Aspirin Use and Survival After Diagnosis of Colorectal Cancer

Andrew T. Chan, MD, MPH Shuji Ogino, MD, PhD Charles S. Fuchs, MD, MPH

JAMA, August 12, 2009 Vol 302, No. 6 Angela Jung, MD

Background
Derivatives of salicylic acid have been used for medicinal purposes since ancient times. Willow-bark extract became recognized for its specific antipyretic, analgesic and antiinflammatory effects in the mid-18th century. Acetylsalicylic acid (ASA) was isolated mid-19th century and aspirin was patented in 1899.

Background

Aspirin a chemopreventive agent?

irreversibly inhibits Cyclooxygenase (COX)-1 and modifies enzymatic activity of COX-2 thought to at least in part prevent colorectal neoplasia through COX-2 inhibition
promotes inflammation and cell proliferation overexpressed in 80-85% of colorectal cancers

COX-2

Eberhart CE, Coffey RJ, Rhadhika A, Giardiello FM, Ferrenbach S, Dubois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107(4):1183-1188.

Background

A systematic review prepared for the U.S. Preventive Services Task Force showed:
Fair to good evidence - ASA in higher doses and longer periods reduces risk of developing adenomatous polyps. Fair evidence - ASA in doses higher than recommended for cardiovascular prevention and longer periods may be associated with reduced incidence of colorectal cancer. Poor evidence ASA use leads to a reduction in colorectal cancerassociated mortality.

ASA was NOT recommended for primary prevention of colorectal cancer.

Potential side effects (esp. GI bleeding)

Dube C, Rostrom A, Lewin G, et al; US Preventive Services Task Force. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the US Preventive Services Task Force. Ann Intern Med. 2007;146(5):365-375.

Background

Two randomized controlled trials:

ASA reduces the risk of recurrent adenomas in those with a history of colorectal cancer or adenomas. Numbers needed to treat to prevent adenomas suggest moderate benefit BUT: risks > benefits most adenomas do not progress to cancer endoscopic surveillance for recurrent neoplasia would result in detection/removal anyway

Imperiale, TF. Aspirin and the Prevention of Colorectal Cancer. N Engl J Med. 2003;348(10):879-880.

Background

Animal models have shown anti-COX-2 activity can inhibit colorectal tumor growth and metastases as well as prolong survival.
Yao M, Zhou W, Sangha S, et al. Effects of nonselective cyclooxygenase inhibition with low-dose ibuprofen on tumor growth, angiogenesis, metastasis, and survival in a mouse model of colorectal cancer. Clin Cancer Res. 2005;11(4):1618-1628. Yao M, Lam EC, Kelly CR, Zhou W, Wolfe MM. Cyclooxygenase-2 selective inhibition with NS-298 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer. Br J Cancer. 2004;90(3):712-719.

Patients with stage III colon cancer in an adjuvant chemotherapy trial had lower risk of disease recurrence and death with ASA.

ASA use only assessed after initial diagnosis

Fuchs C, Meyerhardt JA, Heseltine DL, et al. Influence of regular aspirin use on survival for patients with stage III colon cancer: finders from intergroup trial CALGB 89803 [abstract]. J Clin Oncology. 2005;23(suppl 16):3530.

Objective
Examine association between ASA use pre and post-diagnosis and colorectal cancer-specific and overall survival Hypothesis: ASA use after diagnosis is associated with lower risk of colorectal cancerrelated deaths among patients with nonmetastatic colon cancer. Examine effect of ASA according to levels of tumoral expression of COX-2

Methods

2 prospective cohort studies

Nurses Health Study (NHS), established 1976

121,706 US women aged 30-55 years Registered nurses

Health Professionals Follow-up Study (HPFS) established 1986

51,529 US men aged 40-75 years Dentists, optometrists, osteopathic physicians, podiatrists, pharmacists, veterinarians

Methods

Biennial questionnaire: new diagnosis, ASA use, physical activity, BMI

NHS -1980 baseline questionnaire

Regularly use ASA most weeks? # of pills/week? (325mg, 81mg included in 1992) # of years of use? 1993: supplementary questionnaire on chemotherapy if diagnosed

HPFS -1986 baseline questionnaire

Regularly use ASA 2+ times/week? 1992: # of pills/week?

In total: 1279 participants: 840 women, 439 men

Diagnosed through 2002 Had ASA data pre- and post-diagnosis Excluded: Stage IV, prior cancer diagnosis

Methods

Validation questionnaire: reasons for ASA use

Review of hospital records and pathology reports: disease staging

NHS - 1990: 182/840 women Headache, arthritis, other musculoskeletal pain, combo, cardiovascular disease (CVD) prevention, other HPFS - 1993: 186/429 men CVD, CVD prevention, headache, musculoskeletal pain

Tissue specimens of recurrent cancers were not obtained.

