编者按：子宫内膜癌是妇科恶性肿瘤中的常见类型，其发病率在全球范围内呈上升趋势。近年来，免疫联合化疗作为一种新兴的治疗策略，已在改善原发性晚期或复发性子宫内膜癌患者的生存期和治疗反应持久性方面展现出显著优势。然而，随着免疫联合化疗的广泛应用，其安全性问题也逐渐受到关注。

 

3月28～30日在美国奥兰多召开的美国国立综合癌症网络（NCCN）2025年会上，一项免疫联合化疗治疗原发性晚期或复发性子宫内膜癌不良事件发生率的荟萃分析入选大会壁报展示。《肿瘤瞭望》荣幸邀请到中山大学肿瘤防治中心刘继红教授就上述研究进行点评，现将内容整理如下，以飨读者。

 

 

免疫联合化疗在改善原发性晚期或复发性子宫内膜癌患者生存期及治疗反应持久性方面展现出显著优势，但其免疫相关不良事件（iRAEs），如甲状腺功能减退和皮疹/皮炎，以及静脉血栓栓塞（VTE）等安全问题仍需深入评估。本研究旨在通过荟萃分析明确免疫联合化疗相较于单纯化疗的VTE及iRAEs发生率差异。

 

 

 

系统性检索Medline、Embase及Cochrane数据库（截至2024年8月10日），纳入报道甲状腺功能减退、皮疹/皮炎及VTE事件的II/III期随机对照试验（RCT）。

 

 

由两名研究者独立提取数据，如有分歧则由第三方评审者判定。

 

 

主要终点：甲状腺功能减退、皮疹/皮炎及VTE事件的发生率。

 

 

采用随机效应模型及Mantel-Haenszel方法计算危险比（RR）和危险差（RD），并计算95%置信区间（CI）。异质性通过I2统计量和Cochran’s Q检验评估，P<0.05视为具有统计学意义。

 

 

 

共纳入4项III期RCT（AtTEnd、NRG-GY018、RUBY、DUO-E）及1项II期RCT（MITO END-3），涉及2 624例患者。所有试验均比较免疫联合化疗（卡铂+紫杉醇）与安慰剂联合化疗的疗效与安全性。

 

图1.纳入研究结果及特征

 

 

●甲状腺功能减退：免疫联合化疗组12.53%，单纯化疗组3.61%（RR：3.27；95%CI:2.34～4.57；P<0.00001）（图2A）；

 

●皮疹/皮炎：免疫联合化疗组12.07%，单纯化疗组6.85%（RR：1.80；95%CI:1.39～2.33；P<0.00001）（图2B）；

 

●VTE：免疫联合化疗组3.56%，单纯化疗组2.07%（RR：1.60；95%CI:0.97～2.64；P=0.07）（图2C）。

 

图2.不良反应发生率结果：A.甲状腺功能减退；B.皮疹/皮炎；C.VTE

 

 

免疫联合化疗组甲状腺功能减退及皮疹/皮炎的发生率显著高于单纯化疗组，需在临床中加强监测与管理。虽然免疫联合化疗组的VTE发生率更高，但差异无统计学意义，需更大样本研究明确关联性。本研究强调需权衡免疫联合化疗方案的生存获益与潜在风险，建议强化个体化治疗决策及不良事件管理以优化患者结局。

 

 

在肿瘤综合治疗领域，关注免疫治疗联合化疗方案的安全性管理极具临床价值。然而，本荟萃分析将"不良事件发生率"作为核心研究指标存在一定局限性。从药理学机制分析，化疗基础上叠加其他治疗手段（包括免疫治疗或其他抗肿瘤药物）必然导致毒性增加，这一规律本已众所周知。以甲状腺功能减退和皮肤毒性事件为例，其发生率差异本质上源于治疗方案的叠加效应，因此该研究结论的得出缺乏足够的临床创新价值。当然，本研究仍为临床工作者提供了重要的安全性警示，强调在实施联合治疗方案时需建立完善的监测体系与应急预案。

