Sugumar Kavin, Lie Jessica Jin, Stucky Chee-Chee, Chang Yu-Hui, Brady Justin, Wasif Nabil, Sonbol Mohamad Bassam, Etzioni David, Mamon Harvey, Bekaii-Saab Tanios, Fong Zhi Ven
Department of Surgery, Tulane University, New Orleans, Louisiana.
Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
JAMA Netw Open. 2025 Jul 1;8(7):e2521197. doi: 10.1001/jamanetworkopen.2025.21197.
Pathologic complete response (pCR) is increasingly used as a surrogate end point for survival in randomized clinical trials (RCTs) in the field of gastrointestinal oncology. Although this approach has been endorsed by the US Food and Drug Administration, it is still novel and incompletely verified.
To evaluate the trial-level association between pCR and survival in rectal cancer RCTs examining the effectiveness of neoadjuvant therapy.
A meta-analysis was conducted to identify eligible RCTs in PubMed, EMBASE, and Cochrane databases published between database inception to January 3, 2024.
RCTs evaluating neoadjuvant therapies in patients with rectal cancer who underwent subsequent surgical resection and reported pCR, overall survival (OS), and disease-free survival (DFS) were included.
Two investigators extracted the data, which were verified by a third author. The risk of bias and the certainty of the evidence were evaluated using the Cochrane Risk of Bias Tool, version 2, and the Grading of Recommendations Assessment, Development, and Evaluation tool, respectively. Adjusted odds and hazard ratios with their 95% CIs were extracted. Weighted linear regression was used to assess the correlation between pCR and both OS and DFS.
Trial-level correlation between pCR and both OS and DFS.
Twenty-five RCTs, including 11 882 patients, met the inclusion criteria. On meta-regression analysis, pCR was not correlated with OS (β = 0.37; 95% CI, -0.98 to 1.71; P = .57). Similarly, pCR was not correlated with DFS (β = -0.84; 95% CI, -2.55 to 0.87; P = .32). Two studies (8%) used in the meta-analysis had high risk of bias. On sensitivity analysis excluding these studies, pCR was still not associated with OS or DFS. Subgroup analysis of RCTs using total neoadjuvant therapies was not possible due to limited sample size.
In this systematic review and meta-analysis of RCTs comparing neoadjuvant therapies in rectal cancer, there was no trial-level association between pCR and survival. These results suggest that the use of pCR as a surrogate end point for survival should be reexamined and used more cautiously.
病理完全缓解（pCR）在胃肠道肿瘤领域的随机临床试验（RCT）中越来越多地被用作生存替代终点。尽管这种方法已得到美国食品药品监督管理局的认可，但它仍然新颖且未得到充分验证。
评估在检测新辅助治疗有效性的直肠癌RCT中，pCR与生存之间的试验水平关联。
进行一项荟萃分析，以识别在PubMed、EMBASE和Cochrane数据库中从建库至2024年1月3日发表的符合条件的RCT。
纳入评估接受后续手术切除的直肠癌患者新辅助治疗并报告pCR、总生存期（OS）和无病生存期（DFS）的RCT。
两名研究人员提取数据，由第三位作者进行核实。分别使用Cochrane偏倚风险工具第2版和推荐分级评估、制定与评价工具评估偏倚风险和证据的确定性。提取调整后的比值比和风险比及其95%置信区间。采用加权线性回归评估pCR与OS和DFS之间的相关性。
pCR与OS和DFS之间的试验水平相关性。
25项RCT（包括11882例患者）符合纳入标准。在meta回归分析中，pCR与OS不相关（β = 0.37；95%置信区间，-0.98至1.71；P = 0.57）。同样，pCR与DFS也不相关（β = -0.84；95%置信区间，-2.55至0.87；P = 0.32）。荟萃分析中使用的两项研究（8%）存在高偏倚风险。在排除这些研究的敏感性分析中，pCR仍与OS或DFS无关。由于样本量有限，无法对使用全新辅助治疗的RCT进行亚组分析。
在这项比较直肠癌新辅助治疗的RCT系统评价和荟萃分析中，pCR与生存之间不存在试验水平的关联。这些结果表明，将pCR用作生存替代终点的做法应重新审视并更谨慎地使用。
