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研究生:黃冠瑋
研究生(外文):Kuan-Wei Huang
論文名稱:某醫學中心骨肉瘤患者使用高劑量Methotrexate及合併用藥之肝毒性研究
論文名稱(外文):Study of High-dose Methotrexate and Co-medications on Hepatotoxicity for Osteosarcoma Patients at a Medical Center
指導教授:周月卿周月卿引用關係張豫立張豫立引用關係李新城李新城引用關係洪君儀洪君儀引用關係
指導教授(外文):Yueh-Ching ChouYuh-Lih ChangHsin-Chen LeeGiun-Yi Hung
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:藥理學研究所
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:2019
畢業學年度:107
語文別:中文
論文頁數:111
中文關鍵詞:高劑量methotrexate骨肉瘤肝毒性氫離子幫浦抑制劑trimethoprim-sulfamethoxazole非類固醇消炎止痛藥藥物交互作用無疾病惡化存活率
外文關鍵詞:high dose methotrexateosteosarcomahepatotoxicityproton-pump inhibitorstrimethoprim-sulfamethoxazolenon-steroidal anti-inflammatory drugsdrug-drug interactionprogression free survival
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骨肉瘤為常見的原發性惡性骨腫瘤,好發於兒童、青少年及年輕成人,目前標準治療以手術切除並輔助搭配術前及術後之化療為主。根據2019年National Comprehensive Cancer Network公佈之骨癌之骨肉瘤治療指引,第一線化療組套為MAP,含高劑量methotrexate (M)、adriamycin (doxorubicin, A) 及鉑金類 (platinum, P)。然而,包含台灣在內的多數亞洲國家 ,MAP化療組合中高劑量的methotrexate (MTX) 比西方人更易引起嚴重肝毒性,為避免副作用的產生,會在給藥後監測MTX血中濃度,另alanine aminotransferase (ALT) 上升後須俟其下降至安全數值 (≤200 U)才能在7天後施打下一個化療藥物。基於此,臺北榮民總醫院骨肉瘤治療團隊在2003年調整治療方針為TVGH OGS 治療指引,將MAP組套中高劑量methotrexate施打次數下降,並加上高劑量ifosfamide,以期保有相當的療效並降低肝毒性之發生率。此外,骨肉瘤病患會因其他病症而使用其他藥物,然而,依過去相關文獻顯示氫離子幫浦抑制劑 (proton-pump inhibitors, PPIs)、trimethoprim-sulfamethoxazole (TMP-SMX)及非類固醇消炎止痛藥 (anti-inflammatory drugs, NSAIDs) 都可能與高劑量methotrexate併用時發生交互作用,導致MTX延遲排除。由於TVGH OGS之療效已由Hung等人之研究證實療效與MAP組套相當,但肝毒性與併用藥物之影響尚待確認,因此本研究目的為探討TVGH OGS組套是否可降低發生嚴重肝毒性的比例?分析是否在七天內ALT下降至≤200U?另研究併用PPIs或TMP-SMX或NSAIDs是否影響MTX療效及安全性?
