Colorectal cancer is cancer of the colon and rectum, sometimes collectively referred to as colorectal cancer. It is the third most common cancer in the United States in terms of incidence and mortality. In China, it is estimated that the incidence rate of colorectal cancer in 2012 was 16.9/100,000 for men and 11.6/100,000 for women, and the mortality rate was 9.0/100,000 and 6.1/100,000, respectively; and the incidence and mortality rate will continue to increase.
Colorectal cancer occurs in men over 50 years of age, and family history, smoking, obesity, alcohol consumption, and lack of exercise are all risk factors for colorectal cancer. Not long ago, the World Health Organization declared processed meat (meat that has been salted, cured, fermented, smoked, etc.) to be carcinogenic precisely because there is ample evidence that it can cause colorectal cancer.
In order to reduce the risk of colorectal cancer, firstly, some of the risk factors can be removed through lifestyle changes, secondly, screening tests such as fecal occult blood and colonoscopy can be enhanced for early detection of the disease, and the use of drugs to prevent colorectal cancer is also of great concern.
In addition, the use of drugs to prevent colorectal cancer has also received attention. The most popular drug for colorectal cancer prevention is the role of aspirin. The molecular mechanism by which aspirin prevents colorectal cancer is not clear, but the prevailing view is that it is related to reducing the production of prostaglandin-like pro-inflammatory substances by inhibiting cyclooxygenase. Some studies suggest that aspirin may reduce the incidence of colorectal cancer, but aspirin application may also increase the risk of bleeding disorders. In order to illustrate the role and risk of aspirin in the prevention of colorectal cancer, we would like to share a few papers with you here.
I. General population
The role of aspirin in the general population without a history of colorectal cancer, familial adenomatous polyposis, or Lynch syndrome is to share the latest systematic review report (PMID: 26491758) provided by Kaiser Permanente for the United States Preventive Services Task Force (USPSTF) in September 2015. The report included a total of 14 randomized controlled studies and 7 cohort studies. The results of these studies answered the following questions.
1. whether regular aspirin use in the general population reduces colorectal cancer mortality or overall mortality.
Eleven randomized controlled studies on the prevention of coronary heart disease were used to evaluate the effect of aspirin on overall mortality. In these studies, the median observation time was 4.2 to 8.2 years, the applicable dose of aspirin was 75 mg/day to 1200 mg/day, and the duration of use was 1 to 10.5 years. A pooling of these studies showed a 6% reduction in the overall risk of death during the first 10 years of aspirin use.
Four randomized controlled studies on coronary heart disease prevention were used to evaluate the effect of aspirin on colorectal cancer mortality. A total of 14,033 patients were included in these studies, and their results showed that long-term aspirin use (0 to more than 20 years) reduced deaths due to colorectal cancer by approximately 33%. The limited data suggest that it is primarily the duration of dosing rather than the dose of dosing that affects this effect of aspirin.
The effect of aspirin on total mortality and colorectal cancer mortality in patients who have had colonic adenomas cannot be determined because of the small number or lack of studies that could be included.
2. Whether regular aspirin use in the general population reduces colorectal cancer.
Six randomized controlled studies were used to evaluate the effect of aspirin on the incidence of invasive colorectal cancer in the general population, and a total of 75,980 patients were included in these studies. The indicated doses of aspirin in these studies ranged from 75 mg/day to 1200 mg/day, with a median observation period of 6 years.
Four studies showed no change in the incidence of colorectal cancer during the first 10 years of aspirin use. three studies showed that the use of 100 mg to 1200 mg aspirin daily or every other day reduced the incidence of colorectal cancer by approximately 40% after 10 years. Overall, long-term aspirin use (0 to more than 20 years) reduced colorectal cancer by about 20% to 24%.
In addition, aspirin primarily reduces the risk of proximal colon cancer rather than distal colon cancer. In terms of aspirin dose, there is no significant difference in effectiveness as long as the dose is greater than 75 mg daily or every other day; therefore, a low dose of aspirin (less than 325 mg) is sufficient, and increasing the dose may not be necessary.
For patients who have had colonic adenomas, the effect of aspirin on the incidence of colorectal cancer cannot be determined because of the small number of studies that could be included and the inconsistent results.
