大腸直腸癌接受抗血管內皮生長因子標靶治療產生血栓栓塞事件和主要不良心血管事件的風險：一個以臺灣人口為基礎的世代研究

Risk of Thromboembolic Events and Major Cardiovascular Events with the Anti-Vascular Endothelial Growth Factor Therapy in Colorectal Cancer: A population-based cohort study

陳彥誠(Yen-Cheng Chen)

指導教授 ： 葉兆斌

共同指導教授 ： 周明智(Ming-Chih Chou)

中山醫學大學/醫學院/醫學研究所/碩士(2022年)

https://doi.org/10.6834/csmu202200088

摘要

研究背景：
抗血管內皮生長因子標靶治療已成為轉移性大腸直腸癌患者的標準治療方法之一。 然而，與此類治療之相關血栓栓塞事件和主要不良心血管事件的風險仍然存在爭議。

研究目的：
闡明抗血管內皮生長因子標靶治療是否會增加大腸直腸癌患者產生血栓栓塞事件或主要不良心血管事件的風險。

研究方法及資料：
我們將此研究設計為以台灣人口為基礎的世代研究，使用並串聯了台灣癌症登記檔(Taiwan Cancer Registry datasets)、健保資料庫(National Health Insurance Research Database, NHIRD)和台灣國家死因統計檔(National Death Index Database)的全國性數據庫。我們將診斷為第三期或第四期的大腸直腸癌患者作為主要研究對象，依據他們是否接受抗血管內皮生長因子治療分為兩組。主要觀察事件為血栓栓塞事件或主要不良心血管事件。我們運用Kaplan-Meier方法來產生累積發生率曲線。並使用Log-rank tests檢驗是否有顯著差異。更進一步執行傾向分數配對（PSM）來平衡兩組之間的差異。

研究結果：
從台灣癌症登記檔、健保資料庫和台灣國家死因統計檔的全國性數據庫中，我們在 2009 年至 2016 年期間納入189,708 位初診斷的晚期大腸直腸癌患者。我們透過使用 1:1 的年齡、性別、臨床分期和診斷日期配對，在每組中納入了 4,635 名患者，來研究抗血管內皮生長因子治療與血栓栓塞事件和主要不良心血管事件之風險關係。結果指出，兩組在血栓栓塞事件和主要不良心血管事件的風險無顯著差異。 血栓栓塞事件的校正風險比 (aHR) 為 1.028 (95% CI = 0.789-1.340)，主要不良心血管事件的校正風險比為 0.989 (95% CI = 0.769-1.273)。另外，血栓栓塞事件的競爭型風險比(competing HR) 為 0.908（95% CI=0.704-1.171），主要不良心血管事件為 0.862（95% CI=0.675-1.101）。使用傾向分數配對 (PSM) 後，兩組在血栓栓塞事件 (aHR=1.053, 95% CI=0.821-1.352) 和主要不良心血管事件 (aHR=1.004, 95% CI=0.796-1.267) 的風險依然沒有統計學上的差異。而最終在傾向分數配對 (PSM) 後的 Kaplan–Meier 曲線亦顯示血栓栓塞事件 (Log-rank p=0.6825) 和主要不良心血管事件 (Log-rank p=0.9707) 的風險在兩組之間是沒有差異的。

結論與建議：
曾經接受抗血管內皮生長因子治療的晚期大腸直腸癌患者與未接受該治療的患者相比，不會增加血栓栓塞事件和主要不良心血管事件的風險。在臨床實務上，台灣的晚期大腸直腸患者中，在用藥的策略上，可能會更放心地使用抗血管內皮生長因子之標靶治療。

關鍵字

抗血管內皮生長因子治療 ； 大腸直腸癌 ； 血栓栓塞事件 ； 主要不良心血管事件

並列摘要

Background
Anti-vascular endothelial growth factor (anti-VEGF) therapy has been one of the standard treatments for patients with metastatic colorectal cancer (CRC). However, the risk of thromboembolic events and major cardiovascular events associated with the therapy remains controversial.
Objective
Clarify whether anti-VEGF therapy increased the risk of thromboembolic events or major cardiovascular events (MACEs) in colorectal cancer patients.
Material and Methods
We designed a retrospective cohort study by using linked nationwide databases including the Taiwan Cancer Registry (TCR) datasets, National Health Insurance Research Datasets (NHIRD), and the National Death Index Database in Taiwan, the time frame of datasets is 2009-2016. The patients with advanced CRC further categorized into two groups based on ever received anti-VEGF therapy or not. The study event was defined as the diagnosis of thromboembolic events or MACEs. The Kaplan–Meier method was used to create cumulative incidence curves. Log-rank tests were used for comparison. Propensity score match (PSM) was further performed to balance the baseline characteristics between two groups.
Results
From the NHIRD, TCR, and the National Death Index Database in Taiwan, we enrolled 189,708 patients with newly diagnosed advanced CRC from 2009 to 2016. We investigated the relationship between anti-VEGF therapy and the risk of thromboembolic events and MACEs by using 1:1 age-, sex-, clinical-stage-, and diagnosis-date- matching, and recruited 4,635 patients in each group. The risk of thromboembolic events and MACEs had no significant difference in the two groups. The adjusted hazard ratio (aHR) of thromboembolic events was 1.028 (95% CI=0.789-1.340), and of MACEs was 0.989(95% CI=0.769-1.273). The competing HR of thromboembolic events was 0.908(95% CI=0.704-1.171), and of MACE was 0.862(95% CI=0.675-1.101). After using the PSM, the risks of thromboembolic events (aHR=1.053, 95% CI=0.821-1.352) and MACEs (aHR=1.004, 95% CI=0.796-1.267) were also neutral in two groups. The Kaplan–Meier curve after PSM showed no difference in the risk of thromboembolic events (Log-rank p=0.6825) and MACEs (Log-rank p=0.9707).
Conclusion
Patients with advanced CRC who had ever received anti-VEGF therapy did not increase the risks of thromboembolic events and MACEs more than patients without anti-VEGF therapy. For clinical practice, we might be more comfortable using anti-VEGF therapy in advanced colorectal patients in Taiwan.

並列關鍵字

Anti-vascular endothelial growth factor therapy ； Colorectal cancer ； Thromboembolic events ； Major cardiovascular events

參考文獻

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