Progression-Free Survival as Early Efficacy Endpoint in Resectable Esophageal Cancer Treated With Neoadjuvant Therapy: A Systematic Review

Jie Zhu,Jin Tao,Qifeng Wang,Zhen Dai,Li Jiang,Jinyi Lang,Yan Tan

doi:10.3389/fonc.2021.771546

Abstract

To investigate literature-based evidence regarding progression-free survival (PFS) as an early efficacy endpoint in patients with resectable esophageal or gastroesophageal junction (GEJ) cancer receiving neoadjuvant therapy, this study identified large-scale randomized controlled trials (RCTs) with strict quality control. Twenty-four RCTs involving 7,514 patients were included. Trial-level correlation analysis was conducted to analyze the relationship between PFS hazard ratio (HR) and overall survival (OS) HR, Δ median PFS and Δ median OS. Correlation analysis at the neoadjuvant treatment arm level was performed between 1- to 5-year PFS and 5-year OS, median PFS and median OS. Subgroup analysis was performed in patients treated with standard neoadjuvant chemoradiotherapy (NCRT). The correlation was evaluated using the Pearson correlation coefficient r in weighted linear regression, with weight equal to patient size. In trial-level correlation, PFS were strongly associated with OS HR (r, 0.82 [95% confidence interval (CI), 0.42-0.97]) and Δ median survival (r, 0.83 [95% CI, 0.54-0.96]). In neoadjuvant treatment arms, there was a strong correlation between 1 to 5-year PFS rates and 5-year OS (r, 0.83-0.95), and median PFS and median OS (r, 0.97 [95% CI, 0.85-0.99]). NCRT subgroup analysis demonstrated acceptable consistency. In conclusion, we recommend PFS as an early efficacy endpoint in resected esophageal or GEJ cancer treated with neoadjuvant therapy.

Highlights

Esophageal or gastroesophageal junction (GEJ) cancer is the seventh most common cancer worldwide, causing an estimated 509,000 deaths in 2018 [1]
The eligibility criteria included randomized controlled trials (RCTs) investigating long-term survival in patients with resectable esophageal or GEJ cancer who underwent neoadjuvant therapy followed by surgical resection
This large-scale, comprehensive study included high-quality RCTs to investigate the association between early efficacy endpoints and Overall survival (OS) in patients with resectable esophageal or GEJ cancer who underwent neoadjuvant therapy followed by surgical resection

Summary

Introduction

Esophageal or gastroesophageal junction (GEJ) cancer is the seventh most common cancer worldwide, causing an estimated 509,000 deaths in 2018 [1]. Even after standard NCRT plus surgical resection, about one-third of patients experience distant metastasis with or without local recurrence, which has poor outcomes with post-progression survival ranging from months to a few years [2]. There is an urgent need to find more effective neoadjuvant therapies to improve the long-term survival in patients with resectable esophageal or GEJ cancer. Effective post-progression treatment can reduce or even eliminate the apparent benefit of local tumor control and long-term recurrence, which results in non-significant OS prolongation. The evaluation of early efficacy endpoints, such as progression-free survival (PFS) or disease-free survival (DFS), requires a smaller sample size and shorter evaluation time than OS, which allows the implementation of more RCTs and accelerates the approval of novel drugs. If the early efficacy endpoint of PFS is successfully established in resectable esophageal or GEJ cancer, the exploration of preoperative use of ICIs will be significantly accelerated

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