Radiofrequency ablation combined with interventional chemoembolization for unresectable primary hepatocellular carcinoma (Published) Yuehua Wang, Jiafeng Liu, Fei Li Department of General Surgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Xuanwu District, Beijing 100053, China Yuehua Wang Abstract: To evaluate the effect of radiofrequency ablation (RFA) followed by transcatheter hepatic artery chemoembolization (TACE) for hepatocellular carcinoma in the treatment of The purpose: To evaluate the effect of radiofrequency ablation (RFA) combined with transcatheter hepatic artery chemoembolization (TACE) in the treatment of inoperable hepatocellular carcinoma. Methods: 127 cases of inoperable hepatocellular carcinoma were treated with RFA combined with TACE during 5 years. Among them, 106 cases were male and 21 cases were female, with an average age of 56.4±8.8 years. The maximum tumor length was 1.5-10 cm, among which 26 cases had major tumor lesions ≤3 cm, 33 cases had 3.1-5 cm, and 68 cases had >5 cm. The author proposed to classify the RFA effect of local tumor ablation into three levels: ① complete ablation: for single nodal tumors, the tumor foci were completely (100%) necrotic and the ablation range reached 0.5-1 cm ablation margin; ② basic ablation: for single nodal tumors, although the tumor foci were completely (100%) necrotic, the ablation range reached 0.5-1 cm ablation margin; ② basic ablation: for single nodal tumors, the tumor foci were completely (100%) necrotic. For single nodal tumors, although the tumor foci are completely (100%) necrotic, the ablation margin in some parts is less than 0.5~1cm; or for tumors with only 2~3 foci and all of them are less than 5cm, the tumor foci are completely necrotic, regardless of the ablation margin; ③ Partial ablation (incomplete ablation): for single nodal tumors, only most of the tumors are ablated, but there are clear residual tumor margins or unablated metastases left behind (3) partial ablation (complete ablation): for single nodal tumors, only most of the tumor was ablated, but there were clear residual tumor margins or unablated metastases; or there were more than 4 hepatocellular carcinoma lesions (suggesting multiple metastases); or there were combined portal vein branches, hepatic vein branches or bile duct cancer emboli. RESULTS: All 127 cases in this group underwent RFA successfully, with smooth postoperative recovery and no serious complications, including 16 (13.5%) cases of percutaneous puncture RFA, 19 (15.7%) cases of laparoscopic RFA, and 92 (72.4%) cases of open RFA. The RFA effect of liver cancer was classified into three levels, namely complete ablation (48 cases), basic ablation (28 cases) and partial ablation (51 cases). The overall 1-, 2-, and 3-year survival rates were 83.1%, 55.7% , and 43.7%, respectively, since the follow-up after RFA. The 3-year survival rates were 69.8%, 59.6% and 12.2% (x2=27.4, P<0.01) for patients with maximum tumor diameter ≤3 cm, 3.1-5 cm and >5 cm, respectively, and 78.6%, 28.1% and 0 (x2=39.1, P<0.1) for patients with complete ablation, basic ablation and incomplete ablation, respectively, according to the tumor size or RFA effect. 39.1, P<0.01). The four factors with highly significant correlation with survival time were analyzed by Cox regression model, and RFA effect (Wald=24.709, P<0.01) and liver function (Wald=8.990, P<0.01) were the final factors with significant correlation with survival time in the Cox regression model. CONCLUSION: Preferred RFA can rapidly ablate major lesions of inoperable hepatocellular carcinoma, and then TACE can play a therapeutic role in residual cancer foci or micro-metastatic lesions after RFA. Keywords: liver tumor; interventional radiotherapy; radiofrequency ablation; therapeutic chemoembolization Fundamental project: This work was supported by the National Natural Science Foundation of China (Grant No. 30772122). (See attached information) Most of the treatment options for patients with primary liver cancer (hereafter referred to as hepatocellular carcinoma) are limited by liver insufficiency due to severe liver disease such as chronic hepatitis and cirrhosis. Although surgical resection was once the gold standard of treatment for liver cancer, there are alternative treatment options for the many hepatocellular carcinomas that are not amenable to surgical resection. Since the 1980s, transcatheter hepatic artery chemoembolization (TACE) [1,2,3] has become one of the local treatments for hepatocellular carcinoma that is not amenable to surgical resection. However, TACE is not a curative treatment based on the principle of local chemotherapy combined with partial blood flow blockage. For hepatocellular carcinoma resected after TACE, only 30%-64% of the patients achieve complete necrosis [3,4,5], without damage to the non-cancerous liver tissue surrounding the tumor. Since Rossi et al [6] reported radiofrequency ablation (RFA) for hepatocellular carcinoma in 1995, RFA has become