碘-125粒子條腔內近程放射治療局部進展期胰腺導管腺癌伴梗阻性黃疸的初步臨床研究

趙 倩 楊敏捷 劉凌曉 劉清欣 張 雯 羅劍鈞△ 顏志平 李文會

(1復旦大學附屬中山醫院介入科 上海 200032; 2上海市影像醫學研究所 上海 200032;3江蘇省鹽城市第三人民醫院介入科 鹽城 224001)

碘-125粒子條腔內近程放射治療局部進展期胰腺導管腺癌伴梗阻性黃疸的初步臨床研究

趙 倩1,2楊敏捷1,2劉凌曉1,2劉清欣1,2張 雯1,2羅劍鈞1,2△顏志平1,2李文會3

(1復旦大學附屬中山醫院介入科 上海 200032;2上海市影像醫學研究所 上海 200032;3江蘇省鹽城市第三人民醫院介入科 鹽城 224001)

目的 探索碘-125粒子條腔內近程放射治療局部進展期胰腺導管腺癌伴梗阻性黃疸的安全性及可行性。方法 對2010年1月至2015年2月復旦大學附屬中山醫院介入科收治的17例局部進展期(4例為T4N0M0,13例為T4N1M0)胰腺導管腺癌伴梗阻性黃疸患者行碘-125粒子條腔內近程放射治療的臨床資料進行回顧性分析。用配對t檢驗分析患者術前、術后肝功能變化。碘-125粒子條放射劑量由碘-125粒子條放射區域分布計算軟件(0.1版,復旦大學影像研究所)根據美國醫學物理協會TG43U1近程放射公式計算。用Kaplan-Meier曲線分析無梗阻生存期和累計生存期。術后并發癥根據美國國立癌癥研究所通用毒性標準4.0版評估。結果 碘-125粒子條累計劑量(r=5 mm,240天)為164.19～170.05 Gy,平均為167.38Gy。平均、中位無梗阻生存期分別為(9.62±1.47)個月(95%CI:6.73～12.50)和(7.26±1.71)個月(95%CI:3.90～10.62),平均、中位總生存期分別為(9.89±1.59)個月(95%CI:6.78～13.00)和(7.26±1.71)個月(95%CI:3.90～10.62)。患者術前、術后總膽紅素和直接膽紅素差異具有統計學意義。研究中2例患者發生3級術后并發癥,1例患者發生4級并發癥。1例患者出現支架再狹窄(5.9%)。結論 碘-125粒子條腔內近程放射治療是局部進展期胰腺導管腺癌伴梗阻性黃疸的一種安全可行的治療方法。

近程放射治療; 胰腺導管腺癌; 碘-125粒子條; 梗阻性黃疸

胰腺導管腺癌是全球癌癥致死率最高的腫瘤之一,其5年生存率小于5%[1-3]。多達30%的患者首次診斷時已為局部進展期,失去了手術機會。大約70%的胰腺癌患者伴有梗阻性黃疸[4]。膽道支架植入能迅速恢復膽汁引流、提高生活質量,是姑息治療的有效手段[5-8]。目前有多種上市的支架可供選擇,但各種支架都可能出現再狹窄。據報道即使使用覆膜支架或藥物洗脫等新型支架,仍有10%～54%的患者發生支架再狹窄[9-13],分析其狹窄原因主要為腫瘤向支架內生長、黏膜增生及膽汁淤積。支架再狹窄不但影響患者的生活質量,而且二次手術增加了患者的損傷及經濟負擔[14-17]。近年,文獻報道膽道腔內放射支架植入治療可提高各種腺癌造成的惡性梗阻性黃疸支架的通暢期[18]。本文對2010年1月至2015年2月復旦大學附屬中山醫院介入科收治的17例局部進展期胰腺導管腺癌伴梗阻性黃疸患者行碘-125粒子條腔內近程放射治療的臨床資料進行回顧性分析,現報道如下。

資 料 和 方 法

臨床資料 經復旦大學附屬中山醫院倫理委員會批準(批號:2009-080),對2010年1月至2015年2月在介入科接受膽道支架+碘-125粒子條腔內近程放射治療的胰腺導管腺癌伴梗阻性黃疸患者的病例資料進行回顧性分析。納入標準:美國東部腫瘤協作組(eastern cooperative oncology group,ECOG)狀態評分0-2;胰腺導管腺癌根據臨床表現和影像診斷、病理活檢診斷,伴肝內外膽管擴張;局部晚期、非轉移、不可手術切除。排除標準:美國東部腫瘤協作組狀態評分>2;腫瘤轉移;任何一項肝穿刺禁忌癥:凝血功能異常(血小板計數<50×109/L或凝血酶原活性<50%);肝、腎功能衰竭;心臟射血分數<50%;疾病終末期患者不能耐受手術者。所有患者均簽署知情同意書接受膽道支架及碘-125粒子條植入。

