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Hepatocellular carcinoma (HCC) is a major health concern worldwide. Several therapeutic options are available, but transplantation is the only curative option; for the vast majority of patients, the remaining alternative is palliative care. There is some hope however with Lipiodol which, when injected into the hepatic artery remains concentrated in the liver and specifically within the malignant tumor for a long period of time. This feature has been used for internal radiation therapy using (131)Iodine-labeled Lipiodol. Phase III studies with (131)I-Lipiodol have demonstrated, in an adjuvant setting improved recurrence-free and overall survival compared with surgery alone and in a palliative setting improved survival among patients with portal thrombosis. Comparison with chemoembolization has shown similar results in terms of efficacy but with better tolerance for (131)I-lipiodol. The method would also be useful for small nodules not amendable to surgery or percutaneous treatment. The use of another radionuclide, (188)Re, could probably improve the current method by reducing the need for radioprotection. New perspectives will be forthcoming with the advent of targeted drugs using combinations in sequential or concomitant regimens.

Objective: Vectorized internal radiation therapy using lipiodol-labelled with iodine-131 (131 I-lipiodol) is an effective treatment for inoperable hepatocellular carcinomas. However, few dosimetric data are available based on this approach. We have developed a dosimetric protocol based on scintiscan imaging and that is designed to calculate the tumoural absorbed dose during the treatment of hepatocarcinoma by 131 I-lipiodol., Methods: This concept was developed on a gamma-camera coupled to a computed tomography scanner. It integrates corrections for attenuation phenomena, scattering and dead time. The tumoural absorbed dose calculation was carried out according to the Medical Internal Radiation Dose Committee formalism. This protocol was applied to a series of 41 patients in the framework of a retrospective study., Results: The mean tumoural absorbed dose with the first treatment is 248 Gy (+/-176), as opposed to 152 Gy (+/-122) during the second. We highlighted a correlation between the tumoural absorbed dose, calculated in tomographic mode, and the morphological response to the first treatment (P=0.0071). Moreover, a tumoural absorbed dose of 280 Gy seems to be an effective absorbed dose threshold in our population. Above this absorbed dose, 84% of the patients are responders after the first treatment, whereas no responses are recorded below this threshold., Conclusion: These results are promising because, for the first time, they allow us to predict the effectiveness of a treatment by 131 I-lipiodol. They are required to be validated on a broader exploratory trial, including a dosimetric study of the critical organs, so an individualized dosimetry can be defined for each patient.

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.

Unlabelled: Recurrences after resection of hepatocellular carcinoma are frequent. A single postoperative injection of (131)I-labeled lipiodol in the hepatic artery was shown in 1999 by Lau and colleagues to be an effective adjuvant treatment, and those results were strengthened by our experience with a case-control study, reported in 2003. The goal of this paper is to update the 2003 results for a minimal follow-up of 5 y., Methods: Between January 1999 and September 2001, 38 patients were given an adjuvant postoperative intraarterial injection of (131)I-lipiodol and were matched (for Okuda group and tumor size) with 38 patients who had undergone resection between January 1997 and January 1999 without postoperative treatment. The 2 groups were similar., Results: There were 28 recurrences in the control group and 22 in the (131)I-lipiodol group (not statistically significant), and the mean time of recurrence was 21 and 26.5 mo, respectively, after surgery (statistically significant). The number of recurrences was lower in the first 2 y in the (131)I-lipiodol group (statistically significant). Disease-free survival was better (P < 0.03) in the (131)I-lipiodol group than in the control group (2-, 3-, and 5-y rates [+/-95% confidence interval] of 77% +/- 7%, 63% +/- 8%, and 42% +/- 8.5%, respectively, for the (131)I-lipiodol group vs. 47% +/- 8%, 34% +/- 8%, and 27% +/- 8%, respectively, for the control group). Overall survival did not differ between the 2 groups (P = 0.09), even though there was a trend toward better survival in the (131)I-lipiodol group (2-, 3-, and 5-y rates of 76% +/- 7%, 68% +/- 7.5%, and 51% +/- 9%, respectively, vs. 68% +/- 7.5%, 53% +/- 8%, and 39% +/- 8%, respectively, in the control group)., Conclusion: With a longer follow-up, the results of this retrospective case-control study still favor a single postoperative injection of (131)I-lipiodol. These retrospective findings point out the need for a large-scale, prospective, randomized 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.