the basic treatment for small hepatocellular carcinoma (≤4 cm) [7]. In recent years, RFA has started to receive attention for the treatment of medium (3.1-5 cm) and large (>5 cm) hepatocellular carcinoma [8]. In addition to techniques to improve the outcome of RFA for large hepatocellular carcinoma, recent research hotspots tend to be the combination of interventional and local ablative treatments. For the treatment of small hepatocellular carcinoma (≤3 cm), TACE followed by combined RFA has been reported to be superior to RFA or TACE alone in terms of improving survival [9]. In contrast, studies of adjuvant combined TACE after RFA for inoperable resectable hepatocellular carcinoma have not been reported. The aim of this study was to investigate the need for combined TACE treatment after RFA for hepatocellular carcinoma by evaluating the effect of combined RFA + TACE treatment for hepatocellular carcinoma. Methods Patient data From May 2003 to March 2008, 127 cases of inoperable resectable hepatocellular carcinoma were treated with RFA and combined with TACE. Among them, 106 cases were male and 21 cases were female, aged 37-72 years, with a mean of 56.4±8.8 years. These cases were all patients with hepatocellular carcinoma that were not suitable for surgical resection for various reasons. The cases included in this study met the following criteria: (a) liver function reserve due to severe cirrhosis was difficult to withstand hepatic resection, (b) the tumor was close to major blood vessels and difficult to be resected radically, (c) imaging confirmed that one lesion or less than five lesions were located in the liver without distant metastases, (d) the largest tumor diameter did not exceed (d) the largest tumor diameter does not exceed 10 cm, (e) liver function Child-Pugh classification is limited to grade A or B. Contraindications are more than 5 lesions in the liver or diffuse lesions within the liver, portal vein trunk thrombosis, and grade C liver function Child-Pugh classification. The general clinical characteristics are listed in Table 1. RFA method The RITA radiofrequency ablation tumor treatment system (RF-1500) with machine power of 150 watts and electrode needles of 15 cm or 25 cm long expandable umbrella-shaped radiofrequency electrode needles was used for RFA in this group, which could be expanded into 9 fine electrode needles after the outer sheath of electrode needles was inserted into the tumor under ultrasound guidance. The RF strategy was determined according to the tumor size, morphological location and other factors, including the mathematical model of RF ablation, individualized protocol, RF range and treatment route, and RFA was selected to be performed under ultrasound-guided percutaneous puncture, under laparoscopy or via open surgery. for small and medium-sized tumor lesions and located in liver tissue, ultrasound-guided percutaneous hepatic puncture RFA was used; for small and medium-sized tumor lesions and located on the surface of the liver, RFA was performed under In other cases, such as those with deep tumor location or close to large blood vessels, or those with tumors larger than 5 cm that are difficult to operate and not suitable for percutaneous aspiration or laparoscopic RFA, RFA is performed via the open route. For tumor lesions less than 3 cm in diameter, single-stitch ablation centered on the tumor is used, and ablation up to 5 cm in diameter takes 15 to 25 minutes. For moderate (3.1-5 cm) tumors multiple RFA overlays were used to ablate tumors and non-tumor tissue up to 1.0 cm from the tumor margin, and the basic protocol was a 6-stitch overlay method (Figure 1). The first RFA stitch is performed under ultrasound guidance against the deep part of the tumor, then the stitches are withdrawn and then placed 1.0~2.1cm from the center of the tumor. With more ideal needle placement, 6 stitches of sub-RFA eventually achieve ablation of 3.1~5 cm tumor and 1.0 cm of ablation margin in the periphery. For tumors larger than 5 cm, more needles are used for overlapping ablation. For multiple tumor lesions, separate ablation is required. For tumors with rich blood supply, the arterial and venous blood flow to the hepatoportal is briefly blocked during open RFA (Pringle method). For all ablation routes, the extent of ablation was monitored intraoperatively by real-time ultrasound, and the changes in vital signs were monitored until 1 hour after the operation. TACE method Using the Seldinger method [3], the hepatic artery and superior mesenteric artery were cannulated via the femoral artery, and digital subtraction angiography was performed before perfusion chemotherapy and iodinated oil embolization with chemotherapy (TACE) in the hepatic branches of the innominate or superior mesenteric artery. The chemotherapy consisted of 500-1000 mg of 5-fluorouracil, 20-40 mg of mitomycin, and 20-40 mg of adriamycin, of which 20 mg of adriamycin was emulsified with 5-10 ml of iodinated oil and then used to