劉啟領(lǐng)

上海市公共衛(wèi)生臨床中心普外一科，上海 201508

胃癌根治術(shù)聯(lián)合脾臟切除治療胃癌的Meta分析

劉啟領(lǐng)

上海市公共衛(wèi)生臨床中心普外一科，上海 201508

目的 評(píng)估胃癌根治術(shù)(radical gastrectomy, RG)聯(lián)合脾臟切除術(shù)(splenectomy, SE)治療進(jìn)展期胃癌的長期效果。方法 以PubMed、Cochrane、Web of knowledge、Ovid SpringerLink、中國知網(wǎng)、萬方、維普為數(shù)據(jù)源，檢索相關(guān)文獻(xiàn)，采用RevMan對(duì)切脾與保脾的RG隨機(jī)對(duì)照試驗(yàn)(RCT)進(jìn)行Meta分析，結(jié)局變量為患者5年生存率、手術(shù)操作相關(guān)并發(fā)癥、術(shù)后30 d死亡率。結(jié)果 符合納入標(biāo)準(zhǔn)的RCT研究共5篇，包括1 344例病例，切脾組588例，保脾組756例，切脾組與保脾組5年生存率比較，差異無統(tǒng)計(jì)學(xué)意義(OR=0.80，95%CI： 0.60～1.06,P>0.05)，靈敏性分析切脾組患者5年生存率低于保脾組(OR=0.72，95%CI： 0.53～0.97,P<0.05)；切脾組操作相關(guān)并發(fā)癥發(fā)生率明顯高于保脾組(OR=2.51，95%CI： 1.90～3.33,P<0.05)，兩組術(shù)后30 d死亡率比較差異無統(tǒng)計(jì)學(xué)意義(OR=1.57，95%CI： 0.59～4.23,P>0.05)。結(jié)論 SE并不能有效改善患者預(yù)后，反而增加了術(shù)后并發(fā)癥的發(fā)生，暫不推薦SE作為進(jìn)展期胃癌的常規(guī)術(shù)式。

進(jìn)展期胃癌；胃癌根治術(shù)；脾切除；隨機(jī)對(duì)照試驗(yàn)；Mate分析

胃癌根治術(shù)(radical gastrectomy, RG)是進(jìn)展期近端胃癌的標(biāo)準(zhǔn)術(shù)式[1]。臨床上由于近端胃癌、胃食管交界癌以及淋巴轉(zhuǎn)移性癌更易出現(xiàn)于脾門，因此，常聯(lián)合脾切除術(shù)(splenectomy, SE)清掃脾動(dòng)脈旁及脾門淋巴結(jié)，以保證手術(shù)根治的徹底性[2]；然而，SE對(duì)預(yù)后的影響是有爭議的。先前的報(bào)道表明，胃切除術(shù)聯(lián)合脾切除術(shù)(radical gastrectomy combined splenectomy, RGSE)較單純的RG能更為有效地延長患者生存期[3]。但有學(xué)者認(rèn)為，SE非但不會(huì)提高胃癌患者存活率[4]，反而脾切除后其免疫功能的喪失將導(dǎo)致不良后果[5]。最近的臨床試驗(yàn)顯示，RGSE可能導(dǎo)致更高的術(shù)后發(fā)病率和死亡率[6-7]。本Meta分析旨在評(píng)價(jià)SE對(duì)胃癌患者遠(yuǎn)期生存的影響，并比較切脾和保脾患者術(shù)后手術(shù)相關(guān)并發(fā)癥發(fā)生率和死亡率的差異。

1 資料與方法

1.1 資料來源 研究以PubMed、Cochrane臨床試驗(yàn)中心、Web of knowledge、Ovid醫(yī)學(xué)期刊數(shù)據(jù)庫、SpringerLink為外文檢索數(shù)據(jù)庫；中國知網(wǎng)、萬方、維普為中文文獻(xiàn)檢索數(shù)據(jù)庫；外文檢索關(guān)鍵詞為“Stomach Neoplasms” (Mesh)、 “Carcinoma” (Mesh)、“splenectomy” (MeSH)、“spleen dissection” (textword)、“spleen resection” (textword)、“splenic preservation” (textword)、“Comparative Study” (Publication Type)、“follow-up studies” (Mesh)、“Clinical Trial” (Publication Type)、“Evaluation Studies” (Publication Type)、“Multicenter Study” (Publication Type)、“Random allocation” (Subheading)、“Randomized”。中文檢索關(guān)鍵詞為胃癌、胃腫瘤、胃新生物、脾切除術(shù)。此外，研究通過引用列表篩選相關(guān)文章，合格的未發(fā)表的論文中也被納入在內(nèi)，篩選文獻(xiàn)過程中未設(shè)定發(fā)表日期與語言限制，檢索截止日期2014年6月30日。

