臺灣博碩士論文加值系統

雖然近十年來在治療癌症的觀念和方法上都有顯著的進步，但是在食道癌的治療上卻進步相當有限。食道切除術(Radical esophagectomy)仍為可切除性食道癌的治療主軸，提供長期存活的機會及較佳的局部控制。但事實上，五年的存活率仍低，大約為0~10%。 目前治療趨勢為術前化學及放射治療合併手術，目前大約有數十篇臨床隨機分派試驗報導相關之結果，討論術前化放療加手術比上單獨手術組對增加長期存活率的影響，但都無法獲得一致性的結論，使得臨床治療異常困難。本研究利用之前的臨床隨機試驗結果，重新模擬存活曲線，加以分析各個試驗是否符合固定危險比例，是否有時間交叉項的存在(Hazard ratio，HR，隨著時間變動)。並試著利用合併分析(pooled analysis)及統合分析(meta-analysis)來重新統合整理這些臨床隨機試驗的結果。結果顯示，若依追蹤年分不同，在各別隨機臨床試驗的兩組之間的相對危險值並非恆定，回隨著時間變動。而利用圖形檢定後發現只有Walsh和Tepper這兩個臨床隨機試驗符合固定危險比例，若利用時間相依的Cox-regression model加以分析後，發現雖然在各別臨床隨機試驗中無法得到時間交叉項的顯著意義，但可將之約略分為三組，無交叉反應組、正交叉反應組及負交叉反應組。而利用合併分析的結果可發現，在負交叉反應組中，時間交叉項可達統計上的顯著意義(p-value=0.027)，而正交叉反應組中，時間交叉項則接近統計上顯著意義(p-value=0.10)。顯示或在食道癌術前化放療加手術比上單獨手術的這些臨床試驗分析中，存在著時間變動項，不能用一般的log-rank test或傳統的Cox regression model的加以分析，應先予以檢驗時間變動項的存在與否，再選擇分析方法。

Although the concept and method of treating cancer have substantial improvement in recent years, there is limited improvement in treatment of esophageal cancer. Radical esophagectomy is still the mainstay for the resectable esophageal cancer, which provided the chance for long-term survival and better local control rate. However, the five-year survival is still low for esophagectomy, which is only 0~10%. Current trend of treatment in locally advanced esophageal cancer is tri-modality treatment (neoadjuvant chemoradiotherapy and surgery). Over ten randomized controlled tries have been conducted to elucidate the following question:” Is tri-modality treatment better than surgery alone?” However, as the results of these trials are not consistent the clinical decision-makers are puzzled. More importantly, one of reasons accounting for the discrepancy of results is attributed to the cross-over phenomenon of neoadjuvant therapy. The current thesis aimed to investigate this issue. We first generated the data from randomized controlled trials by using the simulation approach. We assessed the proportional hazard assumption of these trials by checking the cross-over of survival with time-dependent Cox regression model. We also tried to conduct a meta-analysis to get the pooled estimates by three categories in the light of presence of cross-over phenomenon. It is found that relative risk of death between two groups changed by different follow-up times. Only Walsh and Tepper’s study fitted the proportional hazard assumption. After using time-dependent Cox regression model, we found that we could divide the nine trials into three groups: no cross-over, positive cross-over and negative cross-over. The time dependent variables were not statistically significant in individual trial. However, in pooled analysis, the time-dependent interaction term was statistically significant in pooled negative cross-over group (p=0.027) and marginally statistically significant (p=0.10) in positive cross-over group. All results show that the hazard ratio of treatment group varied with time. We conclude it is inappropriate to use log-rank test or the time-independent Cox-regression model before testing whether the cross-over survival exists.

