This international multi-centre phase 3 randomized control trial investigates whether giving a very high dose of radiation in a single treatment session (ultra-high dose: experimental) using advanced technology called MR-Linac is more effective than a high dose (control) for treating liver tumors that have spread from other parts of the body (liver metastases). This study also aims to identify predictors of treatment response and side effects by analyzing various factors such as imaging markers and genetic profiles.
Liver metastases are common in several cancers, but surgery is often not feasible for many patients. Stereotactic body radiotherapy (SBRT), which delivers focused radiation to tumors, is an alternative treatment option. Previous studies have shown promising results with SBRT, but the optimal radiation dose for liver metastases is still uncertain.
This study will look at patients with specific types of primary cancers known to respond well to SBRT. Treatment effectiveness will be assessed by monitoring tumor control, overall survival, and quality of life.
By comparing ultra-high dose SBRT with standard high dose, the study aims to determine if the former can provide better tumor control with fewer side effects. If successful, this approach could offer a significant advancement in the treatment of liver metastases, potentially improving outcomes and quality of life for patients.
Histologically confirmed malignancy (colorectal adenocarcinoma, pancreatic adenocarcinoma, head and neck SCC, cervix SCC, skin SCC and NSCLC) with metastatic liver disease detected on imaging. Biopsy of metastasis is preferred, but not mandatory.
One, two or three liver metastases "target lesion", ≥ 2 cm from luminal and biliary structures
Target lesions(s) that can receive high/ultra-high dose SBRT: Maximum number: 3, Maximum diameter of each target lesion: 6cm
Non-target lesion(s) can be treated with 3- or 5-fraction SBRT for non-target liver metastases
Liver metastases from primary cancer other than listed in the eligibility criteria (i.e., tumor with low α/β ratio).
Target lesion "planned for high/ultra-high dose SBRT" in proximity (<2cm) to luminal or biliary structures.
Evidence of > 5 liver metastases (exception is in cases of oligoprogression, patients may have more than 5 liver metastases, but SBRT for target lesions will be required for 1, 2, or 3 liver metastases only).
Any previous RT to the abdomino-pelvic region that would result in significant overlap of RT volume for the current study.
Parallel
Magnetic resonance (MR)-guided stereotactic ablative single-fraction (SBRT)
RadiationPrecise radiation therapy delivered in a single session using magnetic resonance imaging for guidance.
Local control (LC) of treated target lesion compared to high dose MR-guided stereotactic single-fraction radiation.
The primary endpoint is LC defined as time from randomization to local failure of the treated target lesion. The LC will be estimated by cumulative incidence function with death and/or progression outside the treated target lesion (without local failure) as competing risk factors.
Overall survival (OS)
Endpoints related to patterns of failure, disease control, and survival will be determined by study investigators using standard-of-care imaging and clinical surveillance.
Progression free survival (PFS)
Endpoints related to patterns of failure, disease control, and survival will be determined by study investigators using standard-of-care imaging and clinical surveillance.
Intra-hepatic progression
Endpoints related to patterns of failure, disease control, and survival will be determined by study investigators using standard-of-care imaging and clinical surveillance.
Widespread progression.
Endpoints related to patterns of failure, disease control, and survival will be determined by study investigators using standard-of-care imaging and clinical surveillance.
Changes in the levels of circulating biomarkers (cell-free tumor DNA) in response to SBRT.
Correlation analysis to determine the association between dynamic changes in biomarker levels and tumor response to SBRT and clinical outcomes. Biomarker analyses will be exploratory, involving various techniques such as quantitative analysis of circulating tumor DNA.
Changes in the levels of circulating biomarkers (cytokines) in response to SBRT.
Correlation analysis to determine the association between dynamic changes in biomarker levels and tumor response to SBRT and clinical outcomes. Biomarker analyses will be exploratory, involving electrochemiluminescence assays for cytokine analysis.
Changes in the levels of circulating biomarkers (metabolites) in response to SBRT.
Correlation analysis to determine the association between dynamic changes in biomarker levels and tumor response to SBRT and clinical outcomes. Biomarker analyses will be exploratory, involving liquid chromatography/mass spectrometry for metabolomics profiling.
Changes in the levels of circulating biomarkers (immune cell populations) in response to SBRT.
Correlation analysis to determine the association between dynamic changes in biomarker levels and tumor response to SBRT and clinical outcomes. Biomarker analyses will be exploratory, involving flow cytometry analysis.
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