本研究共收集17例患者,平均年齡(67.65±14.64)歲,其中男性12例、女性5例。ECOG評分11例為0分、6例為1分。腫瘤TNM分期:4例為T4N0M0,13例為T4N1M0,腫瘤最大徑平均為(3.23±1.03)cm (2.2～4.8 cm)。腫瘤位于胰頭者10例,胰頭頸2例,胰頭頸體5例。17例患者中13例患者有疾病治療史:2例開腹探查、7例化療、1例放療、3例內鏡下逆行胰膽管造影(endoscopic retrograde cholangiopancreatography,ERCP)支架植入失敗。所有患者均行經皮穿肝膽道引流術(percutaneous trans-hepatic biliary drainage,PTBD),術前一天查腫瘤相關抗原199,3例為陰性,其余患者平均值為(1 323.24±2 541.23)U/mL。

膽道支架+碘-125粒子條植入治療 手術采用利多卡因局麻。患者仰臥位,心電監護,取原PTBD引流管入路,引入導絲,通過閉塞段,進入腸道,沿導絲植入自膨式金屬裸支架(美國波士頓公司)及碘-125粒子條。金屬裸支架直徑為8 mm,長度為6 cm或8 cm。碘-125粒子條由6711型碘-125粒子(上海欣科醫藥有限公司)封裝于4Fr無菌醫用導管內。單枚粒子的放射性活度為25.9 MBq,半衰期為59.4天,主要射線包括27.4、31.4KeV的X線和35.5KeV的γ射線,組織半價層為17 mm,初始劑量率為7cGy/h。碘-125的數目由膽道梗阻段的長度決定:N=L/4.5+4,L為膽道梗阻段的長度,單位:毫米,N為粒子數,單位:粒。未獲得病理診斷的患者手術中行細針穿刺抽吸活檢。患者術前、術后3天預防性使用抗生素。

術后治療及隨訪 術后所有患者均行吉西他濱經動脈灌注化療,每月1次,每次1 000 mg/m2。收集患者術前、術后肝腎功能及腹部增強CT檢查的影像學資料(圖1)。收集患者術后第1天單光子激發斷層掃描(SPECT/CT)影像資料(圖2),評估碘-125粒子條的活性和粒子條的位置。

A:Pre-operation contrast-enhanced CT shows pancreatic head and neck and body tumor with the expansion of internal and external bile duct and main pancreatic duct (artery phase).B:Post-operation contrast-enhanced CT (artery phase).The fifty-seven years old male patient was found pancreatic head and neck and body tumor by contrast-enhanced CT owing to abdominal discomfort.He could not ndergo surgical resection and received PTBD and iodine-125 seed strand +bare metal stent.The patient complained with abdominal distention 9 months after iodine-125 seed strand implantation,and portal vein stricture was revealed by subsequent contrast-enhanced CT.He received portal vein implantation with iodine-125 seed strand.The patient had a survival time of 22.23 months.

A:Transverse sections;B:Coronal sections.

結 果

治療情況及粒子條劑量的計算 所有患者病理診斷均為胰腺導管腺癌(2例外科術中活檢、3例ERCP下穿刺活檢、8例經皮穿刺活檢、4例細針穿刺抽吸活檢)。所有患者均成功施行膽道支架+碘-125粒子條植入(圖3)。膽道梗阻段長度為27～72 mm,平均43.4 mm。碘-125粒子數10～20粒,平均13.64粒。術后1天,患者接受SPECT/CT掃描檢查,所有植入的碘-125粒子條均準確位于膽道梗阻段,粒子條無移位(圖2)。碘-125粒子條指示點(粒子條中點軸距5 mm處,r=5 mm)240天累計劑量由碘-125粒子條放射區域分布計算軟件(0.1版,復旦大學影像研究所)[19]根據美國醫學物理協會TG43U1近程放射公式計算。累計劑量為164.19～170.05 Gy(r=5 mm,240天),平均為167.38 Gy。

