Gastroenterology
Volume 134, Issue 1 , Pages 341-343, January 2008

Chemoprevention for Colorectal Cancer: Some Progress But a Long Way to Go

  • Peter Lance

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Peter Lance, MD, Arizona Cancer Center, 1515 N. Campbell Avenue, P.O. Box 245024, Tucson, Arizona 85724. fax: (520) 626-5348.

Article Outline

 

See “Aspirin dose and duration and risk of colorectal cancer in men” by Chan AT, Giovannucci EL, Meyerhardt JA, et al on page 21; and “Aspirin and folic acid for the prevention of recurrent colorectal adenomas” by Logan RFA, Grainge MJ, Shepherd VC, et al on Behalf of the ukCAP Trial Group on page 29.

Approximately 10% or less of colorectal adenomas (CRAs) at greatest risk for progressing to colorectal cancer (CRC) are termed adenomas with advanced pathology (advanced CRAs), which are characterized by a diameter of ≥ 1 cm or villous histology. CRCs and advanced CRAs are the primary targets of colorectal screening.1 Most CRAs can be removed by endoscopic polypectomy. After polypectomy, metachronous or recurrent CRAs develop at a rate of 10% to 15% per year. Therefore, patients should undergo periodic surveillance colonoscopy following earlier polypectomy. The development of orally administered chemopreventive agents that could reduce the rate at which CRAs recur has been pursued as an adjunct to surveillance colonoscopy. The rationale for developing chemopreventive approaches to prevent CRC came from epidemiologic and observational studies indicating that long-term ingestion of aspirin, a nonselective cyclooxygenase (COX) inhibitor, could reduce CRC mortality. An underlying, although not necessarily validated, assumption in the CRC chemoprevention field is that measures preventing CRA recurrence will also prevent CRC.

Significant reductions in CRA recurrence were reported in 3 previous randomized controlled aspirin trials in patients with a prior history of colorectal neoplasia;2, 3, 4 the prior history was of CRAs2, 4 in 2 trials and of surgically resected CRC in the third. Patients in the 3 trials took aspirin or placebo for 1 to 3 years, and reductions of 19% to 35% in CRA recurrence were observed in the aspirin groups compared with the placebo groups. In 2 of the trials, a single daily aspirin dose of 325 mg was tested. Two dosages of aspirin, 81 and 325 mg daily, were tested in the third trial.2 In this trial, a modest but significant 19% reduction in CRA recurrence occurred with the 81 mg but not the 325 mg aspirin dose; other than chance, a convincing explanation for finding an effect with the lower but not the higher aspirin dose has not been advanced, and the finding has not been reproduced. A variety of agents other than aspirin have been investigated for CRC chemopreventive potential.

Concerns regarding the gastrointestinal and other toxicities of aspirin drove the quest for selective COX-2 inhibitors (coxibs) that would have the antineoplastic actions of aspirin without its toxicity. The increased cardiovascular risk unexpectedly associated with celecoxib5 and rofecoxib6 in CRA recurrence trials and their resulting premature termination is a familiar story. Before discarding the coxibs from further consideration for clinical use in CRC chemoprevention, it is worth noting that both celecoxib and rofecoxib reduced CRA recurrence and that the size of this effect appeared to increase with the extent of COX-2 inhibition.7 The association between consumption of a Western diet and high CRC rates led to macro- and micronutrient approaches to CRC chemoprevention.

Despite epidemiologic and observational evidence that dietary factors such as low fiber and high red meat content are CRC risk factors, evidence from CRA recurrence trials that dietary macronutrient manipulation might reduce CRC risk is lacking. Trials of a global eating plan that included high-fiber, high-fruit, and high-vegetable content as well as low-fat content8 and fiber supplementation9 failed to reduce CRA recurrence rates. Results from CRA recurrence trials of 2 micronutrients have been reported. Supplemental calcium yielded a modest 24% reduction in CRA recurrence.10 However, folic acid supplementation (1 mg daily) failed to reduce CRA recurrence and may have increased the risk for advanced CRA and multiple CRA recurrences.11 Two studies in this issue provide confirmatory and new information about CRC chemoprevention and the roles of aspirin and folic acid supplementation.

