崔文霞 黃明敏 郭愛斌 尹震宇

·專題論壇·

癌癥與營(yíng)養(yǎng)

崔文霞 黃明敏 郭愛斌 尹震宇

尹震宇 教授

癌癥病人營(yíng)養(yǎng)不良的發(fā)生率約為40%～80%[1]。體質(zhì)量減輕常是癌癥病人的首發(fā)癥狀,在癌癥首次診斷前6月,15%的病人已有非刻意的體質(zhì)量減輕>10%。體質(zhì)量減輕的發(fā)生率及嚴(yán)重程度與腫瘤類型及分期密切相關(guān)[2],在消化道癌癥中體質(zhì)量減輕的發(fā)生率最高[3]。癌癥病人體質(zhì)量減輕的原因主要包括攝入減少及代謝異常。營(yíng)養(yǎng)不良狀態(tài)可導(dǎo)致癌癥治療獲益減少[4],化療相關(guān)毒性風(fēng)險(xiǎn)增加[5],術(shù)后并發(fā)癥增多[6],生存質(zhì)量降低[4, 7],從而一定程度上影響疾病預(yù)后。

本文旨在探討癌癥病人營(yíng)養(yǎng)不良的原因,營(yíng)養(yǎng)不良與疾病預(yù)后的關(guān)系以及營(yíng)養(yǎng)支持的相關(guān)內(nèi)容。

1 癌癥與營(yíng)養(yǎng)不良

1.1 癌癥病人營(yíng)養(yǎng)不良的原因 不同于單純營(yíng)養(yǎng)不良,癌癥病人的能量負(fù)平衡和骨骼肌減少是由食物攝入減少和代謝紊亂共同造成的。如果病人>1周不能進(jìn)食,或超過(guò)1～2周總能量攝入小于所需的60%則被認(rèn)為存在食物攝入不足[8-9]。食物攝入量減少的主要原因?yàn)樵l(fā)性厭食(中樞神經(jīng)系統(tǒng)性),次要原因?yàn)榭谇粷?、腸梗阻、消化不良、便秘、腹瀉、惡心、嘔吐,腸蠕動(dòng)減少,無(wú)法控制的疼痛和藥物不良反應(yīng)等[10]。代謝紊亂包括基礎(chǔ)代謝率增高,胰島素抵抗,脂肪和蛋白分解增加及全身炎癥反應(yīng)等。在肺癌、血液系統(tǒng)惡性腫瘤的病人中均可觀察到基礎(chǔ)代謝率升高,目前認(rèn)為基礎(chǔ)代謝率升高可能是癌癥病人體質(zhì)量減輕的促進(jìn)因素[11]。部分研究認(rèn)為腫瘤壞死因子α、白細(xì)胞介素-1β及白細(xì)胞介素-6等細(xì)胞因子與基礎(chǔ)代謝率升高及厭食相關(guān)[12-13]。很多癌癥病人早期即出現(xiàn)胰島素抵抗、皮質(zhì)醇分泌增加、胰島素/皮質(zhì)醇比降低,從而導(dǎo)致葡萄糖轉(zhuǎn)化和糖異生增加[14]。癌癥病人常伴有脂質(zhì)動(dòng)員率增高,一種由腫瘤產(chǎn)生的脂質(zhì)動(dòng)員因子(LMF)可能促使了脂肪消耗[15]。癌癥病人中ATP-泛素-蛋白酶體系統(tǒng)的激活使蛋白質(zhì)分解增多,從而引起骨骼肌減少[16]。在中樞神經(jīng)系統(tǒng)中,炎癥細(xì)胞因子可影響控制食物攝入的下丘腦功能,引起食欲減退[17]。

1.2 癌癥惡液質(zhì) 從臨床的角度來(lái)看,癌癥惡液質(zhì)是一種復(fù)雜的綜合征,其特征為慢性的、進(jìn)行性的、非刻意的體質(zhì)量減輕,對(duì)常規(guī)營(yíng)養(yǎng)支持治療反應(yīng)欠佳或無(wú)反應(yīng)[18]。肌蛋白消耗是癌癥惡病質(zhì)的標(biāo)志。對(duì)癌癥病人身體組成的研究揭示,骨骼肌的減少(不管是否伴隨體脂減少)是癌癥相關(guān)營(yíng)養(yǎng)不良的主要表現(xiàn),可預(yù)測(cè)身體損傷風(fēng)險(xiǎn)、術(shù)后并發(fā)癥、化療不良反應(yīng)和死亡率[19]。癌癥惡液質(zhì)病人常合并明顯的營(yíng)養(yǎng)代謝改變,包括高血糖、高三酰甘油血癥等,這可能與細(xì)胞因子釋放增加及胰島素抵抗有關(guān)[20]。