圖3 數字減影(Digital subtraction angiography,DSA)示碘-125粒子條及支架位于膽總管內Fig 3 DSA shows iodine-125 seed strand and stent within the common bile duct

支架通暢率及生存期 所有患者行PTBD術后1個月總膽紅素和直接膽紅素明顯下降,平均總膽紅素從(215.18±75.91) μmol/L降至(45.14±36.80) μmol/L (P<0.05),直接膽紅素平均值從(181.91±63.82) μmol/L降至(40.65±35.32) μmol/L (P<0.05),總膽紅素、直接膽紅素術前、術后差異具有統計學意義(表1)。本研究平均無梗阻生存期及中位無梗阻生存期分別為(9.62±1.47)個月(95%CI:6.73～12.50)和(7.26±1.71)個月(95%CI:3.90～10.62)(圖4)。平均、中位總生存期分別為(9.89±1.59)個月(95%CI:6.78～13.00)和(7.26±1.71)個月(95%CI:3.90～10.62)(圖5)。1例患者(5.9%,1/17)術后17.74個月出現支架再狹窄,后行PTBD膽汁引流,患者總生存期為22.44個月。另1例患者碘-125粒子條植入9個月后訴腹脹,行增強CT檢查示門靜脈狹窄,行門靜脈碘-125粒子條植入術,該患者總生存期為22.23個月。

術后并發癥及處理 疼痛是最常見的術后并發癥,本研究中有8例患者出現疼痛,給予鎮痛藥后24 h內疼痛緩解。1例患者出現膽管炎,抗生素治療后好轉。1例患者手術過程中出現迷走神經反應,血壓從135/90 mmHg降至97/53 mmHg (1 mmHg=1.133 kPa),心率從80次/分降至45次/分,立即給予0.5 mg阿托品,患者血流動力學恢復。胰腺炎、十二指腸炎、粒子條移位等后期并發癥在本研究中未發生(表2)。

表1 術前、術后肝功能變化Tab 1 Liver function changes between pre-operation and post-operation

TB:Total bilirubin; CB:Conjugated bilirubin;γ-GT:γ-Glutamyl transferase;ALB:Albumin.Pre-operation samples were acquired one day before PTBD.Post-operation samples were acquired one month after PTBD.

圖4 無梗阻生存曲線Fig 4 Kaplan-Meier obstruction-free survival curve

圖5 總生存曲線Fig 5 Kaplan-Meier overall survival curve

表2 美國國立癌癥研究所通用毒性標準4.0版評估并發癥Tab 2 Procedure-related complications assessed by CTCAE 4.0

CTCAE 4.0:Common Terminology Criteria for Adverse Event version 4.0;aOccurred during the procedure:hemodynamic instability.

討 論

目前化療、放療是局部進展期胰腺導管腺癌的主要治療方法[4,20]。伴有梗阻性黃疸的患者可行內鏡下逆行胰膽管造影或者經皮穿肝途徑植入支架以解除膽道梗阻、緩解臨床癥狀[21]。如何減少支架再狹窄發生率、提高支架的通暢時間,對于改善患者生活質量至關重要。

本研究回顧性分析碘-125粒子條腔內近程放射治療局部進展期胰腺導管腺癌伴梗阻性黃疸。膽道腔內放射治療能抗黏膜增生、抗腫瘤生長以延長支架通暢期。動物實驗表明碘-125粒子條腔內近程放射治療惡性梗阻性黃疸是安全可行的[22]。自1980年以來,金屬裸支架植入已成為惡性梗阻性黃疸患者的姑息治療方法[22-25]。早期的長期隨訪研究發現,9名患者發生支架再狹窄(占35%),平均支架通暢期為39.9周[26-27]。研究報道支架再狹窄的主要原因為腫瘤過度向內生長。與覆膜支架或藥物洗脫支架相比,裸支架的再狹窄率約為30%[11-12,28]。Isayama等[28]研究顯示,覆膜支架組平均304天,有14%發生支架閉塞,金屬裸支架組平均166天,有38%發生支架閉塞。亞組分析顯示覆膜支架中胰腺癌支架通暢率低于總體。本研究中位無梗阻生存期為(7.26±1.71)個月,17例患者中僅1例患者(5.9%,1/17)出現支架再狹窄,與近期覆膜支架、藥物洗脫支架研究結果相比,本研究支架再狹窄率更低[9-12,18,29]。分析其再狹窄的原因可能為膽汁淤積,因此后期再行PTBD膽汁引流。聚四氟乙烯/氟化乙烯丙烯共聚物覆膜支架可阻止腫瘤向支架內生長,相較于鎳鈦裸支架可能提高支架通暢期,但是覆膜支架更容易發生膽汁淤積、支架移位等并發癥。藥物洗脫支架現主要是紫杉醇藥物洗脫覆膜支架,通過紫杉醇抗腫瘤,防止腫瘤向內生長,避免支架發生再狹窄,但是目前研究并未顯示出藥物洗脫支架的優越性[11]。其原因可能為支架藥物劑量逐漸減少,不能抑制腫瘤向內生長,另外藥物洗脫支架并不能降低支架移位率[30]。

