Federico Rotolo1,2,3, Jean-Pierre Pignon1,2,3, Jean Bourhis4, Sophie Marguet1,2, Julie Leclercq1,3, Wai Tong Ng5, Jun Ma6, Anthony T C Chan7, Pei-Yu Huang6, Guopei Zhu8, Daniel T T Chua9, Yong Chen6, Hai-Qiang Mai10, Dora L W Kwong11, Yoke Lim Soong12, James Moon13, Yuk Tung14, Kwan-Hwa Chi15, George Fountzilas16, Li Zhang10, Edwin Pun Hui7, Anne W M Lee5, Pierre Blanchard1,2,17, Stefan Michiels1,2,3. 1. Service de Biostatistique et d'Epidémiologie, Gustave Roussy Cancer Campus, Villejuif, France. 2. INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. 3. Ligue Nationale Contre le Cancer Meta-Analysis Platform, Gustave Roussy Cancer Campus, Villejuif, France. 4. Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 5. Pamela Youde Nethersole Eastern Hospital, Hong Kong, China. 6. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China. 7. Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China. 8. Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China. 9. Hong Kong Sanatorium and Hospital, Hong Kong, China. 10. Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China. 11. Queen Mary Hospital, Hong Kong, China. 12. National Cancer Centre, Singapore, Singapore. 13. SWOG Statistical Center, Seattle, WA, USA. 14. Tuen Mun. Hospital Hong Kong, China 15. Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. 16. Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. 17. Department of Radiation Therapy, Gustave Roussy, Villejuif, France.
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.
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.
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