【摘要】 目的 通过经皮射频消融（RFA）对临床多见的中晚期肝癌治疗方案策略性应用，探讨RFA治疗的可行性。 方法 655例非手术适应证的肝细胞癌（HCC）患者行经皮RFA治疗，以其中随访资料完整的中晚期癌92例136个病灶（直径 ≤7.0 cm）为研究对象。RFA前行超声造影（CEUS）检查51例（55.4%）；采用优化方案策略行规范化治疗67例（72.8%），规范化方案包括根据CEUS筛选适应证、界定浸润范围以制定根治消融方案，及根据数学方案计算行多灶重叠覆盖消融、2～3支双极针立体定位布针适形消融、血供丰富肝癌采用彩色多普勒超声或CEUS引导经皮阻断荷瘤动脉或经动脉插管化疗栓塞后行RFA。另25例常规RFA治疗。所有患者在RFA后均经西医及中医中药保肝治疗。RFA后1个月用增强CT判断肿瘤早期灭活率，其后每3个月用CT并结合甲胎蛋白检查评价疗效。早期灭活率、局部复发率的比较用x2检验或Fisher精确法检验，生存率计算采用Kaplan-Meier方法及Log-rank检验。 结果 肿瘤早期灭活率为90.4%（123/136），严重并发症2例（2.2%），无相关死亡病例。随访3～134个月，局部复发率16.9%（23/136），1、3、5年总生存率分别为83.3%、48.3%、21.9%，中位生存期35个月。分层分析显示，Child-Pugh A级、应用CEUS及采用规范化治疗患者的早期灭活率均明显提高，分别为98.3%、98.0%、97.0%；肿瘤直径 ≤3.0 cm、应用CEUS及规范化治疗患者的局部复发率均减低，分别为5.9%、11.8%、16.4%，与相应对照组比较，差异均有统计学意义（P < 0.05）。Child-Pugh A级、肿瘤直径 ≤3.0 cm、应用CEUS及规范化治疗患者的5年生存率更高（P < 0.05）。 结论 证实对直径 ≤7.0 cm、无主脉管癌栓的中晚期HCC行RFA治疗是可行的治疗方法，尤需重视采取规范化治疗以降低复发率。
【关键词】癌，肝细胞； 超声检查，介入性； 射频消融； 策略 Efficacy of radiofrequency ablation to treat advanced hepatocellular carcinoma WU Jie, CHEN Min-hua, YANG Wei, WU Wei, YAN Kun. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100142, China
Corresponding author: CHEN Min-hua, Email: minhuachen@vip.sina.com
【Abstract】 Objective To retrospectively investigate the feasibility of radiofrequency ablation (RFA) in treating advanced hepatocellular carcinoma (HCC) using standard ultrasound-guided percutaneous RFA. Methods A total of 655 patients with unresectable advanced HCC underwent ultrasound-guided percuatenous RFA therapy at our insitution between July 2000 to September 2001. Ninety-two of those patients, representing 136 tumors, were selected for analysis based on the following criteria: presence of UICC/AJCC-TNM (6th edition) stage III and IV advanced HCC, (III: n = 82 patients, with 126 tumors; IV: n = 10 patients, with 10 tumors); extensive portal vein or inferior vena cava tumor thrombus; extrahepatic metastasis after surgical resection; and complete follow-up data. Follow-up consisted of enhanced computed tomography (CT) performed at one month post-RFA treatment, then every three months. Contrast-enhanced ultrasound (CEUS) was performed in 51 (55.4%) patients before RFA. The standard treatment using optimal strategies were applied in (72.8%) 67 patients. The