Background/aim: The therapeutic effect of intra-arterial injection of 131-iodine-labeled lipiodol for treatment of hepatocellular carcinoma in palliative or adjuvant settings has been promising. We report, the results of an open study of this therapy in cirrhotic patients with small hepatocellular carcinoma., Patients and Method: Forty patients with hepatocellular carcinoma were given intra-arterial injections of 131-iodine-labeled lipiodol. These injections were repeated if necessary every 3 months. Tumor response (WHO criteria) was determined on CT scans performed after each treatment and every 3 months during the follow-up. Side effects and the cause of death were recorded. Therapeutic response and survival were analyzed., Results: The median number of treatment was 2 (1-4). There was one complete response, 18 partial responses (47.5% response rate); 19 had stable disease and 2 progressions. Overall survival rates (+/-CI 95%) at 1, 2 and 3 years were: 90+/-4.7%, 60.3+/-8%, and 39+/-8.3%, respectively. Median survival was 27 months; 25 patients have died (4-56 months), 8 of tumor progression with a multifocal spread in the liver. Tolerance was good except for 2 patients who develop a fatal drug-related pulmonary insufficiency., Conclusion: These data suggest that intra-arterial therapeutic injection of 131-iodine-labeled lipiodol for treatment of hepatocellular carcinoma can provide high rate response and long survival for individuals not eligible for surgery or local treatment.

Purpose: Intra-arterial injections of 131I-lipiodol (131I-Lip) provide an effective treatment for hepatocellular carcinoma. In hepatocellular carcinoma cell cultures, concurrent administration of cisplatin increases the cytotoxicity of 131I. The efficacy and tolerance of intra-arterial injections of 131I-Lip combined with systemic cisplatin was tested in a phase II trial., Methods and Materials: The inclusion criteria were proven unresectable nonmetastatic hepatocellular carcinoma, compensated liver disease, and adequate laboratory test findings. Treatment comprised the combination of intra-arterial injection of 131I-Lip (2.2 GBq) with intravenous infusion of low-dose cisplatin. The combined treatment could be repeated., Results: A total of 41 patients were included; 37 had cirrhosis and 38 had measurable tumors. One to four treatments (median, two) were given. The cisplatin dose was 75 mg for the first course and 72 mg for the second. Grade 3-4 (n/n) adverse effects were observed in 14 patients, polymorphonuclear leukocytes (3/0), platelets (5/1), asthenia (1/0), pain (1/0), and vomiting (1/0). Four patients developed pulmonary toxicity; 2 cases were likely related to 131I-Lip administration and 1 was fatal. The response rate was 47% (18 of 38), and the 1- and 2-year survival rate was 73% +/- 7% and 48% +/- 9%, respectively., Conclusion: This combination had a tolerable toxicity profile and provided an objective response rate, warranting a phase III trial.

Background: We develop a method for the radiolabelling of Lipiodol with Tc, using a lipophilic complex, [99mTc-(S2CPh)(S3Ph)2], dissolved in Lipiodol (99mTc-SSS Lipiodol)., Results: The labelling yield is high (96 +/- 0.8%), and the radiochemical purity satisfactory (92 +/- 2.6%). This labelling is reproducible and stable for up to 24 h in vitro. Studies carried out after injection into the hepatic artery of the healthy pig show that the biodistribution of 99mTc-SSS Lipiodol is comparable with that observed for 188Re Lipiodol., Materials and Methods: The 99mTc-SSS lipiodol was obtained after dissolving a chelating agent, previously labelled with 99mTc, in cold lipiodol. The radiochemical purity (RCP) of the labelling was checked immediately and at 24 h. The 99mTc-SSS lipiodol was injected into the hepatic artery of four healthy pigs for an ex-vivo biodistribution study. An autoradiographic study was performed in two cases., Conclusions: Apart from the specific interest of a Lipiodol-bearing technetiated agent for carrying out dosimetric studies, the labelling of Lipiodol with 99mTc is a preliminary step towards the use of radiolabelling with the 188Re analogue.

