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研究生:葉盈池
研究生(外文):Ying-Chih Yeh
論文名稱:Trastuzumab emtansine 用於治療 HER2 陽性轉移性乳癌病患之療效與成本效益
論文名稱(外文):Effectiveness and Cost-Effectiveness of Trastuzumab Emtansine in Women with HER2-Positive Locally Advanced or Metastatic Breast Cancer: A Systematic Review and Meta-Analysis
指導教授:戈鈺
指導教授(外文):Yu Ko
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:藥學系(碩博士班)
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:英文
論文頁數:55
中文關鍵詞:HER-2陽性轉移性乳癌T-DM1統合分析成本效果分析
外文關鍵詞:HER2-positive metastatic breast cancerT-DM1meta-analysiscost-effectiveness analysis
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背景: 轉移性乳癌是一種無法治癒的疾病,顯著的影響病人的生活品質。轉移性乳癌的治療目標是延長存活期及透過減少藥品相關的不良反應,而提升生活品質。過去的統合分析結果已經顯示trastuzumab emtansine (T-DM1) 可以顯著延長有第二型人類表皮生長因子受體 (HER-2) 陽性轉移性乳癌病人的存活時間。近來,許多隨機分派研究的最終結果被發表,但是目前為止並沒有統合這些最新研究結果的統合分析。

目的:進行收納檢驗T-DM1用於治療HER-2陽性、轉移性乳癌病人使用T-DM1療效與副作用隨機分派研究的系統性綜論與統合分析。此外,另一個目的是系統性的回顧現有針對此藥品的經濟學研究結果,目前並沒有收納T-DM1用於HER-2陽性、轉移性乳癌病人經濟學研究的系統性綜論。

檢索方法:電子檢索線上資料庫 (Medline、CENTRAL與Embase)。除此之外,也檢索正在進行中或未發表研究的臨床試驗註冊資料庫。

挑選條件:挑選評估T-DM1使用於HER-2陽性、局部進展性或轉移性乳癌病人療效的隨機分派研究。至於針對T-DM1經濟學效應的研究,納入條件為T-DM1作為治療比較對象之一的經濟效應評估研究。

資料收集與分析:兩位研究者獨立評估隨機分派研究的符合條件、擷取納入研究的資料,並評估偏誤風險。擷取的數據將進行統合分析,以風險比值的對數及其變異數統合研究結果。我們以the DerSimonian-Laird隨機效應模式進行所有結果的統合分析,並以Cochrane Q統計數據及I2分數計算研究之間的統計異質性。擷取符合收納條件的T-DM1經濟效應評估的必須資訊,並且以CHEERS指引評估這些研究的品質。

結果:四項隨機分派研究共2,462位受試者被納入這些統合分析中。合併結果顯示,T-DM1顯著改善整體存活率 (風險比值為0.75,95%信賴區間為0.67-0.85:I2分數為0%) 及未惡化存活率 (風險比值為0.67,95%信賴區間為0.52-0.85:I2分數為75%)。除此之外,相較於其他療程,T-DM1與嚴重(第三級及以上)的血小板低下及肝臟功能異常(轉氨酶濃度增加)有關,但是中性球低下、白血球低下、發熱性中性球低下、倦怠與腹瀉風險較低。納入統合分析的所有研究,偏誤風險整體而言為低。檢索到兩篇與T-DM1有關的成本效用分析,這兩篇研究的整體品質為高。Diaby等人的研究利用Markov模型評估T-DM1於不同給藥順序計算總療程花費的經濟效益,結果顯示如以trastuzumab合併pertuzumab及docetaxel為第一線治療,而T-DM1為二線治療時,進藥價需降低50%才符合經濟效益;另外Le等人的研究結果則為當患者每多活一生活品質調整生活年,給予T-DM1所需多花的費用(ICER)相較於lapatinib合併capecitabine為183,828美金。

結論:T-DM1相較於其他治療,為HER-2陽性、轉移性乳癌病人的有效治療藥物,且具有可耐受的副作用。有關於T-DM1的成本效益證據相當有限,並不能做出結論。
Background: Metastatic breast cancer is an incurable disease that significantly decreases patients’ quality of life. As such, the goals of treatment for metastatic breast cancer are to prolong survival and improve quality of life by reducing drug-related adverse events. Previous meta-analyses have shown that trastuzumab emtansine (T-DM1) can improve survival in patients with human epidermal growth factor receptor-2 (HER2) - positive, metastatic breast cancer. Recently several randomized controlled trials (RCTs) have published their final analyses, but no study has yet integrated all the evidence of T-DM1 from the latest RCTs.

