新辅助化疗后病理完全缓解 (pCR) 率的差异并未反映治疗对实验组残留癌症分期的影响。我们开发了一种方法来比较临床试验组之间残余癌症负担 (RCB) 值的整体分布，以更好地量化治疗的细胞毒性疗效差异。

治疗功效评分 (TES) 反映了来自两个试验组的 RCB 值的加权累积分布函数之间的面积。 TES 基于改进的 Kolmogorov-Smirnov 检验，增加了权重函数来捕捉高 RCB 值的重要性，并使用两个分布函数之间差异下的面积作为统计指标。 TES 越高，实验组中向较低 RCB 值的转移越大。我们从德瓦鲁单抗+ 奥拉帕尼组 (n = 72) 和 I-SPY2 试验的相应对照 (n = 282) 中开发了 TES。其他 11 个实验组和对照组（n = 947）被用作验证集来评估 TES 的性能。我们将 TES 与 Kolmogorov-Smirnov、Mann-Whitney 和 Fisher 的精确检验进行了比较，以确定具有更高细胞毒性功效的试验组，并评估了与试验组水平生存差异的关联。用置换检验评估显着性。

在验证集中，TES 确定了 pCR 率较高的组，但如果治疗没有降低高 RCB 值的频率，即使 pCR 率有所提高，TES 也能更准确地确定方案效果较差。 TES与生存率的相关性高于pCR率差异与生存率的相关性。TES 量化了试验组中观察到的病理反应的整个分布之间的差异，并且可以作为预测试验组水平生存差异的更好的早期替代指标，而不是单独的 pCR 率差异。

Abstract

Background: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments.

Patients and methods: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test.

Results: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival.

Conclusions: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

原文链接

https://www.annalsofoncology.org/article/S0923-7534(22)00762-1/fulltext

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