多支雙電極射頻電燒針以不接觸腫瘤之包圍式燒灼法對比單電極射頻電燒針在肝硬化患者初診斷之不大於四公分的肝細胞癌長期治療成效比較:一個多中心的研究

Abstract

研究背景： 因為慢性病毒性肝炎的盛行，原發性肝細胞癌長期是台灣十大癌症死因的前三名。目前對於原發性肝細胞癌的根除性治療主要有三大方式：外科手術切除、局部腫瘤消融治療以及肝臟移植。局部腫瘤消融治療在1990年代開始蓬勃發展，目前在台灣絕大數的局部腫瘤消融治療是使用單電極射頻電燒針進行燒灼，單電極射頻電燒針的燒灼治療是以離心方式（centrifugal ablation）進行，所以主要會有下列幾個缺點：單一次燒灼直徑至多三公分，燒灼範圍不夠廣泛，無法形成足夠的安全燒灼邊界（safety margin），所以容易造成局部腫瘤復發（local tumor recurrence），患者常需重複接受治療以達成腫瘤廓清。雙電極射頻電燒針從2005年開始使用在肝腫瘤治療，因為電流可以在電極跟電極之間形成迴路，所以對於不大於4公分之腫瘤，可以實行不接觸腫瘤之包圍式燒灼（no-touch ablation），用此種燒灼法可以得到比較大的燒灼範圍，理論上應該可以降低局部腫瘤復發率，甚至達到比較好的無病存活（disease-free survival）。目前並無任何本土資料來比較此兩種射頻燒灼術的長期治療效果。 研究目的： 本研究旨在透過多中心的回溯性分析，來評估肝硬化患者中初診斷且不大於四公分的原發性肝細胞癌，分別接受傳統的單電極射頻燒灼治療以及多支雙電極射頻電燒針以不接觸腫瘤的包圍式燒灼的長期預後比較。 研究方法： 本研究有雙和醫院、成大醫院、萬芳醫院共同參與。針對肝硬化患者中初診斷且最大腫瘤直徑不大於四公分，最多腫瘤數目不大於三顆的原發性肝細胞癌，分別於各家醫院接受單電極射頻燒灼治療或是多支雙電極射頻電燒針以不接觸腫瘤的包圍式燒灼法治療。於治療後續以電腦斷層或是磁振造影追蹤治療成效以及評估腫瘤是否復發。以統計軟體分析治療成效以及腫瘤復發及存活的各項預測因子。 研究結果： 以腫瘤位置、腫瘤大小、是否鄰近大血管、病患肝臟功能、性別、年紀、是否有病毒性肝炎平均分組後，共有234個病人331顆腫瘤平均分佈於兩個不同的治療組別中。經過一次燒灼治療之後的完整腫瘤廓清率（Complete ablation rate）分別是98.2%（多針組）及77.6%（單針組），接受單針射頻燒灼治療以及腫瘤直徑大於兩公分，是造成無法達到完整腫瘤燒灼的兩個最顯著影響因子。於追蹤過程中，一年、三年、五年的局部腫瘤復發率分別是4.2%、5.7%、5.7%（多針組）以及30.0%、41.3%、41.3%（單針組），安全燒灼邊界小於零點五公分、接受單針射頻燒灼治療以及腫瘤靠近大於3mm的血管，是造成局部腫瘤復發最顯著的影響因子。一年、三年、五年的肝內遠端腫瘤復發率分別是12.8%、24.9%、35.9%（多針組）以及36.3%、57.3%、65.6%（單針組），腫瘤數目大於一顆、安全燒灼邊界小於零點五公分以及接受單針射頻燒灼治療是造成肝內遠端腫瘤復發之三個最顯著影響因子。至於兩組之整體存活率並無顯著差別。治療初始之肝臟功能（Child-Pugh score）對於整體之存活有最大的影響。兩組之嚴重併發症比率亦無顯著差別。 結論： 跟傳統的單電極射頻電燒術相較，多支雙電極射頻電燒針以不接觸腫瘤之包圍式燒灼法對於不大於四公分的初診斷原發性肝細胞癌，可以提供比較好的完整腫瘤廓清率以及比較低的腫瘤復發率，降低患者重複接受治療的需要。治療初始的肝臟功能對於長期存活有最顯著的影響。

