劉波 羅強(qiáng) 王洪林

·綜述與講座·

射頻消融在肝癌治療中的應(yīng)用進(jìn)展

劉波 羅強(qiáng) 王洪林

射頻消融治療肝癌具有微創(chuàng)、相對(duì)安全、療效可靠及并發(fā)癥少等特點(diǎn)，筆者就國內(nèi)外射頻消融治療肝癌的最新的應(yīng)用策略、療效對(duì)照、并發(fā)癥以及對(duì)肝癌細(xì)胞的生物學(xué)行為的影響等方面進(jìn)行綜述，以期為臨床射頻治療肝癌的應(yīng)用提供參考。

射頻消融;肝癌;綜述

肝細(xì)胞癌是最常見的惡性腫瘤之一,復(fù)發(fā)率高，預(yù)后差，病死率僅次于肺癌和胃癌居第三位[1]。到目前為止，外科手術(shù)仍是首選的治療手段，但總體切除率只有30%～35%[2]。目前治療肝癌的方法有肝切除、肝移植、經(jīng)皮動(dòng)脈化療栓塞術(shù)、經(jīng)皮無水酒精注射、射頻消融、微波及高頻超聲等[3-5]。肝臟腫瘤手術(shù)切除是原發(fā)性肝癌治療策略的常規(guī)選擇，然而實(shí)施肝臟外科手術(shù)需要對(duì)患者的腫瘤特征、肝功能及機(jī)體狀況等進(jìn)行全面的評(píng)估[6]，且大部分的肝癌在診斷明確時(shí)已經(jīng)不適宜進(jìn)行手術(shù)切除[7]。射頻消融(radiofrequency ablation,RFA)治療作為肝癌的輔助治療在國外20世紀(jì)90年代就有報(bào)道，Rossi等[8]在上個(gè)世紀(jì)90年代初期首先報(bào)道了其在動(dòng)物上進(jìn)行超聲引導(dǎo)下射頻治療肝癌的實(shí)驗(yàn)，并提出小于2 cm的肝癌可通過射頻進(jìn)行治療，Rossi首次在臨床進(jìn)行RFA治療并取得成功，之后大量的科研人員對(duì)射頻消融進(jìn)行了深入的研究。射頻消融目前被認(rèn)為是最有效的經(jīng)皮消融法，在很多的醫(yī)療中心已經(jīng)成為一線的治療策略，包括對(duì)于一些能夠手術(shù)切除的病例[9]。

1 射頻消融的原理

射頻消融主要是通過射頻發(fā)生器提供300～500 kHz 范圍的交流電，通過電線連接穿刺針和貼在患者皮膚上的中性電極板組成1個(gè)射頻循環(huán)體，刺入腫瘤的電極針發(fā)出的能量能激發(fā)組織中的離子振動(dòng)摩擦發(fā)熱而產(chǎn)生損毀腫瘤組織作用，此過程中隨電極針周圍組織的受熱干燥脫水，會(huì)導(dǎo)致受熱區(qū)組織阻抗增加降低導(dǎo)電性，使最終熱損毀的腫瘤組織范圍減少[10]。隨著科學(xué)的進(jìn)步和臨床經(jīng)驗(yàn)的積累，為達(dá)到足夠的消融范圍和治療效果，電極針及操作程序進(jìn)行了不斷的改進(jìn)，最初的單電極針僅能達(dá)到1.3 ml體積的組織損毀，之后通過改進(jìn)發(fā)明了中空的可灌注水冷凝電極針、鹽水增強(qiáng)電極針、傘狀多電極以及復(fù)合集束電極等以使消融范圍達(dá)3～5 cm以上甚至更大。

2 射頻消融與肝切除術(shù)治療的療效對(duì)比

2.1 原發(fā)性肝癌 盡管目前認(rèn)為經(jīng)皮肝癌射頻消融術(shù)具有相對(duì)安全、微創(chuàng)、操作容易、可重復(fù)性強(qiáng)等特點(diǎn)，已經(jīng)廣泛應(yīng)用與原發(fā)性肝癌的治療[9,11]，但目前對(duì)于其療效依然爭議很大，不同的學(xué)者的研究有不同的結(jié)果。