1.2 排除與納入標(biāo)準(zhǔn) 文獻(xiàn)納入標(biāo)準(zhǔn)：(1)隨機(jī)對(duì)照試驗(yàn)(RCTs)；(2)評(píng)估RGSE和RG手術(shù)的有效性和安全性；(3)術(shù)前通過內(nèi)鏡或活檢確診。排除標(biāo)準(zhǔn)：(1)其他類型的胃腫瘤，如淋巴瘤或多個(gè)胃腫瘤；(2)其他器官腫瘤；(3)文章重復(fù)發(fā)表。

1.3 數(shù)據(jù)提取 嚴(yán)格按照預(yù)先制定的納入標(biāo)準(zhǔn)，由2人獨(dú)立查閱文獻(xiàn)題目、摘要和關(guān)鍵詞選擇納入的研究，如文章滿足納入標(biāo)準(zhǔn)則通讀全文提取相關(guān)信息，包括作者、出版年份、樣本量、研究對(duì)象年齡、性別、腫瘤部位、TNM分期、手術(shù)入路、切除范圍、術(shù)后并發(fā)癥、5年生存率、復(fù)發(fā)率。所有數(shù)據(jù)提取工作由2人獨(dú)立完成，出現(xiàn)不一致時(shí)由第三人或協(xié)商確定。

1.4 文獻(xiàn)治療評(píng)估 采用如下7項(xiàng)評(píng)價(jià)指標(biāo)對(duì)納入文章進(jìn)行質(zhì)量評(píng)估：(1)是否真正做到隨機(jī)；(2)是否有分配隱藏；(3)RGSE與RG手術(shù)患者基線是否保持均衡；(4)是否采用盲法干預(yù)和評(píng)估結(jié)局；(5)納入排除標(biāo)準(zhǔn)是否合適;(6)是否有失訪；(7)是否為意向性分析。7項(xiàng)中如果滿足6項(xiàng)則被評(píng)為高質(zhì)量；5項(xiàng)或4項(xiàng)為中質(zhì)量；3項(xiàng)或更少為低質(zhì)量[8]。

1.5 結(jié)局事件定義 結(jié)局事件為5年總體生存率、術(shù)后死亡率以及與手術(shù)操作相關(guān)的并發(fā)癥發(fā)生率。其中術(shù)后死亡率為住院期間死亡率或手術(shù)后30 d死亡率，手術(shù)操作相關(guān)的并發(fā)癥包括胰漏、胰腺炎、胸腔積液、腹腔膿腫、傷口感染、腸梗阻和吻合口漏、肺部感染等多種術(shù)后不良反應(yīng)的總和。

1.6 統(tǒng)計(jì)學(xué)方法 分類數(shù)據(jù)采用相對(duì)危險(xiǎn)度(relative risk,RR)表示，采用Review manager 5.3對(duì)數(shù)據(jù)進(jìn)行分析。根據(jù)齊性檢驗(yàn)結(jié)果選擇計(jì)算模型，若研究效應(yīng)量呈同質(zhì)。則采用固定效應(yīng)模型加權(quán)合并：若為異質(zhì)，則采用隨機(jī)效應(yīng)模型加權(quán)合并，最終獲得OR值、95%CI及P值，P<0.05為差異有統(tǒng)計(jì)學(xué)意義

2 結(jié)果

2.1 納入研究基本特征 共檢索到相關(guān)文獻(xiàn)564篇，通過題目和摘要閱讀， 493篇文獻(xiàn)被排除，其余文章通讀全文后，共納入RCT研究5篇，包括1 344例病例，切脾組588例，保脾組756例。最終納入文獻(xiàn)和提取數(shù)據(jù)見表1。

2.2 納入文獻(xiàn)質(zhì)量評(píng)估 納入文獻(xiàn)均為隨機(jī)對(duì)照研究，但是否分配隱藏和是否盲法均不清楚，文獻(xiàn)質(zhì)量中等，具體見表2。