embolize the intrahepatic arterial branches. Follow-up All patients were followed up since RFA to observe the occurrence of acute and chronic complications. Abdominal CT, laboratory tests for AFP and liver function were routinely repeated 1 month after RFA, 1 month after TACE and every 3-6 months thereafter. Whether patients received TCM treatment or immunotherapy during the follow-up period was not restricted by this study. Statistical analysis Data analysis was performed using the computer statistical software SPSS (version 11.5.0). A P value of less than 0.05 (P < 0.05) was used as the criterion for determining statistical significance. Results General A total of 16 cases (13.5%) of RFA were performed using ultrasound-guided percutaneous liver puncture, 19 cases (15.7%) of RFA were performed under laparoscopy, and 92 cases (72.4%) of RFA were performed via the open route. All 127 cases in this group underwent RFA successfully without serious related complications. Thirteen cases developed ascites after RFA for more than 1 week, which improved within one month after liver preservation therapy. Other treatments performed at the same time as RFA included splenic artery ligation in 23 cases due to combined hypersplenism, cholecystectomy in 13 cases, and bile duct dissection to remove cancer emboli in 3 cases. All cases were diagnosed pathologically, with percutaneous puncture biopsy in 25 cases and intraoperative puncture biopsy or excisional tissue biopsy in 102 cases, and 113 cases of hepatocellular carcinoma and 14 cases of cholangiocellular hepatocellular carcinoma were diagnosed. RFA effect The effect of tumor ablation was observed in three-dimensional space by enhanced CT scan 1 month after RFA and before TACE. According to the judgment criteria of relevant literature, complete necrosis of tumor foci was determined when no enhanced subfoci were found in and around the tumor by CT scan [8]. The author further proposed a classification of the RFA effect of local tumor ablation into three levels: ① complete ablation: for single nodal tumors, the tumor foci are completely (100%) necrotic, and the ablation range reaches 0.5-1 cm ablation margin (Figure 2); ② basic ablation: for single nodal tumors, although the tumor foci are completely (100%) necrotic, the ablation margin in some parts is less than 0.5-1 cm For single nodal tumors, only most of the tumor is ablated, but there are clear residual tumor margins or unablated metastases; or there are more than 4 hepatocellular carcinoma lesions (suggesting multiple metastases); or there are combined portal vein branches, hepatic vein branches or bile duct emboli. or bile duct embolism. The results were divided into 48 cases of complete ablation, 28 cases of basic ablation and 51 cases of incomplete ablation. Among them, 96.2% (25/26) of patients with the largest tumor lesion below 3 cm and 57.6% (19/33) of patients with the largest tumor lesion between 3.1-5.0 cm achieved complete ablation. In one case with two larger tumors (9 cm and 6 cm in diameter), RFA took up to 6 hours. The correlation between tumor size and RFA effect was strongly correlated by Spearman's rank correlation analysis (r=0.819, P<0.01). The first TACE was performed 1~2 months after RFA, and CT examination (iodine oil CT) was routinely performed 3 weeks afterwards. The examination revealed residual cancer at the edge of the lesion or lesions that were not ablated (with iodine oil deposits) in 10.4% (5/48) of cases with complete ablation, 14.3% (4/28) of cases with basic ablation, and 76.5% (39/51) of cases with incomplete ablation. This is similar to the results of the RFA response assessed on CT scan after RFA and before TACE, and is generally consistent. Of the 90 cases with elevated AFP values (≥25 μg/L), 55.6% (51/90) decreased to less than 25 μg/L 1 to 3 months after RFA + first TACE. Overall outcome In this group, 127 patients underwent at least 1 TACE after RFA. patients who obtained basic ablation or incomplete ablation underwent another TACE every 3 to 6 months, up to 3 times. All cases were followed up for 5 to 48 months, with a median time of 15 months and a mean of 18.9±12.4 months. By the end of follow-up, 50 cases had died, including 31 deaths due to recurrence of hepatocellular carcinoma, 19 deaths due to liver failure, and 7 cases lost to follow-up (analysis by death). The overall 1-, 2-, and 3-year survival rates were 83.1%, 55.7% , and 43.7%, respectively, when analyzed by the life table method. The survival curves for each group, grouped by tumor size or RFA effect, are shown in Figure 3. 