Cho等[12]的隨機(jī)對(duì)照分析結(jié)果表明<2 cm的極早期肝癌RFA能夠達(dá)到手術(shù)的同等效果。Huang等[13]通過隨機(jī)對(duì)照實(shí)驗(yàn)顯示符合米蘭標(biāo)準(zhǔn)的肝癌RFA組總體生存要高于手術(shù)組，但手術(shù)組的復(fù)發(fā)率要更低。肝切除術(shù)對(duì)于腫瘤結(jié)節(jié)小于2 cm的早期肝癌肝功能較好、膽紅素正常且沒有臨床門脈高壓征的患者，術(shù)后不會(huì)出現(xiàn)肝功能失代償且5年生存率可達(dá)75%以上，解剖性肝切除相對(duì)于非解剖性切除效果更佳[14]。邱寶安等[15]研究表明，符合米蘭標(biāo)準(zhǔn)的多發(fā)性肝癌行手術(shù)切除能夠取得相對(duì)RFA高的生存率，RFA 圍術(shù)期并發(fā)癥的發(fā)生率及術(shù)后肝功能損害程度上優(yōu)于手術(shù)組。研究表明對(duì)于2 cm以下非肝包膜下或血管周圍的肝癌結(jié)節(jié),RFA的完全消融可達(dá)到97%，5年生存率在68%。RFA幾乎能達(dá)到與手術(shù)同等的效果，這也使其已經(jīng)成為許多醫(yī)療中心采取的標(biāo)準(zhǔn)策略[16]。

Buscarini等[17]報(bào)道RFA治療直徑<3.5cm肝癌的1，3，5年生存率分別為89%、62%、33%，與手術(shù)治療已經(jīng)沒有明顯區(qū)別。Chen等[18]前瞻性隨機(jī)實(shí)驗(yàn)對(duì)比肝癌小于5 cm直徑的結(jié)節(jié)采用RFA和手術(shù)切除的方法，兩者在統(tǒng)計(jì)學(xué)上無顯著差異，而手術(shù)的并發(fā)癥相對(duì)還要多一些。

2.2 轉(zhuǎn)移性肝癌 通過前瞻性隨機(jī)對(duì)照試驗(yàn)分析結(jié)果顯示，孤立性的結(jié)腸癌肝臟轉(zhuǎn)移在分別進(jìn)行常規(guī)肝臟切除術(shù)和局部射頻治療后，肝切除組的3年和5年累計(jì)原位無復(fù)發(fā)生存率明顯高于射頻治療組，但在RFA組的5年總生存率則要明顯低于肝臟手術(shù)切除組[19]。Reuter等[20]對(duì)結(jié)腸癌肝轉(zhuǎn)移手術(shù)治療和射頻治療的回顧性分析顯示，RFA復(fù)發(fā)的中位時(shí)間要短于切除組(分別是12.2月和31.1月)，但RFA治療組在原位復(fù)發(fā)和遠(yuǎn)處轉(zhuǎn)移相比手術(shù)切除組更容易發(fā)生。

White等[21]報(bào)道結(jié)腸癌轉(zhuǎn)移性肝癌開放楔形切除和RFA的總體中位生存時(shí)間分別是80個(gè)月和31個(gè)月，認(rèn)為肝腫瘤切除術(shù)對(duì)于能夠切除的肝癌患者仍然是首選，RFA等只能作為不適宜手術(shù)患者的輔助選擇。Aloia報(bào)道[22]對(duì)于結(jié)腸癌單個(gè)肝癌轉(zhuǎn)移結(jié)節(jié)手術(shù)和RFA的5年總體生存率分別是71%和27%，RFA不理想的結(jié)果與腫瘤的直徑并無相關(guān)性。Hur等[23]對(duì)67例轉(zhuǎn)移性肝癌中手術(shù)組和RFA組進(jìn)行比較，手術(shù)組5年總生存率明顯高于RFA組，分別是50.1%和25.5%，無復(fù)發(fā)生存率分別是89.7%和69.7%。然而在小于3 cm的轉(zhuǎn)移性肝癌手術(shù)切除組和RFA組在5年總生存率(分別為56.1% 和 55.4%)與無復(fù)發(fā)生存率(95.7%和 85.6%)方面卻無明顯差異，因此建議RFA作為癌結(jié)節(jié)直徑3 cm以下且因?yàn)檗D(zhuǎn)移性肝癌局部解剖差、術(shù)后肝儲(chǔ)備功能不足等不適宜手術(shù)患者的替代治療。