The high rate of recurrence after surgical resection of hepatocellular carcinoma (HCC) is a major therapeutic challenge. Postoperative injection of 131-iodine-labeled lipiodol (131I-Lip) into the hepatic artery has been proposed as adjuvant treatment (Lau et al.). We analyzed 2 retrospective series of matched patients treated in our unit before and after addition of 131I-Lip adjuvant therapy to our standard surgical strategy. Thirty-eight patients who had undergone surgical resection of HCC after January 1999 were given adjuvant intra-arterial injection of 131I-Lip after surgery. These patients were matched with 38 other patients who had undergone surgical resection only between January 1997 and January 1999. The frequency of recurrences, disease-free rates, and overall survival rates were compared. The 2 groups were similar for clinical, biologic, or histologic parameters studied and Cancer Liver Italian Program scores. There were 15 recurrences in the group without adjuvant treatment and 9 in the group with 131I-Lip adjuvant treatment. The 1-, 2-, and 3-year disease-free survival rates (+/-95% confidence interval) were different (P <.02): 94.7% +/- 3.6%, 83.7% +/- 6.1%, and 68.4% +/- 9.7%, respectively, in the 131I-Lip group versus 73.7% +/- 7.1%, 54.3% +/- 8.2%, and 41.5% +/- 10.5% in the surgery group. The 1-, 2-, and 3-year survival rates (+/-95% confidence interval) also were different (P <.02): 94.7% +/- 3.6%, 91.7% +/- 4.6%, and 91.7% +/- 4.6%, respectively, in the 131I-Lip group versus 94.7% +/- 3.6%, 71.3% +/- 7.8%, and 49.9% +/- 10% in the surgery group. In conclusion, this retrospective analysis supports the promising contribution of postoperative injection of 131I-Lip after resection of HCC. A randomized study including more patients would be necessary to confirm its contribution to therapeutic management.

Background: Recurrence is common after surgery for hepatocellular carcinoma (HCC)., Methods: The efficacy of, and tolerance to, preoperative intra-arterial injection of (131)I-labelled lipiodol was examined in 34 patients with HCC, including 29 with cirrhosis. Twenty-five patients had a single hepatic tumour and the mean(s.d.) tumour size was 5.2(3.7) (range 2-15) cm. The patients received between one and three injections of (131)I-labelled lipiodol (60 mCi per injection) before surgery. Operations included 14 liver transplants, 13 minor hepatectomies, six major hepatectomies and one exploratory laparotomy., Results: There was one complication after lipiodol injection due to acute ischaemia of the small bowel. Three of 34 patients died within 28 days, two after transplantation and one after resection. An objective tumour response (decrease in tumour size) was observed in 19 of 34 patients, and a complete histological response in eight of 34. There was an objective tumour response or major histological necrosis of lesions in 25 of 34 patients. The 5-year survival rate was 48.4(8.0) per cent, 69.0 per cent after transplantation and 36.0 per cent in patients who underwent resection., Conclusion: This preoperative method appeared to be well tolerated, and provided promising results in terms of macroscopic and microscopic tumour responses., (Copyright 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Chemoembolisation has been extensively used as primary treatment for unresectable hepatocellular carcinoma (HCC). In this unit, 185 patients with a new diagnosis of HCC not amenable to surgery were seen between 1988 and 1991. Intended therapy for these patients was chemoembolisation with doxorubicin (60 mg/m2) and lipiodol, repeated at six week intervals until it was technically no longer possible or until complete tumour response had been obtained. Chemoembolisation was possible in 67 of the 185 (37%). Reasons for exclusion were portal vein occlusion (n = 36), decompensated cirrhosis (n = 44), distant metastases (n = 5), diffuse tumour or unsuitable anatomy (tumour or vasculature) (n = 11), patient refusal (n = 11), and other (n = 11). Patients excluded from treatment survived for a median of 10 weeks (range 3 days-19 months). In patients treated, 18 had small HCC (4 cm) and 49 had large or multifocal HCC. Chemoembolisation was carried out a median of two sessions for small and three sessions for large tumours. Ten of 18 patients with small HCC showed a 50% or greater reduction in tumour size. Five of 49 patients with large or multifocal tumours showed a response to treatment. Median overall survival for treated patients was 36 weeks (range 3 days-4 years). One patient has subsequently undergone liver transplantation with no recurrence and minimal residual disease at transplantation. Two other patients are alive three years after chemoembolisation, one with no evidence of recurrent disease. No patient was thought suitable for surgery after their response to chemoembolisation. Chemotherapy related complications were seen in 22%. Complications were significantly more common in patients with larger tumours and poor liver reserve. Five patients died as a result of chemotherapy related complications. In conclusion, only one third of UK patients with unresectable HCC are treatable by chemoembolisation. Results with small tumours are encouraging, with a high response rate and the possibility of surgical intervention in previously inoperable disease. Large tumours, however, show a poor response and significant incidence of side effects, suggesting that this treatment offers little benefit in advanced disease.

