具表皮生長因子受體突變之非小細胞肺癌病人其腦轉移治療的回溯性研究

Management of Brain Metastases in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer：A Retrospective Multi-Institutional Analysis

陳建宏(Chien-Hung Chen)

指導教授 ： 鍾飲文

共同指導教授 ： 黃旼儀(Ming-Yii Huang)

高雄醫學大學/醫學院/醫學研究所碩士班/碩士(2019年)

摘要

引言： 腦轉移是非小細胞肺癌患者死亡的主要原因之一。在診斷腦轉移後，優先使用表皮生長因子受體酪氨酸激酶抑制劑(epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKI)進行治療控制手段，而推遲全腦放射線治療(whole-brain radiation therapy, WBRT)是有爭議的。我們針對全腦放射線治療對此類病人總存活率的影響，進行臨床紀錄的回溯性研究。

研究方法：本研究共納入一百四十一例，診斷腦轉移且具表皮生長因子受體突變的非小細胞肺癌患者進行分析。所有患者在2011年至2015年期間皆有接受表皮生長因子受體酪氨酸激酶抑制劑治療，部分並有接受全腦放射線治療。本研究通過門診或電話進行患者追蹤直至2018年6月。總存活率起算日期以腦轉移診斷日開始測量。通過Kaplan-Meier分析和Cox迴歸方法分析及計算各項因子和存活數據。

研究結果： 所有患者均有接受表皮生長因子受體酪氨酸激酶抑制劑治療。表皮生長因子受體酪氨酸激酶抑制劑使用時間的中位數為12.5個月(95％信賴區間，10.5-14.4個月)。九十四名患者(66.7％)接受了全腦放射線治療治療，平均輻射劑量為3781±749cGy。 追蹤時間的中位數為為20.3個月(95％信賴區間，16.9-23.7個月)，在有接受全腦放射線治療組和僅使用表皮生長因子受體酪氨酸激酶抑制劑治療組的腦轉移後總存活中位時間分別為14.3個月(95% CI, 9.5到18.3個月)和2.3個月(95% CI, 2到2.6個月; P <0.001)。 在多變量分析中：接受全腦放射線治療、女性和肺部手術此三因子與總存活率改善有顯著相關。 一年存活率在有接受全腦放射線治療組和僅使用表皮生長因子受體酪氨酸激酶抑制劑治療組分別為81.9％和59.6％(P = 0.002)，具有顯著差異。

結論： 發生腦轉移且具表皮生長因子受體突變的非小細胞肺癌病患，總存活率受益於表皮生長因子受體酪氨酸激酶抑制劑和全腦放射線治療的組合。有必要在允許的情況下進行進一步的前瞻性研究，以確認臨床治療結果。

關鍵字

全腦放射線治療 ； 腦轉移 ； 非小細胞肺癌 ； 肺腺癌 ； 酪氨酸激酶抑制劑

並列摘要

Introduction： Brain metastases (BM) are the major cause of death in patients with non-small-cell lung cancer (NSCLC). The use of upfront epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the withholding of whole-brain radiation therapy (WBRT) is controversial. We aimed at the impact of WBRT on overall survival (OS).

Methods and Materials： A total of 141 EGFR-mutated NSCLC patients with BM were included. All patients received EGFR-TKIs with or without WBRT between 2011 and 2015 at three cancer centers. Patient follow-ups were conducted by clinic visits or telephone calls until June 2018. OS was measured from the date of brain metastases. The survival data were collected and calculated by Kaplan-Meier analysis and the Cox regression method.

Results： All patients had TKIs. The median duration of TKIs use was 12.5 months (95% confidence interval (CI), 10.5-14.4). Ninety-four patients (66.7 %) had been treated with WBRT (TKI + WBRT group) with mean radiation dose of 3781±749cGy to brain metastases. With a median follow-up of 20.3 months (95% CI, 16.9-23.7), the median survival after BM was 14.3 months (95% CI, 9.5 to 18.3) in the TKI + WBRT group and 2.3 months (95% CI, 2 to 2.6) in the TKI alone group (P < 0.001). On multivariate analysis, WBRT, female gender and lung surgery were associated with improved OS (P < 0.001). The 1-year survival rate were 81.9% versus 59.6% in TKI+WBRT group and TKI alone group, respectively (P = 0.002).

Conclusions： EGFR-mutant NSCLC patients with BM benefited from the combination of EGFR-TKIs and WBRT. Further prospective study is warranted.

並列關鍵字

whole brain radiotherapy ； brain metastases ； non-small-cell lung cancer ； adenocarcinoma ； tyrosine kinase inhibitors

參考文獻

1. Taiwan health promotion administration ministry of health and welfare, Cancer registry annual report, 2016. December 2018

2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians.

3. Ezzati M, Henley SJ, Lopez AD, et al. Role of smoking in global and regional cancer epidemiology： current patterns and data needs. Int J Cancer 2005;116(6)：963–971.

4. National Comprehensive Cancer Network, Non-small cell lung cancer (Version 3.2019). https：//www.nccn.org/professionals/physician_gls/pdf/nscl.pdf Accessed February 6, 2019.

5. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363(8)：733–742.