3 提高RFA療效的策略

提高療效的策略包括如設(shè)計(jì)有效降低RFA過程中阻抗的器械、減少組織溫度過高的碳化以及聯(lián)合其他的有效的治療策略等。RFA要成為原發(fā)性肝癌的首選治療策略則其原位復(fù)發(fā)率需要至少低于9%[12]。不同的學(xué)者對(duì)RFA如何降低原位復(fù)發(fā)率進(jìn)行了深入研究，有報(bào)道只要有超過結(jié)節(jié)的足夠的消融邊界，小于3 cm的腫瘤結(jié)節(jié)RFA后原位復(fù)發(fā)率僅為2%[4]。對(duì)于小于5 cm的腫瘤結(jié)節(jié)消融邊界超過4～5 mm可使腫瘤的原位復(fù)發(fā)率降低至5%以下[24-26]，故有觀點(diǎn)提出對(duì)于符合米蘭標(biāo)準(zhǔn)的肝癌，RFA和肝癌切除術(shù)都可作為患者首選的治療策略，如果RFA沒有消融到足夠的安全邊界(4～5 mm)則可行手術(shù)補(bǔ)救性治療[12,27]。在射頻消融后行無水酒精注射，可以使無水酒精在熱力的作用下達(dá)到射頻能量無法達(dá)到的范圍，從而擴(kuò)大腫瘤壞死面積[28]。但在有血管或其他重要管道的位置的腫瘤聯(lián)合PEI和RFA對(duì)提高腫瘤消融率收效甚微[29]。而聯(lián)合TACE可使RFA的臨床療效明顯得到提高，研究認(rèn)為相比單獨(dú)使用射頻消融法，聯(lián)合介入化療栓塞的射頻消融能夠明顯增加射頻消融治療中凝固的范圍[9]。通過聯(lián)合TACE[30]，可以減少RFA治療直徑過大的腫瘤結(jié)節(jié)過程中減少血液流動(dòng)導(dǎo)致熱量的損失，從而提高RFA的治療效果,降低局部腫瘤進(jìn)展率[31]。

4 射頻消融對(duì)肝癌的生物學(xué)影響

研究表明RFA能夠通過局部的凝固性壞死刺激局部炎性反應(yīng)，增加腫瘤特異性T細(xì)胞的免疫反應(yīng)[32]，經(jīng)RFA的肝癌組織相對(duì)于未行RFA肝癌組織和正常肝組織，能夠通過暴露腫瘤抗原、促進(jìn)抗原提呈細(xì)胞成熟而促進(jìn)肝癌特異性T細(xì)胞反應(yīng)[33]。閆景彬等[34]RFA 治療后機(jī)體抗腫瘤免疫功能短時(shí)間內(nèi)有明顯改善，能產(chǎn)生較為明顯的 Th1 型免疫應(yīng)答，顯著提高患者機(jī)體的抗肝癌免疫功能。

實(shí)驗(yàn)證實(shí)不完全消融后殘余肝癌細(xì)胞的增殖、轉(zhuǎn)移和侵襲力在RFA后增強(qiáng)，Schuld等[35]研究顯示通過在結(jié)腸癌肝轉(zhuǎn)移模型中通過RFA、冷凍和激光等治療后灌注離體肝臟后收集灌注液細(xì)胞，可檢測(cè)到MMP-2和 MMP-9表達(dá)相對(duì)對(duì)照組不同程度地升高。體內(nèi)外實(shí)驗(yàn)均發(fā)現(xiàn)RFA后造成的燒灼邊緣的缺氧過渡區(qū)出現(xiàn)CD95和CD95L表達(dá)升高，過渡區(qū)肝癌細(xì)胞增殖加速，轉(zhuǎn)移侵襲力增加[36]。Ke等[37]通過低溫造成不完全消融建立兔肝癌RFA后殘癌模型，發(fā)現(xiàn)RFA后殘癌迅速增生，肺轉(zhuǎn)移侵襲增加，同時(shí)檢測(cè)發(fā)現(xiàn)相對(duì)于未行RFA癌組織，殘癌PCNA、MMP-9、VEGF、HGF及IL-6等蛋白過表達(dá)，Liu等[38]通過體外模擬射頻不完全消融，發(fā)現(xiàn)肝癌細(xì)胞VEGF表達(dá)增加而促進(jìn)肝癌細(xì)胞增殖。而上皮間質(zhì)轉(zhuǎn)化也參與了不完全消融后肝癌細(xì)胞轉(zhuǎn)移及侵襲增加的過程[39]。這些證據(jù)為臨床行RFA要求達(dá)到完全消融至足夠的安全邊界提供了理論依據(jù)。

