Paul Lyon DPhil, MRCS Academic Clinical Fellow in Radiology Oxford University Hospitals NHS Foundation Trust Oxford, UK

TARDOX Study: Targeting liver tumours with focused ultrasound for triggered drug delivery of thermosensitve liposomes is safe, feasible and enhances delivered dose Interview with:

Paul Lyon DPhil, MRCS Academic Clinical Fellow in Radiology Oxford University Hospitals NHS Foundation Trust Oxford, UK

Dr. Lyon

Paul Lyon DPhil, MRCS
Academic Clinical Fellow in Radiology
Oxford University Hospitals NHS Foundation Trust
Oxford, UK What is the background for this study? What are the main findings?

Response: Delivering therapeutic doses of systemic chemotherapy to solid tumours, whilst ensuring side effects remain tolerable, has a presented a long-standing and unsolved challenge in oncology. With the advent of smart nanomedicines for clinical use, such as Lyso-Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®, Celsion, USA), which has been formulated to release its doxorubicin content at 2.5°C above body temperature, there is now opportunity for targeted tumour therapy in combination with therapeutic devices.

Much like a magnifying glass can focus energy from the sun to burn a hole in paper, ultrasound can be focused deep within the body to induce therapeutic effects in tumours, including ablation, hyperthermia and other bioeffects. Since its inception in the 1940s, focused (or therapeutic) ultrasound has evolved and is now FDA-approved for a variety of indications including ablation of several tumour types, virtue of being safe, non-invasive and non-ionising.

Building on decades of preclinical research efforts worldwide, the TARDOX study is the first clinical trial to attempt triggered drug delivery to a target tumour non-invasively using an external focused ultrasound device. This phase 1 study which ran between March 2015-March 2017 in Oxford, UK, treated 10 patients with inoperable primary or secondary liver tumours which were either stable or refractory to previous chemotherapies. In each patient, a single intervention under general anaesthetic was performed during which a selected liver tumour was targeted and gently heated with focused ultrasound following an intravenous infusion of LTLD. Biopsies were used to determine the quantity of intratumoral doxorubicin before and after the ultrasound exposure. What should readers take away from your report?

Response: The Lancet Oncology publication details how these combined technologies were used to safely deliver therapeutic doses of chemotherapy to a precisely targeted liver tumour, from a single drug cycle. Analysis of tumour biopsies demonstrated a between two-ten-fold increase in the amount of drug in the target tumour in 7/10 patients following ultrasound, satisfying the primary endpoint of at least doubling the intratumoural drug concentration in at least half the patients. Further, localised chemoablative radiological response was demonstrated on imaging at 2 weeks, including PET-CT scans, whilst adjacent unheated tumours showed no response. This is of particular interest, given that doxorubicin has been previously demonstrated to have little therapeutic value in some of the tumour subtypes treated, including colorectal metastases. 

In the 30-day follow-up period self-resolving grade 4 neutropenia was seen in 50% of patients, which is an expected adverse event for LTLD. All other adverse events were of lesser grade and were attributable to either the drug or the intervention, for example grade 1-2 musculoskeletal pain following biopsy. What recommendations do you have for future research as a result of this work?

Response: It is anticipated that future ultrasound-targeted drug delivery studies will see treatment of patients at an earlier stage, for a variety of solid organ tumours, were survival benefits may be realised. Continued research into the development of nanomedicines, including targeted immunotherapies, and focused ultrasound technologies, including both ultrasound- and MR-guided devices, may transform oncological therapies of the future. Is there anything else you would like to add?

Response: This study was funded by National Institute for Health Research Oxford Biomedical Research Centre and further supported by the Oxford Centre for Drug Delivery Devices under a programme grant (EP/L024012/1) from the Engineering and Physical Sciences Research Council. It was conducted by researchers from the University of Oxford and Oxford University Hospitals NHS Foundation Trust. ThermoDox® was provided free of charge to the trial by Celsion Corporation, USA.

Citation: Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial

Lancet Oncology. 2018 July 9th. S1470-2045(18)30332-2 [e-pub ahead of print]  

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