雷鑫明 黎紅光 吳深寶 莊李磊 陸小鋒 傅志成
[摘要] 目的 探討瑞格非尼在難治性轉(zhuǎn)移性結(jié)腸癌(Patients with metastatic colorectal cancer,mCRC)中的療效和安全性。方法 檢索瑞格非尼治療難治性轉(zhuǎn)移性結(jié)直腸癌的對照試驗(yàn),年限為2009~2019年,采用Revman 5.3軟件進(jìn)行系統(tǒng)Meta分析。 結(jié)果 本研究經(jīng)過系統(tǒng)的篩選和評價(jià),總共5篇文獻(xiàn)符合標(biāo)準(zhǔn)。Meta分析結(jié)果表明:在3年總生存率和3年無瘤生存率方面,瑞格非尼組患者的生存率高于對照組,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。在不良反應(yīng)方面,瑞格非尼組患者發(fā)生率低于對照組,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。 結(jié)論 瑞格非尼治療難治性轉(zhuǎn)移性結(jié)腸癌療效好且安全性高。
[關(guān)鍵詞] 難治性;轉(zhuǎn)移性;結(jié)腸癌;瑞格非尼;Meta 分析
[中圖分類號(hào)] R735.3? ? ? ? ? [文獻(xiàn)標(biāo)識(shí)碼] A? ? ? ? ? [文章編號(hào)] 1673-9701(2020)05-0025-05
Meta-analysis on the efficacy and safety of regorafenib in the treatment of refractory metastatic colon cancer
LEI Xinming? ?LI Hongguang? ?WU Shenbao? ?ZHUANG Lilei? ?LU Xiaofeng? ?FU Zhicheng
Department of Gastroenterology, Yiwu Central Hospital in Zhejiang Province, Yiwu? ?322000, China
[Abstract] Objective To investigate the efficacy and safety of regorafenib in the patients with refractory metastatic colorectal cancer (mCRC). Methods A controlled trial of regorafenib in the treatment of refractory metastatic colorectal cancer was performed. The period was from 2009 to 2019, and the literature articles were screened and evaluated according to the quality evaluation criteria in the Cochrane System Evaluation Manual. Systematic meta-analysis was performed using Revman 5.3 software. Results A total of 5 articles were included in the study. Meta-analysis showed that the 3-year overall survival rate and the 3-year tumor-free survival rate in the regorafenib group were higher than those in the control group, and the differences were statistically significant(P<0.05). The incidence rate of adverse reactions in the regorafenib group was lower than that in the control group, and the difference was statistically significant(P<0.05). Conclusion Regorafenib has a favorable efficacy and high safety in the treatment of refractory metastatic colon cancer.
[Key words] Refractory; Metastatic; Colon cancer; Regorafenib; Meta-analysis
