Curr. Treat. Options in Oncol. (2015) 16:43 DOI 10.1007/s11864-015-0359-z

Lower Gastrointestinal Cancers (AB Benson, Section Editor)

The Role of Aspirin, Vitamin D, Exercise, Diet, Statins, and Metformin in the Prevention and Treatment of Colorectal Cancer Amikar Sehdev, MD, MPH1,* Bert H. O’Neil, MD2 Address *,1 Division of Hematology Oncology, Department of Medicine, Indiana University, 535 Barnhill Dr., RT 130B, Indianapolis, IN 46202, USA Email: [email protected] 2 Division of Hematology Oncology, Indiana University, Indianapolis, IN, USA

* Springer Science+Business Media New York 2015

This article is part of the Topical Collection on Lower Gastrointestinal Cancers Keywords Colorectal cancer I Aspirin I NSAIDS I Celecoxib I Vitamin D I Diet I Physical activity I Statins I Metformin Abbreviations CRC Colorectal cancer steroidal anti-inflammatory drugs

I

RR Relative risk

I

OR Odds ratio

I

CI Confidence interval

I

NSAID Non-

Opinion statement Colorectal cancer (CRC) is a worldwide health problem leading to significant morbidity and mortality. Several strategies based on either lifestyle modifications or pharmacological interventions have been developed in an attempt to reduce the risk of CRC. In this review article, we discuss these interventions including aspirin (and other non-steroidal antiinflammatory drugs), vitamin D, exercise, diet, statins, and metformin. Depending upon the risk of developing CRC, the current evidence supports the beneficial role of aspirin, vitamin D, diet, and exercise especially in high-risk individuals (advanced adenoma or CRC). However, even with these established interventions, there are significant knowledge gaps such as doses of aspirin and 25-hydroxy vitamin D are not well established. Similarly, there is no convincing data from randomized controlled trials that a high fiber diet or a low animal fat diet reduces the risk of CRC. Some potential interventions, such as statins and metformin, do not have convincing data for clinical use even in high-risk individuals.

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However, these may have emerging roles in the prevention and treatment of CRC. Greater understanding of molecular mechanisms and the application of genomic tools to risk stratify an individual and tailor the interventions based on that individual’s risk will help further advance the field. Some of this work is already underway and is a focus of this article.

Introduction Colorectal cancer (CRC) is the second most commonly diagnosed cancer in females and the third most commonly diagnosed cancer in males worldwide. Over 1.2 million incident cases and 608,700 deaths were recorded globally in 2008 [1]. A better understanding of risk factors and molecular mechanisms that lead to CRC carcinogenesis has enabled us to develop strategies to reduce the risk of CRC. These strategies can be simple lifestyle modifications or pharmacological interventions. The latter requires safe and efficacious drugs that can be widely used. Most of the supporting evidence in this area emerged from observational studies that were subsequently tested in randomized controlled trials

(RCT) and meta-analyses. These observational studies tested an association between a risk factor, or a drug, and CRC. These associations were either discovered serendipitously (such as aspirin and colorectal cancer) or conceived because of an astute observation (such as sunlight’s effects on CRC risk (surrogate for vitamin D)). Below, we describe the current evidence, mechanism of action, and ongoing trials as they relate to these lifestyle factors and pharmacological agents that have or may have a role in CRC risk reduction (Table 1). Lastly, we summarize the strengths and limitations of the current evidence and conclude by proposing future directions.

Aspirin, non-steroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors Aspirin is one of the most well-studied drugs for cancer prevention and treatment. Aspirin has been shown to reduce the incidence [2, 3] as well as mortality [2–4] from CRC. The beneficial effect of aspirin was discovered incidentally in 1988 when a large case-control study reported an inverse association between aspirin use and risk of CRC [5]. Subsequently, data from a multitude of studies including RCTs from cardiovascular literature and meta-analyses of these RCTs convincingly established the chemopreventive efficacy of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC [6, 7]. A pooled metaanalysis of eight RCTs with a total of 25,570 patients showed a 59 % decrease in CRC mortality beginning 5 years after starting aspirin treatment (HR 0.41, 95 % confidence interval (CI) 0.17–1.00, P=0.05) [4]. In this meta-analysis, the daily dose of aspirin ranged from 75 to 1200 mg. The study was unable to ascertain a relationship between the dose of aspirin and benefit. Similarly, aspirin use was shown to reduce the incidence of colorectal adenoma. A meta-analysis of epidemiological studies and RCT showed a significant decrease in the incidence of colonic adenomas irrespective of study design: case-control studies (RR 0.87, 95 % CI 0.77–0.98), cohort studies (RR 0.72, 95 % CI 0.61–0.85), and randomized controlled trials (RR 0.82, 95 % CI 0.7–0.95) [6]. An aspirin dose of 81–325 mg has been shown to reduce the risk

