意大利欧洲肿瘤研究所Fabio Conforti团队研究了早期乳腺癌新辅助化疗随机临床试验中病理完全缓解是否可作为替代终点。相关论文于2021年12月21日发表在《英国医学杂志》上。
为了评估病理完全缓解是否可作为早期乳腺癌新辅助试验中无病生存和总生存的替代终点，研究组在Medline、Embase和Scopus等数据库中检索从建库至2020年12月1日关于评估单用或联合其他治疗（包括抗人表皮生长因子2（抗HER2）药物、靶向治疗、抗血管药物、双膦酸盐和免疫检查点抑制剂）的新辅助化疗的随机临床试验，并进行系统回顾和荟萃分析。
对替代终点病理完全缓解与无病生存和总生存之间的水平关联进行分析。对对数转换的疗效评估（无病生存和总生存的危险比以及病理完全缓解的相对风险）进行加权回归分析，并使用决定系数（R2）量化相关性。
第二个目标是探索预先计划的亚组分析结果的异质性，根据试验组的治疗类型、病理完全缓解（仅乳腺和淋巴结与乳腺）的定义、疾病的生物学特征（HER2阳性或三阴性乳腺癌）对试验进行分层。评估替代阈值效应，指出病理完全缓解的相对风险最小值，以预测无病生存或总生存的风险比的非零效应。
54项随机临床试验中共有32611名患者被纳入分析。病理完全缓解的对数（相对风险）与无病生存率（R2=0.14）和总生存率（R2=0.08）的对数（危险比）之间的相关性较弱。在评估的所有亚组中都发现了类似的结果，与病理完全缓解的定义、试验组的治疗类型以及疾病的生物学特征无关。
无病生存率的替代阈值效应为5.19，但总生存率无法估计。在三项敏感性分析中证实了一致的结果：排除小型试验（<200名入选患者），排除中位随访时间较短（<24个月）的试验，以及用治疗组之间病理完全缓解率的绝对差异代替病理完全缓解相对风险的试验。
研究结果表明，在试验水平上，病理完全缓解不能替代无病生存和总生存指标。研究结果表明，病理完全缓解不应作为早期乳腺癌新辅助治疗试验的主要终点。
附：英文原文
Title: Evaluation of pathological complete response as surrogate endpoint in neoadjuvant randomised clinical trials of early stage breast cancer: systematic review and meta-analysis
Author: Fabio Conforti, Laura Pala, Isabella Sala, Chiara Oriecuia, Tommaso De Pas, Claudia Specchia, Rossella Graffeo, Eleonora Pagan, Paola Queirolo, Elisabetta Pennacchioli, Marco Colleoni, Giuseppe Viale, Vincenzo Bagnardi, Richard D Gelber
Issue&Volume: 2021/12/21
Abstract:
Objective To evaluate pathological complete response as a surrogate endpoint for disease-free survival and overall survival in regulatory neoadjuvant trials of early stage breast cancer.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, and Scopus to 1 December 2020.
Eligibility criteria for study selection Randomised clinical trials that tested neoadjuvant chemotherapy given alone or combined with other treatments, including anti-human epidermal growth factor 2 (anti-HER2) drugs, targeted treatments, antivascular agents, bisphosphonates, and immune checkpoint inhibitors.
Data extraction and synthesis Trial level associations between the surrogate endpoint pathological complete response and disease-free survival and overall survival.
Methods A weighted regression analysis was performed on log transformed treatment effect estimates (hazard ratio for disease-free survival and overall survival and relative risk for pathological complete response), and the coefficient of determination (R2) was used to quantify the association. The secondary objective was to explore heterogeneity of results in preplanned subgroups analysis, stratifying trials according treatment type in the experimental arm, definition used for pathological complete response (breast and lymph nodes v breast only), and biological features of the disease (HER2 positive or triple negative breast cancer). The surrogate threshold effect was also evaluated, indicating the minimum value of the relative risk for pathological complete response necessary to confidently predict a non-null effect on hazard ratio for disease-free survival or overall survival.
Results 54 randomised clinical trials comprising a total of 32611 patients were included in the analysis. A weak association was observed between the log(relative risk) for pathological complete response and log(hazard ratio) for both disease-free survival (R2=0.14, 95% confidence interval 0.00 to 0.29) and overall survival (R2 =0.08, 0.00 to 0.22). Similar results were found across all subgroups evaluated, independently of the definition used for pathological complete response, treatment type in the experimental arm, and biological features of the disease. The surrogate threshold effect was 5.19 for disease-free survival but was not estimable for overall survival. Consistent results were confirmed in three sensitivity analyses: excluding small trials (<200 patients enrolled), excluding trials with short median follow-up (<24 months), and replacing the relative risk for pathological complete response with the absolute difference of pathological complete response rates between treatment arms.
Conclusion A lack of surrogacy of pathological complete response was identified at trial level for both disease-free survival and overall survival. The findings suggest that pathological complete response should not be used as primary endpoint in regulatory neoadjuvant trials of early stage breast cancer.
DOI: 10.1136/bmj-2021-066381
Source: https://www.bmj.com/content/375/bmj-2021-066381
BMJ-British Medical Journal:《英国医学杂志》，创刊于1840年。隶属于BMJ出版集团，最新IF：93.333
官方网址：http://www.bmj.com/
投稿链接：https://mc.manuscriptcentral.com/bmj
本期文章：《英国医学杂志》：Online/在线发表
