Comparison of the Outcomes of Hepatocellular Carcinoma Patients Following Local Ablation Therapy and Hepatectomy

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1 Original Article Original Comparison of the Outcomes of Hepatocellular Carcinoma Patients Following Local Ablation Therapy and Kiyohide Kioka ) *, Takashi Nakai ), Yasuko Kawasaki ), Ayako Ueno 2), Yuhei Wakahara 2) Hirotsugu Maruyama 2), Shinsuke Hiramatsu 2), Takehisa Suekane 2), Tomoaki Yamasaki 2), Koji Sano 2) Eiji Sasaki 2), Hiroko Nebiki 2), Hiroshi Sato 2), Sadatoshi Shimizu 3), Akishige Kanazawa 3) Tadashi Tsukamoto 3), Yoichi Koda 4), Katsuko Murata 4), Takao Manabe 4) Comparison of the Outcomes of Hepatocellular Carcinoma Patients Following Local Ablation Therapy and Kiyohide Kioka ), Takashi Nakai ), Yasuko Kawasaki ), Ayako Ueno 2), Yuhei Wakahara 2), Hirotsugu Maruyama 2) Shinsuke Hiramatsu 2), Takehisa Suekane 2), Tomoaki Yamasaki 2), Koji Sano 2), Eiji Sasaki 2), Hiroko Nebiki 2), Hiroshi Sato 2) Sadatoshi Shimizu 3), Akishige Kanazawa 3), Tadashi Tsukamoto 3), Yoichi Koda 4), Katsuko Murata 4) and Takao Manabe 4) Abstract Of the 635 patients with hepatocellular carcinoma receiving initial treatment at our hospital, 297 received local ablation therapy and 592 underwent hepatectomy. The prognosis and background factors of these patients were compared in this study. No significant difference was noted in the cumulative survival rate between the local ablation therapy and hepatectomy groups. However, with regard to background factors, the local ablation therapy group had significantly poorer hepatic functional reserve, smaller tumor size, and a lower proportion of patients with progressive stage disease. Accordingly, further investigation was conducted in a similar manner to correct for these differences in background factors. We limited the target hepatocellular carcinoma patients to those with liver damage grade A and a single tumor of 2 cm. Although no difference was found in the cumulative survival rate between the local ablation therapy and hepatectomy groups, the cumulative non-recurrence survival rate was significantly more favorable in the latter. However, serum albumin levels were significantly lower and tumor size was smaller in patients who received local ablation therapy than in those who underwent hepatectomy, despite the inclusion of only those patients who met the aforementioned conditions of liver damage grade and tumor size. Similarly, the results of specific local ablation therapies, including percutaneous ethanol injection therapy, percutaneous microwave coagulation therapy, and percutaneous radiofrequency ablation, were compared with those of hepatectomy in patients with liver damage grade A and a single tumor of 2 cm in size. However, the results indicated no difference in the cumulative survival rate. In conclusion, the cumulative survival rate did not differ between patients who received local ablation therapy and those who underwent hepatectomy, even on limiting the subjects to patients with liver damage grade A and a single tumor of 2 cm. Key words: hepatocellular carcinoma, percutaneous microwave coagulation therapy, percutaneous ethanol injection therapy, percutaneous radiofrequency ablation, hepatectomy Accepted on July. 25, 23 Department of Hepatology ), Gastroenterology 2), Hepatobilliary and Pancreatic Surgery 3), and Radiology 4), Osaka City General Hospital Address: , Miyakojima-hondori, Miyakojima-ku, Osaka, 534-2, Japan *Author for correspondence and reprint requests: Kiyohide Kioka M.D., Ph.D. Department of Hepatology, Osaka City General Hospital Address: , Miyakojima-hondori, Miyakojima-ku, Osaka, 534-2, Japan TEL: FAX: J. Microwave Surg. Vol.3 No 23 33

2 Introduction Local ablation therapy has progressed from percutaneous ethanol injection therapy ) to percutaneous microwave coagulation therapy, 2) and more recently, many institutions perform percutaneous radiofrequency ablation. 3) Percutaneous microwave coagulation therapy was introduced in our hospital in 994 and percutaneous radiofrequency ablation was introduced in 2, primarily for the treatment of hepatocellular carcinoma involving a tumor of 3 cm. 4),5) In addition to these types of local ablation therapy, therapies such as hepatectomy and transcatheter arterial chemoembolization are used for the treatment of hepatocellular carcinoma. According to the liver cancer treatment algorithm described in the Guideline for liver cancer treatment based on scientific ground, the treatment method is determined according to the liver damage grade and the number and size of tumors. 6) Since the opening of our hospital in 994, the following principle has been followed for the treatment of hepatocellular carcinoma: hepatectomy for resectable cases; local ablation therapy for cases with tumor size and number of 3 cm and 3, respectively, and the possibility of securing a safety margin of approximately 5 mm around the tumor; and transcatheter arterial chemoembolization, as far as possible, for other cases. 