5 射頻消融治療的并發(fā)癥

在20世紀(jì)90年代，RFA容易發(fā)生血胸、腹腔出血、膽囊炎等并發(fā)癥[40]。隨著RFA電極的改進(jìn)、影像學(xué)的發(fā)展及臨床經(jīng)驗(yàn)的積累，越來越多的報(bào)道顯示RFA的并發(fā)癥逐漸減少[11,41]。Livraghi等[41]回顧分析218例行RFA病例僅4例(1.8%)出現(xiàn)嚴(yán)重并發(fā)癥，分別為腹腔出血、血胸、腫瘤種植和持續(xù)1個(gè)月的高膽紅素血癥。Rhim等[42]對(duì)多個(gè)中心的調(diào)查數(shù)據(jù)顯示在接受RFA治療的1139名患者中發(fā)生嚴(yán)重并發(fā)癥的有37例(2.43%)，主要有肝膿腫 (0.66%)、腹膜出血 (0.46%)、膽汁瘤 (0.20%)、燒傷 (0.20%)、氣胸 (0.20%)及血管迷走神經(jīng)反射等 (0.13%)。

Akahane等[43]總結(jié)RFA術(shù)后并發(fā)癥主要有：(1)血管方面如門靜脈血栓、肝靜脈血栓性肝淤血、肝梗塞及肝胞膜下血腫；(2)膽管方面包括膽道狹窄、膿腫和膽道出血；(3)肝外方面比如胃腸道損傷、血?dú)庑睾湍[瘤種植等。大多數(shù)的并發(fā)癥均可通過保守治療、外科修補(bǔ)、引流及預(yù)防性使用抗生素等緩解。而Hiraoka等[11]回顧性分析105例RFA患者和59例手術(shù)患者的術(shù)后并發(fā)癥，2組在5年生存率和無病生存率方面無明顯差異，RFA組未出現(xiàn)嚴(yán)重的并發(fā)癥，手術(shù)組出現(xiàn)1例術(shù)后肝衰竭和2例術(shù)后膿腫。亦有報(bào)道在行RFA治療18個(gè)月后罕見發(fā)生的右側(cè)膈疝而致絞窄性腸梗阻[44]。總的來說，RFA術(shù)后并發(fā)癥具有發(fā)生率低、可控和病死率低的特點(diǎn)。認(rèn)識(shí)RFA的并發(fā)癥和處理有助于更好地指導(dǎo)RFA的實(shí)施，減少并發(fā)癥發(fā)生提高療效。

綜上所述，RFA作為肝癌治療方法具有療效可靠、相對(duì)安全、操作容易、并發(fā)癥少的特點(diǎn)，值得我們深入研究和發(fā)展，尤其對(duì)于小肝癌以及肝功能不良不能行手術(shù)切除的肝癌患者可作為首選方案。同時(shí)需要更多的大樣本的隨機(jī)對(duì)照試驗(yàn)和長期的隨訪觀察比較RFA在各種肝癌治療過程中的療效，更積極地研究RFA的適應(yīng)證、禁忌證及可能的并發(fā)癥及處理，學(xué)習(xí)積累更多的臨床經(jīng)驗(yàn)技術(shù)，最大化提高RFA在臨床肝癌上的治療效果并減少并發(fā)癥的發(fā)生，為肝癌的臨床治療增加更多的治療策略和工具。

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10.3969/j.issn.1002-7386.2017.06.039

611730 四川省郫縣人民醫(yī)院普外科(劉波、羅強(qiáng))；重慶醫(yī)科大學(xué)附屬第一醫(yī)院肝膽外科(王洪林)

羅強(qiáng)，611730 四川省郫縣人民醫(yī)院普外科；

E-mail:pxpwlq@126.com

R 735.7

A

1002-7386(2017)06-0926-04

2016-10-11)