Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: Ethanol injection therapy and radiofrequency ablation

Abstract

In Japan, ∼30,000 patients died of hepatocellular carcinoma (HCC) in 2003. Ten percent had hepatitis B virus infection and 80% had hepatitis C virus (HCV) infection, indicating that viral hepatitis accounted for >90% of cases of HCC. In comparison, only 3% (1.5%, hepatitis B virus; 1.5%, HCV) of the general population is infected with these viruses. We treated 1238 patients between 1992 and the end of 2003 by means of percutaneous tumor ablation (PTA): 524 patients, by percutaneous ethanol injection therapy (PEIT); 85 patients, by percutaneous microwave coagulation therapy; and 629 patients, by radiofrequency ablation (RFA). Three-, 5-, 7-, and 10-year survival rates of the 1238 patients were 69%, 50%, 34%, and 19%, respectively. When limited to tumors ≤3 cm in diameter and ≤3 in number of cancer nodules (3-3 rule), 5-year survival rates reached 64.7% for PEIT. However, to achieve a 40% survival rate in year 5 after PEIT, the indication for treatment can be expanded to a 4 (size)-3 (number) rule or 5 (size)-1 (number) rule. The recent introduction of RFA may further change the rules. HCV-related HCC generally develops on the background of advanced fibrosis/cirrhosis. An issue of much concern is that it may subsequently recur in a location other than that of the primary lesion. We initiated a prospective controlled study to evaluate treatment with PTA and interferon. Results suggest that if the virus is eradicated, a 5-year survival rate as high as 80% can be expected. In Japan, ∼30,000 patients died of hepatocellular carcinoma (HCC) in 2003. Ten percent had hepatitis B virus infection and 80% had hepatitis C virus (HCV) infection, indicating that viral hepatitis accounted for >90% of cases of HCC. In comparison, only 3% (1.5%, hepatitis B virus; 1.5%, HCV) of the general population is infected with these viruses. We treated 1238 patients between 1992 and the end of 2003 by means of percutaneous tumor ablation (PTA): 524 patients, by percutaneous ethanol injection therapy (PEIT); 85 patients, by percutaneous microwave coagulation therapy; and 629 patients, by radiofrequency ablation (RFA). Three-, 5-, 7-, and 10-year survival rates of the 1238 patients were 69%, 50%, 34%, and 19%, respectively. When limited to tumors ≤3 cm in diameter and ≤3 in number of cancer nodules (3-3 rule), 5-year survival rates reached 64.7% for PEIT. However, to achieve a 40% survival rate in year 5 after PEIT, the indication for treatment can be expanded to a 4 (size)-3 (number) rule or 5 (size)-1 (number) rule. The recent introduction of RFA may further change the rules. HCV-related HCC generally develops on the background of advanced fibrosis/cirrhosis. An issue of much concern is that it may subsequently recur in a location other than that of the primary lesion. We initiated a prospective controlled study to evaluate treatment with PTA and interferon. Results suggest that if the virus is eradicated, a 5-year survival rate as high as 80% can be expected. The recent increase in incidence of hepatocellular carcinoma (HCC) in Japan has been remarkable, with 34,000 deaths occurring in 2003, almost 5 times as many as in 1970. There are several possible explanations for the increase. Our data, as well as those of others, indicate that the majority of the increment is caused by hepatitis C virus (HCV) infection. We have shown that seropositivity rates for HCV antibody and hepatitis B surface antigen in patients with HCC are 81% and 10%, respectively.1Omata M. Yoshida H. Prevention and treatment of hepatocellular carcinoma.Liver Transpl. 2004; 10: S111-S114Crossref PubMed Scopus (21) Google Scholar, 2Shiratori Y. Shiina S. Imamura M. Kato N. Kanai F. Okudaira T. Teratani T. Tohgo G. Toda N. Ohashi M. Ogura K. Niwa Y. Kawabe T. Omata M. Characteristic difference of hepatocellular carcinoma between hepatitis-B and -C viral infection in Japan.Hepatology. 1995; 22: 1027-1033Crossref PubMed Google Scholar Although previously, ∼30% of HCC cases were caused by hepatitis B virus, the contribution of this virus has declined, to be replaced by HCV, which continues to increase dramatically. Thus, it is crucial to understand the natural course of HCV infection to prevent the occurrence of HCC.3Takano S. Yokosuka O. Imazeki F. Tagawa M. Omata M. Incidence of hepatocellular carcinoma in chronic hepatitis B and C a prospective study of 251 patients.Hepatology. 