Chemopreventive candidate agents
Background[edit source]
Chemoprevention is the regular use of drugs to prevent or delay the development of cancers. As chemoprevention strategies require regular use of agents over many years by people who are disease free and may never develop cancers, chemopreventive agents need to be easily administered with a convenient dosing schedule, inexpensive and with very few side effects.
Trials of chemoprevention (calcium, some vitamin supplementation, selenium, statins) have provided mixed evidence of benefit. The strong evidence for benefit has emerged from observational studies of exposure to nonsteroidal anti inflammatory drugs (NSAIDs), especially aspirin.
Results of randomised controlled trials (RCTs) of aspirin in the primary and secondary prevention of colorectal cancer and adenomas are now available and point to a benefit similar to that associated with screening by colonoscopy in people under 70 years of age. Aspirin is cheap, readily available, has other benefits such as cardiovascular protective effects, and a relatively benign side-effects profile, although these side effects increase with age and the benefits for cancer prevention occur only after a latent period of 10 years and are less studied in older people, especially women.
Aspirin[edit source]
Systematic review evidence[edit source]
In an asymptomatic population at average risk or increased risk of colorectal cancer, what is the cost-benefit ratio of prophylactic Aspirin use in reducing the mortality and incidence of colorectal cancer? (PPR1)
A systematic review was undertaken to evaluate the effectiveness of aspirin in the primary prevention of colorectal cancer in people at average or higher risk. A total of 10 clinical trials reported in 17 articles[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] examining effects of aspirin on colorectal cancer outcomes met the criteria and were included in the systematic review. The trials included were specifically of average or high-risk populations.
The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.
Average-risk population[edit source]
Five randomised controlled trials compared aspirin use with placebo or no aspirin use.[3][4][5][6][9][10][11][17] Four were at low risk of bias[3][4][9][10][11][17] and one, the British Doctors Aspirin Trial (BDAT),[6] was at high risk of bias.
Three trials recruited participants with a transient ischemic attack or minor ischaemic stroke or those who were at high risk of ischaemic heart disease. Primary endpoints in these trials were various cardiovascular endpoints.[9][10][11][17] Two trials recruited healthy participants.[3][4][5][6]
Based on a weighted average calculation, the average trial duration (duration taking aspirin) was 8.9 years.[3][4][5][6][9][10][11][17]
A limitation to these trials is that none of them had colorectal cancer as the primary endpoint. Secondary study outcomes included colorectal cancer incidence and mortality, gastrointestinal side effects, incidence of other cancers, and fatal or non-fatal cardiovascular events. Most studies did not report on aspirin exposure after the randomised interventional period.
Colorectal cancer incidence[edit source]
Three trials reported a statistically significant reduction in colorectal cancer incidence in average-risk populations.[3][4][5][6][10][11]
The BDAT trial showed a statistically significant reduction in colorectal cancer incidence in those taking 300 mg/day aspirin, compared with no aspirin, at 23 years’ follow-up (hazard ratio [HR] 0.7, p = 0.04).[7] The Women’s Health Study, which used an aspirin dosage of 100 mg on alternate days, found a statistically significant reduction in colorectal cancer incidence after 16 years’ follow-up (HR 0.80, p = 0.021), but not after 10 years’ follow-up (RR 0.97).[3][4][5] No difference was found for colon polyps (type not specified) between groups (HR 1.00), though the trial was not colonoscopically controlled.[3][4][5]
Pooled data from the BDAT and the United Kingdom Transient Ischaemic Attack Trial (UK-TIA) trials with up to 23 years’ follow-up[7] showed that aspirin use (BDAT used 300 mg/day or 500 mg/day, UK TIA used 300 mg/day or 1200 mg/day) demonstrated a reduction in colorectal cancer incidence (HR 0.74, p = 0.02). This reduction was not seen in the first 10 years after intervention (HR 0.92; 95% confidence interval [CI] 0.56 to1.49). In non-pooled data from the UK-TIA and BDAT trials individually, each showed a reduction in colorectal cancer incidence only after 10 years of follow up (HR 0.50, p = 0.05 and HR 0.64, p = 0.05, respectively).[6][10][11] Pooled analysis of data from the BDAT, SALT, TPT and UK-TIA trials also showed a significant reduction in colorectal cancer incidence in those taking aspirin during the trial period and followed for a median of 18.3 years (HR 0.75 p = 0.02).[8] Subgroup analysis of this pooled dataset also showed that 2.5–5 years of aspirin consumption was just as beneficial as ≥ 5 years of aspirin consumption (HR 0.69 and 0.62 respectively, p = 0.003 for both).[8] In addition, subgroup analysis on the location of cancer showed that, reflecting the incidence data, aspirin was beneficial for preventing proximal colon cancer (HR 0.45, p = 0.001), but not for distal colon cancer (HR 1.10, p = 0.66) or rectal cancer (HR 0.90, p = 0.58), with a median of 18.3 years’ follow-up.
It should be noted that these trials (BDAT and UK-TIA) were the pivotal trials demonstrating the secondary protective effects of aspirin against cardiovascular disease. Thus, the benefits of taking aspirin for cancer prevention can be expected to be enhanced by the benefits of protection against adverse cardiovascular outcomes (transient ischaemic attacks, stroke, and heart attacks), especially in those who carry excess risk of these latter outcomes. Modelling of results from the cardiovascular prevention trials to date shows that the cancer prevention effects dominate over the cardiovascular benefits. It must be noted that in these trials the participants were mainly men.[18]
In modelling data reported on the Women’s Health Study, aspirin (mean duration 10.1 years) was shown to be associated with a modest decreased 15-year risk of colorectal cancer in women under 65 years, and the highest net benefit was only seen in the 10-year risk of colorectal cancer in women ≥ 65 years of age (number needed to treat [NNT] = 369). In this dataset, cardiovascular benefits dominated over colorectal cancer incidence.[4]
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Colorectal cancer mortality[edit source]
Four trials reported individual data for mortality due to colorectal cancer in the average-risk population.[6][9][10][11][17] Only one reported a significant benefit (reduction) in colorectal cancer mortality for those taking aspirin with 17–20 years of follow-up (odds ratio [OR] 0.73; 95% CI 0.49 to 1.10).[9]
A meta-analysis of these trials found aspirin to be beneficial with a median of 18.3 years follow-up (OR 0.66, p = 0.002).[8] Subgroup analysis reported that this benefit was only for those who took 300 mg or less per day during the trial period.[8] The benefit from aspirin consumption was seen irrespective of aspirin consumption duration (≥ 2.5 years’ versus ≥ 5 years’ duration).