1.3 營(yíng)養(yǎng)狀態(tài)與臨床進(jìn)程及預(yù)后 盡管癌癥分期和抗腫瘤治療效果是影響病人生存期的主要預(yù)后因素,但文獻(xiàn)顯示體質(zhì)量減輕也是癌癥病人生存期縮短的顯著甚至獨(dú)立的預(yù)測(cè)因素[21-22]。營(yíng)養(yǎng)不良的癌癥病人總體生存率較差,化療反應(yīng)速率較低,化療有效持續(xù)時(shí)間較短。此外,該類病人再入院率高,住院時(shí)間長(zhǎng),生活質(zhì)量低。因此,營(yíng)養(yǎng)不良是疾病嚴(yán)重程度和預(yù)后不良的標(biāo)志。4%～23%的終末期癌癥病人最終死于惡液質(zhì)[9]。對(duì)癌癥病人進(jìn)行早期營(yíng)養(yǎng)篩查,并予以適當(dāng)?shù)臓I(yíng)養(yǎng)支持治療可部分改善疾病預(yù)后。

2 癌癥的營(yíng)養(yǎng)支持

癌癥的營(yíng)養(yǎng)支持治療包括營(yíng)養(yǎng)篩查,口服營(yíng)養(yǎng)補(bǔ)充劑(ONS),人工營(yíng)養(yǎng),抗炎或抗分解藥物以及身體鍛煉。

2.1 營(yíng)養(yǎng)篩查 營(yíng)養(yǎng)篩查有助于識(shí)別早期營(yíng)養(yǎng)不良并指導(dǎo)干預(yù)時(shí)機(jī)。營(yíng)養(yǎng)篩查量表包括營(yíng)養(yǎng)風(fēng)險(xiǎn)篩查2002(NRS2002),主觀整體營(yíng)養(yǎng)評(píng)估量表(SGA), 病人自評(píng)主觀整體營(yíng)養(yǎng)評(píng)估量表(PG-SG)等[23-24]。一個(gè)較簡(jiǎn)單的篩查工具是營(yíng)養(yǎng)風(fēng)險(xiǎn)指數(shù)(NRI),已被運(yùn)用在胃腸道腫瘤等疾病的臨床評(píng)估中。營(yíng)養(yǎng)篩查應(yīng)在適當(dāng)?shù)臅r(shí)間間隔重復(fù)評(píng)估(如每2周、每月、每6月),以確定是否需要營(yíng)養(yǎng)干預(yù)及觀察營(yíng)養(yǎng)治療效果。雖然目前仍缺乏高質(zhì)量的文獻(xiàn)數(shù)據(jù)以確定啟動(dòng)營(yíng)養(yǎng)支持的最佳時(shí)間,但因合并代謝紊亂的明顯營(yíng)養(yǎng)不良較難糾正,所以營(yíng)養(yǎng)支持需要在病人處于輕度營(yíng)養(yǎng)不良狀態(tài)時(shí)即開始。指南推薦,對(duì)于進(jìn)食減少的營(yíng)養(yǎng)不良或有營(yíng)養(yǎng)不良風(fēng)險(xiǎn)的癌癥病人需盡早開始營(yíng)養(yǎng)干預(yù),包括飲食指導(dǎo),治療影響進(jìn)食的相關(guān)癥狀(如惡心、嘔吐、腹瀉等)及提供ONS。

2.2 人工營(yíng)養(yǎng)

2.2.1 腸內(nèi)營(yíng)養(yǎng)(EN):如果病人進(jìn)食明顯減少(如>1周未進(jìn)食或超過(guò)1～2周總攝入量在需要量的60%以下),則建議開始人工營(yíng)養(yǎng)。對(duì)于胃腸道功能保留的癌癥病人,如果已經(jīng)進(jìn)行了營(yíng)養(yǎng)干預(yù)(飲食指導(dǎo)、ONS),經(jīng)口營(yíng)養(yǎng)仍不足時(shí),建議開始EN。

20%進(jìn)行EN的病人有早飽、惡心、嘔吐等胃腸道反應(yīng),其最主要的誘因是胃排空延遲。如懷疑病人存在胃排空延遲可考慮減慢EN速度,減少阿片類藥物使用,使用低脂配方,必要時(shí)可使用促動(dòng)力藥物。吸入性肺炎是EN最嚴(yán)重的、可能危及生命的相關(guān)并發(fā)癥。如果進(jìn)行EN的癌癥病人出現(xiàn)發(fā)熱,則需要排除吸入性肺炎的可能。機(jī)械性并發(fā)癥主要是導(dǎo)管相關(guān)的,如導(dǎo)管脫落、移位、堵塞等。

