Preoperative transcatheter arterial chemoembolization for resectable large hepatocellular carcinoma: a reappraisal. Adjuvant chemotherapy with epirubicin and carmofur after radical resection of hepatocellular carcinoma: a prospective randomized study. A prospective randomized trial of the preventive effect of pre-operative transcatheter arterial embolization against recurrence of hepatocellular carcinoma. Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma. Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. Effect of long-term postoperative interferon therapy on intrahepatic recurrence and survival rate after resection of hepatitis C virus-related hepatocellular carcinoma. Multidisciplinary management of hepatocellular carcinoma. Hepatocellular carcinoma: surgical resection versus surgical resection combined with pre- and post-operative locoregional immunotherapy-chemotherapy. A prospective randomized study.
Transcatheter arterial chemoembolization (TACE) improves the treatment of hepatocellular carcinoma (HCC) by causing tumour necrosis and shrinkage. Fifty-two patients with resectable large HCC (defined as a maximal tumour diameter of 10 cm or more) were prospectively randomized into two groups: group 1 comprised 24 patients who had 1-5 sessions of TACE before operation; group 2 consisted of the other 28 patients, on whom surgery was performed without delay. Tumour volume was reduced to a mean (s.d.) of 42.8 (15.3) per cent in 16 patients in group 1, but remained unchanged in four and increased in size in a further four. Patients in group 1 had a slightly longer operating time (5.5 versus 4.6 h, P = 0.09), a higher rate of concomitant resection of adjacent organs (58 versus 25 per cent, P = 0.03) and a higher rate of histological invasion to these organs (33 versus 4 per cent, P = 0.01). No difference was found between the two groups in operative blood loss, operative morbidity and mortality rates, and pathological staging. The disease-free survival rate in the two groups was similar, but the incidence of extrahepatic cancer recurrence was higher in group 1 (57 versus 23 per cent, P = 0.03). The actuarial survival rate was also significantly worse in group 1 when determined from the time of detection of the tumour (P = 0.03) or from operation (P = 0.01). It is concluded that preoperative TACE for resectable large HCC should be avoided because it does not provide complete necrosis in large tumours and results in delayed surgery and difficulty in the treatment of recurrent lesions, without any benefit. The intrahepatic recurrence rate is extremely high, even after radical resection of hepatocellular carcinoma (HCC). One report showed intra-arterial administration of epirubicin to be effective in the treatment of nonresectable HCC. We evaluated the effect of postoperative adjuvant chemotherapy including this drug. Fifty-seven patients who had undergone radical resection of HCC were entered in this study. Using the sealed-envelope method, 27 patients were assigned to a group undergoing resection only and 29 patients to a group also receiving adjuvant chemotherapy after resection. The protocol of the chemotherapy was intra-arterial administration of epirubicin (40 mg/m2) at 1 month after resection followed by intravenous administration of epirubicin (40 mg/m2) every 3 months for 2 years. In addition, 1-hexylcarbamoyl-5-fluorouracil (HCFU; carmofur), 300 mg/d, was administered orally every day, beginning from 1 month after the resection and continuing (in principle) for 24 months. The clinicopathologic backgrounds were well randomized between the two groups. The chemotherapy protocol was performed completely in only five patients (7.2%). Twenty-four (82.8%) patients had to cease the protocol due to various reasons: change to a new therapy after recurrence of HCC in 19 cases (79.2%), severe side effects of the chemotherapy in three cases (12.5%), liver failure in one case (4.2%), and a postoperative complication in one case (4.2%). The mean total doses were 128 +/- 114 mg for epirubicin and 144 +/- 84 g for HCFU. The cumulative overall and disease-free survival rates for 5 years were not significantly different between the two groups. The results of this prospective randomized study suggest that this adjuvant chemotherapy protocol with epirubicin and HCFU after radical resection of HCC was not effective. To clarify whether pre-operative transcatheter arterial embolization (TAE) improves survival after hepatectomy, a prospective randomized comparative study was done. Of a total of 115 registered patients having solitary hepatocellular carcinoma (HCC) 2 to 5 cm in diameter, 18 (15.7%) were excluded after randomization. As a result, 97 patients were chosen as subjects and divided into two groups: hepatectomy with (group A: n=50) and without (group B: n=47) pre-operative TAE. The period of observation of the patients who survived the surgery was between 4.0 and 6.6 years. The randomization appeared to have provided well-balanced groups of patients and the clinico-pathological characteristics of the two groups were quite similar. The necrotic part of the cancerous lesions, as confirmed by operative specimens, amounted to 74.8+/-33.4% (mean +/-SD) in group A and 6.8+/-7.2% in group B (P<0.01). However, the cancer-free