carriers

CRC incidence

Omega-3 fatty

CRC incidence CRC incidence

Statins

Metformin

OR, 0.88, 95 % CI, 0.77–1.00

RR 0.92; 95 % CI, 0.90 to 0.95

RR 0.92; 95 % CI, 0.89–0.95

OR, 0.88; 95 % CI, 0.80–0.95

RR=0.94 95 % CI, 0.86–1.03*

RR 0.75, 95 % CI 0.65–0.87

RR, 0.73; 95 % CI, 0.66–0.81

HR 0.55 (95 % CI=0.33–0.91)

95 % CI 0.35–68)

CI 0.93–0.98 to OR 0.49,

5–51 % benefit (RR 0.95, 95 %

Case-control study [161•]

studies [147]

Meta-analyses of observational

studies [105••]

Meta-analysis of observational

[95•]

analysis of observational studies

Systematic review and meta-

Cohort Studies [80]

Pooled Analysis of Prospective

[68••]

Meta-analyses of Cohort studies

studies [61••]

Meta-analyses of observational

studies [28•]

Meta-analyses of observational

studies [39••]

Meta-analyses of observational

RCT [9]

Meta-analysis of RCTs [6]

Meta-analysis of RCTs [4]

Meta-analysis of RCTs [3]

Best evidence

Further studies are needed

2. Further studies are needed

1. Lack of convincing data.

effectiveness

RCTs needed to validate the dose and

effectiveness.

RCTs needed to validate the dose and

Lack of convincing data.

Lack of supportive data from RCTs.

2. Ideal 25(OH)D level unknown.

1. Lack of supportive data from RCTs.

analyses of cardiovascular trials.

2. Data primarily comes from secondary

for average-risk individuals.

1. Ideal dose and duration is unclear

Knowledge gaps

NCT01926769

NCT01941953 and

NCT02026583

NCT00208793

Prevention Trial

seAFOod Polyp

NCT00339469

NCT00819208

NCT02250053

NCT00208793

(VITAL trial)

NCT01169259

NCT01150045

(ASCOLT trial)

NCT00565708

Ongoing trials (ClinicalTrials.gov identifier)

CRC colorectal cancer, HR hazard ratio, OR odds ratio, RR relative risk, CI confidence interval, RCT randomized controlled trial, ASCOLT aspirin in patients with Dukes’ C or high-risk Dukes’ B colorectal cancer, VITAL VITamin D and OmegA-3 TriaL *not significant

CRC incidence

Calcium

acids

CRC incidence

CRC mortality

CRC incidence

CRC mortality

CRC incidence

Dietary fiber

Exercise

Vitamin D

HR, 0.41; 95 % CI, 0.19–0.86

CRC risk in HNPCC

adenomas

RR 0.82, 95 % CI 0.7–0.95

Incidence of colonic

HR 0·76, 95 % CI 0·60–0·96, HR 0.41, 95 % CI 0.17–1.00,

CRC incidence

Aspirin

Benefit (all with significant P value)

CRC mortality

Endpoint

Agent

Table 1. Summary of current evidence, knowledge gaps, and ongoing clinical trials for pharmacological and dietary interventions in prevention and treatment of colorectal cancer

