耿紀(jì)群， 翁 鳶， 蔡 銘

無錫市第四醫(yī)院胸外科，江蘇 無錫 214062

其他論著

DP方案化療結(jié)合胸腺肽α1對(duì)Ⅱ、Ⅲ期老年食管癌患者新輔助化療及手術(shù)后免疫功能的影響

耿紀(jì)群， 翁 鳶， 蔡 銘

無錫市第四醫(yī)院胸外科，江蘇 無錫 214062

目的 探討DP(多西他賽+奈達(dá)鉑)方案化療結(jié)合胸腺肽α1對(duì)Ⅱ、Ⅲ期老年食管癌患者新輔助化療(neoadjuvant chemotherapy,NC)及手術(shù)后免疫功能的影響。方法 將2013年3月-2014年9月在無錫市第四醫(yī)院住院治療的80例Ⅱ、Ⅲ期老年食管癌患者隨機(jī)分為治療組和對(duì)照組，每組40例，治療組采用術(shù)前DP方案化療結(jié)合胸腺肽α1治療，對(duì)照組只用DP方案化療。分別于化療前1 d、化療1個(gè)周期、2個(gè)周期后及手術(shù)后7 d抽取患者外周血，運(yùn)用流式細(xì)胞術(shù)(flow cyometry，F(xiàn)CM)檢測(cè)T細(xì)胞亞群(CD3+、CD4+、CD8+、CD4+/CD8+)的百分率及NK細(xì)胞含量變化。結(jié)果 化療前，兩組CD3+、CD4+、CD8+、CD4+/CD8+水平差異無統(tǒng)計(jì)學(xué)意義(P>0.05)；化療1個(gè)周期、2個(gè)周期后及術(shù)后7 d，治療組CD3+、CD4+、CD8+、CD4+/CD8+水平顯著高于對(duì)照組(P<0.05)，且化療2個(gè)周期后和術(shù)后7 d，治療組CD3+、CD4+、CD8+、CD4+/CD8+水平較化療前增加幅度顯著；治療組NK細(xì)胞含量顯著高于對(duì)照組(P<0.05)；同時(shí)發(fā)現(xiàn)治療組化療不良反應(yīng)顯著低于對(duì)照組(P<0.05)，且在粒細(xì)胞減少上，治療組更著低于對(duì)照組(P=0.001)；在術(shù)后并發(fā)癥方面，兩組總發(fā)生率相比，差異無統(tǒng)計(jì)學(xué)意義(P=0.356)，但治療組肺部感染發(fā)生率顯著低于對(duì)照組(P<0.05)。結(jié)論 DP方案化療結(jié)合胸腺肽α1應(yīng)用于Ⅱ、Ⅲ期老年食管癌患者NC，可有效增強(qiáng)患者免疫功能，提高患者對(duì)化療及手術(shù)的耐受性，且不良反應(yīng)小，有利于改善患者生活質(zhì)量。

胸腺肽α1；免疫功能；晚期食管癌；新輔助化療

食管癌在我國是最常見的惡性腫瘤之一，因其發(fā)病隱匿、早期診斷困難，50%的患者確診時(shí)已是晚期[1]。Ⅱ、Ⅲ期食管癌患者除接受大范圍手術(shù)外，常需接受輔助化療以改善其預(yù)后[2]。新輔助化療(neoadjuvant chemotherapy，NC)是指在惡性腫瘤局部實(shí)施手術(shù)或放療前應(yīng)用的全身性化療，目的是使腫瘤縮小、降低病理分期和控制遠(yuǎn)處微小轉(zhuǎn)移病灶，從而使不能直接手術(shù)切除或難以切除的病灶轉(zhuǎn)化為可以切除的病灶，提高手術(shù)切除率，進(jìn)而提高生存率[3]。NC聯(lián)合手術(shù)治療可以提高食管癌患者的生存率，但化療的不良反應(yīng)可能對(duì)患者造成沉重的身心負(fù)擔(dān)，尤其是老年食管癌患者因高齡、器官功能衰退等各種因素，對(duì)化療的耐受性差，如何提高老年食管癌患者的免疫功能，增強(qiáng)其對(duì)化療及手術(shù)的耐受性，成為食管癌治療的熱點(diǎn)。人工合成的胸腺肽α1是一種較為有效的提高機(jī)體免疫功能的生物反應(yīng)調(diào)節(jié)劑，國內(nèi)外用于肝炎和惡性腫瘤的治療已取得滿意療效[4]。本研究通過對(duì)80例Ⅱ、Ⅲ期老年食管癌患者的前瞻性研究，旨在探討DP(多西他賽+奈達(dá)鉑)方案化療結(jié)合胸腺肽α1對(duì)Ⅱ、Ⅲ期老年食管癌患者NC及手術(shù)后免疫功能的影響，現(xiàn)報(bào)道如下。