3-year survival rates were 69.8%, 59.6% and 12.2% for patients with maximum tumor diameter ≤3 cm, 3.1-5 cm and >5 cm, respectively (x2=27.4, P<0.01); 3-year survival rates were 78.6% for patients who obtained complete ablation, basic ablation and incomplete ablation, respectively, The 3-year survival rates were 78.6%, 28.1% and 0 ( x2=39.1, P<0.01) for patients who obtained complete ablation, basic ablation and incomplete ablation, respectively. Recurrent metastases had been detected in 16 of the 48 cases with complete ablation at follow-up (Figure 2), with a median time to recurrence of 3 to 44 months, and a median time of 24 months, with a mean of 22.4±11.3 months; recurrent metastases had been detected in 18 of the 28 cases with basic ablation at follow-up, with a median time to recurrence of 3 to 39 months, and a median time of 16.5 months, with a mean of 14.9±9.8 months. The 1-, 2- and 3-year tumor-free survival rates were 93.3%, 76.1% and 50.5% and 69.0%, 32.0% and 21.3% in the two groups that obtained complete ablation and basic ablation, respectively, with significant differences between the two groups (x2=11.260, P<0.01). Univariate Log-Rank analysis showed that tumor size, liver function, type of pathology, and RFA effect were factors with highly significant correlation with survival time (P<0.01). In contrast, gender, age, hepatitis type and AFP value were factors that were not significantly correlated with survival time (P > 0.05). Cox regression model analysis was performed for the four factors with highly significant correlation with survival time, and RFA effect (Wald=24.709, P<0.01) and liver function (Wald=8.990, P<0.01) were the final factors with significant correlation with survival time in the Cox regression model. Discussion Effectiveness of RFA for unresectable hepatocellular carcinoma Although the types of electrode needles used for radiofrequency ablation of hepatocellular carcinoma are different, the mechanism of thermal ablation that causes necrosis of hepatocellular carcinoma tissue is the same. A newer type of electrode needle is an extendable multibeam electrode that can be inserted into the tumor by extending from the tip portion of the needle sheath. The ablation range due to RFA is known exactly and can completely cover the tumor and certain tumor surrounding tissues. Tumor RFA is equivalent to functional resection of the tumor and can even achieve near resection effect. It has been reported that for the treatment of small hepatocellular carcinoma (≤3 cm), RFA alone is superior to TACE [11] and local ethanol injection therapy [12], and among thermal ablation methods RFA is again superior to microwave ablation [13], indicating that for small hepatocellular carcinoma RFA is equivalent to radical resection treatment. The author performed RFA on tumors less than 5 cm in diameter, and most (44/59) could achieve complete ablation, and then combined with TACE treatment, a relatively satisfactory 3-year survival rate was obtained (Figure 3). For large hepatocellular carcinoma larger than 5 cm that could not be surgically resected, which had poor treatment effect in the past, the 3-year survival rate has reached 12.2% in this group after RFA + TACE treatment, indicating that large hepatocellular carcinoma that could not be surgically resected is also worthy of RFA. Compared with the effect of previous TACE treatment alone, RFA has the feature of fast and complete local destruction of tumor. Studies have shown that no other local treatment is more effective than RFA in treating invasive large hepatocellular carcinoma [8]. Therefore, for hepatocellular carcinoma that is not suitable for surgical resection, RFA capable of rapid ablation should be preferred in order to obtain a radical treatment effect. The limited nature of RFA for hepatocellular carcinoma The type of radiofrequency electrode, the intensity and duration of radiofrequency current, etc., determine the size and effectiveness of the scope of radiofrequency ablation. It also determines that the scope of single-shot sub-ablation is extremely limited. With single-shot RFA, complete ablation can often be obtained for tumors ≤3 cm, and some studies have shown that for tumors below 3 to 5 cm, complete necrosis can be demonstrated on CT in 80% to 90% of cases [14]. For large hepatocellular carcinomas the rate of complete necrosis is, however, suboptimal, and for tumors larger than 5 cm in diameter or infiltrative, the chances of obtaining complete ablation are relatively low [8]. In a study using cluster electrode RFA, the complete necrosis rate for ablation of 3.1-9.5 cm (mean 5.4 cm) tumors was only 48%[8] , and the rate of recurrent metastasis after RFA for hepatocellular carcinoma was high[15] . According to the principles of surgical oncology, normal liver tissue of 0.5-1.0 cm or more around the tumor should also be completely ablated to achieve a radical result[16] . Tumors up to 5 cm in diameter can be ablated using superimposed multi-stitch ablation, but it is technically challenging. Prof. Minhua Chen et al [17] have used a mathematical model to explain the RFA method graphically, for a tumor with a diameter of 5 cm the ablation range needs to be 7 cm (ensuring a 1 cm ablation margin), and with a radiofrequency needle of 5 cm per ablation, 12 ablation strokes are needed to destroy the tumor radically. The author used a modified and