In addition, subgroup analysis on the location of colorectal cancer showed that, reflecting the incidence data, aspirin reduced mortality for proximal colon cancer (HR 0.34, p = 0.001), but not for distal colon (HR 1.21, p = 0.54) or rectal cancer (HR 0.80, p = 0.35), with a median 18.3 years’ follow-up.[8] The benefit for proximal cancer is particularly important, given the concern that colonoscopic screening in many studies has not been shown to be protective against proximal colorectal cancer. This failure is thought to be due to poor bowel preparations, incomplete examinations, flat (sessile serrated) polyps easily overlooked, and difficulty completely removing these polyps.
The Women’s Health Study[4] did not report on mortality.
Adverse effects[edit source]
Two trials reported adverse effects from aspirin consumption.[3][4][5][10][11]
In the Women’s Health Study, those taking aspirin experienced greater gastrointestinal bleeding and peptic ulcers (HR 1.14 and 1.17 respectively, p < 0.001) compared with the placebo group.
In UK-TIA, participants taking aspirin at a dosage of 300 mg/day or 1200 mg/day experienced significantly greater gastrointestinal haemorrhage, compared with the placebo group (300 mg/day: OR 1.32; 95% CI 1.06 to 1.65; 1200 mg/day: OR 1.54, 95% CI 1.25 to 1.89).[10][11] Participants taking aspirin also experienced greater upper gastrointestinal symptoms (OR 1.32, p < 0.05), and more so with a higher aspirin dose of 1200 mg/day (OR 1.54, p < 0.05 compared with 300 mg/day).[10][11] Fatal gastrointestinal bleeding rates did not differ between aspirin and placebo groups.[19]
Trials documented adverse effects well during intervention, but less well during the long periods of follow-up. However, aspirin side effects related to long-term use in other large population studies are well documented, and there is little reason to consider that dose-equivalent side effects would be different for the participants in the trials considered.
Many commentators question the clinical impact of side effects (lower) than the incidence and mortality benefits (higher), leading to analyses that provide estimates of side effects weighted downwards.[4] These point to higher benefit estimates than analyses that do not take this into account.
High-risk population[edit source]
Five randomised controlled trials compared daily aspirin use with placebo.[1][2][12][14][15][16] Two trials compared lower-dose aspirin (defined as 81 mg/day or 160 mg/day) and higher-dose aspirin (defined as 300 mg/day or 325 mg/day) with placebo.[12][14] The remaining trials compared higher-dose aspirin with placebo (325 mg/day, 600 mg/day, or 300mg/day, respectively).[1][2][15][16] All studies were at low risk of bias.[1][2][12][14][15][16]
Eligibility requirements for the trials differed. In the Colorectal Adenoma/Carcinoma Prevention Programme 2 (CAPP2) trial, eligible participants were > 25 years of age and proven carriers of a pathologic mismatch-repair mutation or members of a family that met the Amsterdam diagnostic criteria and had a personal history of a cured Lynch syndrome neoplasm but with at least some residual colon or rectum.[1][2] Colonoscopic examination and clearance of polyps within 3 months after recruitment were prerequisites to study entry. The Aspirin/Folate Polyp Prevention Study (AFPPS), the Association pour la Prevention par l’Aspirine du Cancer Colorectal (APACC) study, and the United Kingdom Colorectal Adenoma Prevention Study (ukCAP) recruited participants who had a recent history of sporadic colorectal adenomas and excluded individuals with a history of invasive large-bowel cancer.[12][14][15]
The Colorectal Adenoma Prevention Study (Cancer and Leukemia Group B [CALGB]) trial specifically recruited patients who had been treated for colorectal cancer.[16] Other eligibility criteria for these four trials were similar – all excluded individuals with inflammatory bowel disease, those with a clinical need for aspirin treatment, and those who could not take aspirin.[16][12][14][15]
The trial duration ranged from 1 month to 67 months. Based on a weighted average calculation, the average trial duration (duration taking aspirin) was 2.3 years.[12][14][15][1][2][16]
Study primary outcomes included the detection of at least one adenoma or colorectal carcinoma at follow up. Four trials used adenoma incidence as a primary endpoint.[16][12][14][15] The CAPP2 trial[1][2] had a mean follow-up of 5.5 years, and the other trials had a median follow-up between 31.3 and 47.2 months.[16][12][14][15]
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Colorectal cancer incidence[edit source]
For the CAPP2 trial in a high-risk population, no benefit in colorectal cancer incidence was reported after mean follow-up of 29.1 months or 66.1 months (RR 1.0; HR 0.63, p = 0.12, respectively) using intention-to-treat analysis.[1][2] The most convincing benefit was found with per-protocol analysis, where aspirin reduced colorectal cancer incidence after ≥ 2 years on trial treatment compared with placebo (HR 0.41, p = 0.02), with a mean of 66.1 months follow up.[1][2] Analyses including all Lynch Syndrome-associated cancers (colorectal and other cancers) provided the strongest outcome benefit. Both intention-to-treat and per-protocol analyses reported significant benefit after ≥ 2 years on trial treatment compared with placebo (HR 0.65, p = 0.05 and HR 0.45, p = 0.005 respectively) for all Lynch Syndrome-associated cancers.[1][2] Note that there was no effect on adenomas, suggesting that the effect was on the progression of adenomas to cancers.
