Liu Ruifeng, Wei Shihong, Zhang Qiuning, Zhang Xueliang, Luo Hongtao, Tian Jinhui, Li Yi, Ge Long, Wang Xiaohu
The First Clinical Medical College of Lanzhou University.
Radiotherapy Oncology Department, Gansu Provincial Cancer Hospital.
Medicine (Baltimore). 2019 Jul;98(29):e16427. doi: 10.1097/MD.0000000000016427.
Preclinical in vitro experiments demonstrated that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) might have synergistic effect in combination with radiotherapy on Non-small cell lung cancer (NSCLC), but the clinical trials showed inconsistence results in NSCLC patients with EGFR status unknow or mutations. This study aimed to determine if added TKIs to Thoracic radiotherapy (TRT) improve primary disease response rate (RR) and survival outcomes in advanced or metastatic NSCLC.
We searched MEDLINE, EMBASE, and Cochrane Library from January 2000 to December 2017 for eligible studies where patients received concurrent EGFR TKIs and TRT or CRT. Concerned outcomes were primary tumor RR, overall survival (OS), and adverse events (AEs). The meta-analysis was performed using Stata software (version 12.0). Random effects models were used to pool outcomes across studies. Sensitivity analysis was performed to determine if the results would be different.
We found 16 prospective clinical trials with mature results for meta-analyses. Twelve studies including 446 patients reported the RR and survival outcomes of TRT combined TKIs. The CR, PR, SD, and PD, respectively, were 0.06 (95% CI 0.03-0.09, I = 0%), 0.44 (95% CI 0.38-0.49, I = 64.9%), 0.29 (95% CI 0.24-0.34, I = 78.4%), and 0.15 (95% CI 0.11-0.19, I = 84.2%). One- and 2-year OS, respectively, were 0.52 (95% CI 0.44-0.60, I = 38.8%) and 0.26 (95% CI 0.18-0.33, I = 0%). Four studies including 182 patients reported the RR and survival outcomes of CRT combined TKIs. The pooled CR, PR, SD, and PD, respectively, were 0.12 (95% CI 0.02-0.22, I = 69.1%), 0.41 (95% CI 0.27-0.55, I71.6%), 0.31 (95% CI 0.16-0.46, I = 79%), and 0.14 (95% CI -0.01-0.30, I = 87.8%). Only 1 study reported the survival event rate, 1- and 2-year OS, respectively, were 0.83 (95% CI 0.71-0.94) and 0.67 (95% CI 0.54-0.81). There were not severe adverse events (SAEs) reported either TRT combined TKIs or CRT combined TKIs.
There is evidence, albeit of low quality, that added the TKIs to TRT or CRT may improve RR and survival outcomes in patients with EGFR mutant status unknown advanced or metastatic NSCLC relative to other studies of TKIs alone, TRT alone or CRT.
临床前体外实验表明，表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）与放疗联合应用于非小细胞肺癌（NSCLC）可能具有协同作用，但在EGFR状态未知或存在突变的NSCLC患者中，临床试验结果并不一致。本研究旨在确定在胸部放疗（TRT）中添加TKIs是否能提高晚期或转移性NSCLC的原发疾病缓解率（RR）和生存结局。
我们检索了2000年1月至2017年12月的MEDLINE、EMBASE和Cochrane图书馆，以查找符合条件的研究，这些研究中的患者接受了EGFR TKIs与TRT或同步放化疗（CRT）联合治疗。关注的结局指标为原发肿瘤RR、总生存期（OS）和不良事件（AEs）。使用Stata软件（12.0版）进行荟萃分析。采用随机效应模型汇总各研究的结局。进行敏感性分析以确定结果是否会有所不同。
我们发现16项有成熟结果的前瞻性临床试验可用于荟萃分析。12项研究（共446例患者）报告了TRT联合TKIs的RR和生存结局。完全缓解（CR）、部分缓解（PR）、疾病稳定（SD）和疾病进展（PD）分别为0.06（95%可信区间[CI]0.03 - 0.09，I² = 0%）、0.44（95%CI 0.38 - 0.49，I² = 64.9%）、0.29（95%CI 0.24 - 0.34，I² = 78.4%）和0.15（95%CI 0.11 - 0.19，I² = 84.2%）。1年和2年总生存率分别为0.52（95%CI 0.44 - 0.60，I² = 38.8%）和0.26（95%CI 0.18 - 0.33，I² = 0%）。4项研究（共182例患者）报告了CRT联合TKIs的RR和生存结局。汇总的CR、PR、SD和PD分别为0.12（95%CI 0.02 - 0.22，I² = 69.1%）、0.41（95%CI 0.27 - 0.55，I² = 71.6%）、0.31（95%CI 0.16 - 0.46，I² = 79%）和0.14（95%CI - 0.01 - 0.30，I² = 87.8%）。只有1项研究报告了生存事件率，1年和2年总生存率分别为0.83（95%CI 0.71 - 0.94）和0.67（95%CI 0.54 - 0.81）。未报告TRT联合TKIs或CRT联合TKIs有严重不良事件（SAEs）。
有证据表明，尽管质量较低，但相对于单独使用TKIs、单独使用TRT或CRT的其他研究，在TRT或CRT中添加TKIs可能改善EGFR突变状态未知的晚期或转移性NSCLC患者的RR和生存结局。