口試委員會審定書……………………………………………………………........... I
目錄…………………………………………………………………………………..II
表目錄........................................................................................................................ III
圖目錄..........................................................................................................................V
中文摘要.....................................................................................................................VI
英文摘要....................................................................................................................VII
第一章 前言…………………………………………………………....................1
第二章 文獻探討……………………………………..............................................2
2. 1食道癌之流行病學現況……………………………………………………………………3
2.2. 治療技術之演進…………………………………………………………………………4
2.3. 術前化放療隨機試驗結果之回顧…………………………………………………6
2.4. 評論……………………………………………………………………………………13
2.5. 統合分析……………………………………………………………………………16
第三章 研究方法………………………………………………………………18
第四章 研究結果…………………………………………………………………25
4.1. 術前化放療+手術比上單獨手術的勝算比(Odds Ratio)…………………………26
4.2. 模擬存活圖……………………………………………………………………………27
4.3. 危險比例原則(Proportional hazard assumption)檢定 ………………………27
4.4. 合併分析 (Pooled Analysis) ……………………………………………………32
4.5. 統合分析 (Meta-analysis) …………………………………………………………33
第五章 討論……………………………………………………………………34
第六章 結論………………………………………………………………………40
參考文獻…………………………………………………………………………….41

表目錄
表2.1 Features of the Randomized Controlled Trials of Efficacy on surgical
treatment and neoadjuvant therapy for esophageal cancer………………..47
表 2.2 Meta-analysis on neoadjuvant chemoradiotherapy for esophageal cancer and
the included randomized controlled trials….………………………………49
表 2.3 A Review of Meta-analysis in Neoadjuvant Chemoradiotherapy for
Esophageal cancer………………………………………………………….50
表 4.1 Individual Hazard ratio of Neoadjuvant Chemoradiothrapy vs. Surgery in
Esophageal Cancer divided by Followed-up Year……………………….51
表 4.2-4.10 Estimated Result of Time-Dependent Cox Regression Model……54-62
表4.11 Estimated Result of Time-Dependent Cox Regression Model for Pooled
Analysis with total 9 Study……………………………………………......63
表 4.12 Estimated Result of Time-Dependent Cox Regression Model for Pooled
Analysis of no cross-over studies….…………..……………………….…64
表4.13 Estimated Result of Time-Dependent Cox Regression Model for Pooled
Analysis of positive cross-over studies…….…..…………………………65
表 4.14 Estimated Result of Time-Dependent Cox Regression Model for Pooled
Analysis of negative cross-over studies………..…………………………66
表4. 15 Estimated results of the extended Cox regression model with
continuous-time approach……………………..………………………….67
表4.16 Estimated Result of Time-Dependent Cox Regression Model for pooled
analysis of positive cross-over studies with RT dosage and 5FU dosage
……………………..………………………………………………...…….68
表4.17 Estimated Result of Time-Dependent Cox Regression Model for pooled
analysis of Negative cross-over studies with RT dosage and 5FU dosage
……………………..…………………………………………………….69

圖目錄
圖1 Nyggard study……………….…………………………………………………70
圖 2 Le Prise Study………… …....…………………………………………………71
圖 3 Walsh Study……………………………………………………………………72
圖 4 Bosset Study……………………………… …..………………………………73
圖 5 Urba Study…………………………………..…………………………………74
圖 6 Lee Study………………………………………………………………………75
圖 7 Burmeister Study………………………………………………………………76
圖8 Natsugoe Study…………………………………………………………………77
圖9 Tepper Study……………………………………………………………………78
圖10 Pooled Analysis for All Nine Trials………..…………………………………79
圖11 Pooled Analysis for No Cross-Over Studies……………………………….….80
圖 12 Pooled Analysis for Positive Cross-Over Studies……………………………81
圖 13 Pooled Analysis for Negative Cross-Over Studies………………………..…82
圖 14 Iteration history and kernel densities for parameter estimates for the meta-analysis with no cross-over studies…………………………..………..83
圖 15 Iteration history and kernel densities for parameter estimates for the meta-analysis with positive cross-over studies………………………………84
圖 16 Iteration history and kernel densities for parameter estimates for the meta-analysis with negative cross-over studies……………………………...85
圖 17 Iteration history and kernel densities for parameter estimates for the meta-analysis with all studies………………………………………………..86