1 資料與方法

1.1 一般資料 選取2013年3月-2014年9月在無錫市第四醫(yī)院住院治療的老年食管癌患者，納入標(biāo)準(zhǔn)：① 年齡60～72歲；② 纖維胃鏡確診食管癌，經(jīng)肝臟B超、胸片等檢查，無遠(yuǎn)處轉(zhuǎn)移，臨床分期為有手術(shù)切除適應(yīng)證的T3N0M0、T2N1M0和T3N1M0期；③ 所有患者KPS評(píng)分≥80分，患者入院前均未接受過放化療及其他抗腫瘤治療，肝腎功能、血常規(guī)、心肺功能均能耐受化療及手術(shù)治療。入選患者80例，隨機(jī)分為治療組和對(duì)照組，每組40例，其中對(duì)照組男25例，女15例，年齡60～71歲，平均年齡(62.8±5.2)歲；病理類型為鱗癌29例，腺癌11例；臨床分期為Ⅱ期18例(T3N0M0 10例、T2N1M0 8例)，Ⅲ期(T3N1M0) 22例。治療組男29例，女11例，年齡60～72歲，平均年齡(63.1±4.9)歲；病理類型為鱗癌32例，腺癌8例；臨床分期為Ⅱ期15例(T3N0M0 9例、T2N1M0 6例)，Ⅲ期(T3N1M0) 25例。兩組患者年齡、性別比例、病理類型、病理分期等方面相比，差異無統(tǒng)計(jì)學(xué)意義(P>0.05)，具有可比性(見表1)。

表1 兩組患者臨床資料比較

Tab 1 Comparison of clinical data between two groups

例數(shù)性別(男/女)平均年齡(歲)病理類型(鱗癌/腺癌)臨床分期(Ⅱ期/Ⅲ期)治療組4029/1163.1±4.932/815/25對(duì)照組4025/1562.8±5.229/1118/22χ2值0.1800.0210.0180.015P值0.7240.8740.9910.913

1.2 方法 所有患者均采用術(shù)前DP方案(多西他賽75 mg/m2，靜脈滴注，第1天；奈達(dá)鉑80 mg/m2，靜脈滴注，第2天)化療，3周為1個(gè)周期，共計(jì)2個(gè)周期，化療結(jié)束后2周進(jìn)行手術(shù)。不同之處：治療組于化療前3 d開始，皮下注射胸腺肽α1(1.6 mg/次，1次/d)，直至化療結(jié)束后1周。

1.3 細(xì)胞免疫功能檢測(cè) 分別于化療前1 d、化療1周期、2周期結(jié)束后3 d、手術(shù)后7 d于早晨(8∶00～9∶00)空腹采集患者靜脈血，應(yīng)用流式細(xì)胞儀檢測(cè)外周血淋巴細(xì)胞及其亞群。分別計(jì)數(shù)患者CD3+、CD4+、CD8+的陽性百分率，CD4+/CD8+及NK細(xì)胞含量變化。用藥前、后各取患者2 ml EDTA抗凝的新鮮血液備用。采用鼠抗人CD3+、CD4+、CD8+、CD16+56+直標(biāo)熒光抗體(Immunotech公司，法國)標(biāo)記樣本，Blying solytion(Immunotech 公司，法國)溶解紅細(xì)胞后，以Beckman Coulter Epics XL流式細(xì)胞儀檢測(cè)淋巴細(xì)胞亞群水平(CD3+、CD4+、CD8+)及NK(CD16+56+)細(xì)胞數(shù)量。CD3+、CD3+/CD4+、CD3+/CD8+、CD16+/CD56+分別主要代表T細(xì)胞、Th細(xì)胞、Ts細(xì)胞及NK細(xì)胞。

