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系統識別號 U0026-1408202014412300
論文名稱(中文) 晚期膽道癌治療發展及相關基因變異之綜觀
論文名稱(英文) Exploration of treatment strategy and associated mutation profiling in advanced biliary tract cancer
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 108
學期 2
出版年 109
研究生(中文) 姜乃榕
研究生(英文) Nai-Jung Chiang
學號 S98031041
學位類別 博士
語文別 英文
論文頁數 114頁
口試委員 指導教授-沈延盛
召集委員-洪澤民
口試委員-陳立宗
口試委員-顏家瑞
口試委員-李健逢
中文關鍵字 膽道癌  化學治療  標靶治療  EB病毒相關之淋巴上皮瘤樣膽管癌 
英文關鍵字 Biliary tract cancer  chemotherapy  targeted therapy  EBV-lymphoepithelioma like cholangiocarcinoma 
學科別分類
中文摘要 膽道癌是一個難以治癒的癌症,其根據不同發生位置分為肝內、肝門和肝外膽道癌及膽囊癌,一般來說亞洲國家發生率比西方國家高,不同種族發生膽道癌的原因也不相同,且不同部位的膽道癌其基因變異的種類和發生率也不一樣。目前針對不可切除局部晚期性和復發或轉移性膽道癌的標準化學治療為gemcitabine和platinum,整體存活期一般來說大概為12個月。對於台灣膽道癌的病人來說,可以使用的藥物仍相當有限,治療方面仍具有相當的醫療迫切需求,需要再持續地努力。本論文主要著重於膽道癌相關研究,主要包含兩部份:第一部份為膽道癌藥物臨床試驗的結果發表,及試驗後續生物標記對預後的分析;第二部份為針對EB病毒相關之類淋巴上皮瘤樣膽管癌,其基因變異及腫瘤微環境中免疫細胞組成及活化路徑剖析的研究結果。
在第一部份研究中,我們利用組織免疫染色法評估了ROS-1,ALK及c-MET (RAM)三個蛋白在參與T1210臨床試驗的病人腫瘤組織上表現之情形,以及其與臨床療效及預後之相關性。T1210試驗為單獨使用化療或合併抗表皮生長因子抗體(cetuximab)當作膽道癌第一線治療的隨機分配第二期雙臂臨床研究。結果顯示若腫瘤具有RAM蛋白高度表達者(組織免疫染色結果呈現任一個蛋白質為三價陽性),比起RAM蛋白低度表達者有較差的整體平均存活期。若僅考慮RAM蛋白低表現組的病患,相較於化療單獨使用,使用化療合併cetuximab則具有較好之療效,較高的疾病控制率,較長的疾病無惡化存活期及整體存活期。此一臨床試驗後續生物標記分析顯示,將來使用抗表皮生長因子抑制劑用於肝內膽道癌的臨床試驗,可以考慮將RAM蛋白高度表現當作篩選病人的生物標記。
雖然Gemcitabine和Cisplatin複方化療 (簡稱GC)是目前最常作為無法手術局部晚期或轉移性膽道癌的標準化學治療處方,但此複方使用在亞洲族群比西方族群的病人有較高的第三級以上之中性白血球低下之副作用及腸胃不適的症狀,值得發展其他替換的化療處方,讓台灣病人能得到有效且低副作用的治療。此研究為一個第二期的單臂臨床試驗,使用每兩週一次800 mg/m2的Gemcitabine,加上根據體表面積每天給予80/100/120 mg 的S-1,連續投予十天且休息四天,稱為modified GS處方,當作局部晚期無法開刀或轉移性膽道癌病人的第一線治療。病人接受modified GS處方的疾病無惡化存活期和整體存活期分別為5.4個月和12.7個月,12週的疾病控制率為69.6%,且第三級以上治療相關的副作用只發生在<6%的患者中,顯示modified GS處方對膽道癌患者有不錯的療效,並且具有良好的安全性,值得進一步發展及應用於日常臨床治療。
在第二部份的研究中,我們針對EB病毒相關之淋巴上瘤樣膽管癌進行研究,此為一特殊肝內膽管癌亞型,具有獨特的病理特徵及大量腫瘤旁的免疫細胞浸潤。研究結果顯示EB病毒相關之淋巴上瘤樣膽管癌中的T細胞和巨噬細胞比起腫瘤細胞有更高度PDL1蛋白的表現,較少的基因突變表現,及具有後天性免疫路徑的活化。其腫瘤微環境的組成顯示此腫瘤對免疫檢查點抑制劑可能較有效,EB病毒相關之淋巴上瘤樣膽管癌的病人在化學治療失敗後,可以優先考慮免疫治療。
英文摘要 Biliary tract cancer (BTC) is a lethal malignancy, which includes intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC) with significant variations in incidence ethnically and geographically. Different distribution of genetic mutations was also noted in different subtypes of BTC. The current standard of care for patients with advanced BTC (ABTC) is gemcitabine plus platinum combination chemotherapy. However, the achievable median overall survival (OS) with such regimens is generally around 12 months. In Taiwan, there is an unmet medical need in the treatment of ABTC, which is worthy to have further investigation. In this thesis, we focus on the clinical trials of drug development with post-hoc biomarker analysis in ABTC and exploration of immune profiling in Epstein-Barr Virus-lymphoepithelioma like cholangiocarcinoma (EBV-LELCC), a rare subtype of IHCC.