Logan et al12 report results of the ukCAP trial. In this randomized controlled trial of aspirin (300 mg daily) and folic acid (0.5 mg daily), 945 patients were randomized within 6 months of CRA polypectomy. Of those randomized, 853 (90.3%) underwent a surveillance colonoscopy approximately 3 years later. Patients receiving aspirin had a modest but significant 21% reduction in CRA recurrence compared to placebo. The likelihood of recurrence with an advanced CRA was a more substantial 37% less in the aspirin group. Folic acid supplementation had no effect on CRA recurrence.

Although not deliberately enriched for patients with baseline advanced CRAs, a distinguishing feature of the ukCAP trial compared with an unselected population of CRA patients and most other CRA recurrence trials is that the majority of ukCAP participants had baseline advanced CRAs. The eligibility requirement of a baseline CRA of ≥ 0.5 cm after fixation accounts for this characteristic of the ukCAP study population. In most recurrence trials, the CRA diameter recorded is that estimated by the colonoscopist before shrinkage due to fixation, and a minimum diameter criterion of 0.3 cm is typical. Thus, in most CRA recurrence trials, the majority of baseline adenomas are small or diminutive tubular CRAs, and the majority of patients in these trials are, therefore, likely to have been at lesser risk for CRC than the ukCAP study population.

The ukCAP trial folic acid dose was 0.5 mg, compared with 1 mg in the recently published US study.11 The authors suggest that the folic acid supplementation in the ukCAP trial might be equivalent to the effect of folate fortification of cereals that was introduced a decade ago in the United States. Although confirmatory evidence will be required, it is reassuring that folic acid supplementation at the 0.5 mg dose did not increase the risk for advanced CRA and multiple CRA recurrences, particularly given the high proportion of ukCAP patients with advanced baseline CRAs. The ukCAP trial does not shed light on the effects of aspirin and folic acid on CRC risk. The other study in this issue of relevance to CRC chemoprevention examines directly the effect of aspirin on CRC risk.

Chan et al13 examined the influence of aspirin on CRC risk in 47,363 men enrolled in the Health Professionals Follow-up Study (HPFS). Data on aspirin use are reported over 18 years of follow-up with 975 documented CRC cases. This study confirms that prolonged aspirin use substantially reduces the risk of developing CRC. The effect was dose-related, increasing from a relative risk of 0.94 for men who used 0.5 to 1.5 standard (325 mg) aspirin/week compared to men who denied any aspirin use, to a relative risk of 0.30 for those using >14 aspirin/week compared with nonusers. Significant reduction in CRC risk required at least 6 to 10 years of aspirin use. The aspirin dosage required for CRC chemoprevention in the HPFS study was much higher than the lowest aspirin dose (81 mg) and treatment period (3 years) required to reduce CRA recurrence.2 As Chan et al point out, in the context of CRC chemoprevention, this dosage causes prohibitive rates of gastrointestinal and other toxicities.

Screening colonoscopy was associated with a lower risk of CRC in the HPFS cohort, but an observational study such as this is not well suited to investigating strategies for combining multiple interventions. To be useful, any modeling of CRC chemoprevention strategies must include screening and surveillance colonoscopy, including polypectomy where necessary. Once CRAs have been cleared, initiation of metachronous CRAs is the chemoprevention target. In cohort studies such as the HPFS that investigate CRC endpoints, CRA progression to invasive CRC is the focus in addition to initiation. It is entirely possible that effective inhibition or reversal of neoplastic progression involves different mechanisms and requires higher doses of aspirin and other chemopreventive agents than prevention of initiation. Thus, in patients who have undergone surgical resection for CRC or had clearing colonoscopies to remove all CRAs, effective CRC chemoprevention may require less intensive and toxic interventions than if neoplastic lesions had not been cleared; the HPFS study by Chan et al does not address this hypothesis. The methodologic limitations of CRA recurrence trials and prospective cohort studies are distinct, and neither approach can fully complement deficiencies of the other.