survival rates after hepatectomy in both groups showed little difference (39.1+/-7.0 (%+/-SE) and 31.1+/-0.1, respectively). We speculate that TAE is not effective against such HCC accessory lesions as minute intrahepatic metastasis and tumor thrombus and that pre-operative TAE does not improve post-operative survival. Adjuvant oral chemotherapy was studied in 67 patients with stage II hepatocellular carcinoma who underwent curative resection between May 1988 and December 1990. Patients were stratified into two groups according to preoperative liver dysfunction: 55 had stage I disease (mild dysfunction) and 12 had stage II (moderate dysfunction). A randomized controlled study of postoperative oral administration of 1-hexylcarbamoyl-5-fluorouracil (HCFU) was conducted in each group. From October 1994 HCFU administration was suspended because of side-effects in nine patients with stage I liver dysfunction and in three with stage II dysfunction who had received the drug for more than 4 weeks. Cumulative survival and recurrence-free survival rates of patients with stage I disease in the treatment group were higher (P = 0.08 and P = 0.04 respectively) than those in the control group. However, in patients with stage II disease no significant difference was observed (P = 0.77 and P = 1.0 respectively). This study suggests that the potential benefits of HCFU on tumour recurrence should be weighed against the risk of adverse reactions in patients with mild liver dysfunction. Vascular invasion and intrahepatic metastasis by hepatocellular carcinoma are important factors predisposing to tumor recurrence. Recurrences of this malignancy occur frequently in residual liver, and its prevention is one of the most important factors in obtaining better surgical survival. Fifty patients who underwent hepatectomy for invasive hepatocellular carcinoma with vascular invasion and/or intrahepatic metastases were studied to evaluate the effect of adjuvant bolus hepatic arterial infusion of iodized poppyseed oil (Lipiodol) containing anticancer drugs in preventing recurrence and in prolonging survival. Patients were assigned to two treatment groups. Twenty-three of the fifty patients received adjuvant bolus infusion of Lipiodol containing doxorubicin and mitomycin C, whereas 27 patients received no therapy. The disease-free survival rate for the patients who received adjuvant therapy was significantly better (p < 0.05) than that for those who did not when measured at 172, 516, 688 and 860 days after hepatectomy, and the disease-free survival curve for patients with adjuvant therapy was significantly (p = 0.0237) better than that without adjuvant therapy. The cumulative survival rates and curves were not significantly different between the two groups. While adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs was effective in improving disease-free survival, the effect was not satisfactory. Further trials of adjuvant chemotherapy are required to improve the surgical survival of hepatocellular carcinoma patients. Postsurgical recurrence of hepatocellular carcinoma (HCC) is frequent and fatal. Adoptive immunotherapy is active against HCC. We assessed whether postoperative immunotherapy could lower the frequency of recurrence.
                Between 1992 and 1995, we did a randomised trial in which 150 patients who had undergone curative resection for HCC were assigned adoptive immunotherapy (n=76) or no adjuvant treatment (n=74). Autologous lymphocytes activated vitro with recombinant interleukin-2 and antibody to CD3 were infused five times during the first 6 months. Primary endpoints were time to first recurrence and recurrence-free survival and analyses were by intention to treat.
                76 patients received 370 (97%) of 380 scheduled lymphocyte infusions (mean cell number per patient 7.1x10(10) [SD 2.1]; CD3 and HLA-DR cells 78% [16]), and none had grade 3 or 4 adverse events. After a median follow-up of 4.4 years (range 0.2-6.7), adoptive immunotherapy decreased the frequency of recurrence by 18% compared with controls (45 [59%] vs 57 [77%]) [corrected] patients. Time to first recurrence in the immunotherapy group was significantly longer than that in the control group (48% [37-59] vs 33% [22-43] at 3 years, 38% [22-54] vs 22% [11-34] at 5 years; p=0.008). The immunotherapy group had significantly longer recurrence-free survival (p=0.01) and disease-specific survival (p=0.04) than the control group. Overall survival did not differ significantly between groups (p=0.09).
                Adoptive immunotherapy is a safe, feasible treatment that can lower recurrence and improve recurrence-free outcomes after surgery for HCC. To study the effect of adjuvant chemotherapy after curative hepatic resection in patients with hepatocellular carcinoma.
                A randomized controlled trial.
                A tertiary referral center.
                During a 54-month period, 142 patients with hepatocellular carcinoma underwent hepatic resection at 1 institution. Sixty-six patients who survived the operation and had no demonstrable evidence of residual disease on ultrasonographic examination and hepatic angiographic testing at 1 month after surgery agreed to participate in the study. The median follow-up time was 28.3 months.