結(jié)腸癌(Colorectal cancer,CRC) 作為消化系統(tǒng)最常見的腫瘤之一,在我國非常常見,且死亡率有逐漸上升的趨勢[1]。隨著醫(yī)療技術(shù)的飛速發(fā)展,結(jié)腸癌無論從診斷、治療、預(yù)后方面已經(jīng)有了明顯的改善[2]。然而,由于結(jié)腸癌早期無明顯特異性表現(xiàn),大多數(shù)患者在早期無明顯臨床表現(xiàn),發(fā)現(xiàn)后大多已經(jīng)轉(zhuǎn)移并失去手術(shù)機(jī)會(huì)[3]。以往對轉(zhuǎn)移性結(jié)腸癌的治療以化療為主[4],近年來,隨著醫(yī)療技術(shù)的飛速發(fā)展,靶向藥物已經(jīng)逐漸用于轉(zhuǎn)移性結(jié)腸癌的治療,靶向藥物主要包括抗表皮生長因子受體(Anti-epidermal growth factor receptor,EFGR)抗體及抗血管內(nèi)皮生長因子(Antivascular endothelial growth factor,VEGF)抗體[5]。然而以上藥物對難治性轉(zhuǎn)移性結(jié)腸癌的療效目前尚有較大爭議。目前國內(nèi)外較多研究發(fā)現(xiàn),瑞格非尼治療難治性轉(zhuǎn)移性結(jié)腸癌具有較好的治療效果,本研究通過搜集國內(nèi)外關(guān)于瑞格非尼治療結(jié)腸癌的研究并進(jìn)行Meta分析,進(jìn)而為瑞格非尼治療的效果和安全性提供循證醫(yī)學(xué)依據(jù),現(xiàn)報(bào)道如下。
1 資料與方法
1.1 檢索方法
至少2人檢索于2009~2019年期間國內(nèi)外公開數(shù)據(jù)庫有關(guān)瑞格非尼治療結(jié)腸癌的相關(guān)文獻(xiàn),其中中文檢索平臺(tái)主要包括中國知網(wǎng)、萬方、維普、生物醫(yī)學(xué)數(shù)據(jù)庫,而國外檢索平臺(tái)主要包括PubMed、The Cochrane Library等。英文檢索詞主要包括“Regorafenib”、“Metastatic colorectal cancer”,而中文檢索詞主要包括“瑞格非尼”、“結(jié)腸癌”。
1.2 納入及排除標(biāo)準(zhǔn)
1.2.1 納入標(biāo)準(zhǔn)? (1)所選擇的研究對象必須確診為初診的結(jié)腸癌;(2)必須為難治性的且伴有遠(yuǎn)處器官和組織轉(zhuǎn)移的結(jié)腸癌患者;(3)必須不存在瑞格非尼以外的治療方式。
1.2.2 排除標(biāo)準(zhǔn)? (1)非原發(fā)性結(jié)腸癌的患者;(2)屬于原發(fā)性結(jié)腸癌的患者但非初診;(3)不屬于難治性轉(zhuǎn)移性的結(jié)腸癌患者;(4)所選擇的研究為預(yù)后隨訪時(shí)間過短、實(shí)驗(yàn)數(shù)據(jù)過少、失訪人數(shù)過多的研究。
1.3 相關(guān)文獻(xiàn)評價(jià)
以Cochrane系統(tǒng)評價(jià)手冊為文獻(xiàn)評價(jià)標(biāo)準(zhǔn)進(jìn)行篩選和評價(jià), 研究者人數(shù)為2人,評價(jià)標(biāo)準(zhǔn)主要內(nèi)容:(1)隨機(jī)方法是否正確;(2)是否做到分配隱藏,分配方法是否正確;(3)是否實(shí)施盲法;(4)是否報(bào)告失訪和退出情況;(5)基線是否可比;(6)是否存在其他影響真實(shí)性的因素。
1.4 統(tǒng)計(jì)學(xué)處理
用I2表示其異質(zhì)性,當(dāng)I2<50%,P>0.1時(shí), 運(yùn)用固定效應(yīng)模型進(jìn)行Meta分析,此時(shí)提示異質(zhì)性較低或不存在;當(dāng)I2≥50%,P≤0.1時(shí),運(yùn)用隨機(jī)效應(yīng)模型進(jìn)行Meta分析,此時(shí)提示異質(zhì)性較高,而對于研究的偏倚評價(jià)則采用漏斗圖。
2 結(jié)果
2.1 文獻(xiàn)質(zhì)量評價(jià)和文獻(xiàn)患者基本情況
在所有文獻(xiàn)數(shù)據(jù)庫中輸入以上關(guān)鍵詞,得出總文獻(xiàn)254篇,剔除重復(fù)文獻(xiàn)、會(huì)議記錄等[5]得到文獻(xiàn)9篇,并篩選文章標(biāo)題、摘要及全文內(nèi)容后最終得到5篇文獻(xiàn)[6-10]。各文獻(xiàn)質(zhì)量評價(jià)見表1,各文獻(xiàn)患者基本情況見表2。
2.2 Meta分析情況
2.2.1 3年總生存率? 對瑞格非尼組和對照組組間異質(zhì)性檢測得出P=0.01,I2=70%,則用隨機(jī)效應(yīng)模型進(jìn)行Meta分析,結(jié)果顯示OR=0.79,95%CI(0.69,0.91),P=0.001(P<0.05)。見圖1。
2.2.2 3年無瘤生存率? 對瑞格非尼組和對照組組間異質(zhì)性檢測得出P<0.00001,I2=97%,則用隨機(jī)效應(yīng)模型進(jìn)行Meta分析,結(jié)果顯示OR=0.52,95%CI(0.34, 0.79),P=0.002(P<0.05)。見圖2。