3. Whether regular aspirin use in the general population reduces the incidence of colorectal adenomas.
Only 1 cohort study was included for the general population, and only 3 randomized controlled studies were included for patients with previous adenomas. Due to the small number of included studies, the report is inconclusive in this regard.
4. What are the risks of regular aspirin use in the general population.
Gastrointestinal bleeding is one of the risks of long-term aspirin use. 11 relevant studies were included in this report, most of which showed an increased risk of GI bleeding with aspirin. Due to the different definitions of bleeding and inclusion criteria across studies, it was not possible to synthesize these results.
Severe GI bleeding was defined as those bleeds that required blood transfusion, hospitalization, and resulted in death or surgical procedures. Combining the eight studies included in this report (37,451 cases in total) showed that the risk of severe GI bleeding was 94% higher in the aspirin group than in the control group. In contrast, for the risk of fatal gastrointestinal bleeding, aspirin did not appear to have a significant effect on it.
Intracranial hemorrhage and hemorrhagic stroke are another risk of taking aspirin. The report included 11 of the 12 RCT studies (84,681 total cases) that showed a higher or equal risk of intracranial hemorrhage in the aspirin group than in the control group. The combined evaluation resulted in a 53% higher risk of intracranial hemorrhage in the aspirin group compared with the control group.
Eleven RCTs reported on the risk of hemorrhagic stroke, and almost all of these studies showed a higher risk of hemorrhagic stroke in the aspirin group than in the control group. Combined, the included studies found that aspirin increased the risk of hemorrhagic stroke by approximately 47%.
II. Patients with a diagnosis of colorectal cancer
There are four recent papers to share with you on whether patients with a diagnosis of colorectal cancer can benefit from the use of aspirin.
1. Aspirin and recurrence of colorectal cancer
A multicenter randomized double-blind controlled study reported by Ishikawa H et al (Gut. 2014 Nov;63(11):1755-9) examined the effect of aspirin on recurrence rates after transendoscopic resection of colorectal adenomas and adenocarcinomas. The study included 311 patients, and the aspirin group was given 100 mg/day of aspirin for 2 consecutive years. The study found that aspirin use reduced the risk of recurrence of colorectal tumors (adenomas and carcinomas) by approximately 40%. Interestingly, further analysis found that aspirin use by nonsmokers reduced the risk of tumor recurrence by 63%, but aspirin use by smokers increased the risk of tumor recurrence by more than twofold. It is particularly noteworthy that the population of the study was Asian (Japanese).
2. Aspirin and colorectal cancer metastasis
Rothwell PM et al. (Lancet. 2012 Apr 28;379(9826):1591-601.) analyzed data from five UK studies on aspirin. The analysis of 775 of these tumor patients found 41% fewer tumor metastases in the aspirin group than in the control group, including 64% fewer tumor metastases in the aspirin group of patients with colorectal cancer than in the control group. For patients with tumors that had not metastasized distantly at the time of first tumor diagnosis, patients in the aspirin group had a 55% reduced risk of subsequent tumor metastasis compared to controls, including a 74% reduced risk of subsequent metastasis in colorectal cancer patients in the aspirin group. The effects of slow-release low-dose aspirin and high-dose aspirin were comparable in reducing tumor metastasis.
3. aspirin and risk of death in colorectal cancer patients
Li P et al. (Gut. 2015 Sep;64(9):1419-25.) compared the effect of aspirin use before and after diagnosis of colorectal cancer on patient survival in their meta-analysis. A pooling of the 11 studies they included found that patients with colorectal cancer who used aspirin after diagnosis had a 16% lower overall risk of death; however, there was no significant effect on the risk of disease-specific death from colorectal cancer. In contrast, pre-diagnostic aspirin use did not appear to alter the overall risk of death and the disease-specific risk of death from colorectal cancer after the onset of colorectal cancer.
Ye XF et al (Br J Cancer. 2014 Nov 25;111(11):2172-9) in their meta-analysis, on the other hand, found that aspirin use after colorectal cancer diagnosis reduced the overall risk of death by 26%. This analysis also found that the use of aspirin after diagnosis reduced the overall risk of death, regardless of whether aspirin had been used before diagnosis. However, there was no reduction in the risk of disease-specific death from colorectal cancer with aspirin.
