Safety and efficacy of intra-arterial hepatic chemotherapy with doxorubicin-loaded nanoparticles in hepatocellular carcinoma

Abstract

BackgroundDoxorubicin Transdrug (DT), a nanoformulation of doxorubicin, was demonstrated to overcome the chemoresistance of hepatocellular carcinoma (HCC) in preclinical models. Its efficacy and safety were thus investigated in phase I and randomised phase II trials in unresectable HCC.Patients and methodsPhase I was a single dose of DT through the hepatic intra-arterial (HIA) route, dose-escalating 3+3 trial, evaluating five-dose levels from 10 to 40 mg/m2 with maximal tolerated dose (MTD) as primary endpoint. The multicentre phase II trial randomly assigned (2:1 ratio) patients to receive either 30 mg/m2 of DT through HIA route every 4 weeks for up to three courses or best standard of care (BSC). Progression-free survival (PFS) rate at 3 months was the primary endpoint. Overall survival (OS) and disease control rate (DCR) were secondary endpoints.ResultsIn phase I, haematological and respiratory limited toxicities were reported at 35 and 40 mg/m2, giving MTD at 30 mg/m2. Partial response rate was 10%, and stable disease 70%. Phase II was discontinued due to three severe acute respiratory distress events in the DT group while 17 patients had received 30 mg/m2 DT and 11 BSC. At 3 months, PFS was 64% (95% CI 31 to 89) vs 75% (95% CI 35 to 97), and DCR 35% vs 27% in DT and BSC, respectively (p=NS). Median OS was 32.6 months (95% CI 8.2 to 34.1) in DT group and 15 months (95% CI 8.0 to 18.8) in BSC group (p<0.05).ConclusionDT increased OS in unresectable HCC but induced severe respiratory distress. Efficacy data deserve further investigation using a safer dosing and schedule regimen.Trial registration numberEUDRACT 2006-004088-77; Results.

Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial

“…Consistent with previously published data, clinically significant (observed in at least 10% of patients) drug related treatmentemergent adverse events of any grade attributable to doxorubicin were mostly asthenia, nausea, vomiting, and neutropenia, whereas thrombo cytopenia (probably due to gemcitabine) and par aesthesia (probably due to oxaliplatin) were observed in the control group. Although acute respiratory distress syndrome occurred in some patients due to intrahepatic arterial injection of doxorubicinloaded nanoparticles in the phase 1-2 trial, 24 no clinically significant pulmonary treatmentemergent adverse events were observed after 6 h of intravenous perfusion in RELIVE. Headache was more prevalent in the patients who received the nanoparticleloaded doxorubicin, which might be specific to the nanoformu lation, since this is not commonly reported with free doxorubicin, but is reported with other forms of nano formulation of doxorubicin such as liposomal doxo rubicin.…”

“…Treatment could be continued beyond progression at the decision of the principal investigator. To prevent the occurrence of acute respiratory adverse events that we observed in our phase 1-2 trial, 24 perfusion of doxorubicinloaded nanoparticles was done over 6 h intravenously with safety measures (premedication with methyl prednisolone 32 mg orally and one antihistamine drug given 24 h and 1 h before perfusion and 24 h after perfusion). Respiratory symptoms and oxygen saturation were continuously monitored during the 6 h of perfusion: in case of dyspnoea or oxygen saturation decrease from 95% or more to 93% or less, the infusion rate was reduced by half (to a 12 h infusion) without changing the total dose; in case of persistence of dyspnoea beyond 1 h or oxygen saturation decrease to 90% or less, perfusion was immediately and definitively stopped.…”

“…22,23 A phase 1-2 trial suggested a potential benefit of doxorubicinloaded nano particles on overall survival of patients with hepato cellular carcinoma, although the trial was prematurely stopped because of lung toxicity associated with doxorubicin loaded nanoparticles injected by the hepatic arterial route. 24 Preclinical data from Wistar rats showed that this lung toxicity was reduced when doxorubicinloaded nanoparticles were infused over 2 h. 24 Thus, here, we assessed the efficiency of doxorubicinloaded nano particles admin istered by a 6 h intravenous infusion in patients with hepatocellular carcinoma after failure of sorafenib therapy.…”

Therapeutic Efficiency of Multiple Applications of Magnetic Hyperthermia Technique in Glioblastoma Using Aminosilane Coated Iron Oxide Nanoparticles: In Vitro and In Vivo Study

“…The PET images were performed before (at the 13th day) and after three MHT applications (at the 22nd day), as depicted in Figure 10, using a small animal equipment Triumph ® II preclinical scanner (Gamma Medica-Ideas, Nortridge, CA, USA). 18 F-FDG (38)(39)(40) was injected in the penile vein and after 45 min, the animal was posionited with the brain in the center of the field of view. Image was acquired for 30 min and reconstructed using OSEM 3D algoritm, 20 interactions, and 4 subgroups.…”

“…MHT therapy outcome evaluation has been reported by different approaches using conventional techniques as follows: trypan blue [19,32,33], MTT [19,[34][35][36], tunnel assay [32], live/dead assay [37,38], and Western blot [32] that in most cases have limitations for longitudinal analysis.…”