Chemopreventive strategies for sporadic colorectal cancer: a narrative review

Introduction

Colorectal cancer (CRC) now represents the first- and second-leading cause of death in U.S. men and women, respectively, under 50 years of age (1). Globally, CRC represents the third most diagnosed cancer with an estimated 1.9 million new cases and the second-leading cause of cancer death with an estimated 930,000 deaths in 2020 (2). Even though CRC constitutes a large public health burden, there exists no established method of primary prevention. Screening colonoscopies and preventive colectomy represent the only methods of secondary prevention for CRC (3,4).

CRCs arise from precancerous lesions known as adenomas where evolution from the normal colorectal epithelium to adenomas and ultimately to invasive cancer can take up to 10 years to develop (5). Although certain hereditary CRC syndromes are characterized by germline mutations [e.g., Adenoma Prevention with Celecoxib (APC)] resulting in the formation of thousands of polyps and a high lifetime risk of CRC [i.e., familial adenomatous polyposis (FAP) syndrome], most CRCs (approximately 75%) are sporadic, arising from well-described early and frequent molecular alterations in key genes implicated in colorectal tumorigenesis (6,7). The progression from normal epithelium to CRC in sporadic cases typically follows the chromosomal instability (CIN) pathway, which is similar to the molecular etiology seen in FAP (8,9). The process often begins with mutations in the APC gene, occurring in approximately 70–80% of cases (10,11). These mutations disrupt the Wnt signaling pathway, promoting cell proliferation and inhibiting differentiation, leading to early adenoma formation (12-14). As the adenoma grows, additional mutations accumulate, frequently including activating mutations in KRAS (40–50% of cases), which further promote cell proliferation and survival (15,16). The transition to carcinoma is marked by the loss of function in tumor suppressor genes like TP53 (50–70% of cases) and SMAD4, allowing cells to evade apoptosis and promote invasive growth. Finally, additional genetic and epigenetic alterations accumulate, leading to metastatic potential (17,18).

The U.S. Preventive Services Task Force (USPSTF) currently recommends screening colonoscopies for standard-risk individuals at age 45 years (3). Colonoscopy is unique among cancer screening tools, as it is both diagnostic and therapeutic since removal of precancerous polyps can be achieved. Although CRC chemoprevention, which is the use of supplements, synthetic or natural as a means of primary prevention for CRC, has undergone active investigation, there exists no approved chemopreventive agent for CRC (19).

In this review, we highlight CRC chemoprevention trials that have investigated chemopreventive agents aiming to prevent CRC development through reduction of CRC itself or through reduction of known precursor lesions such as adenomas and aberrant crypt foci (ACF). We specifically aimed to identify randomized controlled trials (RCTs) that have examined potential chemopreventive agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), minerals, vitamins, and metabolic agents with published results for the prevention of sporadic CRC. We present this article in accordance with the Narrative Review reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-97/rc).

Methods

Search engines including PubMed, Science Direct, and Google Scholar were used to identify articles (Table 1). For articles discussing RCTs, there was no year specification, and we selected for all other articles discussing CRC chemoprevention we felt to be of relevance to highlight in this review. The inclusion criteria for this review include RCTs with or without a placebo, chemopreventive trials in sporadic CRC, and trials with available results. Exclusion criteria include study populations with a confirmed genetic predisposition to CRC, including Lynch and FAP syndromes. Observational, prospective or retrospective cohort, case-controlled, animal, in vitro studies, and trials without published results were excluded. The purpose of this review is to focus solely on potential chemopreventive agents that have been clinically studied in humans for sporadic CRC prevention.

NSAIDs

Aspirin

Aspirin has been the most studied CRC chemopreventive agent. Classified as an NSAID, aspirin’s chemopreventive potential against CRC appears rooted through its effects on prostaglandin synthesis and catabolism via cyclooxygenase (COX) 1/2 enzymes in colorectal epithelial cells, inhibition of WNT-β-catenin signaling, platelet inactivation, and immunosurveillance (20,21). Early evidence supportive of aspirin’s ability to reduce CRC cases in patients with cardiovascular disease (CVD) led to the USPSTF draft statement in 2015 recommending the use of aspirin for the primary prevention of CRC and CVD (20). Specifically, aspirin was recommended for adults aged 50–59 years (grade B recommendation) or aged 60–69 years (grade C recommendation) with a ≥10% 10-year CVD risk with a life expectancy of ≥10 years willing to take aspirin for ≥10 years without an increased risk of bleeding (20). This recommendation was noticeably withdrawn in an update of the USPSTF 2016 recommendation, following a systematic review of RCTs of aspirin in CRC chemoprevention wherein the USPSTF concluded that there was inadequate evidence to support the daily use of low-dose aspirin in reducing CRC incidence and mortality (22).