Intra-arterial injection of radioactive Lipiodol has shown promising results in patients with hepatocellular carcinoma (HCC) and portal obstruction. The aim of this prospective, randomized trial was to compare the efficacy and tolerance of 131I-labeled Lipiodol and chemoembolization for the treatment of patients with HCC. From September 1990 to September 1993, 142 patients (135 men, 7 women; age: 65 +/- 6.6 years) were randomly assigned to treatment groups and given either intra-arterial injections of 131I-labeled Lipiodol (60 mCi; 2.2 GBq) (n = 73) or chemoembolization (70 mg cisplatin) (n = 69). Subsequent injections were given at 2, 5, 8, 12, and 18 months. Tumor response was assessed on the basis of tumor size and serum alpha-fetoprotein levels. Patient tolerance was assessed clinically and angiographically. Survival rate was the main end-point. A total of 129 patients (65 in the 131I-labeled Lipiodol group and 64 in the chemoembolization group) were available for analysis; 13 were excluded, mainly because of portal vein thrombosis. The two groups were comparable. Actuarial survival curves were not significantly different between the two groups. Overall survival rates at 6 months, 1, 2, 3, and 4 years were 69%, 38%, 22%, 14%, and 10%, and 66%, 42%, 22%, 3%, and 0% in the 131I-labeled Lipiodol and chemoembolization groups, respectively. Reduction in tumor size was similar for the two groups, with complete response in 1 and 0 patients and partial response in 15 and 16 patients in the 131I-labeled Lipiodol and chemoembolization groups, respectively. Tolerance was significantly better in the 131I-labeled Lipiodol group both clinically (3 severe side effects vs. 29 in the chemoembolization group; P < .001) and angiographically (1 arterial thrombosis vs. 10 in the chemoembolization group; P < .01). In terms of patient survival and tumor response, radioactive 131I-labeled Lipiodol and chemoembolization were equally effective in the treatment of HCC, but tolerance to 131I-labeled Lipiodol was significantly better.

The authors report the case of a cirrhotic patient with a multinodular hepatocellular carcinoma. Two nodules were located in the right liver lobe and a minute nodule was in the left lobe. Because of poor liver function, two injections of iodine-131-labeled Lipiodol were delivered in the right hepatic artery to protect the left lobe. The efficacy was obvious in the treated areas, but the minute lesion enlarged dramatically and was responsible for the patient's death.

Unlabelled: Portal vein thrombosis is a poor prognostic factor in patients with hepatocellular carcinoma (HCC) and a contraindication for chemoembolization. Intra-arterial injection of 131I-iodized oil which does not modify arterial flow, is feasible in this condition. The aim of this prospective randomized controlled trial was to compare the efficacy of treatment with radiolabeled oil (treated group) versus medical support (control group) in patients with stage I or II HCC (classification of Okuda) with portal vein thrombosis., Methods: Twenty-seven HCC patients (26 males, 1 female), aged 53-79 yr, with portal vein thrombosis were randomly assigned to Lipiocis group (n = 14) or Control group (n = 13). Additional injections of radiolabeled oil were given 2, 5, 8 and 12 mo after initial therapy. Medical support treatment consisted of: tamoxifen (n = 5), 5 FU intravenously (n = 1), NSAIDs or corticosteroids (n = 5). Efficacy was evaluated according to survival rate (Kaplan-Meier method; log rank test), AFP serum values (measured at 2, 5, 8 and 12 mo) and angiography., Results: The two groups were comparable (Child's classification, Okuda's classification, liver function tests, location of the thrombus). Tolerance was excellent in the Treated group. The actuarial survival curves were significantly different (p < 0.01) between the two groups, the survival rates (Cl 95%) at 3, 6 and 9 mo being 71% (48%-95%), 48% (12%-55%), 7% (1%-31%) for the Treated group; and 10% (1%-33%), 0% and 0% for the Control group., Conclusion: Intra-arterial hepatic injection of 131I-labeled iodized oil is a safe and effective palliative treatment of HCC with portal vein thrombosis.

This study assesses the usefulness of intra-arterial injection of iodized oil (Lipiodol) as a tool for evaluating the therapeutic choice in a series of 72 consecutive patients with hepatocellular carcinoma (HCC). In 52 of these patients a scintigraphic study of the biodistribution of iodized oil was done, using 131I-iodized oil injection. A single tumor was detected in only 17 cases; 18 patients had a tumor involving only 1 lobe; in 7 cases CT scan disclosed a minute nodule in the opposite lobe of the main tumor. Eighteen patients had a portal thrombosis; in 12 of these cases CT scan showed iodized oil in the tumor emboli. The degree of intratumoral retention of iodized oil depended on the size of tumors and on the presence of arterioportal shunts. Our study demonstrates that only a few patients (4%) with HCC might benefit from curative surgery. The therapeutic benefit of methods using iodized oil injection might be estimated by means of its biodistribution variables (CT and/or scintigraphic data).

