Colorectal Cancer _ ___________________________________________________________________________
Chemoprevention Chemopreventive agents are often prescribed to healthy subjects at risk for colorectal cancer, who will take the agent for the rest of their lives to prevent a potential cancer. In addition to the preventive benefit, this raises the bar very high when defining acceptable safety and toxicity [46]. Practice guidelines and expert opinion have been hesitant to recommend chemoprevention of colorectal cancer. One reason is that very promising earlier findings have often washed out under rigorous evaluation. Epidemiologic and large cohort studies have found a number of agents with significant association to reduced colorectal cancer risk. Not infrequently, these findings were verified by other observational studies, followed by identification in pre-clinical research of plausible mechanisms for a cause-effect relationship. However, results from rigorous investigation using well-designed randomized controlled trials reveal new safety concerns or fail to confirm the significant relationships suggested by data from uncontrolled trials. Thus, guideline authors and experts are reluctant to suggest chemoprevention in the absence of large- scale, long-term, randomized controlled trials [47]. Use of surrogate endpoint markers in many chemoprevention trials may also dissuade recommendation. As the precursor of most colorectal cancers, adenomas have often been used as surrogate endpoints in efficacy evaluation of agents for prevention. Their use as surrogate markers of colorectal cancer in chemoprevention randomized controlled trials permits the reduction of the study observation period from roughly 10 years required for assessing colorectal cancer development to around 2 years. Despite the theoretical and pragmatic basis, preventive efficacy based on this surrogate endpoint may contribute to reluctance in recommending colorectal cancer chemoprevention [46]. The true benefit of chemoprevention is reliant on lifetime colorectal cancer risk in the patient population. Greatest potential benefit may come from use in patients diagnosed by colonoscopy with pre-malignant lesions, with family history of colorectal cancer, or genetically diagnosed and surgically resected for colorectal tumors. Chemoprevention will probably show modest benefit at best when used as prevention in
taking aspirin (vs. no aspirin), recurrence-free survival (i.e., time period until tumor recurrence, death with recurrence, or development of a new invasive colon cancer) was increased by 49%, disease-free survival (i.e., time period until tumor recurrence, occurrence of a new colon cancer, or death from any cause) was increased by 32%, and overall survival (i.e., time period until death from any cause) was increased by 37%. Adjusted hazard ratios were censored at five years to minimize misclassification from non-cancer death and showed increases in disease-free survival by 39% and overall survival by 52% (vs. no aspirin). Patients taking a COX-2 inhibitor (vs. no COX-2 inhibitor) found increases in recurrence-free survival by 47%, disease-free survival by 40%, and overall survival by 50%. Censor of survival data at five years found disease-free survival increased by 53% and overall survival by 74% [50]. Although this study was not designed to identify the optimal dose and duration of aspirin or COX-2 inhibitors for protection against colorectal cancer, the data suggest a dose- response relationship in aspirin with increased frequency, while any dose of COX-2 inhibitors was associated with benefit. The statistically significant associations between aspirin and COX-2 inhibitor use and reduced colon cancer recurrence and mortality found in this study will continue to be evaluated [50]. Celecoxib, rofecoxib, and aspirin share a similar mechanism of action in colon (and presumably rectal) cancer involving COX-2 inhibition. COX synthesizes the conversion of arachidonic acid to prostaglandins. Prostaglandins mediate tumor growth by altering stem cell gene expression, hypermethylating genes involved in proliferation and differentiation, promoting angiogenesis and Wnt/CTNNB1 signaling, and inhibiting apoptosis. Thus, suppression of prostaglandin synthesis through COX inhibition interferes with the processes involved in tumor promotion and growth [50; 51]. Long-term follow-up data from two large studies initiated in the 1980s found that ≥300 mg aspirin daily taken for five or more years was associated with a 37% overall reduction in colorectal cancer risk. In subjects who remained adherent to the protocol for 5 or more years, those randomized to aspirin were found to have a 40% risk reduction in colorectal cancer mortality after 20 years and absolute risk reduction from 3.1% to 1.9% relative to those receiving placebo. Mortality reduction was primarily from the effect of aspirin on proximal colon cancer. These findings were serendipitous, because the research was designed to examine the protective effects of aspirin against cardiovascular events [52; 53]. Prospective studies have demonstrated significant reduction in colorectal cancer among regular aspirin users [54]. In a randomized controlled trial of 861 persons with Lynch syndrome, primary colorectal cancer developed in 4.2% of patients taking daily aspirin 600 mg, compared with 6.9% in those receiving daily placebo (mean follow-up: 55.7 months). Time to first colorectal cancer was increased 37% with aspirin versus placebo; with regression analysis incorporating multiple primary events, aspirin led to a 44% reduction in colorectal
average-risk patients [48; 49]. Cyclooxygenase Inhibitors
A 2015 prospective observational study published the first- ever results of cyclooxygenase-2 (COX-2) inhibitor and aspirin use as adjuvant therapy following resection in patients with stage III colon cancer. All patients received standard adjuvant chemotherapy with fluorouracil (5-FU) plus leucovorin with or without irinotecan. In the aspirin arm of 799 patients, 75 (9.4%) used aspirin during and after chemotherapy. In the COX-2 inhibitor arm of 843 patients, 59 (7.5%) used celecoxib or rofecoxib after completing chemotherapy. Both groups had a median follow-up of 6.5 years [50]. Among patients
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