The AFPPS, APACC, CALGB, and ukCAP trials only report incidence of adenoma and advanced lesions.[16][12][14][15] While the primary endpoint of these trials was the incidence of new adenomas following randomisation and during follow-up, in the pooled meta-analysis, aspirin was shown to significantly reduce the risk of adenoma when comparing any dose of aspirin with placebo (RR 0.83, p = 0.012).[13] A reduction in advanced lesion risk was also reported when comparing any dose of aspirin with placebo (RR 0.72, p = 0.0046) in pooled meta-analysis.[13] In the individual trials, a reduction in adenoma incidence for any dose of aspirin was reported for the CALGB (RR 0.61, 95% CI 0.44 to 0.86)[16] and ukCAP (RR 0.79, 95% CI 0.63 to 0.99) trials[15] only (325 mg/day and 300 mg/day, respectively). However, a reduction in adenoma incidence for any dose of aspirin was not observed in the AFPPS (RR 0.88, p > 0.05)[12] or APACC (RR 0.95, p > 0.05)[14] trials. In the individual trials, a reduction in advanced lesions incidence was reported only in the ukCAP trial (RR 0.63; 95% CI 0.43 to 0.91), but then only for any dose of aspirin compared with placebo.[15]
A significant reduction in the risk of any colorectal adenoma (RR 0.83, p = 0.012) was also reported in pooled meta-analysis comparing only low-dose aspirin (81 mg or 160 mg/day) with placebo in the AFPPS and APACC trials.[13] No risk reduction was reported in pooled data comparing only low-dose aspirin (81 mg or 160 mg/day) with placebo for advanced lesion (RR 0.83, p = 0.57) in the AFPPS and APACC trials.[13] As individual trials, significant risk reduction in the risk of any colorectal adenoma was only reported for the AFPPS trial (RR 0.81; 95% CI 0.69 to 0.96).[12]
A significant risk reduction was reported for advanced lesions when comparing higher-dose aspirin (300 mg or 325 mg/day) with placebo in pooled meta-analysis (RR 0.71, p = 0.0089),[13] but no such difference was found for any colorectal adenoma (RR 0.85, p = 0.099) in the AFPPS, CALGB, ukCAP and APACC trials.[13]
In pooled analysis of the adenoma trials, rates of colorectal cancer did not differ significantly between treatment groups: 9 cases (0.54%, N = 1678) were diagnosed among participants taking aspirin (any dose), compared with 8 cases (0.62%, N = 1289) diagnosed in the placebo groups (p = 0.81).[13]
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Colorectal cancer mortality[edit source]
None of the five trials reported colorectal cancer mortality data in the high risk population.[1][2][12][14][15][16]
Adverse effects[edit source]
In pooled analysis of the AFPPS, APACC, CALGB, and ukCAP trials, stroke was the only adverse event for which a significant (p = 0.002) reduction was reported in the aspirin treatment group compared with the placebo group.[13] The CAPP2 trial did not report statistical analysis of serious adverse events, but there was no numerical difference in adverse outcomes.[1][2]
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Additional considerations[edit source]
Non-RCT evidence[edit source]
In addition to the evidence from RCTs evaluating long-term aspirin treatment in the prevention of various conditions, there is substantial and consistent evidence from case control studies and cohort studies to support the association between aspirin exposure and colorectal cancer prevention.[7][20]
Cardiovascular benefits[edit source]
The aligned benefits of cardiovascular and cancer prevention, well demonstrated through the analysis of the BDAT and the UK-TIA, point to synergies in prevention, especially for those who have already sustained a TIA or myocardial ischaemic event. The US Preventive Services Task Force has quantified this benefit and, taking the cancer prevention into account, extends the advice on use of aspirin to also those whose risk of a cardiovascular event is at least a 10% over the following 10 years.[21]
Analysis of the range of data available suggest that the beneficial effects of aspirin are strongest for cancer prevention, dominating over cardiovascular prevention. However, the relative risks of each disease depend on age and sex.
Adverse effects[edit source]
An analysis of benefits versus risks of aspirin[18] based on pooled data from the BDAT, SALT, TPT and UK-TIA trials,[8] which were predominantly for males, found that the benefits of aspirin use include a reduction in risk of cancer (including colorectal cancer), myocardial infarction and ischemic stroke. The harms include increased risk of haemorrhagic stroke, gastrointestinal bleeding and peptic ulcer. Overall, the estimates of the benefits outweigh the harms. The analysis[18] made the following conclusions:
- Taking aspirin for 15 years is five times more likely to reduce morbidity than increase morbidity.
- Taking aspirin for 10 years is 10 times more likely to prevent death than cause death at age 50 years and five times more likely at age 65 years.
- Among 50-year-old males, one death would be prevented for every 106 men taking aspirin for 10 years.
- Among 50-year-old females, one death would be prevented for every 213 women taking aspirin for 10 years.
- Among 65-year-old males, one death would be prevented for every 46 men taking aspirin for 10 years.
- Among 65-year-old females, one death would be prevented for every 89 women taking aspirin for 10 years.
The side effects of aspirin use are well known. The most useful evidence on treatment-related adverse effects of long-term use comes from sources other than RCTs, because long-term follow-up of studies assessing cancer prevention did not report side effects. From available evidence, it can be concluded that there is a dose relationship, with higher doses associated with more adverse events, and that the rate of adverse events is higher in people aged over 70 years. Covering the risk of gastrointestinal ulceration with a proton pump inhibition can be considered although the benefit with low dose aspirin is controversial.
