August 08, 2018
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Ultrasound-guided doxorubicin increases chemotherapy concentration for liver tumors

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Noninvasive focused ultrasound hyperthermia enhanced intratumoural delivery of doxorubicin among patients with liver tumors, according to study results published in The Lancet Oncology.

“A major challenge of systemic anticancer therapy is achieving the delivery of a therapeutic dose to the tumor without exceeding the maximum tolerated dose and causing toxicity in healthy tissues,” Paul C. Lyon, BSc, MSc, MRes, BMBS, MRCS, clinical research fellow in the Nuffield department of surgical sciences at University of Oxford, and colleagues wrote. “Several device-based approaches are under investigation to address this challenge, including the use of focused ultrasound, magnetic field, laser, radio-frequency, and microwave techniques for activation of stimuli-responsive drug delivery systems.”

Preclinical research has shown that hyperthermia-triggered release of a therapeutic drug encapsulated in thermosensitive liposomal carriers can enhance the intratumoural concentration, distribution and therapeutic efficacy of systemic therapy; however, this finding had not been proven clinically. Focused ultrasound is the only noninvasive means of generating a targeted mild hyperthermia and “is thus an attractive method for triggered drug release,” the researchers wrote.

Researchers conducted an open-label, phase 1 trial at a single UK hospital between March 13, 2017 and March 27, 2017 to evaluate the safety and feasibility of targeted release and enhanced

delivery of doxorubicin from thermosensitive liposomes triggered by mild hyperthermia, induced noninvasively by focused ultrasound.

The analysis included 10 adult patients with unresectable and nonabatable primary or secondary liver tumors of any histological subtype. Patients received a single IV 50 mg/m2 infusion of lyso-thermosensitive liposomal doxorubicin (ThermoDox, Celsion Corporation) followed by extracorporeal-focused ultrasound exposure of a single target liver tumor.

Six patients had baseline implanted thermometry devices to assess real-time temperature during ultrasound exposures. The remaining four patients did not have these devices, and researchers used a patient-specific model to predict optimal exposure parameters.

The researchers assessed tumor biopsies for doxorubicin concentration and distribution.

Ultrasound-targeted doxorubicin treatment resulted in a 3.7-times increased concentration of doxorubicin on average, from about 2.34 g/g immediately after infusion to 8.56 g/g after focused ultrasound.

Among seven of ten patients, researchers observed twofold to tenfold increases in doxorubicin concentrations. Thus, the trial met its primary endpoint.

“To our knowledge, our study was the first to attempt noninvasive ultrasound-mediated targeted hyperthermia for triggered drug release and enhanced drug delivery in a clinical setting,” the researchers wrote. “Apart from the existing risks associated with general anesthesia, the overall intervention posed no additional safety concerns to the patient other than those typically associated with chemotherapy alone.”

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Serious adverse events included grade 4 transient neutropenia (n = 5) and prolonged hospital stay due to unexpected grade 1 confusion (n = 1). The most common grade 3 or grade 4 adverse events included neutropenia (n = 6) and anemia (n =1).

The limitations of the study included constraints in the prescribed tumor treatment volumes

by the presence of ribs in the acoustic field and by the focused ultrasound system itself; tumor heterogeneity; the lack of time-matched control biopsies; and potential risk for contamination.

Further research needs to be done in this area, Dieter Haemmerich, PhD, Dsc, professor at Medical University of South Carolina, wrote in an accompanying editorial.

“Notably, the duration of hyperthermia required to achieve an optimal clinical response still needs to be established. Even preclinical studies used widely varying heating durations, from 2 minutes to 60 minutes, and this duration is now known to directly dictate the amount of drug that is delivered,” he wrote. “Nevertheless, Lyon and colleagues’ study represents a first important step toward 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.” – by Cassie Homer

Disclosures: Lyon reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Haemmerich reports stock ownership in Medical Engineering Innovations.