Sumito Igawa

Preoperative portal vein embolization for hepatocellular carcinoma

Advances in diagnostic imaging and new surgical techniques have improved the outcome for many patients with hepatocellular carcinoma (HCC). However, in Japan, more than 70% of patients with HCC have cirrhosis of the liver [1], and resection of the liver of such patients is often limited by the cirrhosis. Therefore, nonsurgical treatments such as transcatheter arterial embolization (TAE) or percutaneous ethanol injection therapy have been developed and are used widely as adjuvant therapy. TAE was first used to treat HCC patients by Goldstein et al. [2], who reasoned that most of the blood flow to the tumor is supplied by the hepatic artery. However, according to a study by the Liver Cancer Study Group of Japan [3], TAE is effective against the main tumor, but not against small intrahepatic metastases or tumor thrombi; it is particularly ineffective against tumor thrombi.

Effects of Long-Term Postoperative Interferon-α Therapy on Intrahepatic Recurrence after Resection of Hepatitis C Virus–Related Hepatocellular Carcinoma: A Randomized, Controlled Trial

Hepatitis C virus (HCV) is an important cause of hepatocellular carcinoma in many areas of the world (1). The recurrence rate at 5 years after resection of HCV-related hepatocellular carcinoma has been reported as 70% to 80% (2-4). Recurrences after resection of hepatocellular carcinoma may be either metastases from the primary carcinoma or new foci of carcinomas (multicentric occurrence) (4-8). Chronic active hepatitis is a risk factor for recurrence, including multicentric carcinogenesis, after resection (4, 7, 8). In addition, the recurrence rate after the resection of HCV-related hepatocellular carcinoma is higher in patients with HCV viremia than in those without viremia (4). Interferon treatment decreases the incidence of hepatocellular carcinoma in patients with chronic hepatitis C (9-16). We conducted a randomized, controlled trial to evaluate whether postoperative therapy with interferon- would decrease the incidence of recurrence after resection of HCV-related hepatocellular carcinoma. Methods Patients and Trial Profile Between November 1993 and March 1997, 112 HCV-positive patients underwent resection for hepatocellular carcinoma at Osaka City University Hospital or Osaka City General Hospital, Osaka, Japan. Seventy-seven patients met the eligibility criteria: 1) single tumors less than 5 cm in maximum diameter on preoperative imaging; 2) detectable HCV RNA without hepatitis B surface antigen or HIV antibodies; 3) chronic hepatitis C or a ChildPugh score of A or B for compensated cirrhosis [17]; and 4) no severe thrombocytopenia (platelet count < 50 109 cells/L). Before resection, 31 of the 77 eligible patients gave written informed consent to participate in the trial; however, one patient was later excluded because resection was not curative. Forty-six patients declined to participate because they were unwilling or unable to agree to twice-weekly hospital visits for 2 years or were concerned about widely publicized side effects of interferon use. A curative operation was defined as complete resection of all macroscopically evident tumor tissue. Specifically, no tumors could be detected in the remnant liver on computed tomography performed 3 to 4 weeks after resection. In the one patient excluded from the trial after resection, a residual tumor was found on computed tomography 3 weeks after resection. In all, 30 patients were enrolled and randomly allocated to the interferon- group (n = 15) or a control group (n = 15). Randomization was done by using a random-numbers table, and patient assignments were withheld from the investigators. During the trial, no patient in the control group received any type of treatment; no patient in the interferon group received chemotherapy or any treatment other than interferon-. This study was done in accordance with the Helsinki Declaration and was approved by the ethics committees of our institutions. Interferon- Treatment Patients received 6 MIU of interferon- (human lymphoblastoid interferon, Sumiferon, Sumitomo Pharmaceuticals, Osaka, Japan) intramuscularly every day for 2 weeks, then 3 times weekly for 14 weeks, and finally twice weekly for 88 weeks (total dose, 1572 MIU). Interferon- therapy was started 5 to 15 weeks (mean, 9 weeks) after resection. In 1 of the 15 patients in the interferon- group, treatment was delayed until 7 months after resection at the patients request. Laboratory tests were done at least once monthly during interferon- therapy and at least once every 3 months thereafter for evaluation of the response to therapy and identification of side effects of interferon-. Serum HCV RNA was detected by using a method reported previously (9), and viral load was measured by using a branched-DNA probe assay (Quantiplex HCV-RNA, Chiron Corp., Emeryville, California). Response to Interferon- Therapy A complete response was defined as the absence of serum HCV RNA (virologic remission) and serum alanine aminotransferase (ALT) activity within the reference range ( 750 nkat/L [ 45 U/L]) for at least 6 months after interferon- therapy (biochemical remission) (9). A biochemical response was defined as a decrease in serum ALT activity to within the reference range but with persistently detectable serum HCV RNA. Nonresponse was defined as persistence of HCV RNA and no decrease in ALT activity. Detection of Recurrence Serum concentrations of -fetoprotein and protein induced by