This study is an investigator-initiated, randomized controlled trial enrolling patients with colorectal liver metastases. The objectives are to evaluate the safety and efficacy of contrast-enhanced ultrasound (CEUS)-mediated sonoporation as a potential therapeutic intervention and to investigate whether sonoporation can modulate the tumor microenvironment toward a more immune-active state
The trial is designed as an investigator-initiated, multicenter, prospective, randomized, controlled, two-arm, intervention trial with a matched historical control group aims to evaluate the therapeutic potential of contrast-enhanced ultrasound (CEUS) in patients with colorectal liver metastases (CLM). The primary objectives are to assess whether CEUS can modulate the tumor microenvironment and to determine the safety, tolerability, and feasibility of CEUS as a therapeutic modality. Eligible patients will be randomized to receive either low-intensity CEUS (LI-CEUS) or high-intensity CEUS (HI-CEUS) focused on a designated study metastasis. Safety, feasibility, and success-rate of the intervention will be registered. Minimum seven days post-intervention a biopsy of the study metastasis will be conducted. Subsequent analyses will compare immune cell infiltration, immune-related gene expression, and stromal and vascular remodeling in LI-CEUS- and HI-CEUS-exposed metastases versus historical controls.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
48
The LI-CEUS arm will receive a 30-minute contrast-enhanced ultrasound session targeting a designated study metastasis. During the procedure, 1 mL of the ultrasound contrast agent SonoVue will be administered every 3 minutes throughout the entire session. Minimum 7 days after the intervention a biopsy of the study metastasis will be conducted.
The HI-CEUS intervention group will recieve a 30-minute CEUS procedure targeting a designated study metastasis. During the procedure, 1 mL of the ultrasound contrast agent SonoVue will be administered every 3 minutes throughout the entire session. A high-intensity ultrasound "flash" will be applied every 30 seconds. This "flash" consists of a brief sequence of ultrasound waves with a high mechanical index that causes complete destruction of microbubbles within the imaging field. Minimum 7 days after the intervention a biopsy of the study metastasis will be conducted.
Rigshospitalet
Copenhagen, Denmark
RECRUITINGSurgical Department, Zealand University Hospital
Køge, Denmark
RECRUITINGImmune cell density (CD8+, CD3+) in colorectal liver metastases exposed to LI-CEUS or HI-CEUS, compared to controls.
Time frame: ≥7 days after postinterventional
Number of participants in the intervention group with treatment-related adverse events assessed by CTCAE v5.0
Time frame: Daily, until 7 days post-interventional
Procedure success of LI-CEUS and HI-CEUS procedures as assessed by operator-defined completion of the planned intervention
Time frame: Periinterventional
Differential expression of immune-related genes between CEUS-exposed and control liver metastases
Tissue bulk transcriptional analyses will be evaluated by the Nanostring nCounter platform. Immune-related spatial protein profiling of tumor regions will be evaluated by the GeoMx digital spatial profiler
Time frame: ≥7 days postinterventional
Systemic immune response assessed by changes in the circulating cytokine profiles following LI-CEUS and HI-CEUS
Time frame: Pre- and ≥7 days postinterventional
Frequency and type of technical issues encountered during LI-CEUS and HI-CEUS procedures assessed by the operator
Time frame: Periinterventional
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