朱海東等[18]報道放射性支架用于治療各種腫瘤導致的膽道梗阻患者,所納入的患者大部分有遠處轉移。其研究所用支架為載碘-125粒子支架重疊于自膨式膽道鎳鈦記憶合金支架,試驗組中12例患者,5例(占42%)患者術后6個月內發生支架再狹窄,研究未說明支架再狹窄原因。載碘-125粒子支架重疊于自膨式膽道鎳鈦記憶合金支架外,使支架網孔密度增加,導致膽汁淤積的可能性加大。相比較而言,本研究采用金屬裸支架+碘-125粒子條可降低膽汁淤積導致的再狹窄及移位。

不同類型腫瘤對射線敏感性及總生存期存在差異。與局部進展期胰腺導管腺癌相比,伴有轉移行放射治療生存獲益更低[4,14]。因此本研究所納入患者僅包括診斷為局部進展期的胰腺導管腺癌患者。本研究中多名患者既往接受過其他治療,和初次治療的患者相比,這部分患者一般情況相對較差。值得注意的是,3例患者內鏡下逆行胰膽管造影術支架植入失敗,經皮穿肝途徑成功,因此經皮穿肝可作為此類患者的另一治療途徑。

Park等[31]對81名行膽道支架及放、化療治療的惡性膽道梗阻患者的臨床資料進行回顧性分析,放、化療結合組中位支架通暢期明顯長于單純化療組(17.7個月vs.8.7個月),亞組分析覆膜支架與金屬裸支架總通暢期無明顯差異。研究所納入的患者包括胰腺癌、膽囊癌、膽管癌及壺腹癌。研究顯示放、化療相結合明顯提高支架的通暢期,分析其原因主要為放療結合化療對腫瘤的積極治療作用。本研究所納入病例均為胰腺導管腺癌,術前平均總膽紅素為(215.18±75.91) μmol/L,患者一般情況差、腫瘤惡性程度高,術后其支架通暢期接近于總生存期。分析其原因可能是腫瘤控制不理想,患者出現惡病質、多器官功能衰竭死亡。因此膽道支架及碘-125粒子條植入后患者生存期很可能取決于腫瘤的控制及治療。Alden等[32]及Montemaggi等[33]的相關研究表明多種治療方法(如放、化療等)結合腔內近程放療可有效延長膽道支架通暢期及生存期。

本研究采用碘-125粒子條腔內近程放射治療,其優點在于[19]:放射性粒子條可提高腫瘤靶區與正常組織的劑量分配比。由于碘-125 γ射線組織半價層為17 mm,使得腫瘤周圍正常組織獲得的輻射劑量明顯小于外放療,因而具有良好的適形性,更少產生臨床不良反應。本研究先行經皮肝穿刺膽道引流以緩解梗阻癥狀、改善肝功能,再行碘-125粒子條植入術,能夠減少術后并發癥發生。本研究中未發生膽道感染、穿孔等嚴重并發癥。若發生膽道感染可行敏感抗生素抗感染和引流治療;若發生膽道穿孔,患者一般情況可,腹部體征輕,可行保守抗感染治療,待竇道形成,反之則外科手術治療。粒子移位是植入放射源近程放療的主要顧慮之一。本研究中碘-125粒子封裝于4Fr無菌醫用導管內,且粒子條被支架的徑向力所固定,隨訪中未出現粒子條移位。證明碘-125粒子條植入是安全可行的。