4),5) The outcomes of patients who received local ablation therapy or hepatectomy as the initial treatment as per this algorithm were compared in this study. I. Patients and methods This study included 635 hepatocellular carcinoma patients who received initial treatment at our hospital between 994 and 2. Of these patients, 592 underwent hepatectomy, 344 received transcatheter arterial chemoembolization plus local ablation therapy, 336 received local ablation therapy, 228 received transcatheter arterial chemoembolization, received other treatment, and 25 did not receive treatment. Initially, the cumulative survival rate and cumulative nonrecurrence survival rate in these patients were compared according to the type of initial treatment. In the next step, the background factors and the cumulative survival rate/cumulative non-recurrence survival rate were compared between the 297 patients who had only received local ablation therapy (excluding the 39 patients who received concomitant local ablation therapy) and the 592 patients who underwent hepatectomy (Table.). Of the patients who received only local ablation therapy, 36, 59, and 2 received percutaneous ethanol injection therapy, percutaneous microwave coagulation therapy, and percutaneous radiofrequency ablation, respectively. Patients who received only local ablation therapy comprised 7 men and 26 women, and their mean age was 69±9 years. Patients who underwent hepatectomy comprised 443 men and 49 women, and their mean age was 67± years. Table. Background Factors of Hepatocellular Carcinoma Patients who Underwent or Local Ablation Therapy Factor Local ablation therapy (n=297) (n=592) P value Age 68.7± ±9.7 <. Sex (male/female) 7/26 443/49 <. Liver damage grade (A/B/C) 43/27/27 4/87/4 <. Child-Pugh grade (A/B/C) 26/77/4 54/5/ <. Stage (I/II/III/IV-A/IV-B) 88/87/2// 8/298/57/45/2 <. Tumor number (solitary/multiple) 23/66 39/22 <. Tumor size (mm) 8± 45±32 <. To correct for the differences in background factors between the local ablation therapy only group and the hepatectomy group, the target patients were limited to those with a single tumor of 2 cm in size. This was to allow direct comparisons between the local ablation therapy only group (2 patients) and the hepatectomy group (57 patients) (Table 2.). Furthermore, among those hepatocellular carcinoma patients with liver damage grade A and a single tumor of 2 cm, the cumulative survival rate of patients undergoing hepatectomy was compared with that of those who received only local ablation therapy (i.e., percutaneous ethanol injection therapy, percutaneous microwave coagulation therapy, or percutaneous radiofrequency ablation). The cumulative survival rate and cumulative nonrecurrence survival rate were calculated using the Kaplan- Meier method. For comparison of cumulative survival rate 34 J. Microwave Surg. Vol.3 No 23

3 Comparison of the Outcomes of Hepatocellular Carcinoma Patients Following Local Ablation Therapy and Table 2. C omparison of Background Factors of Hepatocellular Carcinoma Patients with Liver Damage Grade A and a Single Tumor of 2 cm between the and Local Ablation Therapy Groups Local ablation therapy (n=2) Factor (n=57) P value Age 68.7± ±8.9 <.5 Sex (male/female) 62/4 4/7 n.s. Albumin (g/dℓ) 3±.3 3.9± <.5 Prothrombin time (%) 92±4 95±5 n.s. Tumor size (mm) 5±3 7±3 <. n.s., not significant Similarly, no significant difference in the cumulative survival rate was noted between the 297 patients who received local ablation therapy only and the 592 patients who underwent hepatectomy (Figure 3), but the non-recurrence survival rate was more favorable in the latter (Figure 4). Comparison of the background factors showed that the local ablation therapy only group had a significantly poorer hepatic functional reserve, smaller tumors, and a lower proportion of patients with progressive stage disease (Table ). To correct for differences in background factors, and thus enable a direct comparison, the target patients were limited to those with liver damage grade A and a single tumor between the 2 groups, the log-rank test was employed. The of 2 cm. The results indicated no difference in the cumulative background factors between the 2 groups were compared survival rate between the local ablation therapy group and the using the χ2 test, Fisher s exact test, and the Mann-Whitney U hepatectomy group (Figure 5). However, the cumulative non- test. The results are presented as mean ± standard deviation, recurrence survival rate was more favorable in the latter and P<.5 was considered statistically significant. (Figure 6). However, serum albumin levels were significantly lower and tumor size was smaller in the local ablation therapy group than in the hepatectomy group, even when study II. Results Comparison of the cumulative survival rates among participants were limited