1995; 21: 650-655Crossref PubMed Google Scholar With better understanding of the natural course of HCV infection, the optimal way to treat HCC at tertiary-care centers like our hospital will be well elucidated. It appears that HCC develops with a stepwise progression of hepatic fibrosis.1Omata M. Yoshida H. Prevention and treatment of hepatocellular carcinoma.Liver Transpl. 2004; 10: S111-S114Crossref PubMed Scopus (21) Google Scholar, 3Takano S. Yokosuka O. Imazeki F. Tagawa M. Omata M. Incidence of hepatocellular carcinoma in chronic hepatitis B and C a prospective study of 251 patients.Hepatology. 1995; 21: 650-655Crossref PubMed Google Scholar Thus, even if we find HCC nodules while small and surgically resect them successfully, remote or de novo recurrence of HCC is inevitable.4Koike Y. Shiratori Y. Sato S. Obi S. Teratani T. Imamura M. Hamamura K. Imai Y. Yoshida H. Shiina S. Omata M. Risk factors for recurring hepatocellular carcinoma differ according to infected hepatitis virus—an analysis of 236 consecutive patients with a single lesion.Hepatology. 2000; 32: 1216-1223Crossref PubMed Scopus (132) Google Scholar, 5Omata M. Yoshida H. Resolution of liver cirrhosis and prevention of hepatocellular carcinoma by interferon therapy against chronic hepatitis C.Scand J Gastroenterol. 2003; 237: S47-S51Crossref Scopus (25) Google Scholar At the Gastroenterology Department of the University of Tokyo, Japan, we have used treatment modalities less invasive than surgical resection for the last 12 years.6Shiina S. Tagawa K. Unuma T. Takanashi R. Yoshiura K. Komatsu Y. Hata Y. Niwa Y. Shiratori Y. Terano A. Percutaneous ethanol injection therapy for hepatocellular carcinoma. A histopathologic study.Cancer. 1991; 68: 1524-1530Crossref PubMed Scopus (302) Google Scholar, 7Shiina S. Imamura M. Omata M. Percutaneous ethanol injection therapy (PEIT) for malignant liver neoplasms.Semin Interv Radiol. 1997; 14: 295-303Google Scholar The number of treated cases has now reached 2780 among 1238 patients. In this report, we present our experience and discuss future tactics against HCC. This is a single-institute experience. We analyzed clinical features of consecutive patients treated by means of percutaneous tumor ablation (PTA) from 1992 to the end of 2003 at the Department of Gastroenterology, University of Tokyo. The diagnosis of HCC was made by means of imaging modalities, including ultrasound and computed tomography (CT), and confirmed by means of tumor-targeted biopsies. Patients were referred from all over the country, and some were from outside Japan (Figure 1). In this study, patients treated with transarterial embolization (TAE) alone or those sent to the Surgery Department for resection or transplantation without undergoing PTA at our department were not included. Those treated by means of surgical resection or TAE at other hospitals were included in the analysis if they subsequently were treated using PTA at our department. Several methods of PTA were used, including percutaneous ethanol injection therapy (PEIT), percutaneous microwave coagulation therapy (PMCT), and radiofrequency ablation (RFA). All treatments were performed on an in-patient basis. Details of the procedure were described previously.8Shiina S. Hata Y. Niwa Y. Komatsu Y. Tanaka T. Yoshiura K. Hamada E. Ohshima M. Mutoh H. Kurita M. Multiple-needle insertion method in percutaneous ethanol injection therapy for liver neoplasms.Gastroenterol Jpn. 1991; 26: 47-50PubMed Google Scholar In short, after local anesthesia, a 21 G needle (PEIT needle; Silux, Saitama, Japan) is inserted into the distal edge of the lesion. Before injecting ethanol, additional needles are inserted to the proximal edge and midposition of the cancer nodule. Ethanol is injected through the first needle, which is withdrawn before the second injection of ethanol. The amount of ethanol injected by a single shot is 0.5–1.0 mL; a total of 2–8 mL is injected in this multiple-insertion technique.8Shiina S. Hata Y. Niwa Y. Komatsu Y. Tanaka T. Yoshiura K. Hamada E. Ohshima M. Mutoh H. Kurita M. Multiple-needle insertion method in percutaneous ethanol injection therapy for liver neoplasms.Gastroenterol Jpn. 1991; 26: 47-50PubMed Google Scholar However, it varies depending on the size of cancer nodules, distribution pattern of the liquid, and patient compliance. After local anesthesia, a microwave electrode, 1.6 mm in diameter and 25 cm in length, connected to the microwave generator (Microtaze; Azwell, Osaka, Japan) with a soft coaxial cable inserted under ultrasound guidance. The generator emits a 2450-MHz microwave, and radiation for dielectric heating is performed at 