopreventive agents for colorectal polyp, colon and rectal carcinoma for its capability of reducing the risk of cardio-cerebral vascular disease as well.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colorectal Neoplasms; Female; Humans; Ibuprofen; Logistic Models; Male; Middle Aged; Piroxicam; Polyps; Rectal Neoplasms; Risk Factors; Sulindac; Time Factors

Surgery is the definitive treatment in familial adenomatous polyposis coli (FAP). Proctocolectomy with ileal pouch anal anastomosis is recommended for the majority of FAP patients. Only in patients with attenuated FAP, is a colectomy with ileorectal anastomosis (IRA) accepted, although the risk for rectum carcinoma remains increased. Sulindac, a chemoprophylactic agent, regresses colorectal adenomas in patients with FAP. Under systemic Sulindac-therapy, three carcinomas in the rectum after colectomy with IRA have been described. We report the first known case of rectum carcinoma in a patient with FAP, 51 months after IRA and local Sulindac therapy.

Topics: Adenocarcinoma; Adenomatous Polyposis Coli; Adult; Antineoplastic Agents; Colectomy; Colonic Pouches; Humans; Ileum; Proctoscopy; Rectal Neoplasms; Rectum; Sulindac; Suppositories; Time Factors

Sulindac causes the reduction of adenomas in familial adenomatous polyposis (FAP) patients, but complete regression is unusual, and breakthrough of colorectal carcinoma during sulindac treatment has been described. The molecular features related to sulindac resistance are unknown. Therefore, we investigated molecular alterations in adenomas from FAP patients with complete adenoma regression on sulindac (responsive patients) and from FAP patients with sulindac-resistant adenomas (resistant patients).. Fourteen baseline adenomas (removed before sulindac treatment) from six responsive patients were studied. Also, 9 baseline adenomas and 34 resistant adenomas (removed during sulindac treatment) from three resistant patients were analyzed. Using immunohistochemistry, we evaluated the expression of beta-catenin, cyclooxygenase-2 (Cox-2), p53, Bcl-2, and Bax. K-ras codon 12 mutations, loss of heterozygosity at 5q (APC locus), and microsatellite instability were studied with PCR-based techniques.. There were no significant differences between baseline adenomas from sulindac-responsive and -resistant patients (P > 0.05). There was less loss of membranous beta-catenin staining and less nuclear beta-catenin accumulation in resistant adenomas compared with baseline adenomas from the same (sulindac-resistant) patients (P < 0.01) or baseline adenomas from responsive patients (P < 0.01). Epithelial Cox-2 expression was less, though not significant, in resistant adenomas compared with baseline adenomas from resistant patients, but was significantly less in baseline adenomas from responsive patients (P < 0.01). K-ras mutations were found in 8 of 34 resistant adenomas (24%) and in none of the baseline adenomas (P < 0.05). Stromal Cox-2 expression, staining of p53 and Bcl-2, and loss of heterozygosity at 5q were comparable in both groups. Loss of Bax staining and microsatellite instability were not found in any adenoma.. Sulindac-resistant adenomas display less alteration in beta-catenin staining and less epithelial Cox-2 expression when compared with adenomas removed before sulindac treatment. K-ras mutations may contribute to sulindac-resistance. Continued research is needed to investigate molecular alterations related to sulindac resistance.

Topics: Adenoma; Adenomatous Polyposis Coli; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; beta Catenin; Biomarkers, Tumor; Codon; Cyclooxygenase 2; Cytoskeletal Proteins; Drug Resistance, Neoplasm; Genes, ras; Humans; Immunohistochemistry; Isoenzymes; Loss of Heterozygosity; Membrane Proteins; Mutation; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rectal Neoplasms; Sulindac; Trans-Activators; Tumor Suppressor Protein p53

Ileorectal anastomosis (IRA) is still used in the treatment of familial adenomatous polyposis (FAP). Sulindac appears to induce regression of colorectal adenomas; however, its effects in long-term therapy and in preventing carcinoma remain unclear.. Fifteen FAP patients treated by IRA received sulindac (200 mg/day) for a mean period of 48.6 +/- 28.7 (range 12-124) months. Number, size, and type of rectal polyps were assessed by endoscopic and histological evaluation every 6 months.. Significant regression of polyps was observed in all patients after 6 months (P < 0.02). However, after a mean of 48.6 +/- 28.7 months, both number and size of polyps increased again, showing no statistical difference with baseline values. Minute polyps appeared reddish, while the largest lesions were flat or slightly elevated. Endoscopic polypectomy was necessary in 9 patients and transanal surgical excision in 3. Two patients were submitted to restorative proctectomy because of a large polyp with severe dysplasia and a rectal cancer, respectively.. Sulindac appears to influence the morphological appearance of polyps in FAP patients, inducing apparent regression. However, at a dose of 200 mg, it does not influence the progression of polyps toward a malignant pattern.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Male; Middle Aged; Proctocolectomy, Restorative; Rectal Neoplasms; Sulindac

Colorectal cancer is the second leading cause of death from cancer in The United States. During the last fifteen years, emphasis has been placed on identification of high risk patients and families and outline of appropriate surveillance regimens for normal and high risk patients for colorectal cancer. Parallel to this effort, abundant clinical data has been accumulated that chemoprevention of colorectal cancer with nonsteroidals and aspirin may be possible. Interruption of prostaglandin metabolism appears to be one of the mechanisms of action but not the only therapeutic arm. Currently, sulindac, aspirin, calcium and selenium supplementation are attractive recommendations to at risk patients awaiting results of clinical trials. Other agents in development add excitement to the concept of colorectal cancer chemoprevention.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colonic Neoplasms; Folic Acid; Humans; Rectal Neoplasms; Selenium; Sulindac

Like adenomatous polyps in familial adenomatous polyposis, some sporadic colorectal polyps have been reported to regress in response to sulindac administration. However, a rapidly growing invasive rectal cancer developed in one of 15 patients with sulindac-treated sporadic adenomatous colorectal polyps 16 months after sulindac treatment. In this patient, both the adenomatous polyp that responded partially to sulindac and the rectal cancer developing after sulindac therapy showed immunostaining for cyclooxygenase-2. Although short term sulindac therapy seems to be able to cause some adenomatous colorectal polyps to regress, 4 months of sulindac therapy may not reliably prevent colorectal cancer development in these patients.

