Treatment strategy for hepatocellular carcinoma in China: radiofrequency ablation versus liver resection

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1 JJCO Japanese Journal of Clinical Oncology Japanese Journal of Clinical Oncology, 2016, 46(12) doi: /jjco/hyw134 Advance Access Publication Date: 27 September 2016 Original Article Original Article Treatment strategy for hepatocellular carcinoma in China: radiofrequency ablation versus liver resection Ze-xin Zhu, Ji-wei Huang, Ming-heng Liao, and Yong Zeng* Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China *For reprints and all correspondence: Yong Zeng, Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu , China. Received 15 May 2016; Accepted 26 August 2016 Abstract Hepatocellular carcinoma is the most common malignancy in liver, is also a global problem and is the fourth most commonly diagnosed cancers among men and the fourth leading causes of cancer death among both men and women in China. Liver resection or hepatic resection and radiofrequency ablation is widely accepted as a first-line surgical approach for hepatocellular carcinoma in China. However, the indications of radiofrequency ablation or hepatic resection are different and not unified in China. In this article, we review the current status of hepatic resection and radiofrequency ablation therapies in hepatocellular carcinoma management in China. Key words: hepatocellular carcinoma (HCC), radiofrequency ablation (RFA), liver resection (LR), hepatic resection (HR), China Introduction Hepatocellular carcinoma (HCC) is the most common malignancy in liver and is also a global problem. Its global incidence has been reported to be on the rise and is predicted to exceed a million cases per year by 2025 (1). According to Chen et al., HCC is the fourth most commonly diagnosed cancers among men and the fourth leading causes of cancer death among both men and women in China (2). The main etiological factor is chronic hepatitis B virus (HBV) infection in northeast and southeast Asia, including China, Indonesia and Korea. In China, there is wide variation in the prevalence of HBV infection: 6 10% in northern China and >10% in southern China. The high prevalence of chronic HBV carriers in Asia constitutes the majority of the 360 million carriers worldwide (3). Treatment of HCC should be carefully selected. In the current clinical practice, liver resection (LR) or hepatic resection (HR), liver transplantation (LT), radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE) and sorafenib are the main therapeutic modalities (4). HCC can be treated curatively with HR or LT if diagnosed at an early stage; however, since most patients with HCC present with advanced disease and underlying liver dysfunction, only 15% are eligible for curative treatments (5). RFA achieve complete necrosis of almost 100% in HCCs <2 cm; however, effective and complete ablation rate with RFA monotherapy decline sharply when treating larger lesions (>3 cm) (6,7). In this article, we review the current status of HR and RFA therapies in HCC management in China. Search strategy We searched PubMed and the Cochrane Library database, Chinese BioMedical Literature Database (CBM), using hepatocellular carcinoma, liver cancer, as free text words and in combination with randomized, controlled clinical trials, clinical trials, phase III studies, double-blind, review, meta-analysis, therapy and treatment. We also did a manual search and review of reference lists. We selected for inclusion randomized controlled trials published as full papers both in English and Chinese. The search included literature published until 10 May Hepatic resection Although the number of patients who are eligible for curative resection is really small, it is still considered as the first-line treatment in The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com 1075

2 1076 The treatment of hepatocellular carcinoma in China China, especially for patients with solitary tumors confined to the liver without radiographic evidence of invasion of the vasculature and well liver function (8). With the development of surgical and anesthetic techniques and the application of intraoperative ultrasound (IOUS), the security of the liver cancer resection and postoperative quality of life have been improved significantly. There is no indication of HR for HCC patients in China, but the early stage HCC should be recommended for resection. Shi et al. reported 169 cases of early HCC (single lesion, <5 cm, no intrahepatic metastasis or vascular invasion); data show