肝细胞癌放射治疗研究进展

2015-02-09 19:38综述何克菲审校
医学综述 2015年16期
关键词:肝细胞癌索拉非尼

梁 永(综述),何克菲(审校)

(1.桂平市人民医院肿瘤科,广西 桂平 537200; 2.南方医科大学珠江医院肿瘤科,广州 510282)

肝细胞癌放射治疗研究进展

梁永1※(综述),何克菲2(审校)

(1.桂平市人民医院肿瘤科,广西 桂平 537200; 2.南方医科大学珠江医院肿瘤科,广州 510282)

原发性肝癌年病死率居全球恶性肿瘤的第3位,年新发病人数74.8万,约50%发生在中国[1]。肝细胞癌占原发性肝癌的85%~90%,70%在确诊时已失去根治性手术治疗的机会[2]。目前常用的治疗手段对失去根治性手术治疗机会的患者可延长生存期,然而5年生存率极低。放射治疗(放疗)在肝细胞癌治疗史上地位并不重要,是因为二维放疗局部控制率低、肝损伤大。但近年随着放疗技术和设备的不断发展,通过精确定位、三维适形计划精确设计和精确治疗,促使在正常肝组织或周围危重器官耐受剂量条件下病灶能获更高剂量,甚至达根治剂量,使疗效明显提高,同时放射损伤控制在可接受范围。现就肝细胞癌放疗的研究进展予以综述。

1单纯放疗

1.1立体定向放疗立体定向放疗是指采用非共面多弧小野三维集束少次数大分割照射病灶,特点为靶区剂量高,周围正常组织剂量迅速下降,用于治疗直径<3 cm的病灶。立体定向放疗现在已能应用于受呼吸运动影响较大的胸腹部恶性肿瘤的治疗。1991年,Blomgren等[3]首先采用该技术治疗 20例肝癌,有效率为70%。2006年以来,学者们分别针对肝细胞癌进行前瞻性的立体定向放疗研究,靶区体积1~1913 mm3,肿瘤大小1~23.1 cm,分割剂量24~60 Gy/3~6次,随访时间2~52个月,1~2年内局部控制率为87%~100%,2年总生存率为60%~69%[4-7]。另外,Takeda等[8]回顾性分析63例平均直径2.6 cm不适合做根治性手术治疗的患者,行35~40 Gy/5次立体定向放疗,达类似手术治疗效果,1年、2年局部控制率分别为95%和92%,3年总生存率为73%;而在日本<2 cm 和2~5 cm的单发性肝细胞癌根治术后的3年总生存率分别为83%~90%和70%~81%;这类患者如果行射频消融治疗,3年总生存率分别为82%~88%和66%~82%。虽然立体定向放疗有治愈患者的潜力,但有许多内容还需深入研究,如分次剂量和总剂量尚无统一标准。每例患者的病灶大小、数目、部位、基础肝病、残留正常肝代偿能力不相同,各个治疗单位的处方剂量也不一样[4-13],如Cardenes等[4]采用36~48 Gy/3 次,Andolino等[7]采用40 Gy/5 次,Bujold等[5]采用24~54 Gy/6次、Kang等[6]采用24~60 Gy/3次。但是,这些分次剂量和总剂量的差异均是根据正常肝组织受放疗体积与发生并发症概率模型决定的,当接受放疗的正常肝体积<25%时,采用54 Gy/ 6次,当接受放疗的正常肝体积25%~60%时,采用30~45 Gy/6次[14]。