Despite much effort over 2 decades, no chemopreventive intervention for CRC has yet entered routine clinical practice as part of usual care for healthy members of the general population. Funding agencies are unlikely to continue supporting chemoprevention studies indefinitely unless agents and strategies of proven clinical and public health benefit can be identified. A framework for future chemoprevention studies and their implementation is depicted in Figure 1. This framework assumes that CRC screening has been implemented according to current guidelines1, 14 before chemoprevention is contemplated. Chemoprevention is not a consideration for individuals in their 6th decade or older with normal screening examinations or in those who have 1 or 2 small tubular adenomas amenable to polypectomy. Future chemoprevention studies should target patients with advanced adenomas and individuals with more than 2 adenomas regardless of histology. Factors that further compound CRC risk, such as family history of CRC in a first-degree relative (FDR) and lifestyle, are shown in Figure 1. These patients may benefit most from chemoprevention, and they are obvious candidates for chemoprevention studies.

With regard to agent selection, safety is of paramount importance.15 Too little attention has been paid to combining low, safe doses of 2 or more agents, each targeting a different enzyme or cellular pathway. Personalizing chemoprevention has considerable potential. For example, prevention of CRA recurrence in response to aspirin has been shown to be dramatically enhanced in individuals with a particular single nucleotide polymorphism in the promoter region of the ornithine decarboxylase gene.16

Adoption of methods for hastening the completion of chemoprevention trials is another aspect of improving trial design. The clinical importance of statistically significant but modest effects is questionable: How useful is an intervention that reduces recurrence of small tubular CRAs by 15% to 25% after 3 to 5 years of use? Studies that are powered for a clinically useful intervention effect of, say, 50% or greater would require enrollment of fewer participants than in most previous CRA recurrence trials. Each investigator will have suggestions for improving the design and implementation of CRC chemoprevention studies. The escalating need for evidence of clinically useful efficacy if CRC chemoprevention is to remain a viable objective is clear. Answering this challenge might involve the introduction of new CRC chemopreventive agents, innovative combinations of new and existing agents, and the development of improved clinical trial methodologies for their more rapid evaluation.

Back to Article Outline

References 

  1. Winawer SJ, Fletcher RH, Rex DK, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale—update based on new evidence. Gastroenterology. 2003;124:544–560
  2. Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003;348:891–899
  3. Sandler RS, Halabi S, Baron JA, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med. 2003;348:883–890
  4. Benamouzig R, Deyra J, Martin A, et al. Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial1. Gastroenterology. 2003;125:328–336
  5. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071–1080
  6. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092–1102
  7. Bertagnolli MM. Chemoprevention of colorectal cancer with cyclooxygenase-2 inhibitors: two steps forward, one step back. Lancet Oncol. 2007;8:439–443
  8. Schatzkin A, Lanza E, Corle D, et al. Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. N Engl J Med. 2000;342:1149–1155
  9. Alberts DS, Martínez ME, Roe DJ, et al. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. N Engl J Med. 2000;342:1156–1162
  10. Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas (Calcium Polyp Prevention Study Group). N Engl J Med. 1999;340:101–107
  11. Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007;297:2351–2359
  12. Logan RFA, Grainge MJ, Shepherd VC, et al. ukCAP Trial Group Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology. 2008;134:29–38
  13. Chan AT, Giovannucci EL, Meyerhardt JA, et al. Aspirin dose and duration of use and risk of colorectal cancer in men. Gastroenterology. 2008;134:21–28
  14. Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. CA Cancer J Clin. 2006;56:143–159quiz 184–185
  15. Ulrich CM, Bigler J, Potter JD. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer. 2006;6:130–140
  16. Martinez ME, O’Brien TG, Fultz KE, et al. Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene. Proc Natl Acad Sci U S A. 2003;100:7859–7864

PII: S0016-5085(07)02067-7

doi:10.1053/j.gastro.2007.11.024

Refers to article:

  • Aspirin Dose and Duration of Use and Risk of Colorectal Cancer in Men , 27 September 2007

    Andrew T. Chan, Edward L. Giovannucci, Jeffrey A. Meyerhardt, Eva S. Schernhammer, Kana Wu, Charles S. Fuchs
    Gastroenterology January 2008 (Vol. 134, Issue 1, Pages 21-28)

  • Aspirin and Folic Acid for the Prevention of Recurrent Colorectal Adenomas , 11 October 2007

    Richard F.A. Logan, Matthew J. Grainge, Vic C. Shepherd, Nicholas C. Armitage, Kenneth R. Muir, ukCAP Trial Group
    Gastroenterology January 2008 (Vol. 134, Issue 1, Pages 29-38)

Gastroenterology
Volume 134, Issue 1 , Pages 341-343, January 2008