In the years preceding and postdating the USPSTF 2016 recommendation, there have been over a dozen RCTs involving aspirin in CRC chemoprevention (Table 2). The British Doctors Aspirin Trial, UK Transient Ischemic Attack Trial (UKTIA), Physician’s Health Study (PHS), Thrombosis Prevention Trial (TPT), Swedish Aspirin Low-dose Trial (SALT), The Women’s Health Study (WHS), and Aspirin in Reducing Events in the Elderly (ASPREE) were randomized trials that looked at the outcome of CRC incidence using at least 75 mg of aspirin daily, except for the WHS which used alternate day dosing of 100 mg aspirin (23-29). Among these early RCTs, the British Doctors Aspirin Trial, TPT, and WHS demonstrated reductions in the incidence of CRC with up to 500 mg of daily aspirin, while the UKTIA, PHS, and SALT studies did not demonstrate significant reductions in CRC incidence with up to 300 mg of daily aspirin (23-28). In a pooled analysis of The British Doctors Aspirin Trial, SALT, UKTIA, and Dutch TIA Aspirin trials, there appeared not to be a reduction of CRC incidence for doses greater than 75 mg daily but the benefit increased with 5 years or longer of aspirin with differential benefit based on tumor subsite location: 70% reduction for proximal colon cancer [hazard ratio (HR) 0.35, 95% confidence interval (CI): 0.20–0.63, P<0.0001], and 42% reduction for rectal cancer (HR 0.58, 95% CI: 0.36–0.92, P=0.02) (27).

The ASPREE trial was a recent RCT where elderly subjects >70 years of age (≥65 years if Black or Hispanic) without CVD, dementia, or disability were randomly assigned to take 100 mg of aspirin or a placebo once a day for a median of 4.7 years (29). There was an increased incidence of CRC with daily aspirin use compared to placebo (HR 1.77, 95% CI: 1.02–3.06) and, surprisingly, a higher incidence in deaths due to gastrointestinal (GI) cancers in the aspirin group (risk of cancer-related death of 6.7 events/1,000 person-years) compared to the placebo group (5.1 events/1,000 person-years, HR 1.31, 95% CI: 1.10–1.56).

The Cancer & Leukemia Group B (CALGB), Aspirin/Folate Polyp Prevention Study (AFPPS), United Kingdom Colorectal Adenoma Prevention Trial (UKCAP), Association Pour la Prevention par l’Aspirine du Cancer Colorectal (APACC), Japan Colorectal Aspirin Polyp Prevention (JCAPP) trial, and Systematic Evaluation of Aspirin and Fish Oil Polyp Prevention Trial (SeAFOod) were all RCTs that looked at polyp occurrence as the outcome (30-36). These studies enrolled subjects with either prior CRC or adenomas that have been resected to receive daily aspirin of 81–325 mg showed a significant reduction in adenoma risk in all but one study, when compared to placebo (Table 2). A meta-analysis including the AFPPS, CALGB, UKCAP, and APACC trials found adenomas in 37% of the participants assigned to the placebo group and 33% assigned to the intervention group, which translated to a statistically significant 17% relative reduction in adenoma risk with aspirin (any dose) vs. placebo (pooled risk ratio of 0.83, 95% CI: 0.72–0.96, absolute risk reduction of 6.7%) (37). However, when looking at the incidence of CRC in the AFPPS, UKCAP and APACC trials (excluding the CALGB trial as some of its participants had been previously diagnosed with CRC), there were no significant difference in CRC rates between the placebo and aspirin (intervention groups, P=0.81) (37).

Although these RCTs presented aspirin as one of the earliest potential chemopreventive agents for sporadic CRC, major bleeding events have been a key side effect (37,38). Meta-analyses of over 54,000 subjects randomized to aspirin and over 52,000 subjects randomized to placebo across 11 RCTs have identified an excess risk of major GI bleeding in those receiving aspirin [relative risk (RR) 1.55, 95% CI: 1.32–1.83], equivalent to approximately 1 per bleed per 1,000 persons per year (38). In a pooled analysis of RCTs of aspirin for adenoma prevention, there was no significant differences in rates of major bleeding across doses of aspirin (2.5%) compared to placebo (2.79%) (37).

Non-aspirin (NA)-NSAIDs

Celecoxib, rofecoxib, sulindac & etodolac

Other NSAIDs besides aspirin include celecoxib, etodolac, ibuprofen, nabumetone, naproxen/naproxen sodium, rofecoxib, sulindac, valdecoxib that are routinely available. We will focus NA-NSAIDs, celecoxib, rofecoxib, sulindac, and etodolac, based on published results from 5 RCTs using these NA-NSAIDs for sporadic CRC chemoprevention (39-43). NA-NSAIDs competitively inhibit COX-1 and COX-2 as their mechanism of action, but due to increased GI bleeding risk potentially associated with COX-1 inhibition, NA-NSAIDs that selectively inhibit COX-2 have been tested in RCTs for adenoma prevention (19).