1.2三维适形放疗适形放疗是近20多年放疗史上发展最快、最大的成就之一,它分为三维靶区适(传统三维适形放疗)、静态剂量适形(调强放疗)、实时剂量适形(图象引导放疗)三类。因为它可应用于不同大小的肿瘤,且对直径>3 cm形状不规则的肿瘤三维适形放疗的剂量分布要优于立体定向放疗,故三维适形放疗的适应证比较宽,从早期不适合做手术或射频消融的患者到中期不适合做肝动化疗栓塞或肝动化疗栓塞后效果差的患者,甚至出现门静脉癌栓或淋巴结、脑、肺、骨转移的晚期肝细胞癌患者,均有稳定的局部控制率。Dawson 等[15]提出,根据正常组织并发症控制概率方法计算放疗剂量,解决个体化计算放疗剂量问题之后,涌现大量肝细胞癌放疗的成果报道。Mornex等[16]报道,对27例无手术指征的小肝癌行Ⅱ期前瞻性研究,放疗剂量为66 Gy/33次,1年局部控制率为76%,同时发现,肝功能 B级患者放疗毒性明显增加。同年,Liang等[17]对几组大样本进行回顾性分析发现,1年生存率为45%~70%,2年生存率为22%~50%,并指出生存率与总放疗剂量及肝功能相关,>53.1 Gy明显优于低于此剂量者,肝功能A级明显优于肝功能 B级患者。肝细胞癌患者易发生门静脉左右分支或主干癌栓,门静脉癌栓是独立预后不良因素,这些患者已失去行手术、射频消融、肝动脉化疗栓塞等治疗的机会,三维适形放疗在这类患者中有独特优势。Takagi等[18]报道,放疗对29%肝细胞癌并门静脉癌栓有效。此后有几篇文献相继回顾分析报道,在放疗毒性可接受前提下给处方剂量30~60 Gy,分次剂量1.8~3 Gy,但中位生存期报道差异较大,从4~15个月[19-20]。门静脉癌栓消退较慢,但有再通的报道。Zeng等[21]报道,肝细胞癌对射线敏感,相当于低分化鳞状细胞癌,α/β值为11.2 Gy,故放疗在晚期患者缓解症状方面亦表现较好疗效。Jiang等[22]报道,放疗控制肝细胞癌骨转移引起的疼痛有效率为73%~83%,对肝细胞癌合并肺、脑或淋巴结转移患者采用8 Gy/次或60 Gy/20次亦可延长生命或减轻痛苦。

1.3粒子射线放疗粒子射线放疗治疗肝癌包括质子放疗和碳离子放疗,因能更好地保护正常肝组织,故能给予病灶更高剂量,其治疗效果优于立体定向放疗和适形放疗,1年生存率为53%~90%,2年生存率为45%~88%,3年生存率为56%~62%,5年生存率为37%~39%[23-25]。Nakayama等[25]报道,318例患者(其中肝功能B级占24%,肝功能C级占2%)采用质子放疗,剂量为55~77 Gy/10~35次,结果1年生存率为90%,5年生存率为45%,1.5%的患者出现3级以上放射损伤。Mizumoto等[26]报道266例患者接受质子放疗,剂量为:病灶离胃肠<2 cm者,77 Gy/35次,病灶离肝门<2 cm者,72.6Gy/22次,其他66 Gy/10次,结果不同剂量组间生存率无差异,1、3、5年生存率分别为87%、61%和48%。虽然粒子放疗费用昂贵,但因它对肝脏功能放射损伤相对较轻,值得与手术、射频消融等进行Ⅲ期临床研究。

