周小林
?
·論 著·
CRP和Alb與初診斷的非小細(xì)胞肺癌臨床病理特征聯(lián)系及預(yù)后價(jià)值分析
周小林
目的 分析初診非小細(xì)胞肺癌(NSCLC)患者血清C-反應(yīng)蛋白(CRP)、血清白蛋白(Alb)水平與臨床病理特征及患者總生存期的聯(lián)系,探討其在NSCLC患者預(yù)后轉(zhuǎn)歸的臨床意義。方法 回顧性分析2011年1月-2013年1月醫(yī)院收治的105例NSCLC患者的臨床資料,根據(jù)患者術(shù)前外周血CRP和Alb中位值,分別分為高值組和低值組,分析CRP、Alb水平高低與臨床病理特征的關(guān)系,根據(jù)隨訪生存情況,采用Kaplan-Meier法單因素、Cox比例風(fēng)險(xiǎn)回歸模型多因素分析術(shù)前CRP、Alb等因素對(duì)NSCLC患者總生存期的影響。結(jié)果 治療前NSCLC患者血清CRP的水平為(18.14±10.75)mg/L,Alb值為(35.32±12.83) g/L。Alb低值組與高齡、淋巴結(jié)轉(zhuǎn)移、較晚的臨床分期相關(guān),而CRP高值組與淋巴結(jié)轉(zhuǎn)移、較晚的臨床分期相關(guān),具有統(tǒng)計(jì)學(xué)意義(P<0.05)。單因素分析顯示高CRP和低Alb水平與較差的總生存期有關(guān),多因素生存分析顯示淋巴結(jié)轉(zhuǎn)移,較晚的臨床分期和高CRP值是影響NSCLC患者生存預(yù)后的獨(dú)立危險(xiǎn)因素。結(jié)論 CRP和Alb兩項(xiàng)指標(biāo)對(duì)肺癌的診斷、預(yù)后判斷和療效監(jiān)測(cè)具有重要應(yīng)用價(jià)值,是NSCLC預(yù)后潛在的生物標(biāo)志物。
非小細(xì)胞肺癌;C反應(yīng)蛋白;血清白蛋白;生存分析;預(yù)后
非小細(xì)胞肺癌(nonsmall cell lung carcinoma,NSCLC)占肺癌的80%,其5年生存率僅不到20%,惡性程度較高,往往初診斷時(shí)已經(jīng)惡化甚至轉(zhuǎn)移,失去了手術(shù)機(jī)會(huì)[1-3]。盡管手術(shù)、化療、放療和生物免疫治療不斷發(fā)展,但NSCLC患者的預(yù)后仍較差。在我國肺癌已經(jīng)分別居男女惡性腫瘤發(fā)病率的首位和第二位,且在未來肺癌發(fā)病率和死亡率仍將繼續(xù)保持上升趨勢(shì)。目前對(duì)肺癌療效檢測(cè)主要根據(jù)影像學(xué)變化評(píng)估,費(fèi)用高昂且不能從代謝角度反映腫瘤的進(jìn)展。近年來越來越多的研究支持慢性肺部炎癥在致癌中的作用,炎癥相關(guān)基因的多態(tài)性等都和患癌風(fēng)險(xiǎn)增加有關(guān)[4-5]。炎癥細(xì)胞及炎癥因子組成的腫瘤微環(huán)境參與了腫瘤的形成和發(fā)展,癌癥相關(guān)炎癥分子通路逐漸闡明,因此炎癥也作為腫瘤的特征之一被廣泛接受[6-7]。血清C-反應(yīng)蛋白(C-reactive protein, CRP)是經(jīng)典的最敏感的炎性反應(yīng)急性時(shí)相蛋白,在健康人血清中含量極微,惡性腫瘤患者尤其是在晚期血清CRP往往升高,一般認(rèn)為肺癌患者CRP的增高具有一定診斷價(jià)值。血清白蛋白(serum albumin, Alb)反映機(jī)體內(nèi)營養(yǎng)狀況,腫瘤患者蛋白質(zhì)代謝異常,呈負(fù)氮平衡狀態(tài),機(jī)體對(duì)化療反應(yīng)及耐受力均下降[8]。本研究回顧性分析初診NSCLC患者血清CRP、Alb水平與臨床病理特征及總生存期的聯(lián)系,探討其對(duì)NSCLC臨床預(yù)后的評(píng)估作用。
1.1 對(duì)象 2011年1月-2013年1月我科室收治的初診NSCLC患者105例,研究病例納入標(biāo)準(zhǔn):① 均由細(xì)胞學(xué)或病理學(xué)確診為NSCLC;② 之前未接受過化療、放療治療,無感染等急性炎癥特征; ③ 均有較完整的臨床資料,均簽署知情同意書,且本研究經(jīng)醫(yī)院倫理委員會(huì)通過。男72例,女33例,年齡47~82歲,中位年齡為65歲。根據(jù)WHO發(fā)布的2004年肺部腫瘤組織學(xué)分類,其中肺鱗狀細(xì)胞癌59例,腺癌25例,大細(xì)胞肺癌6例,低分化癌15例。根據(jù)2009年IASLC肺癌分期標(biāo)準(zhǔn),Ⅰ期48例,Ⅱ期22例,Ⅲ期28例,Ⅳ期7例。
