Liver Metastases From Colorectal Cancer
Conditions
Keywords
liver metastasis, CEUS, Sonoporation, Contrast enhanced ultrasound, colorectal cancer, liver metastases, tumor microenvironment
Brief summary
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
Detailed description
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.
Interventions
OTHERLow-intensity contrast enhanced ultrasound
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.
OTHERHigh-intensity contrast enhanced ultrasound
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.
Sponsors
Zealand University Hospital
Rigshospitalet, Denmark
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
Patients in the intervention group will be randomized to receive either high-intensity CEUS or low-intensity CEUS. Patients in the intervention group will be compared to a historical control group.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients (≥18 years) * Ability to provide written informed consent * Histopathological confirmed colorectal adenocarcinoma * Scheduled for liver resection or ablation at the Rigshospital, or admitted to oncologic treatment due to colorectal liver metastases (CLM) at Zealand University Hospital * Presence of at least one CLM evaluable and accessible by CEUS * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. * Follow the conditions regarding fertility, pregnancy, or lactation: * Women of childbearing potential (WOCBP) are defined as women ranging from the period of menarche till the post-menopausal period, unless permanently sterile (e.g. hysterectomy, bilateral salpingectomy and bilateral oophorectomy), Post-menopause is defined as no menses for 12 months without an alternative medical cause. * WOCBP should use a secure and highly effective birth control (as stated in the "Recommendations related to contraception and pregnancy testing in clinical trials", version 1.1, section 4.1, from the Clinical Trials Facilitation and Coordination Group) during the entire period of the trial. In cases of uncertainty regarding pregnancy, pregnancy testing either as highly sensitive serum or urine pregnancy test will be used.
Exclusion criteria
* Oncologic systemic treatment 2 weeks prior to inclusion * Prior treatment with an immune checkpoint inhibitor (e.g. anti-PD-L1, anti PD-1, or anti-PD-L2) * Inability to reliably distinguish the study metastasis from other hepatic metastases using CEUS * Systemic treatment with either corticosteroids (\>10 mg daily prednisolone equivalents) or other immunosuppressive medications within 2 weeks prior inclusion. Inhaled or topical steroids and adrenal replacements doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. * Known history of human immunodeficiency virus (HIV), active or chronic hepatitis B, or C. * Pregnancy or lactation. * Confirmed dMMR positive primary tumors * Inability to comply with study protocol due to psychological, social, or logistical reasons. * Contraindications for CEUS: * Known hypersensitivity to SonoVue® or any other ultrasound contrast agent * Uncontrolled atrial hypertension * Known right-to-left intracardiac shunt * Severe pulmonary hypertension (SAP \>90 mmHg) * Adult respiratory distress syndrome. * Known hypersensitivity to macrogols * Unstable ischemic heart disease or acute coronary syndrome * Severe lung disease, e.g. severe chronic obstructive lung disease
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Immune cell density (CD8+, CD3+) in colorectal liver metastases exposed to LI-CEUS or HI-CEUS, compared to controls. | ≥7 days after postinterventional |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants in the intervention group with treatment-related adverse events assessed by CTCAE v5.0 | 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 | Periinterventional | — |
| Differential expression of immune-related genes between CEUS-exposed and control liver metastases | ≥7 days postinterventional | 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 |
| Systemic immune response assessed by changes in the circulating cytokine profiles following LI-CEUS and HI-CEUS | Pre- and ≥7 days postinterventional | — |
| Frequency and type of technical issues encountered during LI-CEUS and HI-CEUS procedures assessed by the operator | Periinterventional | — |
Countries
Denmark
Contacts
CONTACTMaja M Jeppesen, M.D
PRINCIPAL_INVESTIGATORChristian P Nolsøe, Professor
Center of Surgical Ultrasound, Surgical department of Zealand University Hospital
STUDY_DIRECTORIsmail Gögenur, Professor
Center of Surgical Science, Surgical department of Zealand University Hospital
Outcome results
None listed