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Curr. Treat. Options in Oncol. (2015) 16:43 of any colorectal adenoma (RR, 0.83; 95 % CI, 0.72–0.96) after at least 3 years of regular use [8]. The non-aspirin NSAIDs have been shown to decrease the incidence of colorectal adenomas in a systematic review of observational studies (cohort studies (RR 0.64, 95 % CI 0.48–0.85); and case-control studies (RR 0.54, 95 % CI 0.40–0.74)) [7]. Of important note, however, serious cardiovascular events were seen more commonly in individuals taking non-naproxen NSAIDs (RR, 1.86, 95 % CI, 1.33 to 2.59) [7]. Aspirin use has also been shown to reduce the risk CRC in individuals who are carriers of hereditary non-polyposis colon cancer (HNPCC; Lynch syndrome) [9]. The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP2 trial) demonstrated that daily aspirin use of 600 mg for a mean of 25 months was effective in reducing the incidence of CRC by 59 % (HR, 0.41; 95 % CI, 0.19–0.86; P=0.02) in carriers of HNPCC during prolonged follow-up period (mean, 55.7 months; range 1–128) [9]. However, not all aspirin studies have been positive. For example, two randomized placebo-controlled trials, the Physician Health Study [10] (PHS, aspirin 325 mg/every other day) and Women’s Health Study [11] (WHS, aspirin 100 mg/every other day), did not demonstrate a benefit of cancer reduction after 10 years of follow-up (PHS, RR 1.03, 95 % CI, 0.83–1.28 and WHS, RR 0.97, 95 % CI, 0.77–1.24, respectively). Although speculative, under-dosing, and short follow-up period are considered the primary reasons for the failure of these trials [12•]. Interestingly, an extended follow-up of WHS did find a benefit of alternate-day aspirin [13•]. The cyclooxegenase-2 (COX-2) inhibitor, celecoxib, generated a lot of enthusiasm based on the results of RCTs in familial adenomatous polyposis (FAP) patients [14, 15] as well as non-FAP patients [16, 17]. A systematic review of these RCTs showed that the COX-2 inhibitors were associated with a 28 % reduction in the incidence of sporadic colorectal adenomas (RR 0.72, 95 % CI 0.68–0.77) [7]. However, celecoxib has also shown to have an increased incidence of cardiovascular complications [16] especially in patients with atherosclerotic disease [18, 19]. Therefore, it seems unlikely that COX-2 inhibitors will be used for primary prevention of CRC as there are many common risk factors for heart disease and CRC. Notably, rofecoxib, a COX-2 inhibitor, has been withdrawn from the market due to increased incidence of cardiovascular and bleeding complications. The aspirin and non-aspirin NSAIDs are primarily believed to exert their beneficial effect by inhibition of arachidonic acid metabolism through either cyclooxygenase or prostaglandin H synthase (Fig. 1) [20•]. COX-2 is a ratelimiting enzyme that catalyzes prostaglandin synthesis and is blocked by aspirin [21••, 22]. Loss of prostaglandins in the tumor environment is thought to lead to inhibition of growth, invasion, and angiogenesis, while promoting apoptosis. Experimental studies have shown that COX-2 overexpression in CRC tumors (as detected by immunostaining) correlates with mortality benefit if aspirin is used after chemotherapy treatment (RR 0.39 (COX-2 positive) vs. RR 1.22 (COX-2 negative)) [23]. Furthermore, prostaglandin synthesis is enhanced by activating mutations of PIK3CA [21••] suggesting that aspirin would have greater effects in tumors with mutations affecting this pathway. Liao et al. recently conducted a recent retrospective analysis (N=964; 161 patients with PIK3CA mutation) to see if there was a differential response to aspirin therapy based on the PIK3CA mutation status in CRC [21••]. They found a higher CRC-

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specific survival among aspirin-using patients with mutated-PIK3CA tumors as compared to wild type PIK3CA tumors (multivariate HR 0.18; 95 % CI, 0.06 to 0.61; PG0.001) [21••]. A subsequent study (N=1487; 185 patients with PIK3CA mutation) by Kothari et al. did not find this survival benefit with regular use of aspirin in CRC patients with PIK3CA mutation [24•]. Similarly, Nan et al. found the protective effect of aspirin to be highly correlated with two single-nucleotide polymorphisms (rs2965667 and rs10505806), which are found in 96 % of the population [25••]. However, individuals lacking these polymorphisms (4 % of the population) were found to have an increased risk of CRC with aspirin use. The application of genomics has a potential for a better risk-benefit assessment in the future.