表1 105例NSCLC患者中CRP、Alb水平與臨床病理特征的聯(lián)系
臨床病理特征AlbCRP低值組(n=52)高值組(n=53)χ2/t值P值低值組(n=52)高值組(n=53)χ2/t值P值年齡(歲)72.18±12.5464.86±11.193.1570.00267.43±12.2171.21±13.541.5010.126性別 男 女322040132.3640.124371535180.3190.572淋巴結(jié)轉(zhuǎn)移 否 是143830239.4980.002282416376.0340.014臨床分期 Ⅰ~Ⅱ Ⅲ~Ⅳ282442117.6200.006421028259.2200.002病理類型 鱗癌32272930 腺癌12131.6450.43914110.7960.672 其他813912吸煙 否/偶爾 是153723302.4060.121203218350.2300.631飲酒 否/偶爾 是183414390.8330.361124020332.6620.103
1.2 檢測(cè)方法 開始接受治療前,所有患者空腹取外周靜脈血,標(biāo)本4 ℃保存送檢,以4000 r/min離心分離血清,采用全自動(dòng)生化檢測(cè)儀測(cè)定NSCLC患者治療前CRP和Alb水平。遠(yuǎn)期預(yù)后通過門診復(fù)查、電話及信訪方式,隨訪至患者死亡或者截止2015年8月1日。
2.1 NSCLC患者血清CRP、Alb水平與臨床病理特征聯(lián)系 治療前NSCLC患者血清CRP的水平為(18.14±10.75) mg/L,Alb值為(35.32±12.83)g/L。根據(jù)CRP和Alb的中位值將NSCLC患者分為高、低CRP組,高、低Alb組。血清CRP、Alb水平與患者臨床病理特征的聯(lián)系見表1,Alb低值組與高齡、淋巴結(jié)轉(zhuǎn)移、較晚的臨床分期相關(guān),而CRP高值組與淋巴結(jié)轉(zhuǎn)移、較晚的臨床分期相關(guān),具有統(tǒng)計(jì)學(xué)意義(P<0.05)。
A:不同Alb組患者總生存期曲線圖;B:不同CRP組患者總生存期曲線圖圖1 血清Alb、CRP水平與NSCLC患者生存預(yù)后的關(guān)系
2.2 血清Alb、CRP水平與NSCLC患者生存預(yù)后的關(guān)系 采用Kaplan-Meier法分析血清Alb、CRP水平與NSCLC患者生存預(yù)后的關(guān)系,結(jié)果如圖1生存曲線所示,Alb低值組患者中位生存期為13.1個(gè)月,高值組中位生存期為19.9個(gè)月,Alb低值組的總生存期明顯差于高值組(P=0.015);CRP水平與預(yù)后生存曲線顯示低值組患者中位生存期為22.3個(gè)月,高值組中位生存期為12.4個(gè)月,CRP高值組總生存期明顯差于低值組(P=0.007)。
2.3 Cox回歸多因素生存預(yù)后分析 將臨床病理因素和Alb、CRP納入Cox回歸模型分析,結(jié)果顯示淋巴結(jié)轉(zhuǎn)移(風(fēng)險(xiǎn)比:4.61, 95%置信區(qū)間:0.20~6.85),較晚的臨床分期(風(fēng)險(xiǎn)比:7.51,95%置信區(qū)間:1.04~11.25),高CRP值(風(fēng)險(xiǎn)比:6.42,95%置信區(qū)間:1.23~18.21)是影響NSCLC患者生存預(yù)后狀況的獨(dú)立危險(xiǎn)因素(表2)。
表2 105例NSCLC患者Cox多因素預(yù)后生存分析
