Hepatic artery injection of I-131-labeled lipiodol. Part II. Preliminary results of therapeutic use in patients with hepatocellular carcinoma and liver metastases

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.     

Transarterial internal radiation therapy with I-131 lipiodol for multifoca hepatocellular carcinoma: Immediate and long-term results

Transarterial internal radiation with I-131 Lipiodol (TAIR) was performed in 21 patients with multifocal hepatic carcinoma. Eight patients were treated by TAIR alone and 13 by combination of TAIR and intraarterial infusion ofcis-diamminedichloroplatinum (CDDP) and/or adriamycin mitomycin C oil suspension (ADMOS). TAIR was found effective immediately and long-term. Serum α-fetoprotein (AFP) levels dropped to 50% or less in 7 of 14 patients. Eleven of 21 patients (52%) showed 50% or greater decrease in tumor size. The overall 1-year survival rate was 43% and 67% in patients who received 50 Gy or greater tumor dose. Lipiodol distribution pattern of the tumor indicated some difference in the prognosis between the scattered pattern and solid pattern. The solid pattern showed a statistically significant better survival rate. Patients treated with TAIR alone versus those treated with TAIR and chemotherapy showed no difference in their survival rate.     

Hepatic artery injection of 131I-labelled metuximab combined with chemoembolization for intermediate hepatocellular carcinoma: a prospective nonrandomized study

Purpose

Hepatocellular carcinoma (HCC) is the fifth and seventh most common cause of cancer in men and women, respectively. Transcatheter arterial chemoembolization (TACE) is the standardized therapy for the intermediate stage of HCC. However, the 3-year overall survival remains low (<30?%) in these patients. Thus, there is a critical need for the development of treatment modalities to improve the survival rate. This study aimed to evaluate whether the combination of ¹³¹I-metuximab with chemoembolization could improve treatment efficiency.

Methods

Between January 2009 and January 2010, a prospective two-arm nonrandomized study was performed in patients with intermediate HCC. Of 138 patients, 68 (combination therapy group) received 132 courses of intraarterial ¹³¹I-metuximab injections combined with chemoembolization (mean 1.94 per patient, median 2, range 1–2), followed by 152 sessions of TACE (mean 2.24 per patient, median 2, range 0–4). The remaining 70 patients (monotherapy group) received 296 sessions of TACE (mean 4.23 per patient, median 4, range 1–7).

Results

The overall median survival times for the combination therapy group and the group treated only with TACE were 26.7?months (95?% CI 20.7–31.3?months) and 20.6?months (95?% CI 15.3–24.7?months), respectively. The combination therapy group had a significantly higher survival rate than the TACE-only group (P?=?0.038). Age ≥65?years, serum albumin ≤35?g/l, and treatment category (combination therapy or TACE only) were independent prognostic factors for survival according to multivariate analysis.

Conclusion

The combination of ¹³¹I-metuximab and chemoembolization extended survival in patients with intermediate HCC compared with TACE only, and was well tolerated by patients with Child-Pugh class A or B disease. This combination seems to be a promising treatment modality for patients with intermediate HCC.     

Biodistribution and in vivo kinetics of iodine-131 lipiodol infused via the hepatic artery of patients with hepatic cancer

The biodistribution and in vivo kinetics of [131I]lipiodol infused into the hepatic artery were studied to estimate the potential of internal radiotherapy of hepatic cancer in five patients. It accumulated only in the vascular tumors and adjacent hepatic tissue (AHT) supplied by the infused artery, and to a lesser extent in the lung throughout 8 days imaging sequence. Iodine-131 lipiodol appeared to lead to oil embolization of the tumor and AHT followed by secondary embolization to the lungs and finally the activity was mainly excreted into urine. Four tumors had rapidly and slowly decreasing components, while the AHT activity decreased exponentially from the beginning. The effective half life in tumors was longer with the slow component (mean +/- s.d.: 5.7 +/- 1.2 days) than the AHT (3.7 +/- 0.6 days). The tumor/AHT concentration ratio in three patients at 2 hr was estimated to be 7.5-21. The activity was lower in the lungs than in the AHT in four patients. Iodine-131 lipiodol thus may be used as an intra-arterial infusion agent to treat certain vascular hepatic cancers.     