The following should also be taken into consideration:
- There is non-clinical and clinical evidence that gastric mucosal injury is attenuated with repeated administration of aspirin over time.[22][23][24]
- Most of the trials excluded patients with risk factors for aspirin use. Therefore, recommendatons for individuals must take account relative contraindications to the use of aspirin.
Notwithstanding the findings of the CAPP2 trial,[1][2] the current dose recommended for prevention of Lynch Syndrome-associated cancers, including colorectal cancer, is 100 mg daily, based on evidence that this lower dose will be effective without the dose-related side effects of the higher dose used in CAPP2. This advice could be modified when results are reported from the current CAPP3 trial, which is investigating the optimal dose of aspirin.[25]
Evidence summary and recommendations[edit source]
Average-risk population evidence summary table[edit source]
| Evidence summary | Level | References |
|---|---|---|
| Colorectal cancer incidence and mortality In the post hoc analyses of the cardiovascular prevention trials, predominantly in males, there was evidence for a real but small reduction in incidence and mortality from colorectal cancer commencing 10 years after starting aspirin. |
I, II | [3], [26], [5], [6], [7], [8], [27], [10], [11], [17] |
| Evidence from all trials showed a significant reduction in the incidence of proximal colon cancer compared to distal colon cancer in those taking aspirin. Benefit is attenuated distally. | I, II | [5], [8] |
| It is not known if the colorectal cancer risk reduction and mortality reduction benefits can be extrapolated to populations without cardiovascular risk. The risk of aspirin in these average risk settings still needs more empirical data. | I | [7], [8] |
| Aspirin commencement age Most of the studies recruited participants aged 50 years or older. Based on the age range of recruitment into the trials, the evidence supported commencing aspirin between the ages of 50 and 70 years. |
I, II | [3], [26], [5], [6], [7], [8], [27], [10], [11], [17] |
| Aspirin duration Taking aspirin for 2.5 years was shown to be just as effective as taking it for 5 years, when considering colorectal cancer incidence and mortality, but only after a latent period of 10 years. The benefit extends to older ages with longer duration of use. |
I | [8] |
| Aspirin dose and frequency A low dose of aspirin (100–300 mg per day) is as effective at reducing colorectal mortality as a higher dose. |
II | [8], [10], [11] |
| Potential harms of aspirin Aspirin was shown to be associated with increased incidence of the following adverse events:
Aspirin should be avoided in those with:
|
I, II | [3], [26], [5], [18], [10], [11] |
| Overall health benefit over harm The overall health benefit over risk depends on the likelihood of a clinically significant bleeding risk, particularly gastrointestinal and intracerebral haemorrhage. The likelihood of health benefit was 5 times greater than the health harm. The likelihood of preventing death is 5 to 10 times greater than the likelihood of causing death. Aspirin demonstrated a benefit in reducing thrombotic strokes. |
I, II | [8], [18] |
| Sex and age considerations The evidence reported from the cardiovascular risk trials was from a predominantly male population (92%). In the only trial conducted in an average-risk population with cancer as the primary endpoint (which recruited only women at average risk of cardiovascular disease and cancer), there was evidence of colorectal cancer prevention in women under 65 years taking alternate-day 100 mg aspirin. There was a suggestion of overall health benefit in women over 65 years, but not from colorectal cancer prevention. |
I, II | [3], [26], [5], [6], [7], [8], [27], [10], [11] |
High-risk population evidence summary table[edit source]
| Evidence summary | Level | References |
|---|---|---|
| Colorectal cancer incidence and mortality In the high-risk population (notably, people with Lynch Syndrome), benefits for aspirin compliers were unequivocally greater than risks. |
II | [1], [2] |
| Aspirin dose and frequency The dose demonstrated in the pivotal CAPP2 trial was 600 mg daily taken for at least 2 years. |
II | [1], [2] |
| Adverse events The only adverse event reporting a significant reduction in participants on aspirin compared to placebo was stroke. The CAPP2 trial did not report statistical analysis of serious adverse events but numerically there was no difference in adverse outcomes. |
I, II | [1], [2], [13] |
Recommendations[edit source]
Evidence-based recommendation
|
Grade |
|---|---|
 The choice to take aspirin should be personalised based on age, sex and potential reduction in cardiovascular events, cerebrovascular events and thrombotic stroke. The individual should take into account the potential risks of taking aspirin. Aspirin should be avoided in patients with current dyspepsia, any history of peptic ulcer, aspirin allergy, bleeding diathesis, an increased risk of gastrointestinal haemorrhage (such as associated with use of oral anticoagulants or antiplatelet agents), or renal impairment. The benefit in colorectal cancer risk reduction in women over 65 is less clear cut. However, based on limited data available, older women with cardiovascular risk factors may derive a greater overall benefit than harm. |
B |
| Practice point
|
|---|
|
Aspirin should be avoided in patients with uncontrolled hypertension. |
| Practice point
|
|---|
|
Breath testing for Helicobacter pylori (and treatment for those who test positive) can also be considered, as gastrointestinal toxicity from aspirin is enhanced in the presence of Helicobacter pylori. |
| Evidence-based recommendation
|
Grade |
|---|---|
|
A |
| Evidence-based recommendation
|
Grade |
|---|---|
600 mg/day has been shown to be effective, but lower dose (100 mg/day) may be as effective and is recommended based on the data available at the time of the systematic review. |
B |
Considerations in making these recommendations[edit source]
There was robust discussion within the chapter subcommittee regarding the clinical background of the participants in the reported randomised controlled trials; the gender imbalance across these trials; and the potential harms and benefits of taking aspirin, both in the context of colorectal cancer prevention, prevention of other cancers, and the role of aspirin in preventing cardiovascular events. However the group was able to come to a decision about the guidance in this chapter, based on the interpretation of the systematic review evidence.