Vitamin D The hypothesis that vitamin D may have a role in CRC emerged from initial studies that used sunlight exposure as a surrogate for in vivo vitamin D levels. These studies reported an increased incidence of CRC in populations living away from the equator (thereby receiving less exposure to sunlight) [26, 27]. A large body of epidemiological evidence supports an inverse association between vitamin D and CRC incidence and mortality [28•, 29]. The majority of these studies used either circulating 25-hydroxy vitamin D [24• (OH)D] levels [30–33, 34•] or total vitamin D intake (dietary plus supplemental) [35–38] to assess the vitamin D status. At least two systemic reviews and seven metaanalyses of these observational studies [39••] have shown a consistent and statistically significant benefit in individuals with high 25(OH)D as compared to those with low 25(OH)D ranging from 5 % (RR 0.95, 95 % CI 0.93–0.98, P= 0.002) [40, 41••, 42•] to 51 % (OR 0.49, 95 % CI 0.35–68, PG0.0001) [43]. Despite this compelling evidence for the beneficial effect of vitamin D from observational studies, there is lack of supportive data from RCTs [39••, 41••, 42•]. Additionally, a substudy within the Women’s Health Initiative (WHI) study found no significant benefit of vitamin D supplementation (HR 1.08, 95 % CI 0.86–1.34, P=0.51) [44]. Although the reason for these unexpected findings remains unclear, it is possible that low dose of vitamin D (400 IU per day) and/or limitation of study design contributed to these results. Notably, a latter post-hoc analyses of the WHI study suggested a significant reduction in total cancer risk (HR 0.86, 95 % CI 0.78–0.96, P=0.007) and a non-significant reduction in CRC risk (HR 0.83, 95 % CI 0.60–1.15, P=0.27) [45]. However, this study has been criticized for subgroup analyses and methodology [46]. A large RCT of vitamin D and calcium to prevent recurrence of colonic adenomas is nearing completion, and results are expected soon (John Baron, personal communication). While human studies have been inconclusive, a large number of preclinical studies in animal models of colon cancer support a chemopreventive effect of vitamin D. Vitamin D mediates its effects through vitamin D receptors (VDR) via both genomic and non-genomic actions (Fig. 1). Of note, about 3–5 % of the human genome is regulated by vitamin D [47]. Specifically in CRC, vitamin D inhibits WNT–β-catenin signaling, which is one the most important signaling pathways in sporadic CRC. Possible anti-cancer mechanisms include anti-inflammatory, anti-angiogenic, and inhibition of proliferation and metastasis [48••].

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Curr. Treat. Options in Oncol. (2015) 16:43 Fig. 1. Mechanism of action of key dietary and pharmacologic interventions that have a convincing or potential role in prevention and/or treatment of colorectal cancer.

There is no universal agreement on the optimal serum concentration of 25(OH)D. Most experts and guidelines generally agree on a level below 50 nmol/L (20 ng/mL) as indicative of deficiency [42•], and levels above 75 nmol/L (30 ng/mL) are necessary for multiple potential beneficial effects of vitamin D including CRC risk [42•, 49]. Some experts recommend a vitamin D intake of at least 1000 IU/day [50•, 51] as the currently recommended vitamin D intake of up to 800 IU/day may be insufficient [52]. Notably, there are potential harms of aggressive vitamin D supplementation such as hypercalcemia, hyperphosphatemia, nephrolithiasis, and parathyroid hormone suppression [53•, 54, 55].

Exercise It would seem plausible that physical activity (PA) would counter obesity and obesity-related health risks such as cancer. Some of the proposed mechanisms by which PA may lead to beneficial effect are decreased intestinal transit time, immune up-regulation, and suppression of insulin and insulin-like growth factor-1 (IGF-1) mediated growth; however, the exact mechanism(s) remain unclear (Fig. 1) [56]. Most of the evidence in support of beneficial effect of PA again comes from observational studies [57–60]. A recent meta-analyses of 21 case-control and cohort studies reported a statistically significant benefit of 27 % with PA irrespective of location of CRC (RR, 0.73; 95 % CI, 0.66–0.81) [61••]. There are some inherent challenges in conducting a controlled clinical trial to assess the effect of physical activity. First, it would be unethical to limit people from exercising in a control group. Second, the effect of exercise intervention may even out between the two groups during follow-up. Despite these challenges, there are five small RCTs (N=18 to 102) that evaluated the effect of high

