Prevention of Colorectal Cancer by Aspirin and/or Calcium: Efficacy, Mechanisms, and Cost Effectiveness
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- Pence, B.C., Belasco, E.J. & Lyford, C.P. Curr Colorectal Cancer Rep (2012) 8: 51. doi:10.1007/s11888-011-0115-0
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Chemoprevention of colorectal cancer (CRC) by aspirin use or calcium supplementation has been studied for almost two decades. Recently, the use of aspirin has been reported to be efficacious for the chemoprevention of CRC at the lowest dose ever, one that corresponds to that recommended for the primary prevention of cardiovascular disease. There is also new evidence that aspirin at higher doses may be helpful in controlling familial adenomatous polyposis (FAP). Several cost effectiveness studies have emerged to demonstrate that use of aspirin in combination with colonoscopy is cost-effective compared with colonoscopy alone in prevention of CRC. Likewise, calcium supplementation in a chemoprevention strategy also has been shown to be cost-effective when used alone or in combination with colonoscopy in CRC prevention, compared to natural history. The chemopreventive mechanisms of these agents continue to be studied, and prominent molecular targets for aspirin are cyclooxygenase (COX)-2, and perhaps COX-1, as well as the calcium-sensing receptor (CaSR) as the likely target for calcium supplementation. The evidence is compelling for the widespread use of these non-prescription agents, either alone or in combination, for either primary prevention of CRC in the general population, or as part of a colonoscopy surveillance program in high-risk populations with a prior adenoma.
KeywordsColorectal cancerChemopreventionColonoscopyAspirinCalciumCost-effectivenessMarkov simulationCOX-2Calcium-sensing receptor
Chemoprevention for colorectal cancer (CRC) has been a realistic goal for more than two decades. In 1988, our group published the first experimental animal study demonstrating that supplemental dietary calcium could prevent the development of chemically induced colon cancer in rodents [1•], and this was followed by a number of clinical trials that indicated the effectiveness of calcium in decreasing polyp recurrence  and thus, the incidence of CRC. The association between aspirin use and decreased CRC was also established in 2003 [3••]. Since that time an enormous amount of progress has been achieved in the research and development of both aspirin and calcium as realistic candidates for the first effective non-prescription cancer prevention agents in history. While we have tamoxifen and raloxifene for chemoprevention of breast cancer, and finasteride for prevention of prostate cancer, the entire chemoprevention field has had few successes in terms of non-prescription primary prevention approaches.
Review of Aspirin Chemoprevention Clinical Studies
The United States Preventive Services Task Force (USPSTF) has evaluated the use of aspirin for the prevention of CRC and has published its findings in an extensive data synthesis of a review of all the clinical studies from the existing literature . In this data synthesis paper , they concluded from their analysis that 1) regular use of aspirin reduced the incidence of colonic adenomas in randomized controlled trials (RCTs) with a relative risk (RR) = 0.82 (95% CI, 0.7–0.95); 2) in case-control studies (RR = 0.87 [CI, 0.77–0.998]); and 3) in cohort studies (RR = 072 [CI, 0.61–0.85]). AIso in cohort studies, regular use of aspirin was associated with a RR reduction of 22% for incidence of CRC . These were summary figures from all of the studies that were reviewed and analyzed. Thus, overall, they concluded, aspirin chemoprevention can reduce colorectal adenomas by 18%–28% and colorectal cancers by 22%. More recently, Rothwell et al. [5••] published a 20-year follow-up of the effects of aspirin used in cardiovascular disease prevention on CRC, and found that low-dose aspirin can reduce CRC incidence by 38% and mortality by 52% [5••]. These are exciting reductions in pre-cancerous lesions and cancers. In another recent analysis, published in this journal, of prevention by aspirin of adenoma recurrence relevant to the latest results of the APACC Trial , the authors concluded that “the preventive effect of aspirin on adenoma recurrence is now established, but its use in clinical practice is far from widespread because information is still lacking on which subgroups of patients would benefit most from aspirin according to their benefit/risk ratio, the optimum dose, and the duration of treatment.” In this APACC Trial, which was completed in 2005, the findings were that aspirin decreased adenoma recurrence significantly at 1 year, marginally at year 1 or 4, and not at year 4, possibly due to attrition but also to a differential effect according to polyp natural history . Thus, it has become clear among the RCTs that the number of patient subgroups, doses of aspirin used, and the durations of aspirin chemoprevention have confused the clinical message. However, recent studies of aspirin use in general populations and in cost-effectiveness simulation studies may serve to clarify the clinical recommendations.
