Lanza E, Binbing Y, Murphy G, et al. The Polyp Prevention Trial-Continued Follow-up Study: no effect of a low-fat, high-fiber, high-fruit, and -vegetable diet on adenoma recurrence eight years after randomization. Cancer Epidemiol Biomarkers Prev 2007;16:1745–1752. Colorectal adenomas have been widely employed as surrogate biomarkers in colorectal cancer (CRC) chemoprevention trials. However, despite their acceptance as proximate, although nonobligate, CRC precursor lesions, adenoma end points remain challenging to interpret for a variety of reasons, as evidenced by reports from the main Polyp Prevention Trial (PPT; N Engl J Med 2000;342:1149–1155) and the subsequent PPT-Continued Follow-up Study (PPT-CFS; Cancer Epidemiol Biomarkers Prev 2007;16:1745–1752). In the initial PPT (n = 2,079), subjects with a history of ≥1 recently resected, histologically confirmed adenomatous polyp were randomly assigned to receive (1) intensive counseling on a low-fat, high-fiber, high fruit and vegetable diet (modified diet intervention arm) or (2) a standard brochure on healthy eating (usual diet control arm). Nutritional habits were assessed at baseline (T0) and at 4 years postrandomization (T4), using an established, self-reported food frequency questionnaire. Adenoma recurrence rates were initially compared at T4, with no statistically significant differences observed between the modified diet and usual diet intervention arms (relative risk [RR], 1.00; 95% confidence interval [CI], 0.90–1.12), despite favorable changes in the targeted dietary parameters among subjects assigned to the former group. To explore the possibility that limited PPT follow-up duration contributed to the apparent lack of chemopreventive benefit, Lanza et al organized the PPT-CFS, which extended the monitoring period by an additional 4 years (without active dietary intervention). Willing, consented subjects were recruited from among PPT participants who completed the original study (1,192/1,905; 62.6%). The final PPT-CFS analytic cohort was then subset to 801 subjects (405 and 396 subjects randomized to the modified diet and usual diet intervention arms, respectively) for whom repeat colonoscopy during the extended monitoring period could be confirmed. Of note, even in the absence of active counseling during the PPT-CFS, statistically significant differences in the dietary targets were maintained between randomization arms. Recurrent adenomas were measured and compared again at T8, with rates of 35.6% in the modified diet group and 37.1% in the usual diet group. After adjusting for missing responses (by imputation), the overall RR for recurrent adenomas did not differ from unity (RR, 0.98; 95% CI, 0.88–1.09). Similarly, risk estimates for multiple (RR, 0.92; 95% CI, 0.77–1.10), advanced (RR, 1.06; 95% CI, 0.81–1.39), proximal (RR, 0.86; 95% CI, 0.73–1.01), and distal (RR, 0.94; 95% CI, 0.75–1.18) adenomas did not demonstrate convincing chemopreventive benefits from the proscribed dietary intervention. With 2 possible exceptions (calcium and selenium), diet-related CRC chemopreventive interventions have generally failed to corroborate the promise of supportive observational and laboratory data. As noted by others (Gastroenterol Clin North Am 2008;37:73–82; Curr Opin Gastroenterol 2008;24:48–50), complex interactions between dietary components make the identification of individual candidate agents quite difficult. Accordingly, multimodality nutritional intervention strategies are highly attractive, as adeptly employed in the main PPT. Further pursuit of an alternate hypothesis in the PPT-CFS, rather than simply discarding low-fat, high-fiber, high fruit and vegetable intake as nonchemopreventive, is laudable. Moreover, even though adenoma recurrence rates remained statistically similar after 8 years of follow-up, Lanza et al offered several credible explanations for their findings, including inappropriate timing of the intervention (ie, later in life, postadenoma formation), inadequate degree of dietary modification (ie, further decrease in fat and/or increases in fiber, fruits, and vegetables), and imperfect surrogacy of the intermediate end point (ie, mostly small, tubular adenomas with low-grade dysplasia and relatively low premalignant potential), as well as the lingering possibility that still longer follow-up might have revealed divergent adenoma recurrence rates between the dietary intervention arms. Whether lessons learned from the PPT and PPT-CFS can be used to better inform the dose, duration, and monitoring of diet-related chemopreventive interventions remains to be determined. However, given the substantial resource requirements of such trials, the study design challenges highlighted by the PPT and PPT-CFS merit careful consideration. With respect to interpretation and application of the reported results, coupled with data from other randomized trials that failed to show any effect of low-fat, high-fiber, and/or high fruit and vegetable interventions on adenoma recurrence (J Clin Epidemiol 1994;47:525–536; J Natl Cancer Inst 1995;87:1760–1766; and N Engl J Med 2000;342:1156–1162), it seems logical, for now, to focus on the potential extracolonic benefits of these low-risk, readily achievable dietary modifications, such as prevention of cardiovascular disease (J Nutr 2006;136:2588–2593).