The combination of calcitriol, aspirin, and calcium carbonate did not prevent recurrence of colorectal adenomas over a 3-year period, found a prospective study published in the January issue of Gastroenterology. This negative result might have been affected by the numbers of smokers included in the study or low doses of the tested agents.
Death from colorectal cancer (CRC) can be prevented with screening. However, screening tests are not perfect and cannot prevent all cases of CRC. Screening is also a secondary form of prevention—it detects cancers after they have already formed.
Chemoprevention, however, could reduce the risk of CRC without invasive or expensive screening tests. Trials have shown that aspirin, vitamin D, and calcium reduce risk for colorectal adenoma. The combination of these agents reduced carcinogen-induced lung and bladder tumors in animals, and clinical studies have shown a synergistic effect of this combination in preventing colorectal adenomas. This synergy might allow the use of reduced doses of individual drugs, to decrease the risk of adverse effects related to aspirin.
Hans-Christian Pommergaard et al. therefore investigated the effect of a “cocktail” of acetylsalicylic acid (aspirin), calcitriol (a vitamin D metabolite), and calcium to prevent colorectal adenoma recurrence in 1107 patients with 1 or more sporadic adenoma removed from the colon or rectum. Inclusion criteria were 1 adenoma greater than 1 cm in diameter, more than 1 adenoma of any size, or an adenoma of any size and first-degree relatives with colorectal cancer.
Subjects were assigned randomly to groups given 0.5 μg calcitriol, 75 mg acetylsalicylic acid, and 1250 mg calcium carbonate (n = 209), or placebo (n = 218), each day for 3 years.
The primary outcome was adenoma recurrence, assessed by colonoscopy after 3 years. Ideally, this type of trial would use CRC as an endpoint, but adenomas were as a surrogate outcome because most sporadic CRC are thought to arise from adenomas. In addition, the risk factors for colorectal adenomas closely resemble those for CRC.
The trial was stopped before completion because of futility. At this time, the authors found only minor differences between groups in the rate of recurrence, adverse effects, or secondary outcomes.
Adenomas had recurred in 24.9% of subjects given the chemopreventive agents vs 26.6% of subjects given placebo. Among the recurrent adenomas, 9.6% of those in the chemoprevention group features of advanced pathology, vs 12.1% of patients in the placebo groups. Most recurrent adenomas were tubular with low-grade dysplasia.
Interestingly, adenomas recurred in 40% of smokers in the chemoprevention group vs 27.8% of smokers in the placebo group. However, adenomas recurred in only 15.1% of nonsmokers in the chemoprevention group, vs 26.5% of nonsmokers in the placebo group. So, the combination might be of benefit to only nonsmokers—and conversely harmful to current smokers.
The most serious adverse events were gastrointestinal disorders and infections. No patients in either group suffered from gastrointestinal bleeding, myocardial infarction, or kidney stone disease.
Pommergaard et al. state that given the results from earlier studies, the lack of effect in the present study was surprising. They explained that previous randomized controlled trials found doses of 81 mg and 325 mg aspirin to reduce adenoma recurrence, so the dose used in this study (75 mg) might have been too low.
In an editorial that accompanies the article, Seth D. Crockett and John A. Baron add that the dose of calcium used in this study (1250 mg calcium carbonate) provides 500 mg of elemental calcium—substantially less than the calcium doses used in other studies that reported a benefit (1200–2000 mg of elemental calcium). The high proportion of smokers among the participants might have also contributed to the overall negative result.
Crockett and Baron discuss the features of the study that may have contributed to its negative findings, including a high dropout rate, the low dose of calcium and use of calcitriol, and a low observed overall rate of adenoma recurrence . It is also possible that unanticipated negative interactions among individually effective agents could have led to a negative overall result. The study illustrates the difficulties of conducting adenoma prevention trials.