In the JournalsPerspective

Ultrasound-guided doxorubicin increases chemotherapy concentration for liver tumors

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.”

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.

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.

    Perspective

    Author Name

    Although progress has been made in the treatment of unresectable liver cancers — both primary tumors and metastatic disease from other sites — outcomes remain suboptimal. New agents and approaches continue to be explored, and although some have demonstrated significant benefits, outcomes, ultimately, remain suboptimal.

    Lyon and colleagues reported a novel therapeutic approach to these diseases, building on preclinical data that suggests that hyperthermic conditions enhance the extravasation of liposomal particles in tumors. In this phase 1 study, TARDOX, the investigators tested a liposomal formulation, called lyso-thermosensitive liposomal doxorubicin, or LTLD, which is administered intravenously and, when heated to 40°C, results in the release of doxorubicin from the liposomes into the targeted tissue.

    In the initial studies of LTLD, researchers used radiofrequency ablation to achieve the targeted temperature. This process is invasive, and a phase 3 study (HEAT) in hepatocellular carcinoma did not demonstrate a significant survival or PFS benefit. However, there was a suggestion that with a radiofrequency ablation dwell time of 45 minutes or more, patients with a solitary liver lesion did have superior outcomes. Still, such a requirement could significantly limit the applicability of this approach for patients, due to risk and cost.

    Lyon and colleagues and their patients should be commended on successfully conducting an ambitious study investigating the use of ultrasound as the thermogenic agent with LTLD. Although this study was small — including a total of 10 patients with tumors in the liver including one with hepatocellular carcinoma —  it did demonstrate that ultrasound could be used to activate the liposomes and enhance delivery of doxorubicin. This was confirmed by measurement of doxorubicin concentrations in the tumor after LTLD infusion, and again after ultrasonic activation, which demonstrated that seven of the 10 patients achieved the primary endpoint of doubling the concentration of doxorubicin in tissue after ultrasonic activation. Moreover, there was some radiographic evidence of necrosis and response in some patients.

    However, there were some notable limitations to this technique and study. The most obvious is the small patient population studied. The ultrasound device was not one that is typically used in most radiology departments, and would require additional investment, should this prove an effective approach. Not all tumors in the liver were able to be visualized, hence, accessed by the ultrasound. Finally, although a goal of liposomal therapy is to improve the therapeutic index of the agent that is being delivered, it should be recognized that both in this small study and in the larger HEAT clinical trial, thermally activated LTLD does appear to result in more systemic exposure to doxorubicin, as manifested by severe neutropenia, than either drug eluting doxorubicin by transarterial chemoembolization, or IV pegylated liposomal doxorubicin.

    Nonetheless, using an ultrasound to activate LTLD is an intriguing approach to cancer therapy that potentially lends itself to other localized disease settings that have been, to date, resistant to systemic therapy, with perhaps other payloads as well.

    References:

    Kong G, et al. Cancer Res. 2000;60:4440-4445.

    Tak WY, et al. Clin Cancer Res. 2018;doi:10.1158/1078-0432.CCR-16-2433.

    Wood BJ, et al. J Vasc Interv Radiol. 2012;doi:10.1016/j.jvir.2011.10.018.

    Jimmy J. Hwang, MD

    HemOnc Today Editorial Board Member
    Levine Cancer Institute
    Atrium Health

    Disclosure: Hwang reports no relevant financial disclosures.