碘-125粒子条腔内近程放射治疗局部进展期胰腺导管腺癌伴梗阻性黄疸的初步临床研究

赵 倩 杨敏捷 刘凌晓 刘清欣 张 雯 罗剑钧△ 颜志平 李文会

(1复旦大学附属中山医院介入科 上海 200032; 2上海市影像医学研究所 上海 200032;3江苏省盐城市第三人民医院介入科 盐城 224001)

碘-125粒子条腔内近程放射治疗局部进展期胰腺导管腺癌伴梗阻性黄疸的初步临床研究

赵 倩1,2杨敏捷1,2刘凌晓1,2刘清欣1,2张 雯1,2罗剑钧1,2△颜志平1,2李文会3

(1复旦大学附属中山医院介入科 上海 200032;2上海市影像医学研究所 上海 200032;3江苏省盐城市第三人民医院介入科 盐城 224001)

目的 探索碘-125粒子条腔内近程放射治疗局部进展期胰腺导管腺癌伴梗阻性黄疸的安全性及可行性。方法 对2010年1月至2015年2月复旦大学附属中山医院介入科收治的17例局部进展期(4例为T4N0M0,13例为T4N1M0)胰腺导管腺癌伴梗阻性黄疸患者行碘-125粒子条腔内近程放射治疗的临床资料进行回顾性分析。用配对t检验分析患者术前、术后肝功能变化。碘-125粒子条放射剂量由碘-125粒子条放射区域分布计算软件(0.1版,复旦大学影像研究所)根据美国医学物理协会TG43U1近程放射公式计算。用Kaplan-Meier曲线分析无梗阻生存期和累计生存期。术后并发症根据美国国立癌症研究所通用毒性标准4.0版评估。结果 碘-125粒子条累计剂量(r=5 mm,240天)为164.19～170.05 Gy,平均为167.38Gy。平均、中位无梗阻生存期分别为(9.62±1.47)个月(95%CI:6.73～12.50)和(7.26±1.71)个月(95%CI:3.90～10.62),平均、中位总生存期分别为(9.89±1.59)个月(95%CI:6.78～13.00)和(7.26±1.71)个月(95%CI:3.90～10.62)。患者术前、术后总胆红素和直接胆红素差异具有统计学意义。研究中2例患者发生3级术后并发症,1例患者发生4级并发症。1例患者出现支架再狭窄(5.9%)。结论 碘-125粒子条腔内近程放射治疗是局部进展期胰腺导管腺癌伴梗阻性黄疸的一种安全可行的治疗方法。

近程放射治疗; 胰腺导管腺癌; 碘-125粒子条; 梗阻性黄疸

胰腺导管腺癌是全球癌症致死率最高的肿瘤之一,其5年生存率小于5%[1-3]。多达30%的患者首次诊断时已为局部进展期,失去了手术机会。大约70%的胰腺癌患者伴有梗阻性黄疸[4]。胆道支架植入能迅速恢复胆汁引流、提高生活质量,是姑息治疗的有效手段[5-8]。目前有多种上市的支架可供选择,但各种支架都可能出现再狭窄。据报道即使使用覆膜支架或药物洗脱等新型支架,仍有10%～54%的患者发生支架再狭窄[9-13],分析其狭窄原因主要为肿瘤向支架内生长、黏膜增生及胆汁淤积。支架再狭窄不但影响患者的生活质量,而且二次手术增加了患者的损伤及经济负担[14-17]。近年,文献报道胆道腔内放射支架植入治疗可提高各种腺癌造成的恶性梗阻性黄疸支架的通畅期[18]。本文对2010年1月至2015年2月复旦大学附属中山医院介入科收治的17例局部进展期胰腺导管腺癌伴梗阻性黄疸患者行碘-125粒子条腔内近程放射治疗的临床资料进行回顾性分析,现报道如下。

资 料 和 方 法

临床资料 经复旦大学附属中山医院伦理委员会批准(批号:2009-080),对2010年1月至2015年2月在介入科接受胆道支架+碘-125粒子条腔内近程放射治疗的胰腺导管腺癌伴梗阻性黄疸患者的病例资料进行回顾性分析。纳入标准:美国东部肿瘤协作组(eastern cooperative oncology group,ECOG)状态评分0-2;胰腺导管腺癌根据临床表现和影像诊断、病理活检诊断,伴肝内外胆管扩张;局部晚期、非转移、不可手术切除。排除标准:美国东部肿瘤协作组状态评分>2;肿瘤转移;任何一项肝穿刺禁忌症:凝血功能异常(血小板计数<50×109/L或凝血酶原活性<50%);肝、肾功能衰竭;心脏射血分数<50%;疾病终末期患者不能耐受手术者。所有患者均签署知情同意书接受胆道支架及碘-125粒子条植入。