Background： Radiofrequency（RF）ablation is a curative therapy for small hepatocellular carcinoma（HCC）. Although mono-polar electrode with centrifugal ablation method is the mainstream in current clinical practice, a higher local recurrence rate and need of repeated treatment sessions are the main drawbacks of mono-polar RF ablation in comparison with surgical resection. Multi-bipolar RF ablation is a newly developed method for HCC therapy by using multiple bipolar electrodes simultaneously. The concept of “No-touch ablation” enables centripetal ablation of tumor and is the most important technical progress of bipolar electrodes. However, the comparison of long-term treatment outcomes between no-touch multi-bipolar RF ablation and mono-polar RF ablation remains unclear. Aim： In this multicenter retrospective study, we aimed to compare the long-term outcomes of no-touch multi-bipolar versus mono-polar radiofrequency ablation for patients with hepatocellular carcinoma ≤4 cm. Methods： From January 2010 to December 2017, a total of 385 cirrhotic patients with newly diagnosed HCC in three medical centers were surveyed. The maximal tumor size was 4 cm and the maximal tumor number was three. After propensity score matching for baseline characteristics, a total of 234 patients with 331 tumors were enrolled and allocated equally in both treatment groups. About 68% of patients had more than one tumor and 82% of tumors were more than 2 cm in diameter（mean：2.66 ± 0.83）. About 22% of tumors were in the subcapsular area which was considered to be a difficult location for RF ablation. For the no-touch treatment group, 2 ~ 5 bipolar electrodes were deployed outside the tumor margin with centripetal ablation. For the mono-polar treatment group, one electrode was applied into the tumor center with centrifugal ablation. Most procedures were performed in the operation room under general anesthesia. Percutaneous approach with ultrasound guidance was used for all of the patients. Contrast-enhanced dynamic computed tomography（CT）or magnetic resonance images（MRI）were performed one month after ablation and every 3 months for one year and every 6 months thereafter. Kaplan-Meier method was used to assess the survival probability and the Cox proportional hazard method was used to assess the predictive parameters for complete ablation rate, local and distant tumor progression rate and overall survival. Among these endpoints, complete ablation was calculated as per tumor basis and tumor progression as well as overall survival were assessed as per patient basis. Results： Complete ablation rate after one session of treatment was 98.2% for the no-touch treatment group and 77.6% for the mono-polar treatment group. Mono-polar method and tumor size > 2 cm were the two predictive factors for incomplete ablation（P<0.001 and 0.001, respectively）. After repeated treatment sessions, there were 2 patients in the no-touch treatment group and 4 patients in the mono-polar treatment group failed to achieve complete ablation of the original index tumor. After a median follow-up of 2.14 years（range：3 ~ 96 months）, the cumulative 1-year、3-year、5-year local recurrence rate were 4.2%、5.7%、5.7% for the no-touch treatment group, respectively and 30.0%、41.3%、41.3% for the mono-polar treatment group, respectively. Safety margin less than 5 mm , mono-polar method and tumor abutting vessel >3 mm were three significant factors for local tumor progression（P=0.001, P=0.006, P=0.015 respectively）. The cumulative 1-year、3-year、5-year distant recurrence rate were 12.8%、24.9%、35.9% for the no-touch treatment group, respectively and 36.3%、57.3%、65.6% for the mono-polar treatment group, respectively. Tumor number more than one and safety margin less than 5 mm were the two main factors contributing to distant recurrence（P<0.001）. Mono-polar treatment group also had a higher risk of distant recurrence（P=0.013）. The 1-year、3-year、5-year overall survival were 93.6%、84.8%、65.3% for the no-touch treatment group, respectively and 91.3%、70.3%、58.0% for the mono-polar treatment group, respectively. Liver reserve of Child-Pugh B class was the most significant factor for poor overall survival. There was no difference about major complication rate between these two groups （4.27% vs. 6.84%）. Conclusions： This is the largest cohort in Asia to compare the long-term outcomes of two commonly used RF ablation methods for treatment-naïve patients with small HCC. No-touch multi-bipolar RF ablation method may provide better disease free survival and less need of repeated treatment sessions with similar complication rate to mono-polar method. Child-Pugh B disease is found to be the most significant factor affecting overall survival in our study. Taken together, no-touch ablation method is not only an effective and safe method to treat small HCC no more than 4 cm but also provides better life quality for HCC patients.