Combination radiofrequency thermal ablation and adjuvant IV liposomal doxorubicin increases tissue coagulation and intratumoural drug accumulation

Abstract

There has been marked interest in minimally-invasive, image-guided radiofrequency (RF) tumour ablation (i.e. coagulating tumour using short duration heating ( < 15 min) by directly applying temperatures > 50 degrees C via needle electrodes) to treat focal liver, renal, breast, bone and lung tumours. In spite of advances in RF technology and improved understanding of tumour biophysiology that now enable experimental treatment of tumours up to 5cm, investigators have been unable to achieve complete ablation in many cases, particularly at the tumour margins and adjacent to blood vessels. One strategy for overcoming these limitations has been to take advantage of complementary interactions between RF thermal ablation and chemotherapy, particularly liposomal doxorubicin preparations, to attempt more complete tumour destruction. This paper will review published laboratory investigations demonstrating that this combined treatment paradigm has the unique potential both to potentiate preferential delivery of cytotoxic agents in liposome vehicles and to maximize the completeness of ablation of a treated tumour. New confirmatory data describing increased tumour destruction with RF ablation combined with different liposome preparations, documenting increased lipid peroxidation and expanding on previously published tumour growth studies is presented. Additionally, early clinical data including a randomized, pilot clinical study on 10 patients with primary and metastatic liver tumours, in which a non-optimized combination of RF ablation and IV liposomal doxorubicin (Doxil) increased the volume of tumour destruction 25-30% compared to RF alone, will also be described in detail.

Radiofrequency ablation of small hepatocellular carcinoma with intravenous pegylated liposomal doxorubicin

“…The mechanism of the synergistic effect for regional hyperthermia by RFA and chemotherapy has been demonstrated in experimental studies in an animal breast cancer model [15]. The interaction between chemotherapeutic agents and the large zone of sub-lethal heating at the periphery of the ablation focus potentially increases tumor destruction diameter.…”

“…For HCC with RFA alone, the ablation volume contracted with time. However, ablation volume increased with time after combination therapy from studies in animal and human with hepatic metastasis [15,16]. Only one patient with HCC received combination therapy of liposomal doxorubicin and RFA in the literature [16].…”

“…Studies with intra-arterial administration of doxorubicin without embolizing agents were necessary to clarify the role of doxorubicin in effect of RFA on HCC. Instead of local administration in animal study, intravenous doxorubicin had been demonstrated to enhance the effect of RFA on hepatic metastasis in animal and pilot human studies [15,16]. There were no studies in patients with HCC.…”

“…It might be too early to reach the conclusion that there is no synergistic effect of chemotherapeutic agents and RFA in delaying recurrence and prolonging survival for patients with small HCC. The synergistic effect might be affected by the dosage, timing of administration, circulation time and administrative agents [15,27]. Studies with more patients, uniform protocol and long-term follow-up are necessary to clarify whether or not PLD before RFA offered survival benefit for patients with HCC.…”

“…RFA at a temperature lower than 50°C induces reversible microvascular stasis and increases endothelial permeability and cytotoxicity of some chemotherapeutic agents [13,14]. On the basis of this synergistic antineoplastic effect, it has been demonstrated that combined RFA and intravenous liposomal doxorubicin increases intratumoral accumulation of doxorubicin, increases coagulation necrosis, reduces tumor growth and increases animal survival in rat breast tumor model studies [15]. A pilot clinical study has also suggested that adjuvant liposomal doxorubicin chemotherapy increases tumor destruction, in contrast to RFA alone, in a variety of focal liver tumors [16].…”