本研究共收集17例患者,平均年龄(67.65±14.64)岁,其中男性12例、女性5例。ECOG评分11例为0分、6例为1分。肿瘤TNM分期:4例为T4N0M0,13例为T4N1M0,肿瘤最大径平均为(3.23±1.03)cm (2.2～4.8 cm)。肿瘤位于胰头者10例,胰头颈2例,胰头颈体5例。17例患者中13例患者有疾病治疗史:2例开腹探查、7例化疗、1例放疗、3例内镜下逆行胰胆管造影(endoscopic retrograde cholangiopancreatography,ERCP)支架植入失败。所有患者均行经皮穿肝胆道引流术(percutaneous trans-hepatic biliary drainage,PTBD),术前一天查肿瘤相关抗原199,3例为阴性,其余患者平均值为(1 323.24±2 541.23)U/mL。

胆道支架+碘-125粒子条植入治疗 手术采用利多卡因局麻。患者仰卧位,心电监护,取原PTBD引流管入路,引入导丝,通过闭塞段,进入肠道,沿导丝植入自膨式金属裸支架(美国波士顿公司)及碘-125粒子条。金属裸支架直径为8 mm,长度为6 cm或8 cm。碘-125粒子条由6711型碘-125粒子(上海欣科医药有限公司)封装于4Fr无菌医用导管内。单枚粒子的放射性活度为25.9 MBq,半衰期为59.4天,主要射线包括27.4、31.4KeV的X线和35.5KeV的γ射线,组织半价层为17 mm,初始剂量率为7cGy/h。碘-125的数目由胆道梗阻段的长度决定:N=L/4.5+4,L为胆道梗阻段的长度,单位:毫米,N为粒子数,单位:粒。未获得病理诊断的患者手术中行细针穿刺抽吸活检。患者术前、术后3天预防性使用抗生素。

术后治疗及随访 术后所有患者均行吉西他滨经动脉灌注化疗,每月1次,每次1 000 mg/m2。收集患者术前、术后肝肾功能及腹部增强CT检查的影像学资料(图1)。收集患者术后第1天单光子激发断层扫描(SPECT/CT)影像资料(图2),评估碘-125粒子条的活性和粒子条的位置。

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.

结 果

治疗情况及粒子条剂量的计算 所有患者病理诊断均为胰腺导管腺癌(2例外科术中活检、3例ERCP下穿刺活检、8例经皮穿刺活检、4例细针穿刺抽吸活检)。所有患者均成功施行胆道支架+碘-125粒子条植入(图3)。胆道梗阻段长度为27～72 mm,平均43.4 mm。碘-125粒子数10～20粒,平均13.64粒。术后1天,患者接受SPECT/CT扫描检查,所有植入的碘-125粒子条均准确位于胆道梗阻段,粒子条无移位(图2)。碘-125粒子条指示点(粒子条中点轴距5 mm处,r=5 mm)240天累计剂量由碘-125粒子条放射区域分布计算软件(0.1版,复旦大学影像研究所)[19]根据美国医学物理协会TG43U1近程放射公式计算。累计剂量为164.19～170.05 Gy(r=5 mm,240天),平均为167.38 Gy。

图3 数字减影(Digital subtraction angiography,DSA)示碘-125粒子条及支架位于胆总管内Fig 3 DSA shows iodine-125 seed strand and stent within the common bile duct

支架通畅率及生存期 所有患者行PTBD术后1个月总胆红素和直接胆红素明显下降,平均总胆红素从(215.18±75.91) μmol/L降至(45.14±36.80) μmol/L (P<0.05),直接胆红素平均值从(181.91±63.82) μmol/L降至(40.65±35.32) μmol/L (P<0.05),总胆红素、直接胆红素术前、术后差异具有统计学意义(表1)。本研究平均无梗阻生存期及中位无梗阻生存期分别为(9.62±1.47)个月(95%CI:6.73～12.50)和(7.26±1.71)个月(95%CI:3.90～10.62)(图4)。平均、中位总生存期分别为(9.89±1.59)个月(95%CI:6.78～13.00)和(7.26±1.71)个月(95%CI:3.90～10.62)(图5)。1例患者(5.9%,1/17)术后17.74个月出现支架再狭窄,后行PTBD胆汁引流,患者总生存期为22.44个月。另1例患者碘-125粒子条植入9个月后诉腹胀,行增强CT检查示门静脉狭窄,行门静脉碘-125粒子条植入术,该患者总生存期为22.23个月。