2 結(jié)果

2.1 細(xì)胞免疫情況 化療前，兩組患者外周血CD3+、CD4+、CD8+、CD4+/CD8+水平差異無統(tǒng)計(jì)學(xué)意義(P>0.05)；化療1周期、2周期后和術(shù)后7 d，治療組CD3+、CD4+、CD8+、CD4+/CD8+水平顯著高于對(duì)照組(P<0.05)，且化療2周期后和術(shù)后7 d，治療組CD3+、CD4+、CD8+、CD4+/CD8+水平較化療前增加幅度顯著；治療組NK細(xì)胞含量顯著高于對(duì)照組(P<0.05，見表2)。

例數(shù)CD3+(%)CD4+(%)CD8+(%)CD4+/CD8+NK細(xì)胞治療組40 化療前72.8±4.748.2±3.724.6±2.61.8±1.48.1±2.1 化療1周期72.5±5.1*Δ49.7±1.4*Δ25.7±2.4*Δ1.9±2.1*Δ8.5±2.5*Δ 化療2周期78.3±6.2*Δ50.2±2.1*Δ27.9±2.2*Δ2.3±1.7*Δ10.6±2.3*Δ 術(shù)后7d79.6±3.6*Δ51.6±2.3*Δ29.1±2.1*Δ2.5±1.9*Δ11.1±2.9*Δ對(duì)照組40 化療前72.3±4.947.8±3.923.7±2.61.6±1.57.8±2.1 化療1周期69.7±5.1*47.2±1.4*22.9±2.4*1.7±2.0*7.3±2.5* 化療2周期58.1±6.2*37.2±2.1*21.4±2.2*1.9±1.3*7.1±2.6* 術(shù)后7d54.4±3.6*36.8±2.3*21.1±2.1*1.4±1.2*5.9±2.9*

注：與本組化療前相比，*P<0.05；與同期對(duì)照組相比，ΔP<0.05。

2.2 不良反應(yīng)發(fā)生情況 所有患者完成化療，全部病例無術(shù)中死亡者。臨床主要不良反應(yīng)有惡心、嘔吐、粒細(xì)胞減少和食管炎等?；?周期后，治療組惡心、嘔吐反應(yīng)、粒細(xì)胞減少程度和食管炎與對(duì)照組相比，差異無統(tǒng)計(jì)學(xué)意義(P>0.05)；化療2周期后，治療組惡心、嘔吐反應(yīng)、粒細(xì)胞減少程度和食管炎顯著低于對(duì)照組(P<0.05，見表3)。

2.3 術(shù)后并發(fā)癥的發(fā)生情況 術(shù)后并發(fā)癥主要為吻合口瘺、肺部感染、肺不張、心律失常、呼吸衰竭、切口感染等，治療組并發(fā)癥總發(fā)生率為20.0%(8/40)，對(duì)照組總發(fā)生率為37.5%(15/40)，兩組相比，差異無統(tǒng)計(jì)學(xué)意義(χ2=1.578，P=0.356)。其中，肺部感染發(fā)生率差異有統(tǒng)計(jì)學(xué)意義(P<0.05，見表4)。

表3 化療期間兩組患者不良反應(yīng)發(fā)生情況比較[例數(shù)(%)]

Tab 3 Comparison of occurrence of adverse reactions during chemotherapy between two groups [n(%)]