Twelve patients with hepatocellular carcinoma and cirrhosis were investigated by Lipiodol injection into the hepatic artery. A CT scan was done 4-6 days later. Lipiodol was retained by hepatic tumors in each case. This method emphasized the extension of the carcinoma and allowed to discover daughter tumors. I131-lipiodol was also injected in 4 of the 12 patients and then its biodistribution was evaluated. At the 6th hour after injection, I131-lipiodol was detected by scintigraphy over the liver (74-91 percent) and over the lungs (9-16 percent) only. The tumor to normal liver pixel count ratio was about 5. These results indicate that there is a preferential arterial blood flow towards the hepatic tumors, and that we can consider a therapeutic use of I131-Lipiodol in hepatocellular-carcinoma.

Biodistribution of iodine-131-labeled Lipiodol Ultra-Fluide (I-131 LUF) injected into the hepatic artery was studied scintigraphically in 47 patients with hepatocellular carcinoma (n = 23), hepatic metastases (n = 14), or normal livers (n = 10). The investigation was extremely well tolerated. I-131 LUF concentrated mainly in the liver (L) and the lungs (l), with L/L + l activity ratios greater than 75% for all three groups of patients. I-131 LUF distribution was homogeneous in normal livers and heterogeneous in cirrhotic livers. I-131 LUF concentrated in the tumor with a tumorous (T) to nontumorous (NT) activity ratio (T/NT) of 4.3 +/- 3.6 for hepatocellular carcinoma and 2.4 +/- 0.7 for hepatic metastases. The effective half-life of I-131 LUF is more than 4.5 days for the three groups. It was eliminated mainly through the urine. Clearance from tumor is slower than from normal liver, as shown by the increase in T/NT at day 18. Biodistribution did not change in patients who had a second injection, which indicates that there is no saturation phenomenon. The results of this study suggest that LUF may be considered as a potential carrier vehicle for therapeutic agents.

Intra-arterial injection of lipiodol-adriamycin mixtures are commonly used in the treatment of hepatic tumors based on the progressive release of adriamycin. This study was undertaken to assess, in vitro, the influence of mixture formulations on the adriamycin release pattern. Eight mixtures containing 10 mg of adriamycin were tested. Adriamycin was tested in solution (mixture A) in suspension (mixture B), or in emulsions with Hexabrix 320 (mixtures C to F). Ratios between Hexabrix and lipiodol volumes were 2/1, 1/1, 1/2, and 1/4 for emulsions C, D, E, and F, respectively. Emulsions G and H corresponded to emulsions E and F, with Arlacel A as emulsifying agent. All mixtures were prepared in triplicate and added with water. Samples of 200 microliters were taken from the aqueous phase after 10, 20, 30 min, 1, 2, 4, 8, 24, 48, 72, and 120 h for adriamycin dosage. Lipiodol-adriamycin mixture formulation significantly influenced the release pattern of adriamycin. Three formulations (suspension, emulsions 2/1 and 1/4) induced the most progressive release of adriamycin from lipiodol. This release was dramatically retarded by the addition of an emulsifying agent.

Internal radiation therapy with transarterial injection of iodine-131-labeled iodized oil (Lipiodol Ultra-Fluide [LUF]) was evaluated in 15 patients with hepatocellular carcinoma and eight with hepatic metastases. Five patients with hepatocellular carcinoma received more than one injection. Treatment tolerance was excellent, as assessed clinically and by means of liver function tests. An analgesic effect was noted in the two patients with painful hepatocellular carcinomas. Serum alpha 1-fetoprotein levels dropped rapidly in 11 of the 12 patients with elevated basal values. An average reduction in tumor size of 50% was observed in the nine cases followed up with computed tomography. After 5-12 months of follow-up, six of the 15 patients with hepatocellular carcinoma were alive. Two of them had undergone liver transplantation. Histologic examination of one of the livers, removed 3 months after a third injection, revealed microscopic features highly suggestive of radiation effect in LUF-containing areas. In the group with widespread hepatic metastases, no objective response was noted, except for an analgesic effect in three cases.