James Cross, MS

Pharmaceutical Outcomes Research and Policy Program

University of Washington-----

Biobehavioral Cancer Fellows DayApril 20, 2007

A risk-benefit analysis of celecoxib

for the prevention of colorectal cancer

A risk-benefit analysis of celecoxib

for the prevention of colorectal cancer

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The framework & decision problem

The framework & decision problem

• Nonsteroidal antiinflammatories (NSAIDs) risk of colorectal adenoma.

• NSAIDs risk of gastrointestinal & cardiovascular adverse events.

• What is the risk-benefit profile of these drugs for colorectal cancer chemoprevention?

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Colorectal cancer: US estimates for 20061Colorectal cancer: US estimates for 20061

• Lifetime risk: 1 in 18 diagnosed with CRC.

• Diagnoses: 148,610

• Deaths: 55,170

1 Ries L et al. SEER Cancer Statistics Review, 1975-2003, NCI. Bethesda MD. http://seer.cancer.gov/csr/1975_2003/ Based on November 2005 SEER data submission.

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Polyps: precursors to adenocarcinoma

Polyps: precursors to adenocarcinoma

Standard colonoscopy

Zielinski SL. JNCI 2004.

Colonoscopy: current surveillance methodamong “high-risk” patients.

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NSAIDsNSAIDs

• Non-selective inhibitors• Ibuprofen, naproxen, diclofenac• Aspirin

• COX-2 selective inhibitors• Celecoxib

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Inflammation in colorectal cancer

Inflammation in colorectal cancer

Ulrich C, Nat Rev Cancer 2006

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Evidence of benefit:NSAID vs. placebo at 3 yearsEvidence of benefit:

NSAID vs. placebo at 3 years

1Baron JA, NEJM 2003 2Bertagnolli MM, NEJM 20063Arber N, NEJM 2006.

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Evidence of risk (CV, GI)Evidence of risk (CV, GI)

1Derry L BMJ 2000. (RCT meta-analysis, n=66,000)2USPhysician Health Study NEJM 1989. 3 Solomon SD Circulation 2006.

• GI bleed risk for ASA:• OR: 1.59 (1.40-1.81)1

• OR: 1.77 (1.07-2.94)2

• CV risk for Celecoxib:

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Current opinion of celecoxibCurrent opinion of celecoxib

…Due to the increased risk of CV events associated with their use, COX-2 inhibitors are not recommended routinely for sporadic adenomas.

-Practice Guideline in Oncology v1.2007, Nat’l Comprehensive Cancer Network

…It is reasonable to conclude that celecoxib has no role as a chemopreventive agent either in patients with nonfamilial colonic adenomas or the general population.

-Psaty and Potter NEJM 2006

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Reasons for doing a risk benefit analysis

Reasons for doing a risk benefit analysis

• Proposed risks:• Cardiovascular (celecoxib)• Gastrointestinal (aspirin)

• Proposed benefits:• Colonoscopies not perfectly sensitive • Slows carcinogenesis process• Decreases # of adenomas

• Decision problems:• Efficacy data based on surrogate endpoint• No methodical, quantitative assessment

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Risk benefit analysis: methodsRisk benefit analysis: methods

• Objective:

• compare the net health outcomes (risk & benefit) between 3 CRC prevention strategies

• ASA vs celecoxib vs colonoscopy alone

• Perspective:

• societal perspective, 20 years

• Population:

• 60 years, prior finding of adenoma

• Approach:

• health-state transition model quantifying health outcomes over 20 year period

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Polyp free(Post-

polypectomy)DeathAdvanced

adenomaCRC

GI Tox

CV Tox

Discontinue ASA/COX

Health-state transition model of CRC preventionHealth-state transition model of CRC prevention

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Methods: Model assumptionsMethods: Model assumptions

• GI/CV serious adverse events require drug discontinuation.

• Those who discontinue drug assume health state transitions as though they were receiving only colonoscopy.

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Results: Net health impactResults: Net health impact

# cancer case/death

+ # cardiovascular event/death

= net health impact

COMPARATOR[net health impact – REFERENCE[net health impact]

• For a cohort of 100,000 (undiscounted):

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LimitationsLimitations

• Scarcity of data: • correlation between surrogate endpoints

and outcomes used in decision-making. How should this be handled here, & in general?

• ASA use: • How best to model cardioprotective effect

of ASA use, which celecoxib users may also take?

• For calculations, 1 cancer case/death = 1 GI/CV event.

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AcknowledgementsAcknowledgements

• Dissertation committee:• Lou Garrison (UW, chair)

• Scott Ramsey (UW & FHCRC)

• Dave Veenstra (UW)

• Funding:• Biobehavioral Cancer Prevention & Control Training Program (NCI & UW)