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, 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

REFERENCES

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

METHODS

1.00.0 2.0

Study O/N O/N HR CI Hazard ratio

(a) Historical trials 5FU+LV 5FU

Crema 49 / 49 99 / 99 0.26 [0.16-0.41]

Crema 49 / 49 99 / 99 0.42 [0.28-0.64]

NCCTG 69 / 69 137 / 137 0.66 [0.48-0.91]

NCCTG 68 / 69 136 / 137 0.78 [0.58-1.06]

Siena 91 / 91 94 / 94 0.86 [0.64-1.15]

Siena 91 / 91 94 / 94 0.68 [0.5-0.92]

EORTC 162 / 164 315 / 326 0.86 [0.71-1.05]

EORTC 142 / 164 283 / 326 0.93 [0.76-1.14]

SWOG 93 / 93 176 / 178 0.89 [0.69-1.15]

SWOG 93 / 93 176 / 178 0.96 [0.75-1.25]

SAKK 154 / 157 150 / 152 0.92 [0.74-1.16]

SAKK 153 / 157 150 / 152 0.89 [0.71-1.12]

HECOG 58 / 67 61 / 68 0.95 [0.66-1.36]

HECOG 47 / 67 53 / 68 0.99 [0.66-1.47]

Hungary 33 / 33 37 / 37 1.08 [0.67-1.75]

Hungary 33 / 33 37 / 37 1.31 [0.81-2.11]

Subtotal 709 / 723 1069 / 1091 0.82 [0.74-0.91]

Subtotal 676 / 723 1028 / 1091 0.85 [0.77-0.95]

(b) Historical trials 5FU+LV Tomudex

Pazdur 205 / 216 192 / 206 0.62 [0.51-0.76]

Pazdur 163 / 216 136 / 206 0.74 [0.59-0.92]

Cocconi 209 / 246 195 / 243 0.75 [0.61-0.91]

Cocconi 123 / 246 119 / 243 0.87 [0.67-1.12]

Cunningham 211 / 222 204 / 212 0.93 [0.77-1.13]

Cunningham 165 / 222 152 / 212 1 [0.81-1.25]

Subtotal 625 / 684 591 / 661 0.76 [0.68-0.86]

Subtotal 451 / 684 407 / 661 0.87 [0.76-0.99]

(c) Validation trials 5FU+LV+CPT11 5FU+LV

Douillard 159 / 199 161 / 188 1.32 [1.05-1.64]

Douillard 126 / 199 136 / 188 1.31 [1.02-1.67]

Saltz 201 / 230 209 / 226 1.22 [1-1.48]

Saltz 168 / 230 184 / 226 1.24 [1-1.53]

Subtotal 360 / 429 370 / 414 1.26 [1.09-1.46]

Subtotal 294 / 429 320 / 414 1.27 [1.08-1.49]

(d) Validation trial 5FU+LV+Oxali 5FU+LV

de Gramont 162 / 210 177 / 210 1.53 [1.23-1.9]

de Gramont 120 / 210 131 / 210 1.21 [0.94-1.55]

Subtotal 162 / 210 177 / 210 1.53 [1.23-1.9]

Subtotal 120 / 210 131 / 210 1.21 [0.94-1.55]

(e) Validation trial 5FU+LV+Oxali 5FU+LV+CPT11

Goldberg 259 / 267 256 / 264 1.3 [1.09-1.55]

Goldberg 228 / 267 249 / 264 1.56 [1.3-1.87]

Subtotal 259 / 267 256 / 264 1.3 [1.09-1.55]

Subtotal 228 / 267 249 / 264 1.56 [1.3-1.87]

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

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: = 0.986 (very high)

OBSERVED EFFECTS IN IRINOTECAN TRIALS

PREDICTION OF TREATMENT EFFECTON OS IN IRINOTECAN TRIALS

Trial Observed log HR (SE)

Predicted log HR (SE)

Douillard et al. -0.27 (0.12) -0.29 (0.15)

Saltz et al. -0.21 (0.11) -0.22 (0.14)

Excellent prediction

OBSERVED EFFECTS IN OXALIPLATIN TRIALS

PREDICTION OF TREATMENT EFFECTON OS IN OXALIPLATIN TRIALS

Trial Observed log HR (SE)

Predicted log HR (SE)

de Gramont et al. -0.19 (0.13) -0.42 (0.16)

Goldberg et al. -0.43 (0.09) -0.28 (0.14)

Prediction inaccurate because of effective second line therapies

PREDICTION OF TREATMENT EFFECTON OS IN OXALIPLATIN TRIALS

Proportion of patients offered effective second-line treatment

Trial in 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