65–85 W for 60 seconds. Because the necrotized volume produced by 1 ablation of PMCT is 2.5 × 1.5 cm, we designed an introducing needle (Daimon, Saitama, Japan), a stopper for the electrode (Daimon), and guide needles with scales (Daimon) so the electrode can be inserted systematically into each portion of the lesion. After local anesthesia, an 17 G cooled-tip electrode with a 2- or 3-cm exposed tip (Radionics, Burlington, MA) is attached to a radiofrequency generator (CC-1 Cosman Coagulator; Radionics) and inserted under ultrasound guidance.9Shiina S. Teratani T. Obi S. Hamamura K. Koike Y. Omata M. Nonsurgical treatment of hepatocellular carcinoma from percutaneous ethanol injection therapy and percutaneous microwave coagulation therapy to radiofrequency ablation.Oncology. 2002; 62: S64-S68Crossref PubMed Scopus (168) Google Scholar Temperature and tissue impedance are monitored during ablation. Cooled saline is infused to maintain the tip temperature at <20°C. Radiofrequency energy is delivered for 6–12 minutes for each application. For large lesions, the electrode is inserted into additional sites of the tumor nodule. Spiral CT is used to judge whether the tumor nodule has been completely ablated and necrotized after a few days of PTA. If ablation is suspected to be incomplete, treatment is repeated until sufficient areas surrounding the tumor nodule have been ablated. With the use of spiral CT after each ablation, complete necrosis of tumor nodules is achieved. After treatment, patients are followed up at the outpatient clinic of the University of Tokyo Hospital 3–4 times/y. At every visit, serum is obtained to test tumor markers (α-fetoprotein, des-carboxy abnormal prothrombin, and α-fetoprotein lectin-binding 3 fraction), and abdominal ultrasound is performed. If recurrence is suspected by the incremental increase in levels of tumor markers and/or abnormal ultrasound findings, the presence of recurrent tumor is confirmed immediately by means of spiral CT and CT-angiography. If the tumor recurs, PTA usually is repeated. However, if the tumor nodules exceed 5 in number or are diffuse, TAE is performed. In selected and advanced cases, an indwelling catheter is inserted, and continuous infusion of a chemotherapeutic agent is added. From 1992 to the end of 2003, a total of 1238 patients were treated. Because many patients were treated more than twice, 2780 treatments were given to 1238 patients (Table 1). Thus, on average, 1238 patients underwent PTA on 2.2 occasions (treatments).Table 1Percutaneous Tumor Ablation Performed at the Gastroenterology Department, University of Tokyo Hospital, on 1238 Patients from 1992 to 2003Treatment modalityNo. of patientsNo. of treatmentsPercutaneous ethanol injection therapy5241230Percutaneous microwave coagulation therapy85176Radiofrequency ablation6291374Total12382780 Open table in a new tab The first percutaneous procedure introduced to treat HCC was the ethanol injection method (Figure 2). After that, PMCT was used in Japan. This method used a large introducing needle (14 G). Then RFA became available as one of the percutaneous methods of treating HCC.10Rossi 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. 1995; 1: 73-81PubMed Google Scholar As shown in Figure 2, currently, the majority of our patients are treated by the RFA method. We analyzed survival rates of the 1238 patients treated by one of the PTA (PEIT, PMCT, and RFA) methods at our department. Patient demographic features are listed in Table 2. Overall survival of 1238 patients treated by means of PTA is shown in Figure 3A. Three-, 5-, 7-, and 10-year survival rates are 68.8%, 49.6%, 34.2%, and 18.7%, respectively.Table 2Demographic Features of the 1226 Patients Treated by Percutaneous Transluminal Ablation at the Department of Gastroenterology, University of TokyoPercutaneous ethanol injection therapy (N = 524)Percutaneous microwave coagulation therapy (N = 85)Radiofrequency ablation (N = 629)Age64.1 ± 8.763.6 ± 8.466.1 ± 8.2Male (%)373 (71.2)56 (65.9)424 (67.4)Hepatitis B surface antigen positive (%)56 (10.7)10 (11.8)73 (11.6)Hepatitis C virus antigen positive (%)443 (85)70 (82)494 (79)Hepatitis B surface antigen negative/Hepatitis C virus antibody negative (%)32 (6.1)7 (8.2)69 (11.0)Albumin (g/dL)3.5 ± 0.53.5 ± 0.43.6 ± 0.5Bilirubin (mg/dL)1.0 ± 0.61.0 ± 0.50.9 ± 0.5Child’s classA (%)299 (57.1)51 (60.0)440 (70.0)B (%)199 (38.0)34 (40.0)182 (28.9)C (%)26 (5.0)0 (0.0)7 (1.1)TumorSize (mm)29.7 ± 15.828.8 ± 17.527.9 ± 12.3No.2.3 ± 2.22.0 ± 1.32.1 ± 1.8 Open table in a new tab Many patients had been treated