In this prospective, randomized clinical trial, six-month interventions with sulindac, atorvastatin and ORAFTI®Synergy1 did not yield significant reductions in rectal ACF number, as compared to control (maltodextrin), among subjects at increased risk for sporadic CRC. To our knowledge, this study represents the largest ACF-based CRC chemoprevention trial reported to date, and the first such trial to be conducted in stand-alone fashion, rather than ancillary to or embedded within a larger parent study. Further, secondary analyses of tissue-based biomarkers (assessed from normal-appearing rectal mucosa) in our study revealed that none of the interventions had a statistically significant effect on cellular proliferation, while all of interventions (including the maltodextrin control) were associated with increased apoptosis. Yet, since the observed pro-apoptotic effects did not differ appreciably between the active and control interventions, the relevance of these latter data to defining the CRC chemopreventive potential of sulindac, atorvastatin and ORAFTI®Synergy1 remains indeterminate.
Only two other prospective CRC chemoprevention trials have been reported with change in rectal ACF number as the primary endpoint (17
). Takayama, et al. initially described the results of an open-label trial of sulindac 100 mg tid conducted among a subset of subjects (n=20) enrolled in a MCE study designed to evaluate ACF prevalence across CRC risk groups (20
). Compared to 9 untreated subjects, 11 subjects who received sulindac for 8–12 months had significantly fewer rectal ACF at the post-treatment MCE exam (p <0.001 for difference between groups). More recently, Cho and colleagues (17
) used a substudy design to assess change in ACF number among 45 participants enrolled in the Adenoma Prevention with Celecoxib (APC) trial. Following an 8–12 month intervention period, celecoxib (200 mg or 400 mg bid) did not appear to beneficially modulate rectal ACF number, with average +/− SE values for pre- to postintervention change in ACF number of 1.8 +/− 1.1 and 2.3 +/−1.7 among subjects assigned to the active versus placebo arms, respectively (p=0.77). Up to 5 rectal ACF per subject were biopsied at baseline; however, accounting for baseline ACF removal did not meaningfully alter the primary endpoint comparison (p=0.60).
Although rectal ACF have been widely discussed as a putative precursor to colorectal adenoma and cancer (20
), concerns have been recently raised regarding measurement of these lesions as an intermediate endpoint for CRC chemoprevention trials (23
), due in large part to the low prevalence of histologically-confirmed dysplasia. Indeed, in the aforementioned studies by Takayama (20
) and Cho (17
), dysplastic ACF comprised only 5% (161/3155) and 0% (0/70), respectively, of the microscopically analyzed lesions. In our trial, dysplastic ACF were similarly infrequent (2%; based on histologic review of post-intervention ACF biopsy samples). Previous observational studies have reported a somewhat wider range of dysplastic ACF (0–23%), albeit from variably defined subject populations (26
). Nonetheless, further investigation seems prudent to clarify the validity of rectal ACF as a surrogate marker for CRC risk prior to incorporating these lesions as intermediate endpoints in future prevention studies.
Emerging data suggest that the natural history of rectal ACF could also influence the results of short-term CRC chemoprevention trials. In an ancillary study to the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, Schoen and colleagues performed follow-up MCE exams at one year on 64 subjects with rectal ACF identified (mean = 2.1 per subject), but not removed, at the baseline evaluation (31
). Forty-three percent of the baseline ACF were re-identified at follow-up. Moreover, 56% of the subjects had newly-identified rectal ACF. A subsequent analysis of subjects who underwent rectal ACF removal at baseline and returned for follow-up MCE exam one year later showed relatively little change in the mean number of lesions per subject (2.25 vs. 1.93)(32
), indicating a dynamic change in ACF progression, regression and/or detection rates over the lifespan of a typical phase II CRC chemoprevention trial. To explore this possibility in our intervention cohort, we conducted sensitivity analyses based on incident versus prevalent ACF and observed no appreciable differences in the agent-specific effects (data not shown).
Potential challenges related to the MCE exam should also be considered when interpreting the results of our phase II CRC chemoprevention trial. Most notably, based again on data from the PLCO ancillary ACF study, the interrater agreement for most endoscopic criteria used to identify rectal ACF appears to be low (33
). In addition, up to 55% of endoscopically-identified ACF have not been confirmed by histology in other North American studies (27
), which is consistent with the “false positive” rate observed in our trial. Thus, variability in the endpoint assessment might have contributed to our generally null results.
Major strengths of our study include the prospective, multi-center trial design that afforded successful achievement of our revised accrual target. We also utilized a standardized MCE exam protocol, which incorporated pre-trial ACF knowledge assessment and uniform, prototype endoscopy equipment across study sites, to minimize potential influence from technical challenges on the primary endpoint evaluation. Yet, even with this rigorous approach, striking standard deviations were observed in the %ΔACF data. Several additional factors might have affected our ability to detect a significant benefit from sulindac, atorvastatin or ORAFTI®
Synergy1. First, polymorphisms in flavin monooxygenase 3 have been shown to influence sulindac efficacy in other high-risk populations (34
), but were not measured in our study cohort. Second, based on a recently published meta-analysis of data from 18 studies and involving more than 1.5 million subjects (35
), the magnitude of CRC risk reduction associated with statin use may be much lower (8%) than anticipated during the design phase of our trial. In fact, observational data from the APC trial cohort imply that statin drug use may be associated with increased adenoma risk among subjects with previously resected colorectal neoplasia (36
). Third, while prebiotic dietary fiber alone might be anticipated to provide a somewhat lesser degree of CRC risk reduction than candidate pharmaceutical agents, limited available data suggest that ORAFTI®
Synergy1 could have greater anti-cancer potential if given in combination with probiotic agents (16
). Fourth, despite being larger than any previously reported CRC chemoprevention trial with an ACF endpoint (17
), our study was only moderately powered to detect the defined intervention effect. Lastly, since the assessed biomarkers (endoscopic and tissue-based) were measured from the rectum only, it remains conceivable that chemopreventive effects confined to the colon could have gone undetected.
In summary, data from this phase II randomized, partially-blinded chemoprevention trial do not provide convincing evidence of CRC risk reduction from atorvastatin, sulindac, or ORAFTI®Synergy1. Larger sample size, longer intervention period, and/or alternate endpoints should be considered if further evaluation of these candidate agents is pursued. Ongoing investigation of the endoscopic, histologic and molecular characteristics of rectal ACF that accurately reflect CRC risk may also serve to clarify if, or how, these lesions can be effectively applied as surrogate markers in future prevention studies.