In the APC Trial, 2,035 participants aged 31–88 years of age who had previously undergone colonoscopic removal of adenomas were randomized to take 200 or 400 mg of celecoxib twice daily, or placebo with repeat colonoscopies after 1 and 3 years of intervention (41). The trial found adenomas in 60.7% in those who were allocated to the placebo group, 43.2% in those who were allocated to the 200 mg celecoxib group, and 37.5% in those assigned to the 400 mg celecoxib group at 3 years, corresponding to a RR of 0.67 (95% CI: 0.59–0.77) for the 200 mg celecoxib group and a RR of 0.55 (95% CI: 0.48–0.64) for the 400 mg celecoxib group (Table 3). In a subsequent celecoxib trial, the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial, 1,738 participants who had all polyps removed by colonoscopy within 3 months of enrollment were randomized to 400 mg of celecoxib daily or placebo for 3 years (39). The 3-year estimated cumulative adenoma rate was 33.6% with celecoxib vs. 49.3% with placebo (RR 0.64, 95% CI: 0.56–0.75, P<0.001). The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial studied the effect of another COX-2 inhibitor, rofecoxib, on adenomas diagnosed during 3 years of intervention (40). In APPROVe, 2,587 participants of ≥40 years of age with at least 1 histologically confirmed large-bowel adenoma within 12 weeks of study entry were randomized to 25 mg of rofecoxib daily or placebo with colonoscopy at 1 and 3 years. Rofecoxib conferred a significant reduction at 1 year (RR 0.65, 95% CI: 0.57–0.73) than the subsequent 2 years (RR 0.81, 95% CI: 0.71–0.93) (40).

Notably, despite the promise of these COX-2 inhibitors in adenoma prevention, rofecoxib was associated with increased thrombotic cardiovascular events (RR 1.89, 95% CI: 1.18–3.04) and upper GI perforation, obstruction, symptomatic ulcers, or bleeding (RR 4.91, 95% CI: 1.98–14.5), relative to placebo (40), resulting in the halting of the APPROVe trial and the voluntary withdrawal of new drug applications (NDAs) for rofecoxib submitted to the U.S. Food and Drug Administration (FDA). Although the PreSAP trial did not identify a significant increase in cardiovascular risk with celecoxib, the concurrent APC Trial showed a significantly increased risk of serious cardiovascular events (i.e., death from cardiovascular events, nonfatal myocardial infarction, stroke, or heart failure) with both low-dose (risk ratio 2.6, 95% CI: 1.1–6.1) and high-dose celecoxib (risk ratio 3.4, 95% CI: 1.5–7.9), when compared to placebo, leading to suspension of celecoxib administration in both the PreSAP and APC trials on December 17, 2004 (39,41).

In a recent RCT, sulindac (COX-1/2 inhibitor) and etodolac (more selective for COX-2 than COX-1 inhibition) were investigated on the prevention of ACF and adenomas after 2 months (43). One hundred and eighty-nine subjects who had prior history of ACF or polyps removed were randomized to 300 mg of sulindac once a day, 400 mg of etodolac once a day, or placebo (Table 3). The frequency of ACF at 2 months was significantly reduced in the sulindac group relative to the placebo group (P=0.0075), but the ACF number in the etodolac group was not significantly different relative to placebo (P=0.67). There were no cardiovascular events observed and no significant difference in adverse events across groups, the majority of which were grade 1 in severity (43). Polyamine inhibition has been shown to prevent colon carcinogenesis in mouse models as well in human clinical trials (44). In another RCT, 305 subjects with a prior adenoma resected within 5 years of study entry were randomized to placebo or DFMO (500 mg daily)/sulindac (150 mg daily). The safety and chemopreventive effects of sulindac (which, in addition to COX-1/2 inhibitory effects, also exports polyamines from cells via a PPAR-gamma mechanism) were highlighted in combination with difluoromethylornithine or eflornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC) (42). At 3-year colonoscopy, there was a significant reduction in colorectal adenomas with the combination compared to placebo (RR 0.30, 95% CI: 0.18–0.49, P<0.001) with a more marked reduction with advanced adenomas (RR 0.085, 95% CI: 0.011–0.65, P<0.001). Of note, there was a non-significant but numeric increase in serious cardiovascular events in the combination (8.4%) vs. placebo (4.9%) groups, which in subset analysis appeared to be limited to those in the trial having elevated CVD risk at baseline (42,45). There were no significant differences in grade ≥3 adverse events or hearing changes from baseline (side effect unique to DFMO) between groups (42).

Metabolic agents

Agents commonly used to treat diabetes and hyperlipidemia, henceforth referred to as metabolic agents, have also been investigated as potential chemopreventive strategies for sporadic CRC (Table 4). These RCTs often occurred in patients with obesity or preexisting risk factors for CVD with the intent to decrease risks and complications from metabolic syndrome (46-57).

Statins

Lipid-lowering agents of the statin class are competitive hydroxymethylglutaryl-CoA reductase (HMG-CoA) inhibitors and have been shown to inhibit the growth and development of colorectal tumors in preclinical models of chemically or genetically-induced colorectal tumorigenesis (19,58).

The West of Scotland Coronary Prevention Study was an RCT comparing pravastatin (40 mg oral daily) with placebo in 6,595 men with hypercholesterolemia who did not have a history of myocardial infarction, with a mean follow-up of 13.2 years for incident cancers (50). Of 122 incident CRC detected during the total follow-up period, there was no significant reduction in CRC incidence between pravastatin (56/3,291 or 1.7%) and placebo (66/3,286 or 2.0%) groups (HR 0.82, 95% CI: 0.58–1.17, P=0.28). The CARE trial randomized 4,159 men and postmenopausal women with prior myocardial infarction to 40 mg oral daily of pravastatin or placebo and similarly found no significant reduction in CRC incidence (RR 0.57, 95% CI: 0.28–1.16) with a median follow-up of 5 years (48,55).