III. Patients with hereditary colorectal cancer
The most common hereditary colorectal cancers are familial adenomatous polyposis (FAP) and Lynch syndrome. Familial adenomatous polyposis (FAP) is an inherited disease caused by mutations in the APC gene on chromosome 5, which manifests as multiple adenomatous polyps in the colorectum, and without intervention almost all patients will eventually develop polyp malignancy and become colorectal cancer. Lynch syndrome is an inherited non-polyposis colorectal cancer with a mismatch repair protein gene mutation, manifesting as a family aggregation of colorectal cancer and other related tumors.
1. Aspirin and polyps in FAP
Malignant transformation of colorectal adenomas occurs in almost 100% of FAP patients without intervention, and FAP patients account for about 1% of colorectal cancer patients. Because of the small number of patients with FAP, very little is known about the efficacy of aspirin in FAP.
In Burn J et al (Cancer Prev Res (Phila). 2011 May;4(5):655-65.) in an international multicenter randomized double-blind controlled study (CAPP1), the investigators evaluated the role of aspirin, as well as resistant starch, an indigestible carbohydrate that acts as a fermentation substrate for probiotics in the intestine, in alleviating intestinal polyps in FAP. A total of 133 patients aged 10 to 21 years without previous colorectal surgery completed the study, in which patients in the aspirin group were treated with aspirin at a dose of 600 mg/day for 1 to 12 years, and the results did not reveal a clear effect of aspirin in reducing the number and size of polyps in FAP patients. The results of the subgroup analysis only showed a significant reduction (p=0.02) in the mean maximum adenoma diameter in the aspirin group (3 mm) compared to the control group (6 mm) for those patients who were on the drug for >1 year. In contrast, no effect of resistant starch was found on adenomas in FAP patients.
In another randomized controlled study including 34 patients with FAP published by Ishikawa H et al (Cancer Med. 2013 Feb;2(1):50-6), patients in the aspirin group were given 100 mg/day of aspirin for 6 to 10 months. Their results suggest that aspirin may help slow the growth and development of colorectal adenomas in FAP patients, but ulcerative and bleeding-type side effects require increased attention.
2. Aspirin and colorectal cancer in Lynch syndrome
In another international multicenter randomized double-blind controlled study (CAPP2) by Burn J et al (Fam Cancer. 2013 Dec;12(4):707-18.), investigators evaluated the role of aspirin as well as resistant starch in preventing cancer in patients with Lynch syndrome. A total of 746 patients carrying the causative gene for Lynch syndrome completed the study, with a mean observation time of 55.7 months, with patients in the aspirin group using a 600 mg/day dose of aspirin. The results showed that aspirin did not significantly reduce colorectal cancer during a mean treatment period of 29 months; however, when the observation follow-up was extended to 4 years, aspirin reduced colorectal cancer by 63%. The effect of resistant starch on cancer in patients with Lynch syndrome was not found.
In another retrospective study that included 1858 patients (J Natl Cancer Inst. 2015 Jun 24;107(9). pii: djv170.), the investigators found that the use of aspirin or ibuprofen for 1 month to 5 years reduced the risk of colorectal cancer by 51% and 62%, respectively, and the risk of colorectal cancer was reduced by about 75% when the duration of drug use was greater than 5 years, by reviewing the tumor history and medication history of those included.
In summary: 1. For the general population, aspirin may need to be used for more than 10 years to reduce the risk of colorectal cancer incidence and death, and the use of aspirin is accompanied by an increased risk of gastrointestinal and intracranial bleeding. Therefore, it is best for clinicians to decide whether to use aspirin for colorectal cancer prevention on a patient-by-patient basis, weighing the pros and cons.2. For patients with a diagnosis of colorectal cancer, aspirin may help reduce recurrence and metastasis, and lower the overall risk of death. Therefore, long-term use of aspirin may be considered unless there is a clear contraindication to its use.3. The effects of aspirin in patients with both FAP and Lynch syndrome have been less well studied, but given the potential benefits of aspirin even in the general population and the high risk of colorectal cancer in these two groups of patients, long-term use may also be considered. The risk of complications such as gastrointestinal bleeding and intracranial hemorrhage should be guarded against during all use of aspirin.