表1 納入RCT試驗(yàn)資料來源和數(shù)據(jù)提取

Tab 1 RCT test data source and data extraction

納入研究年份總例數(shù)切脾組保脾組5年生存切脾組保脾組并發(fā)癥切脾組保脾組術(shù)后死亡切脾組保脾組Csendes等[9]200290973241613943Toge等[10]198541382921————Yu等[11]2006104103575016921Oh等[12]20099926745173293121Sano等[13]2010254251——774212

表2 納入文獻(xiàn)質(zhì)量評(píng)估

Tab 2 Quality assessment of included literature

資料來源年份隨機(jī)分配隱藏基線特征評(píng)估標(biāo)準(zhǔn)盲法失訪意向性分析研究質(zhì)量Csendes等[9]2002是不清楚是是不清楚是否中Toge等[10]1985是不清楚否否不清楚不清楚不清楚差Yu等[11]2006是不清楚是是不清楚是不清楚中Oh等[12]2009是不清楚是是不清楚是否中Sano等[13]2010是不清楚是是不清楚是否中

2.3 切脾組與保脾組生存率比較 切脾組和保脾組5年生存率比較差異無統(tǒng)計(jì)學(xué)意義(OR=0.80,95%CI:0.60～1.06,P=0.12)，為保證研究結(jié)果的可靠性，通過靈敏性分析，排除低質(zhì)量文獻(xiàn)后，Meta分析結(jié)果顯示切脾組患者5年生存率低于保脾組(OR=0.72，95%CI：0.53～0.97，P=0.03，見圖1)。

2.4 切脾術(shù)與保脾術(shù)安全性比較 5篇RCT文獻(xiàn)中，僅有4篇報(bào)道了術(shù)后并發(fā)癥、死亡發(fā)生情況，對(duì)文獻(xiàn)提取數(shù)據(jù)進(jìn)行分析，結(jié)果顯示，切脾組并發(fā)癥發(fā)生率明顯高于保脾組，差異有統(tǒng)計(jì)學(xué)意義(OR=2.51，95%CI：1.90～3.33，P<0.05，見圖2)。兩組術(shù)后死亡率比較，差異無統(tǒng)計(jì)學(xué)意義(OR=1.57，95%CI：0.59～4.23，P=0.37，見圖2、圖3)。

圖2 切脾組與保脾組術(shù)后并發(fā)癥發(fā)生率Meta分析

圖3 切脾組與保脾組術(shù)后死亡率Meta分析

3 討論

流行病學(xué)調(diào)查顯示，近端胃癌的發(fā)病率有所增加。RG是近端胃癌的標(biāo)準(zhǔn)術(shù)式，但在手術(shù)中胃的切除范圍、淋巴結(jié)清掃范圍以及是否聯(lián)合脾臟切除等細(xì)節(jié)問題尚缺乏統(tǒng)一認(rèn)識(shí)。淋巴管造影結(jié)果表明淋巴流從左側(cè)胃上部區(qū)域進(jìn)入脾門淋巴結(jié)，沿著脾動(dòng)脈主干前往腹腔周圍的節(jié)點(diǎn)[14]，因此，近端胃癌發(fā)生脾門淋巴結(jié)或脾動(dòng)脈轉(zhuǎn)移的概率為8%～10%[16]。在近端胃癌手術(shù)治療時(shí)，通常需要聯(lián)合SE以徹底清除脾門淋巴結(jié)和脾動(dòng)脈淋巴結(jié)。但脾切除術(shù)為高危手術(shù)，且脾臟為機(jī)體免疫系統(tǒng)的一部分，行SE后患者獲益多少已經(jīng)引起了關(guān)注[16]。國內(nèi)外學(xué)者進(jìn)行了多項(xiàng)前瞻性隨機(jī)對(duì)照試驗(yàn)和回顧性分析探討SE的臨床價(jià)值[17]，但主要結(jié)果尚存爭議。