to those patients who met the the initial treatment methods showed no significant difference aforementioned conditions (Table 2). The cumulative non- between the local ablation therapy group and the hepatectomy recurrence survival rates of patients who received group (Figure ). However, the cumulative non-recurrence percutaneous ethanol injection therapy, percutaneous survival rate was more favorable in the latter (Figure 2). m i c r o w a v e c o a g u l a t i o n t h e r a p y, a n d p e r c u t a n e o u s () (Other) (TAE) (TAE+) () (No treatment) 2 Other TAE TAE+ No treatment Figure. C umulative survival rate of hepatocellular carcinoma patients according to initial treatment types, as assessed using the KaplanMeier method Figure 2. C umulative non-recurrence survival rate of hepatocellular carcinoma patients according to initial treatment types *P<. vs. (log-rank test) : local ablation therapy : local ablation therapy TAE: transcatheter arterial chemoembolization TAE: transcatheter arterial chemoembolization J. Microwave Surg. Vol.3 No 23 35

4 Figure 3. s of hepatocellular carcinoma patients in the hepatectomy (n=592) and local ablation therapy (n=297) groups : local ablation therapy Figure 4. Cumulative non-recurrence survival rates of hepatocellular carcinoma patients in the hepatectomy (n=592) and local ablation therapy (n=297) groups *P<. vs. (log-rank test) : local ablation therapy Figure 5. s of hepatocellular carcinoma patients with liver damage grade A and a single tumor of 2 cm in the hepatectomy (n=592) and local ablation therapy (n=297) groups Figure 6. Cumulative non-recurrence survival rates of hepatocellular carcinoma patients with liver damage grade A and a single tumor of 2 cm in the hepatectomy (n=592) and local ablation therapy (n=297) groups *P<. vs. (log-rank test) : local ablation therapy 36 J. Microwave Surg. Vol.3 No 23

5 Comparison of the Outcomes of Hepatocellular Carcinoma Patients Following Local Ablation Therapy and Kaplan-Meier PEIT PMCT PRFA Figure 7. s of hepatocellular carcinoma patients with liver damage grade A and a single tumor of 2cm according to initial treatment types PEIT: percutaneous ethanol injection therapy PMCT: percutaneous microwave coagulation therapy PRFA: percutaneous radiofrequency ablation radiofrequency ablation were similarly compared with that of patients who underwent hepatectomy; no differences were noted between the groups (Figure 7). III. Discussion Treatment strategies for hepatocellular carcinoma vary from transhepatic arterial infusion chemotherapy to liver transplantation, as well as hepatectomy, local ablation therapy, and hepatic transcatheter arterial embolization. According to the liver cancer treatment algorithm described in the Guideline for liver cancer treatment based on scientific ground, the treatment method is determined according to the liver damage grade and the number and size of tumors. 6) In line with this algorithm, local ablation therapy is indicated for cases involving 3 tumors of 3 cm (also applicable to cases of hepatic disorder B and tumor size 2 cm, if a single tumor is present). At our hospital, the indication employed for percutaneous local ablation therapy is mostly according to the same treatment algorithm. Thus, for resectable cases, hepatectomy is selected, but local ablation therapy is indicated if the tumor size is 3 cm, if the number of tumors is 3, and if a safety margin of approximately 5 mm can be secured around the tumor. 4),5) Accordingly, local ablation therapy is not necessarily conducted if it is difficult to secure the safety margin, and hepatectomy is conducted in resectable cases. Further to these criteria, hepatectomy was performed in approximately 36% of all the hepatocellular carcinoma cases. This rate is slightly higher than the national mean value reported by the Liver Cancer Study Group of Japan. 7) Huang et al. 8) compared hepatectomy with percutaneous radiofrequency ablation for hepatocellular carcinoma cases corresponding to the Milan criteria. 9) They reported that both the survival rate and the non-recurrence survival rate were higher in the hepatectomy group. Further, Wang et al. ) compared hepatectomy with percutaneous radiofrequency ablation for hepatocellular carcinoma cases involving very early/early stage disease according to the BCLC staging system. ) They reported that, despite no difference in the survival rate, the non-recurrence survival rate was superior in the hepatectomy group. Takayama et al. 2) also compared hepatectomy with percutaneous radiofrequency ablation for hepatocellular carcinoma cases involving a single hepatocellular carcinoma smaller than 2 cm. They reported that the non-recurrence survival rate was higher in the hepatectomy group, although no difference was noted in the survival rate. In our study, we also evaluated hepatocellular carcinoma patients with liver damage grade A and a single tumor of 2 cm. Our results