established strategies included: (1) select RFA indications based on CEUS results; (2) design radical protocols based on invasive range showed by CEUS; (3) multiple overlapping ablations based on mathematical protocols; (4) two or three bipolar RFA electrodes with three-dimensional localization; (5) color ultrasound-guided percutaneous ablation of tumor feeding artery (PAA)/transcatheter arterial chemoembolization (TACE) + RFA for HCC with rich supply. The other 25 patients (27.2 %) were treated with conventional RFA protocols. The ablation procedure was considered a success if no abnormal enhancement or wash-out was detected in the treated area on the CT scan at one month. All patients had received liver protection treatments following RFA. Chi-squared test or Fisher's exact test were used to compare the early complete tumor necrosis rates and the local recurrence rates. Survival was estimated by Kaplan-Meier analysis and log-rank test. P < 0.05 was considered statistically significant. Results The RFA-treated tumors ranged in size from 1.5 to 7.0 cm (average: 4.5 cm). Fifty-nine patients had solitary tumor, and the remaining 33 had multiple tumors (2 ~ 4 tumors). Patients were classified by Child-Pugh score as A ( n = 58), B ( n = 32) and C ( n = 2). Early complete tumor necrosis rate after initial RFA was 90.4% (123/136 tumors). Serious complications developed in two patients (2.2%). No treatment-related death occurred. Follow-up ranged from 3-134 months. Local recurrence rate was 16.9% (23/136 tumors). The 1-, 3- and 5-year overall survival rates were 83.3%, 48.3% and 21.9%, respectively, and the median survival time was 35 months. Stratification analysis indicated the early complete tumor necrosis rate was higher in groups of patients with Child-Pugh A score (98.3%) , CEUS admistration (98.0%), and standard treatment (97.0%). The local recurrence rate was lower in groups of patients with tumors ≤ 3.0 cm (5.9%), CEUS administration (11.8%), and standard treatment (16.4%). The 5-year survival was significantly higher in patients with Child-Pugh A, tumors ≤ 3.0 cm, CEUS administration, and standard treatment (all, P < 0.05). Conclusion RFA treatment of patients with advanced HCC, tumors < 7.0 cm, and without thrombosis in the main vessels was efficacious. The RFA treatment strategy and subsequent liver protection therapy in RFA may improve survival.
