Numerous epidemiological and preclinical studies have demonstrated the chemopreventive effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on gastrointestinal cancers, particularly colorectal cancers.
In 1988, the use of aspirin was first reported to be associated with a reduced risk of colorectal cancer. Later, researchers found that 300 mg daily was associated with a reduced risk of colorectal cancer compared to 75/150 mg daily of aspirin for long-term use.
The use of NSAIDs other than aspirin also reduced the risk of colorectal cancer, but this effect was seen after 6 months of continuous use and disappeared after 1 year of discontinuation of the drug.
Mechanisms of Gastrointestinal Tumor Risk Reduction
NSAIDs work by inhibiting the cyclooxygenase activity in enzymatic prostaglandin (PG) G/H synthesis, resulting in blocked prostaglandin synthesis. Prostaglandin G/H synthesizes two products, COX-1 and COX-2, respectively.
COX-1 is expressed in most tissues and plays an important role in platelet agglutination and protection of gastric cells.
COX-2 is thought to be an inducible enzyme that is expressed in most tissues only during inflammation, trauma and carcinogenesis and is a mediator of pain, inflammation and fever.
Conventional NSAIDs (aspirin, ibuprofen, etc.) inhibit both isozymes, while selective COX-2 inhibitors (cibotropic drugs) mainly inhibit COX-2.
Preventive effect of aspirin on colorectal cancer
Aspirin inhibits platelet COX-1 approximately 50-100 times more than monocyte COX-2. Due to the limited protein synthesis of platelets, the reversible inhibition of COX-1 by aspirin persists for the duration of platelet presence.
Maximum inhibition is seen at low doses of 75-100 mg, where aspirin inhibits more than 95% of platelet COX-1 activity after 1 hour of application, and this effect persists for up to 24 hours.
In contrast, inhibition of COX-2 by aspirin requires higher doses and shorter dosing intervals.
The two traditional NSAIDs, diclofenac/ibuprofen, have increased cardiovascular risk at high doses (1800/2400 mg) compared to ciclosporin. However, this high-dose usage is rare in most areas. Methylphenidate at high doses did not significantly increase cardiovascular risk.
Inhibition of colorectal cancer with cebuximab
Cibotropic drugs are selective COX-2 inhibitors that inhibit the development of colorectal tumors. The incidence of upper gastrointestinal complications and ulcers was significantly lower in patients on celecoxib than on non-selective COX-2 inhibitor NSAIDs.
Studies have shown that celecoxib 400 mg bid treatment for 6 months resulted in significant regression of colorectal adenomas in patients with familial adenomatous polyposis, which was not seen with 100 mg dosing. Rofecoxib also significantly reduced the risk of colorectal adenomas.
Unfortunately, despite the effectiveness of ciboside in inhibiting colorectal adenoma recurrence, the proven dose-escalating cardiovascular toxicity (e.g., death due to cardiovascular events, myocardial infarction, stroke, heart failure, etc.) has not been incorporated into gastrointestinal tumor chemoprevention.
Gastrointestinal side effects of NSAIDs and cribrials
For upper gastrointestinal side effects, cebuximab and NSAIDs were associated with increased upper gastrointestinal side effects (e.g., symptomatic gastrointestinal ulcers, ulcerative bleeding, ulcer perforation, obstruction, etc.) compared with placebo in the following order: cebuximab < diclofenac < ibuprofen < methylphenidate.
Gastrointestinal side effects were more likely to occur with rofecoxib and low-dose aspirin (average daily dosage ≤ 162.5 mg), and at ages ≥ 65 years.
How is aspirin used for colorectal cancer chemoprevention?
The U.S. Preventive Medicine efforts recommend against the approval of NSAIDs for colorectal cancer prevention in general risk populations because of cardiovascular toxicity and gastrointestinal toxicity.
However, there is an opportunity to use NSAIDs for related colon cancer prevention.
Studies have been conducted to show that cancer mortality is reduced in those who have used NSAIDs before colorectal cancer diagnosis compared to those who have not. This relationship correlates with tumor site, timing of drug use, and distal location of the lesion.
The only agent among NSAIDs with low gastrointestinal risk and no cardiovascular risk is aspirin. The protective effect of aspirin in colorectal cancer has been confirmed by a large number of epidemiological studies published to date.
Aspirin has not been recommended for primary prevention because its optimal effective dose, age of initiation of therapy, and treatment period are controversial.
Clinical trials have shown that aspirin may reduce the risk of adenoma recurrence and the risk of adenoma in patients with a history of colorectal cancer.
It is currently believed that the maximum preventive effect occurs at higher doses (more than 14 tablets per week) and that this occurs with both short-term (≤ 5 years) or long-term use. It has also been suggested that a significant risk reduction requires at least 6-10 years of use, and that the effect is no longer apparent within 4 years of discontinuation.
It has also been suggested that aspirin not only prevents colorectal cancer but also reduces cancer mortality. In terms of reducing cancer mortality, 75-100 mg daily and 300-1200 mg daily were comparable for those on the drug for less than 5 years; at 20-year follow-up, the effective tumor types were mainly esophageal, colorectal, and lung cancers, with histology limited to adenocarcinoma.
Three major unanswered questions
A 2012 study also found that aspirin application was also associated with a 30%-40% reduction in the risk of distant metastases from cancer, and that ASA-controlled agents that selectively inhibited platelet COX-1 had a chemopreventive effect at long-term follow-up, suggesting that the effect of aspirin on metastases may be platelet-mediated.
The topic of aspirin for the prevention and treatment of colorectal cancer has received much attention, yet 3 questions remain to be addressed: What is the optimal dose and timing of dosing? Who are the beneficiary groups? How effective is aspirin in combination with other chemotherapeutic agents and currently used screening methods (e.g., colonoscopy)?
In this regard, studies have evaluated the efficacy of aspirin in combination with colonoscopy, depending on the magnitude of the reduction in risk of colorectal cancer with aspirin and the population’s compliance with screening. On the other hand, the simultaneous application of calcium with aspirin may reduce the risk of progressive colorectal neoplastic polyps.
The search for biomarkers to help identify and screen populations that may have aspirin prophylaxis benefit is also on the agenda.
The use of conventional NSAIDs and cibotropic agents is associated with a reduced risk of colorectal cancer and colonic adenoma, but the associated increase in cardiovascular events and gastrointestinal toxicity offset their benefit, and the net benefit/risk balance prevents their use in the general population. The current promising agent for chemoprevention is low-dose aspirin.