| dc.description.abstract | Pancreatic ducal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a very short life expectancy. Together with late diagnosis and aggressive biology, chemoresistance is one important cause of poor survival. Diagnostic imaging has become more available in the past decades, contributing to modestly improved survival. However, chemoresistance remains a hurdle, keeping the survival rates at advanced stages low at a time when research on other cancer types has made progress.
Despite the introduction of targeted cancer therapy, conventional, untargeted cytotoxic small molecular drugs remain the cornerstone of cancer treatment. These drugs represented a significant breakthrough at their time of introduction. However, only a tiny fraction of the systemically administered drugs are taken up in solid tumors. At the same time, dose-limiting and life-threatening side-effects occur due to off-target accumulation.
Conventional cytotoxic drugs have an untapped potential. Preclinical trials have demonstrated promising results for increasing local uptake and therapeutic effect of cytotoxic drugs by focused ultrasound (FUS) combined with microbubbles (MBs). Clinical studies are far less frequent, and results are more uncertain and ambiguous.
The aim of this project was to investigate whether FUS and MBs could improve the therapeutic effect of chemotherapy in patients with colorectal cancer with liver metastases, as proof of concept, and in patients with locally advanced PDAC. The patients received conventional cytotoxic drugs according to national guidelines. A novel, dual-frequency ultrasound transducer was used in the PDAC trial, enabling the use of different frequencies for imaging and therapy. We also measured drug uptake and tumor volume response after treatment with chemotherapy combined with FUS and MBs in preclinical studies with a murine, orthotopic PDAC tumor model.
Seventeen patients with colorectal cancer with inoperable liver metastases were enrolled in the first clinical trial. Two preselected liver metastases in the same patient were randomized 1:1 for either FUS + MBs combined with chemotherapy, or to control arm receiving chemotherapy and systemic MBs only. The primary endpoint of this trial was volume change of treated metastases, compared to controls within the same patient’s liver. Twenty patients with inoperable PDAC were included in a randomized controlled trial, with 1:1 allocation for FUS + MBs combined with chemotherapy or to control arm, receiving chemotherapy only. The primary endpoint of this trial was volume change of FUS + MB- treated tumors compared to controls. The secondary endpoints of both clinical trials was safety and feasibility. In preclinical studies with orthotopic tumors in mice, our endpoints were change in tumor size, determined by ultrasound imaging, and difference in tumor uptake of platinum, a key constituent of platinum-based cytotoxic drugs, measured by inductively coupled mass spectroscopy.
FUS combined MBs improve the uptake of clinically relevant conventional cytotoxic drugs in murine orthotopic PDAC tumors. Treatment with FUS + MBs is safe and feasible for patients with locally advanced PDAC and for patients with colorectal liver metastases. Therapeutic effect for patients was not demonstrated. | en_US |
