癌症免疫疗法的疗效与患者性别：系统评价和荟萃分析。

Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis.

机构信息

Division of Medical Oncology for Melanoma & Sarcoma, European Institute of Oncology, Milan, Italy.

出版信息

Lancet Oncol. 2018 Jun;19(6):737-746. doi: 10.1016/S1470-2045(18)30261-4. Epub 2018 May 16.

DOI:10.1016/S1470-2045(18)30261-4

PMID:29778737

Abstract

BACKGROUND

Despite the acknowledged sex-related dimorphism in immune system response, little is known about the effect of patients' sex on the efficacy of immune checkpoint inhibitors as cancer treatments. We did a systematic review and meta-analysis to assess the heterogeneity of immune checkpoint inhibitor efficacy between men and women.

METHODS

We systematically searched PubMed, MEDLINE, Embase, and Scopus, from database inception to Nov 30, 2017, for randomised controlled trials of immune checkpoint inhibitors (inhibitors of PD-1, CTLA-4, or both) that had available hazard ratios (HRs) for death according to patients' sex. We also reviewed abstracts and presentations from all major conference proceedings. We excluded non-randomised trials and considered only papers published in English. The primary endpoint was to assess the difference in efficacy of immune checkpoint inhibitors between men and women, measured in terms of the difference in overall survival log(HR) reported in male and female study participants. We calculated the pooled overall survival HR and 95% CI in men and women using a random-effects model, and assessed the heterogeneity between the two estimates using an interaction test.

FINDINGS

Of 7133 studies identified in our search, there were 20 eligible randomised controlled trials of immune checkpoint inhibitors (ipilimumab, tremelimumab, nivolumab, or pembrolizumab) that reported overall survival according to patients' sex. Overall, 11 351 patients with advanced or metastatic cancers (7646 [67%] men and 3705 [33%] women) were included in the analysis; the most common types of cancer were melanoma (3632 [32%]) and non-small-cell lung cancer (3482 [31%]). The pooled overall survival HR was 0·72 (95% CI 0·65-0·79) in male patients treated with immune checkpoint inhibitors, compared with men treated in control groups. In women treated with immune checkpoint inhibitors, the pooled overall survival HR compared with control groups was 0·86 (95% CI 0·79-0·93). The difference in efficacy between men and women treated with immune checkpoint inhibitors was significant (p=0·0019).

INTERPRETATION

Immune checkpoint inhibitors can improve overall survival for patients with advanced cancers such as melanoma and non-small-cell lung cancer, but the magnitude of benefit is sex-dependent. Future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of immunotherapies in women, perhaps exploring different immunotherapeutic approaches in men and women.

FUNDING

None.

摘要

背景

尽管免疫系统反应的性别相关差异已得到公认，但对于患者性别对免疫检查点抑制剂作为癌症治疗效果的影响知之甚少。我们进行了一项系统评价和荟萃分析，以评估男性和女性之间免疫检查点抑制剂疗效的异质性。

方法

我们系统地检索了 PubMed、MEDLINE、Embase 和 Scopus 数据库，检索时间从数据库建立到 2017 年 11 月 30 日，以获取根据患者性别报告的死亡风险比（HR）的免疫检查点抑制剂（PD-1、CTLA-4 或两者的抑制剂）的随机对照试验。我们还审查了所有主要会议论文集的摘要和演示文稿。我们排除了非随机试验，仅考虑以英文发表的论文。主要终点是评估男性和女性之间免疫检查点抑制剂疗效的差异，以男性和女性研究参与者报告的总生存对数（HR）差异来衡量。我们使用随机效应模型计算男性和女性的汇总总生存 HR 和 95%CI，并使用交互检验评估这两个估计值之间的异质性。

结果

在我们的搜索中，有 7133 项研究符合条件，其中有 20 项关于免疫检查点抑制剂（依匹单抗、替西木单抗、纳武单抗或派姆单抗）的随机对照试验根据患者性别报告了总生存情况。总体而言，纳入分析的晚期或转移性癌症患者有 11351 名（7646 名男性和 3705 名女性）；最常见的癌症类型是黑色素瘤（3632 名，占 32%）和非小细胞肺癌（3482 名，占 31%）。接受免疫检查点抑制剂治疗的男性患者的汇总总生存 HR 为 0.72（95%CI 0.65-0.79），与接受对照组治疗的男性相比。接受免疫检查点抑制剂治疗的女性患者的汇总总生存 HR 与对照组相比为 0.86（95%CI 0.79-0.93）。男性和女性接受免疫检查点抑制剂治疗的疗效差异具有统计学意义（p=0.0019）。