Objectives: We conducted a systematic review and meta-analysis of published trials to examine the efficacy and safety of T-DM1 for patients with HER2-positive metastatic breast cancer. Additionally, our second objective was to systematically review existing economic evaluations of T-DM1, as there is currently no systematic review of cost-effectiveness analyses of T-DM1 in HER2-positive metastatic breast cancer patients.

Search methods: An electronic literature search of online databases (Medline, CENTRAL, and Embase) was performed. Moreover, trial registries were searched for ongoing and unpublished studies.
Selection criteria: For the selection of studies that assessed the effectiveness of T-DM1, RCTs that compared T-DM1 with other active treatment agents in HER2-positive locally advanced or metastatic breast cancer patients were eligible for inclusion. For the selection of studies that assessed the economic outcomes of T-DM1, those that involved T-DM1 as one of the treatment comparators in an economic evaluation of metastatic breast cancer were included.

Data collection and analysis: Two reviewers independently evaluated the eligibility of the RCTs, extracted the data, and assessed risk for bias of the included studies. The data extracted from the selected RCTs were pooled in a meta-analysis, and log hazard ratios (HRs) and variances were estimated. In addition, the DerSimonian-Laird random effects model was used for the meta-analysis of all outcomes, and the Cochran Q statistic and I2 score were used to detect heterogeneity. The essential information was extracted for those selected economic evaluations of T-DM1, and their quality was assessed by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guidelines.

Results: Four trials involving 2,462 participants were included in this meta-analysis. Pooled results showed T-DM1 substantially improved OS (hazard ratio [HR], 0.75; 95% CI, 0.67–0.85; I2 = 0%) and PFS ([HR, 0.67; 95% CI, 0.52–0.85; I2 = 75%). In addition, T-DM1 showed greater association with severe (grade 3 and higher) thrombocytopenia and liver dysfunction (increased aspartate aminotransferase) than other regimens, but a significantly lower rate of neutropenia, leukopenia, febrile neutropenia, asthenia, and diarrhea. All four trials included in the meta-analysis overall had a low risk of bias. Two cost-utility analyses involving T-DM1 were identified, and overall their quality was high. Diaby et al. developed a Markov model to assess the cost-effectiveness of various treatment sequences that involved T-DM1 and concluded that, to be a cost-effective scheme, the combination of trastuzumab plus pertuzumab plus docetaxel as a first-line regimen, followed by T-DM1 as second-line would need at least a 50 % reduction in the total drug acquisition cost. In the study by Le et al., the incremental cost effectiveness ratios (ICER) for T-DM1 treatment compared with lapatinib plus capecitabine was $183,828 per QALY.

Conclusions: T-DM1 is effective in the treatment of patients with HER2-positive metastatic breast cancer, and it has tolerable treatment toxicities compared with active controls. Little evidence was available regarding the cost-effectiveness of T-DM1 so no conclusions can be drawn.
Abbreviations 1
Contents 2
中文摘要 4
Abstract 6
List of figures 10
List of tables 11
Chapter 1 Introduction 12
1.1 Background 12
1.1.1 Epidemiology and etiology of breast cancer 12
1.1.2 Staging and prognosis of breast cancer 12
1.1.3 Metastatic breast cancer: therapy concepts 13
1.1.4 Management of HER2-positive metastatic breast cancer 14
1.1.5 The role of T-DM1 as a second-line treatment of advanced or metastatic HER2-positive breast cancer 16
1.2 Economic evaluation of T-DM1 17
1.3 Study aims 18
Chapter 2 Methods 20
2.1 Outcomes of interest 20
2.2 Identification of eligible studies 21
2.3 Data extraction 22
2.4 Study quality assessment 23
2.5 Meta-analysis of selected RCTs 23
Chapter 3 Results 25
3.1 Studies identified 25
3.2 Efficacy and safety of T-DM1 31
3.3 Subgroup analysis 37
3.4 Publication bias 39
3.5 Cost effectiveness of T-DM1 39
3.6 Quality of evidence 40
Chapter 4 Discussion 44
4.1 Description of the main findings 44
4.2 Comparison with previous meta-analyses 44
4.3 Strengths and weaknesses of this study 45
Chapter 5 Conclusions 47
References 48
Appendices 52
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