Role of NSAIDs in the Adjuvant Therapy of Colon Cancer
Charles S. Fuchs, MD, MPH
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Experimental, epidemiologic, and clinical data provide rectal cancer, regular aspirin or selective COX-2 inhibitor strong evidence for a causative link between chronic use conferred a signifıcant improvement in survival, and this inflammation and colorectal cancer (CRC) risk, including benefıt was greatest in patients whose tumors overexpressed the well-described association between inflammatory bowel COX-2. In the fırst study, we prospectively assessed aspirin disease and colonic dysplasia. Inflammation predisposes to use in 1,279 men and women diagnosed with stage I, II, or III cancer through enhanced cellular proliferation and mu- colorectal cancer, with a median follow-up of 11.8 years.6 tagenesis, inability to adapt to oxidative stresses, promotion Compared with nonusers, participants who regularly used of angiogenesis, inhibition of apoptosis, and secretion of aspirin after the diagnosis of colorectal cancer experienced a mediators that may promote tumorigenesis.1 One specifıc multivariate HR for colorectal cancer–specifıc mortality of mechanism through which inflammation leads to both 0.71 (95% CI, 0.53-0.95) and for overall mortality of 0.79 colitis-associated and sporadic carcinogenesis is the pro- (95% CI, 0.65-0.97). Of note, the effect of aspirin differed inflammatory cyclooxygenase (COX) pathway.
signifıcantly according to COX-2 expression (p value for in- Observational studies and randomized clinical trials teraction ϭ 0.04). Regular aspirin use after diagnosis was as- (RCTs) fınd that aspirin, nonsteroidal anti-inflammatory sociated with a lower risk of colorectal cancer–specifıc drugs, and selective COX-2 inhibitors reduce CRC and ad- mortality among participants in whom primary tumors enoma risk. In four randomized, placebo-controlled trials of overexpressed COX-2 (multivariate HR, 0.39; 95% CI, 0.20- patients who had undergone a colonoscopic resection of an 0.76), whereas aspirin use was not associated with lower risk adenomatous polyp, daily aspirin conferred a signifıcant re- among those with primary tumors with weak or absent ex- duction in the risk of recurrent adenomas at 3 years (relative pression (multivariate HR, 1.22; 95% CI, 0.36-4.18).
risks [RRs] 0.61-0.83).2 In the British Doctors Aspirin Trial In an independent study of patients with stage III colon (7,588 participants followed for more than 20 years), sub- cancer enrolled in a National Cancer Institute (NCI)- jects randomly assigned to aspirin experienced a 26% reduc- sponsored cooperative trial of adjuvant chemotherapy tion in the risk of developing colorectal cancer compared (CALGB 89803), we prospectively assessed the influence of with those receiving placebo (hazard ratio [HR] ϭ 0.74; 95% aspirin and selective COX-2 inhibitor use on patient out- come.7 Patients with stage III colorectal cancer reporting To defıne potential mechanisms by which aspirin affects consistent aspirin use experienced an adjusted HR of 0.46 colon carcinogenesis, we estimated COX-2 expression by (95% CI, 0.23-0.95) for disease-free survival (DFS) and 0.49 immunohistochemistry in CRC specimens from two large (95% CI, 0.19-1.30) for overall survival. Moreover, users of prospective cohorts of healthy participants who provided either celecoxib or rofecoxib (5% of the cohort) experienced data on aspirin use from a questionnaire every 2 years.4 Of an HR for DFS of 0.47 (95% CI, 0.17-1.28) when compared the 636 incident colorectal cancers, 423 (67%) had COX-2 to nonusers. These observational studies suggest that, overexpression. The effect of aspirin use differed signifı- among patients with stage I to III colorectal cancer, regular cantly in relation to COX-2 expression (p value for hetero- aspirin or selective COX-2 inhibitor use may substantially geneity ϭ 0.02). Regular aspirin use conferred a signifıcant improve both cancer-specifıc and overall survival.
