中 文 摘 要
研究目的: 許多phase II臨床試驗的結果顯示gemcitabine單獨治療從未接受過化學治療的晚期非小細胞肺癌患者，腫瘤反應率(RR)約18-26 %。而以含有5-fluorouracil (5-FU)的化學藥物組合，治療非小細胞肺癌其RR為20-36 %。目前對於無法手術的晚期非小細胞肺癌之化學治療仍以cisplatin為主流，新組合之一的gemcitabine與cisplatin，其RR為26-54 %，可是部分患者無法忍受cisplatin的毒性與大量靜脈輸液之不方便性。由於體外試驗發現，gemcitabine與5-FU會互相加強抗癌作用，且已有幾個phase I/II臨床試驗併用gemcitabine與5-FU之報告。又因為5-FU的療效與給藥時間有關，已知高劑量連續輸注5-FU加上leucovorin，治療腸胃道癌症，證實有緩和療效。所以，我們採用gemcitabine 加上高劑量5-FU 與leucovorin的組合(GFL)進行phase II臨床試驗，期待出現高反應率、高症狀緩解率與低的化學治療毒性，以增加晚期非小細胞肺癌患者的生活品質。
研究方法: 本研究採單組、臨床試驗第二階段之初步試驗 (single arm, phase II, pilot study)。研究對象來自新樓與成大醫院，以前從未接受過化學治療之無法手術的stage IIIB/IV非小細胞肺癌患者，其活動力狀態(PS)為0-3 (ECOG)分。化學治療為gemcitabine 1000 mg/m2輸注半小時加上5-fluorouracil 2600 mg/m2合併leucovorin 500 mg/m2輸注24小時，每週化學治療一天，每連續三週休息一週，此即為一循環。每二循環結束時測一次胸部電腦斷層掃描，判讀療效RR (CR、PR、MR)。每一循環結束時測一次胸部X光攝影。每週評估與記錄之項目為肺癌症狀、臨床效益(PS、體重及止痛藥用量之變化)與化學治療之毒性。
研究結果: 從87年3月到88年6月共有27位患者接受治療，總計21位可評估。年齡分佈為29-79歲，平均63歲。PS≧2者佔71.4%，PS=3者佔33.3 %。76.2 % 為腺癌，81 %為stage IV，腦部轉移佔19%。腫瘤反應為4人PR，8人MR，總反應率為19 % (4/21)。腫瘤反應時間平均3.7週，中位數為4週，疾病開始惡化的時間之中位數為14週，相當於3.5個月。症狀緩解率分別為咳嗽63.2 % (12/19)，呼吸急促61.5 % (8/13)，疲倦感47.6 % (10/21)，虛弱無力23.1 % (3/13)，肋膜積水90 % (9/10)、咳血100 % (3/3)、胸痛80 % (4/5)、骨頭疼痛70 % (7/10)。臨床效益方面，42.9 % PS分數降低，19 % 體重增加、38.1 % 體重不變，41.2 % 止痛劑使用減少。grade 3/4毒性發生率分別為嗜中性白血球減少症9.6 %，貧血19 %，血小板減少症4.8 %。其中grade 2-4貧血發生率高達52.3 %。非血液毒性grade 3/4的發生率為: 噁心嘔吐9.6 %，腹瀉4.8 %、口唇炎14.3 % 和暫時性GOT/GPT過高4.8 %；grade 4感染為14.3 %。腫瘤反應率、症狀緩解率及毒性發生率與患者特質間皆不具有統計上之相關性。另外，本研究1位69歲女性患者出現與5-FU有關的腦病變之藥物不良反應。
結論: 本研究結果GFL有接近20 % 之腫瘤反應率、高症狀緩解率、高臨床效益與很低的毒性。所以GFL治療晚期非小細胞肺癌仍是可行的。特別對於無法手術之stage IV、PS=3又有腦部轉移之臨床不易治療的晚期非小細胞肺癌患者，當治療的主要考慮為緩解症狀、增加臨床效益，而又期望有相當的腫瘤反應時，GFL是可以選擇的化學治療組合。

Abstract
Purpose: Gemcitabine (GEM) monotherapy produced an objective tumor response in 18 to 26 % of patients with advanced non-small cell lung cancer (NSCLC) from several phase II studies. Treatment of 5-fluorouracil (5-FU) contained regimens in NSCLC had response rate (RR) of 20 to 36 %. Currently cisplatin-based chemotherapy may have modest survival benefit in most patients with NSCLC. However, cisplatin-associated toxicities and inconvenience limit its clinical use. GEM and 5-FU had been demonstrated to have synergistic effects on colorectal cancer cell line cells in vitro, and some phase I/II trials had reported this combination in the colorectal, gastrointestinal cancers. Weekly continuous infusion with high dose (HD) 5-FU and leucovorin is an effective regimen with few toxicities in colorectal cancer. Thus we design the study of "weekly gemcitabine plus HD 5-FU and leucovorin" (GFL) regimen to evaluate its effects and toxicities in advanced NSCLC.
