1. Stage-specific survival of screen-detected versus clinically diagnosed colorectal cancer - evidence from the FOBT screening trials- Iris Lansdorp-Vogelaar Janneke Wilschut Marjolein van Ballegooijen Methods and Applications for Population Based Survival Frascati, 20 September 2010

2. Outline  Background  Microsimulation modeling and length and lead-time bias  Analysis  Results  Future work

3. Colorectal Cancer  Colorectal cancer (CRC) 2 nd leading cause of cancer death worldwide  CRC develops through adenoma-carcinoma pathway:

4. FOBT Screening  Three randomized trials showed 15-33% reduction in CRC mortality from fecal occult blood testing (FOBT)  Mortality reduction assumed to be result of more favorable stage distribution with screening  Mapp et al. found different survival between screendetected CRC and CRC in control group after correcting for stage (Mapp et al, Br J Surg; 1999)

5. Lead-time and length bias  Lead-time bias: longer survival of screendetected CRC because of earlier detection and not by later death  Length bias: longer survival of screendetected CRC because slower- growing tumors are detected by screening

6. Correcting for lead-time and length bias  Kafadar & Prorok: Compare survival of cases in screen and control groups of randomized trial using time since entry of the trial (Kafadar & Prorok, Stat Med; 1994)  Key assumption:  Cases in two groups are comparable  Limitations:  No correction for overdiagnosis  Comparison stage-specific survival not possible

7. Research objective  To test hypothesis that stage-specific survival of screen-detected CRC is the same as of clinically diagnosed CRC.

8. Microsimulation modeling of colorectal cancer

9. Simulation of a life-history

10. Simulating the effect of screening

11. Microsimulation modeling & lead-time bias

12. Microsimulation modeling & length bias Screening Intervention

13. Validation of MISCAN-Colon model  Used model to try and reproduce results of randomized trials of Minnesota, Nottingham and Funen simultaneously  Model was adjusted to account for differences in demography, background incidence, and trial design  The model with a higher sensitivity shortly before clinical diagnosis gave the best fit  This model reproduced CRC incidence and detection rates by stage well

14. Analysis  Use validated MISCAN-colon model that reproduces observed incidence and CRC detection by stage for three trials  Assume same stage-specific survival for screendetected and clinically diagnosed CRC  Compare simulated mortality reduction with observed for three trials

15. Results Observed mortality reduction Simulated mortality reduction Minnesota, annual screening 32.5%20.6% Minnesota, biennial screening 17.3%11.3% Nottingham13.4%5.1% Funen17.8%8.9%

16. First approach to modeling within stage shift  Model validation suggested higher screendetection in the stage in which the cancer would have been diagnosed in the absence of screening than in earlier stages  Of the screendetected cancers, the cases that are detected in the same stage as they would have become clinical, are the most likely candidates for better survival because of within stage-shift

17. Survival assumptions for within stage shift  Assumed following survival for these screendetected cancers:  Survival in stage I is 100%  Survival in stage II = Survival in stage I of clinical cases  Survival in stage III = Survival in stage II of clinical cases  Survival in stage IV of these cases was not improved

18. Results with within-stage shift Observed mortality reduction Simulated mortality reduction (no within shift) Simulated mortality reduction (within shift) Minnesota, annual screening 33%20.6%33.5% Minnesota, biennial screening 21%11.3%21.2%

19. Future work  Current approach for effect of within-stage shift quite arbitrary  Estimate effect of within-stage shift through hazard ratio for survival of cancers screendetected in same stage as clinical diagnosis  Explore alternative approaches to obtain estimate for improvement that is independent of screening intensity

20. Conclusions  The improvement in stage-distribution from FOBT screening is insufficient to explain the observed mortality reduction  Even after correcting for lead-time en length bias, stage-specific survival of screendetected cases needs to be better than of clinically diagnosed cases