Familial Cancer

, Volume 7, Issue 1, pp 59–64 | Cite as

Chemoprevention with special reference to inherited colorectal cancer

  • Patrick M. Lynch


Familial Adenomatous Polyposis (FAP) is a model for the adenoma-carcinoma sequence in several respects. One important area in which FAP serves as a model is chemoprevention. Early prevention trials mainly utilized micronutrients and were largely unsuccessful in preventing or causing regression of adenomas. A new era was ushered in by the recognition that antiarthritic doses of a nonsteroidal anti-inflammatory agent (NSAID), sulindac, could actually induce regression of colorectal adenomas in patients with FAP. Follow-up studies showed positive but variable long-term efficacy for colorectal adenomas, but sulindac appears to lack significant benefit in regressing duodenal adenomas or preventing initial occurrence of adenomas in APC mutation carriers. Due to the well-known side effects of traditional NSAIDs, selective COX-2 inhibitors have been studied rather extensively. Celecoxib has shown benefit in regressing colorectal adenomas and appears to have some duodenal activity as well. Rofecoxib, in smaller trials, showed efficacy as well. However, the entire field of NSAID research in chemoprevention is undergoing reexamination in light of recent demonstration of cardiovascular toxicity in nonfamilial or sporadic adenoma prevention trials. Whether NSAIDs will have a significant future in FAP chemoprevention will depend on a sober assessment of risks and benefits. These same issues will likely foster a more intensive search for new agents. FAP will undoubtedly continue to have a lead role in the testing of new agents, both in the interest of FAP management as such, and in anticipation of trials in nonfamilial adenomas, a problem with even greater societal impact. The historical development of chemoprevention in FAP will be presented, with an emphasis on issues of trial design.


Celecoxib Chemoprevention Colorectal adenomas Colorectal cancer COX-2 inhibition Familial Adenomatous Polyposis Rofecoxib Sulindac 


