Targeted Delivery of Chemotherapy With Ultrasound and Microbublles

Despite the increasing number of active molecules and the availability of news targeted therapies for cancer, therapeutic achievements remain modest for a number of tumor types. One of the major obstacles is inherent to the absence of specific delivery in the tumor tissue.

We have demonstrated recently that the oscillations of ultrasound (US) contrast agent microbubbles under their activation by US waves engender a modulation of the permeability of biological barriers amplifying hence the extravasation of drugs and/or fluorescent markers through a process known as sonoporation. In such a way, the bioavailability of the therapeutic agent is augmented only in the area where US waves are focused. The objective now is to translate this therapeutic approach to the clinic by performing a feasibility study with the development of a therapy regime optimized for hepatic metastases of colorectal cancer.

In order to demonstrate the clinical feasibility of the therapeutic approach based on ultrasound and microbubbles, we will focus on patients with liver metastases of colorectal cancer treated with monoclonal antibodies in combination with chemotherapy.

The work aims into evaluating the therapeutic efficacy of the proposed approach on a number of selected patients. We will follow the usual treatment schemes and we will apply imaging protocols to visualize tumor progression.

This technique of optimization of the intratumoral availability of anticancer drugs and based on sonoporation will improve the efficacy and safety of systemic chemotherapy by providing increased tumor uptake relative to normal tissue. This technique provides an ideal and easy strategy to optimize intratumoral drug delivery.

Inclusion criteria

• patient with liver metastases from colorectal cancer; patient with minimum two liver metastases which satisfy all the following criteria: diameter between 10 and 35 mm; arterially enhancing liver metastases detected with contrast enhanced ultrasound (CEUS); measurable liver metastases with CT-scan (Acceptability of a patient with more than 4 metastases or a patient with an odd number of metastases ≥ 2).
• age ≥ 18 years;
• ECOG/OMS 0-1;
• life expectancy of at least 12 weeks;
• adequate bone marrow, liver and kidney function;
• written informed consent obtained from subject;
• subjects covered by or having the rights to social security;
• bi-weekly chemotherapy regimen
• neo-adjuvant standard chemotherapy or palliative standard chemotherapy (first or second metastatic line) following the recommendations in force (national thesaurus of digestive oncology - colorectal cancer chapter: Phelip JM, Benhaim L, Bouché O, Christou N, Desolneux G, Dupré A, Léonard D, Michel P, Penna C, Rousseaux B, Tougeron D, Tournigand C. "Cancer colorectal métastatique". Thésaurus National de Cancérologie Digestive, Janvier 2019, http://www.tncd.org).

Exclusion criteria

• Previous local treatment of selected liver metastases (radiofrequency, radioembolization, …);
• Indication for local ablative therapy of selected liver metastasis (radiofrequency ablation or other validated hepatic-directed modality of treatment);
• Previous malignancy other than colorectal adenocarcinoma within 3 years prior to the inclusion with the exception for curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical or breast cancer;
• Known contraindication to the injection of Sonovue®, of Gadolinium, of iodated contrast agent;
• contraindication to MRI or perfusion CT scan;
• Patient under legal protection;
• Pregnant or lactating woman, or woman with ability to procreate and without contraception;
• Inclusion in another therapeutic trial
• Uracilemia greater than or equal to 150ng/mL (suggestive of a complete DPD deficiency).
• Presence of any material with potential interaction with ultrasound beam (metal, etc.) or healing tissue, and which cannot be bypassed