Another recent topic in aspirin chemoprevention involved the first report of the effective use of aspirin with or without resistant starch in a randomized placebo-controlled prevention trial in young people with familial adenomatous polyposis (FAP) [7•]. This was the largest trial ever conducted in the setting of FAP and found a non-significant trend (RR = 0.77 [0.95% CI, 0.54–1.10]) of reduced polyp load (both number and size) with 600 mg of aspirin daily. The resistant starch had no clinical effect. However, in an accompanying Perspective paper, Dr. Andrew Chan points out that the work presents important consideration of a role for aspirin in the clinical management of FAP patients, as well as for chemoprevention in the larger population . He also re-affirms the consensus of the literature in this area which implicates COX-2 pathways in the anticancer effect of aspirin as well as other NSAIDs . In application to the general population, Din et al. [9•] had also reported the first study to demonstrate a protective effect against CRC with a low dose of aspirin (75 mg per day) after only 5 years use in a Scottish population of average risk. In this study, low-dose aspirin was associated with a decreased CRC risk of OR = 0.78 (95% CI 0.65–0.92, P = 0.004), evident after 1 year and increasing with duration of use. This was the first study to demonstrate a protective effect of aspirin at a very low dose (75 mg per day), after only 5 years’ use, and in the general population, not a high-risk adenoma population.
Review of Calcium Chemoprevention Clinical Studies
The use of calcium supplementation for the prevention of colorectal adenomas was first reported by Baron’s group in 1999 . In this randomized clinical trial, the adjusted RR based on the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95% CI, 0.67–0.99, P = 0.04) and the effect of calcium supplementation was independent of initial dietary fat and calcium intake. The intervention involved 1200 mg of elemental calcium daily as calcium carbonate versus placebo and the primary end point was the recurrence of colorectal adenomas . Since that time a number of RCTs have been conducted and reported . A recent systematic review and meta-analysis of studies published through January, 2010, indicated that the published reports that they analyzed demonstrated that supplemental calcium was effective for the prevention of adenoma recurrence in populations with a history of adenomas, but no similar effect was demonstrated in populations that were at higher (FAP and advanced adenoma) or lower (general population) risk . The meta-analysis of three RCTs showed a significant reduction in adenoma recurrence (RR = 0.80 [95% CI, 0.69–0.94, P = 0.006]) for those receiving calcium. However, the two trials in normal-risk populations showed a nonsignificant RR of 0.62 (95% CI, 0.11–3.40). Also, in the Women’s Health Initiative (WHI), calcium plus vitamin D supplementation were studied with the outcome being the treatment effect on incidence and mortality for invasive CRC . However, in this general population of women, calcium/vitamin D supplementation had no effect on the incidence of CRC among postmenopausal women or on mortality . The doses of calcium and vitamin D were 1000 mg as calcium carbonate with 400 IU of vitamin D3, respectively, per day.
Summary of aspirin and calcium clinical studies
Baron et al. , 2003
ASA, 81 mg/d
↓ adenomas 19%, advanced adenomas ↓ 41%
Rothwell et al. , 2010
ASA, 75 mg/d, ≥5 years
ASA CVD trials
↓ CRC incidence and mortality
38% and 52%, respectively
Benamouzig et al. , 2011
ASA, 160 mg/d, 1 year
↓ adenomas 27%, advanced
adenomas ↓ 45%, NS
Burn et al. , 2011
ASA, 600 mg/d, ≥1 year
↓ Polyp recurrence 23%, NS
Din et al. , 2010
ASA, 75 mg/d, 1–5 years
↓ CRC risk 22% at 1 year
Baron et al. , 1999
Calcium,1200 mg, 1–4 years
↓ Adenomas 22% at 1 year, 19% at 4 years
Wactawski-Wende et al. , 2006
Calcium + vitamin D, 1000 mg/400 IU/d, 7 years
WHI women, average risk
Grau et al. , 2005
ASA + calcium, 81 mg
↓ Advanced adenomas
+ 1200 mg/d, 3–4 years
Cost-Effectiveness of Aspirin and/or Calcium for CRC Primary Prevention
Summary of recent chemoprevention cost-effectiveness studies
Dupont et al. , 2007
Markov, Monte Carlo simulation
325 mg/d ASA
ICER (COL) = $78,226 (vs natural history)
100% compliance rate for COL uptake
ICER (COL + ASA) = $60,942 (vs natural history)
COL SURV efficacy 100%
50 years until death
ICER/CRC prev. = $140,167 (ASA + COL)
ICER/CRC prev. = $74,615 (COL alone)
Hassan et al. , 2011
ICER (COL alone) = $6307 (vs no screening)
COL efficacy 56%
50–80 year of age
ICER (ASA alone) = - $436 (saved, vs no screen)
100% compliance for COL screening every 10 years
ICER (COL + ASA) = $6237 (vs no screening)
Life ASA mortality 0.1%
Squires et al. , 2011
State transition model
ICER (ASA + COL) = £10,169 (vs screening)
Compliance 75% for
Squires et al. , 2011
State transition model
1200 mg/d Ca carbonate
ICER (Ca + COL) = £8046 (vs screening)
Added Ca complications to model
Shaukat et al. , 2009
ICER (Ca alone) = $49,900 (vs natural history)
COL surveillance 3–5 years
Age 50–80 years