【Key words】Carcinoma, hepatocellular; Ultrosonography, interventional; Rradiofrequency ablation; Strategies
近年来，射频消融（radiofrequency ablation, RFA）微创治疗肝肿瘤取得较大进展，但多数研究报道RFA适用于直径 < 3.0 cm的小肝癌，整体灭活效果与手术切除相当[1-2]。本中心较早开展了经皮RFA的规范化治疗研究，通过采取系列方案策略，在中晚期肝癌治疗方面获得一定经验[3-6]。
资料与方法
1. 研究对象：收集本中心2000年7月至2011年9月超声引导下经皮RFA治疗非手术适应证的肝癌（HCC）患者资料。患者入选标准：（1）HCC经临床或穿刺病理组织学确诊；（2）无广泛门静脉或下腔静脉癌栓；（3）肝外转移已手术切除或放化疗后疗效稳定；（4）RFA治疗后随访资料较完整；（5）按照UICC/AJCC-TNM第六版分期标准，选择Ⅲ-Ⅳ期中晚期HCC[7]。
2. 仪器与方法：超声造影（contrast-enhanced ultrasound, CEUS）检查用Aloka α_10（购自日本Aloka公司）、GE LOGIQ 9（购自美国GE公司），探头频率2.5～5.0 MHz，造影时机械指数设定为0.09。引导RFA治疗的超声仪主要有Aloka SSD-4000（购自日本Aloka公司）、Aloka α_10，探头频率2.5～5.0 MHz，配备穿刺引导架。RFA采用两种仪器：Rita肿瘤消融系统1500型（购自美国Rita公司）以及Olympus Celon多针双电极冷循环消融系统（购自德国Olympus Celon公司）。CEUS检查时先用等渗盐水5 ml溶解超声造影剂SonoVue冻干粉(购自意大利Bracco公司)，震荡混匀后经肘部浅静脉2～3 s内快速注射，单次2.4 ml。根据增强CT、MRI及（或）CEUS检查结果，确定肿瘤浸润范围、数目、位置及与周围重要结构（如肠管、膈肌、血管等）的关系，RFA规范化治疗组应用的方案策略：（1）根据CEUS筛选适应证[8]；（2）根据CEUS界定的浸润范围，制定根治消融方案[9]；（3）> 3 cm肿瘤用数学公式计算行多灶重叠消融[3]；（4）2～3支双极针立体定位布针适形消融；（5）富血供HCC采用彩色多普勒超声或CEUS引导经皮阻断荷瘤动脉（percutaneous ablation of feeding artery, PAA）或经动脉插管化疗栓塞（transcatheter arterial chemoembolization, TACE）后RFA[9-11]。对照组为本中心早期未系统应用规范化治疗方案病例。麻醉一般采用1%利多卡因局部浸润麻醉 + 清醒镇静术(静脉注射咪唑安定2.5～5.0 mg + 芬太尼50～100μg)，术中监测血压、心率及呼吸等生命体征。本组病例均由2名有10年以上超声介入诊治经验的医师完成RFA治疗。
3. 随访及疗效评价：治疗后根据第1个月的增强CT判断肿瘤早期灭活率；此后第1年每3个月、1年后4～6个月复查增强CT并监测甲胎蛋白（AFP）水平。若增强CT显示消融肿瘤内部或周边强化，考虑局部复发。
4. 统计学方法：早期灭活率及局部复发率比较用x2检验或Fisher精确检验。生存期计算采用Kaplan-Meier方法及Log-rank检验，时间从第1次RFA治疗起至死亡或随访截止期。以P < 0.05为差异有统计学意义。统计软件采用SPSS 13.0。
结 果
1. 患者资料：经RFA治疗的非手术适应证HCC共655例，符合入选标准的92例。其中III期82例126个病灶，IV期10例10个病灶，男性80例，女性12例；年龄24～87（59 ± 12）岁；肿瘤大小1.5～7.0（4.5 ± 1.3）cm；单发肿瘤59例，多发肿瘤（2～4个病灶）33例；Child-Pugh A级58例，B级32例，C级2例；AFP > 20 ng/ml者43例（46.7%），最高1591 ng/ml。51例（55.4%）RFA前行CEUS检查，67例（72.8%）采用上述规范化方案策略治疗。另25例（27.2%）为本中心早期未系统应用规范化治疗方案病例，采用常规RFA治疗。治疗前发现肝外转移者10例，包括肺转移3例，骨转移6例，脑转移1例；增强CT诊断腹腔淋巴结转移或可疑转移17例，2例有末梢门静脉癌栓。
2. 总体疗效：随访3～134个月，中位随访时间25个月。治疗后3个月88.4%（38/43）患者AFP水平较治疗前减低或恢复到正常水平。肿瘤早期灭活率90.4%（123/136），局部复发率16.9%（23/136），局部复发时间2～38个月。1、3、5年总生存率分别为83.3 %、48.3 %、21.9 %，中位生存期35个月，平均46.5个月。
