International Atomic Energy Agency-sponsored multination study of intra-arterial rhenium-188-labeled lipiodol in the treatment of inoperable hepatocellular carcinoma: results with special emphasis on prognostic value of dosimetric study.

A multicenter study was sponsored by the International Atomic Energy Agency (IAEA) to assess the safety and efficacy of transarterial rhenium-188 ((188)Re) HDD lipiodol (radioconjugate to lipiodol using an HDD kit) in the treatment of unresectable hepatocellular carcinoma. During 5 years, 185 patients received at least 1 treatment of radioconjugate, and 51 were retreated. The level of radioconjugate administered was based on radiation-absorbed dose to critical normal organs, calculated after a "scout" dose of radioconjugate. The total injected activity, including the scout dose during the first treatment, ranged from 21 to 364 mCi (mean, 108 mCi/4 GBq). Immediate and late side-effects were minimal. Tumor size could be evaluated in 88 patients. Among these patients, the objective response rate was 25%; stable disease was observed in 53% and tumor progression in 22%. With a median follow-up of 455 days, the estimated 12- and 24-month overall survival was 46% and 23%. This multicenter study shows that (188)Re lipiodol is a safe and cost-effective method to treat primary hepatocellular carcinoma via the transarterial route and requires further evaluation by treatment of greater numbers of patients.

Intra-arterial rhenium-188 lipiodol in the treatment of inoperable hepatocellular carcinoma: results of an IAEA-sponsored multination study.

PURPOSE: Intra-arterial injections (IAI) of 131I-lipiodol is effective in treating hepatocellular carcinoma patients, but is expensive and requires a 7-day hospitalization in a radioprotection room. 188Re is inexpensive, requires no patient isolation, and can be used with lipiodol. METHODS AND MATERIALS: This International Atomic Energy Agency-sponsored phase II trial aimed to assess the safety and the efficacy of a radioconjugate 188Re + lipiodol (188Re-Lip) in a large cohort of hepatocellular carcinoma patients from developing countries. A scout dose is used to determine the maximal tolerated dose (lungs <12 Gy, normal liver <30 Gy, bone marrow <1.5 Gy) and then the delivery of the calculated activity. Efficacy was assessed using response evaluation criteria in solid tumor (RECIST) and alpha-feto-protein (alpha FP) levels and severe adverse events were graded using the Common Toxicity Criteria of the National Cancer Institute scale v2.0. RESULTS: The trial included 185 patients from eight countries. The procedure was feasible in all participating centers. One treatment was given to 134 patients; 42, 8, and 1 received two, three, and four injections, respectively. The injected activity during the first treatment was 100 mCi. Tolerance was excellent. We observed three complete responses and 19 partial responses (22% of evaluable patients, 95% confidence interval 16-35%); 1- and 2-year survivals were 46% and 23%. Some factors affected survival: country of origin, existence of a cirrhosis, Cancer of the Liver Italian Program score, tumor dose, absence of progression, and posttreatment decrease in alpha FP level. CONCLUSIONS: IAI of 188Re-Lip in developing countries is feasible, safe, cost-effective, and deserves a phase III trial.

Preliminary results of transarterial rhenium-188 HDD lipiodol in the treatment of inoperable primary hepatocellular carcinoma.

A multicentre study was sponsored by the International Atomic Energy Agency (Vienna) to assess the safety and efficacy of trans-arterial rhenium-188 HDD conjugated lipiodol (radioconjugate) in the treatment of patients with inoperable hepatocellular carcinoma (HCC). The radioconjugate was prepared by using an HDD (4-hexadecyl 1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol) kit developed in Korea, and lipiodol. Over a period of 18 months, 70 patients received at least one treatment of radioconjugate. Some patients were re-treated if there was no evidence of disease progression. The level of radioconjugate administered was based on radiation-absorbed dose to critical normal organs, calculated following a "scout" dose of radioconjugate. The organs at greatest risk for radiation toxicity are the normal liver, the lung and the bone marrow. An Excel spreadsheet was used to determine maximum tolerated activity (MTA), defined as the amount of radioactivity calculated to deliver no more than 12 Gy to lungs, or 30 Gy to liver, or 1.5 Gy to bone marrow. These doses have been found to be safe in multiple trials using external beam therapy, but this has not been confirmed for systemically administered radiopharmaceuticals. Patients were followed for at least 12 weeks after therapy, until recovery from all toxicity. The clinical parameters evaluated included toxicity, response as determined by contrast-enhanced computed tomography, palliation of symptoms, overall survival, performance status (Karnofsky) and hepatic function (Child's classification). Liver function tests, serum alpha-fetoprotein (AFP) levels and complete blood counts were done at each follow-up visit. In the majority of patients, the scout dose studies indicated the radiation absorbed dose to normal liver to be the limiting factor to the treatment dose, while in a few patients dose to lung was the limiting factor. Radiation dose to bone marrow was negligible and was thus not a factor for the MTA calculations. Side-effects were minimal and usually presented as loss of appetite, right hypochondrial discomfort and low-grade fever, even at high levels of administered radioactivity. The symptoms resolved with simple supportive therapy within 3 days of onset. Liver function tests at 24 and 72 h showed no significant changes and complete blood counts at 1 week, 4 weeks and 12 weeks showed no changes (no bone marrow suppression). Sixteen patients were treated in the dose escalation phase of the study, when the activities administered started at 1.8 GBq (50 mCi) and rose to 7.7 GBq (206 mCi). In the efficacy phase of the study a further 54 patients were treated. Both groups of patients are included in this paper. The treatment activity of 188Re-lipiodol administered transarterially ranged from 1.8 to 9.8 GBq (50-265 mCi), with a mean activity of 4.6 GBq (124 mCi). Survival at 3 months was 90%, and at 6 months, 60%; 19% survived for 1 year. Mean survival after treatment in the total treated group of 70 patients was 9.5 months, with a range of 1-18 months. The results of this multicentre study show that 188Re-lipiodol is a safe and cost-effective method to treat primary HCC via the transarterial route. In terms of efficacy, it is potentially a new therapeutic approach for further evaluation by treatment of larger numbers of patients.