術前化放療對食道癌交叉存活之影響

The Cross-over Survival curve of Neoadjuvant Chemoradiation in Locally Advanced Esophageal Cancer

羅若玲(Jo-Lin Lo)

指導教授 ： 陳秀熙

國立臺灣大學/公共衛生學院/流行病學研究所/碩士(2010年)

https://doi.org/10.6342/NTU.2010.01773

摘要

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。

關鍵字

食道癌 ； 危險比 ； 統合分析 ； 存活曲線 ； 交叉反應

並列摘要

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.

並列關鍵字

esophageal cancer ； hazard ratio ； meta-analysis ； survival curve ； cross-over

參考文獻

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