Method: From National Cheng-Kung University hospital and Shin-Lau hospital, previously untreated patients meeting the following criteria were eligible : advanced (stage IIIb/IV) NSCLC, ECOG performance status of ≦3, normal renal and liver function. Weekly intravenous gemcitabine 1000mg/m2 infusion over half an hour plus 5-FU 2600mg/m2 and leucovorin 500mg/m2 continuous infusion over 24 hours on day 1, 8, 15. The cycle was repeated every 28 days. Overall tumor response, clinical benefit response and WHO toxicity are evaluated regularly. Tumor response was classified as complete response (CR), partial response (PR), minor response (MR) and stable disease (SD). Clinical benefit response (CBR) include performance improvement, symptom relief, body weight gain, and decreasing the usage of analgesics. Patients received GFL regimen until disease progression or maximal 6 cycles of treatment were completed.
Results: Twenty-seven patients enrolled and 21 patients were assessable from March 1998 to June 1999. Patients had a median age of 63 years (range, 29 to 79 years). Fifteen (71.4 %) were ECOG performance status of 2, 3 and seventeen (81 %) were stage IV. Four patients (19 %) had PR, eight (38.1 %) had MR, and seven (33.3 %) had SD. Median time to progression was 14 weeks, median duration of response was 4 weeks. Performance status improved in nine patients (42.9 %), and showed no change in eleven (52.3 %). Symptom relief were notable, including cough (63.2%), hamoptysis (100 %), pleural effusion (90 %), chest pain (80 %), bone pain (70 %), dyspnea (61.5 %), anorexia (33.3 %), and fatigue (47.6 %). Twelve patients (57.1 %) had body weight gain or stable, seven (41.2 %) decreased analgesic use after treatment. Two patients (9.6 %) occurred grade 3/4 neutropenia, two (4.8 %) did thrombocytopenia, four (19 %) did anemia, two (9.6 %) did nausea/vomiting, three (14.3 %) did stomatitis. We analyze the association between RR, CBR, toxicity and patient characteristics (gender, age, performance status, stage, histology, and metastatic sites), these are non-correlated statistically (p> 0.05).
Conclusion: Response rate and toxicities of GFL are comparable to gemcitabine alone, but GFL maybe have higher clinical benefit than gemcitabine alone, and lower toxicities than traditional cisplatin-based combination. GFL could be a palliative regimen, especially in improving quality of life for inoperable advanced NSCLC patients with poor performance.

目 錄
頁碼
中文摘要………………………………………………………I
英文摘要………………………………………………………III
誌謝……………………………………………………………V
目錄……………………………………………………………VI
表目錄…………………………………………………………VIII
圖目錄…………………………………………………………X
第壹章 研究背景………………………………………………1
第貳章 文獻回顧………………………………………………4
第一節 肺癌之流行病學……………………………………4
第二節 肺癌之病理學、分期與臨床表徵…………………7
第三節 非小細胞肺癌之處理………………………………9
第四節 非小細胞肺癌之化學治療…………………………10
第五節 非小細胞肺癌之新藥………………………………15
第六節 新藥Gemcitabine ………………………………… 19
第七節 5-Fluorouracil與Leucovorin ……………………… 23
