ジャーナル オブ グライコミックス & リピドミクス
オープンアクセス
ISSN: 2153-0637
ISSN: 2153-0637
王寧
降圧薬であるアンジオテンシン変換酵素阻害薬（ACEI）とアンジオテンシン受容体拮抗薬（ARB）が肺がん患者の臨床転帰に与える影響については、依然として議論が続いています。このメタ分析は、ACEI/ARBの使用と肺がん患者の生存との関連性を調査するために実施されました。対象となる研究は、2017年2月までのPubmed、Embase、Cochraneライブラリを検索して特定しました。ACEI/ARBが肺がんの生存に及ぼす影響について、95%信頼区間（CI）を伴うプールされたハザード比（HR）を計算しました。異質性と感度も分析しました。最終的に、合計29,156人の患者を対象とした9つの対象となる研究（8つの論文）をこのメタ分析に含めました。我々の研究結果では、ACEI/ARBの使用は肺がん患者の全生存率（OS）の良好さと関連していることが示された（HR、0.86、95% CI、0.76～0.98）。さらに、進行期臨床病期（IIIb～IV）（HR、0.77、95% CI、0.64～0.92）および非小細胞肺がん（NSCLC）（HR、0.78、95% CI、0.65～0.93）のサブグループで有意な関連が認められた。しかし、ACEI/ARBの使用と無増悪生存期間（PFS）の間には有意な関連は認められなかった（HR、0.84、95% CI、0.70～1.02）。ACEI/ARBは肺がん患者、特に進行期臨床病期またはNSCLC患者のOSを統計的に有意に延長する。しかし、PFSには実証可能な影響はない。肺がんは、世界中で男性のがんによる死亡原因の第 1 位、女性のがんによる死亡原因の第 2 位 (乳がんに次ぐ) であり、年間 160 万人が死亡していると推定されています。近年の診断と治療の進歩にもかかわらず、肺がん患者の予後は依然として満足のいくものではありません。症状をさらに緩和し、生存期間を延長するために、潜在的に有効な薬剤を探すための多大な努力が払われてきました。最近、肺がんの進行と死亡率に影響を与える可能性のある要因として、レニン アンジオテンシン系阻害薬 (RASB) に注目が集まっています。レニン アンジオテンシン系 (RAS) は腫瘍の成長と関連していることがわかっており、その主要なシグナル伝達分子はアンジオテンシン II (Ang II) です。Ang II の腫瘍促進効果は、アンジオテンシン 1 型受容体 (AT1R) として知られる G タンパク質共役受容体によって媒介されているようで、その発現はがん組織で増加していると報告されています。実際、 AT1R in tumor tissues and the clinical stage of the cancer. Namely, higher level has been detected in advanced stage. Although the concrete mechanism behind the tumor-promoting process of Ang II remains unclear, several relevant aspects have been discussed: (1) Ang II binds with AT1R and then the G-protein pathway is activated, followed by enhanced expression of cell growth-related factors, such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF1) and basic fibroblast growth factor (bFGF). These factors can promote tumor proliferation and angiogenesis. (2) The interaction of Ang II and AT1R leads to some receptors transactivation, such as epidermal growth factor receptor (EGFR). The increased expression and activity of these receptors has already been demonstrated to be associated with angiogenesis and metastasis of tumor cells. (3) The inflammation and oxidative stress are also regulated by Ang II binding with AT1R, releasing a series of pro-inflammatory mediators like TNF-α, ROS and various prostaglandins. Furthermore, the inflammatory cytokines are connected to cancer cachexia. Collectively, Ang II and AT1R play crucial roles in tumor initiation and development by stimulating proliferation, angiogenesis and inflammation. The effects of Ang II can be inhibited by renin-angiotensin system blockers (RASBs), including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). ACEIs prevent the generation of angiotensin II by inhibiting angiotensin-converting enzymes (ACEs) while ARBs selectively block angiotensin II binding to the AT1R. In addition, as a kind of metalloproteinase inhibitors, ACEIs might prevent the progression of cancer directly since metalloproteinase is related to tumor metastasis. Therefore, ACEIs/ARBs hold great promise for antitumor activity. Preclinical studies have suggested that RASBs might decrease tumor growth, inhibit tumor-associated angiogenesis and improve cancer survival, but clinical data have been mixed Results from observational studies in lung cancer patients are controversial and the potentiality of ACEIs/ ARBs in cancer treatment is still not fully understood. In order to shed light on possible roles of ACEIs/ARBs in antitumor treatment, we conducted the meta-analysis to determine the impact of ACEIs/ARBs on progression-free survival (PFS) and overall survival (OS) in lung cancer patients. Systematic literature search and quantitative analysis were conducted and reported according to a predefined protocol following