1.WHO. The global burdens of cancer. http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf 2004.
2.國健局, Y-96 癌症登記年報. 2007. http://www.bhp.doh.gov.tw/DOWNLOAD/Statistics/1.癌症登記年度報告（全）(92年以後資料僅含侵襲癌)/Y96-癌症登記年度報告（全).pdf.
3.Holmes, R.S. and T.L. Vaughan, Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol, 2007. 17(1): p. 2-9.
4.Lee, C.H., et al., Independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer in Taiwan. Int J Cancer, 2005. 113(3): p. 475-82.
5.Suntharalingam, M., Definitive Chemoradiation in the Management of Locally Advanced Esophageal Cancer. Semin Radiat Oncol, 2006. 17: p. 22-28.
6.al-Sarraf, M., et al., Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol, 1997. 15(1): p. 277-84.
7.Roth, J.A., et al., Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg, 1988. 96(2): p. 242-8.
8.Nygaard, K., et al., Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg, 1992. 16(6): p. 1104-9; discussion 1110.
9.Maipang, T., et al., Induction chemotherapy in the treatment of patients with carcinoma of the esophagus. J Surg Oncol, 1994. 56(3): p. 191-7.
10.Schlag, P.M., Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. The Chirurgische Arbeitsgemeinschaft Fuer Onkologie der Deutschen Gesellschaft Fuer Chirurgie Study Group. Arch Surg, 1992. 127(12): p. 1446-50.
11.Law, S., et al., Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg, 1997. 114(2): p. 210-7.
12.Kelsen, D.P., et al., Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med, 1998. 339(27): p. 1979-84.
13.Ancona, E., et al., Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer, 2001. 91(11): p. 2165-74.
14.MRC, Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet, 2002. 359(9319): p. 1727-33.
15.Malthaner, R.A., et al., Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a systematic review and meta-analysis. BMC Med, 2004. 2: p. 35.
16.Gebski, V., et al., Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol, 2007. 8(3): p. 226-34.
17.Tepper, J., et al., Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol, 2008. 26(7): p. 1086-92.
18.Walsh, T.N., et al., A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med, 1996. 335(7): p. 462-7.
19.Lee, J.L., et al., A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol, 2004. 15(6): p. 947-54.
20.Le Prise, E., et al., A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer, 1994. 73(7): p. 1779-84.
21.Natsugoe, S., et al., Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution. Dis Esophagus, 2006. 19(6): p. 468-72.
22.Urba, S.G., et al., Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol, 2001. 19(2): p. 305-13.
23.Bosset, J.F., et al., Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med, 1997. 337(3): p. 161-7.
24.Burmeister, B.H., et al., Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol, 2005. 6(9): p. 659-68.
25.Geh, J.I., et al., Systematic overview of preoperative (neoadjuvant) chemoradiotherapy trials in oesophageal cancer: evidence of a radiation and chemotherapy dose response. Radiother Oncol, 2006. 78(3): p. 236-44.
26.Lv, J., et al., Effect of neoadjuvant chemoradiotherapy on prognosis and surgery for esophageal carcinoma. World J Gastroenterol, 2009. 15(39): p. 4962-8.
27.Fiorica, F., et al., Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis. Gut, 2004. 53(7): p. 925-30.
28.Urschel, J.D. and H. Vasan, A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg, 2003. 185(6): p. 538-43.
29.Kaklamanos, I.G., et al., Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: a meta-analysis of randomized clinical trials. Ann Surg Oncol, 2003. 10(7): p. 754-61.
30.Jin, H.L., et al., Neoadjuvant chemoradiotherapy for resectable esophageal carcinoma: a meta-analysis. World J Gastroenterol, 2009. 15(47): p. 5983-91.
31.Greer, S.E., et al., Neoadjuvant chemoradiotherapy for esophageal carcinoma: a meta-analysis. Surgery, 2005. 137(2): p. 172-7.
32.Apinop, C., P. Puttisak, and N. Preecha, A prospective study of combined therapy in esophageal cancer. Hepatogastroenterology, 1994. 41(4): p. 391-3.
33.van Heijl, M., et al., Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS). BMC Surg, 2008. 8: p. 21.
34.Stahl, M., et al., Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol, 2005. 23(10): p. 2310-7.
35.Stahl, M., et al., Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol, 2009. 27(6): p. 851-6.