that 5-year was 74% (9). Meanwhile, the liver function should be well evaluated pre-operation. Child-Pugh classification is the most commonly used system for evaluating the liver function. Resection also can be performed for HCC inside Milan criteria when patients are not suitable for LT. Poon et al. reported 204 cases of HCC patients who, meeting Milan criteria with well liver function (Child-Pugh A), underwent surgical resection; 5-year survival rate was 68 75% (10,11). Indocyanine green (ICG) can also be used to evaluate the liver function. The result of the ICG-15 test can accurately assess the liver function and suggested the acceptable limits of the liver volume in resection, a study showed toward zero hospital deaths under the ICG-15 test guided (12). IOUS should be used. IOUS was first used by Makuuchi in 1985, and then the technology quickly used widely around the world (13). The use of IOUS in surgery of HCC in China was started in the late 1980s (14). Chen et al. reported that IOUS found 114 of 116 foci in 69 patients; however, preoperative ultrasound and computed tomography (CT) scanning missed 34.5% and 33.6% of them, respectively (15). According to Wu et al. contrast-enhanced intraoperative ultrasonography (CE-IOUS) performs better in detection and in differentiation of small metastasis and regenerative nodules; the operation strategy of 18.0% (9/50) cases was changed according to the results of CE-IOUS (16). These studies showed that IOUS was remarkably sensitive in finding small foci. Nowadays, the specific way of hepatectomy in China is different according to the judgment of the surgeons. Hepatic vascular inflow occlusion (Pringle maneuver) is often used to minimize blood loss, but hepatic ischemia-reperfusion may result with an increased risk of postoperative liver failure. Selective hepatic vascular exclusion (SHVE) is only occlusion of inflow and outflow blood of the liver with preservation of caval flow so that general hemodynamics remains stable (17,18). Zhou et al. compared these two methods: this study showed that SHVE is much more effective than Pringle maneuver in controlling intraoperative bleeding and it can prevent massive blood loss and air embolism from hepatic veins rupture and can reduce the postoperative complication rate and mortality rate (19). A prospective randomized controlled trial even showed that LR carried out using the Harmonic scalpel (HS) without hepatic vascular occlusion was better than using Pringle maneuver; the use of HS allowed LR to be safely performed, with earlier recovery of liver function and less surgical complication (18). Anatomical resection (AR, the systematic removal of a hepatic segment) or non-ar (NAR, leave a greater portion of parenchyma of the functional unit, preservation of a 1-cm tumor-free margin) (20) are both used in China. To the best of our knowledge, whether hepatectomy for HCC should be performed as an AR or a NAR still remains unclear, because no randomized controlled trials are currently available on this topic. A meta-analysis included nine retrospective studies indicating AR is associated with better disease-free survival than NAR (21). Another meta-regression included 18 observational studies also showed a similar result (22). A prospective control study comparedarandnarforearlyhccintwocenters(aneasternand a Western surgical unit) suggested that AR of the early HCC can reduce the early recurrence rate after HR and this is true for patients having poorly differentiated HCC. Nevertheless, AR cannot be applied to all patients with cirrhosis because of the risk of postoperative insufficiency, whereas NAR will not worsen the recurrence rate in well/moderately differentiated tumors or in the absence of microvascular invasion (20). Briefly, AR might be recommended in appropriately selected patients with HCC, NAR is considered to be an alternative treatment for patients if AR cannot be performed. Better designed and adequately powered RCTs on this topic are required. Laparoscopic hepatectomy (LH) was first reported by Reich et al. in 1991 (23), and then widely used in LR. In China, it is first reported by Zhou et al. in 1994 (24). Cheung et al. compared 32 patients who underwent pure laparoscopic LR with casematched control patients (n = 64) who received open LR for HCC; the result showed that laparoscopic LR for HCC is associated with less blood loss, shorter hospital stay and fewer postoperative complications in selected patients with no compromise in survival (25). Da Vinci robotic surgery is also used and more and more