2综合治疗

2.1放疗与经导管动脉化疗栓塞术(transcatheter arterial chemoembolization,TACE)联合治疗2002年以来,多个经随机分组的研究证实TACE治疗不能手术切除的肝细胞癌患者可提高2年生存率,目前TACE已成为不能手术切除肝细胞癌患者的首选治疗方法[2]。但单纯TACE治疗局部控制率和长期生存率仍不理想,Zeng等[21]和Xu等[27]分别报道TACE联合放疗提高不能手术切除肝细胞癌患者生存率,其中Zeng等[21]对54例无淋巴结转移、无门静脉癌栓及远处转移,不能手术切除的肝细胞癌患者行TACE后联合放疗,与149例仅TACE治疗对比,肿瘤客观缓解率76%比31%,1、2、3年生存率分别为71.5%、42.3%和24.0%比59.6%、26.5%和11.1%,显示TACE联合放疗优于仅TACE治疗。Koo等[28]进行TACE后联合放疗的前瞻性研究,对42例伴下腔静脉癌栓形成的晚期肝细胞癌患者TACE后联合放疗与29例单纯TACE治疗相比发现,中位生存时间分别为11.7个月比4.7个月。Kim等[29]报道,对59例不能手术切除的肝细胞癌患者行TACE后2周行放疗,分次剂量2 ~4.5 Gy,以α/β=10计算,放疗总生物剂量为39~65.25 Gy,中位剂量47.25 Gy,有53例患者放疗后还继续行1~8次TACE治疗,中位次数为2次,截至结课题时还有32例存活,肿瘤客观缓解率58%,1、2年生存率分别为60.1%和47.2%。另外,还有多个类似报道证实TACE联合放疗取得有利结果[30-34]。

2.2放疗与靶向药物联合治疗索拉非尼是目前唯一有Ⅰ级循证医学证据证实对肝细胞癌有效的靶向药物,它是多靶点多激酶抑制剂,既抑制促进肿瘤增殖的丝裂原活化蛋白激酶信号通路,又抑制血管内皮生长因子和血小板衍生因子。Kuo等[35]进行的肠癌细胞实验显示,放疗联合索拉非尼具有协同细胞毒性,增加细胞凋亡的作用,放射诱导的核因子κB活性被抑制而降低肿瘤增殖能力和侵袭能力。Yadav等[36]的动物实验表明,放疗联合索拉非尼通过抑制X线修复交叉互补基因1和降低DNA修复蛋白错配除交叉互补修复酶1含量,明显抑制肿瘤细胞克隆形成。Girard和Morner[37]研究表明,索拉非尼可使肿瘤细胞同步化于对射线较敏感的细胞周期。临床研究方面,Cha等[38]的局部放疗联合索拉非尼治疗晚期肝细胞癌Ⅰ期临床研究显示了治疗的安全性和有效性,其主要毒性为血小板减少,按美国国立癌症研究所常见毒性评价标准3~4级血小板减少为17%。 Chen等[39]的放疗联合索拉非尼同步加维持治疗晚期肝细胞癌Ⅱ期研究中,纳入40例既不能手术切除也不适合TACE治疗(其中24例并有门静脉癌栓)的晚期肝细胞癌患者,放疗剂量40~60 Gy,中位剂量50 Gy,索拉非尼 400 mg,每日2次,结果38例完成局部放疗,肿瘤客观缓解率为55%,2年放疗野内无进展生存率为39%。

2.3放疗与化学药物联合治疗化学药物治疗(化疗)是治疗恶性肿瘤的三大主要手段之一,但化疗在肝细胞癌治疗中的历史地位并不高,被认为对传统细胞毒性药物存在原发多药耐药,其有效率低于10%[40]。但近年伴随抗肿瘤新药的出现,化疗的历史地位有所提高。Qin等[40]进行的Ⅲ期临床研究证实,采用FOLFOX4方案(奥沙利铂+亚叶酸钙+氟尿嘧啶)化疗晚期肝细胞患者获得近似索拉非尼的效果。Mclntosh等[41]报道,对20例不能手术切除的晚期肝细胞癌患者放疗50 Gy/20次,同期用卡培他滨增敏,结果客观有效率达94%,肝功能A级者中位生存期为22.5个月。Lee等[42]对18例因伴门静脉癌栓或残留肝体积不足的肝细胞癌患者行同步放化疗,肿瘤大小7~16 cm,放疗剂量 45 Gy/25次,同时肝动脉灌注氟尿嘧啶和顺铂,结果2个月后影像学评价完全缓解率、部分缓解率、稳定率分别为11.1%、72.2%和16.7%;术前影像学评价完全缓解率、部分缓解率、稳定率分别为33.3%、61.1%和5.6%,中位手术时间为6.2个月;术后病理100%坏死占22.2%、>80%坏死占61.1%,3年生存率为59.3%,平均总生存率为61.8个月。Park等[43]对肝细胞癌并门静脉癌栓和肝内转移患者,行肝动脉灌注氟尿嘧啶增敏,放疗45 Gy/25次亦取得了较好效果。另外,Chuma等[44]和Murakami等[45]分别报道放疗联合氟尿嘧啶和干扰素治疗取得有利结果。

