Heating Liver Tumors With Highly Focused Ultrasound Improves Chemotherapy's Effect

A new liver tumor approach heats the tumor externally with highly focused ultrasound, enabling doxorubicin chemotherapy formulated as heat-sensitive lipid nanoparticles to act at up to 4 times higher concentration in the tumor.

Results of the TARDOX phase-1 trial were published on 9 July 2018 in Lancet Oncologyas the journal.

This is the first study showing highly focused ultrasound can improve chemotherapy effectiveness in deep tissues.

Chemotherapies are highly effective at killing cancer cells, but their greatest challengeis achieving high tumor concentrations because higher doses also damage normal cells. Without harming normal cells, delivering cancer drugs to tumorsis a major oncology research field.

Sound waves used in radiological imagingfor diagnosis characterize ultrasound, which in recent years has also been tested as treatment in its own right. A high-intensity form, HIFU (high intensity focused ultrasound)received FDA approval for prostate cancer treatment in 2015.

TARDOX enrolled incurable primary (the liver's own cancer) or secondary (liver metastases) tumor patients.

Patients underwent focused USG in a special bath under general anesthesia. The first stage enrolled 6. A thermometer entered the tumor through a fine needle to confirm temperature at least 39.5 degrees Celsius (up to 43 degrees). Heat-sensitive liposomal doxorubicin at 50 mg/metrekare was infused intravenously over 30 minutes. Biopsy was performed 2 times, during needle placement and after chemotherapy, enabling calculation of tumor destruction and drug concentration from focused ultrasound.

Doxorubicin was designed to leak from its liposomal (lipid nanoparticle) capsule into heated tumor tissue.

Another biopsy afterward brought the total to 3. The 3rd measured increased tumor drug concentration. The study's 2nd stage enrolled 4 patients, who had only 1 biopsy after the procedure.

TARDOX Results

• Of the initial 46 patients, only 10 had tumors targetable with focused ultrasound.
• Biopsy doxorubicin levels were 3.7 times higher in ultrasound-treated tumors than untreated ones.
• Whether the tumor was primary liver cancer or a metastasis did not alter tissue drug concentration results.
• At weeks 2 and 4, CT, MRI and PET-CT assessed response. Of 9 patients, 1 was suitable for imaging analysis. Their tumor receiving ultrasound plus chemotherapy responded better than one receiving chemotherapy alone.

In conclusion, combined heat-sensitive liposomal doxorubicin and focused-ultrasound hyperthermia proved clinically feasible, safe and capable of raising tumor drug concentration. In chemotherapy-resistant liver tumors, it may become a nonsurgical cancer treatment option in future.