术后并发症及处理 疼痛是最常见的术后并发症,本研究中有8例患者出现疼痛,给予镇痛药后24 h内疼痛缓解。1例患者出现胆管炎,抗生素治疗后好转。1例患者手术过程中出现迷走神经反应,血压从135/90 mmHg降至97/53 mmHg (1 mmHg=1.133 kPa),心率从80次/分降至45次/分,立即给予0.5 mg阿托品,患者血流动力学恢复。胰腺炎、十二指肠炎、粒子条移位等后期并发症在本研究中未发生(表2)。

表1 术前、术后肝功能变化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.

图4 无梗阻生存曲线Fig 4 Kaplan-Meier obstruction-free survival curve

图5 总生存曲线Fig 5 Kaplan-Meier overall survival curve

表2 美国国立癌症研究所通用毒性标准4.0版评估并发症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.

讨 论

目前化疗、放疗是局部进展期胰腺导管腺癌的主要治疗方法[4,20]。伴有梗阻性黄疸的患者可行内镜下逆行胰胆管造影或者经皮穿肝途径植入支架以解除胆道梗阻、缓解临床症状[21]。如何减少支架再狭窄发生率、提高支架的通畅时间,对于改善患者生活质量至关重要。

本研究回顾性分析碘-125粒子条腔内近程放射治疗局部进展期胰腺导管腺癌伴梗阻性黄疸。胆道腔内放射治疗能抗黏膜增生、抗肿瘤生长以延长支架通畅期。动物实验表明碘-125粒子条腔内近程放射治疗恶性梗阻性黄疸是安全可行的[22]。自1980年以来,金属裸支架植入已成为恶性梗阻性黄疸患者的姑息治疗方法[22-25]。早期的长期随访研究发现,9名患者发生支架再狭窄(占35%),平均支架通畅期为39.9周[26-27]。研究报道支架再狭窄的主要原因为肿瘤过度向内生长。与覆膜支架或药物洗脱支架相比,裸支架的再狭窄率约为30%[11-12,28]。Isayama等[28]研究显示,覆膜支架组平均304天,有14%发生支架闭塞,金属裸支架组平均166天,有38%发生支架闭塞。亚组分析显示覆膜支架中胰腺癌支架通畅率低于总体。本研究中位无梗阻生存期为(7.26±1.71)个月,17例患者中仅1例患者(5.9%,1/17)出现支架再狭窄,与近期覆膜支架、药物洗脱支架研究结果相比,本研究支架再狭窄率更低[9-12,18,29]。分析其再狭窄的原因可能为胆汁淤积,因此后期再行PTBD胆汁引流。聚四氟乙烯/氟化乙烯丙烯共聚物覆膜支架可阻止肿瘤向支架内生长,相较于镍钛裸支架可能提高支架通畅期,但是覆膜支架更容易发生胆汁淤积、支架移位等并发症。药物洗脱支架现主要是紫杉醇药物洗脱覆膜支架,通过紫杉醇抗肿瘤,防止肿瘤向内生长,避免支架发生再狭窄,但是目前研究并未显示出药物洗脱支架的优越性[11]。其原因可能为支架药物剂量逐渐减少,不能抑制肿瘤向内生长,另外药物洗脱支架并不能降低支架移位率[30]。

朱海东等[18]报道放射性支架用于治疗各种肿瘤导致的胆道梗阻患者,所纳入的患者大部分有远处转移。其研究所用支架为载碘-125粒子支架重叠于自膨式胆道镍钛记忆合金支架,试验组中12例患者,5例(占42%)患者术后6个月内发生支架再狭窄,研究未说明支架再狭窄原因。载碘-125粒子支架重叠于自膨式胆道镍钛记忆合金支架外,使支架网孔密度增加,导致胆汁淤积的可能性加大。相比较而言,本研究采用金属裸支架+碘-125粒子条可降低胆汁淤积导致的再狭窄及移位。

