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A risk-benefit analysis of celecoxib for the prevention of colorectal cancer. James Cross, MS Pharmaceutical Outcomes Research and Policy Program University of Washington ----- Biobehavioral Cancer Fellows Day April 20, 2007. The framework & decision problem.

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a risk benefit analysis of celecoxib for the prevention of colorectal cancer

A risk-benefit analysis of celecoxib for the prevention of colorectal cancer

James Cross, MS

Pharmaceutical Outcomes Research and Policy Program

University of Washington

-----

Biobehavioral Cancer Fellows Day

April 20, 2007

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?
colorectal cancer us estimates for 2006 1
Colorectal 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.
polyps precursors to adenocarcinoma
Polyps: precursors to adenocarcinoma

Standard colonoscopy

Colonoscopy: current

surveillance method

among “high-risk”

patients.

Zielinski SL. JNCI 2004.

nsaids
NSAIDs
  • Non-selective inhibitors
    • Ibuprofen, naproxen, diclofenac
    • Aspirin
  • COX-2 selective inhibitors
    • Celecoxib
inflammation in colorectal cancer
Inflammation in colorectal cancer

Ulrich C, Nat Rev Cancer 2006

evidence of benefit nsaid vs placebo at 3 years
Evidence of benefit:NSAID vs. placebo at 3 years

1Baron JA, NEJM 2003

2Bertagnolli MM, NEJM 2006

3Arber N, NEJM 2006.

evidence of risk cv gi
Evidence of risk (CV, GI)
  • 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:

1Derry L BMJ 2000. (RCT meta-analysis, n=66,000)

2USPhysician Health Study NEJM 1989. 3 Solomon SD Circulation 2006.

current opinion of celecoxib
Current 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

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
r isk benefit analysis methods
Risk 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
health state transition model of crc prevention
Health-state transition model of CRC prevention

Polyp free

(Post-polypectomy)

Advanced adenoma

Death

CRC

GI Tox

Discontinue ASA/COX

CV Tox

methods model assumptions
Methods: 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.
results net health impact
Results: 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):
limitations
Limitations
  • 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.
acknowledgements
Acknowledgements
  • Dissertation committee:
    • Lou Garrison (UW, chair)
    • Scott Ramsey (UW & FHCRC)
    • Dave Veenstra (UW)
  • Funding:
    • Biobehavioral Cancer Prevention & Control Training Program (NCI & UW)