RCT findings lead to the guarded conclusion that aspirin is effective in the primary prevention of colorectal cancer. After taking into account the observational epidemiological data and other potential benefits, we have made a strong recommendation to consider universal aspirin chemoprevention except where contraindicated, especially for those with excess cardiovascular risk.
Benefits and harms[edit source]
With appropriate consideration of risks and benefits for the individual, the benefits are considered to substantially outweigh the harms following implementation of these recommendations.
Health system implications of these recommendations[edit source]
Clinical practice[edit source]
Aspirin is cheap and readily available. The major health system implication is the dissemination of this recommendation to primary care providers. Modelled benefits of colorectal cancer incidence can be anticipated, and due to the differential site-specific preventative benefits of aspirin (proximal) and colonoscopy (better for distal colorectal cancer), the two approaches can be considered complementary.
The national guidelines for managing absolute cardiovascular risk[28] do not recommend aspirin for primary prevention of cardiovascular disease. However, the analyses of the existing cardiovascular prevention trials and the Women’s Health Study to now include cancer prevention (especially colorectal), add a new compelling perspective for the use of aspirin in preventative medicine. The current recommendations take a broader view of the benefits of aspirin to include people even at average risk of cardiovascular disease, because of the added benefits from cancer prevention.
Resourcing[edit source]
Education for GPs on the risks and benefits will be needed to engage their support for the recommendations. Renal function will need to be measured if there is doubt about aspirin usage. It is anticipated most dispensing will be over the counter and user paid (rather than reimbursed by the Pharmaceutical Benefits Scheme).
Barriers to implementation[edit source]
Aspirin is off patent and widely available. However, there professional education is needed about its appropriate use.
Discussion[edit source]
Unresolved issues[edit source]
The following issues are unresolved:
- The optimal dose for colorectal cancer protection (100 mg/day, 300 mg/day or 600 mg/day) has not been identified. More data are needed before specific recommendations can be made.
- There is a lack of RCTs of aspirin in average-risk populations with colorectal cancer (CRC) as the primary endpoint.
- There is no information on aspirin use in the elderly.
- There is no information on the optimal target age range (including starting and stopping ages) for aspirin use in average-risk populations.
- Better analysis is needed of dose-related risk versus benefit of aspirin use stratified by age as the balance of benefit and harm is unknown in those of 70 years.
Studies currently underway[edit source]
CAPP3[25] may demonstrate if lower doses of aspirin are as effective for people with Lynch syndrome. People with Lynch syndrome are encouraged to join trials investigating optimal aspirin dose.
The current ongoing ASPREE trial will add information on the primary prevention benefits of low-dose aspirin and its risks in older healthy individuals.[29] Since the guidelines publication the ASPREE study was published in December 2018[30]. ASPREE is a randomized trial of over 19,000 patients (the vast majority of patients were over the age of 70 years) comparing low dose daily aspirin to placebo. The study showed no benefit for aspirin after a short median follow up of 4.7 years, with preliminary findings indicating that CRC was more common in the patients receiving aspirin.[30] More mature results are awaited however for now these results reinforce the 2018 Guidelines which limit the recommendation for the initial prescription of aspirin for the prevention of colorectal cancer, to those aged 50 to 70 years of age.
Future research priorities[edit source]
Future research can help provide clarity about the unresolved questions in regards to the use of aspirin to prevent colorectal cancer. Potential future research questions include:
- Is there evidence of differential benefit of aspirin on preventing sessile serrated versus pedunculated polyps?
- Is there benefit if people start taking aspirin at 40 years of age, to prevent the increase in CRC that is currently seen after age 50 years? (Current evidence suggests a 10 year lag time before CRC prevention is evident.)
Other chemopreventive candidate agents[edit source]
Overview of evidence (non-systematic literature review)[edit source]
Two comprehensive literature reviews undertaken jointly by the World Cancer Research Fund and the American Institute for Cancer Research have reported the evidence for chemopreventive candidate agents in the prevention of cancers:
- the Second Expert Report (SER) on food, nutrition and physical activity in the prevention of cancer (2007)[31]
- the Continuous Update Project (CUP) review of food, nutrition and physical activity in the prevention of colorectal cancer (2011).[32]
The information on non-aspirin chemopreventive candidate agents in this chapter is primarily summarised from these reviews. Updated information was included, where available. New systematic reviews were not undertaken for this guideline.
Updated systematic reviews are currently in progress by World Cancer Research Fund/American Institute for Cancer Research.i
iThese guidelines may be updated after 2017 as a result of updated guidance from the World Cancer Research Fund/American Institute for Cancer Research. The provisional publication dates for The Colorectal Cancer Report and the Expert Report are April 2017 and November 2017, respectively.
Nonsteroidal anti-inflammatory drugs (NSAIDs)[edit source]
There is strong evidence supporting the chemopreventive activity of non-steroidal anti-inflammatory drugs (NSAIDs) other than aspirin against colorectal cancer. However, data on the risk–benefit profile of these drugs are currently insufficient to allow definitive recommendations for their use at a population level for primary cancer prevention.
See High-risk familial syndromes chapter
| Practice point
|
|---|
|
Where surgery is inappropriate for people with familial adenomatous polyposis, an NSAID (e.g. sulindac) is recommended. (Kim B et al 2011) |
Statins[edit source]
The commonly prescribed cholesterol-lowering statin drugs have chemopreventive properties. They are very well tolerated and serious adverse effects of these drugs are rare.
