Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. A randomized trial of hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma. Alternatives to albumin administration in hepatocellular carcinoma patients undergoing hepatectomy: an open, randomized clinical trial of efficacy and safety. Multidisciplinary management of hepatocellular carcinoma. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study. Hepatocellular carcinoma: surgical resection versus surgical resection combined with pre- and post-operative locoregional immunotherapy-chemotherapy. A prospective randomized study.
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. 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. A randomized trial of hepatic arterial chemoembolization was conducted in 42 patients with unresectable hepatocellular carcinoma. These patients represented 41% of patients with hepatocellular carcinoma seen during the inclusion period. In the remaining 59%, 9% had resectable tumours and 50% had unresectable tumours with contraindication for chemoembolization. Patients received either repeated chemoembolization with gelfoam powder and doxorubicin (group 1) or symptomatic treatment (group 2). There was no difference in age, prevalence of cirrhosis or staging according to Okuda between the two groups of patients. A complete tumour response (assessed by arteriography, ultrasonography and serum alphafetoprotein) was observed in four patients, and a partial response in three other patients from group 1. Actuarial survival rates were 33 and 24% in group 1 and 52 and 31% in group 2 at 6 and 12 months, respectively (differences were not significant--logrank test). With the treatment used in our study, chemoembolization did not prolong the survival time of patients with unresectable hepatocellular carcinoma. There were, however, some complete or partial responses. The high spontaneous 1-year survival rate of untreated patients was probably due to the exclusion of the most severely ill patients. Our results do not support the use of this method of chemoembolization in the treatment of hepatocellular carcinoma. The value of artificial colloids in treating patients with liver disease is controversial. The effects of intravascular volume replacement regimens on liver function secondary to alteration of the postoperative inflammatory response are not known. In this study, we evaluated the effects of different volume replacement regimens in hepatocellular carcinoma patients undergoing hepatectomy to clarify whether albumin administration can be replaced by other volume replacement products.
                Ninety consecutive hepatocellular carcinoma patients scheduled for hepatectomy were prospectively randomized to receive 20% human albumin (HA), 6% hydroxyethyl starch (HES) or lactated Ringer's solution (LR) for postoperative volume replacement. Hemodynamic, liver function and inflammatory response parameters were recorded on postoperative days one, three, and five throughout the investigation period.
                Significantly less volume was required in the HA and the HES groups. Although patients in all groups had similar baseline values, the plasma osmolality was significantly higher in the HA and HES groups. Total bilirubin (TB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) increased from baseline in all groups, and did not differ significantly between groups. C-reactive protein (CRP) was significantly lower in the HES group compared with the other groups.
                In hepatocellular carcinoma patients undergoing hepatectomy, HA can be replaced by HES or LR in well selected patients. Hemodynamic stability, liver function, and postoperative clinical outcomes could be equivalently achieved in the HES group; also, HES may exert more favorable effects on the acute phase response. 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. 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. This randomized, controlled trial assessed the effect of transarterial embolization (TAE) (without associated chemotherapy) on the survival of patients with nonsurgical hepatocellular carcinoma (HCC). Eighty consecutive patients were randomized to treatment with embolization (Group A, n = 40), or to symptomatic treatment (Group B, n = 40), there being no differences between both groups regarding the degree of liver function impairment and tumor stage. Eighty-two percent of the patients presented a self-limited postembolization syndrome, without treatment-related mortality. Fifty-five percent of the treated cases exhibited a partial response, which resulted in a lower probability of tumor progression during follow-up (57% vs. 77% at 1 year; P < .005). However, after a median follow-up of 24 months (30 deaths in each group), there are no differences in survival (Group A: 49% and 13%; Group B: 50% and 27%, at 2 and 4 years, respectively; P = .72). The absence of differences was maintained even when dividing patients according to Child-Pugh's grade, Okuda stage, or performance status test (PST). Furthermore, there were no differences in the probability of complications or in the need of hospital admissions. In conclusion, TAE has a marked antitumoral effect associated to a slower growth of the tumor, but it does not improve the survival of patients with nonsurgical HCC. To compare disease recurrence and survival among patients with small hepatocellular carcinoma after surgical resection or percutaneous ethanol injection therapy, 2 treatments that have not been evaluated with a prospective study.
                A total of 76 patients were randomly assigned to 2 groups based on treatment; all had one or 2 tumors with diameter </=3 cm, with hepatitis without cirrhosis or Child class A or B cirrhosis without evident ascites or bleeding tendency.
                Follow-up ranged from 12 to 59 months. Among percutaneous injection patients, 18 had recurrence 1 to 37 months after treatment (true recurrence, 11; original safety margin inadequate, 3; limitation of imaging technology to detect tiny tumors, 4). Three injection therapy patients died of cancer 25, 37, and 57 months after treatment. For the surgical resection group, 15 had recurrence 2 to 54 months after treatment (true recurrence, 12; limitation of imaging, 2; neck metastasis, 1). Five resection patients died of cancer at 11, 20, 23, 26, and 52 months, respectively. By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for recurrence and survival between treatment groups. However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival.
                Percutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma. 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.
At present, there is no evidence to recommend or refute cryotherapy for patients with hepatocellular carcinoma. Randomised clinical trials with low-risk of bias may help in defining the role of cryotherapy in the treatment of hepatocellular carcinoma.