大腸直腸癌病人使用顆粒球群落形成刺激因子(G-CSF)與發生靜脈血栓風險之探討

Risk of Developing Venous Thromboembolism Associated with Granulocyte-Colony Stimulating Factors (G-CSF) in Colorectal Cancer Patients

李玟勳(Wen-Hsun Lee)

指導教授 ： 楊奕馨

高雄醫學大學/藥學院/藥學系碩士在職專班/碩士(2016年)

摘要

背景：
化學治療（以下簡稱化療）可有效增加癌症病人之存活率，治療過程中使用的顆粒球群落形成刺激因子(granulocyte colony-stimulating factor, G-CSF)可降低化療所造成的嗜中性白血球低下症之嚴重程度；但同時也有研究指出，大腸直腸癌病人使用G-CSF可能會增加靜脈血栓栓塞(venous thromboembolism, VTE)的發生風險；在台灣，大腸直腸癌為十大惡性腫瘤死亡排名之第三名，在癌症治療方面，目前尚未有針對台灣大腸直腸癌病人使用G-CSF與發生VTE間關聯性的相關研究。
目的：
探討接受化療之大腸直腸癌病人使用顆粒球群落形成刺激因子與發生靜脈血栓栓塞之風險。
方法：
本研究以特殊需求申請之2002年至2012年癌症患者之健保資料檔進行回顧性世代研究，擷取2003年至2011年大腸直腸癌病人（ICD-9-CM碼：153-154）且於癌症診斷後一年內曾接受化療者，並排除：(1) 大腸直腸癌診斷前一年內曾罹患癌症者；(2) 大腸直腸癌診斷後一年內死亡者，或年齡大於等於90歲者；(3) 首次化療前一年內，或使用G-CSF前曾經發生過VTE者；(4) 首次接受化療前一年內曾使用G-CSF者；以及未接受化療但接受G-CSF治療者。病人分為兩組：(1)未曾使用G-CSF者（對照組）；(2)使用過G-CSF者。統計分析以Kaplan-Meier存活曲線及Cox迴歸分析比較組別間發生靜脈血栓之風險；並根據病人接受手術治療或放射線治療之狀態進行次族群分析。
結果：
2003年1月至2011年12月共41,736名大腸直腸癌病人納入本研究分析樣本，其中男性共23,837人(57.11%)，平均年齡（±標準差）為62.76 (± 13.01)歲；未曾使用G-CSF者占多數，共39,345人，占全部的94.27%；使用過G-CSF者僅2,391人（5.73%）。曾使用G-CSF者發生VTE之風險為未使用G-CSF者的1.02倍（HR=1.02，95%信賴區間為0.95至1.10）。曾接受過大腸直腸癌相關手術的30,510人(73.10%)當中，使用過G-CSF者發生VTE風險為未使用G-CSF者的1.05倍（HR=1.05，95%信賴區間為0.97至1.13）；而未接受手術治療者（11,226人，26.90%）當中，使用過G-CSF者發生VTE風險為未使用G-CSF者的0.96倍（HR=0.96，95%信賴區間為0.84至1.11）。接受放射線治療者（6,663人，15.96%）當中，使用過G-CSF者發生VTE風險為未使用G-CSF者的0.97倍（HR=0.97，95%信賴區間為0.82至1.16）；而未接受放射線治療者（35,073人，84.04%）當中，使用過G-CSF者發生VTE風險為未使用G-CSF者的1.03倍（HR=1.03，95%信賴區間為0.96至1.12）；但上述結果皆未達統計上的顯著差異。
結論：
使用G-CSF來預防或治療化療副作用的大腸直腸癌病人，無論是否接受大腸直腸癌相關手術治療或放射線治療，與未使用G-CSF者相比，並未顯著增加發生靜脈血栓栓塞之風險；但對於較容易發生靜脈血栓栓塞之高危險群，仍應審慎地評估嗜中性白血球低下之風險與發生靜脈血栓栓塞風險後，再決定是否使用G-CSF，且給藥後需監測是否有出現類似VTE的症狀，及早介入治療，以提供病人最佳的腫瘤治療與照護。

關鍵字

大腸直腸癌 ； 化學治療 ； G-CSF ； 顆粒球群落形成刺激因子 ； 靜脈血栓栓塞

並列摘要

Background:
Chemotherapy (CT) is an effective treatment for increasing survival rates in various cancer patients. Usually, the bone marrow suppressive effect of CT may also cause severe febrile neutropenia, and granulocyte colony-stimulating factor (G-CSF) is often used for reducing the risk, severity, and duration of febrile neutropenia. However, some studies reported that G-CSF may also be associated with venous thromboembolism (VTE) in patients with cancer. Colorectal cancer is ranked the 3rd cancer death in Taiwan, and the association between G-CSF and VTE has not yet been investigated.
Objective:
To investigate whether the use of G-CSF in colorectal cancer (CRC) patients who received CT is associated with an increased risk of VTE.
Methods:
We conducted a retrospective cohort study using National Health Insurance Research Database (NHIRD) from 2002 to 2012. Patients who were diagnosed with CRC in 2003-2011 and received CT within 1 year after CRC diagnosis were included. We excluded patients who (1) were diagnosed with cancer within 1 year before the date of colorectal cancer diagnosis, (2) died within 1 year of colorectal cancer diagnosis, or were > 90 years old, (3) were diagnosed with VTE within 1 year before the first date of receiving CT, or before the date of receiving G-CSF, (4) received G-CSF within 1 year before the date of receiving CT, or received G-CSF without receiving CT. The remaining patients were further classified into two groups: (1) non-users of G-CSF (as reference group), (2) users of G-CSF. Patients were also divided into subgroups according to the status of receiving surgery or radiation therapy. Cox proportional hazards models were performed to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CI).
Results:
Among 41,736 eligible patients, there were more men (n =23,837, 57.11%) then women, and the average age was 62.76 (± 13.01) years old. 39,345 patients were non-users of G-CSF (94.27%), only 2,391 (5.73%) patients received G-CSF. The risk of VTE was not significantly different between users and non-users of G-CSF (HR 1.02, 95% CI 0.95-1.10). Among 30,510 (73.10%) patients who received surgery, similar HR was observed between users and non-users of G-CSF (HR 1.05, 95% CI 0.97-1.13). Among 11,226 (26.90%) patients without surgery, the HR became less than 1.0 (HR 0.96, 95% CI 0.84-1.11). Among 6,663 (15.96%) patients who received radiation therapy, the HR of VTE in users of G-CSF was 0.97 (HR 0.97, 95%CI 0.82-1.16), compared to non-users. Among 35,073 (84.04%) patients without radiation therapy, the HR of VTE was 1.03 (HR 1.03, 95%CI 0.96-1.12). However, all analyses of subgroups still revealed null effects.

Conclusion:
The risk for developing VTE was not significantly different between users and non-users of G-CSF in colorectal cancer patients who received CT. Patients with high-risk for developing VTE, the use of G-CSF should be reserved for patients for whom the benefits outweigh the risks.

並列關鍵字

colorectal cancer ； chemotherapy ； colony-stimulating factor ； venous thromboembolism

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