In the Scandinavian simvastatin survival study, 4,444 patients who have been previously diagnosed with a myocardial infarction or angina were randomized to receive 20 mg of simvastatin once a day or placebo with a median follow-up of 10.4 years (48,56). Out of 57/4,444 incident CRCs during this follow-up period, there was no significant reduction in CRC incidence (RR 0.78, 95% CI: 0.46–1.32).

The AFCAPS/TEXCAPS study randomized 6,605 men and women with average cholesterol risk to 20–40 mg of daily lovastatin or placebo and identified a nonsignificant increase in CRC incidence (RR 1.25, 95% CI: 0.70–2.24) with a mean follow-up of 5.2 years (48,49). A nonsignificant increased risk of CRC was also observed in the ALLHAT-LLT trial that randomized 10,355 patients with ≥1 CVD risk factor and stage 1–2 hypertension to pravastatin 40 mg daily or placebo (RR 1.21, 95% CI: 0.79–1.86) (47,48).

Several subsequent pravastatin trials such as the LIPID and GISSI Prevenzione trials randomized patients with prior myocardial infarction or unstable angina pectoris to pravastatin 20–40 mg oral daily or control have similarly shown no significant reduction in CRC incidence or incidence of other cancer sites (Table 4) (46,54).

Metformin

Metformin is a biguanide used to treat individuals with type 2 diabetes and having been shown to elicit potential antitumor properties and reduce ACF and polyp formation in genetic mouse models of FAP and azoxymethane-treated animals, a mouse model of chemically-induced CRC (19,58). To date, 2 RCTs and 1 single-arm phase IIa trial have been published on metformin’s chemopreventive potential in sporadic CRC (Table 4).

Zell et al. conducted a phase IIa trial of 32 subjects with obesity and a prior history of adenomas to receive metformin beginning at 500 mg oral daily escalated up to 2,000 mg daily for 12 weeks and did not identify a significant difference in rectal tissue pS6^Ser235/236 or Ki67 immunostaining levels as surrogate biomarkers of metformin’s chemopreventive potential in sporadic CRC (57). Of note, in contrast to RCTs, biomarker testing in this trial was done on the target tissue of origin (normal rectal mucosa) rather than in adenomas.

In an RCT by Higurashi et al., nondiabetic participants with a prior history of resected adenomas were assigned to one of two groups: 250 mg of metformin (n=79) once a day or matching placebo (n=72) once a day with a colonoscopy at 1 year (52). The trial found that the metformin group showed a decrease in the number of polyps compared to the placebo group [total polyps 27/71 subjects with metformin (38.0%, 95% CI: 26.7–49.3%) vs. 35/62 with placebo (56.5%, 95% CI: 44.1–68.8%)] for a RR of 0.67 (95% CI: 0.47–0.97, P=0.034). The rate of adenomas with metformin was 22/71 (30.6%, 95% CI: 19.9–41.2%) vs. 32/62 with placebo (51.6%, 95% CI: 39.2–64.1%) for a RR of 0.60, 95% CI: 0.39–0.92, P=0.016).

Hosono et al. conducted a randomized study to investigate the use of metformin on ACF prevention (53). Twenty-six nondiabetic patients with prior history of ACF were randomized to 250 mg of metformin (n=12) once a day or matching placebo (n=14) for 1 month. The metformin group had a significantly lower mean number of ACF at 1 month (8.78±6.45 pretreatment vs. 5.11±4.99 at 1 month, P=0.007) than the control group (7.23±6.65 baseline vs. 7.56±6.75 at 1 month, P=0.609).

Minerals and vitamins

There has been interest in exploring the potential of minerals or vitamins including folate, calcium, and vitamin D to prevent sporadic CRC with results published from multiple RCTs (Table 5).

Folate

Folate or folic acid is a B vitamin (vitamin B9) that is critical to DNA synthesis and cell division, and its chemopreventive effects in CRC have been purported to involve its regulation of normal DNA synthesis and repair (19,58). There have been 5 RCTs investigating folate in sporadic CRC chemoprevention (Table 5).

The AFPPS was a phase III RCT that sought to investigate the impact of folic acid supplementation and aspirin in the development of colorectal adenomas (59,60). Of 1,021 participants with a history of a previous adenoma, 516 participants were randomized to 1 mg of folic acid oral daily and the remainder to placebo. They were then randomized again and assigned to take 81 or 325 mg of aspirin a day. The trial ultimately did not show any decrease in colorectal adenomas with folic acid (44.1% adenomas) relative to placebo (42.4% adenomas, unadjusted RR 1.04, 95% CI: 0.90–1.20, P=0.58). Following a second colonoscopy, the risk of ≥1 adenoma was 41.9% with folic acid vs. 37.2% with placebo (unadjusted RR 1.13, 95% CI: 0.93–1.37, P=0.23).