Results from a prospective case-control study indicating that the use of statins for more than 5 years was associated with a reduced relative risk of colorectal cancer (OR 0.53; 95% CI 0.38 to 0.74) pointed to the potential colorectal cancer-protective properties of statins.[33] There has now been a number of trials with widely variable findings ranging from strong reduction in colorectal cancer risk to no association between statin usage and colorectal cancer risk. A recent meta-analysis of 27 clinical trials found no benefit from statin use for either incidence or recurrence of a number of cancers, including colorectal cancer.[34] Despite these inconsistent and findings, the accumulating clinical evidence still suggests a significant association between statin usage and reduced colorectal cancer risk.[34]
More nuanced studies suggest statin protection is strongest when consumed for > 3 years or > 5 years in modest doses (e.g. 40 mg simvastatin). The effects seem more reproducible where the lipophilic statins are used.[35]
However, the impact of statin use on colorectal adenoma remains unclear. Statin use was associated with an increased risk of adenoma recurrence in a secondary analysis of a prospective cohort study (RR 1.39; 95% CI 1.04 to 1.46).[36] A negative association between prior statin use and adenoma diagnosis (OR 0.40; 95% CI 0.24 to 0.76) has also been reported in a smaller retrospective case-control study.[37]
More data from randomised control trials with colorectal cancer as a primary end point are required before any clear recommendations for the use of statins for colorectal cancer prevention can be made.
| Practice point
|
|---|
|
Without RCT evidence, statins cannot be recommended for chemoprevention at this time. |
Metformin[edit source]
Patients with diabetes mellitus have an increased risk of colorectal cancer.[38] Metformin is an oral hypoglycaemic drug, widely prescribed for the treatment of type-2 diabetes with few side effects. Metformin lowers intestinal glucose absorption, hepatic glucose production and improves insulin sensitivity in the peripheral tissues, leading to lower levels of circulating insulin.[39] Elevated insulin levels have been associated with an increased risk of colorectal cancer.
Two early meta-analyses of cancer incidence in patients with type-2 diabetes have both shown an inverse association between metformin use and colorectal cancer: RR 0.63 (95% CI 0.50 to 0.79, p < 0.001), and RR 0.66 (95% CI 0.49 to 0.88), respectively.[40][41] Since then numerous other meta-analyses and observational studies of metformin use and colorectal cancer risk in diabetes patients have been published showing a range of outcomes, but with a general trend towards metformin being protective. A recent systematic review of the effect on colorectal cancer risk and mortality amongst diabetes patients receiving and not receiving metformin treatment reported a reduction of colorectal cancer incidence (OR 0.9, 95% CI 0.85 to 0.96) and improved survival (HR 0.68; 95% CI 0.58 to 0.81), while a recent retrospective chart review of 1304 colorectal cancer patients revealed that, amongst those patients with diabetes, those receiving metformin treatments survived significantly longer (overall survival 91% at year 1, 80.5% at year 2) than those taking other treatments (including diet control) (overall survival 80.6% at year 1, 67.4% at year 2) with multivariate analysis suggesting that colorectal cancer patients with diabetes taking treatments other than metformin (diet control, insulin or non-metformin oral hypoglycaemics) had a worse prognosis (HR 1.35; 95% CI 1.039 to 1.753, p = 0.025) than those taking metformin (HR 0.807; 95% CI 0.601 to 1.084, p = 0.154).[42]
Given the increased risk of colorectal cancer associated with type-2 diabetes, metformin’s potent hypoglycaemic activity and protective activity against colorectal cancer make it an attractive drug for the management of diabetes patients, particularly amongst those who have had colorectal cancer. Whether metformin can be beneficial in reducing the incidence of or increase survival after colorectal cancer in non-diabetic patients remains unclear and randomised placebo controlled trials to address this question are needed. Of 11 currently active clinical trials listed in the US clinical trials registry that are evaluating the effect of metformin on colorectal cancer risk, four use metformin alone as the intervention, while the others involve the use of metformin as an adjunct to other interventions.
Overall, it is unclear whether metformin is protective against colorectal cancer in non-diabetic populations, either by reducing incidence or increasing survival.
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Without RCT evidence, metformin cannot be recommended for chemoprevention at this time. |
Bisphosphonates[edit source]
Bisphosphonates are used in treatment of osteoporosis, multiple myeloma, and bone overgrowth in malignancy, and for the prevention or treatment of solid tumour metastases to the bone.[43] Their anti-cancer activity is likely mediated through inhibition of angiogenesis and cell proliferation, induction of cell-cycle arrest and apoptosis in cancer cells, and immune cell activation.[43]
No RCTs have evaluated the use of bisphosphonates in the primary prevention of colorectal cancer. Several observational studies of bisphosphonate use have recorded cancer-related outcomes as secondary end-points. Three studies in women found quite substantial reductions in the risk of colorectal cancer.[44][45][46] In the first, receipt of 2–13 bisphosphonate prescriptions over a period of ≥ 5 years was associated with a reduced risk of colorectal cancer (O 0.84; 95% CI 0.71 to 1.00), while for those receiving ≥ 14 prescriptions over ≥ 5 years the colorectal cancer risk reduction was stronger (OR 0.78; 95% CI 0.65 to 0.94) with the effect significant only where risedronic acid was the agent used.[44] In the second, colorectal cancer risk was reduced with the use of bisphosphonates for more than 1 year before diagnosis (OR 0.50; 95% CI 0.35 to 0.85).[45] In the third study, a reduced risk of colorectal cancer was again associated with bisphosphonates use (OR 0.50; 95% CI 0.35 to 0.71), with the reduced risk comprising the following components: a lower colorectal cancer incidence (adjusted HR 0.69; 95% CI 0.6 to 0.79) and a lower mortality rate post colorectal cancer diagnosis (HR 0.82; 95% CI 0.70 to 0.97).[46]
In contrast, analyses of data from the Women’s Health Initiative and the Nurse’s Health Study found no such reduction: adjusted HR 0.88 (95% CI 0.72 to 1.07, p = 0.19) and HR 1.04 (95% CI 0.82 to 1.33), respectively.[47][48] Further, a recent analysis of the post-diagnostic use of oral bisphosphonates on colorectal cancer mortality revealed no benefits from bisphosphonate use (adjusted HR 1.11; 95% CI 0.80 to 1.54),[49] while a recent meta-analysis of 10 clinical studies comprising four case-control and six cohort studies showed borderline significant colorectal cancer risk reduction from bisphosphonate usage (pooled risk estimate 0.89; 95% CI 0.79 to 1.00, p=0.04).[50]
Meta-analyses of these observational studies are subject to a number of methological limitations that could compromise their findings with respect to colorectal cancer prevention:
- The number of studies was relatively small.
