Surrogate End Points for Overall Survival in Loco-Regionally Advanced Nasopharyngeal Carcinoma: An Individual Patient Data Meta-analysis

Abstract

Background: Our objective was to evaluate progression-free survival (PFS) and distant metastasis-free survival (DMFS) as surrogate end points for overall survival (OS) in randomized trials of chemotherapy in loco-regionally advanced nasopharyngeal carcinomas (NPCs).

Methods: Individual patient data were obtained from 19 trials of the updated Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) plus one additional trial (total = 5144 patients). Surrogacy was evaluated at the individual level using a rank correlation coefficient ρ and at the trial level using a correlation coefficient R² between treatment effects on the surrogate end point and OS. A sensitivity analysis was performed with two-year PFS/DMFS and five-year OS.

Results: PFS was strongly correlated with OS at the individual level (ρ = 0.93, 95% confidence interval [CI] = 0.93 to 0.94) and at the trial level (R² = 0.95, 95% CI = 0.47 to 1.00). For DMFS, too, the individual-level correlation with OS was strong (ρ = 0.98, 95% CI = 0.98 to 0.98); at trial level, the correlation was high but the regression adjusted for measurement error could not be computed (unadjusted R² = 0.96, 95% CI = 0.94 to 0.99). In the sensitivity analysis, two-year PFS was highly correlated with five-year OS at the individual level (ρ = 0.89, 95% CI = 0.88 to 0.90) and at the trial level (R² = 0.85, 95% CI = 0.46 to 1.00); two-year DMFS was highly correlated with five-year OS at the individual level (ρ = 0.95, 95% CI = 0.94 to 0.95) and at the trial level (R² = 0.78, 95% CI = 0.33 to 1.00).

Conclusions: PFS and DMFS are valid surrogate end points for OS to assess treatment effect of chemotherapy in loco-regionally advanced NPC, while PFS can be measured earlier.

Figure 1.

Survival curves for overall survival, progression-free survival, and distant metastasis–free survival in chemotherapy and control arms. Overall survival, progression-free survival, and distant metastasis–free survival in the chemotherapy and control arms. CT = chemotherapy; DMFS = distant metastasis–free survival; no CT = control; PFS = progression-free survival; OS = overall survival.

Figure 2.

Correlation between treatment effects on the surrogate and overall survival in loco-regionally advanced nasopharyngeal carcinomas. A) Progression-free survival. B) Distant metastasis–free survival. Each circle is a trial, and its size is proportional to the number of patients. STE = surrogate threshold effect.

Figure 3.

Leave-one-out cross-validation analysis for the model predicting the treatment effect on overall survival based on progression-free survival (A) and distant metastasis-free survival (B) effects. Circles are the observed hazard ratios for the effect on overall survival. Horizontal segments correspond to 95% prediction intervals (PI). The vertical segments are the predicted effects on overall survival using the observed hazard ratio on progression or distant metastasis-free survival of each trial and using the surrogate model fitted on the other trials. *The surrogate model could not be fitted due to convergence issues. Individual trials are grouped according to the timing of chemotherapy and are named the same way as in our initial publication(2), while references can be found in the Supplementary Table 1. Adjv = adjuvant; Conc = Concomitant.