例數(shù)惡心嘔吐粒細(xì)胞減少食管炎化療1周期 治療組409(22.5)7(17.5)5(12.5)3(7.5) 對(duì)照組4016(40.0)11(27.5)12(30.0)8(20.0)χ2值0.1210.1630.1190.161P值0.6280.7140.5310.752化療2周期 治療組403(7.5)4(10.0)2(5.0)1(2.5) 對(duì)照組4029(72.5)23(57.5)31(77.5)18(45.0)χ2值3.8963.1583.9174.012P值0.0030.0030.0010.002

表4 兩組患者術(shù)后并發(fā)癥發(fā)生情況比較[例數(shù)(%)]

Tab 4 Comparison of postoperative complication between two groups [n(%)]

例數(shù)吻合口瘺肺部感染肺不張心律失常治療組401(2.5)2(5.0)3(7.5)2(5.0)對(duì)照組403(7.5)9(22.5)2(5.0)1(2.5)χ2值0.0171.8170.0120.011P值0.9110.0410.9840.986

3 討論

食管癌是我國常見的惡性腫瘤，手術(shù)是目前治療的首選方法。早期食管癌的手術(shù)切除率高，療效較好，但大多數(shù)患者確診時(shí)已是中晚期，長期生存率較低[5]。部分生活質(zhì)量評(píng)分較高的局部晚期食管癌患者需行綜合治療，手術(shù)前行NC的意義在于縮小瘤體從而減少手術(shù)的范圍及創(chuàng)傷，使部分無法根治的腫瘤降期達(dá)到可以手術(shù)根治[6]。腫瘤患者免疫功能相對(duì)低下，免疫細(xì)胞不能有效識(shí)別、排斥和殺滅腫瘤細(xì)胞是腫瘤發(fā)生的根本原因[7]。機(jī)體抗腫瘤的主要免疫機(jī)制為細(xì)胞免疫，其效應(yīng)是通過體內(nèi)的免疫活性細(xì)胞，主要是NK細(xì)胞、T淋巴細(xì)胞、巨噬細(xì)胞完成的。T淋巴細(xì)胞需致敏后才對(duì)腫瘤細(xì)胞有特異性的殺傷作用。因此，患者外周血T細(xì)胞亞群及NK細(xì)胞的變化是機(jī)體抗腫瘤免疫能力的一個(gè)側(cè)面反映[8]。老年食管癌患者大多免疫功能低下，腫瘤細(xì)胞的增生和增殖通常伴有免疫應(yīng)答的減弱[9]，因此，采取措施提高腫瘤患者免疫功能對(duì)腫瘤治療具有重要意義。

胸腺肽α1是由28個(gè)氨基酸組成的多肽，有研究[10]認(rèn)為，胸腺肽α1可增強(qiáng)抗腫瘤療效。其主要是通過促進(jìn)T淋巴細(xì)胞的成熟、分化，調(diào)控T淋巴細(xì)胞功能，從而增強(qiáng)機(jī)體免疫效應(yīng)；同時(shí)，還可使受抑制的免疫功能得到部分恢復(fù)，增強(qiáng)機(jī)體抗腫瘤能力。機(jī)體在患腫瘤狀態(tài)下，T細(xì)胞功能不全和受到抑制，表現(xiàn)為數(shù)量減少、功能改變和T細(xì)胞亞群比例失調(diào)[11]。應(yīng)用胸腺肽α1治療后，多項(xiàng)免疫學(xué)指標(biāo)包括T細(xì)胞亞群，尤其是NK細(xì)胞活性得到明顯改善，對(duì)晚期的惡性腫瘤患者化療有明顯的輔助治療作用[12]。

