Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu City, Oita, 879-5593, Japan.
BMC Cancer. 2019 Jan 11;19(1):56. doi: 10.1186/s12885-019-5268-2.
Overall survival is the true endpoint for most randomized controlled trials (RCTs) of malignant tumors, whereas progression-free survival (PFS) is considered the most reliable surrogate endpoint for overall survival (OS). The present study aimed to evaluate the correlation between surrogate endpoints and OS in randomized trials of first-line chemotherapy with doxorubicin (DOX), the standard treatment for advanced and metastatic soft tissue sarcomas (ASTS), using a meta-analytic approach.
In a systematic review, we identified RCTs of first-line chemotherapy for ASTS that compared single-agent doxorubicin (DOX) with other chemotherapy regimens, and were published in English during January 1974-December 2017. A meta-analysis was performed to evaluate the efficacy of first-line treatments for ASTS. Surrogacy of the intermediate endpoints for OS was investigated using weighted linear regression analysis. Correlation strength was examined using the coefficient of determination (R).
Twenty-seven randomized trials, comprising 6156 patients (3371 patients in the experimental arm and 2785 patients in the DOX arm) were identified. The hazard ratios for OS and PFS showed that the efficacy of treatment for ASTS was not significantly different between standard DOX and experimental treatments. The median OS was significantly prolonged in RCTs published after 2012 when pazopanib was approved for treating ASTS. The median PFS, however, did not differ significantly. The correlation between PFS and OS was moderate (R = 0.557), but better than that between OS and 3-month PFS, 6-month PFS, and response rate (R = 0.200, 0.073, and 0.278, respectively). The correlation between PFS and OS tended to be more favorable in RCTs published after 2012 (R = 0.586 and 0.459, respectively).
The trial-level correlation between PFS and OS was only modest; it tended to be better in RCTs published after 2012. While the effective lines of chemotherapy and the introduction of new drugs prolonged OS but not PFS, PFS is a better surrogate than other intermediate endpoints in the first-line ASTS trials even in the post-pazopanib era. Although this does not negate the need for more reliable surrogate endpoints for OS.
对于大多数恶性肿瘤的随机对照试验（RCT），总生存是真正的终点，而无进展生存（PFS）被认为是总生存（OS）最可靠的替代终点。本研究旨在通过meta 分析方法，评估蒽环类药物（DOX）一线化疗治疗晚期和转移性软组织肉瘤（ASTS）的随机试验中替代终点与 OS 之间的相关性。
在系统评价中，我们确定了 1974 年 1 月至 2017 年 12 月期间以英语发表的比较单药 DOX 与其他化疗方案作为 ASTS 一线化疗的 RCTs。进行了 meta 分析以评估 ASTS 一线治疗的疗效。通过加权线性回归分析研究中间终点对 OS 的替代作用。使用决定系数（R）检查相关性强度。
确定了 27 项 RCTs，共纳入 6156 例患者（实验组 3371 例，DOX 组 2785 例）。OS 和 PFS 的风险比表明，ASTS 标准 DOX 与实验治疗的疗效无显著差异。当 pazopanib 被批准用于治疗 ASTS 时，2012 年后发表的 RCTs 中 OS 中位数显著延长。然而，PFS 中位数无显著差异。PFS 与 OS 之间的相关性中等（R=0.557），但优于 OS 与 3 个月 PFS、6 个月 PFS 和反应率（R=0.200、0.073 和 0.278）之间的相关性。2012 年后发表的 RCTs 中 PFS 与 OS 之间的相关性更为有利（R=0.586 和 0.459）。
PFS 与 OS 之间的试验水平相关性仅为中等，2012 年后发表的 RCTs 中相关性更好。虽然化疗的有效方案和新药的引入延长了 OS 但未延长 PFS，但即使在 pazopanib 时代后，PFS 也是 ASTS 一线试验中优于其他中间终点的更好替代终点。尽管这并不否定需要更可靠的 OS 替代终点。