不同类型肿瘤对射线敏感性及总生存期存在差异。与局部进展期胰腺导管腺癌相比,伴有转移行放射治疗生存获益更低[4,14]。因此本研究所纳入患者仅包括诊断为局部进展期的胰腺导管腺癌患者。本研究中多名患者既往接受过其他治疗,和初次治疗的患者相比,这部分患者一般情况相对较差。值得注意的是,3例患者内镜下逆行胰胆管造影术支架植入失败,经皮穿肝途径成功,因此经皮穿肝可作为此类患者的另一治疗途径。

Park等[31]对81名行胆道支架及放、化疗治疗的恶性胆道梗阻患者的临床资料进行回顾性分析,放、化疗结合组中位支架通畅期明显长于单纯化疗组(17.7个月vs.8.7个月),亚组分析覆膜支架与金属裸支架总通畅期无明显差异。研究所纳入的患者包括胰腺癌、胆囊癌、胆管癌及壶腹癌。研究显示放、化疗相结合明显提高支架的通畅期,分析其原因主要为放疗结合化疗对肿瘤的积极治疗作用。本研究所纳入病例均为胰腺导管腺癌,术前平均总胆红素为(215.18±75.91) μmol/L,患者一般情况差、肿瘤恶性程度高,术后其支架通畅期接近于总生存期。分析其原因可能是肿瘤控制不理想,患者出现恶病质、多器官功能衰竭死亡。因此胆道支架及碘-125粒子条植入后患者生存期很可能取决于肿瘤的控制及治疗。Alden等[32]及Montemaggi等[33]的相关研究表明多种治疗方法(如放、化疗等)结合腔内近程放疗可有效延长胆道支架通畅期及生存期。

本研究采用碘-125粒子条腔内近程放射治疗,其优点在于[19]:放射性粒子条可提高肿瘤靶区与正常组织的剂量分配比。由于碘-125 γ射线组织半价层为17 mm,使得肿瘤周围正常组织获得的辐射剂量明显小于外放疗,因而具有良好的适形性,更少产生临床不良反应。本研究先行经皮肝穿刺胆道引流以缓解梗阻症状、改善肝功能,再行碘-125粒子条植入术,能够减少术后并发症发生。本研究中未发生胆道感染、穿孔等严重并发症。若发生胆道感染可行敏感抗生素抗感染和引流治疗;若发生胆道穿孔,患者一般情况可,腹部体征轻,可行保守抗感染治疗,待窦道形成,反之则外科手术治疗。粒子移位是植入放射源近程放疗的主要顾虑之一。本研究中碘-125粒子封装于4Fr无菌医用导管内,且粒子条被支架的径向力所固定,随访中未出现粒子条移位。证明碘-125粒子条植入是安全可行的。

胰腺癌综合诊治中国专家共识(2014年版)推荐[34]同步放化疗中放疗剂量为临床靶区45 Gy。美国与法国共同推荐[35]针对局部晚期胰腺癌放疗总剂量为50～54 Gy,每次分割剂量为1.8～2.0 Gy。本研究中240天内碘-125粒子超过90%的剂量被释放,因此计算术后240天累计剂量。累计剂量计算指示点为碘-125粒子条中点水平轴外5 mm (r=5 mm)。240天累计剂量为164.19～170.05 Gy,平均167.38 Gy。碘-125粒子条持续性、低剂量的近程放疗能够抑制肿瘤向支架内生长及黏膜增生,并且对周围胰腺导管腺癌组织有一定杀伤作用。

本研究表明碘-125粒子条腔内近程放射治疗局部进展期胰腺导管腺癌伴梗阻性黄疸是安全、可行的,并有可能提高支架的通畅期。基于胰腺导管腺癌基因及分子水平研究,未来新型的靶向药物可能延长患者的生存期[36-38]。本研究的不足之处包括:研究为回顾性研究;样本量较小;没有设置对照组,不能确定其优效性。这需要未来前瞻性、随机对照临床试验来证明其优效性。

碘-125粒子条腔内近程放射治疗是局部进展期胰腺导管腺癌伴梗阻性黄疸的一种安全可行的治疗方法。

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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;编辑:王蔚)

上海市卫生和计划生育委员会科研项目(201540272);上海市青年科研项目(20134Y165);上海市科学技术委员会科研项目(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).