在本研究中，化療前兩組患者外周血CD3+、CD4+、CD8+、CD4+/CD8+水平無明顯差異；1周期化療結(jié)束、2周期化療結(jié)束和術(shù)后7 d，治療組T細(xì)胞亞群水平均顯著高于對(duì)照組，且術(shù)后7 d治療組的T細(xì)胞亞群比例增加幅度大于2周期化療結(jié)束，更大于1周期化療結(jié)束，說明隨著胸腺肽α1作用時(shí)間的增加，患者淋巴細(xì)胞亞群比例逐漸增加，細(xì)胞免疫功能逐漸增強(qiáng)；2周期化療結(jié)束后，治療組不良反應(yīng)的發(fā)生情況顯著低于對(duì)照組，且在粒細(xì)胞減少上，治療組與對(duì)照組的差異更顯著；在術(shù)后并發(fā)癥方面，兩組的總發(fā)生率未見顯著差異，但治療組肺部感染的發(fā)生顯著低于對(duì)照組，這與胸腺肽α1的作用有著密切關(guān)系；治療組NK細(xì)胞含量顯著高于對(duì)照組，且隨著胸腺肽α1作用時(shí)間的增加，治療組NK細(xì)胞含量不斷增加，這與文獻(xiàn)[12]報(bào)道結(jié)果一致，但術(shù)后7 d的增長幅度較前減小，這可能與外科手術(shù)對(duì)患者的應(yīng)激影響有關(guān)。

綜上所述，DP方案化療結(jié)合胸腺肽α1應(yīng)用于Ⅱ、Ⅲ期老年食管癌患者NC，可有效增強(qiáng)患者免疫功能，提高患者對(duì)化療及手術(shù)的耐受性，且不良反應(yīng)小，有利于改善患者生活質(zhì)量。

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(責(zé)任編輯：李 健)

Effects of DP combined with thymosin α1 on immune function after neoadjuvant chemotherapy and surgery in elderly patients with stage of Ⅱ, Ⅲ esophageal cancer

GENG Jiqun, WENG Yuan, CAI Ming

Department of Thoracic Surgery, Wuxi City Fourth Hospital, Wuxi 214062, China

Objective To study the effects of Docetaxel and Nedaplatin (DP) combined with thymosin α1 on immune function after neoadjuvant chemotherapy (NC) and surgery in elderly patients with stage of Ⅱ, Ⅲ esophageal cancer. Methods Eighty elderly patients in Wuxi City Fourth Hospital from Mar. 2013 to Sep. 2014 with stage of Ⅱ, Ⅲ esophageal cancer were randomly divided into treatment group and control group, each group had 40 patients. The treatment group

chemotherapy with DP plus thymosin α1 before surgery, while the control group received chemotherapy (DP) only. Blood samples were drawn on 1 day prior to the chemotherapy, chemotherapy after one cycle and two cycles as well as 7 days after surgery. Flow cytometry was used to detect the levels of CD3+, CD4+, CD8+, CD4+/CD8+and NK cell. Results There were no differences in the levels of CD3+, CD4+, CD8+, CD4+/CD8+between the treatment group and control group before chemotherapy (P>0.05). The levels of CD3+, CD4+, CD8+, CD4+/CD8+in the treatment group were significantly higher than those in the control group at one cycle and two cycles after chemotherapy and 7 days after surgery (P<0.05), and after 2 cycles of chemotherapy and 7 days after surgery, CD3+, CD4+, CD8+, CD4+/CD8+levels increased more significantly than before chemotherapy in treatment group; NK cell was significantly higher than that in the control group (P<0.05); the toxicity of chemotherapy was less in the treatment group (P<0.05); and the granulocytopenia in treatment group was more significantly lower than that in the control group (P=0.001); there was no significant difference in the total incidence of complications between two groups (P=0.356), but the incidence of pulmonary infection in treatment group was significantly lower than that in control group (P<0.05). Conclusion DP combined with thymosin α1 in elderly patients with stage of Ⅱ, Ⅲ esophageal cancer after NC can enhance the patients’ immune function, improve the tolerance to chemotherapy operation, reduce the toxicity of chemotherapy and improve the quality of life.

Thymosin α1; Immune function; Advanced esophageal cancer; Neoadjuvant chemotherapy

10.3969/j.issn.1006-5709.2016.07.017

耿紀(jì)群，碩士，主治醫(yī)師，研究方向：食管癌、肺癌。E-mail：gengjiqun44@163.com

R735.1

A

1006-5709(2016)07-0787-04

2015-11-07