- Colorectal cancer was a secondary end point in studies on osteoporosis prevention.
- Men were underrepresented in study samples.
- A range of different doses and dose durations were used, making any recommendation difficult.
Bisphosphonates are associated with rare but serious adverse events. Evidence from appropriately designed RCTs, including evidence for treatment-related adverse events, is needed before guidance can be given on their use in the prevention of colorectal cancer. Currently there are no clinical trials in the US clinical trials registry investigating bisphosphonates and their impact on colorectal cancer.
More data from randomised control trials with colorectal cancer as a primary end point are required before any clear recommendations for the use of bisphosphonates for colorectal cancer prevention can be made.
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Bisphosphonates cannot be recommended for chemoprevention. |
References[edit source]
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 Burn J, Bishop DT, Mecklin JP, Macrae F, Möslein G, Olschwang S, et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med 2008 Dec 11;359(24):2567-78 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19073976.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011 Dec 17;378(9809):2081-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22036019.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al. Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005 Jul 6;294(1):47-55 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15998890.
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 van Kruijsdijk RC, Visseren FL, Ridker PM, Dorresteijn JA, Buring JE, van der Graaf Y, et al. Individualised prediction of alternate-day aspirin treatment effects on the combined risk of cancer, cardiovascular disease and gastrointestinal bleeding in healthy women. Heart 2015 Mar;101(5):369-76 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25475110.
- ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 Cook NR, Lee IM, Zhang SM, Moorthy MV, Buring JE. Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 2013 Jul 16;159(2):77-85 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23856681.
- ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 Peto R, Gray R, Collins R, Wheatley K, Hennekens C, Jamrozik K, et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res Ed) 1988 Jan 30;296(6618):313-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/3125882.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Flossmann E, Rothwell PM, British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007 May 12;369(9573):1603-13 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17499602.
- ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 8.13 8.14 Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010 Nov 20;376(9754):1741-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20970847.
- ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Meade TW, Wilke HC, Kelleher CC, Roderick PJ, Brennan PJ, Wilson CW, et al. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework. Lancet 1998 Jan 24;351(9098):233-41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9457092.
- ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 10.14 10.15 United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results. UK-TIA Study Group. Br Med J (Clin Res Ed) 1988 Jan 30;296(6618):316-20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/2894232.
- ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 11.15 Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991 Dec;54(12):1044-54 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1783914.
- ↑ 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 12.10 12.11 12.12 Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003 Mar 6;348(10):891-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12621133.
- ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 13.9 Cole BF, Logan RF, Halabi S, Benamouzig R, Sandler RS, Grainge MJ, et al. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J Natl Cancer Inst 2009 Feb 18;101(4):256-66 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19211452.
- ↑ 14.00 14.01 14.02 14.03 14.04 14.05 14.06 14.07 14.08 14.09 14.10 14.11 Benamouzig R, Deyra J, Martin A, Girard B, Jullian E, Piednoir B, et al. Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial. Gastroenterology 2003 Aug;125(2):328-36 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12891533.
- ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 15.11 15.12 Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR, ukCAP Trial Group. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 2008 Jan;134(1):29-38 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18022173.
- ↑ 16.00 16.01 16.02 16.03 16.04 16.05 16.06 16.07 16.08 16.09 16.10 16.11 Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003 Mar 6;348(10):883-90 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12621132.
- ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 Norrving B, Elwin CE, Peterson B, Blomstrand C, Olsson JE, Nilsson B, et al. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. The SALT Collaborative Group. Lancet 1991 Nov 30;338(8779):1345-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1682734.
- ↑ 18.0 18.1 18.2 18.3 18.4 Cuzick J, Thorat MA, Bosetti C, Brown PH, Burn J, Cook NR, et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann Oncol 2015 Jan;26(1):47-57 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25096604.
- ↑ Chubak J, Kamineni A, Buist DSM, Anderson ML, Whitlock EP. 2015 Sep Available from: http://www.ncbi.nlm.nih.gov/pubmed/26491758.
- ↑ Hawk ET, Limburg PJ, Viner JL. Epidemiology and prevention of colorectal cancer. Surg Clin North Am 2002 Oct;82(5):905-41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12507200.
- ↑ Bibbins-Domingo K, U.S. Preventive Services Task Force. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2016 Apr 12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27064677.
- ↑ St John DJ, Yeomans ND, McDermott FT, De Boer WG. Adaptation of the gastric mucosa to repeated administration of aspirin in the rat. Am J Dig Dis 1973 Oct;18(10):881-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/4582544.
- ↑ Graham DY, Smith JL, Spjut HJ, Torres E. Gastric adaptation. Studies in humans during continuous aspirin administration. Gastroenterology 1988 Aug;95(2):327-33 Available from: http://www.ncbi.nlm.nih.gov/pubmed/3260568.
- ↑ Graham DY, Smith JL, Dobbs SM. Gastric adaptation occurs with aspirin administration in man. Dig Dis Sci 1983 Jan;28(1):1-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/6600426.