2.2.2 腸外營(yíng)養(yǎng)(PN):對(duì)于需要人工營(yíng)養(yǎng)的病人,如果無(wú)法進(jìn)行EN或EN不充分時(shí)可考慮腸外營(yíng)養(yǎng)。在放射性腸炎、慢性腸梗阻、短腸綜合征、腹膜癌或乳糜胸等所致腸道功能不全的情況下,可通過(guò)PN維持營(yíng)養(yǎng)狀態(tài)。

再喂養(yǎng)綜合征是指嚴(yán)重營(yíng)養(yǎng)不良的病人接受人工營(yíng)養(yǎng)(無(wú)論腸內(nèi)或腸外)時(shí)出現(xiàn)的致死性水電解質(zhì)紊亂。在進(jìn)食明顯減少>5 d的病人,前2 d能量供應(yīng)不應(yīng)超過(guò)預(yù)估所需量的一半,如果病人處于嚴(yán)重消耗狀態(tài),初始能量供應(yīng)不應(yīng)>5～10 kcal/(kg·d),在以后的4～7 d內(nèi)逐漸增加能量攝入直至正常[25]。預(yù)防及治療再喂養(yǎng)綜合征需加用維生素B1、磷酸鹽,并注意監(jiān)測(cè)血糖、電解質(zhì)水平。PN最嚴(yán)重的并發(fā)癥是導(dǎo)管相關(guān)血流感染,但這是導(dǎo)管相關(guān)并發(fā)癥,而非單純PN并發(fā)癥。導(dǎo)管相關(guān)并發(fā)癥還包括導(dǎo)管內(nèi)血栓形成。因腫瘤病人深靜脈血栓發(fā)生率高,預(yù)防導(dǎo)管內(nèi)血栓形成尤為重要。使用超聲引導(dǎo)下導(dǎo)管置入、選擇盡可能小口徑的導(dǎo)管、導(dǎo)管頭處于或靠近房腔交界處等適當(dāng)?shù)膶?dǎo)管置入技術(shù)有助于避免血栓形成[26]。

2.2.3 EN和PN選擇:有研究表明,對(duì)癌癥手術(shù)病人進(jìn)行PN可降低術(shù)后并發(fā)癥,但似乎并未帶來(lái)生存獲益[27]。對(duì)進(jìn)行胃腸道惡性腫瘤手術(shù)的營(yíng)養(yǎng)不良病人,術(shù)后采用EN的并發(fā)癥發(fā)生率可能低于PN[28],但該結(jié)論仍有爭(zhēng)議,有研究認(rèn)為,術(shù)后采用EN的病人胃排空延遲的發(fā)生率更高、住院天數(shù)更長(zhǎng),且并未降低術(shù)后并發(fā)癥發(fā)生率[29]。

頭頸部癌放療病人中黏膜炎、食物攝入量減少、體質(zhì)量下降的發(fā)生率高達(dá)80%[30],營(yíng)養(yǎng)支持可以減輕放療對(duì)營(yíng)養(yǎng)狀況的負(fù)面影響。對(duì)于放療誘導(dǎo)的嚴(yán)重黏膜炎或具有阻塞性腫塊的頭頸/胸部癌中可使用鼻胃管(NGT)或經(jīng)皮內(nèi)窺鏡胃造瘺術(shù)(PEG)進(jìn)行EN。約10%頭頸部癌病人需要長(zhǎng)期EN支持治療[31],一般<30 d的短期EN可使用NGT,長(zhǎng)期EN則建議使用PEG。關(guān)于頭頸部癌的系統(tǒng)性綜述表明,PEG較NGT的導(dǎo)管移位發(fā)生率較低,但吞咽困難發(fā)生率較高[32]。盡管頭頸部癌放療病人胃腸道反應(yīng)發(fā)生率較高,但對(duì)該類病人不加選擇的使用PN的風(fēng)險(xiǎn)大于獲益,建議僅在經(jīng)口進(jìn)食或EN無(wú)法提供足夠能量時(shí)選擇PN[21]。

因體質(zhì)量下降和肌肉質(zhì)量減輕可影響化療的療效和不良反應(yīng)發(fā)生率,對(duì)于接受化療時(shí)超過(guò)1～2周無(wú)法攝入足夠能量的營(yíng)養(yǎng)不良或體質(zhì)量減輕的癌癥病人,建議進(jìn)行EN[36]。但并不推薦對(duì)所有接受化療的癌癥病人,不加選擇地使用人工營(yíng)養(yǎng)作為常規(guī)輔助治療[8-9]。