simplified model with an appropriate route, which also requires 6 strokes to obtain a 7 cm ablation foci. The previous evaluation of tumor ablation results only included complete and partial ablation [10], which the author believes does not meet the need for evaluating the efficacy of RFA treatment and further guiding clinical treatment. In this study, the RFA effect after tumor ablation was classified into three different degrees of complete ablation, basic ablation and partial ablation, and Cox regression analysis showed that the degree of tumor RFA effect (treatment factor) and liver function status (non-treatment factor) were statistically significant factors associated with survival time. While the 3-year tumor-free survival rate was significantly higher in those who obtained complete ablation (50.5%) than in those who obtained basic ablation (21.3%), these results suggest that this new classification can better predict the long-term outcome after ablative treatment. The results of this study indicate that the larger the tumor, the lower the rate of complete tumor ablation, and the worse the long-term outcome, further suggesting that RFA is limited for medium to large hepatocellular carcinoma. It also suggests that for hepatocellular carcinoma in which complete ablation is difficult to obtain, the combination of multiple treatments after RFA is necessary to control residual cancer and metastases. Combined application of RFA and TACE RFA and TACE for hepatocellular carcinoma are two different treatment routes and treatment principles. TACE prior to local thermal ablation is a new combined treatment option [18]. Since the cooling effect of blood flow can affect the thermal ablation effect, transvascular embolization can block the tumor blood supply and significantly increase the size of ablation foci. Studies have also shown that the combined application of RFA after TACE is superior to RFA alone [9,11]. However, it has also been reported that for hepatocellular carcinoma that can be surgically resected, preoperative TACE will also decrease the long-term survival rate after hepatectomy [19], and whether preemptive TACE will decrease the long-term survival rate for those who can directly RFA is debatable and needs to be further investigated. In practice, for those who require open surgical RFA, the major blood supply to hepatocellular carcinoma can be reduced intraoperatively by controlling hepatic portal blood flow. Therefore, the author believes that for those who need open RFA, TACE is not needed to reduce blood flow before RFA, but only when the tumor is characterized by multiple blood supply and RFA is performed via laparoscopic or percutaneous puncture route, TACE can be performed first, and the role of TACE is adjunctive compared with the subsequent RFA. In this study, the efficacy of RFA alone is still insufficient for large hepatocellular carcinomas, and most of these hepatocellular carcinomas could only obtain basic ablation with RFA (51/68). Even if complete ablation or basic ablation was obtained, the three-year tumor-free survival rate was very low, 50.5% and 21.3% in the two groups, respectively. The reasons for this are, for example, the fibrous envelope around the tumor affects the effect of RFA heat on the sub-nodes around the tumor [8]; the high local recurrence rate is related to the peripheral residual cancer cells not killed by RFA and the tiny satellite foci around the tumor; and also the recurrent foci after RFA in most tumors are due to the tumor biology of multicentric tumor growth on the basis of cirrhosis [14]. Considering the advantages and disadvantages of RFA and TACE [1-3], the author proposed a two-step treatment protocol with the advantages and disadvantages of both of them. Two-step treatment protocol. In this study, we showed that for hepatocellular carcinoma that could not be surgically resected, RFA was performed to maximize rapid tumor killing, and then TACE was performed to treat the residual cancer tissue and micro-metastases around the tumor after RFA. From the oncological point of view, the number of treatments chosen for TACE is decided according to the RFA effect of hepatocellular carcinoma. For example, for those who obtain complete ablation, the chance of recurrence and metastasis is low, and it is necessary to perform TACE once to evaluate the effect of RFA and control micro-metastases before recurrence and metastases are detected; for those who obtain only basic ablation, the chance of recurrence and metastasis is high, and it is necessary to combine multiple TACE treatments; and for those who obtain partial ablation, which indicates the presence of active tumor lesions, it is necessary to combine not only multiple TACE treatments, but also multiple TACE treatments. The results of this study are summarized below. This work was funded by the National Natural Science Foundation of China (project approval number: 30772122). (See accompanying information) References: (omitted)