complicated surgeries can now be performed robotically, yet there have been very few on robotic hepatectomy (26). Zhou et al. reported 17 patients undergoing robotic hepatectomy, which showed that robotic hepatectomy is safe, feasible and efficacious. Exploration of innovative techniques compatible to robotic surgical system, such as bleedingcontrol maneuver, is mandatory for future robotic LRs (27). Radiofrequency ablation The treatment of RFA for HCC patient was first reported in 1993 (28), RFA relies on a needle electrode to deliver a high-frequency alternating current, resulting in frictional heating of the tissue and subsequent necrosis (29). Percutaneous ethanol injection (PEI), the most widely accepted methods before RFA, was commonly used; however, studies suggest that patients treated with RFA have superior survival and local recurrence-free rates compared with those of PEI (30). RFA is a versatile tool that can be applied percutaneously, laparoscopically or at open surgery. Open and laparoscopic approaches have the potential advantages of being more precise in staging the disease, in treating larger tumors by using the multiple probe or the multiple probe application techniques, in treating lesions near to an adjacent organ by dissecting away or by resecting the organ, in treating lesions inaccessible percutaneously and the use of IOUS to detect additional tumors. In China, the use of RFA for HCC was late but quickly developed in recent years. Chen et al. reported 803 cases of RFA in liver malignancies, and the 1-year is 95.1%, 5-year survival rate is 47.5%. Result showed RFA is a safe and effective method for liver malignancy, and the tumor size and stage are important prognostic factors (31). Although there is no absolute tumor size beyond which RFA should not be considered, according to Yan et al. when treating larger lesions, the rate of local tumor recurrence and progression following RFA treatment increases sharply (32). The complete tumor necrosis rate with RFA for tumors >5 cm is less favorable (33). In fact, the role of RFA alone for treating HCC is limited, so the combination therapy of RFA with other methods has been focused on in China. Chen et al. prospectively compared the combined RFA and PEI with the use of RFA alone in patients with HCC; the 5-year survival rate was 49.3% with RFA-PEI and 35.9% with RFA alone. Local

3 Jpn J Clin Oncol, 2016, Vol. 46, No recurrence was significantly lower with RFA-PEI (4/66) than with RFA alone (14/67) (34). RFA and PEI offered better local tumor control and long-term survival compared with RFA alone. The combination of RFA and radiotherapy is also more effective than RFA alone. The use of combined RFA and percutaneous iodine-125 seed implantation showed significant differences in overall survival and cumulative recurrence compared with RFA alone (for patients with small HCCs ( 3 cm)). Combination therapy provided better local and intrahepatic tumor control and long-term survival (35). Bian et al. reported that iodine-131 metuximab in treatment of HCC after RFA showed a greater anti-recurrence benefit than RFA monotherapy (36). Sorafenib, an oral multikinase inhibitor, has been proved as the firstline therapy method for patients with advanced HCC (37). RFA plus sorafenib also significantly decreased recurrence rates and prolonged the survival time of medium-sized HCC patients. This combination therapy is safer and more effective than the control without unexpected side effects (38). Compare the hepatectomy with RFA Hepatectomy offer the best chance of cure in patients with resectable tumor, but patients suitable for the surgery is limited. RFA for small tumors may offer comparable survival results. Besides, RFA has distinct advantages compared with surgical resection of HCC. it is minimally invasive and has much lower morbidity and mortality rates than surgery. There are really a number of clinical trials compared the RFA with the HR. Chen et al. performed a study of 112 patients with small HCC (with single nodule <5 cm in diameter), 65 of them were in resection group and 47 in RFA group. There were no statistically significant differences between the two groups in the 1-, 2- and 3-year survival rates and recurrence rates. Besides RFA treatment is less invasive for small HCC than surgical resection and suggested that RFA is superior to surgical resection when used in the treatment of patients with HCC <3 cm in diameter. Studies also showed that good candidates for RFA are patients with HCC at an early stage (solitary tumor 5 cm in diameter