previously outside the University of Tokyo Hospital and were referred to us (referral patients; Figure 3), and their prognosis may differ from that of patients who underwent PTA at our department for the first time (naive patients; Figure 3B). When survival time is defined as the interval between the first ablation at our department and either or visit, 5-, 7-, and 10-year survival rates of the patients are and respectively. Three-, 5-, 7-, and 10-year survival rates of the patients are and respectively. The difference between the is Figure 3B). For the 3 we have sufficient for a large number of patients treated by means of (Figure we performed a survival analysis on patients treated by in to the size and number of HCC nodules and background liver Three-, 5-, 7-, and 10-year survival rates of all 524 patients treated by are and respectively. We performed survival on patients who underwent as treatment for HCC for the first time at our department and who were referred to us after treatment at other hospitals Figure was better in patients than patients (Figure There may have been factors in cases were included. Thus, the analysis on the of tumor size and number on survival was among patients treated by means of PEIT. It was that survival was better if the size of the HCC nodules was (Figure was difference in survival rates between the with tumor size in the of cm and the with a size of 3–4 cm (Figure was difference in survival among patients who had HCC nodules (Figure E. R. S. A. F. F. M. A. L. transplantation for the treatment of small hepatocellular in patients with J PubMed Scopus Google Scholar that survival of patients with HCC treated by transplantation was tumor nodules were cm in diameter and in number (3-3 or a single nodule was cm in diameter from our survival was in patients with HCC nodules cm and in Three-, 5-, and survival rates by were and among the patients who of the and and among the patients who were outside the (Figure The difference was Because we treated patients who had HCC nodules cm or in we analyzed the survival of these patients according to and (Table If we can a 5-year survival rate of we can the to a 4 (size)-3 (number) or 5 (size)-1 (number) rule (Table of Patients Treated by Percutaneous Ethanol on Tumor and of of nodule as percent of Open table in a new tab as percent of Because the prognosis of patients with HCC is by background liver we analyzed the survival of our patients treated by means of PEIT. survival rates were and according to of the of 2, and (Figure we have been treating the majority of patients with HCC by means of a number of cases have for analysis for This the to survival rates between and patients. It appears that the patients treated by RFA had the of a better survival (Table of of Patients Treated With Percutaneous Ethanol and Radiofrequency ethanol injection therapy (N = ablation (N = Open table in a new tab our this is the treatment for HCC by PTA as a experience. It appears that the increase in incidence of HCC in Japan and the of patients to our department as a have to that large number (Figure 1). The PTA procedure was performed by at 1 time without other these treatments can be performed with However, this has not been with The number of cases performed in 1992 was only reached in 2003. In during these 12 we the method of PTA from to RFA (Figure 2). In this study, we the survival of all 1238 patients treated by 1 of the 3 Three-, 5-, 7-, and 10-year survival rates are 68.8%, 49.6%, 34.2%, and 18.7%, (Figure There are other on the survival of patients with HCC treated by M. M. N. K. M. K. F. Y. Percutaneous ethanol injection for the treatment of small hepatocellular carcinoma. of PubMed Scopus Google Scholar, S. Tagawa K. Niwa Y. Unuma T. Komatsu Y. Yoshiura K. Hamada E. M. Shiratori Y. Terano A. Percutaneous ethanol injection therapy for hepatocellular carcinoma in J PubMed Scopus Google Scholar, R. F. N. M. Di M. S. M. S. M. of percutaneous ethanol injection therapy for hepatocellular carcinoma in cirrhosis a Radiol. 