Focused Ultrasound Increases Drug Delivery to Liver Tumors

Alexander M. Castellino, PhD

July 09, 2018

A heat-sensitive liposomal preparation loaded with doxorubicin (multiple brands) was able to deliver its contents directly to liver lesions when the temperature was raised above 39.5 °C by focused ultrasound (FUS), according to a report from researchers at the University of Oxford, United Kingdom. Delivery of doxorubicin to the liver tumors was increased about fourfold by using FUS, and the treatment yielded a response in some patients.

The findings come from a phase 1 study in 10 patients, known as TARDOX, details of which were published online July 9 in the Lancet Oncology.

"Our study is the first to show that it is feasible for remote triggering and targeting of chemotherapy deep within the body using FUS," Constantin Coussios, PhD, University of Oxford, who is the corresponding author of the study, told Medscape Medical News.

"Administering the drug alone even as a liposomal formulation is generally not enough to kill tumor cells. Our study shows that focused ultrasound–triggered targeted delivery of doxorubicin from thermosensitive liposomes pushes the local concentrations of doxorubicin above known cytotoxic levels," he said.

This is "a first important step towards clinical translation of this elegant targeted drug delivery approach," Dieter Haemmerich, PhD, DSc, of the Medical University of South Carolina in Charleston, comments in an accompanying editorial.

"This is the first-in-human and proof-of-principle study to show that drug delivery can be enhanced at the site where it is required by heating the tissue with focused ultrasound to activate the liposomes," Haemmerichtold Medscape Medical News.

Although similar to ultrasound used for imaging, FUS provides ultrasound of higher intensity to noninvasively deliver heat to localized tissue, which allows precise local delivery of chemotherapy, Haemmerich explained.

He also noted that doxorubicin has "traditionally had low efficacy in liver cancer."

TARDOX: The Oxford University Study

TARDOX was a phase 1, single-center study that enrolled patients with incurable primary or secondary (metastatic) liver cancer who had experienced disease progression or were stable on their current chemotherapy.

Coussios explained that the FUS device is an improved ultrasound device, which is conventionally used in tumor ablation. The patient is laid over the degassed water bath of the device so as to enable acoustic access to the tumor in the liver. The direct contact between the patient's skin and the degassed water bath ensures that the ultrasound transmission into the skin is very good, he pointed out.

The procedure is typically performed under anesthesia. Jet ventilation provides controlled breathing and prevents movement at the liver site where drug delivery occurs, he added.

There were two parts to the study. In part 1, which included six patients, diagnostic ultrasound guidance allowed the researchers to insert a coaxial needle into the liver lesion. The needle served as a means to obtain three sequential core biopsy samples from each patient and also made it possible to temporarily implant a clinically approved thermometry device during the FUS exposure to note the temperature at the drug-delivery site in real time. Part 1 of the study was designed to determine the safety of the device. The thermometry device measured how much ultrasound was required to heat the tumor to 39.5 °C or higher.

Coussios explained that the first biopsy sample was taken after the needle was inserted. Lyso–thermosensitive liposomal doxorubicin (LTLD) was infused over a 30-minute period into a peripheral vein to a dose of 50 mg/m2. The second biopsy sample was taken after alignment of the FUS, after the drug had been passively delivered intravenously through the needle.

"This allowed us to determine if the FUS on its own had damaged the area and to determine the local concentration of the drug that had passively accumulated into the tumor prior to the ultrasound exposure intended to trigger release," Coussios noted.

After 30 minutes, FUS was used to gently heat the tumor from outside the body so as to release its doxorubicin content. As Coussios explained: "This approach not only deposited the heat into the tumor volume (5 x 5 x 5 cm) but also trapped the heat and prevented it from escaping, such that the temperature at the targeted tissue rose in the range 39.5 to 43 °C with the periphery of the tumor volume barely recording a temperature rise."

As the temperature at the delivery site increases, the liposomes become leaky and deposit their contents into the blood stream at the tumor site, Coussios explained. "Once inside the tumor, the temperature-sensitive liposomes release the drug, supplying a higher dose of doxorubicin directly to the tumor, which may help to treat tumors more effectively," he added.

Paul Lyon, DPhil, University of Oxford


After the ultrasound exposure is completed (from 20 to 70 minutes), the patients are allowed to "cool down," and the final biopsy sample is taken from the same location.

The three biopsy samples taken from each of the first six patients allowed for a per-patient comparison of the cellular impact of ultrasound alone on the tumor tissue (biopsy 2 – biopsy 1), an estimate of the intratumoral concentration of the drug following passive accumulation alone (biopsy 2), and an estimate of the increase in intratumoral drug concentration after it had been released from the thermosensitive liposomes (biopsy 3 –biopsy 2).

For the remaining four patients who entered part 2 of the study, drug delivery was performed completely noninvasively, and the target tumor volume was assessed only by biopsy at the end of the procedure in order to quantify intratumoral drug delivery. This second part of the study was intended to better replicate how the treatment may ultimately be delivered in future clinical practice.

TARDOX Results

Initially, 46 patients were screened, and 10 satisfied the inclusion criteria. Of the 36 patients who did not enter the study, 33 were ineligible, and three declined to participate. Patients were excluded because of the anatomic location of the tumor (19/36) before part 2 was open to recruitment. "The main reason for excluding patients based on tumor location was related to safety," Coussios said. "In part 1, the skin had to be perforated before treatment, and the biopsy needle could not be in direct contact with the FUS water bath for sterility reasons," he explained. "Part 2 of the study, which offered more flexibility in terms of tumor location, could only be opened once a number of patients had been successfully treated in part 1 and the data had been reviewed and approved by the trial management group."

