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Individual differences in dietary intake are thought to account for substantial variation in cancer incidence. However, there has been a consistent lack of effect for low-fat, high-fiber dietary interventions and risk of colorectal cancer. These inconsistencies may reflect the multistage process of cancer as well as the range and timing of dietary change. Another potential reason for the lack of effect is poor dietary adherence among participants in these trials. The authors examined the effect of strict adherence to a low-fat, high-fiber, high-fruit and -vegetable intervention over 4 years among participants (n=1,905) in the US Polyp Prevention Trial (1991–1998) on colorectal adenoma recurrence. There was a wide range of individual variation in the level of compliance among intervention participants. The most adherent participants, defined as “super compliers” (n=210), consistently reported that they met or exceeded each of the 3 dietary goals at all 4 annual visits. Multivariate logistic regression models were used to estimate the association between dietary adherence and adenoma recurrence. The authors observed a 35% reduced odds of adenoma recurrence among super compliers compared with controls (odds ratio=0.65, 95% confidence interval: 0.47, 0.92). Findings suggest that high compliance with a low-fat, high-fiber diet is associated with reduced risk of adenoma recurrence.
Despite a recent drop in incidence rates, colorectal cancer remains the second most commonly diagnosed cancer in men and women in the United States and the second leading cause of cancer death (1). Colorectal adenomatous polyps are considered precursors to colorectal cancer. Identifying modifiable risk factors for colorectal adenomas could pinpoint potential targets for colorectal cancer prevention. Individual differences in dietary intake are believed to attribute to more variation in cancer incidence than any other factor and could account for as many as 90% of colorectal cancer deaths in the United States (2). Observations from ecologic cross-sectional studies of colorectal cancer illustrate that colorectal cancer incidence rates vary dramatically around the world, and by population consumption of fat and fiber, suggesting that diet plays a vital role in the risk of colorectal cancer (3–,5). Findings from most case-control studies have observed a decreased odds of colorectal cancer associated with low-fat, fiber-rich diets (6, 7). However, recent prospective cohort studies and dietary intervention trials of adenoma recurrence have predominantly yielded null results (8–,15).
A number of factors could be responsible for the observed inconsistency in results. First, development of colorectal cancer is a multistage process, and the timing of initiation of the diet or the duration of the intervention may not be appropriate for prevention. Second, the inconsistencies may be due to confounding by other nutritional or lifestyle factors, measurement error, recall bias, or unknown confounding factors. Another potential reason for the lack of effect in dietary intervention trials is the low level of adherence among intervention participants. Intention-to-treat analysis, a conservative approach to address confounding arising in randomized trials, evaluates the effectiveness of the drug (or intervention) in practice, in which the effect of treatment is averaged over those who do and do not adhere to treatment (16). Most trials rarely achieve perfect adherence; if nonadherence exists, the power of the trial to detect an effect of the intervention will be diluted (17, 18).
One question that remains after the completion of the trial is the effect of adherence or efficacy of the treatment. This less conservative approach requires certain assumptions; however, it may provide meaningful observations about efficacy of the treatment (18, 19). For example, early randomized clinical trials of lipid-lowering drugs failed to observe a mortality benefit for patients in the treatment group compared with placebo (20). In a subgroup analysis, good adherers to the treatment had a significantly lower mortality rate than did poor adherers (20). However, the investigators also observed similar mortality benefits among the good adherers in the placebo group and the good adherers in the treatment group (20). Several statistical approaches for evaluating efficacy that go beyond the intention-to-treat analysis have been proposed. However, there are some limitations to evaluating treatment efficacy in subgroups determined by adherence and defined after randomization, as illustrated in the aforementioned study. We evaluated one such approach proposed by Efron and Feldman (21) in this study, which uses an individual's observed compliance to compare treatment groups (21).
The Polyp Prevention Trial was designed to test the effect of a low-fat, high-fiber, and high-fruit and -vegetable dietary intervention on the recurrence of adenomas in the colon (22). After 4 years of the trial, no difference in the rate of adenoma recurrence between the intervention group and the control group was observed (12). The number of dietary goals met by the intervention group varied greatly; thus, it is possible that lack of adherence in fully attaining the intervention goals may account for the lack of observed effect. In this analysis of the Polyp Prevention Trial, we examined whether greater adherence to the low-fat, high-fiber, and high-fruit and -vegetable intervention goals influenced risk of adenoma recurrence.
