PROGRESSION-FREE SURVIVAL (PFS) AS A SURROGATE FOR OVERALL SURVIVAL (OS) IN PATIENTS WITH ADVANCED COLORECTAL CANCER Buyse M 1, Burzykowski T 2, Carroll.

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Presentation transcript:

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) International Drug Development Institute (IDDI), Brussels, Belgium 1 Center for Statistics, Limburgs Universitair Centrum, Diepenbeek, Belgium 2 Oncology Therapy Area, Astra-Zeneca Research and Development, Macclesfield, UK 3 Department of Medical Oncology, Hôpital Henri Mondor, Créteil, France 4 Service de Biostatistique et d’Epidémiologie, Institut Gustave Roussy, Villejuif, France 5

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)? PURPOSE OF THIS WORK

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 DATA

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, Pazdur et al. (1997) Proceedings ASCO, 16 (abstr 801) Cocconi et al. (1998) Journal of Clinical Oncology, 16, FU+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 REFERENCES

l l Individual patient data used to estimate PFS, OS l l 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 l l Correlation between the treatment effects on PFS and OS estimated using hazard ratios over the entire time range METHODS

FOREST PLOTS OF HAZARD RATIOS FOR PFS (RED) AND OS (BLUE) IN ALL TRIALS

CORRELATION BETWEEN 6-Mo PFS AND 12-Mo OS

CORRELATION BETWEEN PFS AND OS l l 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)

OBSERVED EFFECTS IN HISTORICAL TRIALS

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:  = (very high)

OBSERVED EFFECTS IN IRINOTECAN TRIALS

PREDICTION OF TREATMENT EFFECT ON OS IN IRINOTECAN TRIALS TrialObserved log HR (SE) Predicted log HR (SE) Douillard et al (0.12)-0.29 (0.15) Saltz et al (0.11)-0.22 (0.14) Excellent prediction

OBSERVED EFFECTS IN OXALIPLATIN TRIALS

PREDICTION OF TREATMENT EFFECT ON OS IN OXALIPLATIN TRIALS TrialObserved log HR (SE) Predicted log HR (SE) de Gramont et al (0.13)-0.42 (0.16) Goldberg et al (0.09)-0.28 (0.14) Prediction inaccurate because of effective second line therapies

PREDICTION OF TREATMENT EFFECT ON OS IN OXALIPLATIN TRIALS Proportion of patients offered effective second-line treatment Trialin control group in experimental group de Gramont et al.61%58% Goldberg et al.24%60% Prediction too high too low

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 CONCLUSIONS (1)

Validation trials show that Treatment effect on OS, based on the effect on PFS, is predicted extremely well when patients receive no effective second 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 trial by de Gramont et al.) and larger than predicted when more patients in the experimental group receive effective second line therapy (see trial by Goldberg et al.) CONCLUSIONS (2)

We gratefully acknowledge receipt of data for the irinotecan trials from Dr L. Cisar (Pfizer), for the oxaliplatin trials from Dr R. Bigelow (Sanofi- Aventis), Dr D. Sargent and Dr R. Goldberg (NCCTG). We thank E. Quinaux (IDDI) for statistical support. ACKNOWLEDGMENTS