Polyethylene Glycol Drug-Eluting Embolic Microspheres Loaded with Doxorubicin for the Treatment of Hepatocellular Carcinoma: Feasibility, Safety, and Pharmacokinetic Study.

PURPOSE: Polyethylene glycol drug-eluting microspheres (PEG-DEMs) can be loaded to elute doxorubicin. The current study evaluated the pharmacokinetic profile and safety of PEG-DEMs in the treatment of patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The current prospective, multicenter, dose-escalation study enrolled 25 patients (68% men) with early or intermediate stage HCC and a performance status of 0. Patients in Cohort I were assigned to receive target doxorubicin doses of 75, 100, or 150 mg. Analyses were performed on the basis of the specific dose of doxorubicin that the patients received because some patients received less than the assigned dose. Patients in Cohort II received the maximum safe tested dose. Adverse events were classified according to the Common Terminology Criteria for Adverse Events version 4.03. The tumor response was evaluated every 3 months according to the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors. RESULTS: The maximum tested safe dose of doxorubicin was 150 mg. For the groups that received ≤75, 75-100, and 101-150 mg of doxorubicin, the peak plasma concentrations were 286.7 ng/mL ± 220.1, 157.1 ng/mL ± 94.6, and 245.4 ng/mL ± 142.8, respectively; the areas under the curves calculated from 0 to 24 h were 421.7 (ng × h)/mL ± 221.2, 288.1 (ng × h)/mL ± 100.9, and 608.3 (ng × h)/mL ± 319.3, respectively, with almost complete clearance at 24 h. There was no death within 30 d. The best objective response rate was 81%, and the disease control rate was 91%. The median overall survival was 27.2 months (95% confidence interval [CI], 17.5 months to not evaluated [n.e.]); the median progression-free survival was 9.8 months (95% CI, 5.5 months to n.e.). CONCLUSIONS: PEG-DEMs demonstrated a favorable safety profile with low systemic concentration of doxorubicin, and promising efficacy.

Transarterial Chemoembolization of HCC with Radiopaque Microspheres: Evaluation with Computed Tomography and the Complementary Role of Contrast-Enhanced Ultrasonography.

PURPOSE: To assess the diagnostic performance of computed tomography (CT), and of the combination of CT with contrast-enhanced ultrasonography (CT + CEUS), for the early evaluation of local response of hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) with radiopaque drug-eluting microspheres (RO-DEMs). MATERIALS AND METHODS: 30 HCC patients (55 target tumors) were treated with TACE with RO-DEMs (diameter: 70-150 µm) preloaded with 75 mg doxorubicin/2 ml of microspheres. Unenhanced and contrast-enhanced CT, followed by CEUS, were performed 1-3 days post-RO-DEMs-TACE. Contrast-enhanced magnetic resonance (MR) performed 1 month later served as the reference standard. Local tumor response was evaluated with modified Response Evaluation Criteria in Solid Tumors (mRECIST). RESULTS: MR diagnosed 9 tumors with complete response and 46 with residual disease. Compared to MR, CT had 9 false negative and 1 false positive diagnosis for residual tumor. Potential causes for these misdiagnoses were the hyperdensities and associated artifacts (caused by the accumulation of RO-DEMs in the target tumors) and the small size of residual tumor. CT + CEUS had 3 false negative and no false positive diagnosis for residual tumor. The sensitivity, specificity and diagnostic accuracy of CT for detection of residual tumor were, respectively: 80.4%, 88.9% and 81.8%, and for CT + CEUS: 93.5%, 100% and 94.5%, respectively. Agreement (kappa coefficient) in application of mRECIST between MR and CT was lower than between MR and CT + CEUS (0.508 vs. 0.757). CONCLUSION: CT evaluation of TACE with RO-DEMs is associated with limitations which can be partially overcome by combining CT with CEUS.

Pharmacokinetics, Safety, and Efficacy of Chemoembolization with Doxorubicin-Loaded Tightly Calibrated Small Microspheres in Patients with Hepatocellular Carcinoma.

PURPOSE: This study examines safety, efficacy, and pharmacokinetics of chemoembolization with loadable microspheres ≤100 µm for hepatocellular carcinoma. MATERIALS AND METHODS: A pilot safety study was performed in 19 patients with size and dose escalation and then 52 patients were enrolled prospectively and randomly assigned to chemoembolization with TANDEM™ loaded with 150 or 100 mg of doxorubicin. RESULTS: The mean diameter of the tumors was 7.28 ± 2.09 cm (range 4-12) and distribution dominant/multiple 51.9/48.1 %. Child A/B distribution was 32/20 (61.5/38.5 %) and etiology HBV/HCV/HBV/HCV-hemochromatosis was 61.6/9.6/9.6/15.4 %. Twenty-five patients were assigned in the low and 27 in the high loading group. There was 1.92 % thirty-day mortality due to lesion rupture. Biliary damage was seen in 3 patients (5.7 %) in the high loading. Mean maximum plasma concentration of doxorubicin C max ± SD was 284.9 ± 276.2 ng/mL for the high and 108.5 ± 77.6 ng/mL for the low loading (p < 0.001). According to m-RECIST overall objective response after two sessions reached 61.22 and 63.82 % at 6 months. Notably, complete target lesion response (CR) after the second session was observed in 28.57 % and maintained in 23.40 % at 6 months. No statistical differences in the local response rates were observed between the two loading groups. Overall survival (OS) at 6 months, 1 , 2, and 3 years was 98.08, 92.3, 88.46, and 82.6 %, respectively. OS and Progression-Free Survival did not demonstrate statistical significance between the two loading groups. CONCLUSION: Initial evidence shows that (a) TANDEM™ achieves high rates of local response and mid-term survival, (b) high loading provides no clinical benefit and is associated with biliary toxicity.