The data for this study were drawn from the Polyp Prevention Trial. The overall design, rationale, dietary intervention and endpoint procedures, and results of the trial were reported previously (21–24). Briefly, participants had to be at least 35 years of age; had to have at least one histologically confirmed colorectal adenoma identified; must not have had prior surgically resected adenomatous polyps or diagnoses of colorectal cancer, inflammatory bowel disease, or polyposis syndrome; had to be 150% or more of their recommended weight; and could not be currently using lipid-lowering medications. Among the 2,079 participants recruited between 1991 and 1994, 1,905 (control group, n=947; intervention group, n=958) completed the study and were considered in this analysis. A detailed description of the intervention and the dietary changes achieved was published previously (23).
The study was approved by the institutional review boards of the National Cancer Institute and each of the participating centers. All participants provided written informed consent at entry into the study.
At baseline and at each of the 4 annual follow-up visits, participants completed an interviewer-administered questionnaire including demographic, clinical, medication and supplement use, and dietary information. In addition, each participant provided a fasting blood sample for analysis. Diet was assessed at each annual visit with a modified Block–National Cancer Institute food frequency questionnaire and DietSys version 3.7 software (24). This analysis was based on data from the food frequency questionnaire exclusively, which asked about frequency of intake during the past year and average serving sizes. Compared with the 4-day food record and the 24-hour recall, the food frequency questionnaire slightly overestimated fat and underestimated fiber, fruit, and vegetable intake (23, 25).
Participants received full colonoscopies at baseline, their 1-year visit, and the end of the trial intervention, about 4 years after randomization. The colonoscopy at the first annual visit allowed for detection and removal of any lesions missed by the baseline procedure. Pathologically confirmed adenomas diagnosed between the 1-year visit and the end-of-trial colonoscopy were considered recurrent adenomas. Biopsy samples of all adenomas removed during colonoscopy were reviewed independently by 2 pathologists.
The specific goals of the dietary intervention were to limit fat to 20% of energy intake and to consume at least 18 g of fiber and 3.5 servings of fruits and vegetables per 1,000 kcal. Dietary goals were calculated as a proportion of each participant's total caloric intake as determined by the baseline food frequency questionnaire, and the specific individual goals were communicated to each participant. Individual goals were calculated for each participant at each yearly follow-up visit, and achievement of target goals was defined as meeting or exceeding the specific goals communicated at baseline. Composite indices of success in meeting dietary goals were then determined both across years for the individual goals and across years and goals for the entire trial, for a total of 12 goals (3 goals/year for 4 years). Participants were then designated as 1) “poor compliers”=met 0–3 goals, 2) “inconsistent compliers”=met 4–8 goals, and 3) “super compliers”=met 9–12 goals.
Statistical analyses were performed by using Statistical Analysis Systems (SAS) software, version 9.1 (SAS Institute, Inc., Cary, North Carolina). The characteristics of the super compliers and controls were compared with t tests for continuous variables and the χ2 test for categorical variables. Odds ratios and 95% confidence intervals for the association between dietary adherence and (any, multiple, and advanced) adenoma recurrence were estimated by using logistic regression. Our main analyses compared adenoma recurrence among the super compliers with that in the entire control group. We ran several different models, including an unadjusted model (model 1); a model adjusted for those covariates significantly different between the compliers and the controls (model 2); a model adjusted for 41 variables previously reported to be associated with either colorectal cancer or adenoma recurrence (model 3); and a model that included all 41 covariates in model 3 as well as baseline serum biomarkers of lipids, selenium, and carotenoids in a subset of patients with these measurements (158 super compliers, 268 controls) (model 4). To develop categorical variables, dietary variables were grouped into quartiles based on the distribution in the entire study population (n=1,905) and were incorporated into models as indicator variables defined by the second–fourth quartiles of intake, with the lowest quartile as the referent group.
