胰腺導(dǎo)管腺癌肝轉(zhuǎn)移患者姑息性治療后的預(yù)后因素分析

歐陽(yáng)華強(qiáng) 馬維東 劉方 方明慧 權(quán)曼曼 潘戰(zhàn)宇

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·論著·

胰腺導(dǎo)管腺癌肝轉(zhuǎn)移患者姑息性治療后的預(yù)后因素分析

歐陽(yáng)華強(qiáng) 馬維東 劉方 方明慧 權(quán)曼曼 潘戰(zhàn)宇

目的 分析伴肝轉(zhuǎn)移的胰腺導(dǎo)管腺癌(PALM)患者接受姑息性治療后影響預(yù)后的因素。方法 回顧性分析天津醫(yī)科大學(xué)腫瘤醫(yī)院2001年1月至2015年12月間經(jīng)病理確診并僅接受姑息性治療的108例PALM患者的臨床特征、治療方法及生存狀況。采用Kaplan-Meier法計(jì)算生存率，采用單因素及多因素Cox比例風(fēng)險(xiǎn)回歸模型分析影響患者生存時(shí)間的因素。結(jié)果 108例患者中男性68例，女性40例，平均年齡58歲?；颊弑救嘶蚣覍倬芙^接受抗腫瘤治療者77例(71.3%)。所采用的姑息治療方法包括5例次(4.6%)在剖腹探查后行膽總管空腸吻合和(或)胃空腸吻合術(shù)，21例次(19.4%)行經(jīng)皮肝穿刺膽道外引流術(shù)，79例次(73.1%)行藥物鎮(zhèn)痛治療，17例次(15.7%)行藥物聯(lián)合腹腔神經(jīng)阻滯術(shù)鎮(zhèn)痛治療。全組患者的中位生存期為94d?；颊吖δ軤顟B(tài)(KPS)評(píng)分<80分、淋巴結(jié)轉(zhuǎn)移、腹水、空腹血糖≥6.1mmol/L、LDH≥250U/L為影響PALM患者預(yù)后的獨(dú)立危險(xiǎn)因素。按患者同時(shí)有上述0～1、2～3、4～5個(gè)因素分為危險(xiǎn)度低、中、高組，3組患者的中位生存時(shí)間分別為137、95、48d，差異有統(tǒng)計(jì)學(xué)意義(P<0.0001)。結(jié)論KPS評(píng)分、淋巴結(jié)轉(zhuǎn)移、腹水、空腹血糖和LDH水平是PALM患者預(yù)后的危險(xiǎn)因素，據(jù)此進(jìn)行危險(xiǎn)度分組更有利于個(gè)體化的腫瘤預(yù)后判斷，并可為臨床決策提供參考。

胰腺腫瘤； 肝腫瘤，繼發(fā)性； 姑息療法； 預(yù)后

Fund programs: National Natural Science Foundation of China (81503562); National Key Clinical Specialist Construction Programs of China (2013-544)

胰腺癌是惡性程度極高的消化系統(tǒng)腫瘤，2014年全球胰腺癌新發(fā)337 872例，死亡330 391例[1-3]。絕大多數(shù)患者在就診時(shí)已屬晚期，失去根治性手術(shù)機(jī)會(huì)。胰腺癌85%以上為導(dǎo)管腺癌[4]，其5年生存率僅為5%～8%，且在最近10年內(nèi)未見明顯改觀[5-6]。肝臟是胰腺癌遠(yuǎn)處轉(zhuǎn)移最常發(fā)生的臟器，胰腺導(dǎo)管腺癌合并肝轉(zhuǎn)移(pancreatic ductal adenocarcinoma with synchronous liver metastases, PALM)患者因體質(zhì)狀況欠佳或臟器功能不全，無(wú)法接受放、化療等抗腫瘤治療，預(yù)后更差[7]。本研究回顧性分析僅接受姑息治療的PALM患者的臨床資料與隨訪結(jié)果，以探討PALM的臨床特征、生存情況及影響預(yù)后的相關(guān)因素。