近年來對(duì)癌癥及NSCLC相關(guān)性炎癥研究逐漸成為研究熱點(diǎn),有學(xué)者提出炎癥應(yīng)成為癌癥的第七個(gè)特征,炎性指標(biāo)是否與癌癥患者的臨床預(yù)后有關(guān)值得我們?nèi)ヌ接慬9-11]。盡管NSCLC發(fā)病的分子生物學(xué)機(jī)制在基因和蛋白水平上有了很深入的探索,但臨床上患者死亡率居高不下至今未能改善[12-13],因此早期診斷對(duì)患者治療的預(yù)后有著非常重要的意義,臨床上迫切地需要更多有價(jià)值的生物標(biāo)志物對(duì)患者預(yù)后轉(zhuǎn)歸進(jìn)行預(yù)測(cè)。在血清生物標(biāo)志物中越來越多的炎癥相關(guān)因子被發(fā)現(xiàn)與腫瘤有關(guān),此研究中我們采用Kaplan-Meier法分析發(fā)現(xiàn)C反應(yīng)蛋白和血清白蛋白與NSCLC生存預(yù)后有顯著性聯(lián)系。Alb低值組的總生存期明顯差于高值組(P=0.015),CRP高值組總生存期明顯差于低值組(P=0.007)。而且兩項(xiàng)指標(biāo)在臨床上很容易獲取,對(duì)患者預(yù)后評(píng)估具有十分重要的意義。Alb是反映人體內(nèi)蛋白營養(yǎng)狀況的常見指標(biāo),癌癥患者蛋白質(zhì)代謝異常,分解代謝增加,呈負(fù)氮平衡,對(duì)化療反應(yīng)和耐受力均降低。國內(nèi)外有研究發(fā)現(xiàn)腫瘤病灶周圍會(huì)聚集活化巨噬細(xì)胞、淋巴細(xì)胞,其釋放IL-6、TNF-α等炎性因子會(huì)刺激肝細(xì)胞,從而使CRP合成增加[14-16]。本研究利用Cox回歸多因素生存預(yù)后分析顯示血清CRP的升高與腫瘤患病風(fēng)險(xiǎn)、臨床分期、預(yù)后等均相關(guān),提示CRP增高可作為肺癌潛在的生物標(biāo)志物。
本研究中通過分析NSCLC患者的臨床病理特征,Pearson卡方檢驗(yàn)顯示Alb低值組與高齡、淋巴結(jié)轉(zhuǎn)移、較晚的臨床分期相關(guān),而CRP高值組與淋巴結(jié)轉(zhuǎn)移、較晚的臨床分期相關(guān),而二者與患者的性別、病理類型、吸煙或飲酒無關(guān)。29個(gè)腫瘤研究中心臨床流行病學(xué)調(diào)查顯示:白蛋白水平是腫瘤患者存活的預(yù)示因子,60歲以上住院患者死亡率與低蛋白水平有關(guān)[17-18]。年齡較大的患者自身機(jī)體營養(yǎng)狀況較差,腫瘤代謝增強(qiáng),白蛋白消耗大、合成減少,因而血清Alb低于年輕患者。最新研究亦發(fā)現(xiàn)高水平持久的血清CRP是不利的預(yù)后因素,水平愈高預(yù)后愈差[10, 19]。關(guān)于非小細(xì)胞肺癌預(yù)后因素回顧性分析研究很多,得出的結(jié)論不全相同,比較公認(rèn)的因素主要有TNM分期,體重減輕,遠(yuǎn)處器官轉(zhuǎn)移等,其他可能影響預(yù)后的因素有:年齡,性別,病理類型,吸煙與否等尚存在爭議。本研究通過多因素生存分析發(fā)現(xiàn)淋巴結(jié)轉(zhuǎn)移,較晚的臨床分期,高CRP值是影響NSCLC患者生存預(yù)后的獨(dú)立危險(xiǎn)因素。這與McKeown等[20]隨訪或前瞻性研究報(bào)道結(jié)論一致,CRP水平提升癌癥風(fēng)險(xiǎn),提示預(yù)后不良。血清CRP下降50%是一個(gè)預(yù)測(cè)局部晚期或轉(zhuǎn)移性NSCLC患者對(duì)化療敏感性簡單而有效的方法。分期較晚,且有淋巴結(jié)轉(zhuǎn)移的惡性腫瘤侵犯周圍組織亦越嚴(yán)重,促進(jìn)炎性細(xì)胞的集聚,因此肺部癌癥患者CRP水平明顯升高可在一定程度預(yù)示患者預(yù)后。
綜上所述,本研究證實(shí)血清Alb、CRP與高齡、淋巴結(jié)轉(zhuǎn)移、較晚的臨床分期相關(guān),且低Alb、高CRP水平預(yù)示較差的總生存期,多因素生存分析顯示高水平CRP、淋巴結(jié)轉(zhuǎn)移和較晚臨床分期是患者預(yù)后的獨(dú)立影響因素,本課題組將進(jìn)一步分析二者的比值與初診斷NSCLC患者的臨床預(yù)后關(guān)系。CRP、Alb檢測(cè)具有高效、靈敏、便捷、經(jīng)濟(jì)及創(chuàng)傷小等優(yōu)點(diǎn),通過兩者聯(lián)合檢測(cè)對(duì)肺癌的診斷、預(yù)后判斷和療效監(jiān)測(cè)具有重要臨床價(jià)值。