We applied a methodological approach described by Efron and Feldman (21) that relies on use of the compliance variable itself to compare subjects in both the treatment and the control arms of the trial and uses modeling to investigate associations among compliance, drug or intervention dose, and drug or intervention effect (19). This method selects a comparable set of controls based on ranking dietary adherence rates to further explore the association between super compliance and adenoma recurrence. Specifically, the 210 super compliers, defined as having met at least 9 of 12 dietary goals, correspond to 25.6% of the 821 intervention participants who completed the study and for whom no data on dietary goals were missing. The comparative referent group for our percentile-specific analysis was based on assigning the dietary intervention goals to the control group in a similar manner by using data from the control group's annual food frequency questionnaire. After assigning the intervention dietary goals to the control group, a cutpoint to define the controls who met the most goals was set similar to that for the 25.6% of intervention participants designated as super compliers. This cutpoint was set at meeting 2 or more dietary goals, which included 225 (26.8%) of the 840 controls who completed the study and for whom no missing data on yearly dietary goals were missing. We labeled the group of controls who fit into this group (n=225) as “goal-achieving controls.”
Next, we examined whether the effect of the intervention changed by compliance status (i.e., whether there was a stronger intervention effect among the super compliers and goal-achieving controls) by testing for an interaction between randomization group (intervention vs. control) and high compliance (super compliers/goal-achieving controls vs. non-super-compliers/non-goal-achieving controls). Then, we evaluated the association for risk of adenoma recurrence between the super compliers and our defined goal-achieving controls group. All statistical analyses were 2-sided, and P values were considered to be significant if <0.05.
Of 821 (85.9%) of the 956 intervention participants who completed the study, 245 (29.8%) were classified as poor compliers, 366 (44.6%) as inconsistent compliers, and 210 (25.6%) as super compliers. No significant associations were observed among poor compliers or inconsistent compliers compared with controls; thus, there does not appear to be a continuum of the magnitude of association. Therefore, our analysis focused on the associations among super compliers.
Descriptive baseline characteristics of the intervention participants classified as super compliers and participants randomized to the control group are presented in Table 1. The mean age and body mass index of both the super compliers and the controls were very similar, 60.4 years versus 61.1 years and 27.5 kg/m2 versus 27.5 kg/m2, respectively. Compared with participants in the control arm, super compliers were significantly more educated and were less likely to be current or former smokers at the time of randomization (P=0.001). Super compliers also differed significantly from the control group at baseline with respect to dietary intake. Super compliers had a lower intake of fat (percentage of calories) and of red and processed meats and a higher intake of fiber, fruit and vegetables—including cruciferous vegetables—and total carotenoids. Super compliers reported an average baseline intake of 31.7% for fat (percentage of calories), 11.7 g/1,000 kcal for fiber, and 2.8 servings/1,000 kcal of fruit and vegetables. We did not observe any statistically significant differences in adenoma characteristics between the super compliers and the control group, including the size and number of baseline adenomas and the presence of advanced or high-grade adenomas.
The observed effect estimates from 3 different models—unadjusted (model 1), partially adjusted (model 2), and fully adjusted (model 3)—were very similar in magnitude and precision for each of the 3 outcomes. We observed 30% statistically significant decreased odds of adenoma recurrence for super compliers compared with controls in model 1 (odds ratio=0.69, 95% confidence interval: 0.50, 0.95). After adjusting for the covariates in models 2 and 3, we also observed more than a 30% statistically significant decreased odds ratio for any adenoma recurrence among super compliers (Table 2). In addition, super compliance to the intervention over the 4 years of the trial was associated with approximately 50% statistically significant decreased odds of multiple adenomas for models 1–3 (Table 2). Finally, we observed a stronger, but nonsignificant inverse association for advanced adenoma recurrence in all 3 models (Table 2). In a subset of patients with dietary and biomarker measurements, we observed statistically significant decreased odds of any adenoma recurrence among super compliers (odds ratio=0.47, 95% confidence interval: 0.24, 0.94) and nonsignificant decreased odds of multiple and advanced recurrence (odds ratio=0.67, 95% confidence interval: 0.27, 1.67 and odds ratio=0.49, 95% confidence interval: 0.14, 1.68, respectively).
In our test for interaction between the intervention and control randomization groups by super compliers and goal-achieving controls, which examined whether the intervention effect differed by compliance status, we observed statistically significant interaction effects for all 3 types of adenoma recurrence outcomes (P < 0.05) (Table 3). In a separate analysis, we analyzed the association of recurrence between the super compliers and goal-achieving controls, a comparable compliant control population (Table 4). Although the overall sample size for this subanalysis was much smaller than for our analysis including all controls, we observed similar magnitudes of effect for all 3 adenoma outcomes, and we specifically observed more than 50% statistically significant decreased odds of multiple adenoma recurrence in all 3 models (Table 4).
