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

Abstract

Background: Doxorubicin 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 methods: Phase 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.

Results: In 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).

Conclusion: DT increased OS in unresectable HCC but induced severe respiratory distress. Efficacy data deserve further investigation using a safer dosing and schedule regimen.

Trial registration number: EUDRACT 2006-004088-77; Results.

Keywords: doxorubicin; hepatocellular carcinoma; nanoparticle; therapy.

Figure 1

Kaplan-Meier curves for overall survival (OS) probability. (A) Doxorubicin Transdrug (DT; one, two or three injections) and best standard of care (BSC) groups. Median OS of respectively 32.6 months (95% CI 17.9 to 34.5) for DT vs 15.0 months (95% CI 10.3 to 21.5) for BSC. Comparison of survival curves by log-rank test, p=0.0494. (B) Survival curves depending on the number of DT injections: three injections (DT-3 inject) or one to two injections (DT-1/2 inject).

Figure 2

Macroscopical and microscopical examination of Wistar rat lungs after different treatment schedules: EXC (excipient) as control, DOX (doxorubicin) bolus, DT (Doxorubicin Transdrug) bolus at three different dosages (5, 7.5 and 10 mg/kg).