Jaszewski et al. conducted an RCT where 49 participants were randomized to 5 mg of folic acid daily and 45 participants were assigned to the placebo group for 3 years (61). A significantly reduced number of adenomas was detected in the folic acid group vs. placebo [64% lower risk ratio, odds ratio (OR) of 2.77, P=0.02514].

The Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) studied the use of folic acid, vitamin B6, and vitamin B12 in 5,442 women health professionals diagnosed with pre-existing CVD or ≥3 CVD risk factors (62). Participants were randomized to 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or a placebo once daily for up to 7.3 years. The study found no difference in the development of CRC between the intervention and placebo groups (HR 0.81, 95% CI: 0.43–1.50, P=0.50) and no significant difference in any cancer death across groups (HR 0.82, 95% CI: 0.56–1.21, P=0.32).

The Vitamins to Prevent Stroke Trial (VITATOPS) randomized 8,164 patients who had experienced a stroke or transient ischemic attack to the combination of 2 mg folic acid, 25 mg vitamin B6, and 500 µg vitamin B12 or placebo once a day for a median of 3.4 years. Hankey et al. did not find a difference in the development of any cancers between the intervention and placebo groups (4.04% B vitamins group vs. 4.59% placebo group, RR 0.86, 95% CI: 0.70–1.07) and there was no significant reduction in CRC incidence (HR 0.98) (63).

In a clinical trial by Gao et al., participants >50 years with no prior adenoma on colonoscopy were randomized to 1 mg of folic acid daily or no intervention for 3 years (64). The trial found colorectal adenomas in 14.88% of patients in the folic acid group vs. 30.70% in the control group (unadjusted RR 0.49, 95% CI: 0.37–0.63, P<0.01). This potential chemopreventive effect was seen across left-sided adenomas (unadjusted RR 0.54, 95% CI: 0.38–0.76, P=0.001) and advanced adenomas (unadjusted RR 0.36, 95% CI: 0.16–0.81, P=0.01), but there was no significance difference between the groups for ≥3 more adenomas, right-sided adenoma, or CRC incidence.

Calcium and vitamin D

Calcium is the most abundant mineral in the body, while vitamin D is essential for calcium homeostasis; both have been implicated in colorectal adenoma and carcinoma formation through their regulation of growth factor signaling, APC/β-catenin pathway signaling, and bile acid-binding that intersect on proliferation and angiogenesis of colonocytes (19,58,69-71). Unsurprisingly, there have been investigations at the RCT level on the ability of vitamin D and calcium to prevent sporadic CRC (Table 5).

Of the earliest, the Calcium Polyp Prevention Study enrolled 930 patients with a previous diagnosis of adenoma and randomized them to 3 g of calcium carbonate (n=409) oral daily or placebo (n=423) with colonoscopies at 1 and 3 years (65). The intervention group showed a decrease in the number of adenomas found during colonoscopy compared to the placebo group (mean number per patient 0.55 vs. 0.73 with placebo, P=0.03) with an unadjusted RR for having ≥1 adenoma in the calcium group of 0.83 (95% CI: 0.68–1.00, P=0.05) vs. placebo (adjusted RR 0.81, 95% CI: 0.67–0.99, P=0.04). There was a significant reduction in adenoma risk (RR 0.81) in patients that completed both colonoscopies with calcium over placebo.

The European Cancer Prevention Organization (ECP) Intervention Study randomized 665 patients who previously had been diagnosed with colorectal adenomas to 2 g of elemental calcium, 3–5 g of fiber (ispaghula husk), or placebo daily with a colonoscopy at 3 years (66). The trial found a decrease in adenomas in the calcium group, but the fiber group showed an increase in adenoma risk, when compared to placebo (Table 5). When adjusted for recurrence, the odds ratio was 0.66 (95% CI: 0.38–1.17, P=0.16) in the calcium group vs. 1.67 (95% CI: 1.01–2.76, P=0.042) in the fiber group. Notably, the significantly higher odds ratio in the fiber group was associated with a higher baseline dietary calcium intake than those with intake below the median (interaction test, P=0.028).

In a Women’s Health Initiative (WHI) trial involving postmenopausal women aged 50–79 years, 18,176 patients were randomly assigned to 500 mg of calcium carbonate combined with 200 international units (IU) of vitamin D3 twice daily and 18,106 patients were assigned to a matching placebo twice daily for a mean treatment duration of 7 years (67). The trial found no significant difference in CRC incidence between the intervention and placebo groups (HR 1.08, 95% CI: 0.86–1.34, P=0.51).

In the recently conducted Vitamin D and OmegA-3 TriaL (VITAL), 25,871 patients with no cancer or CVD history at baseline were randomized to receive vitamin D3 2,000 IU daily and omega-3 fatty acids at 1 g daily or placebo for a mean treatment duration of 5 years (68). Of 98 CRC diagnosed, there was no significant reduction in CRC incidence (HR 1.09, 95% CI: 0.73–1.62) with the combination compared to placebo.

