Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy.
OBJECTIVE
Our aims were to determine the correlations between progression-free survival (PFS), time to progression (TTP), and response rate (RR) with overall survival (OS) in the first-line treatment of metastatic colorectal cancer (MCRC), and to identify a potential surrogate for OS.


METHODS
Randomized trials of first-line chemotherapy in MCRC were identified, and statistical analyses were undertaken to evaluate the correlations between the end points.


RESULTS
Thirty-nine randomized controlled trials were identified containing a total of 87 treatment arms. Among trials, the nonparametric Spearman rank correlation coefficient (r(s)) between differences (Delta) in surrogate end points (DeltaPFS, DeltaTTP, and DeltaRR) and DeltaOS were 0.74 (95% CI, 0.47 to 0.88), 0.52 (95% CI, 0.004 to 0.81), 0.39 (95% CI, 0.08 to 0.63), respectively. The r(s) for DeltaPFS was not significantly different from the r(s) DeltaTTP (P = .28). Linear regression analysis was performed using hazard ratios for PFS and OS. There was a strong relationship between hazard ratios for PFS and OS; the slope of the regression line was 0.54 +/- 0.10, indicating that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 5.4% +/- 1% risk reduction for OS.


CONCLUSIONS
In first-line chemotherapy trials for MCRC, improvements in PFS are strongly associated with improvements in OS. In this patient population, PFS may be an appropriate surrogate for OS. As a clinical end point, PFS offers increased statistical power at a given time of analysis and a significant lead time advantage compared with OS.
Tang
Patricia A
PA
Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Canada.
Bentzen
Søren M
SM
Chen
Eric X
EX
Siu
Lillian L
LL
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers; D002986:Clinical Trials as Topic / Q000191:economics / Q000379:methods; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018450:Disease Progression; D018572:Disease-Free Survival; D023381:Endpoint Determination; D006801:Humans; D009362:Neoplasm Metastasis; D016032:Randomized Controlled Trials as Topic / Q000191:economics / Q000379:methods; D012044:Regression Analysis; D012107:Research Design; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D015415:Biomarkers