Colorectal cancer is a common type of cancer that often spreads to the liver. When cancer spreads to the liver, treatment becomes very difficult. Many patients will undergo chemotherapy to shrink the tumor. Currently, doctors use CT or MRI scans to assess the effect of chemotherapy, but these examinations usually take about 2 months to show changes in the size of the tumor.

The purpose of this study is to test whether a special type of ultrasound technology called "contrast-enhanced subharmonic ultrasound" can help doctors determine earlier whether chemotherapy is effective compared to conventional scans. This ultrasound detection does not use radiation and can display the blood perfusion status inside liver tumors. We will observe the changes in blood flow perfusion inside the tumor before the start of treatment and after 1-2 chemotherapy cycles to see if these changes can predict whether chemotherapy will be effective in the future.

If this test is effective, it will help doctors adjust the treatment plan more quickly, which may improve the treatment effect for colon cancer patients whose cancer cells have spread to the liver, and also help identify patients who are not responding to chemotherapy as early as possible, reducing the side effects and economic burden of patients.

This is a single-center, prospective observational study conducted at The First Hospital of Jilin University, designed to investigate the value of contrast-enhanced ultrasound (CEUS) subharmonic imaging in the early prediction of response to first-line chemotherapy in patients with colorectal cancer liver metastases (CRLM).

Currently, treatment response in CRLM is primarily evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), which relies on changes in tumor size measured by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). These assessments typically require 6-8 weeks after treatment initiation, which delays the identification of non-responders and limits opportunities for early treatment modification. There is an unmet clinical need for non-invasive, early biomarkers that can predict response before morphological changes become evident.

Contrast-enhanced ultrasound subharmonic imaging is a radiation-free, real-time modality that specifically detects signals from microbubble contrast agents, providing high-sensitivity assessment of tumor microperfusion. Unlike conventional CEUS, subharmonic imaging suppresses tissue background signals, allowing for more accurate quantification of tumor vascularity and perfusion. This study aims to explore whether quantitative parameters derived from subharmonic time-intensity curves (TIC), obtained early in the course of first-line chemotherapy, can predict subsequent treatment response as defined by RECIST 1.1.

All eligible patients with histologically confirmed CRLM who are scheduled to receive first-line systemic chemotherapy will be enrolled. Patients will undergo baseline subharmonic CEUS examination within one week before the initiation of chemotherapy. Follow-up examinations will be performed after the first cycle of chemotherapy, prior to the standard RECIST 1.1 assessment time point. All examinations will be performed using a GE Logiq E20 ultrasound system equipped with subharmonic imaging software. Regions of interest (ROIs) will be carefully placed within the viable portions of the target liver metastases to generate TIC curves. Quantitative perfusion parameters, including peak intensity (PI), time to peak (TTP), area under the curve (AUC), wash-in rate (WIR), and wash-out rate (WOR), will be extracted and analyzed.

Standard chemotherapy regimens will be administered according to clinical guidelines. Treatment response will be assessed using contrast-enhanced CT or MRI at 8-12 weeks after treatment initiation, classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) based on RECIST 1.1 criteria. The correlation between early changes in subharmonic CEUS parameters and the final treatment response will be evaluated using statistical methods, including receiver operating characteristic (ROC) curve analysis to determine the predictive performance of each parameter.

The primary objective is to identify early subharmonic CEUS perfusion parameters that can predict favorable response (CR/PR) versus non-response (SD/PD) to first-line chemotherapy. The findings of this study may provide a novel, non-invasive imaging biomarker for the early prediction of treatment response in CRLM patients, enabling timely treatment adjustments, minimizing unnecessary toxicity, and potentially improving clinical outcomes.

Inclusion Criteria:

1. Age ≥ 18 years.
2. Histologically or radiologically confirmed, initially diagnosed and have not undergone any treatment colorectal liver metastasis (CRLM).
3. Lesion size ≤ 6 cm (preferably located adjacent to major anatomical structures such as large vessels or bile ducts).
4. Lesion depth ≤ 10 cm on ultrasound imaging.
5. Planned to receive guideline-recommended first-line systemic therapy.
6. The target lesion has not undergone any prior systemic or local treatment, including surgery, ablation, embolization, targeted therapy, or investigational agents, before enrollment.
7. Willingness to provide written informed consent.

Exclusion Criteria:

1. Inability to cooperate with contrast-enhanced ultrasound or subharmonic imaging examinations (e.g., dyspnea when lying supine or excessive out-of-plane motion).
2. Know or suspected allergy to the contrast agent or other contraindications to its use.
3. Target lesion not previously evaluated or managed according to standard systemic treatment protocols.
4. Clinically unstable condition, advanced-stage disease, or patients with an unpredictable clinical course that may affect treatment tolerance or follow-up.
5. Pregnant or breastfeeding women.
6. Inability to understand or comply with the study protocol, including the requirement to complete follow-up visits and examinations.

Individual participant data (IPD) will not be shared publicly due to patient privacy protection requirements and institutional data management policies. Data will only be available to the study investigators and authorized personnel involved in this research