Abstract IA11: Chemoprevention in hereditary GI cancer syndromes
Authors: N. Jewel Samadder
Journal: Cancer Research (2017)

Abstract Chemoprevention offers an attractive option to prevent the occurrence of cancer in high risk cancer syndromes, such as familial adenomatous polyposis (FAP) and Lynch syndrome. However, data, especially from clinical trials, is sparse. This presentation will review the state of art concepts of chemoprevention in regards to these hereditary GI cancer syndromes. Lynch Syndrome: In the randomized CAPP2 trial, 861 participants with Lynch syndrome took either daily aspirin (600 mg) or placebo for up to 4 years; the primary endpoint was the development of CRC (1). After a mean follow-up of 55.7 months, participants taking daily aspirin for at least 2 years had a 63% reduction in the incidence of CRC (incidence rate ratio [IRR], 0.37; 95% CI, 0.18–0.78; P = .008). These participants also saw a reduced risk from all Lynch syndrome cancers (IRR, 0.42; 95% CI, 0.25–0.72; P = .001). Risk of colorectal neoplasia was unaffected, and there was no protection seen for participants who completed &amp;lt;2 years of the intervention. Subgroup analyses from this trial showed that the association between obesity and CRC in patients with Lynch syndrome may be attenuated by taking daily aspirin (2). However, limitations of the CAPP2 trial highlight the need for larger and long-term randomized trials in this area (3, 4). Similar findings have been reported in an observational study from the Colon Cancer Family Registry. In 1,858 patients who have Lynch syndrome, aspirin use was associated with reduced risk of CRC, for both patients who took aspirin for 5 or more years (HR, 0.25; 95% CI, 0.10—0.62; P = .003) and between 1 month and 4.9 years (HR, 0.49; 95% CI, 0.27—0.90; P = .02), compared to those who took aspirin for less than 1 month (5) Based on the limited evidence above, we suggest that aspirin may be used to prevent cancer in patients with Lynch syndrome, but it is emphasized that the optimal dose is currently unknown. This is consistent with the stance of the American Gastroenterological Association (6). In contrast, the American College of Gastroenterology does not recommend standard use of aspirin for chemoprevention (7). Many expert clinics advise their patients with LS to use either 81 mg or 300 mg per day of Aspirin, which may provide a chemopreventive benefit while reducing the likelihood of side effects (ie. peptic ulcer disease, gastrointestinal bleeding, hemorrhagic stroke)—but again this dosing has yet to be shown to be effective in clinical trials. The CAPP3 trial which is currently enrolling participants in Europe will involve a double blind dose non-inferiority trial comparing 100, 300 or 600 mg daily in 3,000 Lynch syndrome gene carriers and will provide much needed clarity, however not for at least 5 years. Familial Adenomatous Polyposis: FAP has always been first and foremost a surgical disease, whose treatment with colectomy has long been known to reduce the risk of premature death. Because prophylactic colectomy carries appreciable short and long-term complications, there has always been a desire to reduce polyp burden and potentially delay surgical intervention through the use of medication. However, most of the clinical trials efforts to date have dealt with patients who have already undergone prophylactic colectomy and in whom recurrent adenomas in the retained rectum are being managed. Nonsteroidal anti-inflammatory agents have been the most commonly employed chemopreventive agents, with sulindac being the most extensively studied and clinically used. Review of all the historical clinical trials is beyond the scope of this paper but we will selectively highlight the most significant. The most influential and often cited study supporting the use of sulindac is a relatively small but controlled trial by Giardiello et al. 22 FAP patients (18 of whom had not yet undergone colectomy) were treated for 9 months with sulindac at a dose of 150 mg twice a day and assessed at intervals of 3 months (8). A 56% reduction in adenoma count and 65% reduction in average adenoma diameter were observed. However, no complete adenoma regression was observed and regrowth occurred by 3 months following discontinuation of sulindac, implying the need for continuous therapy. Similar findings have been shown in a number of other studies, varying the dose of the sulindac or route of delivery and length of follow-up (9-11). There is concern that sulindac therapy changes the morphology of adenomas from protruding to flat lesions and that such lesions continue to serve as precursors for CRC development but are more difficult to visualize and remove with optic colonoscopy (12, 13). Celecoxib, a selective Cox-2 inhibitor which potentially has the advantage of reduced gastrointestinal side effects, was found to have an adenoma regression effect only at higher doses of 400 mg twice a day. However, the Food and Drug Administration indication of FAP for Celebrex was withdrawn recently due to a failure to perform a postmarketing study intended to verify clinical benefit. Sulindac, though not available in all countries, is used in the US at a dose of 150 mg twice daily primarily for the control of polyposis in the retained rectum of patients with FAP who have already undergone a colectomy with an IRA or an IPAA with a rectal cuff. It is imperative that these patients continue to undergo annual surveillance due to the risk of subsequent cancers. Patients with FAP are also at greatly increased risk for duodenal neoplasia, with duodenal adenomas eventually forming in &amp;gt;50% of patients and duodenal adenocarcinoma occurring in up to 12% (14, 15). Following colectomy, duodenal adenocarcinoma is the leading cause of cancer death in these patients, and prevention of duodenal adenocarcinomas by endoscopic surveillance with polyp resection, duodenectomy, Whipple surgical procedure, and ampullectomy are often challenging and suboptimal (16). NSAIDs have much less efficacy in duodenal adenomas (17, 18). A recent trial involving 92 FAP patients randomized to therapy with dual COX and epidermal growth factor receptor (EGFR) inhibition, with sulindac 150 mg twice daily and erlotinib 75 mg daily respectively, reported a 71% decrease in duodenal polyp burden after 6 months of therapy (19). However, the frequency of side effects, primarily an acne-like rash, may limit the use of these medications at the doses used in this study. Follow-up clinical trials with EGFR inhibition are now underway to explore reduced dosing options to mitigate these side effects while retaining chemopreventive efficacy. References 1. 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Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. The British journal of surgery. 1993;80(12):1618-9. Epub 1993/12/01. 19. Samadder NJ, Neklason DW, Boucher KM, Byrne KR, Kanth P, Samowitz W, et al. Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial. JAMA : the journal of the American Medical Association. 2016;315(12):1266-75. Epub 2016/03/24. Citation Format: N. Jewel Samadder. Chemoprevention in hereditary GI cancer syndromes. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA11.