Methods

Immunostaining: COX-2 expression

NHS 2001: 207/840 women HPFS 1997: 252/429 men

Methods

Report of adverse affects

GI bleed requiring hospitalization or transfusion NHS 2004 No ASA: 0.77/1000 person yrs 2-5 pills/wk: 1.07 6-14 pills/wk: 1.40 14+ pills/wk: 1.57 HPFS 2006 No ASA: 0.92/1000 person yrs 0.5-1.5 pills/wk: 1.02 2-5 pills/wk: 1.65 6+ pills/wk: 1.84

Deaths

National Death Index, next of kin, cause Mortality follow up 98% complete Included those after completion of baseline questionnaire and before June 2008

Results
ASA use pre and post-diagnosis

183, 14% No ASA pre, No ASA post 194, 15% 536, 42% ASA pre, ASA post ASA pre, no ASA post

366, 29%

no ASA pre, ASA post

Total participants: 1279 222 deaths due to colorectal cancer, 480 total deaths Median follow up time from diagnosis: 11.8yrs

Results
ASA use after dx Participants Total deaths Colorectalcancer specific deaths 81 (15%) 141 (19%) 5 year survival 10 year survival

Used regularly Not used

549 730

193 (35%) 287 (39%)

88% 83%

74% 69%

Regular use of ASA post-diagnosis:

Significant reduction in risk of colorectal cancer-specific mortality (log rank P=0.2), and overall mortality (log rank P=0.3) Regular ASA use after diagnosis compared to nonusers: HR = 0.71 (CI = 0.53-0.95) for colorectal cancer-specific mortality and HR = 0.79 (CI = 0.65-0.97) for overall mortality

Results

Therefore, regular ASA use post-diagnosis had a 29% lower cancer-specific mortality and a 21% lower overall mortality than nonusers. In contrast, ASA use prior to diagnosis was not associated with colorectal-cancer specific mortality or overall mortality

Colorectal cancer-specific mortality

HR = 1.05 (CI = 0.80-1.37)

HR = 0.93 (CI = 0.77-1.11)

Overall mortality

Results

Of those that used ASA post-diagnosis, only those who did NOT use ASA pre-diagnosis showed significant reduction in colorectal cancer-specific mortality and overall mortality

Results

The benefit of ASA use post-diagnosis was also confined to those with COX-2 positive tumors

Results

The association between post-diagnosis ASA use and survival was modestly dose-responsive.

0.5-5 tabs/wk HR=0.57 (CI 0.18-0.99) 6+ tabs/wk HR=0.49 (CI 0.18-1.35)

No significant differences in influence of ASA defined by sex, age, cancer stage, site of primary tumor, year or diagnosis or BMI.

Limited statistical power, but association of postdiagnosis ASA use and mortality did not appear to be changed after accounting for chemotherapy.

Discussion
This suggests tumors initiated in ASA environments may be less susceptible to any potential effect of ASA on tumor progression Previous studies showed regular ASA use was associated with reduction in risk of developing a primary COX-2 positive tumor (but not COX-2 negative tumors)

Suggests ASA works by inhibiting COX-2 or its downstream effectors

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(21):2131-2142. Markowitz SD. Aspirin and colon cancer-targeting prevention? N Engl J Med. 2007;356(21):2195-2855.

Study Strengths
Prospective data collection Data on ASA use was gathered before and after diagnosis Participants were health professionals higher accuracy of self-reported ASA use Fairly large population with cohorts

Study Weaknesses
Observational vs. controlled trial Cohorts were comprised of health-professionals only ASA use was self-selected

Findings could be related to the reason the participants were on ASA

No information on cancer recurrences Limited data on chemotherapy COX-2 immunostaining was not done on all participants

Clinical Implications
Regular ASA use after colorectal-cancer diagnosis may influence colorectal cancer-specific and overall mortality in patients with tumors with overexpression of COX-2. ASA may have the potential as a useful adjuvant therapy for colorectal cancer. COX-2 immunostaining may be used to tailor ASA therapy among patients with new diagnoses Further studies needed placebo controlled trials, ASA in setting of metastatic disease An ongoing randomized trial sponsored by the National Cancer Center of Singapore will potentially confirm these findings.

Neugut, AI. Aspirin as Adjuvant Therapy for Colorectal Cancer: A Promising New Twist for an Old Drug. JAMA 2009; 302(6):688-689.

Thank you