or 3 nodules and 3 cm in diameter) (39,40). Feng et al. reported that in patients with small HCCs, percutaneous RFA may provide therapeutic effects similar to those of resection (41). Peng et al. performed a study compared RFA and open HR for elderly patients (>65 years) with very early or early HCC, suggested Table 1. Survival rate of the trials included in our review Study Arms Design Patients (n) Characteristics of the tumor no difference between the resection and RFA groups for overall survival, but RFA had better efficacy than resection for elderly patients with HCC 3 cm(42). Several clinical trials have shown that RFA is effective in resection for the treatment of small HCC. However, other studies showed the controversial results. According to a randomized trial comparing RFA and surgical resection for HCC conforming to the Milan criteria, overall survival and recurrence-free survival were significantly lower, and the overall recurrence was higher in the RFA group than in the resection group, Indicated that surgical resection may provide better survival and lower recurrence rates than RFA for patients with HCC to the Milan criteria (43). Lai et al. also reported between RFA and surgery: RFA was associated with a significantly higher tumor recurrence rate within the Milan criteria (44) (Table 1). So, we found that the safety and effect of RFA compared with surgery still remain highly controversial. Meta-analysis is a useful tool for revealing trends that might not be apparent in a single study. There are several meta-analysis or system reviews published both in English or Chinese. A recent meta-analysis published has included 31 studies ( patients) performed by Xu et al. (8252 treated with RFA and 7851 with resection). Result showed that compared with the RFA group, the 3-, 5-year overall and disease-free s in the resection group were significantly higher. However, complications were significantly fewer and hospital stay was significantly shorter in the RFA group than in the resection group. In subgroup analyses, for HCCs 3 cm, the overall and disease-free survival in the resection group was also significantly higher than those in the RFA group, whereas there were no significant differences between the two groups for HCC 2 cm. This analysis showed that HR still proposed as the first-line treatment rather than RFA for patients with HCCs >2 cm. For patients with HCCs 2 cm, RFA may be an alternative to HR because of their comparable long-term efficacy (45). Wang et al. also carried out a meta-analysis to assess the efficacy and safety of RFA versus HR for early HCC meeting the Milan criteria. This meta-analysis included patients (6094 patients RFA and 5779 resection), indicating that RFA has higher recurrence and lower s compared with HR, but for patients with very early stage HCC, the effectiveness of RFA is comparable with resection, with fewer complications (46). For some intrahepatic HCC recurrence or recurrence after LT, the surgical resection is difficult to perform. Meta-analysis showed 1-year 2-year 3-year 5-year Chen et al. (39) RFA Clinical trial 47 Single nodule 5 cm 92.8% 82.0% 64.5% NA Resection % 85.7% 67.3% NA Feng et al. (41) RFA RCT 84 Nodular <4 cm and up to 96.0% 87.6% 74.8% NA two nodules Resection % 83.1% 74.2% NA Peng et al. (42) RFA Clinical trial 89 Single nodule 5cmorupto 93.2% NA 71.1% 55.2% 3 nodules each <3cm Resection % NA 62.8% 51.9% Huang et al. (43) RFA RCT 115 Milan criteria 86.96% 76.52% 69.57% 54.78% Resection % 96.52% 92.17% 75.65% Lai et al. (44) RFA Clinical trial 31 Milan criteria 100% 92% NA 84% Resection 80 92% 75% NA 71% RFA, radiofrequency ablation; NA, not applicable; RCT, randomized controlled trial.

4 1078 The treatment of hepatocellular carcinoma in China Figure 1. Process of treatment for HCC patients in China (56). HCC, hepatocellular carcinoma; RFA, radiofrequency ablation; MWA, microwave ablation; TACE, transcatheter arterial chemoembolization. Table 2. Treatment options for HCC in Chinese guidelines (57) Child-Pugh class Extrahepatic metastasis Vascular invasion Tumor number Tumor size Treatment C 1, Palliative care 2, LT A, B Yes 1, RT 2, ChT 3, MoT A, B No Yes 1, TACE 2, RT 3, ChT 4, Res A, B No No 4 1, TACE 2, Res + Abl A, B No No 2, 3 >3 cm 1, Res 2, TACE + Abl A, B No No 2, 3 3 cm 1, Res 2, Abl A, B No No 1 5 cm 1, Res 2, TACE + RFA A, B No No 1 <5 cm 1, Res 2, Abl LT, liver transplantation; RT, radiotherapy; ChT, chemotherapy; MoT, molecular targeting treatment; TACE, transcatheter arterial chemoembolization; Res, resection; Abl, ablation.