reduction in the risk of colorectal cancers that overexpressed Based on results from those studies, NCI-sponsored coop- COX-2 (multivariate relative risk, 0.64; 95% CI, 0.52-0.78), erative group investigators initiated a placebo-controlled whereas regular aspirin use had no influence on tumors with RCT assessing the influence of celecoxib on survival in 2,500 weak or absent expression of COX-2 (multivariate relative patients with stage III colon cancer concurrently receiving risk, 0.96; 95% CI, 0.73-1.26). These fındings strongly sup- standard adjuvant therapy (CALGB/SWOG 80702; Fig. 1).
port the primacy of inhibition of COX-2–mediated synthe- Four to eight weeks following a curative surgical resection of sis of prostaglandins in the prevention of colon cancer.5 stage III colon cancer, patients are being randomized in a 2 x Consistent with the apparent role of COX-2 in colorectal 2 design to (a) 5-fluorouracil, leucovorin, and oxaliplatin carcinogenesis, three placebo-controlled RCTs demon- (FOLFOX) for 3 months versus FOLFOX for 6 months and strated that celecoxib or rofecoxib signifıcantly reduced ad- (b) celecoxib (400 mg per day for 3 years) versus placebo enoma risk in patients with prior polyps (RRs 0.55-0.76; all once per day for 3 years. Celecoxib or placebo is initiated on the fırst day of chemotherapy. The primary objective of the Beyond cancer prevention, animal models of established trial is to compare DFS for celecoxib versus placebo, and colorectal cancers demonstrate that COX-2 inhibitors can with 2,500 subjects enrolled and 775 events expected at anal- reverse tumor growth. In two studies of patients with colo- ysis, there is 91% power (two-sided ␣ ϭ 0.05) to detect an Fig. 1. CALGB 80702 trial design.
HR of 0.79 in favor of celecoxib. A secondary endpoint is to (3) categorizing tumors based on molecular subtypes (e.g., compare DFS for 3 months versus 6 months of chemother- COX-2, NF-␬␤, ␤-catenin expression) and examining cele- apy. Overall survival and treatment-related toxicity are also coxib in relation to these phenotypes, based on hypothesized relations. Such analyses provide further evidence for causal- CALGB/SWOG 80702 will provide invaluable insight into ity, offer critical mechanistic insight, and, most importantly, the influence of inflammation and interventions that target defıne populations most likely to benefıt from interventions inflammation on patient outcome in stage III colon cancer, targeting these pathways. Thus, the results of this trial may including the following: (1) utilizing the largest RCT, where improve our understanding of CRC biology, identify new patient, disease, and treatment characteristics are well con- means to improve patient survival, and, with the extensive trolled and disease follow-up is uniformly conducted, to clinical, pathologic, genomic, and biomarker data available evaluate the effect of COX-2 inhibition and inflammation on for analysis, inform clinicians how to maximally utilize patient survival; (2) leveraging the resources of this RCT and inflammatory-targeted interventions to improve clinical incorporating prospective collection of lifestyle habits, base- line germ-line DNA, plasma, and tumor specimens; and DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediatefamily member; those marked “B” are held by the author and an immediate family member. Relationships marked “U” are uncompensated.
Employment or Leadership Position: None. Consultant or Advisory Role: Charles S. Fuchs, Amgen; AstraZeneca; Genentech; Genomic Health; ImClone
Systems; Merck; Metamark Genetics; Pfizer; Roche; Sanofi. Stock Ownership: None. Honoraria: None. Research Funding: None. Expert Testimony: None.
Other Remuneration: None.
1. Schottenfeld D, Beebe-Dimmer J. Chronic inflammation: a common and im- 5. Markowitz SD. Aspirin and colon cancer—targeting prevention? N Engl J Med.
portant factor in the pathogenesis of neoplasia. CA Cancer J Clin. 2006;56: 6. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of 2. Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroen- colorectal cancer. JAMA. 2009;302:649-658.
7. Fuchs C, Meyerhardt JA, Heseltine DL, et al. Influence of regular aspirin use 3. Flossmann E, Rothwell PM. Effect of aspirin on long-term risk of colorectal on survival for patients with stage III colon cancer: Findings from intergroup cancer: consistent evidence from randomised and observational studies.
trial CALGB 89803. J Clin Oncol. 2005;23 (suppl; abstract 3530).
4. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007;356:2131-2142.


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