Background

Methods

Results

Conclusions

Nonsteroidal anti-inflammatory drugs (NSAID) have been associated with adverse cardiovascular (CV) outcomes in cancer prevention and other clinical trials. A recent meta-analysis suggested that baseline CV risk is associated with NSAID-associated adverse CV events. We evaluated the effect of baseline CV risk on adverse CV events in a phase III trial of difluoromethylornithine (DFMO) plus the NSAID sulindac versus placebo in preventing colorectal adenomas. Trial data were analyzed to determine baseline CV risk. CV toxicity outcomes were then assessed overall and excluding high CV-risk patients. Baseline CV risk scores were evenly distributed within our overall trial population of 184 placebo (low risk, 27%; moderate risk, 34%; high risk, 39%) and 191 DFMO/sulindac (low risk, 30%; moderate risk, 29%; high risk, 41%) patients. In patients with a high baseline CV risk, the number of adverse CV events was greater among DFMO/sulindac (n = 9) than among placebo (n = 3) patients. Excluding patients with a high baseline CV risk, the numbers of adverse CV events were similar in the DFMO/sulindac (n = 7) and placebo (n = 6) arms. A high CV risk score at baseline may confer an increased risk of CV events associated with treatment with DFMO/sulindac, and a low baseline score may not increase this risk. These results have implications for future NSAID-based cancer prevention clinical trials.

A phase III clinical trial assessed the recurrence of adenomatous polyps after treatment for 36 months with difluoromethylornithine (DFMO) plus sulindac or matched placebos. Temporary hearing loss is a known toxicity of treatment with DFMO, thus a comprehensive approach was developed to analyze serial air conduction audiograms. The generalized estimating equation method estimated the mean difference between treatment arms with regard to change in air conduction pure tone thresholds while accounting for within-subject correlation due to repeated measurements at frequencies. Based on 290 subjects, there was an average difference of 0.50 dB between subjects treated with DFMO plus sulindac compared with those treated with placebo (95% confidence interval, -0.64 to 1.63 dB; P = 0.39), adjusted for baseline values, age, and frequencies. In the normal speech range of 500 to 3,000 Hz, an estimated difference of 0.99 dB (-0.17 to 2.14 dB; P = 0.09) was detected. Dose intensity did not add information to models. There were 14 of 151 (9.3%) in the DFMO plus sulindac group and 4 of 139 (2.9%) in the placebo group who experienced at least 15 dB hearing reduction from baseline in 2 or more consecutive frequencies across the entire range tested (P = 0.02). Follow-up air conduction done at least 6 months after end of treatment showed an adjusted mean difference in hearing thresholds of 1.08 dB (-0.81 to 2.96 dB; P = 0.26) between treatment arms. There was no significant difference in the proportion of subjects in the DFMO plus sulindac group who experienced clinically significant hearing loss compared with the placebo group. The estimated attributable risk of ototoxicity from exposure to the drug is 8.4% (95% confidence interval, -2.0% to 18.8%; P = 0.12). There is a <2 dB difference in mean threshold for patients treated with DFMO plus sulindac compared with those treated with placebo.

Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (> or =3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade > or =3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.