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Aspirin Use and Survival AfterDiagnosis of Colorectal Cancer

Andrew T. Chan, MD, MPH

Shuji Ogino, MD, PhDCharles S. Fuchs, MD, MPH

JAMA, August 12, 2009 Vol 302, No. 6

Angela Jung, MD


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Background

Derivatives of salicylic acid have been used formedicinal purposes since ancient times.

Willow-bark extract became recognized for itsspecific antipyretic, analgesic and anti-inflammatory effects in the mid-18th century.

Acetylsalicylic acid (ASA) was isolated mid-19thcentury and aspirin was patented in 1899.


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Background

Aspirin a chemopreventive agent? irreversibly inhibits Cyclooxygenase (COX)-1 and

modifies enzymatic activity of COX-2

thought to at least in part prevent colorectalneoplasia through COX-2 inhibition

COX-2 promotes inflammation and cell proliferation

overexpressed in 80-85% of colorectal cancers

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


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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 forcardiovascular prevention and longer periods may beassociated with reduced incidence of colorectal cancer.

Poor evidence ASA use leads to a reduction in colorectalcancerassociated mortality.

ASA was NOT recommended for primary prevention ofcolorectal 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: asystematic review prepared for the US Preventive Services Task Force. Ann Intern Med. 2007;146(5):365-375.


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Background

Two randomized controlledtrials:

ASA reduces the risk ofrecurrent adenomas in thosewith a history of colorectalcancer or adenomas.

Numbers needed to treat toprevent adenomas suggestmoderate benefit

BUT: risks > benefits

most adenomas do notprogress to cancer endoscopic surveillance for

recurrent neoplasia wouldresult in detection/removalanyway

Imperiale, TF. Aspirin and the Prevention of Colorectal Cancer. N Engl

J Med. 2003;348(10):879-880.


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Background

Animal models have shown anti-COX-2 activitycan inhibit colorectal tumor growth andmetastases 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 ofdisease 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: findersfrom intergroup trial CALGB 89803 [abstract]. J Clin Oncology. 2005;23(suppl 16):3530.


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Objective

Examine association between ASA use pre andpost-diagnosis and colorectal cancer-specific andoverall survival

Hypothesis: ASA use after diagnosis isassociated with lower risk of colorectal cancer-related deaths among patients with non-metastatic colon cancer.

Examine effect of ASA according to levels oftumoral expression of COX-2


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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


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Methods

Biennial questionnaire: new diagnosis, ASA use, physicalactivity, 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


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Methods

Validation questionnaire: reasons for ASA use 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, musculoskeletalpain

Review of hospital records and pathologyreports: disease staging Tissue specimens of recurrent

cancers were not obtained.


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Methods

Immunostaining: COX-2 expression NHS 2001: 207/840 women HPFS 1997: 252/429 men


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Methods

Report of adverse affects GI bleed requiring hospitalization or transfusion

NHS 2004 No ASA: 0.77/1000 person yrs2-5 pills/wk: 1.076-14 pills/wk: 1.4014+ pills/wk: 1.57

HPFS 2006 No ASA: 0.92/1000 person yrs0.5-1.5 pills/wk: 1.022-5 pills/wk: 1.656+ 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


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Results

ASA use pre and post-diagnosis

536, 42%

366, 29%

194, 15%

183, 14%No ASA pre, No ASA

postASA pre, ASA post

ASA pre, no ASA post

no ASA pre, ASA post

222 deaths due to colorectal cancer, 480 total deaths

Median follow up time from diagnosis: 11.8yrs

Total participants: 1279


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ResultsASA useafter dx

Participants Totaldeaths

Colorectal-cancerspecificdeaths

5 yearsurvival

10 yearsurvival

Usedregularly

549 193(35%)

81 (15%) 88% 74%

Not used 730 287(39%)

141 (19%) 83% 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 andHR = 0.79 (CI = 0.65-0.97) for overall mortality


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Results

Therefore, regular ASA use post-diagnosis had a29% lower cancer-specific mortality and a 21%lower overall mortality than nonusers.

In contrast, ASA use prior to diagnosis was notassociated with colorectal-cancer specificmortality or overall mortality

Colorectal cancer-specific mortality HR = 1.05 (CI = 0.80-1.37)

Overall mortality HR = 0.93 (CI = 0.77-1.11)


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Results

Of those that used ASA post-diagnosis, only those whodid NOT use ASA pre-diagnosis showed significantreduction in colorectal cancer-specific mortality andoverall mortality


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Results

The benefit of ASA use post-diagnosis wasalso confined to those with COX-2 positivetumors


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Results

The association between post-diagnosis ASA use andsurvival 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 bysex, age, cancer stage, site of primary tumor, year ordiagnosis or BMI.

Limited statistical power, but association of post-diagnosis ASA use and mortality did not appear to bechanged after accounting for chemotherapy.


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Discussion

This suggests tumors initiated in ASAenvironments may be less susceptible to anypotential effect of ASA on tumor progression

Previous studies showed regular ASA use wasassociated with reduction in risk of developing aprimary COX-2 positive tumor (but not COX-2negative 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 ofCOX-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.


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Study Strengths

Prospective data collection

Data on ASA use was gathered before andafter diagnosis

Participants were health professionalshigher accuracy of self-reported ASA use

Fairly large population with cohorts


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Study Weaknesses

Observational vs. controlled trial

Cohorts were comprised of health-professionalsonly

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


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Clinical Implications

Regular ASA use after colorectal-cancer diagnosismay influence colorectal cancer-specific andoverall mortality in patients with tumors withoverexpression of COX-2.

ASA may have the potential as a useful adjuvanttherapy for colorectal cancer.

COX-2 immunostaining may be used to tailor ASAtherapy among patients with new diagnoses

Further studies needed placebo controlled trials,ASA in setting of metastatic disease

An ongoing randomized trial sponsored by theNational Cancer Center of Singapore willpotentially 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.


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Thank you

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