2.2.3 不良反應(yīng)比較? 對瑞格非尼組和對照組組間異質(zhì)性檢測得出P=0.003,I2=79%,存在異質(zhì)性,則用隨機(jī)效應(yīng)模型進(jìn)行Meta分析,結(jié)果顯示OR=3.73,95%CI(1.68,8.28),P=0.001,(P<0.05)。常見的不良反應(yīng)主要包括:腹瀉、手足皮膚反應(yīng)、血小板減少癥、食欲減退。Meta分析提示:瑞格非尼組中以上不良反應(yīng)的發(fā)生率均低于對照組,差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。見圖3~7。
2.3 發(fā)表偏倚評價(jià)
各個(gè)研究漏斗圖提示無發(fā)表偏倚。見圖8~14。
3 討論
結(jié)腸癌(colorectal cancer,CRC)作為消化系統(tǒng)最常見的腫瘤之一,在我國非常常見,且死亡率有逐漸上升的趨勢。隨著醫(yī)療技術(shù)的飛速發(fā)展,結(jié)腸癌無論從診斷、治療、預(yù)后方面已經(jīng)有了明顯的改善。然而,由于結(jié)腸癌早期無明顯特異性表現(xiàn),大多數(shù)患者在早期無明顯臨床表現(xiàn),發(fā)現(xiàn)后大多已經(jīng)轉(zhuǎn)移并失去手術(shù)機(jī)會(huì)。化療作為治療轉(zhuǎn)移性結(jié)直腸癌的常規(guī)方案,其標(biāo)準(zhǔn)化療方案的藥物包括奧沙利鉑、伊立替康、氟尿嘧啶及其衍生物。然而常規(guī)化療對于轉(zhuǎn)移性結(jié)直腸癌的療效及安全性通常不佳,副作用也較大。隨著生命科學(xué)的深入發(fā)展,針對特異性分子靶點(diǎn)的靶向藥物治療已成為治療的新方向[11-12],瑞格非尼的結(jié)構(gòu)類似于索拉非尼,其化學(xué)式為:C21H15ClF4N4O3,分子量:482.81,是一種小分子多激酶抑制劑,多項(xiàng)研究發(fā)現(xiàn),瑞格非尼具有較強(qiáng)的抗腫瘤活性。Abou-Elkacem L等[13]發(fā)現(xiàn),在裸鼠移植瘤模型中,DC101能顯著延緩腫瘤生長,瑞格非尼卻能完全抑制瘤體生長且具有更強(qiáng)的抗腫瘤血管新生能力。此外,瑞格非尼同時(shí)能較好地遏制腫瘤向肝臟轉(zhuǎn)移。Carr BI等[14]發(fā)現(xiàn)瑞格非尼在體外可能通過抑制 ERK 通路上相關(guān)靶點(diǎn)進(jìn)而對人肝癌細(xì)胞株的HepG2、Hep3B和PLC/PRF/5基因靶點(diǎn)的增殖具有明顯的抑制作用,且該作用具有明顯的時(shí)間依賴性,同時(shí)瑞格非尼能夠減少甲胎蛋白(AFP)的分泌,其作用位點(diǎn)可能為 PLC/PRF/5和 HepG2 細(xì)胞株,且能抑制以上細(xì)胞株的轉(zhuǎn)移與侵襲,抑制作用與瑞格非尼濃度呈正相關(guān)[15]。2012年的一項(xiàng)臨床研究表明,瑞格非尼作為一種靶向藥物可用于難治性轉(zhuǎn)移性結(jié)腸癌的治療[16],Cyran CC等[17]在結(jié)腸癌細(xì)胞 HT-29 裸鼠移植瘤中也得到了相一致的研究結(jié)果,瑞格非尼處理后的裸鼠移植瘤中新生血管、腫瘤灌流、微血管密度等明顯減少,細(xì)胞凋亡增多,此項(xiàng)研究結(jié)果為瑞格非尼應(yīng)用于結(jié)腸癌患者提供了有力的實(shí)驗(yàn)證據(jù),但目前關(guān)于瑞格非尼對難治性轉(zhuǎn)移性結(jié)腸癌的療效及安全性研究仍然較少,本研究在國內(nèi)外研究基礎(chǔ)上,對瑞格非尼的療效和安全性進(jìn)行Meta分析,進(jìn)而提供循證醫(yī)學(xué)相關(guān)的依據(jù)[18-19]。
本研究共納入5篇文獻(xiàn),瑞格非尼組共1320例研究對象,對照組共752例研究對象,Meta分析結(jié)果表明,在3年總生存率和3年無瘤生存率方面,瑞格非尼組患者的生存率高于對照組,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。在不良反應(yīng)方面,瑞格非尼組患者發(fā)生率低于對照組,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。
綜上所述,瑞格非尼治療難治性轉(zhuǎn)移性結(jié)腸癌療效好且安全性高。但此次研究納入的文獻(xiàn)數(shù)目較少,且大部分研究的質(zhì)量為B級(jí),隨機(jī)對照試驗(yàn)較少,本研究無法進(jìn)一步進(jìn)行亞組分析,希望將來會(huì)有較多的隨機(jī)對照試驗(yàn)出現(xiàn),為醫(yī)師的診療提供參考,為結(jié)腸癌患者帶來福音[20]。
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(收稿日期:2019-04-22)