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, 12, 26–,28). 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, 29–,34). 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.
Author affiliations: Epidemiology and Genetics Research Program, Division of Cancer Control and Populations Science, National Cancer Institute, Bethesda, Maryland (Leah B. Sansbury); Office of Behavioral and Social Sciences Research, National Institutes of Health, Bethesda, Maryland (Kay Wanke); Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland (Paul S. Albert); Information Management Services, Inc., Rockville, Maryland (Lisa Kahle); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland (Arthur Schatzkin); and Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (Elaine Lanza).
The authors gratefully acknowledge the National Cancer Institute Cancer Prevention Fellowship Program for their support during the analysis. They also thank Grace Lee for her contributions during preparation of this manuscript and the Polyp Prevention Trial Study Group (refer to the Appendix) for their outstanding contribution to this project.
Conflict of interest: none declared.
The members of the Polyp Prevention Trial Study Group, given below, participated in the conduct of the Polyp Prevention Trial. However, the data presented in this manuscript and the conclusions drawn from them are solely the responsibility of the coauthors listed in the Acknowledgments section.
National Cancer Institute—A. Schatzkin, E. Lanza, D. Corle, L. S. Freedman, C. Clifford, and J. Tangrea; Bowman Gray School of Medicine—M. R. Cooper, E. Paskett (currently at The Ohio State University), S. Quandt, C. DeGraffinreid, K. Bradham, L. Kent, M. Self, D. Boyles, D. West, L. Martin, N. Taylor, E. Dickenson, P. Kuhn, J. Harmon, I. Richardson, H. Lee, and E. Marceau; University of New York at Buffalo—M. P. Lance (currently at the University of Arizona), J. R. Marshal (currently at the Roswell Park Cancer Center), D. Hayes, J. Phillips, N. Petrelli, S. Shelton, E. Randall, A. Blake, L. Wodarski, M. Deinzer, and R. Melton; Edwards Hines, Jr. Hospital, Veterans Administration Medical Center—F. L. Iber, P. Murphy, E. C. Bote, L. Brandt-Whittington, N. Haroon, N. Kazi, M. A. Moore, S. B. Orloff, W. J. Ottosen, M. Patel, R. L. Rothschild, M. Ryan, J. M. Sullivan, and A. Verma; Kaiser Foundation Research Institute—B. Caan, J. V. Selby, G. Friedman, M. Lawson, G. Taff, D. Snow, M. Belfay, M. Schoenberger, K. Sampel, T. Giboney, and M. Randel; Memorial Sloan-Kettering Cancer Center—M. Shike, S. Winawer, A. Bloch, J. Mayer, R. Morse, L. Latkany, D. D'Amato, A. Schaffer, and L. Cohen; University of Pittsburgh—J. Weissfeld, R. Schoen, R. R. Schade, L. Kuller, B. Gahagan, A. Caggiula, C. Lucas, T. Coyne, S. Pappert, R. Robinson, V. Landis, S. Misko, and L. Search; University of Utah—R. W. Burt, M. Slattery, N. Viscofsky, J. Benson, J. Neilson, R. McDivitt, M. Briley, K. Heinrich, and W. Samowitz; Walter Reed Army Medical Center—J. W. Kikendall, D. J. Mateski, R. Wong, E. Stoute, V. Jones-Miskovsky, A. Greaser, S. Hancock, and S. Chandler; Data and Nutrition Coordinating Center (Westat)—J. Cahill, M. Hasson, C. Daston, B. Brewer, T. Zimmerman, C. Sharbaugh, B. O'Brien, L. Cranston, N. Odaka, K. Umbel, J. Pinsky, H. Price, and A. Slonim; Central Pathologists—K. Lewin (University of California, Los Angeles), H. Appelman (University of Michigan); Laboratories—P. S. Bachorik, K. Lovejoy (Johns Hopkins University); A. Sowell (Centers for Disease Control and Prevention); Data and Safety Monitoring Committee—E. R. Greenberg (chair) (Dartmouth University), E. Feldman (Augusta, Georgia), C. Garza (Cornell University), R. Summers (University of Iowa), S. Weiand (through June 1995) (University of Minnesota), and D. DeMets (beginning July 1995) (University of Wisconsin).