1997; PubMed Scopus Google Scholar, T. A. G. A. de L. M. F. S. G. carcinoma and cirrhosis in patients of percutaneous ethanol 1995; Google Scholar However, our patient are from those of in the was used on occasions for cm in This is ethanol is a that necrosis to the total amount of injected ethanol is limited to and it is to through all of the tumor nodules the size of the HCC is In this study, we were to survival according to the size of It appears that survival as tumor size is in survival between and cm (Figure the may be between and cm (Figure This the indication for PTA for size and number of tumor nodules have been by several that included small of patients. We may our for PTA from to cm, a method as RFA ablation of tumors with the indication for treatment on the background of liver we use the total 3 and time less than are not on survival after treatment, are to hepatic these even therapy be and can be performed as as surgical In this study, we analyzed the 5-year survival of patients with and C was much better in with A and B than those with C cirrhosis not Thus, we background liver as well as size and number of HCC nodules, as the factors that the of the We from to RFA in the last 12 (Figure 2). The number of cases treated by RFA now each year and is times the number treated by in In this study, we the survival of consecutive patients treated by RFA (Table and them with patients treated by PEIT. and survival rates were and for and respectively. suggest that the introduction of RFA may have further the prognosis of patients. However, these are study data, and we have to of In this study, we were to treatment modalities of PEIT, PMCT, and However, it is to PTA with other treatment modalities, surgical and controlled may these However, they may or of patients and many to Y. Y. Omata M. in controlled in for 2000; PubMed Scopus Google Scholar In our PTA to be as shown in this If we into a between surgical resection and and is a survival as in this study, the obtained from RFA and surgical resection or and resection a controlled study is However, we patients who the and treatment in use in clinical We are to all available to patients so they can the treatment that In that we a and that The of K. T. H. M. N. H. Y. K. of hepatocellular carcinoma and prognosis in to of PubMed Scopus Google Scholar has been This is on tumor and background liver With the of K. T. H. M. N. H. Y. K. of hepatocellular carcinoma and prognosis in to of PubMed Scopus Google Scholar as a several other have been of the new for hepatocellular a study of the of the PubMed Scopus Google Scholar, of hepatocellular carcinoma the PubMed Scopus Google Scholar, M. H. Y. for hepatocellular carcinoma and and a for a new the Japan Gastroenterol. 2003; PubMed Scopus Google Scholar As of a on the and of HCC for the of Gastroenterology in in we analyzed and M. Y. R. M. T. R. A. and survival of hepatocellular carcinoma among 2002; PubMed Scopus Google Scholar The of K. T. H. M. N. H. Y. K. of hepatocellular carcinoma and prognosis in to of PubMed Scopus Google Scholar was used and prognosis in areas in which the prognosis of patients with HCC is and survival is only However, in much are other for the are in the for tumor is more and with imaging with that of K. T. H. M. N. H. Y. K. of hepatocellular carcinoma and prognosis in to of PubMed Scopus Google Scholar, which was on In our study, and prognosis by were the clinical of this (Figure Thus, one can patients with on the of 5-year survival on the For if a patient has a and 5-year survival by of and by surgical resection of the patient PTA. If can be well using these survival be according to each treatment method each each or even each to be into this be and to or We now a Tokyo that only and serum levels and imaging on tumor number and R. Yoshida H. Shiina S. Imamura H. K. Teratani T. Obi S. Sato S. Koike Y. Hamamura K. M. T. M. T. T. Kawabe T. M. Omata M. of a new for hepatocellular 2003; PubMed Google Scholar This and may better and for patients to treatment are obtained in a large number of patients treated by modalities and in We used PTA to treat our patients, the majority of have tumors small to be Our recurrence tumor to the primary is now as as we we can tumor nodules by means of PTA. However, recurrence in the remote of the liver novo almost in 5 not we a means to prevent the recurrence that survival of patients treated by means of PTA. This is among those infected with we were to that the of HCV by interferon in patients who were treated by PTA in a 5-year survival rate of the rate in those who to to treatment was to the for ablation Y. Shiina S. Teratani T. Imamura M. Obi S. Sato S. Koike Y. Yoshida H. Omata M. therapy after tumor ablation prognosis in patients with hepatocellular carcinoma with hepatitis C 2003; PubMed Scopus Google Scholar indicate is for to treat tumor nodules, that alone is and better means of treatment of HCV is that may background and de novo The of treatment and PTA may to be and the as liver of which the of chronic hepatitis C and M. K. for viral hepatitis and prevention of hepatocellular carcinoma. Scholar