  1. 1.
    Waddell WR, Loughry RW (1983) Sulindac for polyposis of the colon. J Surg Oncol 24:83–87PubMedCrossRefGoogle Scholar
  2. 2.
    Labayle D, Fischer D, Viehl P et al (1991) Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 101:635–639PubMedGoogle Scholar
  3. 3.
    Giardello FM, Hamilton SR, Krush AJ et al (1993) Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. NEJM 328:1313–1316CrossRefGoogle Scholar
  4. 4.
    Cruz-Correa M, Hylind LM, Romans K et al (2002) Long term treatment with sulindac in familial adenomatous polyposis: a prospective cohort study. Gastroenterology 122(3):641–645PubMedCrossRefGoogle Scholar
  5. 5.
    Winde G, Gumbinger HG, Kemper F et al (1993) The NSAID sulindac reverses rectal adenomas in colectomised patients with familial adenomatous polyposis: clinical results of a dose-finding study on rectal sulindac administration. Int J Colorectal Dis 8(1):13–17PubMedCrossRefGoogle Scholar
  6. 6.
    Matsumoto T, Nakamura S, Esaki M et al (2006) Effect of the non-steroidal anti-inflammatory drug sulindac on colorectal adenomas of uncolectomized familial adenomatous polyposis. J Gastro Hepatol 21:251–257CrossRefGoogle Scholar
  7. 7.
    Guldenschuh I, Hurlimannn R, Muller A et al (2001) Relationship between APC genotype, polyp distribution and oral sulindac treatment in the colon and rectum of patients with familial adenomatous polyposis. Dis Colon Rectum 44(8):1090–1097PubMedCrossRefGoogle Scholar
  8. 8.
    Richard CS, Berk T, Bapat BV et al (1997) Sulindac for periampullary polyps in FAP patients. Int J Colorectal Dis 12(1):14–18PubMedCrossRefGoogle Scholar
  9. 9.
    Debinski HS, Trojan J, Nugent KP et al (1995) Effect of sulindac on small polyps in familial adenomatous polyposis. Lancet 345:855–866PubMedCrossRefGoogle Scholar
  10. 10.
    Nugent KP, Farmer KCR, Spigelman AD et al (1993) Randomized controlled trial of the effects of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg 80:1618–1619PubMedCrossRefGoogle Scholar
  11. 11.
    Thorson AG, Lynch HT, Smyrk TC (1994) Rectal cancer in FAP patient after sulindac. Lancet 343:417–418CrossRefGoogle Scholar
  12. 12.
    Giardiello FM, Yang VW, Hylind LM et al (2002) Primary chemoprevention of familial adenomatous polyposis with sulindac. NEJM 346(14):1085–1087CrossRefGoogle Scholar
  13. 13.
    Akasu T, Yokoyama T, Sugihara K et al (2002) Peroral sustained release indomethacin treatment for rectal adenomas in familial adenomatous polyposis: a pilot study. Hepatogastroenterology 49:1259–1261PubMedGoogle Scholar
  14. 14.
    Oshima M, Dinchuk JE, Kargman SL et al (1996) Suppression of intestinal polyposis in APCΔ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87:803–809PubMedCrossRefGoogle Scholar
  15. 15.
    Wallace M, Lynch PM (2006) The current status of chemoprevention in FAP. Fam Cancer 5:289–294PubMedCrossRefGoogle Scholar
  16. 16.
    Steinbach GD, Lynch PM, Phillips RKS et al (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946–1952PubMedCrossRefGoogle Scholar
  17. 17.
    Phillips RKS, Wallace MH, Lynch PM et al (2002) A randomized double blind placebo controlled study of celecoxib, a selective cyclooxygenase –2 inhibitor on duodenal polyposis in familial adenomatous polyposis. Gut 50:657–660CrossRefGoogle Scholar
  18. 18.
    Solomon SD, McMurray JJV, Pfeffer MA et al (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. NEJM 352:1071–1080PubMedCrossRefGoogle Scholar
  19. 19.
    Bresalier RS, Sandler RS, Quan H et al (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. NEJM 352:1092–1102PubMedCrossRefGoogle Scholar
  20. 20.
    Arber N, Eagle CJ, Spicak J et al (2006) Celecoxib for the prevention of colorectal adenomatous polyps. NEJM 355:885–895PubMedCrossRefGoogle Scholar
  21. 21.
    Baron JA, Sander RS, Bresalier RS et al (2006) A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastro 131:1674–1682CrossRefGoogle Scholar
  22. 22.
    Bertagnolli MM, Eagle CJ, Zauber AG et al (2006) Celecoxib for the prevention of sporadic colorectal adenomas. NEJM 355:873–884PubMedCrossRefGoogle Scholar
  23. 23.
    Hallak A, Baron L, Samir R et al (2003) Rofecoxib reduces polyp recurrence in familial polyposis. Dig Dis Sci 49(10):1998–2002CrossRefGoogle Scholar
  24. 24.
    Van Stolk R, Stoner G, Hayton WL et al (2000) Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent in patients with familial adenomatous polyposis. Clin Cancer Res 6(1):78–89PubMedGoogle Scholar
  25. 25.
    Di Sario JA, Ogura MM, Szabo A et al (2005) Exisulind for duodenal adenomas in persons with familial adenomatous polyposis. Gastro (Abst) W970, P A-567Google Scholar
  26. 26.
    Bussey HJ, DeCosse JJ, Deschner EE et al (1982) A randomized trial of ascorbic acid in polyposis coli. Cancer 50(7):1434–1439PubMedCrossRefGoogle Scholar
  27. 27.
    DeCosse JJ, Miller HH, Lesser ML (1989) Effect of wheat fiber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis. J Natl Cancer Inst 81(17):1290–1297PubMedCrossRefGoogle Scholar
  28. 28.
    Cruz-Correa M, Shoskes DA, Sanchez P et al (2006) Combination treatment with curcumin and quercitin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol 4:1035–1038PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2007

Authors and Affiliations

  1. 1.Department of Gastrointestinal Medicine and Nutrition - 436The University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations