Abstract
BackgroundChemoprevention with the polyamine-inhibitory regimen difluoromethylornithine (DFMO) + sulindac markedly reduces risk of recurrent adenoma in colorectal adenoma patients. Obesity is associated with risk of colorectal adenoma and colorectal cancer. This study investigates how obesity influences risk of recurrent adenoma after prolonged treatment with DFMO + sulindac versus placebo.MethodsOur analysis included subjects enrolled in the phase III colorectal adenoma prevention clinical trial investigating DFMO + sulindac versus placebo. Patients were classified by obesity (body mass index, BMI ≥ 30 kg/m2) status at baseline. Pearson χ2 statistic and Mann–Whitney U test were used to compare baseline characteristics, including rectal tissue polyamine levels. Log-binomial regression analysis was used to determine the risk ratio (RR) of recurrent adenomas, adjusted for covariates and an interaction term for obesity and treatment.ResultsThe final analytic cohort was comprised of 267 patients. In separate regression models, the risk of adenoma recurrence after treatment compared to placebo was similar for obese (RR = 0.32, 95 % CI 15–71) and non-obese patients (RR = 0.27, 95 % CI 15–49). No significant interaction was detected between obesity, treatment, and risk of colorectal adenoma in the full regression model (p interaction = 0.91).ConclusionsObesity does not substantially modify the colorectal adenoma risk reduction ascribed to DFMO + sulindac versus placebo.
Highlights
Polyamines are naturally occurring substances that, in excess, are associated with colorectal carcinogenesis in animal models [1]
Obesity does not substantially modify the colorectal adenoma risk reduction ascribed to DFMO ? sulindac versus placebo
We report that obesity does not modify the colorectal adenoma (CRA) risk reduction previously ascribed to DFMO ? sulindac versus placebo
Summary
Polyamines are naturally occurring substances that, in excess, are associated with colorectal carcinogenesis in animal models [1]. In a randomized phase III trial of colorectal adenoma (CRA) patients, the risk of CRA recurrence was decreased by 70 % after 3 years of treatment with the polyamine-inhibitory regimen difluoromethylornithine (DFMO) ? Murine experiments reveal that polyamine inhibition via knockout of spermidine spermine acetyltransferase, SSAT (a gene encoding SSAT, which is responsible for polyamine acetylation and subsequent cellular polyamine export), results in deceased fatty acid catabolism, increased tissue adipose content, and increased weight gain [10]. These findings indicate potential links between obesity and polyamine inhibition in humans. This study investigates how obesity influences risk of recurrent adenoma after prolonged treatment with DFMO ? sulindac versus placebo
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