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intensity exercise (intervention group) vs. low-intensity exercise (control group) in CRC patients [62–66]. A meta-analyses of three of these studies (that reported quantitative results) showed a short-term improvement in physical fitness (standard mean difference (SMD)=0.59, 95 % CI 0.25–0.93, PG0.01); however, no significant benefit for short-term effects on either quality of life or fatigue [67••]. Another meta-analyses of seven prospective cohort studies reported a statistically significant 25 % reduction in CRC-specific mortality in individuals who participated in any PA as opposed to no PA (RR 0.75, 95 % CI 0.65–0.87, PG0.001) [68••]. A recent study by Arem et al. using the National Institutes of Health (NIH)–AARP Diet and Health Study cohort to assess the overall and disease-specific mortality between pre-diagnosis and post-diagnosis leisure time physical activity (LTPA) and TV watching in CRC patients [69•]. The investigators found a 20 % lower risk of all-cause mortality by comparing CRC survivors with more than 7 hours/week (h/wk) of prediagnosis LTPA compared to those reporting no LTPA (HR, 0.80; 95 % CI, 0.68 to 0.95; P for trend=0.021). Additionally, post-diagnosis LTPA of more than 7 h/wk as compared to no LTPA (independent of prediagnosis activity) was associated with a 31 % lower all-cause mortality risk (HR 0.69, 95 % CI 0.49–0.98, P for trend=0.006). However, there was no statistically significant association between CRC-specific mortality in either of the above analyses [69•]. Additionally, in a prospective cohort study of stage III CRC patients, PA 6 months after completion of all therapy was associated with significant improvement in overall survival (P for trend=0.01) and recurrence free survival (P for trend=0.03) [70]. In summary, PA is associated with physical fitness and possibly decreased all-cause mortality. Its effect on quality of life, fatigue, and CRC-specific mortality are not clear. In animal models of colon cancer, exercise has been demonstrated to significantly reduce colon cancer incidence [71, 72].

Diet There are many aspects to diet including dietary composition fiber, fat, vitamins (A, C, E and B vitamins), minerals (selenium, calcium), calorie intake, effects of cooking, and chemical state of food. It is beyond the scope of this short review to address all of these components. We highlight some of the most important aspects of diet that are implicated in CRC risk and prevention. Fiber The fiber derived from fruits, vegetables, and grains is an important component of diet. The hypothesis that fiber intake is associated with reduced incidence of CRC was conceived due to initial observations of lower incidence of CRC in populations consuming a high fiber diet [73]. There are many proposed mechanisms for fiber-induced protection against CRC, including dilution of fecal carcinogens by increased stool mass, decreased colonic transit time, change in colonic pH, modulation of bile acid metabolism, and increased production of short-chain fatty acids (SCFA; Fig. 1) [74, 75]. SCFA, such as butyrate, are major sources of energy for colonocytes and have several anti-cancer properties including anti-inflammatory, anti-

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Curr. Treat. Options in Oncol. (2015) 16:43 proliferative, pro-apoptotic, and immune modulatory effects [76]. Several observational studies [77–79] and RCT [80] have attempted to assess the potential efficacy of fiber, but the results are discordant. For instance, a pooled analysis of 13 prospective cohort studies with 6 to 20 years of follow-up concluded that although dietary fiber intake was significantly and inversely associated with CRC risk, it became nonsignificant after accounting for other dietary risk factors [80]. Similarly, two large well-designed RCTs to assess if dietary fiber supplementation can prevent the development of recurrent colorectal adenomas found no significant effect on the risk of recurrence of adenomas [81, 82]. These results were consistent with previously published RCTs [83, 84]. There can be several explanations for these unanticipated results. First, there may be reporting bias, i.e., over-reporting in the intervention group and underreporting in the control group. Second, the dietary intervention in terms of fiber intake might be inadequate. Third, the period of intervention might be too short (∼4 years) to see an effect. Lastly, there may be a threshold effect (as opposed to dose-response phenomenon) with dietary intervention that might have eliminated the difference between the groups.

