Iris Lansdorp-Vogelaar Janneke Wilschut Marjolein van Ballegooijen

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) 2nd 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. Screening Intervention Microsimulation modeling & length bias

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

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

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