___________________________________________________________________________ Colorectal Cancer
cancer incidence. In subjects completing at least two years of intervention, time to first colorectal cancer was increased 59% and incidence of colorectal cancer was reduced 63%. Adverse events did not differ between aspirin and placebo groups during the intervention [55]. A planned 10-year follow-up to this trial (the double-blind, randomised CAPP2 trial) included 861 patients with Lynch syndrome from 43 international centers worldwide. The participants were randomly assigned to receive either 600-mg aspirin daily (427 participants) or placebo (434 participants). Cancer outcomes were monitored for at least 10 years from recruitment; some of the participants (i.e., English, Finnish, and Welsh participants) were monitored for up to 20 years. The primary endpoint was development of colorectal cancer [56]. Forty (9%) of the aspirin group developed colorectal cancer compared with 58 (13%) of the placebo group. Noncolorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Adverse events between the aspirin and placebo groups were similar [56]. Likewise, a randomized controlled trial of patients with a history of adenomas or colorectal cancer found a statistically significant 21% reduction in risk of adenoma recurrence in patients randomized to aspirin (versus placebo) [57]. A prospective cohort study examined the effects of aspirin in participants following a diagnosis of colorectal cancer. Regular use of aspirin after colorectal cancer diagnosis was associated with a 29% increase in colorectal cancer-specific survival and a 21% increase in overall survival [58]. In the long-term Nurses’ Health Study and the Health Professional Follow-up Study, 964 patients diagnosed with rectal or colon cancers were evaluated. In those with PI3K -mutant colorectal cancer, regular use of aspirin was associated with a 46% increase in overall survival [59]. The benefit of aspirin in prevention of colorectal cancer is not apparent until 10 years after aspirin therapy is started and is most effective when started between 50 and 59 years of age. Because of the time required before a reduced incidence in colorectal cancer is realized, persons 60 years of age and older are less likely to realize a benefit [60]. Additionally, aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with potentially serious adverse effects that should be considered when determining the risk-benefit ratio [57]. Aspirin use can result in excessive bleeding, gastrointestinal bleeds, and hemorrhagic stroke. The estimated average increased risk of upper gastrointestinal complications was 10 to 30 per 1,000 people over a 10-year period, with men on the higher end and women on the lower end. Risk increases with age [60]. While no studies have assessed adenoma or colorectal cancer risk reduction with use of NSAIDs in the general (and presumably average-risk) population, multiple lines of evidence from epidemiologic studies, observational cohort studies, and randomized controlled trials have consistently affirmed the association between NSAID use and a 30% to 50% reduction
in adenomatous polyps, incident disease, and death from colorectal cancer [57; 61; 62; 63]. In one study, patients with familial adenomatous polyposis (FAP) who were followed over four years of treatment with NSAIDs showed a trend in reduction in adenoma incidence and statistically significant reductions in polyp number and size. A 34% reduction in adenoma recurrence risk and a 55% reduction in advanced adenoma incidence were found in patients with a history of adenomas [57]. The NSAIDs sulindac and celecoxib have been shown in randomized controlled trials to induce adenoma regression in patients with FAP, which, together with supportive preclinical data, led the U.S. Food and Drug Administration (FDA) to approve celecoxib for patients with FAP in 1999. However, in 2011, the FDA requested Pfizer voluntarily withdraw the FAP indication for celecoxib, because the company never fulfilled a condition for approval requiring postmarketing evaluation to verify clinical benefit, which Pfizer did [64]. Despite the change of celecoxib use in FAP to off-label status and withdrawal of regulatory approval, several health insurance companies have codified the use of celecoxib in FAP as an authorized indication [65]. The consistently positive findings of NSAID benefit in suppressing the development of adenomas and improving recurrence-free, disease-free, and overall survival in patients with histories of adenomas and colon cancer has posed a dilemma for researchers and clinicians, given the known toxicity profile. NSAID-related morbidity is fairly common and potentially serious and includes upper gastrointestinal bleeding, renal dysfunction, and serious cardiovascular events such as myocardial infarction, heart failure, and hemorrhagic stroke. Among other findings, use of NSAIDS increases the risk of serious cardiovascular events by 50% to 60% [61; 66]. Hormones (for Women Only) The Women’s Health Initiative (WHI) randomized participants to estrogen plus progestin or placebo. At a mean follow-up of 11.6 years, women receiving active hormone therapy had a 28% lower risk of colorectal cancers [67]. However, in the hormone therapy group, colorectal cancers that developed were significantly more likely to exhibit lymph node involvement and higher stages (regional and distant) compared with those in the placebo group. Deaths from colorectal cancers in the active group were somewhat higher, but the difference from placebo was not statistically significant [67]. A meta-analysis of cohort studies observed a 14% risk reduction for incidence of colorectal cancer associated with combined hormone therapy [68]. Conjugated equine estrogens do not improve incidence or survival in invasive colorectal cancer [67]. Definite harms have been established in using combined estrogen plus progestin hormone in postmenopausal women. The WHI trial found increased risks of invasive breast cancer, coronary heart disease events, and thromboembolic events [67; 69].
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