資料與方法

一、研究對(duì)象

2001年1月至2015年12月天津醫(yī)科大學(xué)腫瘤醫(yī)院共收治胰腺癌患者3 592例，其中經(jīng)組織病理學(xué)或細(xì)胞學(xué)檢查證實(shí)為胰腺外分泌癌1 530例，排除724例未發(fā)生肝轉(zhuǎn)移、122例非導(dǎo)管腺癌、177例在胰腺癌確診后超過(guò)3個(gè)月發(fā)現(xiàn)肝轉(zhuǎn)移、399例接受過(guò)根治性手術(shù)及系統(tǒng)化療、放療、靶向治療、介入治療和其他物理治療等患者，共108例單純行姑息性治療患者納入本研究。

二、研究方法

收集患者初次就診時(shí)的基本臨床資料及治療方法，并采用信件、電話、門診復(fù)查等方式進(jìn)行隨訪，截止日期為2016年4月30日。6例失訪，隨訪率為94.4%，中位隨訪35.2個(gè)月。

三、統(tǒng)計(jì)學(xué)處理

采用Stata 12.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。生存時(shí)間為從影像學(xué)檢查確診胰腺導(dǎo)管腺癌伴肝轉(zhuǎn)移到患者死亡或隨訪截止日。失訪病例截止到末次隨訪日，作為截尾數(shù)據(jù)納入統(tǒng)計(jì)學(xué)分析。采用Kaplan-Meier法計(jì)算生存率，Log-rank法進(jìn)行組間比較。影響患者生存時(shí)間的因素先采用單因素分析法，取P<0.05的因素及其他臨床公認(rèn)的因素建立Cox比例風(fēng)險(xiǎn)回歸模型進(jìn)行多因素分析。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

結(jié) 果

一、臨床資料

108例患者中男性68例，女性40例，年齡31～78歲，平均58歲；患者功能狀態(tài)(KPS)評(píng)分40～100分，平均77分；胰腺腫瘤最大徑2～14 cm，平均5.4 cm；肝轉(zhuǎn)移灶最大徑0.4～14.5 cm，平均3.4 cm(表1)。

在PALM診斷明確后，77例(71.3%)患者本人或家屬直接放棄抗腫瘤治療，15例(13.9%)在化療1次后因不良反應(yīng)較大拒絕繼續(xù)化療，9例(8.3%)患者因體能狀況極差(KPS≤60分)不能耐受化療，7例(6.5%)因肝、腎、心功能不全或合并其他特殊疾病不能接受化療(表1)。

二、姑息性治療方法

5例次(4.6%)在剖腹探查后行膽總管空腸吻合和(或)胃空腸吻合術(shù)，21例次(19.4%)行經(jīng)皮肝穿刺膽道外引流術(shù)，17例次(15.7%)行藥物聯(lián)合腹腔神經(jīng)阻滯術(shù)鎮(zhèn)痛治療，79例次(73.1%)行藥物鎮(zhèn)痛治療。同時(shí)，所有患者住院期間均給予對(duì)癥營(yíng)養(yǎng)支持治療。

三、生存率

除6例失訪外，其余患者均隨訪至生命終止。108例患者的生存時(shí)間為13～293 d，中位生存期(MS)為94 d，半年生存率為12.2%。

四、預(yù)后因素分析

單因素分析結(jié)果顯示，KPS評(píng)分、酗酒史、慢性膽囊炎、肝轉(zhuǎn)移灶范圍、淋巴結(jié)轉(zhuǎn)移、阻塞性黃疸、空腹血糖(FBG)及血清GGT、LDH、ALP水平是影響患者預(yù)后的危險(xiǎn)因素(表1)。將這10個(gè)變量以及既往文獻(xiàn)[8-10]與臨床上較為公認(rèn)的胰腺腫瘤大小、腹水、血清白蛋白、CA19-9水平納入Cox比例風(fēng)險(xiǎn)模型進(jìn)行多因素分析，結(jié)果顯示KPS評(píng)分<80分、淋巴結(jié)轉(zhuǎn)移、有腹水、FBG≥6.1 mmol/L及LDH≥250 U/L為影響患者預(yù)后的獨(dú)立危險(xiǎn)因素(表2)。按患者同時(shí)有上述0～1、2～3、4～5個(gè)因素分為危險(xiǎn)度低、中、高3個(gè)組，3組患者的MS分別為137、95、48 d，半年生存率分別為27.7%、9.5%、7.0%，差異有統(tǒng)計(jì)學(xué)意義(χ2=38.38，P<0.0001，圖1)。