Discussion

The complexities of designing chemoprevention clinical trials in CRC have long been well known and have been described extensively elsewhere (19,58). The basic tenets of an ideal chemopreventive agent in CRC have historically included the need for the drug to demonstrate efficacy, safety, tolerability, low cost, widespread availability, and ease of administration (19,58). Over the past 4 decades, numerous RCTs have been performed with hopes of establishing the first chemopreventive drug for sporadic CRC, a disease by in which colonoscopy remains the only consensus guidelines recommended method for prevention (secondary). Where several classes of drugs have failed (48,72), others have shown promise (73-75). Promising agents have shown potential in reducing adenomas but face challenges in balancing efficacy with toxicity. Understanding the latent effects and determining the optimal dosage and targeted population are necessary to maximize benefits and minimize risks. We end this review with a discussion of key concepts that we can learn from previously conducted RCTs and build upon for the next steps in the successful clinical development of chemopreventive strategies for sporadic CRC.

Study population

The choice of patient population to investigate the chemopreventive effects of a drug remains fundamental to the design of a clinical trial and, ultimately, impactful to the population in which the findings can be translated. At one end of the spectrum lies the highest risk patients for colorectal adenomas and CRC. FAP syndrome, for example, is characterized by a lifetime risk of CRC of up to 100% but only about 1% of all CRC cases arise in FAP patients with a prevalence of around 1 in 10,000 live births (76). Inclusion of the highest risk populations would enrich for events of interest in a CRC chemoprevention trial, i.e., adenoma or CRC formation, which could reduce planned sample size (improving feasibility). However, rarer patient subsets may require more patients or longer study durations to meaningfully accrue. Primary prevention clinical trials aiming to prevent the initial occurrence of CRC or precancerous lesions in average risk individuals would, theoretically, yield the highest quality results with practice-changing implications, however such trials are infeasible given the extraordinary sample sizes needed to detect small effects and the duration of follow-up required (decades) (77,78). As sporadic CRC represents the overwhelming majority of CRCs diagnosed globally, striking a balance between the high-risk and low-risk patients for sporadic CRC would be important to account for patient characteristics that could impact how long a study takes, the sample size requirements, and funding needed to support a chemoprevention trial.

Of the positive RCTs published and in recent meta-analyses, it is noteworthy to point out that the majority of these trials were conducted in study populations with a previous history of precursor lesions to CRC, such as ACF or adenoma. These trials focus on secondary prevention, aiming to prevent the recurrence of these lesions. Patients with established lesions are ideal as they are at higher risk, allowing researchers to assess the effectiveness of chemopreventive agents more efficiently than in primary prevention trials, which require larger populations and longer follow-up periods. Additionally, some trials have focused on tertiary prevention, targeting patients with a history of resected CRC. In this group, the goal is to prevent recurrence or progression to metastatic disease, both of which pose significant risks. However, in such patients, the high baseline risk of recurrence and metastasis can complicate efforts to demonstrate the benefits of chemoprevention, as these risks may outweigh the preventive effects on new adenomas or CRC (Tables 2-5).

Overall, the distinction between secondary/tertiary prevention and primary prevention is significant because patients who have already had adenomas/CRC removed are inherently at a higher risk of developing further adenomas or CRC compared to individuals who have never developed adenomas or CRC. Patients with a history of adenomas have a 30–60% recurrence rate within 3–5 years (41,78-80), while those with a history of resected CRC have a 1.5–3% risk of developing metachronous CRC within 5 years after resection (81). Due to the differences in baseline risk, secondary/tertiary prevention trials are often more feasible with shorter follow-up periods and may show effects more quickly. Despite the challenges, they are crucial for advancing chemoprevention strategies.

Another high-risk group to consider targeting includes first-degree relatives of CRC patients especially those diagnosed with early-onset CRC (before age 50 years). First-degree relatives of CRC patients have approximately double the risk of developing CRC compared to the general population. The risk is even higher for first-degree relatives of patients diagnosed with early-onset CRC (82,83). Our search results did not find specific chemopreventive trials targeting this population. This gap in the literature suggests an opportunity for future research to focus on chemoprevention strategies.

Choice of endpoint

Beyond the need to select an ideal study population, the choice of primary endpoint is an important consideration for assessment of chemopreventive effects in sporadic CRC. Building on the promise of NSAIDs such as aspirin, NA-NSAIDs showed chemopreventive potential in sporadic CRC in randomized phase III trials (Table 3). Much can be learned from the developmental pathway for celecoxib, in particular, and the FDA’s initial approval of celecoxib for CRC chemoprevention. The celecoxib experience set a regulatory precedent for using surrogate endpoints like polyp reduction but underscored the importance of long-term follow-up and managing the risk of adverse events, especially in high-risk populations.