Fat and omega-3 fatty acids Increased fat intake has been linked to many health conditions including CRC. The Nurses Health Study indicated that animal fat but not vegetable fat was associated with increased risk of colon cancer [85]. However, several subsequent studies [86–90] and a large meta-analysis [91] reported inconsistent results. Similarly, the WHI Dietary Modification RCT found no reduction in CRC incidence with low fat diet (20 % of energy intake) [86]. Due to their anti-inflammatory properties, omega-3 polyunsaturated fatty acids (PUFAs) have received special attention (Fig. 1). Omega-3 PUFAs have been thought to exert a protective effect against CRC based upon the observations that populations with high consumption of fish have a lower incidence and mortality from CRC [92]. However, the evidence from observational studies is contradictory with some studies reporting a beneficial role [93] whereas others show no relationship [94]. A meta-analysis of 33 observational studies found a 12 % CRC risk reduction with fish consumption. Rectal cancer had a more significant 21 % risk reduction (OR 0.79, 95%CI 0.65–0.97) [95•]. A placebo-controlled RCT in individuals with FAP found decreased incidence of adenoma with administration of 2 g/day of omega-3 PUFAs for 6 months [96]. In preclinical animal studies, dietary fat has been linked to higher incidence of colon cancer, [97] and a number of animal studies have demonstrated efficacy of several fish oil preparations against CRC [98–101]. Calcium Increased calcium intake has been associated with decreased risk of CRC. The evidence in support of calcium comes from observational studies where calcium supplementation was noted to be more strongly associated with protection from distal colon cancer (RR 0.58, 95 % CI 0.32–1.05) [102]. Subsequent intervention studies including RCTs and meta-analyses

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support the role of calcium in risk reduction of colorectal adenomas [103]. However, a substudy within WHI randomizing post-menopausal women to receive either calcium and vitamin D or placebo found no significant reduction in the risk of CRC [44]. The follow-up duration in this trial was 7 years, and the dose of calcium and vitamin D was 1000 mg/day and 400 IU/day, respectively. The main reason for the failure of this trial is thought to be the high baseline calcium intake (1151 mg/day) in WHI participants [104]. A later re-analysis addressed this limitation by only including women who were not taking calcium (or vitamin D) at baseline and found a 17 % reduction in CRC incidence [45]. A recent dose-response meta-analyses by Keum et al. concluded a linear relationship between calcium and CRC risk with approximately 8 % decreased risk with each 300 mg/day increase in calcium intake (RR 0.92, 95 % CI 0.89–0.95) [105••]. Mechanistically, calcium binds to noxious bile and fatty acids resulting in the formation of insoluble complexes (Fig. 1) [106]. At the cellular level, several mechanisms have been proposed for the beneficial effect of calcium such as inhibition of oxidative DNA damage, modulation of cancer signaling pathways, and anti-proliferative and pro-apoptotic actions [107, 108].

Statins Statins inhibit cholesterol synthesis by blocking 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In preclinical experiments, statins have been shown to possess anti-inflammatory, anti-antigeogenic, anti-oxidant, and immunoregulatory properties (Fig. 1) [109••, 110, 111]. These cellular activities have resulted in an interest in exploring their role in cancer. However, a decade of observational studies and post-hoc analyses of RCT from cardiovascular literature has shown at best inconsistent results. Poytner et al. published the first study in 2005, which showed about 50 % lower risk of developing CRC with over 5 years of statin use [112]. From 2007 to 2012, seven other observational studies showed a significant risk reduction of 9–63 % in the incidence of CRC [113, 114, 115•]. More recently, a study published by our group in the non-elderly US population (age 18–64 years) found a reduction of 26 % in CRC risk in statin users (OR 0.74, 95 % CI 0.72– 0.77, PG0.001) as compared to statin non-users [115•]. However, a number of other case-control studies [116–127], cohort studies [128, 129••, 130–137], and secondary analysis of randomized clinical trials [138–146] have shown no significant relationship between statin use and CRC incidence. Finally, two large meta-analyses, including case-control, cohort, and RCTs, have shown a statistically significant but quite modest reduction (∼8–9 %) in CRC risk [147, 148]. Statins reduce cholesterol synthesis by inhibition of the mevalonate pathway. The byproducts of mevalonate pathway are necessary for posttranslational prenylation of cancer-related proteins, such as Kirsten rat sarcoma