表1 108例PALM患者的一般資料及單因素分析

注：a部分患者資料缺如

表2 108例PALM患者預(yù)后的多因素分析

圖1 108例PALM患者危險(xiǎn)度分組的生存曲線

討 論

PALM患者因病灶廣泛，進(jìn)展迅速，基本失去根治性手術(shù)機(jī)會(huì)。盡管小樣本回顧性資料提示對(duì)于經(jīng)過(guò)高度選擇的PALM患者實(shí)行肝、胰腺腫瘤同步切除術(shù)可能有一定價(jià)值[11-13]，但該類手術(shù)適應(yīng)證欠明確，部分報(bào)道對(duì)此持否定態(tài)度[14-15]。化療時(shí)采用吉西他濱聯(lián)合白蛋白結(jié)合型紫杉醇、FOLFIRINOX方案等可在一定程度上延長(zhǎng)轉(zhuǎn)移性胰腺癌患者的生存期，療效優(yōu)于吉西他濱單藥[16-17]。針對(duì)肝轉(zhuǎn)移灶的局部治療可采用肝動(dòng)脈灌注(栓塞)化療、經(jīng)皮肝穿刺射頻消融治療、高強(qiáng)度聚焦超聲、氬氦冷凍及放射性粒子植入術(shù)等[18-22]。但以上治療方法多以小樣本或個(gè)案報(bào)道為主，僅作為綜合治療手段的補(bǔ)充，需要依據(jù)多學(xué)科團(tuán)隊(duì)集體會(huì)診的意見酌情考慮。

本研究探討姑息性治療模式下PALM患者的生存情況與影響患者預(yù)后的相關(guān)因素。結(jié)果顯示，多數(shù)患者在確診時(shí)即已進(jìn)入疾病終末期，無(wú)積極治療的機(jī)會(huì)，患者及其家屬更傾向于實(shí)行無(wú)創(chuàng)性的姑息治療方案，僅少數(shù)患者接受姑息性內(nèi)引流術(shù)、經(jīng)皮肝穿刺膽道引流術(shù)及腹腔神經(jīng)阻滯術(shù)。文獻(xiàn)報(bào)道，各種姑息性減黃術(shù)均以緩解胰腺癌患者的癥狀和改善生活質(zhì)量為目的，內(nèi)鏡下旁路手術(shù)適用于生存預(yù)期在6個(gè)月以內(nèi)者，而對(duì)于生存預(yù)期更長(zhǎng)者，推薦選擇開放性旁路手術(shù)[23]。

本研究重點(diǎn)探討影響姑息性治療的PALM患者的預(yù)后因素。結(jié)果顯示，KPS<80分、淋巴結(jié)轉(zhuǎn)移、有腹水、LDH≥250 U/L、FBG≥6.1 mmol/L是影響PALM患者的獨(dú)立危險(xiǎn)因素。前4個(gè)因素在既往文獻(xiàn)中報(bào)道甚多[9,24-26]，而高血糖則較少提及。胰腺癌常并發(fā)糖尿病，某些患者往往在明確診斷前后偶然發(fā)現(xiàn)血糖升高。本組中有22例為慢性糖尿病患者，但首次就診時(shí)FBG≥6.1 mmol/L者達(dá)57例(52.8%)，不排除部分為新發(fā)糖尿病。PALM合并糖尿病患者的中位生存時(shí)間與無(wú)糖尿病者無(wú)顯著差異(3.5個(gè)月比3.0個(gè)月，χ2=0.001，P=0.99)，但若以空腹血糖≥6.1 mmol/L進(jìn)行比較，則對(duì)應(yīng)兩組的差異具有統(tǒng)計(jì)學(xué)意義(P<0.01)，提示高血糖為PALM獨(dú)立的預(yù)后危險(xiǎn)因素。因本組患者生存期短，絕大多數(shù)患者并未參照糖尿病診斷流程進(jìn)一步完善檢查，是否如Li等[27]報(bào)道的新發(fā)糖尿病為轉(zhuǎn)移性胰腺癌患者死亡風(fēng)險(xiǎn)的獨(dú)立預(yù)測(cè)因子，尚待進(jìn)一步考證。