Polyp reduction has been recognized by the FDA as a valid endpoint when celecoxib became the first drug treatment approved for FAP in 1999 due to a mean reduction in polyps in subjects treated for 6 months compared to placebo (84). Of note, the FDA label was withdrawn in 2012 due to lack of completion of the post-marketing celecoxib study and subsequently when 2 phase III clinical trials showed that although celecoxib significantly reduced the occurrence of sporadic colorectal adenomas, this agent could not be routinely recommended for chemoprevention due to risk of cardiovascular events (39,41). Nevertheless, this approval sets an important precedent and milestone for CRC chemoprevention trials. Accelerated approval was based on a study of 83 patients with FAP syndrome, of whom 25 had an intact colon (84). A mean reduction in the number of polyps was 28% for 400 mg celecoxib twice daily vs. 12% for 100 mg twice daily vs. 5% for placebo from baseline to after 6 months of intervention.

Aside from endpoints using rates of adenoma formation or frank CRC, several CRC chemoprevention trials have employed biomarker endpoints. Unfortunately, multiple clinical trials investigating biomarker endpoints as surrogate markers of a drug’s chemopreventive effects for sporadic CRC have been negative to date (57,69-71). Notably, these trials have measured the experimental treatment’s effects on biomarkers in normal colorectal mucosa. Whether chemopreventive effects are better evaluated via biomarkers assessed in neoplastic colorectal tissues (e.g., ACF or adenomas) remains an important unanswered question. Surrogate biomarker endpoints could circumvent the need for substantially larger sample sizes and longer study durations that can prove prohibitive, while serving as a marker for the agent’s potential to inhibit a key molecular pathway in colorectal tumorigenesis. If positive, these studies would then provide support for larger, prospective RCTs where the potential for CRC chemoprevention could be validated.

Chemopreventive latency and dosage

Whether the chemopreventive effects of a drug is dependent on its dosage remains an active area of investigation in the primary prevention of CRC. Early signals that an increasing dose may have more chemopreventive potential was demonstrated in the APC Trial when celecoxib at 200 mg twice daily showed a RR for adenomas of 0.67, while a higher dose of 400 mg twice daily showed reduced adenoma risk at 3-year colonoscopy (RR 0.55), relative to placebo (41). However, higher doses of celecoxib were significantly associated with increased cardiovascular risk, which were essentially prohibitive to continued use of high-dose celecoxib (80). The body of evidence for aspirin in sporadic CRC chemoprevention has also afforded some insight into the dosage question. Specifically, meta-analyses have identified that low-dose aspirin (OR 0.71, 95% CI: 0.41–1.24) to be effective in preventing advanced colorectal neoplastic lesions, comparable to high-dose aspirin (OR 0.81, 95% CI: 0.50–1.28) while having a more favorable safety profile than high-dose aspirin (73). Therefore, although studies have pointed to potential dose-dependent chemopreventive effects for certain drugs, the applicability of higher doses are often limited by otherwise prohibitive toxicities.

The concept of latency for chemopreventive effects in sporadic CRC has been studied based on follow-up data of more than 20 years from 2 large RCTs of aspirin vs. no aspirin in CRC chemoprevention. The British Doctors Aspirin Trial and UKTIA trials treated patients with aspirin for 5–6 years or 1–7 years, respectively, and firstly demonstrated that patients allocated to aspirin for at least 5 years had a lower incidence of CRC (HR 0.63, 95% CI: 0.47–0.85, P=0.002) than all patients enrolled (HR 0.74, 95% CI: 0.56–0.97, P=0.02), relative to placebo (25). However, when stratified by 10-year follow-up periods, a lower CRC incidence was observed in years 10–19 of follow-up (pooled HR 0.60, 95% CI: 0.42–0.87, P=0.007) than years 0–9 of follow-up (pooled HR 0.92, 95% CI: 0.56–1.49, P=0.73). It has been postulated that ≥300 mg of daily aspirin for 5 years can be effective in CRC chemoprevention, with a 10-year latency of effect that is consistent with observational studies and knowledge of the adenoma-carcinoma sequence (25). This understanding is informative in the design and follow-up considerations for sporadic CRC chemoprevention trials given that the best predicted effect of longer-term aspirin, for example, is estimated to occur 10–14 years after randomization with at least 5 years of continuous dosing of aspirin (25). Even if latent effects of a chemopreventive agent is unknown or nonexistent, the longer follow-up of the APC Trial has provided insight on what happens after withdrawal of an effective chemopreventive agent for sporadic CRC (80). At the time of the year 5 colonoscopy, >90% of participants were off study for 1 year or more (median duration of celecoxib treatment 3.1 years) and the APC Trial reassuringly showed similar rates of adenoma detection across treatment groups and placebo. This addresses a well-known concern that a chemopreventive drug may be active only by inhibition of low-grade lesions rather than preventing disease progression, allowing lesions with higher malignant potential to progress upon withdrawal of the drug (80). One example of this phenomenon would manifest in a drug-associated reduction in adenoma size but not severity that limits colonoscopic detection and removal of more advanced lesions (80).

