Empirical 188Re-HDD/lipiodol intra-arterial therapy based on tumor volume, in patients with solitary inoperable hepatocellular carcinoma
Authors: Shinto Ajit Sugunan , Karuppusamy Kamaleshwaran K. , Kurup Radhakrishnan E.R. , Pandiyan Arun , Jayaraj Arnold V. 
Published: September 2020

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.