Empirical 188Re-HDD/lipiodol intra-arterial therapy based on tumor volume, in patients with solitary inoperable hepatocellular carcinoma

Abstract

Objective This study aimed to assess the potential benefits and tolerability of an empirical dose of approximately 0.8–1.2 mCi (29.6–44.4 MBq) of 188Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol (188Re-HDD/lipiodol) per milliliter of tumor volume, administered after super-selection of the tumor feeding branches of hepatic artery for treatment of inoperable hepatocellular carcinoma (HCC). Methods Patients with advanced HCC or classified as inoperable, with no demonstrated extrahepatic disease and no significant comorbidities were eligible. The patients selected for this study had a single tumoral lesion, measuring less than 150 cc. The range of total activity administered was between 30 and 100 mCi (1.2–3.7) GBq 188Re-HDD/lipiodol, administered in the super selected branches of the hepatic artery supplying the tumor in 42 Patients. Whole-body scintigraphies and single-photon emission computed tomography-computed tomography (SPECT-CT) of the liver including tumor were performed at four-time points after injection. Absorbed doses to the various organs were calculated according to the Medical Internal Radiation Dose formalism. Blood and urine samples were collected at multiple time points until 72 h after injection. Hematological, hepatic and pulmonary toxicity was assessed until 12 weeks after administration using the Common Toxicity Criteria for Adverse Events (version 3.0) scale. Responses were evaluated on contrast enhanced computed tomography (CECT) and by alfa-fetoprotein (AFP) level monitoring. Results About 40.6 ± 4.8% of the injected activity was excreted in the urine by 72 h after injection. The mean absorbed dose to the liver, lungs, stomach, kidney and intestine was 14.4 ± 1.8, 4.8 ± 0.6, 5.5 ± 1.1, 5.1 ± 0.7, and 6.5 ± 1.0 Gy (mean ± SD), respectively. Up to 6 days after administration, 26 of 44 patients had adverse events consisting of aggravations of preexisting laboratory changes (24 patients), fatigue (5 patients), vomiting (6 patients), fever (2 patients), right hypochondrial pain (8 patients), and pain at site of femoral catheter insertion (8 patients). Toxicity assessment at weeks 6 and 12 revealed two cases of mild worsening of liver function tests and no lung or hematological toxicity noted. Two patients were lost to follow-up after the 6-week visit. The response was assessed on CECT in all the remaining patients and the classification of results was more standardized when using European Association for the Study of the Liver (EASL) criteria rather than response evaluation criteria in solid tumors (RECIST) criteria. According to EASL criteria, 8 patients had a partial response, 28 patients had a complete response, 4 patients had progressive disease and 4 patients with stable disease were reported. Thirty-six patients had a baseline elevated AFP and on follow-up at 6 weeks, 6 of these patients showed stable AFP, progression in 4 patients and 26 showed a reduction. Conclusion After the administration of 1.2–3.7 GBq 188Re-HDD/lipiodol based on empirical activity calculation of 0.8–1.2 mCi/mL of tumor volume, more than half of the patients in the present study had an objective response on imaging and biochemically. No significant adverse side effects were noted and most of the laboratory markers as well as symptoms returned to normal after 48–72 h post-administration. Selective administration of the radiopharmaceutical into the tumor feeding arteries gives a good anti-tumoral effect with minimal side effects and damage to surrounding normal liver tissue.

188Re-SSS Lipiodol Radioembolization in HCC Patients: Results of a Phase 1 Trial (Lip-Re-01 Study)

“…Targeting smaller lesions than the ones that have been targeted in this Phase 1 study appears to be another option to increase efficacy. Using the criteria of the European Association of Study of the Liver, Shinto et al reported a 90% response rate, in a study with a mean lesion size of 6.6 cmin, in comparison with 8.9 cm in Lip-Re-1, while using a mean activity of 2 GBq of 188 Re-HDD lipiodol [ 10 ].…”

“…All patients received intra-arterial injection of 188 Re-SSS lipiodol into the hepatic artery under local anesthesia using the classical Seldinger technique, with a whole liver approach, as classically applied with 131 I lipiodol. 188 Re-SSS lipiodol was locally prepared as previously described [ 10 , 12 , 13 ].…”

“…The current labeling is based on the synthesis of a lipophilic complex of 188 Re, which is secondarily solubilized into lipiodol. Several lipiodol labeling attempts with 188 Re have been reported [ 8 , 9 , 10 ], the only one still in clinical use being the 188 Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol lipiodol ( 188 Re-HDD lipiodol) [ 10 ]. Nevertheless, the main drawback of such labeling turns out to be a low in vivo stability, with about 44% of the injected activity being eliminated in urine 46 h post-injection [ 11 ].…”

Radionuclides for Targeted Therapy: Physical Properties

“…The next radionuclides in terms of aggregated research output were rhenium-186 ( 186 Re), rhenium-188 ( 188 Re), strontium ( 89 Sr), and samarium-153 ( 153 Sm), which have—together with other radionuclides—been used in palliative treatment of bone metastases or radiosynovectomy [ 26 , 27 ]. 188 Re has, in recent years, been explored both for melanoma, in a radioimmunoconjugate, and for inoperable hepatocellular carcinoma, with selective administration of [ 188 Re]Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol [ 28 , 29 ].…”

Clinical Management of Liver Cancer in India and Other Developing Nations: A Focus on Radiation Based Strategies

“…A multi-centric study by nuclear medicine departments in India and Vietnam found complete/partial disappearance of tumor or stable disease in [ 68% of patients and survival rates of 58% at 24 months and 30% at 36 months, with a median survival of 980 days [99]. A more recent study showed the utility of 188 Re-HDD/lipiodol for therapy in patients with solitary HCC not amenable to resection [102]. Moreover, post-administration SPECT imaging could be used to assess absorbed doses in target and normal tissue [103].…”