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Curr. Treat. Options in Oncol. (2015) 16:43 viral oncogene homolog (KRAS) [149]. Statins by inhibiting melavonate pathway in-turn results in inhibition of KRAS prenylation. The latter is necessary for KRAS protein to become lipophilic, translocate to cell membrane, and become functional [149]. Based on this preclinical work, a phase II clinical trial was performed, in which 52 KRAS mutant CRC patients with tumors refractory to oxaliplatin or irinotecan based chemotherapy were treated with simvastatin, cetuximab and irinotecan [150•]. The authors reported a median progression-free survival (PFS) of 7.6 months (95 % CI, 4.4–10.8) and a median overall survival (OS) of 12.8 months (95 % CI, 9.5–16.2) with an ORR of 1.9 % (95 % CI 1.8–5.6). They concluded that this represented increased activity over that expected without the addition of the statin. However, a retrospective analysis of the phase III CAIRO2 study, in which patients were randomized to capecitabine, oxaliplatin, and bevacizumab with or without cetuximab did not show any improvement in either PFS or OS in patients with KRAS mutant tumors who were on statin therapy [151•]. An ongoing phase II study is evaluating the effect of adding simvastatin to capecitabine, oxaliplatin, and bevacizumab in the treatment of stage IV CRC with PFS as primary endpoint (ClinicalTrials.gov Identifier: NCT02026583).

Metformin There is growing interest to explore the role of metformin as a chemopreventive agent. A relative wealth of experimental evidence supports the study of metformin as an anti-cancer drug [152, 153]. Metformin is a generic, inexpensive drug with an excellent safety profile that makes it an attractive anti-cancer drug. Metformin is mainly used for treatment of type 2 diabetes mellitus. Substantial evidence suggests that the relative risk of CRC is higher in diabetic patients (predominantly type 2) [154]. Diabetes is thought to promote carcinogenesis through hyperinsulinemia, hyperglycemia, and chronic inflammation [155]. There have been several observational studies form Europe and Asia suggesting a reduced incidence of CRC as well as other cancers including breast, lung, prostate, ovarian, and pancreatic cancer in diabetic patients on metformin [156–160] compared to those using non-metformin regimens. Additionally, in a large case-control study of US patients with diabetes, our group found a 12– 15 % statistically significant reduced risk of developing CRC with any prior or current metformin use [161•]. Additionally, metformin has been shown to inhibit growth and induce apoptosis in cell lines and animal models for various cancers including CRC [153, 162]. Furthermore, in a prospective randomized clinical trial, metformin was shown to decrease the mean number of aberrant cryptic foci (ACF), putative precursor lesion for CRC, in non-diabetic patients [163]. There is a growing body of evidence that metformin’s anti-cancer activity is mediated by both its cellular and systemic effects [164]. The systemic effects of metformin are mainly due to reduction in hyperglycemia that can potentially counteract the Warburg effect (dependence of cancer cells on glucose as predominant source of energy). The cellular or direct effects are believed to involve activation of the AMPK pathway [165, 166•, 167], which can potentially counteract the effects of hyperinsulinemia by systemic inhibition of growth factors including glucose, insulin, IGF-1, and leptin ultimately resulting in

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inhibition of protein synthesis and reduction in cell growth and proliferation (Fig. 1). A number of trials are ongoing to assess the efficacy of metformin in the treatment of CRC (ClinicalTrials.gov Identifier: NCT01941953 and NCT01926769) and other cancers (ClinicalTrials.gov Identifier: NCT01101438, NCT00881725, and NCT01210911).