Biologic dosimetry of 188Re-HDD/lipiodol versus 131I-lipiodol therapy in patients with hepatocellular carcinoma.

One approach to treatment of primary hepatocellular carcinoma (HCC) is intraarterial injection of (131)I-lipiodol. Although clinical results have been positive, the therapy can be improved by using (188)Re instead of (131)I as the radionuclide. (188)Re is a high-energy beta-emitter, has a shorter half-life than (131)I, and has only low-intensity gamma-rays in its decay. The present study compared the cytotoxic effect of the radionuclide therapy in HCC patients treated with (131)I-lipiodol and (188)Re-4-hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD)/lipiodol. To this end, dicentric chromosomes (DCs) were scored in metaphase spreads of peripheral blood cultures. The equivalent total-body dose was deduced from the DC yields using an in vitro dose-response curve. METHODS: Twenty (131)I-lipiodol treatments and 11 (188)Re-HDD/lipiodol treatments were performed on, respectively, 16 and 7 patients with inoperable HCC. Patients received a mean activity of 1.89 GBq of (131)I-lipiodol or 3.56 GBq of (188)Re-HDD/lipiodol into the liver artery by catheterization. For each patient, a blood sample was taken during the week before therapy. A blood sample was also taken 7 and 14 d after administration for the patients treated with (131)I-lipiodol and 1 or 2 d after administration for the patients treated with (188)Re-HDD/lipiodol. RESULTS: The mean DC yield of (188)Re-HDD/lipiodol therapy (0.087 DCs per cell) was significantly lower than that of (131)I-lipiodol therapy (0.144 DCs per cell) for the administered activities. Corresponding equivalent total-body doses were 1.04 Gy for (188)Re-HDD/lipiodol and 1.46 Gy for (131)I-lipiodol. Data analysis showed that, in comparison with (131)I-lipidol, (188)Re-HDD/lipiodol yielded a smaller cytotoxic effect and a lower radiation exposure for an expected higher tumor-killing effect. CONCLUSION: (188)Re is a valuable alternative for (131)I in the treatment of HCC with radiolabeled lipiodol, and a dose escalation study for (188)Re-HDD/lipiodol therapy is warranted.     

Iodine-131-labeled diphosphonates for the palliative treatment of bone metastases: I. Organ distribution and kinetics of I-131 BDP3 in rats

I-131-labeled alpha-amino-(4-hydroxybenzylidene)-diphosphonate (BDP3) was examined in Sprague-Dawley rats for its bone affinity and other biokinetical characteristics. Iodine-131 BDP3 exhibited high bone affinity, with rapid blood clearance and renal excretion. Total-body retention measurements revealed an effective half-life of the activity of t1/2 = 169 hr. Similar kinetics were found in rat femurs, with t1/2 = 158 hr. Rats bearing osteosarcomas showed an enhanced uptake with a slower clearance (t1/2 = 177 hr). The amount of I-131 BDP3 excreted in urine agreed with the total body retention values. Fifty percent was excreted in the urine, as unchanged I-131 BDP3, by 24 hr after application. Almost no activity was found in the feces of the rats. LD50 measurements in rats amounted to 64 mg/kg. Because of these biokinetical characteristics and the simple labeling procedure, I-131 BDP3 is suggested as a radiopharmaceutical for the palliative treatment of pain that often accompanies disseminated bone metastases.     

Hepatic intraarterial 131I iodized oil for treatment of hepatocellular carcinoma in patients with impeded portal venous flow.