5 Jpn J Clin Oncol, 2016, Vol. 46, No that for intrahepatic recurrent HCC 3 cm, the 1-, 3- and 5-year overall did not differ significantly in the comparison of RFA and surgical resection. RFA is less invasive, highly targetselective and repeatable, and it may be the preferred treatment option for selected patients (47). Huang et al. also reported for HCC recurrence after LT, there was no significant difference in overall survival or recurrence-free survival between the surgical resection group and the RFA group. When surgical resection is contraindicated or technically infeasible, RFA provides analogous long-term survival compared with surgery (48). Predictors of overall survival for HCC patients after RFA were still reported. According to a 10-year follow-up in Chinese patients, tumor number, Child- Pugh grade and serum-glutamyl transpeptidase level were independent predictors of overall survival, meanwhile serum alpha fetoprotein level and tumor number were independent predictors of recurrence-free survival (49). There is also an investigation showed that treatment options of LT, TACE and other therapy decreased, while percutaneous local ablation and supportive care increased. Options of surgical resection and systematic therapy had no significant change, over a 10-year period (50). Antiviral therapy According to statistics, ~240 million people are chronically infected with HBV and ~25% of chronically HBV-infected individuals eventually develop HCC globally (51). In China, 80% patients with HCC were caused by HBV infection (52). For HBV-related HCC patients, after the therapy of surgical resection or RFA, antiviral therapy is recommended. Prophylactic antiviral therapy for HBVrelated HCC can decrease the incidence of post-treatment HBV reactivation (53). Meta-analysis also demonstrated that antiviral therapy improves the and decreases recurrences following curative treatment of HBV-related HCC (54). Conclusion China accounts for >50% of HCC cases worldwide (55). Based on the average incidence rates from 2009 to 2011, the number of the new liver cancer cases is 466,100 and 375,000 for liver cancer deaths per year (2). Unfortunately, the number of LR cases or the RFA cases per year in China is difficult to count. We have devised a series of directives on the management of HCC in order to reduce incidence and mortality and to improve health care quality overall. The most recent one is guidelines of diagnosis and treatment for primary liver cancer (published in 2011) (56). According to this guideline, the process of treatment for HCC patient in China is shown in Fig. 1, and the treatment options for HCC in China is shown in Table 2. We can find that we still lack recommendations supported by data provided by a systematic review or evaluation of the literature. Peng et al. identified substantial geographic variation of HCC incidence within a high-risk region of China and found that socioeconomic status might partly explain the statistically significant spatial heterogeneity, suggests that strategies for control and intervention of liver cancer should focus on disadvantaged areas to reduce the HCC disparities (57). In conclusion, for HCC 5 cm, surgical resection is still the first choice in China, but for patients with poor liver functions (Child- Pugh class B) not suitable for surgical resection, local ablation is recommended. For HCC 3 cm, RFA may provide therapeutic effects similar to those of surgical resection; for centrally located liver tumors or the tumor in deep location, local ablation is recommended as the first choice. For HCC 5 cm, ablation is not recommended as monotherapy (56). The majority of HCC patients in China accompanied chronic liver disease or cirrhosis, and surgical management is difficult to implement. Different ways of treatment for HCC patients in China are hardly to review. The effect of monotherapy is limited. Recommendations supported by data are still urgently needed to guide clinical decision-making. Conflict of interest statement None declared. References 1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN Int J Cancer 2015;136:E Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, CA Cancer J Clin 2016;66: Chen CJ, Wang LY, Yu MW. 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