Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies

Abstract

Purpose: A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD). The primary objectives were to determine the safe maximum tolerated dose (MTD), pharmacokinetic properties, and dose-limiting toxicity (DLT) of LTLD during this combination therapy.

Materials and methods: Subjects eligible for percutaneous or surgical radiofrequency (RF) ablation with primary (n = 9) or metastatic (n = 15) tumors of the liver, with four or fewer lesions as large as 7 cm in diameter, were included. RF ablation was initiated 15 minutes after starting a 30-minute intravenous LTLD infusion. Dose levels between 20 mg/m(2) and 60 mg/m(2) were evaluated. Magnetic resonance imaging, positron emission tomography, and computed tomography were performed at predetermined intervals before and after treatment until evidence of recurrence was seen, administration of additional antitumor treatment was performed, or a total of 3 years had elapsed.

Results: DLT criteria were met at 60 mg/m(2), and the MTD was defined as 50 mg/m(2). RF ablation was performed during the peak of the plasma concentration-time curve in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia.

Conclusions: LTLD can be safely administered systemically at the MTD (50 mg/m(2)) in combination with RF ablation, with limited and manageable toxicity. Further evaluation of this agent combined with RF ablation is warranted to determine its role in the management of liver tumors.

Figure 1

Plasma pharmacokinetics for the MTD cohort (50mg/m²) with superimposed median RFA time, showing times that the AUC was exposed to RFA.

Figure 2

Sequential enhanced CT scans in a patient with metastatic breast carcinoma to the liver treated with RFA with IV LTLD. Pre-treatment (a), 10 weeks (b), and 12 months (c) post-treatment imaging demonstrates an enhancing thick rim at 10 weeks, which simulates residual tumor. This has the imaging appearance of benign tissue at 1 year post treatment. Although speculative, this early enhancing region is in the expected location of drug effect, but could be otherwise misinterpreted as tumor.

Figure 3

Enhanced CT scans pre-treatment (a, arrow), 3 days (b), and 20 weeks (c), post treatment of a 49 year old female with adrenal cortical carcinoma metastases to the liver successfully treated with RFA plus simultaneous IV LTLD. Post treatment devascularized zone initially suggests incomplete ablation because the treatment zone is smaller than the tumor, but later proves successful. Whereas devascularized RFA zones typically shrink in the weeks and months following RFA alone, the RFA with LTLD zone grows in the months following treatment, suggestive of augmentation by chemotherapy.

Figure 3

Enhanced CT scans pre-treatment (a, arrow), 3 days (b), and 20 weeks (c), post treatment of a 49 year old female with adrenal cortical carcinoma metastases to the liver successfully treated with RFA plus simultaneous IV LTLD. Post treatment devascularized zone initially suggests incomplete ablation because the treatment zone is smaller than the tumor, but later proves successful. Whereas devascularized RFA zones typically shrink in the weeks and months following RFA alone, the RFA with LTLD zone grows in the months following treatment, suggestive of augmentation by chemotherapy.

Figure 3

Enhanced CT scans pre-treatment (a, arrow), 3 days (b), and 20 weeks (c), post treatment of a 49 year old female with adrenal cortical carcinoma metastases to the liver successfully treated with RFA plus simultaneous IV LTLD. Post treatment devascularized zone initially suggests incomplete ablation because the treatment zone is smaller than the tumor, but later proves successful. Whereas devascularized RFA zones typically shrink in the weeks and months following RFA alone, the RFA with LTLD zone grows in the months following treatment, suggestive of augmentation by chemotherapy.