Conclusion Although a significant body of literature exists about the pharmacological interventions and lifestyle modifications in the prevention and treatment of CRC, there are no definite conclusions that can be drawn at this time. This is mainly true for individuals at low-to-moderate risk of CRC (individuals without large adenoma or CRC). Below, we highlight the knowledge gaps and the ongoing work in regards to these pharmacological interventions and lifestyle modifications (Table 1). Aspirin remains the best-studied drug for prevention and treatment of CRC. As discussed above, a multitude of studies over the last three decades have established the chemopreventive efficacy of aspirin to reduce incidence of colorectal adenomas as well as incidence and mortality from CRC with some caveats. First, it should be noted that the evidence for beneficial effect of aspirin in CRC comes from secondary analyses of cardiovascular studies. Second, although aspirin dose of 81–325 mg for the minimum of 5 years correlates with CRC outcomes, the ideal dose and duration of aspirin use remains unclear for individuals who are at average risk (no prior CRC, advanced adenoma, or cardiovascular disease) of developing CRC. Third, the risks versus potential benefits of aspirin must always be considered when advocating its use in patients. The principal risk of aspirin, independent of dose, is bleeding. The bleeding can be either gastrointestinal (RR 1.62, 95 % CI 1.25–2.09) or intracranial (RR 1.65, 95 % CI 1.06–5.99) [168]. Therefore, aspirin use is justified only in individuals at high-risk of CRC (advanced adenoma or CRC) but not in average-risk individuals [169•]. A randomized, placebo-controlled adjuvant trial, ASCOLT, is currently ongoing to evaluate if aspirin can improve the survival of patients with Dukes C or high-risk Dukes B CRC (ClinicalTrials.gov Identifier: NCT00565708). Another phase III RCT in evaluating the role of celecoxib in treatment of colon cancer (ClinicalTrials.gov Identifier: NCT01150045). In this trial, the patients with resected stage III colon cancer are randomized to 6 vs. 12 cycles of adjuvant FOLFOX plus either celecoxib or placebo. The vitamin D has biological rationale, but no clear benefit has been seen in randomized controlled trials. Additionally, the level of 25(OH)D necessary for CRC prevention is not agreed upon universally. An ongoing randomized clinical trial, VITamin D and OmegA-3 TriaL (VITAL), for the primary prevention of cancer and cardiovascular disease will address these questions (ClinicalTrials.gov identifier: NCT01169259). Similarly, calcium has probably a favorable role in prevention of CRC; however, RCTs with longer follow-up period are needed to validate the dose and effectiveness. Unless otherwise contraindicated and until further evidence is available, individuals at high-risk should be encouraged to take calcium (1000 mg/day) and vitamin D (1000– 2000 IU/day to achieve a 25(OH)D level of ≥30 ng/mL). The current evidence supports the contention that high animal fat (as opposed to vegetarian fat) probably increases the risk of CRC whereas omega-

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3 PUFAs have an opposite effect. Despite the lack of convincing data, most expert panels recommend high fiber intake. This is mainly because the good sources of fiber (beans, whole grains, vegetables, and fruits) also contain other nutrients with proven or suspected health benefits [170•, 171]. Moreover, a high fiber diet is not known to be associated with any adverse outcomes (at least to the best of our current understanding). An ongoing RCT, seAFOod Polyp Prevention Trial, will assess the chemopreventive efficacy of omega-3 PUFAs alone and in combination with aspirin on adenoma recurrence [172]. Similarly, physical activity is associated with physical fitness and possibly decreased allcause mortality. However, its effect on quality of life, fatigue, and CRC-specific mortality are not clear. While awaiting further evidence, regular PA (including moderate and vigorous physical activities and muscle-strengthening activities) should be encouraged based on the goals of Healthy People 2020 [173]. A large number of observational studies and secondary data from cardiovascular RCTs suggest that statins are protective with respect to CRC. There is lack of convincing data, however, to support clinical use of statins for colon cancer prevention. Further studies are needed to test the hypothesis of statin use in CRC prevention and treatment. Similarly, metformin does not have convincing evidence yet in the prevention and treatment of CRC. A number of trials are ongoing to assess the efficacy of metformin combined with 5-fluorouracil-based chemotherapy in the treatment of CRC (ClinicalTrials.gov Identifier: NCT01941953 and NCT01926769). Metformin is also currently being investigated for prevention of polyps in patients with FAP in a double blind RCT (ClinicalTrials.gov Identifier: NCT01725490). The mechanisms by which these agents antagonize tumorigenesis need to be better understood and could perhaps lead to new and more effect agents for chemoprevention. Finally, it should be noted that all the pharmaceutical interventions discussed in this review are repurposed drugs that were not primarily developed for cancer prevention. Hence, these drugs are expected to be less than ideal with respect to efficacy and/or safety. Perhaps with improved understanding of cancer biology and availability of risk prediction tools, we can expect more effective chemopreventive agents.

Compliance with Ethics Guidelines Conflict of Interest Amikar Sehdev and Bert H. O’Neil declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. Financial Disclosure None

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The Role of Aspirin, Vitamin D, Exercise, Diet, Statins, and Metformin in the Prevention and Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is a worldwide health problem leading to significant morbidity and mortality. Several strategies based on either lifestyle mod...
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