PURPOSE: To evaluate the efficacy and safety of intraarterial hepatic iodine 131 iodized oil for treatment of hepatocellular carcinoma in patients with impeded portal venous flow. MATERIALS AND METHODS: Twenty-four patients (mean age, 61 years) with hepatocellular carcinoma underwent 38 courses of 131I iodized oil (one to three per patient), with a mean dose of 2,146 MBq injected into the proper hepatic artery. Hepatocellular carcinoma manifested as single nodules (n = 8; mean, 7.75 cm), multiple nodules (n = 13; mean, 5.46 cm), or a mass (n = 3) occupying more than two hepatic segments. Portal venous thrombosis was complete (n = 10), right (n = 9), left (n = 2), or multisegmental (n = 1). Two patients had hepatofugal portal flow. RESULTS: Among the 23 patients with evaluable results, response to treatment was partial in three, and disease was stable in 12 and progressive in eight. Estimated actuarial survival rates were 70%, 33%, 12%, and 6% at 3, 6, 9, and 12 months, respectively, with two patients alive at 9 and 11 months. The median survival time was 147 days. Adverse events were the early death of one patient owing to hepatic failure and transient symptomatic hepatic failure after 12 courses in nine patients. CONCLUSION: In this preliminary experience, intraarterial hepatic 131I iodized oil did not demonstrate high efficacy in the treatment of hepatocellular carcinoma in patients with portal venous thrombosis, as side effects were not rare.     

Evaluation of intrahepatic I-131 ethiodol on a patient with hepatocellular carcinoma. Therapeutic feasibility study

This study assesses the therapeutic efficacy of radiolabeled iodized oil on a patient with hepatocellular carcinoma (HCC). An iodized oil, such as Lipiodol or Ethiodol (Savage Laboratories, Melville, NY), was retained selectively in the tumor vessels of large tumors as well as in the daughter tumors of HCC for long periods of time following intra-arterial injection into the hepatic artery proper. A small fraction of the stable iodine (1 pg of I-127) of the 37% iodine by weight in Ethiodol was replaced by the I-131 with 100% efficiency. A patient with HCC was injected with I-131 Ethiodol into the hepatic artery. Sequential imaging of organs such as the liver, lung, stomach, and thyroid over an eight-day period demonstrated a high tumor-to-normal-liver ratio and a negligible amount of radioactivity in these organs. These findings indicate that I-131 Ethiodol, or Ethiodol labeled with other pure beta emitters, such as Y-90 or P-32, will be effective delivering a high internal radiation dose to HCC with a small radiation effect to normal tissues. To evaluate its potential as a radiotherapeutic agent for HCC, the kinetics, biodistribution, determination of absolute activity in the tumor following intra-arterial injection of I-131 Ethiodol will be studied in the future. At the same time, an effort will be made to label Ethiodol with Y-90 and P-32.     

Peritoneal carcinomatosis: imaging with intraperitoneal injection of I- 131-labeled B72.3 monoclonal antibody

Monoclonal antibody (MoAb) B72.3 is reactive with a variety of carcinomas such as colorectal and ovarian carcinoma and not reactive with a range of normal tissues in adults. Twelve patients, ranging in age from 16 to 63 years, with metastatic colorectal or appendiceal carcinoma were studied by means of radioimmunoscintigraphy after injection of 5-10 mCi (185-370 MBq) of iodine-131-labeled B72.3 immunoglobulin G (IgG). Eight of the 12 patients had positive scans. In three of these patients the MoAb scan depicted tumors that were not found by other means. Positive scans had excellent correlation with surgical findings in seven patients and caused underestimation of the extent of disease in one patient. In one patient the scan was technically inadequate and could not be evaluated. In three patients the scan was negative. No adverse reactions were associated with the infusions.     

Adjuvant intraarterial injection of 131I-labeled lipiodol after resection of hepatocellular carcinoma: progress report of a case-control study with a 5-year minimal follow-up.

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.     

Iodine-131-labeled diphosphonates for palliative treatment of bone metastases: II. Preliminary clinical results with iodine-131 BDP3

The kinetics, dosimetry, and response of iodine-131 alpha-amino-(4-hydroxybenzylidene)-diphosphonate ([131I]BDP3) treatment were investigated with patients who had pain symptoms from bone metastases of various primary carcinoma. The blood clearance of [131I]BDP3 was rapid. More than 90% disappeared from the blood pool at 2 hr after injection. The excretion of the activity occurred solely through the kidneys and mean total-body retention at 48 hr was 48.6%. The urinary activity showed a metabolite which must be formed by an in vivo cleavage reaction of a phosphorus-carbon bond. The uptake of in vivo cleaved [131I]iodide in the unblocked thyroid was approximately 0.5%. The effective half-life of [131I]BDP3 in metastatic bone (median 182 hr; range 177-205 hr) proved to be longer than in unaffected areas (145 hr; 140-165 hr). Palliative therapies were performed with 18 patients. They received doses ranging between 6 and 48 mCi [131I]BDP3. The response was 44% complete pain relief, 6% substantial pain relief, 22% minimal improvement, and 28% no change. The duration of response ranged between 1 and 8 wk.     

