Zhang Qiman, Zheng Jin, Wang Wen, Cornett Elyse M, Kaye Alan David, Urits Ivan, Viswanath Omar, Wei Fei-Long
Department of Integrated Chinese and Western Medicine Oncology, Shaanxi University of Traditional Chinese Medicine, Xianyang, 712000, China.
Key Oncology Department of Shaanxi Province, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.
Oncol Ther. 2022 Dec;10(2):363-375. doi: 10.1007/s40487-022-00209-0. Epub 2022 Oct 25.
Despite the growing evidence for the anticancer effect of metformin or its combination with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), the efficacies and side effects of such strategies in non-small cell lung cancer (NSCLC) patients with or without type 2 diabetes mellitus (T2DM) are not well understood. This meta-analysis was performed to determine the efficacy and side effects of metformin combined with EGFR-TKIs (MET-EGFR-TKIs) for the treatment of NSCLC with or without T2DM.
PubMed and Cochrane Library databases were used to retrieve relevant studies through August 2020 using the keywords "metformin", "EGFR-TKIs" ("gefitinib" or "erlotinib" or "afatinib" or "icotinib" or "dacomitinib") and "lung cancer". The patients in the experimental group received MET-EGFR-TKIs, while those in the control group received only EGFR-TKIs. The outcome analysis reported overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Random-effect models and fixed-effect models were used to estimate the combined hazard ratio (HR) and odds ratio (OR) depending on the data heterogeneity. Three studies (including 1996 patients) were included in the current meta-analysis.
There were significant differences in PFS (HR 0.84; 95% confidence interval (CI) 0.75-0.95; P = 0.004) and OS (HR 0.77; 95% CI, 0.50-1.04; P < 0.001) between the MET-EGFR-TKI and EGFR-TKI groups. Although the ORR (OR 1.38; 95% CI 0.66-2.88; P = 0.105) and DCR (OR 2.61, 95% CI 0.68-9.95, P = 0.160) were improved, there was no statistical significance. OS subgroup analysis showed that the combination was more effective in NSCLC with T2DM than in NSCLC without T2DM (HR 0.84; 95% CI 0.74-0.95; P < 0.005).
MET-EGFR-TKIs provided benefits for PFS and OS, and OS subgroup analysis showed that patients with NSCLC with T2DM received greater benefit than NSCLC patients without T2DM. However, further large-scale, well-designed randomized controlled trials (RCTs) are warranted to confirm the findings in the present investigation.
尽管越来越多的证据表明二甲双胍或其与表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）联合使用具有抗癌作用，但对于非小细胞肺癌（NSCLC）合并或不合并2型糖尿病（T2DM）患者采用此类治疗策略的疗效和副作用仍了解不足。本荟萃分析旨在确定二甲双胍联合EGFR-TKIs（MET-EGFR-TKIs）治疗合并或不合并T2DM的NSCLC的疗效和副作用。
利用PubMed和Cochrane图书馆数据库，通过检索截至2020年8月的相关研究，检索词为“二甲双胍”、“EGFR-TKIs”（“吉非替尼”或“厄洛替尼”或“阿法替尼”或“埃克替尼”或“达可替尼”）和“肺癌”。实验组患者接受MET-EGFR-TKIs治疗，而对照组患者仅接受EGFR-TKIs治疗。结局分析报告总生存期（OS）、无进展生存期（PFS）、客观缓解率（ORR）和疾病控制率（DCR）。根据数据异质性，采用随机效应模型和固定效应模型估计合并风险比（HR）和比值比（OR）。本荟萃分析纳入了三项研究（共1996例患者）。
MET-EGFR-TKI组与EGFR-TKI组在PFS（HR 0.84；95%置信区间（CI）0.75-0.95；P = 0.004）和OS（HR 0.77；95% CI，0.50-1.04；P < 0.001）方面存在显著差异。尽管ORR（OR 1.38；95% CI 0.66-2.88；P = 0.105）和DCR（OR 2.61，95% CI 0.68-9.95，P = 0.160）有所改善，但无统计学意义。OS亚组分析显示，该联合治疗在合并T2DM的NSCLC患者中比在未合并T2DM的NSCLC患者中更有效（HR 0.84；95% CI 0.74-0.95；P < 0.005）。
MET-EGFR-TKIs对PFS和OS有益，OS亚组分析显示，合并T2DM的NSCLC患者比未合并T2DM的NSCLC患者获益更大。然而，需要进一步开展大规模、设计良好的随机对照试验（RCT）来证实本研究结果。