3毒性反应

正常肝脏及其周围的肾、胃肠和脊髓等都是对射线比较敏感的器官,同时肝细胞癌患者常并有肝硬化,故放射毒性是限制提高靶区剂量的最主要因素,其中最常见是放射性肝炎,一般发生于放疗后2周至3个月,典型表现为黄疸、腹水、转氨酶升高,但也有不少患者为不典型表现;另外,乙型肝炎病毒激活,肝功能下降亦是常见放射毒性之一[46]。放射毒性与放疗总剂量、分次剂量、正常肝受照体积/剂量以及肝功能相关,Cardenes等[4]报道,肝功能A级肝细胞癌患者放疗剂量48 Gy未出现放射性肝炎,而肝功能B级患者放疗剂量42 Gy易发生3级以上放射性肝炎。

4小结

现代放疗技术在肝细胞癌治疗中已取得历史性进步。早期的患者行放疗,可获类似手术治疗的效果;中晚期患者尤其是对手术或TACE有禁忌证的患者行放疗也能延长生存期。但是,中晚期患者病灶大、肝硬化严重、残留正常肝体积少以及周围重要器官耐受量不高等因素,限制了放疗剂量的提高,故只有放疗与其他有效治疗方法联合应用,疗效才有可能进一步提高。

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摘要:近几年,不同的外照射放射治疗技术以及联合其他治疗方法在肝细胞癌治疗中取得了较大进展。单纯放射治疗对早期患者可治愈,对中、晚期患者可延长生命,并可减轻疼痛。放射治疗与经导管动脉化疗栓塞术或口服索拉非尼或静脉化疗等方法联用,疗效可进一步提高,且毒性可耐受。因目前文献均局限于Ⅰ期/Ⅱ期临床试验或回顾性分析,故放射治疗在肝细胞癌综合治疗中的潜在作用,还需要开展Ⅲ期研究来证实。

关键词:肝细胞癌;放射疗法;经导管动脉化疗栓塞;索拉非尼;化学疗法

The Progress of Radiotherapy of Hepatocellular CarcinomaLIANGYong1,HEKe-fei2. (1.DepartmentofOncology,GuipingPeople′sHospital,Guiping537200,China; 2.DepartmentofOncology,ZhujiangHospitalofSouthernMedicalUniversity,Guangzhou510282,China)

Abstract:The external beam radiotherapy alone or combining with other therapy in hepatocellular carcinoma have made greater progress in recent years.It not only can cure hepatocellular carcinoma in early stage,but also can prolong life and reduce pains of patients in advance stage.Radiotherapy may improve the efficiency for advance patients,if combining with transcatheter arterial chemoembolization,sorafenib or chemotherapy,while the toxicity is still tolerable.Since the current literature is from phaseⅠ/Ⅱ clinical study or retrospective analysis,the potential role of radiotherapy in the comprehensive treatment of hepatocellular carcinoma still needs phase Ⅲ study.

Key words:Hepatocellular carcinoma; Radiotherapy; Transactheter arterial chemoembolization; Sorafinib; Chemotherapy

收稿日期:2015-03-10修回日期:2015-05-09编辑:郑雪

doi:10.3969/j.issn.1006-2084.2015.16.018

中图分类号:R730.55

文献标识码:A

文章编号:1006-2084(2015)16-2929-04

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