在進(jìn)行數(shù)據(jù)收集時(shí)，共查找到4篇RCT研究和17篇回顧性研究，在回顧性分析研究中，接受RGSE患者的病變通常出現(xiàn)在上腹部，腫瘤大，伴有3～4級(jí)浸潤性病變，漿膜侵犯深度更大，淋巴結(jié)轉(zhuǎn)移率高。Meta分析結(jié)果顯示，切脾組5年生存率低于保脾組，與手術(shù)操作相關(guān)的并發(fā)癥發(fā)生率明顯高于保脾組?；诒狙芯拷Y(jié)果，Meta分析顯示脾切除術(shù)并不能有效改善患者預(yù)后，反而增加了術(shù)后并發(fā)癥的發(fā)生。這與既往基于回顧性研究的Meta分析結(jié)果相似[18]。

脾臟是人體的“血庫”，具有造血、儲(chǔ)血功能，脾臟切除會(huì)導(dǎo)致機(jī)體儲(chǔ)備的血液大量丟失，如術(shù)中操作不當(dāng)導(dǎo)致脾動(dòng)脈損傷則會(huì)使術(shù)中大出血的風(fēng)險(xiǎn)增加。脾臟是機(jī)體細(xì)胞免疫和體液免疫的中心，脾臟切除后，機(jī)體免疫功能失衡，使正常的免疫因子促吞噬和清除體內(nèi)外抗原無法發(fā)揮作用，易造成感染綜合征的發(fā)生；同時(shí)，脾臟切除后，外周血T淋巴細(xì)胞亞群發(fā)生改變，輔助性T淋巴細(xì)胞數(shù)量減少，抑制性T淋巴細(xì)胞數(shù)量相對(duì)增加，易導(dǎo)致腫瘤免疫抑制，造成腫瘤復(fù)發(fā)。最近歐洲胃切除術(shù)的臨床試驗(yàn)表明，脾切除術(shù)是術(shù)后并發(fā)癥發(fā)生和死亡的一個(gè)重要風(fēng)險(xiǎn)因素[19-20]。SE后常見的并發(fā)癥是胰腺炎、胸腔積液、腹腔膿腫、傷口感染、胰漏、腸梗阻和吻合口漏。脾切除術(shù)易誘發(fā)胃殘余缺血，可能導(dǎo)致吻合口漏和死亡率高發(fā)。

本研究為保證研究結(jié)果的信度和效度，僅納入RCT研究，由于符合條件的高質(zhì)量的相關(guān)研究過少，可能對(duì)最終的結(jié)果帶來偏倚。因此，需要實(shí)施設(shè)計(jì)良好的隨機(jī)對(duì)照試驗(yàn)來探索脾切除術(shù)的有效性。基于本研究，暫不推薦切脾術(shù)作為進(jìn)展期胃癌的常規(guī)術(shù)式。

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(責(zé)任編輯：李 健)

Effect of radical surgery combined with splenectomy in treatment of gastric cancer: a Meta-analysis

LIU Qiling

Department of First General Surgery, Shanghai Public Health Clinical Center, Shanghai 201508, China

Objective To evaluate the effect of radical gastrectomy (RG) combined with splenectomy (SE) on long-term outcomes of patients with gastric cancer by a Meta-analysis. Methods A search of databases to identify randomized controlled trials (RCTs) in PubMed, Cochrane, Web of knowledge, Ovid, SpringerLink, CNKI, WanFang data were performed. Outcome measures were survival rate, operation-related events, postoperative mortality (30 days). The Meta-analysis was performed by RevMan 5.3. Results Five RCT studies met the inclusion criteria, including 588 patients in SE group and 756 patients in splean-preserving group. There was no significant difference in the 5-year overall survival rate between SE group and spleen-preserving group (OR=0.80, 95%CI: 0.60～1.06,P>0.05). Sensitivity analysis indicated the 5-year overall survival rate in SE group was lower than that in spleen-preserving group (OR=0.72, 95%CI: 0.53～0.97,P<0.05); The complications rate in SE group was higher than that in spleen-preserving group (OR=2.51, 95%CI: 1.90～3.33,P<0.05)；There was no significant difference in postoperative mortality (30 days) between the two groups (OR=1.57，95%CI: 0.59～4.23,P>0.05). Conclusion SE did not show a beneficial effect on survival rate compared with splenic preservation. Routinely performing SE should not be recommended.

Advanced gastric carcinoma; Radical gastrectomy; Splenectomy; Randomized controlled trial; Meta-analysis

10.3969/j.issn.1006-5709.2016.08.022

R735.2

A

1006-5709(2016)08-0917-04

2015-08-13