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研究生:黃鈞民
研究生(外文):Chun-Ming Huang
論文名稱:以FOLFOX為基礎的新輔助化學放射療法對局部進行期直腸癌的療效評估與病理完全反應的預測因子之探討
論文名稱(外文):The Efficacy of FOLFOX-Based Neoadjuvant Chemoradiotherapy and Identifying Predictors of Pathological Complete Response for Locally Advanced Rectal Cancer Patients
指導教授:王照元
指導教授(外文):Jaw-Yuan Wang
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:醫學研究所博士班
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:157
中文關鍵詞:直腸癌
外文關鍵詞:rectal cancer
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新輔助同步化學放射治療加上全直腸繫膜切除術是目前局部進行期直腸癌的標準療法。然而,直腸癌對術前化放療的反應率,從療效最好的病理完全反應到最差的完全抗性都會發生。其中,病理完全反應族群有極佳的預後。因此為了提升病理完全反應率,我們於傳統的化學放射治療中,加入oxaliplatin來增加治療效果。結果發現病理完全反應率為31.6%,兩年的總體存活率,兩年的無病存活率,兩年的局部控制率及無轉移存活率分別為94%,87.4%,95.3%及85.1%。低位直腸癌的肛門保留率為92.9%。整體發生第三以上之嚴重急性副作用為25.6%。因此於放療時同步投予FOLFOX化療,於放療結束後仍持續給予FOLFOX鞏固化療,直到開刀前約二至三周才停止。這樣的療法是安全且有效的。
分析直腸癌接受新輔助化放療的個案發現下列因子與病理完全反應的發生有關(1) FOLFOX化放療而且放療結束至開刀超過八週,(2) 化放療期間血紅素數值,(3) 化放療後的癌胚胎抗原數值,(4) 臨床淋巴分期。因此建立一個預測列線圖(nomogram)能預測病理完全反應發生的可能性。
除了傳統預測指標外,吾人等進一步找出ERCC1作為生物標記來找能預測FOLFOX化放療的病人。結果發現,ERCC1的過度表現會讓這樣的療法效果不彰,而且ERCC1過度表現的病人有較差的無疾病存活率及總體存活率。因此,吾人可利用ERCC1的表現來預測病人的預後,並選擇個人化治療的方式。
我們分析直腸癌組織的microRNA表現量發現,miR-148a的過度表現與病理完全反應的發生有關。進一步研究發現miR-148a會透過c-met的抑制,促進大腸癌細胞的凋亡,所以能增強化放療的效果。因此,miR-148a可以是預測生物標記,同時也可能可以發展成抗癌的藥物。
根據我們的研究結果,局部進行期直腸癌接受FOLFOX化放療能增加病理完全反應率,並且與化放療期間血紅素數值,化放療後的癌胚胎抗原數值以及臨床淋巴分期等,都是預測病理完全反應的重要因子。ERCC1及miR-148a都是預測化放療效果的重要生物標記,可以作為發展直腸癌個人化醫療的治療策略。
Neoadjuavnt chemoradiation therapy (CRT) followed by total mesorectal excision has been the standard of care for patients with locally advanced rectal cancer (LARC). However, treatment response to CRT varies from pathological complete response (pCR) to total resistance. Patients with pCR have excellent prognosis. Therefore, we proposed the FOLFOX-based CRT to enhance tumor response. The strategy resulted in a pCR rate of 31.6%. The 2-year overall survival, disease-free survival, loco-regional control, and distant metastasis-free survival were 94%,87.4%,95.3%, and 85.1%, respectively. The sphincter-preserving rate was 92.9% for low-lying rectal cancer. The overall grade 3 or 4 treatment-related toxicity was 25.6%. As a result, the FOLFOX-based CRT is safe and effective.
After analysis of all the LARC patients receiving neoadjuvant CRT, several predictors of pCR were identified. The FOLFOX regimen with long irradiation-surgery interval, hemoglobin level during CRT, post-CRT CEA levels, and clinical nodal status were independent predictors of pCR. The nomogram was built based on the predictors.
Moreover, we aimed to identify predictive biomerkers for LARC patients undergoing FOLFOX-based CRT. In summary, ERCC1 overexpression resulted in poor response to FOLFOX-based CRT compared to ERCC1 nonoverexpression. In addition, patients with ERCC1 overexpression had unfavorable disease-free survival and overall survival. Therefore, ERCC1 was a predictor of prognosis and it can be used to guide personalized treatment.
The other biomarker we identified was miR-148a. Upregulated miR-148a was significantly associated with pCR. Furthermore, miR-148a induced apoptosis via targeting c-met pathway. Therefore, miR-148a was not only a biomarker of predicting pCR but also a potential anticancer agent.
In conclusion, according to our results, the FOLFOX-based CRT resulted in a high pCR rate. In addition to FOLFOX regimen, hemoglobin level, post-CRT CEA levels, and clinical nodal status were significant predictors of pCR. Both ERCC1 and miR-148a are predictive biomarkers for LARC patients receiving CRT. Our results might boost precision medicine in rectal cancer.
目錄
論文總摘要
(一)中文摘要…………………………………………………1
(二)英文摘要………………………………………………… 3
第一章 研究背景及動機
(一)研究背景………………………………………………… 5
(二)研究動機………………………………………………… 9
第二章 延長化療藥物FOLFOX的使用與延長放射線治療結束到開刀的間隔時間能增加局部進行期直腸癌病患接受術前化學放射治療後的病理完全反應率
(一)前言…………………………………………………… 13
(二)材料與方法…………………………………………… 14
(三)結果…………………………………………………… 19
(四)討論…………………………………………………… 23
第三章 FOLFOX為基礎的化療處方、延長放射治療結束至開刀的時 間、血紅素數值、臨床淋巴結陰性和化放療後癌胚胎抗原數值都能預測局部進行期直腸癌病患接受術前化學放射治療後的病理完全反應的發生
(一)前言…………………………………………………… 39
(二)材料與方法…………………………………………… 41
(三)結果.…………………………………………………… 46
(四)討論…………………………………………………… 50
第四章 蛋白質ERCC1 ERCC2及XRCC1的表現與直腸癌病患接受以FOLFOX為基礎之術前化學放射治療的臨床預後關聯性之探討
(一)前言…………………………………………………… 66
(二)材料與方法…………………………………………… 68
(三)結果.…………………………………………………… 72
(四)討論…………………………………………………… 75
第五章 miR-148a能增強直腸癌對化學放射療法的療效並透過直接調控c-met來促進大腸癌的細胞凋亡
(一)前言…………………………………………………… 87
(二)材料與方法…………………………………………… 88
(三)結果.…………………………………………………… 95
(四)討論…………………………………………………… 98
第六章 總結論……………………………………………………… 110
第七章 參考文獻…………………………………………………… 114
第八章 附錄
圖與表目錄……………………………………………… 149
附件 已獲刊登之論文………………………………………… 152
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