[1] Folkert MR, Timmerman R. Review of treatment options for oligometastatic non-small cell lung cancer[J]. Clin Adv Hematol Oncol, 2015, 13(3): 186-193.
[2] Yan JH, Zhao CL, Ding LB,et al. FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer[J]. Biochem Biophys Res Commun, 2015, 466(1):111-116.
[3] Quintyne KI, Walsh L, Coate L. Non-small-cell lung cancer: promising advances in treatment[J]. Lancet Respir Med, 2013, 1(1): e13-14.
[4] Vijayvergia N, Shah PC, Denlinger CS. Survivorship in non-small cell lung cancer: challenges faced and steps forward[J]. J Natl Compr Canc Netw, 2015, 13(9): 1151-1161.
[5] Meoni G, Cecere FL, Lucherini E,et al. Medical treatment of advanced non-small cell lung cancer in elderly patients: a review of the role of chemotherapy and targeted agents[J]. J Geriatr Oncol, 2013, 4(3): 282-290.
[6] Kamp DW, Shacter E, Weitzman SA. Chronic inflammation and cancer: the role of the mitochondria[J]. Oncology (Williston Park), 2011, 25(5): 400-410.
[7] Rivas-Fuentes S, Salgado-Aguayo A, Pertuz Belloso S,et al. Role of chemokines in non-small cell lung cancer: angiogenesis and inflammation[J]. J Cancer, 2015, 6(10): 938-952.
[8] Scott HR, McMillan DC, Forrest LM,et al. The systemic inflammatory response, weight loss, performance status and survival in patients with inoperable non-small cell lung cancer[J]. Br J Cancer, 2002, 87(3): 264-267.
[9] Mantovani A. Cancer: inflaming metastasis[J]. Nature, 2009, 457(7225): 36-37.
[10]Forrest LM, McMillan DC, McArdle CS,et al. Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer[J]. Br J Cancer, 2003, 89(6): 1028-1030.
[11]Liao C, Yu ZB, Meng G,et al. Association between Th17-related cytokines and risk of non-small cell lung cancer among patients with or without chronic obstructive pulmonary disease[J]. Cancer, 2015, 121 (Suppl 17):3122-3129.