3. 肝功能、肿瘤大小、应用CEUS及采取规范化治疗等因素对早期灭活率、局部复发率、生存率的影响：由表1可见肝功能Child-Pugh A级、应用CEUS及规范化治疗患者的早期灭活率更高，分别为98.3 %、98.0 %、97.0 %；肿瘤 ≤3.0 cm、应用CEUS及规范化治疗患者的局部复发率更低，分别为5.9 %、11.8%、16.4 %，与相应对照组比较，差异均有统计学意义（P < 0.05）。直径 ≤3.0 cm与> 3.0 cm肿瘤RFA后早期灭活率相近（88.2%与86.7%，P = 1.000）。Child-Pugh A级与B/C级患者的局部复发率差异无统计学意义。Child-Pugh A级、肿瘤直径 ≤3.0 cm、应用CEUS及规范化治疗的患者生存率更高，差异有统计学意义（P < 0.05）。见图1～4。
4. 并发症：本组有5例（5.4%）发生并发症。3例肝被膜下出血，注射立止血后即刻控制出血。2例（2.2%）发生较严重并发症，1例右侧大量胸腔积液，置管引流后症状改善；1例RFA后3 d多次便血，采用三腔二囊管压迫食管静脉瘤止血。无与治疗相关死亡病例。
讨 论
中晚期肝癌外科手术切除率低、预后差，临床多以TACE和支持治疗为主，但远期疗效仍不理想。陈敏华等[4,6,12]提出在精准的影像指导下，采用规范化治疗及个体化治疗方案策略，在肿瘤位置适宜、不损伤周围重要结构等条件下，确保消融安全范围达瘤周0.5～1.0 cm，有助于提高疗效。本组92例中晚期HCC（肿瘤大小平均4.5 cm）RFA治疗后1、3、5年生存率达83.3%、48.3%、21.9%，中位生存期35个月，证实RFA可明显提高患者的生存率、延长生存期。
不能手术的中晚期HCC多呈浸润性生长、肿瘤较大、边界不清或肝内播散，因此，治疗前用高端影像检查明确肿瘤浸润范围、边界、卫星灶及与周围结构关系等对治疗方案的制定尤显重要。近年的研究结果显示，CEUS比增强CT能更灵敏地反映肝肿瘤微血供和局部组织器官的血流灌注情况[13]。本中心前期研究结果也表明，CEUS显示癌灶边界范围增大或更不规则的HCC中88%瘤周癌细胞浸润性生长[9]；56.4%的HCC造影动脉期肿瘤范围较造影前增大0.4～2.4 cm，并可灵敏地发现常规超声易漏诊的微小肝癌或卫星灶，有助于确认卫星灶、多发小灶，筛选RFA适应证并指导制定治疗方案[8,14-15]。本研究中应用CEUS 51例（55.4%）患者的肿瘤早期灭活率、局部复发率及5年生存率均得到改善。
肿瘤大小是影响中晚期患者生存的因素之一。之前多数研究将RFA用于治疗最大径 ≤3.0 cm、少于3个的HCC[1-2,16]。随着射频仪器性能的改进和治疗技术的成熟，消融5.0 cm以上肿瘤成为可能[17-19]。但RFA治疗大肿瘤的有效性还存在争议，文献报道肿瘤越大，完全彻底灭活率降低[20-21]。本组92例中晚期HCC，直径> 3.0 cm与 ≤3.0 cm肿瘤的早期灭活率相近，两者差异无统计学意义，分析该治疗效果与本组病例采取规范化治疗策略有关，治疗前行CEUS检查改善了大肿瘤及边界不清晰肿瘤（浸润型生长）的显示率，为精准消融打下基础；早期灭活率高，显示对> 3.0 cm肝癌应用CEUS的重要意义。对 ≥3.5 cm肿瘤，本中心早在2002年建立消融模型，用数学计算制定布针方案行重叠消融，减少肿瘤残留。近五年来，采用新型多针双电极冷循环消融系统，根据肿瘤大小、形状布2～3支电极针，电流在有效距离电极间交替循环对流，完成大肿瘤适形凝固消融；其布针方法简便易行，在距瘤周内侧0.5～1.0 cm处布2～3支针，针距约1.5～2.5 cm，在25～40 min内即可获得6.0～7.0 cm消融灶。本组 ≤3.0 cm肿瘤患者5年生存率高于> 3.0 cm肿瘤患者（P = 0.040），提示中晚期肝癌的远期疗效受肝功能等多因素影响。
血供丰富肿瘤直接消融不易彻底灭活。本中心采取阻断荷瘤血管的“PAA”策略，在肿瘤一过性缺血状态下行RFA，可减少布针次数，提高消融效果，减少复发；对血供特丰富者施行优化TACE方案，即先行1～2次超选择TACE，在患者肝功能及其他身体条件允许下，1周内行RFA治疗，可避免多次TACE加重患者肝功能损伤，又提高RFA灭活率。
本研究结果显示，行规范化治疗肿瘤早期灭活率由60.0%提高至97.0%，局部复发率由36.0%降低至16.4%，并提高了5年生存率。因此，采用规范化治疗方案策略是影响中晚期HCC患者疗效的关键。
此外，肝功能越差生存率越低，中晚期HCC患者尤其需强调治疗前后肝功能的调整，肝功能C级者经保肝治疗及影像学评估可消融灭活者，在RFA后行保肝治疗，可获得一定疗效[22-23]。本组病例RFA前均经保肝治疗，尤Child-Pugh B、C级患者，RFA后也需加强中西医保肝治疗，可能有助于延长患者生存期。
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（收稿日期：2012-02-09）
（本文编辑：朱红梅）
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