                Thirty patients received a combination of intravenous epirubicin hydrochloride (8 doses of 40 mg/m2 each at 6-week intervals) and transarterial chemotherapy using an emulsion of iodized oil and cisplatin (3 courses with a maximum dose of 20 mL each at 2-month intervals). Thirty-six patients had no adjuvant treatment.
                Recurrence rate and disease-free survival.
                A total of 138 courses of intravenous epirubicin was given to the 30 patients. Sixty-one courses of transarterial chemotherapy were given to only 29 of the 30 patients assigned to the treatment group, because the hepatic artery in 1 patient was thrombosed. Six patients (20%) had chemotherapy-related complications with no mortality. Twenty-three of 30 patients in the treatment group and 17 of 36 patients in the control group had recurrences (P=.01). Patients who received adjuvant chemotherapy had a higher incidence of extrahepatic metastases (11 patients vs 5 patients; P=.03). The respective disease-free survival rates at 1, 2, and 3 years were 50%,36%, and 18% for the treatment group and 69%, 53%, and 48% for the control group (P=.04).
                In a group of patients who underwent curative resection of hepatocellular carcinoma, postoperative adjuvant chemotherapy using the present regimen was associated with more frequent extrahepatic recurrences and a worse outcome. This study was aimed at evaluating the effects of interferon (IFN)-alpha on survival rate after resection of hepatocellular carcinoma.
                In a randomized, controlled trial by the University Hospital, Medical Center and affiliated hospital in Osaka, Japan, 30 men were after surgery randomly allocated to an IFN-alpha group (15 patients) and to a control group. Patients in the IFN group received 6 MIU of IFN-alpha intramuscularly daily for 2 weeks, then three times a week for 14 weeks, and finally twice a week for 88 weeks. The incidence of recurrence and survival rate were then studied.
                The response to IFN was sustained viral response (SVR) in 2 patients, biochemical response (BR) in 6, partial response (PR) in 5, and no response (NR) in 2. In the control, 8 of the 15 patients demonstrated continuous abnormally high levels of ALT. At the end point of the study, intrahepatic recurrence was detected in 9 of the IFN group and in 13 of the control (p = 0.065, log-rank test). The cumulative survival rate was higher in the IFN group than in the controls (p = 0.041).
                Postoperative IFN therapy improves the outcome after resection of hepatitis C virus-related hepatocellular carcinoma. Hepatocellular carcinoma (HCC) remains a disease with a poor prognosis. Several different therapies have been recommended for use as adjuvant treatment for this disease. One of the most promising therapies is targeted locoregional immuno-chemotherapy.
                From 1990 to 1996, 91 patients who were eligible for liver resection were treated in a prospective randomized study. Forty-two patients received resection alone (Group A) and 49 received resection plus chemoembolization and targeted locoregional immuno-chemotherapy (Group B).
                The mortality rate for these two groups was significantly different (13% vs 4%) favoring Group B. Overall survival was also significantly different (18 months vs 36.3 months) again favoring Group B.
                Although prognosis is still miserable for HCC, the approach of targeted locoregional immuno-chemotherapy can offer new hope of improved resectability and survival. Hepatocellular carcinoma remains a disease with poor prognosis. Liver resection, although the optimal method of management, is associated with a high incidence of intrahepatic tumour recurrence ranging between 50-70%, 12 to 18 months following surgery. This study assesses prospectively the results of liver resection as compared to liver resection combined with pre- and post-operative locoregional chemotherapy-immunotherapy in 40 patients suffering from hepatocellular carcinoma. Patients were randomly assigned to two groups. Group A (20 patients) had liver resection only, while Group B (20 patients) had liver resection combined with pre- and past-operative targeting locoregional chemotherapy-immunotherapy. Five (5) patients died in total: two from Group A and two from Group B, during the first 30 days following surgery due to reasons related to the procedure (post-operative liver failure in three, pulmonary embolism in one). The remaining patient from Group A died 10 months following liver resection due to intrahepatic tumour recurrence. From Group A, 17 patients are alive from 3 to 26 months after surgery. Of the 17 alive patients, 10 are free of disease and 7 show intrahepatic recurrence. Thus, tumour intrahepatic recurrence occurred in 8 patients of group A. From Group B, all 18 patients are alive and free of disease from 4 to 27 months after surgery. No patient died because of the disease nor has any patient shown intrahepatic tumour recurrence. As a conclusion of the present results, liver resection combined with pre- and post-operative targeting locoregional immunotherapy-chemotherapy appears to offer substantial advantages for patients undergoing surgery because of hepatocellular carcinoma.
There is no clear evidence for efficacy of any of the adjuvant and neo-adjuvant protocols reviewed, but there is some evidence to suggest that adjuvant therapy may be beneficial offering prolonged disease-free survival. In order to detect a realistic treatment advantage, larger trials with lower risk of systematic error will have to be conducted.