Topics: Adenocarcinoma; Adenomatous Polyps; Anti-Inflammatory Agents, Non-Steroidal; Colonic Polyps; Humans; Male; Middle Aged; Neoplasms, Second Primary; Rectal Neoplasms; Sulindac

Sulindac is reported to induce regression of colonic adenomas. However, its role as a chemoprophylactic agent for people with familial adenomatous polyposis (FAP) is under consideration.. This case report describes a patient with FAP in whom rectal adenocarcinoma developed 37 years after prophylactic colectomy and 15 months after beginning a course of sulindac. She received endoscopic follow-ups every 3 months during 15 months of 150-mg twice-daily sulindac administration. At 12 months, an endoscopic examination was unremarkable; at 15 months, endoscopic examination revealed several polyps and a flat ulcerated lesion.. Rectal carcinoma developed in a patient 15 months after beginning chemoprophylaxis: there was metastatic adenocarcinoma in 6 of 20 perirectal lymph nodes. In addition to the carcinoma, rectal mucosa contained two adenomas and multiple foci of adenomatous changes in flat mucosa.. Sulindac may not alter the pathogenesis of FAP. Patients undergoing sulindac chemoprevention must be monitored closely, including endoscopic examination. Endoscopic surveillance should include an aggressive biopsy approach because the absence of polyps does not prove the absence of neoplastic change.

Topics: Adenocarcinoma; Adenomatous Polyposis Coli; Aged; Colectomy; Female; Humans; Rectal Neoplasms; Sulindac

Topics: Adenomatous Polyposis Coli; Aged; Female; Humans; Rectal Neoplasms; Sulindac

Sulindac, a nonsteroidal anti-inflammatory drug, causes regression of polyps in familial polyposis coli and may prevent new lesions. However, it is not clear whether the effect of sulindac in preventing polyps also applies to carcinoma. This case report describes a patient with familial polyposis coli who developed a carcinoma in a rectal segment after subtotal colectomy and ileorectal anastomosis. She had been treated with 450 mg sulindac daily for 28 months and was free of polyps during the latter 12 months of this period. However, despite intensive endoscopic follow-up, she developed an adenocarcinoma of the rectum. This finding may have important implications for our understanding of the development of colon cancer in familial polyposis coli and the use of sulindac to prevent it. Development of de novo carcinoma in microadenomatous tissue of the rectal mucosa, which bypasses the polyp-cancer sequence, must be considered as a possibility in these patients.

Topics: Adenocarcinoma; Adenomatous Polyposis Coli; Adult; Anastomosis, Surgical; Colectomy; Female; Humans; Ileum; Postoperative Period; Rectal Neoplasms; Rectum; Sulindac

Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), decreases the occurrence of polyps in patients with familial adenomatous polyposis (FAP). The effects of colectomy with ileorectal anastomosis (IRA) and sulindac treatment on rectal mucosa proliferation and polyp occurrence were examined in patients with FAP.. The number and size of rectal polyps were measured with colonoscopy. The labeling index, the percentage of labeled cells per crypt compartment, was assessed in rectal biopsy specimens with [3H]thymidine incorporation and autoradiography in 6 non-IRA and 14 IRA patients before and after treatment with 200 mg of sulindac/day for 60 days.. The IRA patients had a lower labeling index and a decrease in the percentage of labeled cells in the upper compartment of the crypt (P < 0.01) relative to non-IRA subjects. Sulindac did not influence the labeling index and the distribution of labeled cells along the crypt. On the contrary, a dramatic decrease in the size and number of polyps was observed after sulindac treatment (P < 0.001).. The persistence of a abnormal mucosal proliferation after sulindac therapy, in spite of the reduction of polyp number, suggests caution in assuming a lower risk of rectal cancer in patients with FAP.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Anastomosis, Surgical; Cell Division; Child; Female; Humans; Ileum; Intestinal Polyps; Male; Middle Aged; Rectal Neoplasms; Rectum; Sulindac

The aim of this study was to assess the effectiveness of sulindac therapy for eradication of micropolyps in 8 patients with familial polyposis coli. All patients had undergone colectomy and ileoproctostomy 4.5 years (range 3 months-20 years) before and had tubulous adenomas micropolyps in the rectum. Initial sulindac therapy 200 mg or 300 mg daily was started in all patients and was continued in 7 patients. In these 7 patients macroscopic and microscopic eradication of micropolyps was obtained within 3.4 months (1-8). After discontinuation of sulindac therapy, recurrence of micropolyps occurred in 4 patients within 3 to 4 months. Three patients had no recurrence with a follow-up of 1 to 19 months. A new eradication of micropolyps was obtained in these 4 patients with a second sulindac cure within 3 to 6 months. These observations confirm the effectiveness of sulindac therapy for eradication of tubulous adenomas micropolyps in familial polyposis, but after discontinuation of therapy, recurrence is frequent. Continuous or intermittent therapy might reduce recurrence.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Colectomy; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Polyps; Rectal Neoplasms; Sulindac

Topics: Adult; Colonic Polyps; Female; Humans; Indenes; Intestinal Polyps; Male; Rectal Neoplasms; Sulindac