Haemmerich explained that for 41% of patients (19/46), tumors were inaccessible and could not be penetrated by FUS. In most such cases, the ribcage was the impediment. "Treatment locations need to be accessible by focused ultrasound, with no bone or air structures present that could hinder ultrasound propagation towards the target.... Future focused ultrasound technology advances might expand accessibility," he commented.

However, Coussios pointed out that the majority of patients were not excluded because they had ultrasonically inaccessible tumors but because the location of the tumor was not adequate for part 1 of the study.

Median follow-up was 29.5 days. There were no treatment-related deaths. Anesthesia time was longer for patients in part 1 of the study than for patients in part 2 (369 min vs 214 min), mainly because of time required to optimize the FUS parameters. For FUS, ultrasound powers in the range of 50 to 140 watts were used.

The report provides a per-patient analysis of the doxorubicin concentrations in post-LTLD and post-LTLD+FUS biopsy samples. Overall, the mean doxorubicin concentration in post-LTLD+FUS biopsy samples was estimated to be 8.56 μg/g — an increase of 3.7 times compared with what was seen when the liposomal product was used without ultrasound.

Coussios remarked that they were quite surprised when they noticed that, in the absence of ultrasound exposure, regardless of the tumor site (ie, primary or metastatic), all patients consistently showed remarkably low drug concentration in the tumor tissue, especially in light of the fact that the drug was a liposomal formulation (~2.5 μg/g of doxorubicin in the tissue).

"By heating the tumor locally, we were able to push the local concentration of doxorubicin above the threshold required for cell kill," he said.

The researchers reported sustained and controlled hyperthermia (above 39.5 °C) in 5 of 6 patients in part 1 (mean time: 40.8 minutes). Intratumor temperatures ranged from 38.9 °C to 41.5 °C and were recorded from 33 to 79 minutes.

Thirty days after the procedure, side effects were those expected of general anesthesia and chemotherapy; the procedure provided no additional risks. Five patients experiened grade 4 neutropenia; for these patients, symptoms resolved without treatment. One patient experienced mild confusion after the procedure and remained in the hospital until it resolved.

CT, MRI, and positron-emission tomographic CT assessments were conducted at the 2-week and 4-week follow-up visits. Of the nine patients available for radiologic analysis, the researchers assessed targeted tumor volumes using tumor assessment criteria for a single lesion; these were compared with tumor volumes of control lesions that were exposed to LTLD alone. Partial responses were seen in many of the tumor lesions exposed to LTLD+FUS compared with LTLD alone.

Some Limitations and Further Improvements

Coussios and his colleagues note that the biopsies were performed at a specific region of the tumor and not the entire tumor; the total intratumoral drug concentration reported was a point estimate and was not reflective of the entire tumor.

He explained to Medscape Medical News that, within the constraints of a phase 1 trial, the FUS system allowed for partial sonication of larger tumors. He indicated that in the future, FUS can be modified to treat a much broader patient population. "Custom focused ultrasound devices designed for volumetric hyperthermia...might allow rapid induction of large volume hyperthermia, facilitating the treatment of larger tumour volumes with this strategy," Coussios and his colleagues note.

Haemmerich agreed and indicated there may be ways to improve on how heat is delivered uniformly across the entire tumor, not at localized points. For example, he explained that magnetic resonance thermometry — a special kind of MRI — can be used to provide a heat map of the entire tumor region. "By using this approach, it is possible to adjust the ultrasound for uniform heating," he told Medscape Medical News.

Another area of improvement in the technology pertains to the duration of hyperthermia, Haemmerich said. Temperature affects how much drug is delivered; the longer the duration of the heat, the more drug is released, he noted. The optimal duration of hyperthermia is currently unknown, and larger studies are required to determine this, possibly by beginning with animal studies, he pointed out.

He also indicated that for focused drug delivery to the liver, future improvements in FUS devices may circumvent the restrictions imposed by the ribcage. Other tumors, such as sarcomas, may not meet with such limitations, but it is also important to select tumors that are sensitive to the drug being encapsulated inside the heat-sensitive liposomes. Doxorubicin is the best and most widely studied drug so far using this technology. "Generating thermosensitive liposomes for each drug is largely through trial and error," he said.

Coussios indicated that larger randomized studies are required to see whether multiple treatment cycles of this approach lead to better survival.

The trial was funded by the UK's National Institute for Health Research and the Oxford Biomedical Research Center. The research was supported by the Oxford Center for Drug Delivery Devices under a grant from the Engineering and Physical Sciences Research Council. LTLD was provided by Celsion Corporation. Dr Coussios and a coauthor are shareholders and consultants for a spinout company from Oxford University, OxSonics, which specializes in ultrasound-enhanced drug delivery to tumors. The authors report that the OxSonics technology exploits purely mechanical ultrasound mechanisms for enhanced drug delivery, whereas this study describes the use of thermal ultrasound mechanisms for drug release. Dr Haemmerich reports that he is a shareholder of Medical Engineering Innovations, has a patent for electrode array for tissue ablation licensed to Medical Engineering Innovations, a patent for radiofrequency ablation system using multiple prong probes issued, and a patent for a radiofrequency ablation system using multiple electrodes licensed to Medtronic, for which royalties are paid.

Lancet Oncol. Published online July 9, 2018. Full text, Editorial


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