[12]Chen YY, Wang LW, Wang SY,et al. Meta-analysis of postoperative adjuvant chemotherapy without radiotherapy in early stage non-small cell lung cancer[J]. Onco Targets Ther, 2015, 8: 2033-2043.
[13]Antonoff MB, Hofstetter WL, Correa AM,et al. Clinical prediction of pathologic complete response in superior sulcus non-small-cell lung cancer[J]. Ann Thorac Surg, 2016,101(1):211-217.
[14]Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients?[J]. Curr Opin Pharmacol, 2009, 9(4): 351-369.
[15]Aggarwal BB. Inflammation, a silent killer in cancer is not so silent[J]. Curr Opin Pharmacol, 2009, 9(4): 347-350.
[16]Tolia M, Tsoukalas N, KyrgiasG,et al. Prognostic Significance of Serum Inflammatory Response Markers in Newly Diagnosed Non-Small Cell Lung Cancer before Chemoirradiation[J]. Biomed Res Int, 2015, 2015: 485732.
[17]Gupta D, Vashi PG, Lammersfeld CA,et al. Role of nutritional status in predicting the length of stay in cancer: a systematic review of the epidemiological literature[J]. Ann Nutr Metab, 2011, 59(2-4): 96-106.
[18]Hannan JL, Radwany SM, Albanese T. In-hospital mortality in patients older than 60 years with very low albumin levels[J]. J Pain Symptom Manage, 2012, 43(3): 631-637.
[19]Wang X, Han H, DuanQ,et al. Changes of serum albumin level and systemic inflammatory response in inoperable non-small cell lung cancer patients after chemotherapy[J]. J Cancer Res Ther, 2014, 10(4): 1019-1023.
[20]McKeown DJ, Brown DJ, Kelly A,et al. The relationship between circulating concentrations of C-reactive protein, inflammatory cytokines and cytokine receptors in patients with non-small-cell lung cancer[J]. Br J Cancer, 2004, 91(12): 1993-1995.
(本文編輯:齊 名; 英文編輯:王建東)
Prognostic evaluation of CRP and Alb in newly diagnosed non-small cell lung cancer
ZHOU Xiao-lin.
DepartmentofRespiration,NantongSecondPeople'sHospital,Nantong,Jiangsu226000,China
Objective To analyze the correlation of serum C-reactive protein (CRP), serum albumin (Alb) levels and clinical pathological features and clinical overall survival in newly diagnosed non-small cell lung cancer (NSCLC). To investigate the prognostic evaluation of CRP and Alb in NSCLC. Methods Clinical data of 105 newly diagnosed patients with NSCLC in our department were analyzed retrospectively. They were divided into two groups according to the levels of CRP and Alb. Clinicopathological features and levels of CRP and Alb were compared. In order to determine their prognostic value, overall survival (OS) was evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Results The levels of CRP and Alb in newly diagnosed patients with NSCLC were (18.14±10.75)mg/L and (35.32±12.83)g/L respectively. The low Alb group and the high CRP group were related to old age, tumor lymph node metastasis and late clinical stage significantly. Univariate Kaplan-Meier analysis revealed a significant correlation between low Alb/high CRP level and poor overall survival. Furthermore, high level of CRP was an independent marker for poor clinical outcome as tumor lymph node metastasis and late clinical stage concerning the multivariate analysis of NSCLC patients. Conclusion The two indicators of CRP and Alb have important value in diagnosis, prognosis and therapeutic of NSCLC and could be the potential biomarkers in prognosis of lung cancer.
non-small cell lung cancer (NSCLC); C-reactive protein (CRP); serum albumin (Alb); survival analysis; prognostic evaluation
226000江蘇南通,南通市第二人民醫(yī)院呼吸科
周小林.CRP和Alb與初診斷的非小細(xì)胞肺癌臨床病理特征聯(lián)系及預(yù)后價(jià)值分析[J].東南國防醫(yī)藥,2016,18(5):489-492.
R734.2
A
10.3969/j.issn.1672-271X.2016.05.012
2016-03-23;
2016-06-03)