胰腺癌綜合診治中國專家共識(2014年版)推薦[34]同步放化療中放療劑量為臨床靶區45 Gy。美國與法國共同推薦[35]針對局部晚期胰腺癌放療總劑量為50～54 Gy,每次分割劑量為1.8～2.0 Gy。本研究中240天內碘-125粒子超過90%的劑量被釋放,因此計算術后240天累計劑量。累計劑量計算指示點為碘-125粒子條中點水平軸外5 mm (r=5 mm)。240天累計劑量為164.19～170.05 Gy,平均167.38 Gy。碘-125粒子條持續性、低劑量的近程放療能夠抑制腫瘤向支架內生長及黏膜增生,并且對周圍胰腺導管腺癌組織有一定殺傷作用。

本研究表明碘-125粒子條腔內近程放射治療局部進展期胰腺導管腺癌伴梗阻性黃疸是安全、可行的,并有可能提高支架的通暢期。基于胰腺導管腺癌基因及分子水平研究,未來新型的靶向藥物可能延長患者的生存期[36-38]。本研究的不足之處包括:研究為回顧性研究;樣本量較小;沒有設置對照組,不能確定其優效性。這需要未來前瞻性、隨機對照臨床試驗來證明其優效性。

碘-125粒子條腔內近程放射治療是局部進展期胰腺導管腺癌伴梗阻性黃疸的一種安全可行的治療方法。

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Intraluminal brachytherapy using iodine-125 seed strand for locally advanced pancreatic ductal adenocarcinoma with obstructive jaundice:a retrospective clinical study

ZHAO Qian1,2, YANG Min-jie1,2, LIU Ling-xiao1,2, LIU Qing-xin1,2,ZHANG Wen1,2, LUO Jian-jun1,2△, YAN Zhi-ping1,2, LI Wen-hui3

(1DepartmentofInterventionalRadiology,ZhongshanHospital,FudanUniversity,Shanghai200032,China;2ShanghaiInstitutionofMedicalImaging,Shanghai200032,China;3DepartmentofInterventionalRadiology,TheThirdPeople’sHospitalofYancheng,Yancheng224001,JiangsuProvince,China)

Objective To investigate the safety and feasibility of intraluminal brachytherapy using iodine-125 seed strand for locally advanced pancreatic ductal adenocarcinoma with obstructive jaundice.Methods Clinical data of 17 consecutive patients,from January 2010 to February 2015,diagnosed with pancreatic ductal adenocarcinoma (4 cases of T4N0M0and 13 of T4N1M0) with obstructive jaundice and received intraluminal brachytherapy using iodine-125 seed strand were collected and analyzed retrospectively.Liver function was evaluated using paired-samplesttest.The iodine-125 seed strand radiation doses were calculated using iodine-125 radiation field distribution calculation software (version 0.1,Institute of Radiation Medicine,Fudan University,Shanghai,China) based on the American Association of Physicists in Medicine TG43U1 brachytherapy formula.Obstruction free survival and overall survival were calculated using the Kaplan-Meier method.Complications were assessed according to the CTCAE 4.0 criteria. Results The estimated mean accumulating dose (r=5 mm,240 days) was 167.2Gy,from 164.19Gy to 170.05Gy.The mean and median obstruction free survival time were (9.62±1.47) months (95%CI:6.73-12.50) and (7.26±1.71) months (95%CI:3.90-10.62).The mean and median overall survival time were (9.89±1.59) months (95%CI:6.78-13.00) and (7.26±1.71) months (95%CI:3.90-10.62),retrospectively.Total bilirubin and conjugated bilirubin decreased significantly after the therapy.Two patients had adverse event of Grade 3,one of Grade 4.Stent dysfunction occurred in 1/17 (5.9%) patients. Conclusions Intraluminal brachytherapy using iodine-125 seed strand might be considered as a safe treatment option for the locally advanced pancreatic duct adenocarcinoma complicated by obstructive jaundice.

brachytherapy; pancreatic ductal adenocarcinoma; iodine-125 seed strand; obstructive jaundice

R735.9

A

10.3969/j.issn.1672-8467.2017.02.005

2016-08-26;編輯:王蔚)

上海市衛生和計劃生育委員會科研項目(201540272);上海市青年科研項目(20134Y165);上海市科學技術委員會科研項目(16411968600,16ZR1433000)

△Corresponding author E-mail:luo.jianjun@zs-hospital.sh.cn

*This work was supported by the Project of Scientific Research from Shanghai Municipal Commission of Health and Family Planning (201540272),the Youth Project of Scientific Research from Shanghai (20134Y165),the Project of Scientific Research from Science and Technology Commission of Shanghai Municipality (16411968600,16ZR1433000).