Toxicity

Safety remains paramount in assessments of all chemopreventive strategies for CRC. Although the NA-NSAIDs, particularly celecoxib and rofecoxib, have piqued interest in sporadic CRC chemoprevention given their positive phase III trials building, further evaluation has uncovered safety concerns limiting their use. Notably, rofecoxib was associated with increased thrombotic cardiovascular events (RR 1.89, 95% CI: 1.18–3.04) and upper GI perforation, obstruction, symptomatic ulcers, or bleeding (RR 4.91, 95% CI: 1.98–14.5), relative to placebo (40), resulting in stoppage of the APPROVe trial and the voluntary withdrawal of NDAs submitted to the FDA. Cardiovascular risk with celecoxib was higher in aspirin users and those with CVD risk factors at baseline (e.g., history of atherosclerotic heart disease, age >65 years, smoking, hypertension, or hyperlipidemia), while the rates were lower in those with no baseline risk factors (80).

Indeed, risk stratification by CVD risk may be warranted in future clinical trials for the NSAID class of drugs being evaluated for sporadic CRC chemoprevention (45). Recent meta-analyses of all RCTs of chemopreventive agents for sporadic CRC have corroborated findings that after balancing benefits and harms, routine use of NA-NSAIDs, although most effective for the prevention of colorectal adenomas, cannot be recommended based on current evidence (73,75). Low-dose aspirin, however, appears to have the most favorable risk/benefit profile of all classes of chemopreventive drugs for sporadic CRC (73). The margin of benefit for aspirin use in CRC chemoprevention has not been enough to impact the recommendations of consensus guidelines, however. Ultimately, precedents such as these have reinforced the importance of drug tolerability and the need to weigh the safety profile of an agent against its chemopreventive benefits, as the implementation of chemopreventive agents as a standards-of-care for sporadic CRC chemoprevention have been limited when safety concerns outweigh the benefits.

Future directions

Personalized chemopreventive strategies spanning from vaccines to targeted therapies and biomarkers of chemopreventive effects such as PIK3CA mutations are in active investigation and have bene reviewed elsewhere (19,58). Notably, the NSAID sulindac has shown efficacy in prevention of sporadic colorectal adenomas with a favorable cardiovascular risk profile (42,43). Additionally, there is evidence to support that individuals carrying 2 copies of the G allele of the ornithine decarboxylase-1 (ODC1) gene may have reduced risk of adenoma recurrence following treatment with eflornithine and sulindac providing rationale of a potential population of patients that could be molecularly selected for sporadic CRC prevention (85). The promise of eflornithine and sulindac is currently being investigated in an ongoing randomized, double-blind, placebo-controlled phase III clinical trial (SWOG S0820/PACES) in reducing the risk of adenomas or second primary CRC in survivors of stage 0–III CRC (86). The SWOG S0820/PACES trial is randomized double-blind placebo-controlled trial of combination eflornithine 500 mg daily and sulindac 150 mg oral daily vs. combination matching placebos. Participant eligibility includes those 18 and older who have been diagnosed with stage 0–3 colon or rectosigmoid adenocarcinoma. The trial completed accrual of 354 patients in June 2023, and passed its single planned analysis (for futility) in May of 2023. As such, the intervention continues for enrolled patients and results will be available after June 2026. The primary hypotheses of this study will be that the combination of eflornithine and sulindac will produce a 60% reduction in the rate of high-risk adenomas and second primary CRC vs. placebos, among stage 0–III colon cancer patients (86). The results of the SWOG S0820/PACES trial along with active trials of novel chemopreventive agents are eagerly anticipated as the search for the first established chemopreventive agent in sporadic CRC continues.

Conclusions

Sporadic CRC constitutes a large public health burden. Despite knowledge of the adenoma-carcinoma sequence, there has yet to be a defined method of primary prevention for CRC. Colonoscopy remains the only recommended and standard approach for CRC prevention (secondary). Multiple classes of agents including NSAIDs, metabolic agents, vitamins, and minerals have been explored for their chemopreventive potential in sporadic CRC. Although NSAIDs and NA-NSAIDs have demonstrated positive results for sporadic CRC chemoprevention in RCTs, they have been limited by cardiovascular risk or a lacking of uniform and conclusive results supporting their efficacy. Future trials in this arena are investigating novel NSAIDs and other classes of drugs as the search continues to establish the first sporadic CRC chemoprevention strategy that can be implemented into routine practice.

Acknowledgments

Funding: This manuscript was supported by the 2024 Kure It Cancer Research Grant from Kure It Cancer Research, awarded to J.G.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-97/rc

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-97/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-97/coif). J.G. serves as an unpaid editorial board member of Translational Gastroenterology and Hepatology from August 2024 to December 2026. A.H. reports existing or prior grants from Ipsen and NGM Biopharmaceuticals (Inst); consulting or advisory role at Amgen, Faraday Pharmaceuticals, Ipsen, Merus, Norvartis, Pancreatic Cancer Action Network, Regeneron, Valar Labs, Varian Medical Systems; support for travel from Halozyme; other relationship with Rayzebio. J.A.Z reports existing or prior grants from NIH and consulting fees from Exact Sciences and Tempus. J.G. reports consulting fees and honoraria from EMD Serono, Exelixis, Natera, Eisai, Janssen, Pfizer, Bayer, Taiho, Agenus, Seagen, and serves as the Chair of the Data Safety Monitoring Board at Cedars-Sinai Medical Center. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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