ICER (COL SURV) = $15,900 (vs Ca alone)
No Ca complications in model
ICER (COL SURV + Ca) = $3,090,000 (vs SURV)
While both aspirin and calcium have been shown to be effective in lowering the rate of CRC, the additional costs associated with supplements generally include the cost of the chemoprevention agent(s) and the possible adverse complications that can occur. The cost of aspirin per month is reported in  to be $12, with a sensitivity range of $4–$18. However, Hassan et al. [14••] estimate the annual wholesale cost of a single 81-mg aspirin tablet per day to be $3. Dupont et al.  identify the cost associated with a relatively unlikely aspirin-related complication (1.06% per year) to be around $12,000. Alternatively, Squires et al. [15••] reported the cost from an aspirin-related complication to be between $3870 and $4883 depending on the complication (gastrointestinal bleeding or hemorrhagic stroke). Additionally, there is a 5.2% likelihood assumed  of an initial side effect from aspirin usage with a relatively low associated cost of $250. Alternatively, calcium is typically assumed to be without any additional costs from potential complications . The assumed annual cost of a 1.2-g dose per day of calcium as calcium carbonate is found to be around $53 .
One study  that evaluated the cost-effectiveness of using aspirin chemoprevention in high-risk individuals with prior adenoma (diagnosed with screening colonoscopy and polypectomy) used Markov model analysis and found that the incremental cost effectiveness ratio (ICER) associated with colonoscopy surveillance (relative to no intervention) was $78,226. However, when aspirin chemoprevention was combined with colonoscopic surveillance, the ICER per year of life saved was $60,942 and the cost per CRC prevented was $140,167 . While aspirin chemoprevention alone is identified with an average gain of 0.0092 life years, it is also assumed to cost $144 per year and is associated with costly complications. Overall, the authors  conclude that aspirin chemoprevention is a cost-effective strategy when combined with colonoscopic surveillance for post-polypectomy patients.
Another study evaluated the feasibility of using calcium chemoprevention in combination with or as a substitute for colonoscopic surveillance in post-polypectomy patients . Calcium supplementation was found to be relatively more effective than no intervention, at an incremental cost of $49,900 per life year gained, but recommended surveillance was more cost-effective at only $15,900 per life year gained. When calcium was combined with surveillance, the cost per life year gained was $3,090,000. They concluded that calcium is unlikely to be considered cost-effective as a sole primary prevention strategy, but might be a viable alternative in individuals unwilling or unable to undergo surveillance.
Recently, the cost effectiveness of aspirin, celecoxib, and calcium was estimated using a state transition model [15••]. In contrast to , Squires et al. [15••] found that calcium was likely to be a cost-effective option for post-polypectomy individuals. They find that calcium is estimated to cost somewhere between £8,000 and £30,000 per quality-adjusted life year (QALY) in post-polypectomy individuals.
Chemoprevention is again mentioned to be less desirable for general population prevention strategies. For example, aspirin chemoprevention plus screening is estimated to cost £23,000 per QALY, relative to screening alone, in a general population between the ages of 50 and 60 [15••]. The authors concluded that calcium had a higher probability than aspirin of providing greater value in this population, and that celecoxib chemoprevention is not cost-effective for the general population [15••].
The most recent study examined the cost-effectiveness of low-dose aspirin with endoscopy in the primary prevention of CRC [14••]. The authors use a Markov model analysis with a simulated general population (started at age 50) cohort of 100,000 American subjects and conclude that low-dose aspirin may be a cost-effective strategy in primary prevention due to the suboptimal efficacy for endoscopy in prevention of CRC. More specifically, they reported a substantial increase in death prevention rates related to CRC, when low-dose aspirin is combined with colonoscopy (68% to 81%) and sigmoidoscopy screening (39% to 69%), while aspirin-related mortalities were relatively low at 0.1%. The additional cost per life year saved was $5413, which came at a cost savings of $278 per person when cost of CRC care is considered. Using repeated cohorts, this study found that aspirin was a cost-effective addition to colonoscopy 52% of the time and sigmoidoscopy 94% of the time. The high cost-effectiveness of aspirin with sigmoidoscopy was due to the increased prevention of right-sided CRC, which is not detected by sigmoidoscopy. The authors concluded that the substantial economic savings for avoidable CRC care compensated for the additional cost of low-dose aspirin and aspirin-related complications, compared with sigmoidoscopy alone [14••]. All recent cost-effectiveness studies are summarized in Table 2.