需接受造血干細(xì)胞移植(HCT)的病人入院時(shí)常已合并營(yíng)養(yǎng)不良,而相關(guān)高劑量放化療可誘發(fā)惡心、嘔吐、黏膜炎、腹瀉等并發(fā)癥進(jìn)一步影響進(jìn)食,使病人難以維持充分的能量攝入。對(duì)于該類病人應(yīng)早期進(jìn)行營(yíng)養(yǎng)篩查,評(píng)估是否應(yīng)進(jìn)行ONS、EN和(或)PN。有研究表明,PN因可提供特定配方的營(yíng)養(yǎng)混合劑而效果更好,如對(duì)于同種異體HCT的病人,高長(zhǎng)鏈脂肪酸的PN配方可降低致死性急性移植物抗宿主病的發(fā)生率[33]。但也有研究表明,同種異體HCT中EN與PN相比感染相關(guān)并發(fā)癥更少[34]。同種異體HCT后如發(fā)生嚴(yán)重的毒性黏膜炎、胃腸道感染和胃腸道移植物抗宿主病(GvHD)時(shí),通常需PN支持治療,直至病人可維持充足的經(jīng)口能量攝入。

如病人病情進(jìn)展迅速,全身炎癥反應(yīng)較重,ECOG評(píng)分≥3分時(shí),營(yíng)養(yǎng)支持的獲益較少。有文獻(xiàn)表明,PN可改善慢性腸衰竭的晚期癌癥病人的生活質(zhì)量,延長(zhǎng)生存期[35]。指南認(rèn)為對(duì)于臨終癌癥病人,補(bǔ)液和營(yíng)養(yǎng)支持在逆轉(zhuǎn)體質(zhì)量減輕、延長(zhǎng)生存期方面無(wú)積極作用,因此治療應(yīng)以減輕病人痛苦為主[8-9]。

2.3 抗炎或抗分解藥物 一篇統(tǒng)計(jì)了55項(xiàng)RCT的系統(tǒng)性綜述表明,孕激素、糖皮質(zhì)激素能提高癌癥病人食欲、逆轉(zhuǎn)體質(zhì)量減輕[36]。2016年ESPEN指南建議對(duì)厭食的癌癥晚期病人可考慮短期(1～3周)使用糖皮質(zhì)激素來(lái)增加食欲。但糖皮質(zhì)激素改善厭食的效果較短暫,當(dāng)肌病及免疫抑制出現(xiàn)后幾周作用即消失[37],所以推薦對(duì)于預(yù)計(jì)壽命短的病人,尤其是合并疼痛或惡心等，可用糖皮質(zhì)激素緩解癥狀。孕激素(醋酸甲地孕酮、醋酸甲羥孕酮)可增加食欲和體質(zhì)量,指南建議對(duì)厭食的晚期癌癥病人可考慮使用孕激素增加食欲,但需警惕血栓等嚴(yán)重并發(fā)癥。

2.4 身體鍛煉 一般來(lái)說(shuō),癌癥病人身體活動(dòng)度有不同程度降低,活動(dòng)度低和癌癥治療均對(duì)肌肉質(zhì)量有不良影響[38]。身體鍛煉可以減少肌肉分解代謝,增加肌肉合成,并可能部分減輕炎癥反應(yīng),而這些因素都參與了腫瘤惡液質(zhì)的形成。很多RCT結(jié)果顯示在癌癥的不同階段對(duì)身體鍛煉的耐受性和安全性均較好[39]。癌癥病人進(jìn)行健康鍛煉有助于保持或提高有氧代謝能力、肌力、健康相關(guān)的生活質(zhì)量,并可以減輕乏力、焦慮癥狀[40]。癌癥病人的鍛煉方案與普通人群類似,包括專業(yè)人員指導(dǎo)下的或家庭內(nèi)的中-高強(qiáng)度鍛煉(達(dá)到50%～75%最快心率),1周3次,每次10～60 min。

綜上,癌癥病人營(yíng)養(yǎng)不良發(fā)生率較高,且對(duì)癌癥的治療、預(yù)后均有不良影響,因此定期對(duì)癌癥病人進(jìn)行營(yíng)養(yǎng)篩查,對(duì)于有營(yíng)養(yǎng)風(fēng)險(xiǎn)的病人進(jìn)行飲食指導(dǎo)、ONS、人工營(yíng)養(yǎng)及身體鍛煉指導(dǎo)等有助于改善病人的營(yíng)養(yǎng)狀態(tài),從而一定程度上改善疾病預(yù)后。

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10.3969/j.issn.1003-9198.2017.04.005

2017-02-20)