In this study, we examined the effect of a low-fat, high-fiber, and high-fruit and -vegetable diet on adenoma recurrence among participants in the Polyp Prevention Trial who most successfully complied with the dietary requirements of the 4-year trial. We observed more than 30% lower odds of any adenoma recurrence and nearly 50% lower odds of multiple and advanced adenoma recurrence among the super compliers compared with controls. These results suggest that consistent adherence to a low-fat, high-fiber, and high-fruit and -vegetable diet may be effective in preventing recurrence of colorectal adenomas and possibly in preventing colorectal cancer. After adjustment for a number of known confounders and risk factors for colorectal adenomas and cancer, the magnitude and precision of our observed associations were virtually unchanged. Furthermore, when we added baseline values of dietary serum biomarkers, including carotenoids, lipids, selenium, and γ-tocopherol, to the model, the magnitude and precision of effect remained very similar.
There is the potential for unobserved and residual confounding effects in the 2 groups, which may induce a different intervention effect; therefore, we used compliance information to compare percentile-specific treatment effects to further investigate the relation between compliance and dietary intervention (21
). Our results indicating statistically significant decreased odds of adenoma recurrence among the super compliers compared with goal-achieving controls provided further support for an inverse association between compliance with the intervention diet and adenoma recurrence.
The potential protective effect of a high-fiber and low-fat diet against colorectal cancer has been studied for over 3 decades with inconsistent and inconclusive results. Although evidence from more than a dozen case-control studies of high fiber and high fruit and vegetable intake confers support for the hypothesis, findings from cohort studies failed to confirm this relation. Results from dietary trials of adenoma recurrence investigating a high-fiber, low-fat diet have mostly been null (8
). Explanations for the inconsistent results include recall bias in case-control studies, the short duration of the trial intervention, or the focus on a single nutrient in most interventions. Finally, achieved adherence rates for the intervention—that is, actual intake—may influence the observed risk among trial participants. When we examined whether strict compliance with any 1 of the 3 individual targeted goals was mainly responsible for the effect observed among the super compliers, the magnitudes of effect for each adenoma outcome were very similar; we observed, however, a slightly stronger effect for the association with compliance with the fat intake goal compared with the other 2 goals. It appears that our observed association was due to compliance with a number of dietary changes and over an adequate duration.
Few studies to date have investigated the association between compliance with a healthy dietary pattern and cancer risk, specifically risk of colorectal adenomas or colorectal cancer (9
). A recent investigation of adherence to recommended dietary guidelines observed that men who complied with the US Department of Agriculture Food Guide recommendations, the DASH Eating Plan, and the Mediterranean dietary pattern had, respectively, a 26%, 25%, and 21% reduced risk of colorectal adenoma incidence (30
). Similar inverse associations for adherence and risk of colorectal cancer in men were also observed in a cohort of US retirees (31
). In a meta-analysis of 12 prospective cohort studies (32
), greater adherence to a traditional Mediterranean diet was observed to be inversely associated with death due to cancer.
These studies are subject to a number of biases and lack a number of the strengths of our study. Unlike some of the aforementioned studies that measured dietary adherence or intake at baseline only, we were able to measure adherence to the intervention diet and other lifestyle factors at multiple time points and over a longer duration, which allowed for better representation of participants’ diet. Second, unlike a number of other dietary intervention trials, the Polyp Prevention Trial lasted longer than 1 year, used an intervention that emphasized a number of dietary changes, and included excellent longitudinal follow-up data on dietary intake and compliance. In our study, the magnitude of effects of complying with the 3 goals at each individual time point, however, was not as strong as the effects observed for super compliers. These findings further support the hypothesis that strict adherence to a high-fiber, low-fat diet over a longer duration is important for prevention of adenoma recurrence. Furthermore, all participants underwent a clearing colonoscopy 6 months prior to and 1 year after randomization; thus, we were able to eliminate the bias associated with whether or not the polyp was present before the measure of dietary adherence.
The Polyp Prevention Trial drew a large number of participants from across the country and provided a unique opportunity to assess compliance with multiple dietary changes and risk of adenoma recurrence over a long period of time (4 years); however, it is not without limitations. Trial participants were mostly white, well educated, married, and older than age 50 years, and all participants had a history of a colorectal adenoma before enrolling in the study. In addition, the main dietary variables and most covariates involved self-report, and thus recall bias in self-assessment may have been differentially distributed between super compliers and controls. We recognize that multivariate adjustment does not necessarily rule out a role for unknown or inadequately measured factors associated with both compliance and adenoma recurrence. Randomized controlled trials rely on randomization to help ensure that the proportions of unknown or inadequately measured confounders are equally distributed between the 2 groups.
Further support for a compliance effect on adenoma recurrence comes from our percentile-specific compliance analysis. When we applied the Efron and Feldman method (21
) and used compliance as an explanatory variable and transformed the data into equal distributions of strict compliers, we observed significantly decreased odds of recurrence when we separately ranked compliance in the 2 arms of the trial and compared super compliers with goal-achieving controls. However, one of the major assumptions of this method is that complying in the intervention arm is similar to complying in the control arm (19
). Therefore, we do not actually know what counterfactual results we would observe. That is, the percentile-specific analysis assumes that if a super complier had been randomized to the control arm instead of the intervention arm, he or she would have acted like a goal-achieving control, and vice versa.
The difficulty of this assumption is that compliance can be affected by treatment, as we observed with our tests for interaction. In addition, because subjects essentially select their own doses (e.g., compliance), it is likely that dose is associated with other lifestyle characteristics. However, after we controlled for a large number of covariates, including dietary and lifestyle covariates that were significantly different between super compliers and controls, the magnitude of our effect estimates was very similar, and we still observed statistically significant decreased odds of multiple and advanced adenoma recurrence among super compliers compared with goal-achieving controls.
In summary, our results show that the effectiveness of dietary intervention trials depends upon participants’ adherence to dietary requirements. Findings from our study suggest that strict adherence to a low-fat, high-fiber, and high-fruit and -vegetable diet could prevent colorectal adenoma recurrence and possibly colorectal cancer. Finally, identifying characteristics of participants most likely to comply with the diet or regimen could assist in developing and designing studies and clinical trials of dietary interventions. To focus on testing the biologic effects of an intervention or treatment on the trial, future dietary and treatment trials could target and randomize individuals most likely to comply. Findings from such trials would enhance the validity of our own findings.