indicated a higher non-recurrence survival rate in the hepatectomy group than in the local ablation therapy group, despite there being no difference in the survival rate. However, the serum albumin levels were higher in the hepatectomy group, even when the target patients were limited to those with liver damage grade A. In addition, tumor size was smaller in the local ablation therapy group, even when selection was limited to patients with tumor size of 2 cm. Thus, the background factors were still different between these groups. In comparison with hepatectomy, local ablation therapy is less invasive and can be performed under more lenient standards of hepatic functional reserve; local ablation therapy can be indicated even for those with liver damage grade B. 6),3) However, localized control function following percutaneous radiofrequency ablation has been reported to be inferior to that following hepatectomy in patients with poorly differentiated tumors. 4) At our hospital, hepatectomy is usually selected for operable patients. However, patients with J. Microwave Surg. Vol.3 No 23 37

6 tumor below 3 cm in size, tumor number within 3, and availability of an approximately 5 mm safety margin around the tumor are considered indicated for local ablation therapy. Therefore, the use of the treatment algorithm employed at our hospital may achieve the favorable results. The merits of both hepatectomy and local ablation therapy should be considered, and the safest and most reliable treatment method should be selected without bias. Conclusion The cumulative survival rate did not differ significantly between the local ablation group and the hepatectomy group, even when the target patients were limited to those with liver damage grade A and a single tumor of 2 cm. Accordingly, evaluation of the merits of both hepatectomy and local ablation therapy is considered important in the treatment of hepatocellular carcinoma, and the safest and most reliable treatment method should be selected without bias. References ) Shiina S, Tagawa K, Unuma T, Takahashi R, Yoshimura K, Komatsu Y, Hata Y, Niwa Y, Shiratori Y, Terano A : Percutaneous ethanol injection therapy for hepatocellular carcinoma ; A histopathologic study. Cancer 68:524-53, 99 2) Seki T, Wakabayashi M, Nakagawa T, Itho T, Shiro T, Kunieda K, Sato M, Uchiyama S, Inoue K: Ultrasonically guided percutaneous microwave coagulation therapy for small hepatocellular carcinoma. Cancer 74:87-825, 994 3) Rossi S, Di Stasi M, Buscarini E, Cavanna L, Quaretti P, Squassante E, Garbagnati F, Buscarini L: Percutaneous radiofrequency interstitial thermal ablation in the treatment of small hepatocellular carcinoma. Cancer J Sci Am : 73-8, 995 4) So K, Kioka K, Moriyoshi Y, Oka H, Harihara S, Lee M, Yamasaki O, Murata K, Manabe T, Kuroki T, Kobayashi K : Assessment of the efficacy of microwave coagulation therapy for hepatocellular carcinoma by imaging techniques(in Japanese). Kanzo 37:563-57, 996 5) Kioka K, Kawasaki Y, Nakai T, Ishida Y, Maruyama H, Hiramatsu S, Mori A, Suekane T, Yamasaki T, Sano K, Shiba M, Nebiki H, Sato H, Shimizu S, Kanazawa A, Tsukamoto T : Investigation of different methods, particularly percutaneous ablation therapy, for treating non-b, non-c hepatocellular carcinoma. J Microwave Surg 29:99-4, 2 6) Makuuchi M, Kokudo N, Arii S, Futagawa S, Kaneko S, Kawasaki S, Matsuyama Y, Okazaki M, Okita K, Omata M, Saida Y, Takayama T, Yamaoka Y : Development of evidence-based clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res 38:37-5, 27 7) Ikai I, Arii S, Ichida T, Okita K, Omata M, Kojiro M, Takayasu K, Nakanuma Y, Makuuchi M, Matsuyama Y, Yamaoka Y : Report of the 6th follow-up survey of primary liver cancer. The Liver Cancer Study Group of Japan. Hepatol Res 32:63-72, 25 8) Huang J, Yan L, Cheng Z, Wu H, Du L, Wang J, Xu Y, Zeng Y. : A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg. 252:93-92, 2 9) Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L.: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 334: , 996 ) Wang JH, Wang CC, Hung CH, Chen CL, Lu SN. : Survival comparison between surgical resection and radiofrequency ablation for patients in BCLC very early/early stage hepatocellular carcinoma. J Hepatol. 56:42-48, 22 ) Llovet JM, Brú C, Bruix J.:Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 9: , 999 2) Takayama T, Makuuchi M, Hasegawa K. : Single HCC smaller than 2 cm: surgery or ablation?: surgeon's perspective. J Hepatobiliary Pancreat Sci. 7: , 2 3) Arii S, Yamaoka Y, Futagawa S, Inoue K, Kobayashi K, Kojiro M, Makuuchi M, Nakamura Y, Okita K, Yamada R.:Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology. 32: , 2 4) Imamura J, Tateishi R, Shiina S, Goto E, Sato T, Ohki T, Masuzaki R, Goto T, Yoshida H, Kanai F, Hamamura K, Obi S, Yoshida H, Omata M. :Neoplastic seeding after radiofrequency ablation for hepatocellular carcinoma. Am J Gastroenterol. 3: , J. Microwave Surg. Vol.3 No 23