Ultrasound-induced targeted doxorubicin delivery feasible for liver tumors
medwireNews: Targeted delivery of doxorubicin using a thermosensitive liposomal preparation triggered by focused ultrasound appears to be a viable option for the treatment of liver tumors, according to the proof-of-concept TARDOX study.
“Building on decades of promising preclinical research, in both therapeutic ultrasound and drug delivery systems, our study highlights the clinical potential of device-based drug delivery approaches in general, and ultrasound in particular, to achieve several-fold enhancements in the delivery and distribution of existing and future therapeutic agents to solid tumours, with potentially transformative implications for their therapeutic effectiveness at a given systemic dose,” the investigators comment in The Lancet Oncology.
The UK-based, phase I trial included 10 patients with unresectable and nonablatable primary or secondary liver tumors that were not responsive to conventional chemotherapy. Under general anesthesia, they received a single intravenous infusion (50 mg/m2) of the formulation – termed lyso-thermosensitive liposomal doxorubicin (LTLD) – after which focused ultrasound was used to provide targeted hyperthermia to a single tumor. For the first six participants, an intratumoral real-time thermometry device was used to control temperature, while a patient-specific model was used to predict optimal exposure for the remaining four.
The average intratumoral doxorubicin concentration rose from 2.34 μg/g in biopsy samples obtained after LTLD infusion to 8.56 μg/g following focused ultrasound, a 3.7-fold increase.
And 70% of patients demonstrated at least a doubling of intratumoral doxorubicin levels, which was higher than the 50% rate needed to meet the primary endpoint, say Constantin Coussios, from the University of Oxford in the UK, and team.
Six of the 10 study participants had a partial response to treatment as per the Choi criteria, with responses seen in the target lesion in four patients, while two patients additionally had a response in at least one control tumor, defined as a lesion that received an LTLD drug dose but not focused ultrasound exposure.
Grade 4 neutropenia, which was classed as a serious adverse event (AE), occurred in five patients, but the toxicity was expected and transient, say the researchers. In addition, one patient experienced grade 1 confusion that required prolonged hospitalization, and this was also considered a serious AE, albeit likely unrelated to the drug or intervention.
There was also one case each of grade 3 neutropenia and anemia, but all other reported AEs were grade 1–2 in severity. And there were no treatment-related deaths over the median follow-up of 29.5 days.
Coussios et al therefore conclude that “[f]urther preclinical and clinical research in focused ultrasound-mediated drug delivery might be warranted, with the intention of reducing toxicity and improving therapeutic outcomes in a broad range of solid tumours, potentially across multiple drug classes.”
Writing in a related comment, Dieter Haemmerich (Medical University of South Carolina, Charleston, USA) says that areas of improvement remain, such as an improved hyperthermia device or heating strategy and temperature monitoring method, as well as establishing the duration of hyperthermia to achieve an optimal clinical response.
But he believes that the trial “represents a first important step towards clinical translation of this elegant targeted drug delivery approach, by demonstrating the ability to locally enhance drug uptake, while showing therapeutic response with a drug that traditionally had low efficacy in liver cancer.”
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