- ↑ 25.0 25.1 Burn J, Mathers JC, Bishop DT. Chemoprevention in Lynch syndrome. Fam Cancer 2013 Dec;12(4):707-18 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23880960.
- ↑ 26.0 26.1 26.2 26.3 van Kruijsdijk RC, Visseren FL, Ridker PM, Dorresteijn JA, Buring JE, van der Graaf Y, Cook NR.. Individualised prediction of alternate-day aspirin treatment effects on the combined risk of cancer, cardiovascular disease and gastrointestinal bleeding in healthy women. Heart 2015 Mar;101(5):369-76 Available from: http://www.ncbi.nlm.nih.gov/pubmed/?term=individualised+prediction+of+alternate-day.
- ↑ 27.0 27.1 27.2 Meade TW, Wilke HC, Kelleher CC, Roderick PJ, Brennan PJ, Wilson CW, et al. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework. Lancet 1998 Jan 24;351(9098):233-41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9457092.
- ↑ National Vascular Disease Prevention Alliance. Guidelines for the management of absolute cardiovascular disease risk.; 2012.
- ↑ ASPREE Investigator Group. Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial. Contemp Clin Trials 2013 Nov;36(2):555-64 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24113028.
- ↑ 30.0 30.1 McNeil JJ, Nelson MR, Woods RL, Lockery JE, Wolfe R, Reid CM, et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N Engl J Med 2018 Oct 18;379(16):1519-1528 Available from: https://www.ncbi.nlm.nih.gov/pubmed/30221595.
- ↑ World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, physical activity and the prevention of cancer: a global perspective. 2007 Available from: http://www.dietandcancerreport.org/.
- ↑ World Cancer Research Fund/American Institute for Cancer Research. Continuous Update Project Report: Food, Nutrition, Physical Activity, and the Prevention of Colorectal Cancer. WCRF; 2011.
- ↑ Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, et al. Statins and the risk of colorectal cancer. N Engl J Med 2005 May 26;352(21):2184-92 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15917383.
- ↑ 34.0 34.1 Emberson JR, Kearney PM, Blackwell L, Newman C, Reith C, Bhala N, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One 2012;7(1):e29849 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22276132.
- ↑ Hague A, Manning AM, Hanlon KA, Huschtscha LI, Hart D, Paraskeva C. Sodium butyrate induces apoptosis in human colonic tumour cell lines in a p53-independent pathway: implications for the possible role of dietary fibre in the prevention of large-bowel cancer. Int J Cancer 1993 Sep 30;55(3):498-505 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8397167.
- ↑ Bertagnolli MM, Hsu M, Hawk ET, Eagle CJ, Zauber AG, Adenoma Prevention with Celecoxib (APC) Study Investigators. Statin use and colorectal adenoma risk: results from the adenoma prevention with celecoxib trial. Cancer Prev Res (Phila) 2010 May;3(5):588-96 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20403998.
- ↑ Broughton T, Sington J, Beales IL. Statin use is associated with a reduced incidence of colorectal adenomatous polyps. Int J Colorectal Dis 2013 Apr;28(4):469-76 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23114474.
- ↑ Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 2005 Nov 16;97(22):1679-87 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16288121.
- ↑ Rizza RA VA. In: Waldman S, Terzic A. Pharmacology and Therapeutics: principles to practice. Amsterdam: Elsevier; 2009 Available from: P. 557-70.
- ↑ Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, et al. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care 2011 Oct;34(10):2323-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21949223.
- ↑ Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One 2012;7(3):e33411 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22448244.
- ↑ Ramjeesingh R, Orr C, Bricks CS, Hopman WM, Hammad N. A retrospective study on the role of diabetes and metformin in colorectal cancer disease survival. Curr Oncol 2016 Apr;23(2):e116-22 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27122979.
- ↑ 43.0 43.1 Clarke LC KS. In: Waldman S, Terzic A. Pharmacology and Therapeutics: principles to practice. Amsterdam: Elsevier; 2009 Available from: P. 587-610.
- ↑ 44.0 44.1 Singh H, Nugent Z, Demers A, Mahmud S, Bernstein C. Exposure to bisphosphonates and risk of colorectal cancer: a population-based nested case-control study. Cancer 2012 Mar 1;118(5):1236-43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21823104.
- ↑ 45.0 45.1 Rennert G, Pinchev M, Rennert HS, Gruber SB. Use of bisphosphonates and reduced risk of colorectal cancer. J Clin Oncol 2011 Mar 20;29(9):1146-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21321296.
- ↑ 46.0 46.1 Pazianas M, Abrahamsen B, Eiken PA, Eastell R, Russell RG. Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate--Danish National Register Based Cohort Study. Osteoporos Int 2012 Nov;23(11):2693-701 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22392160.
- ↑ Passarelli MN, Newcomb PA, LaCroix AZ, Lane DS, Ho GY, Chlebowski RT. Oral bisphosphonate use and colorectal cancer incidence in the Women's Health Initiative. J Bone Miner Res 2013 Sep;28(9):2043-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23519920.
- ↑ Khalili H, Huang ES, Ogino S, Fuchs CS, Chan AT. A prospective study of bisphosphonate use and risk of colorectal cancer. J Clin Oncol 2012 Sep 10;30(26):3229-33 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22649131.
- ↑ Hicks BM, Murray LJ, Hughes C, Cardwell CR. Post-diagnostic oral bisphosphonate use and colorectal cancer mortality: a population-based cohort study within the UK Clinical Practice Research Datalink. Br J Cancer 2015 Jun 30;113(1):123-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25989268.
- ↑ Eiken P, Vestergaard P. Oral bisphosphonates and colon cancer: an update. Ther Adv Musculoskelet Dis 2015 Aug;7(4):160-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26288666.
Appendices[edit source]
