非小細胞肺癌常以erlotinib 與gefitinib 治療，兩藥物為弱鹼性需酸性環境確保溶解與吸收。過往研究顯示與胃酸抑制劑交互作用會造成erlotinib 及gefitinib 血中濃度偏低，因倫理疑慮隨機分派試驗實務難執行，因此本篇針對觀察性研究以系統性回顧與統合分析探討此藥物交互作用對於肺癌病人存活率的影響。使用關鍵字 ([proton-pump inhibitor] or [histamine 2-receptor antagonist] or [acid suppressant]) AND (erlotinib or gefitinib or [tyrosine kinase inhibitors]) 搜尋PubMed、Cochrane Library、Embase 及Google Scholar 上，2023 年5 月前的文獻， 納入erlotinib 或gefitinib 併用胃酸抑制劑對存活率影響的觀察性研究，並排除無全文、語言非中文或英文的文獻。採Newcastle-Ottawa scale 評讀， 隨機效應模式統合分析， 並以Cochran Q-test 及I2 評估異質性。15 篇世代研究符合本篇納入條件，共17,455 人。整體納入研究之證據品質優良（高證據品質11 篇，中證據品質4 篇）。統合分析結果，併用胃酸抑制劑顯著縮短整體存活期overall survival (OS) 及無惡化存活期progression-free survival (PFS): OS (hazard ratio [HR]: 1.38; 95% confidence interval [CI]1.18–1.63; I2 = 79%); PFS (HR: 1.50; 95% CI, 1.26–1.79; I2 = 75%)，其中併用protonpump inhibitors (PPIs) 亦影響OS (HR: 1.54; 95% CI, 1.19–1.99; I2 = 92%)，第二型組織胺阻斷器組則無顯著影響OS (HR: 1.08; 95% CI, 0.98–1.19; I2 = 21%)。紅疹副作用發生率併用胃酸抑制劑組顯著較低 (odds ratio: 0.59; 95% CI, 0.45–0.79; I2 = 0%)。統合分析結果顯示，肺癌病人使用erlotinib、gefitinib 等藥物，若同時併用胃酸抑制劑尤其是PPIs，可能顯著減少病人整體存活期及無惡化存活期。

 

Erlotinib and gefitinib are widely used to treat non–small cell lung cancer. They are weakly basic, which increases their solubility in an acidic environment. The concomitant use of acid suppressants with erlotinib or gefitinib decreases the serum concentration of erlotinib or gefitinib. This systematic review evaluated the clinical impact of this drug–drug interaction. We searched PubMed, Cochrane Library, Embase and Google Scholar for observational studies evaluating survival rates in patients with lung cancer and concomitant use of acid suppressants and erlotinib or gefitinib from inception until May, 2023. Studies without full text, studies not written in English or Chinese were excluded. The Newcastle-Ottawa Scale was used to evaluate the risk of bias of included studies. We conducted a random-effects meta-analysis and evaluated heterogeneity between studies by using the Cochran Q-test and I2 statistic. We included 15 cohort studies with a total of 17,455 patients. The overall quality of the included studies is good, with 11 high-quality studies and 4 fair-quality studies. The pooled hazard ratio (HR) for overall survival (OS) was 1.38 (95% confidence interval [CI], 1.18–1.63; I2 = 79%), and that for progression-free survival (PFS) was 1.50 (95% CI, 1.26–1.79; I2 = 75%). In the subgroup analysis by proton-pump inhibitor (PPI), the HR for OS was 1.54 (95% CI, 1.19–1.99; I2 = 92%). The incidence of rash was lower in the concomitant acid suppressant group than in the other groups. (odds ratio: 0.59; 95% CI, 0.45–0.79; I2 = 0%) Our results indicate that the concomitant use of erlotinib or gefitinib with acid suppressants, especially PPIs, can decrease OS and PFS.

 

Submitted for publication: 2023.1.15; Accepted for publication: 2023.6.6