In the first part, we evaluated the aberrant ROS1, ALK or c-MET (RAM) protein expression as predictive and prognostic biomarkers in a prospective cohort of ABTC patients who received gemcitabine plus oxaliplatin (GEMOX) or cetuximab plus GEMOX (C-GEMOX) in a randomized phase II T1210 study. Of 110 tumors with immunohistochemistry (IHC) staining for all three markers, 18 were RAMhigh (IHC intensity 3+ for any markers) and all were IHCC. Of the patients with IHCC, median overall survival (OS) of RAMhigh group was inferior to that of the RAMlow group. RAMhigh remained an independently adverse prognostic factor for OS. In the RAMlow group, C-GEMOX significantly improved the disease control rate (DCR), median progression-free survival (PFS), and marginally prolonged median OS, compared to GEMOX. RAM expression may serve as a stratification factor in future trials of anti-EGFR inhibitors in IHCC.
Gemcitabine and cispaltin (GC) doublet regimen had benn the standard chemotherapy in ABTC. However, GC required vigorous hydration and administration of potent antiemetics to prevent cisplatin-related adverse events and resulted in grade 3/4 neutropenia significantly in the Asian population. We tried to explore another regimen to overcome above limitations. The aim of the current phase II trial is to evaluate the efficacy and safety of biweekly gemcitabine in combination with a full dose of S-1 (80/100/120 mg/day by BSA) on days 1–10 every 2 weeks, termed the ‘modified GS’ regimen, as the frontline treatment in patients with ABTC. The PFS and OS was 5.4 months (95% confidence interval [CI]: 3.5–7.0), and 12.7 months (95% CI: 6.1–15.6), respectively. The study met its primary endpoint with a 12-week DCR of 69.6% in 46 evaluable patients. Grade 3/4 treatment-related adverse events occurred in <6% of patients. Modified GS showed moderate efficacy with a favorable safety profile in ABTC patients, thus mandating further assessment.
In the second part, we focused on the exploration of immune profiling in EBV-LELCC. EBV-LELCC was a rare subtype of IHCC, which was characterized of special pathological findings with dense infiltration of many immune cells. The results showed that PDL1 was expressed mostly in the T cell population and macrophages. Adaptive immune response was generally activated in the microenvironment. The special microenvironment leaded to be more sensitive to immunotherapy. PD1/PDL1 inhibitors could be considered as a therapeutic choice in patients with EBV-LELCC after failure to chemotherapy.
論文目次 中文摘要 I
English Abstract III
致謝 V
List of the content VII
List of tables VIII
List of figures IX
Abbreviations X
Chapter One: Background 1
Chapter Two: Clinical trials and post-hoc analysis 6
Introduction 6
Material and methods 11
Results 20
Chapter Three: The immune profiling in EBV-LELCC 27
Introduction 27
Material and methods 29
Results 34
Chapter Four: General Discussion and Conclusions 38
Chapter Five: Future Work 49
Tables 55
Figures 76
References 95
Appendices 108
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