vitamin K absence and antagonist II were measured within 2 months of resection and every 3 months thereafter. Ultrasonography, computed tomography, magnetic resonance imaging, or some combination of these tests was done within 2 months after the operation and every 3 months thereafter. These examinations were done until the detection of recurrence or until the trial end point (final examination). When tumor recurrence was suspected on the basis of tumor markers, imaging, or both, angiography, ultrasonography-guided biopsy, or both were done to establish a definitive diagnosis. The radiologists who were responsible for diagnosis of tumor recurrences had no contact with the patients and had no information about the trial. Statistical Analysis Time to recurrence was measured from the time of resection to the detection of a recurrent tumor. The recurrence rates (including data on patients who could not complete interferon- therapy) were calculated by using the KaplanMeier method, and significance of between-group differences was assessed by using the log-rank test. All analyses were done by using SAS statistical software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source The funding sources had no role in the collection, analysis, and interpretation of the data or in the decision to submit the paper for publication. Results Most baseline variables were similar in the two groups, as were the operative procedures (Table). The patients who declined participation and the patients who were enrolled were similar with regard to most variables. Table. Patient Demographic and Clinical Characteristics Interferon- could not be administered to one patient because of premature ventricular contractions. Data on this patient were included in the interferon- group for all analyses. Interferon- administration could not be completed in 3 patients because of depression (n = 1, at 17 days), severe general fatigue (n = 1, at 11 months), and renal abscess (n = 1, at 10 months; this patient also had a recurrence detected in the same month). In 4 patients with recurrence, interferon- administration was stopped prematurely to allow treatment of the tumor. In the interferon- group, 2 patients were complete responders, 6 patients were biochemical responders only, and 7 patients were nonresponders. Among the control patients, postoperative serum ALT activity (except immediately after resection) was greater than the reference range, and serum HCV RNA was detected at the follow-up appointments. The median follow-up period (from the operation to the detection of recurrence or to the study end point) was 1087 days (25th and 75th percentiles, 514 and 1376 days) for patients receiving interferon- and 897 days (25th and 75th percentiles, 439 and 1105 days) for the controls. In all patients, examinations for detection of recurrence were done according to schedule. All patients without recurrence were still alive at the end of this trial. Recurrent tumors were detected in 5 patients (including the patient who could not tolerate interferon- therapy) in the interferon- group and in 12 control patients. In the interferon- group, recurrence was definitively diagnosed in 3 patients by using angiography and in 2 patients by using angiography and biopsy. In the control group, definitive diagnoses were made in 8 patients by using angiography, in 3 patients by using biopsy, and in 1 patient by using both methods. No recurrence was detected in either of the 2 complete responders in the interferon- group. One of the 6 biochemical responders and 4 of the 7 nonresponders had recurrent tumors. The recurrence rates increased along similar curves in the two groups in the 2 years after resection; thereafter, 6 controls but no patient receiving interferon- had recurrence (Figure). The recurrence rate was significantly lower in the interferon- group than in the control group (P=0.037). Figure. Recurrence rates in the interferon- ( solid line ) and control ( dotted line ) groups. P Discussion Persistent active hepatitis is a risk factor for development of hepatocellular carcinoma, indicating that treatment of active hepatitis may be important in the management of patients with HCV-related hepatocellular carcinoma (4). In our study, absence of interferon- therapy was a risk factor for recurrence. Although for the first 2 years of follow-up the recurrence rate increased for the two groups in similar curves, the recurrence rate in the interferon- group did not increase after that time. This finding suggests that patients in the interferon- group had been truly cured. Recurrent tumors detected within 2 years of the operation were likely to be either metastases from the primary carcinoma or carcinoma that appeared before or during interferon- therapy but had gone undetected at the operation. Our findings indicate that interferon- therapy does not suppress carcinoma itself. On the other hand, recurrences that appear more than 2 years after resection are likely to have arisen because of new carcinogenesis. Recurrence was detected in 1 of 8 patients with a biochemical remission (including the 2 complete responders) and in 4 of the 7 nonresponders. Recently, several investigators have shown that hepatocellular carcinoma is less likely to develop in patients in whom interferon- decreases ALT activity to within the reference range, even if HCV is not eradicated, probably because of decreased hepatocyte necrosis and liver fibrosis (9, 11, 12, 14-16). Thus, eradication of HCV may not be necessary for reduced risk for recurrenc