the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines. A systematic literature search for eligible studies was conducted in Pubmed, Embase, and Cochrane library from inception to February, 2017. The following keywords and medical subject headings (MeSH) terms were used: anti-hypertensive, renin-angiotensin system blockers, RASBs, angiotensin-converting enzyme inhibitors, ACEIs, angiotensin receptor blockers, ARBs, angiotensin II type 1 receptor blockers, angiotensin receptor antagonists AND pulmonary neoplasm, lung neoplasm, lung cancer, pulmonary cancer, cancer of the lung, AND observational study, cohort study, case-control study, clinical trial. Reviews, case reports and editorials were considered unqualified. We also searched the reference lists of all relevant articles to identify any further potentially eligible articles. Two reviewers independently screened the articles by title and abstract based on pre-specified eligibility criteria. Studies were included if they met the following inclusion criteria: (1) the study design was cohort study or case-control study or randomized controlled trial; (2) the study assessed the usage of ACEIS/ARBs in the study population; (3) the study used clinically relevant outcomes such as PFS, OS, tumor recurrence or metastasis. Discrepancies between the two reviewers’ lists of articles for inclusion were resolved with discussion. When two or more studies had overlapping study samples, only the most recent or the most complete study was involved in the analysis. Two authors conducted the data extraction independently with disagreements resolved by consensus or an experienced third author. Data extracted included the name of the first author, publication year, country, age, histology type, cancer stage, population according to the ACEIs and ARBs type, follow-up period, outcomes, hazard ratios (HRs) with corresponding 95% confidential intervals (95% CIs) and covariates adjusted. If multiple HRs were reported, we chose the one with the most comprehensive adjustment for our meta-analysis. If only Kaplan-Meier curves were available, data were calculated from survival curves and estimation of the HR was then performed by the method reported by Tierney et al.Quality assessment for studies included in this meta-analysis was evaluated by using the Newcastle Ottawa Scale (NOS) criteria. The higher score out of a total of nine points indicated the higher quality, and the studies that met 5 or more of the NOS criteria were considered of adequate quality for the meta-analysis. In this meta-analysis, we calculated pooled HRs with their corresponding 95% CIs to assess the prognostic significance of ACEIs/ARBs use in lung cancer patients, and the HR greater than 1 implied an inferior prognosis for patients with ACEIs/ ARBs use. We used a random effects model approach for our meta-analyses to account for both within and between study heterogeneity. Statistical heterogeneity of effect estimates was carried out using Cochran’s Q test and Higgins I-squared statistic, and the I2 values ≥ 50% indicated significant heterogeneity. For additional analyses, subgroup meta-analysis was performed according to the histology (NSCLC or pan-lung cancer), medication type (ACEIs or ARBs) and the tumor stage (I-IIIa or IIIb-IV) respectively. Sensitivity analysis was performed by sequential omission of individual studies to examine the stability of the outcomes in this meta-analysis. Publication bias was evaluated by Egger’s test and Begg’s funnel plot. We performed all analyses using STATA software (version 12.0, Stata Corp, College Station, Texas, USA). A two-tailed P value less than 0.05 was considered significant in statistical tests.