本研究參照Cox比例風(fēng)險(xiǎn)模型得出的5個(gè)危險(xiǎn)因素，對(duì)108例PALM患者進(jìn)行了危險(xiǎn)度分組，結(jié)果提示各組間生存率差異具有統(tǒng)計(jì)學(xué)意義(P<0.0001)。危險(xiǎn)度分組為評(píng)估患者整體預(yù)后提供了便捷有效的方法，并可為臨床決策奠定基礎(chǔ)。高危組患者中位生存時(shí)間僅48 d，應(yīng)以姑息治療為主要措施；而對(duì)于中、低危組的患者，則有可能通過(guò)積極的多學(xué)科治療方案改善預(yù)后，延長(zhǎng)生存期。

誠(chéng)然，本研究存在一定的局限性。首先，作為回顧性分析難免存在病例選擇上的偏倚。其次，由于樣本量所限，對(duì)于少數(shù)患者合并的臟器功能不全及其他伴隨疾病，并未納入預(yù)后因素分析。此外，由于時(shí)間跨度較長(zhǎng)，患者接受姑息治療前后的某些數(shù)據(jù)記錄不全，難以充分評(píng)估姑息治療的療效及其對(duì)生存期的影響。故本研究的重點(diǎn)為非治療因素的預(yù)測(cè)價(jià)值，以便為將來(lái)的PALM患者可能接受抗腫瘤治療提供參考。

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(本文編輯：呂芳萍)

Analysis of prognostic factors in patients with pancreatic ductal adenocarcinoma and synchronous liver metastases after palliative treatment

OuyangHuaqiang,MaWeidong,LiuFang,FangMinghui,QuanManman,PanZhanyu.

TianjinMedicalUniversityCancerHospital,NationalClinicalResearchCenterofCancer,KeyLaboratoryofCancerPreventionandTherapy,Tianjin300060,China

PanZhanyu,Email:zpan@tmu.edu.cn

Objectives To explore the prognostic factors of patients with pancreatic ductal adenocarcinoma and synchronous liver metastases (PALM) receiving palliative treatment. Methods The clinical characteristics, therapeutic approaches and survival outcomes of 108 consecutive patients with PALM who were pathologically diagnosed and received only palliative treatment at Tianjin Medical University Cancer Hospital from January 2001 to December 2015. were retrospectively analyzed. Survival rates were calculated by Kaplan-Meier method, and factors influencing the survival were analyzed by univariate and multivariate Cox proportional hazard regression model. Results Of these patients, 68 were male and 40 were female, with an average age of 58 years old. Seventy-seven (71.3%) cases or their relatives refused to receive anticancer therapies. Palliative treatments included choledochojejunostomy and/or gastrojejunostomy after exploratory laparotomy for 5 (4.6%) cases, percutaneous transhepatic biliary drainage (n=22, 19.4%), drug analgesia (n=79, 73.1%), drug analgesia combined with percutaneous neurolytic coeliac plexus block (n=17, 15.7%). The median survival time (MS) was 94 days in all patients. Karnofsky performance score (KPS)<80, lymph node metastases, ascites, fasting blood glucose ≥6.1 mmol/L and lactate dehydrogenase (LDH) ≥250 U/L were independent risk factors influencing prognosis of PALM. Three groups were categorized according to the number of the above 5 risk factors for 0～1 in low risk group, 2～3 in middle risk group and 4～5 in high risk group, and the MS of 3 groups was 137, 95 and 48 days, respectively, with an extremely statistical significance (P<0.0001). Conclusions KPS, lymph node metastases, ascites, fasting blood glucose and LDH were the risk factors for prognosis of PALM. Patient stratification according to the above factors is more advantageous for judging individualized prognosis and can provide reference for making clinical decision.

Pancreatic neoplasms; Liver neoplasms, secondary; Palliative care; Prognosis

10.3760/cma.j.issn.1674-1935.2016.06.003

300060 天津，天津醫(yī)科大學(xué)腫瘤醫(yī)院中西醫(yī)結(jié)合科，國(guó)家腫瘤臨床醫(yī)學(xué)研究中心，天津市腫瘤防治重點(diǎn)實(shí)驗(yàn)室

潘戰(zhàn)宇，Email： zpan@tmu.edu.cn

國(guó)家自然科學(xué)基金(81503562)；國(guó)家臨床重點(diǎn)?？平ㄔO(shè)項(xiàng)目(2013-544)

2016-06-29)