第八節 Gemcitabine與5-Fluorouracil的加成作用………… 30
第參章 研究目的………………………………………………33
第肆章 研究方法………………………………………………34
第一節 研究對象……………………………………………34
第二節 研究設計……………………………………………36
第三節 研究流程……………………………………………37
第四節 化學治療計劃………………………………………40
第五節 評估方法與項目……………………………………42
第六節 統計分析方法………………………………………44
第伍章 研究結果………………………………………………46
第一節 研究對象……………………………………………46
第二節 化學治療後的腫瘤反應率…………………………51
第三節 化學治療後的症狀緩解率…………………………62
第四節 化學治療後的臨床效益……………………………65
第五節 化學治療後的毒性發生率…………………………71
第六節 嚴重藥物不良反應事件……………………………79
第陸章 討論……………………………………………………80
第一節 研究對象與腫瘤反應率……………………………80
第二節 症狀緩解率…………………………………………83
第三節 臨床效益……………………………………………84
第四節 毒性發生率…………………………………………86
第五節 晚期非小細胞肺癌化學治療之預後因子…………88
第六節 嚴重藥物不良反應…………………………………90
第柒章 結論與建議……………………………………………92
參考文獻………………………………………………………94
附錄
附錄一 肺癌之病理組織學分類表………………………A-1
附錄二 肺癌之TNM系統分期……………………………A-2
附錄三 臨床試驗計劃書…………………………………A-3
附錄四 腫瘤反應判讀標準………………………………A-4
附錄五 ECOG之PS評分標準 ……………………………A-5
附錄六 臨床試驗之病歷附註單…………………………A-6
附錄七 門診治療計劃與衛教單…………………………A-7
附錄八 輔助性問卷………………………………………A-8
附錄九 藥物不良反應記錄表……………………………A-9
表 目 錄
頁碼
表2.1.1 八十七年台灣地區十大死亡原因……………………………6
表2.1.2 八十七年台灣地區癌症死亡原因……………………………6
表2.1.3 八十七年台灣地區男女性癌症死亡排行序…………………6
表2.3.1 非小細胞肺癌的分期治療……………………………………9
表2.4.1 治療非小細胞肺癌之單獨的有效藥與常用藥………………11
表2.7.1 治療非小細胞肺癌之化學治療中含有5-FU的合併療法……29
表2.8.1 臨床上gemcitabine與5-fluorouracil之合併療法 ……………… 32
表4.4.1 本研究之化學治療藥物組合GFL Regimen ………………… 41
表5.1.1 病患特質………………………………………………………47
表5.2.1 腫瘤反應率(Response Rate)……………………………………53
表5.2.2 腫瘤反應的時間(Response Duration) …………………………54
表5.2.3 不同活動力狀態患者的腫瘤反應率…………………………56
表5.2.4 Stage IV患者不同狀態的腫瘤反應率 ……………………… 57
表5.2.5 四位腦部轉移患者的反應……………………………………57
表5.2.6 治療後腫瘤反應率與病患特質之關係………………………58
表5.3.1 治療後病人症狀緩解情形……………………………………63
表5.3.2 治療後症狀緩解率與病患特質之關係………………………64
表5.4.1 本研究21位病患接受治療前後之「PS分數」的變化………67
表5.4.2 以GFL regimen治療後病患活動力狀態(PS)之改變情形…… 68
表5.4.3 病患活動力狀態(PS)分數之變化與性別年齡的關係….……68
表5.4.4 治療後病人的體重變化………………………………………69
表5.4.5 治療期間止痛劑的處方變化…………………………………70
表5.5.1 化學治療後的毒性發生率 (單位：人)………………………74
表5.5.2 化學治療後的毒性發生率 (單位：人-劑)……………………75
表5.5.3 完全沒有出現化學治療之毒性的人數………………………77
表5.5.4 治療後grade 3/4毒性發生率與病患特質之關係 …………… 78
表6.1.1 比較本研究GFL與已知研究之療效 ………………………… 81
表6.1.2 An ECOG Trial from 1999 ASCO ………………………………82
表6.2.1 比較本研究GFL與已知研究之症狀緩解率…………………83
表6.3.1 比較本研究GFL與已知研究之PS改善率……………………85
表6.4.1 比較本研究GFL與已知研究之毒性發生率…………………86
圖 目 錄
頁碼
圖2.1 非小細胞肺癌的化學治療合併療法之演進………………………14
圖2.2 Gemcitabine的化學結構……………………………………………22
圖2.3 Gemcitabine的抗癌作用機轉………………………………………22
圖2.4 5-Fluorouracil的化學結構……………………………………………28
圖2.5 5-FU與Leucovorin的生物調節作用…………………………… ……28
圖2.6 Gemcitabine與5-Fluorouracil的加成作用機轉理論…………………30
圖4.1 研究流程圖…………………………………………………………39
圖5.1 患者之年齡分佈……………………………………………………48
圖5.2 患者不同性別之年齡分佈…………………………………………49
圖5.3 Stage IV患者各轉移部位之人數……………………………………50
圖5.4 疾病開始惡化的時間(Kaplan-Meier curve for TD)………………… 55
圖5.5 疾病惡化的時間與性別之關係……………………………………59
圖5.6 疾病惡化的時間與年齡之關係……………………………………60
圖5.7 疾病惡化的時間與活動力狀態之關係……………………………61
圖5.8 臨床效益-體重變化…………………………………………………69
圖5.9 臨床效益-止痛劑使用………………………………………………70
圖5.10輕微毒性發生率-low grade…………………………………………76

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