Molecular Mechanisms of Aspirin and Calcium Chemoprevention of CRC
The clinical efficacy and cost effectiveness of aspirin and calcium as chemoprevention strategies for both high-risk and even average low-risk populations has been determined. There is even optimism that aspirin will have a place in the management of FAP patients. This naturally points to questioning the underlying mechanisms of action for aspirin and calcium in the chemoprevention of CRC. Many previous studies have indicated that inducible cyclooxygenase-2 (COX-2) is a central mediator and one of the key enzymes involved in a number of cellular processes, and is overexpressed in many premalignant, malignant, and metastatic neoplasms, including CRC . COX-2 is a known target of the class of NSAIDs of which aspirin is a member. Additionally, COX-2 inhibition is the central mechanism by which NSAIDs, including aspirin, act to prevent adenoma growth and CRC . It is also known that increased COX-2 is associated with adenoma size and degree of dysplasia and that it may be an early marker in the adenoma-to-carcinoma sequence, and thus, is an ideal target for aspirin chemoprevention . High-dose aspirin is considered to act mainly through COX-2 inhibition . However, there are existing data to suggest that low-dose aspirin may prevent adenoma formation via COX-1 inhibition and COX-1–dependent pathways, as well as non-COX targets that might be related to inflammation , and thus, COX-1 may also be important in the carcinogenesis process and chemoprevention by aspirin. This concept is supported by the recent data showing greater chemopreventive efficacy with low-dose versus higher-dose aspirin [5••, 13].
Mechanisms of calcium chemoprevention of CRC have recently been examined in a RCT of the effects of supplemental calcium and vitamin D3 on markers of their metabolism in the normal mucosa of colorectal adenoma patients by Ahearn et al. . They investigated the effects of 2 g/day of elemental calcium and/or 800 IU/day vitamin D3 versus placebo for 6 months, on the expression of the calcium receptor (CaR), also known as the calcium-sensing receptor (CaSR), the vitamin D receptor (VDR), and the P450 cytochromes CYP27B1 and CYP24A1 . In the calcium-supplemented group, the CaSR expression increased 27% (P = 0.03) and CYP24A1 expression decreased 21% (P = 0.79). With vitamin D3 supplementation, CaSR expression increased 39% (P = 0.01) and CYP27B1 increased 159% (P = 0.06). In the group with both calcium and vitamin D3 supplementation, the VDR expression increased 19% (P = 0.13) and CaSR increased 24% (P = 0.05). The authors conclude that these results provide mechanistic insight into these biomarkers as preneoplastic targets for calcium/vitamin D3 chemoprevention against CRC .
Mechanistically, colonic luminal calcium binds to the CaSR and may directly modulate the cell cycle of colonocytes . However, an alternative long-held hypothesis is that luminal calcium may also bind proinflammatory, secondary bile acids and ionized fatty acids, thus rendering them harmless as CRC promoters to the mucosal cells . The CaSR is differentially expressed in well-to-moderately differentiated colon carcinomas, but there is little to no expression of the CaSR in undifferentiated carcinomas . The CaSR gene induces a number of cellular responses such as mitogen-activated protein kinase (MAPK) stimulation and adenylate cyclase inhibition . Calcium from the fecal stream suppresses normal colonocyte proliferation by signaling through the CaSR, potentiating expression of the CaSR gene via the calcium responsive promoter . Colonocytes acquire CaSRs when entering the mid-crypt differentiation zone and CaSR expression is highest among cells at the apex of the crypt, as a result of a calcium gradient from the apex to the basal layer of the colonic crypt . There are several polymorphisms of CaSR that have been identified with CaSRs A986S and LCT 13910 C/T thought to be associated with a higher incidence of CRC . Because CaSR is expressed in a number of different tissues, and has pleomorphic functions in both normal and malignant cells, its utility as a target for therapy is limited .
The evidence from both a clinical and cost-effectiveness perspective points to the potential for low-dose aspirin and/or calcium to prevent CRC. The low risk, low cost of these strategies, as either primary prevention or in combination with colonoscopy, to prevent CRC suggests that these agents are strong candidates for a recommendation for general population use. However, as personalized medicine strategies are developed for cancer prevention, additional analyses will be useful for improving our knowledge and practice of chemoprevention, with the goal of substantially preventing the incidence and mortality of CRC, in those subgroups who would derive the greatest benefit, with the least risk and toxicity. Furthermore, as we continue to explore the mechanisms of these agents, our increased understanding will also lead to discovery of new targets for chemoprevention and/or therapy.
No potential conflicts of interest relevant to this article were reported.