Osteosarcoma (OGS) is a cancerous tumor derived from bone, which is most prevalent in children, teenagers and young adults. The current standard treatment of OGS includes surgical resection and chemotherapy. According to 2019 National Comprehensive Cancer Network guideline of bone tumor, MAP, consisted of high dose methotrexate (M), adriamycin (doxorubicin, A) and platinum (cisplatin, P), is the first line therapy. However, severe hepatotoxicity associated with MAP, especially high dose methotrexate (HD-MTX) is more often encountered in Taiwanese than Western patients. MTX serum level is continuing monitored after infusion to avoid adverse effects. The elevated alanine aminotransferase (ALT) should be ≤ 200U in 7 days before executing the next step of chemotherapy. To ensure equivalent efficacy and reduce the incidence of hepatotoxicity, the chemotherapeutic protocols for OGS were optimized in 2003 at Taipei Veterans General Hospital (TVGH). In TVGH OGS protocol HD-MTX courses were reduced and high dose ifosfamide were added. Additionally, some co-medications during chemotherapy are usually prescribed to reduce cancer related complications. However, it has been reported that proton-pump inhibitors (PPIs), trimethoprim-sulfamethoxazole (TMP-SMX) and non-steroidal anti-inflammatory drugs (NSAIDs) have drug-drug interactions (DDIs) with MTX. The DDIs may cause delayed elimination of MTX. Based on the study of Hung et al., it has been reported that there is no significant difference in outcome between MAP and TVGH OGS protocol. However, the safety of HD-MTX treatment remains uncertain. Therefore, the aim of the study is to investigate: (1) whether the optimize protocol could reduce the risk of hepatotoxicity, (2) whether ALT level could decrease ≤ 200U in 7 days, (3) whether these co-medications (PPIs or TMP-SMX or NSAIDs) would affect the efficacy and safety of HD-MTX treatment.
誌謝 i
中文摘要 ii
英文摘要 v
目錄 viii
圖目錄 x
表目錄 xi
縮寫表 xii
第一章 緒論 1
第一節 研究背景與動機 1
第二節 研究目的 26
第二章 文獻探討 27
第一節 高劑量methotrexate產生急性肝毒性之影響相關研究 27
第二節 合併用藥對methotrexate療效及安全性之影響相關研究 31
第三章 研究方法和設計 35
第一節 研究項目與研究假設 35
第二節 研究設計與研究工具 36
第三節 統計方法 51
第四章 研究結果 53
第一節 研究族群基本特性 53
第二節 高劑量methotrexate引起之副作用 56
第三節 高劑量methotrexate引起之肝毒性相關因子 63
第四節 高劑量methotrexate與合併用藥影響之探討 69
第五章 討論 89
第一節 高劑量methotrexate產生急性肝毒性之影響 89
第二節 合併用藥對methotrexate療效及安全性之影響 93
第三節 研究限制 98
第六章 結論與建議 99
第一節 結論 99
第二節 建議 100
參考文獻 101


圖目錄
圖 1-1-1 MAP組套施打劑量及療程 8
圖 1-1-2 TVGH OGS 2008 protocol以及TVGH OGS M2 protocol施打劑量及療程 9
圖 1-1-3 Leucovorin根據MTX血中濃度的劑量給予調整方式 16
圖 3-2-1 資料處理流程圖 49
圖 4-2-1 ALT值在給與高劑量methotrexate後隨時間變化趨勢 62
圖 4-4-1 PPIs與疾病惡化之存活曲線 84
圖 4-4-2 TMP-SMX與疾病惡化之存活曲線 85
圖 4-4-3 NSAIDs與疾病惡化之存活曲線 86


表目錄
表 1-1-1 MTX上限濃度 15
表 1-1-2 CTCAE第五版評估標準 19
表 1-1-3 合併用藥與methotrexate的交互作用 24
表 3-2-1 研究資料檔名稱與擷取變項 38
表 3-2-2 臺北榮總檢驗部檢驗項目參考值 40
表 3-2-3 年齡分組方式 45
表 3-2-4 身體質量指數(body mass index, BMI)分組方式 46
表 4-1-1 研究族群基本特性 54
表 4-2-1 給與高劑量methotrexate後副作用發生比例 59
表 4-3-1 ALT最大值與各變項之相關性 64
表 4-4-1 高劑量methotrexate波峰濃度(peak level)是否有達到1000μM或以上之潛在相關因子 73
表 4-4-2 影響高劑量methotrexate在給藥後24小時延遲排除之潛在相關因子 76
表 4-4-3 影響高劑量methotrexate在給藥後72小時延遲排除之潛在相關因子 79
表 4-4-4 合併用藥與疾病惡化之風險 87
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