 

 

摘要原文

 

Meta-Analysis of Randomized Controlled Trials(RCTs)to Evaluate the Incidence of Venous Thromboembolism(VTE)and Immune-Related Adverse Events(iRAEs)in Patients with Primary Advanced or Recurrent Endometrial Cancer Treated with Immunochemotherapy

 

INTRODUCTION:

 

Immunochemotherapy，combining immune checkpoint inhibitors(ICIs)with platinum-based chemotherapy，has demonstrated improved survival and durable treatment responses for patients with primary advanced or recurrent endometrial cancer(EC).While enhancing treatment efficacy，immunochemotherapy also raises concerns about adverse events，specifically hypothyroidism，rash/dermatitis，and venous thromboembolism(VTE).This meta-analysis evaluates the incidence and relative risk of iRAEs(hypothyroidism and rash/dermatitis)and VTE in patients with primary advanced or recurrent EC treated with immunochemotherapy compared to chemotherapy alone.

 

METHOD:

 

Literature Search:

 

We conducted a comprehensive literature search using Medline，Embase，and Cochrane databases from inception through August 10th，2024.

 

Eligibility Criteria:

 

Eligible studies included Phase II/III RCTs utilizing immunochemotherapy in primary advanced or recurrent EC reporting hypothyroidism，rash/dermatitis，and VTE(deep vein thrombosis and/or pulmonary embolism)events.

 

Data Extraction:

 

Data extraction was independently conducted by two authors;discrepancies were resolved by a third reviewer.

 

Study Outcome Measures:

 

The primary endpoint of our meta-analysis was the incidence of hypothyroidism，rash/dermatitis，and VTE(deep vein thrombosis and/or pulmonary embolism)events.

 

Data Synthesis and Analysis.The primary meta-analytic approach was a random effects model using the Mantel-Haenszel(MH)method.This method was used to calculate the estimated pooled risk ratio(RR)and risk difference(RD)with 95%confidence intervals(CI).Heterogeneity among the studies was assessed using the I2 statistic and Cochran’s Q-statistic.A p-value of less than 0.05 was considered statistically significant.

 

RESULTS:

 

Search Results:

 

A total of 2624 patients from four Phase III RCTs(AtTEnd，NRG-GY018，RUBY，DUO-E)and one phase II RCT(MITO END-3)were eligible for evaluation of hypothyroidism，rash/dermatitis，and VTE，events.

 

Characteristics of the Studies:

 

All five trials compared immunotherapy combined with chemotherapy versus placebo plus chemotherapy in primary advanced or recurrent EC.

 

Meta-Analysis Results:

 

The incidence of hypothyroidism was 12.53%in the immunochemotherapy arm vs 3.61%in the control arm(RR 3.27;95%CI:2.34-4.57;P<0.00001).The incidence of rash/dermatitis was 12.07%in the immunochemotherapy arm vs 6.85%in the control arm(RR 1.80;95%CI:1.39-2.33;P<0.00001).The incidence of VTE was not statistically significant.3.56%in the immunochemotherapy arm vs 2.07%in the control arm(RR 1.60;95%CI:0.97-2.64;P=0.07).

 

CONCLUSIONS:

 

Patients with primary advanced or recurrent endometrial cancer treated with immunochemotherapy had a significantly higher incidence of hypothyroidism and rash/dermatitis compared to chemotherapy alone，emphasizing the need for proactive monitoring and management of these immune-related adverse events.While the incidence of venous thromboembolism was higher in the immunochemotherapy group，the difference was not statistically significant，suggesting further studies are needed to confirm this trend.The findings underscore the importance of balancing the therapeutic benefits of immunochemotherapy with its potential risks，reinforcing the need for personalized treatment strategies and vigilant adverse event management to optimize patient outcomes.