Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer: findings on the basis of North Central Cancer Treatment Group trials

Cancer. 2011 Mar 15;117(6):1262-71. doi: 10.1002/cncr.25526. Epub 2010 Oct 19.


Background: The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression-free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS.

Methods: Individual patient data from 870 untreated extensive stage small-cell lung cancer patients participating in 6 single-arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient-level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial-level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial-level surrogacy measures included: R(2) from weighted least squares regression model, Spearman correlation coefficient, and R(2) from bivariate survival model (Copula R(2) ).

Results: Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1-10.0) and 5.5 (95% CI, 5.2-5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35-0.51; concordance index 0.63; P < .01), with 6-month PFS being the strongest (HR, 0.41; 95% CI, 0.35-0.49; concordance index, 0.66, P < .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R(2) = 0.79; Copula R(2) = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R(2) ≤0.48).

Conclusions: PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / analysis
  • Biomarkers, Tumor / analysis
  • Clinical Trials, Phase II as Topic / statistics & numerical data
  • Clinical Trials, Phase III as Topic / statistics & numerical data
  • Disease-Free Survival
  • Female
  • Humans
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / mortality*
  • Lung Neoplasms / therapy*
  • Male
  • Middle Aged
  • Prognosis
  • Randomized Controlled Trials as Topic / statistics & numerical data
  • Small Cell Lung Carcinoma / diagnosis
  • Small Cell Lung Carcinoma / mortality*
  • Small Cell Lung Carcinoma / therapy*
  • Survival Analysis
  • Treatment Outcome
  • United States / epidemiology


  • Biomarkers
  • Biomarkers, Tumor