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PROGRESSION-FREE SURVIVAL (PFS) AS A SURROGATE FOR OVERALL SURVIVAL (OS)

PROGRESSION-FREE SURVIVAL (PFS) AS A SURROGATE FOR OVERALL SURVIVAL (OS) IN PATIENTS WITH ADVANCED COLORECTAL CANCER Buyse M 1 , Burzykowski T 2 , Carroll K 3 , Piedbois P 4 , Michiels S 5 , Pignon JP 5 for the Meta-Analysis Group In Cancer (MAGIC)

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PROGRESSION-FREE SURVIVAL (PFS) AS A SURROGATE FOR OVERALL SURVIVAL (OS)

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  1. PROGRESSION-FREE SURVIVAL (PFS) AS A SURROGATE FOR OVERALL SURVIVAL (OS) INPATIENTS WITH ADVANCED COLORECTAL CANCER Buyse M1, Burzykowski T2, Carroll K3, Piedbois P4, Michiels S5, Pignon JP5 for the Meta-Analysis Group In Cancer (MAGIC) International Drug Development Institute (IDDI), Brussels, Belgium1 Center for Statistics, Limburgs Universitair Centrum, Diepenbeek, Belgium2 Oncology Therapy Area, Astra-Zeneca Research and Development, Macclesfield, UK3 Department of Medical Oncology, Hôpital Henri Mondor, Créteil, France4 Service de Biostatistique et d’Epidémiologie, Institut Gustave Roussy, Villejuif, France5

  2. PURPOSE OF THIS WORK FACTS • Survival requires prolonged follow-up • Survival may be confounded by second-line therapies QUESTION Can Progression-Free Survival (PFS) be used as a surrogate for Overall Survival (OS)?

  3. DATA Historical trials: 5FU vs 5FU+LV:8 trials, 1814 patients Tomudex vs 5FU+LV:3 trials, 1345 patients Validation trials: 5FU+LV vs 5FU+LV+irinotecan:3 trials, 843 patients 5FU+LV vs 5FU+LV+oxaliplatin:1 trial, 420 patients 5FU+LV+irinotecan vs 5FU+LV+oxaliplatin:1 trial*, 531 patients * This trial (Goldberg et al.) had an experimental arm combining irinotecan and oxaliplatin, not included in our analyses

  4. REFERENCES 5FU vs 5FU+LV: Meta-Analysis Group In Cancer (MAGIC) (2004) Journal of Clinical Oncology, 22, 3766–3775 Tomudex vs 5FU+LV: Cunningham et al. (1996) Annals of Oncology, 7, 961-965 Pazdur et al. (1997) Proceedings ASCO, 16 (abstr 801) Cocconi et al. (1998) Journal of Clinical Oncology, 16, 2943-2952 5FU+LV vs 5FU+LV+irinotecan: Douillard et al. (2000) Lancet, 355, 1041–1047 Saltz et al. (1997) New England Journal of Medicine, 343, 905–914 5FU+LV vs 5FU+LV+oxaliplatin: de Gramont et al. (2000) Journal of Clinical Oncology, 18, 2938–2947 5FU+LV+irinotecan vs 5FU+LV+oxaliplatin: Goldberg et al. (2004) Journal of Clinical Oncology, 22, 23–30

  5. METHODS • Individual patient data used to estimate PFS, OS • Correlation between PFS and OS estimated using • bivariate distribution of PFS & OS over entire time range • Kaplan-Meier estimates of 6-mo PFS and 12- mo OS • Correlation between the treatment effects on PFS and OS estimated using hazard ratios over the entire time range

  6. FOREST PLOTS OF HAZARD RATIOSFOR PFS (RED) AND OS (BLUE) IN ALL TRIALS

  7. CORRELATION BETWEEN 6-Mo PFS AND 12-Mo OS

  8. CORRELATION BETWEEN PFS AND OS • Correlation between PFS and OS estimated using • bivariate distribution of PFS & OS over entire time range:  = 0.82 (reasonably high) • Kaplan-Meier estimates of 6-mo PFS and 12- mo OS: = 0.39 (low)

  9. OBSERVED EFFECTS IN HISTORICAL TRIALS

  10. CORRELATION BETWEEN TREATMENT EFFECTS ON PFS AND OS Correlation between between the treatment effects on PFS and OS estimated using hazard ratios over the entire time range: = 0.986 (very high)

  11. OBSERVED EFFECTS IN IRINOTECAN TRIALS

  12. PREDICTION OF TREATMENT EFFECT ON OS IN IRINOTECAN TRIALS Excellent prediction

  13. OBSERVED EFFECTS IN OXALIPLATIN TRIALS

  14. PREDICTION OF TREATMENT EFFECT ON OS IN OXALIPLATIN TRIALS Prediction inaccurate because of effective second line therapies

  15. PREDICTION OF TREATMENT EFFECT ON OS IN OXALIPLATIN TRIALS Prediction too high too low

  16. CONCLUSIONS (1) Historical trials show that PFS correlates moderately well with OS Treatment effects on PFS correlate well with treatment effects on OS Therefore, PFS is an acceptable surrogate for OS

  17. CONCLUSIONS (2) Validation trials show that Treatment effect on OS, based on the effect on PFS, ispredicted extremely well when patients receive no effectivesecond line therapy (see trials of irinotecan by Douillard et al. and Saltz et al.) Treatment effect on OS is smaller than predicted when most patients receive effective second line therapy (see trialby de Gramont et al.) and larger than predicted whenmore patients in the experimental group receive effectivesecond line therapy (see trial by Goldberg et al.)

  18. ACKNOWLEDGMENTS We gratefully acknowledge receipt of data for the irinotecantrials from Dr L. Cisar (Pfizer), for the oxaliplatintrials from Dr R. Bigelow (Sanofi-Aventis), Dr D. Sargentand Dr R. Goldberg (NCCTG). We thank E. Quinaux(IDDI) for statistical support.

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