Intra-arterial injection of adriamycin/mitomycin C lipiodol suspension in liver metastases

Intra-arterial injection of a suspension of adriamycin and/or mitomycin C in Lipiodol was performed in 17 patients with hepatic metastases, which at angiography were poorly vascularized. Accumulation of Lipiodol in the tumors was demonstrated at computed tomography (CT) in 15 of 17 patients examined within one week. Follow-up with CT showed that Lipiodol remained in the tumor during the first month in 94 per cent, after 2 months in 31 per cent, and after 3 months in 17 per cent. In the non-tumor part of the liver Lipiodol disappeared earlier, and one month after injection it could no longer be traced on CT. In 8/17 cases (47%) CT, after intra-arterial injection of Lipiodol, gave superior information compared with CT after intravenous contrast enhancement. Tumor response was achieved in 9 of 16 cases. Particularly in metastases originating from cancer of the colon and stomach response was observed with a decrease in tumor size in 8 of 10 patients.     

膈下动脉碘油化疗药物栓塞治疗肝癌

目的　评价膈下动脉碘油化疗药物栓塞对肝癌治疗的疗效及膈下动脉供血的肿瘤的部位。方法　 2 5例肝癌 ,巨块型 12例、结节型 8例、多发结节型 5例。均采用Seldingers法行肝动脉和膈下动脉碘油化疗药物及明胶海绵颗粒栓塞。结果　膈下动脉发自于腹腔干起始处者 16例 ,占 6 4 % ,直接发自主动脉腹腔干周围者 8例 ,占 32 %。其中供应右叶 (Ⅶ ,Ⅷ段 ) 2 3例 ;肿瘤位于左叶 (Ⅳ段 )膈下者2例。膈下动脉碘油化疗药物栓塞后累积 1、2年生存率分别是 84 %和 6 8%。未出现严重并发症。结论　经膈下动脉碘油化疗药物栓塞治疗肝癌是一种安全有效的方法。当肿瘤位于膈下 ,邻近膈肌 ,肝韧带或肝裸区 ,特别是肝动脉造影时肿瘤染色有缺损或无肿瘤染色 ,但肿瘤在CT上有增强或血AFP升高时 ,应考虑到肿瘤由膈下动脉供血。     

Localization of I-131-labeled goat and primate anti-carcinoembryonic antigen(CEA) antibodies in patients with cancer

Thirty patients with anti-carcinoembryonic antigen (CEA)-producing cancers of the colon, breast, or thyroid were injected with 1 to 2 mCi of Iodine-131 (131I)-labeled, affinity-purified, goat or baboon anti-CEA antibodies. Images were obtained daily for four days. Computerized background subtraction using technetium 99m (99mTC)-labeled compounds was used. Images obtained with and without background subtraction were correlated with other evidence of disease. Activity levels in plasma, urine, and thyroid gland were monitored. Significant deiodination of antibody occurred within the first 24 hours. The mean plasma half-disappearance-time of baboon antibody was significantly longer than the mean half-disappearance-time of goat antibody. With exogenous blockade, total thyroid uptake was less than 0.1% of the injected dose. Without background subtraction, scintigraphic localization of known tumor was possible in one of two patients with colon carcinoma, in three of 20 patients with breast cancer, and in one of five patients with medullary carcinoma of the thyroid. With background subtraction, potential false-positive results could be generated for every patients, depending on the normalization site chosen and the degree of subtraction used. In contrast to results of previous reports, CEA-producing tumor was found to be infrequently localized using highly purified goat or primate radiolabeled anti-CEA. Furthermore, the subtraction technique described by previous investigators may lead to a high false-positive rate.