Magnetic Resonance-guided Adaptive Stereotactic Body Radiotherapy for Hepatic Metastases

Study Overview
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Brief Summary
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Stereotactic body radiotherapy (SBRT) is an established local treatment method for patients with hepatic oligometastases. Liver metastases often occur in close proximity to radiosensitive organs at risk (OARs). This limits the possibility to apply sufficiently high doses needed for optimal local control. MR-guided radiotherapy (MRgRT) is expected to hold potential to improve hepatic SBRT by offering superior soft-tissue contrast for enhanced target identification as well as the benefit of daily real-time adaptive treatment. The MAESTRO trial therefore aims to assess the potential advantages of adaptive, gated MR-guided SBRT (MRgSBRT) compared to conventional SBRT at a standard linac using an ITV (internal target volume) approach (ITV-SBRT).

Detailed Description
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Hepatic SBRT is a well-established local treatment method for technically or medically inoperable hepatic metastases. However, clinicians are often restricted in the utilization of hepatic SBRT due to dose limitations of the uninvolved liver and nearby OARs (e.g. small bowel, stomach, kidney). MR-guided radiotherapy with its superior soft-tissue contrast is believed to facilitate the precise detection of tumor position and interfractional changes in patient anatomy. Respiratory gating at the MR-Linac enables real-time visualization of the tumor as well as synchronization of beam delivery to the patient's breathing . Therefore, safety margins and thus the irradiated volume can possibly be decreased with MRgSBRT in comparison to ITV-based SBRT, reducing the risk of treatment-associated toxicity. Hepatic MRgSBRT of smaller target volumes might further offer the possibility of dose escalation for increasing local control. To our knowledge, only two retrospective analyses including 26 and 29 patients as well as one case report about hepatic MR-guided SBRT using a MR-Linac can be found in literature. As MR-guided adaptive SBRT is very staff intense and time consuming compared to standard ITV-based SBRT, prospective studies are needed to demonstrate the expected benefits of MR-guided adaptive SBRT. This trial will be conducted as a prospective, randomized, three-armed phase II study in 82 patients with hepatic metastases (solid malignant tumor, 1-3 hepatic metastases confirmed by magnetic resonance imaging (MRI), maximum diameter of each metastasis ≤ 5 cm (in case of 3 metastases: sum of diameters ≤ 12cm), age ≥ 18 years, Karnofsky Performance Score ≥ 60%). If a biologically effective dose (BED) ≥ 100 Gy is feasible based on ITV-based planning, patients will be randomized to either MRgSBRT (Arm A) or ITV-based SBRT (Arm B). If a lesion cannot be treated with a BED ≥ 100 Gy, the patient will be treated in Arm C with MRgSBRT at the highest possible dose.

Official Title
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Magnetic Resonance-guided Adaptive Stereotactic Body Radiotherapy for Hepatic Metastases - MAESTRO -

Conditions
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Hepatic Metastasis

Intervention / Treatment
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* Radiation: ITV (Internal target volume)-based Stereotactic Body Radiotherapy (ITV-SBRT)
* Radiation: MRgSBRT (Magnetic Resonance-guided Stereotactic Body Radiotherapy)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: confirmed underlying solid malignant tumor (no germ cell tumor, leukemia, lymphoma) 1-3 hepatic metastases confirmed by pre-therapeutic MRI indication for SBRT of 1-3 hepatic metastases maximum diameter each hepatic metastasis ≤ 5 cm (in case of 3 metastases: sum of diameters ≤ 12 cm) age ≥ 18 years of age Karnofsky Performance Score ≥ 60% ability to lie still on the radiotherapy treatment couch for at least one hour ability to hold one's breath for more than 25 seconds for women with childbearing potential, adequate contraception ability of subject to understand character and individual consequences of the clinical trial written informed consent (must be available before enrolment in the trial) Exclusion Criteria: refusal of the patients to take part in the study patients with primary liver cancer (eg. HCC, CCC) patients after liver transplantation impairment of liver function to an extent contraindicating radiotherapy (to the discretion of the treating radiation oncologist) active acute hepatic/biliary infection (e.g. hepatitis, cholangitis, cholecystitis) previous radiotherapy of the hepatobiliary system, if previous and current target volumes overlap MAESTRO Study Studienprotokoll Seite 25 von 54 Version 1.0 vom 17.12.2020 patients who have not yet recovered from acute toxicities of prior therapies claustrophobia pregnant or lactating women contraindications against performing contrast-enhanced MRI scans (pacemakers, other implants making MRI impossible, allergy to gadolinium (GD)-based contrast agent) participation in another competing clinical study or observation period of competing trials

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Magnetic Resonance-guided Stereotactic Body Radiotherapy (MRgSBRT), if a biologically effective dose (BED) of ≥ 100 Gy is achievable using an ITV | Radiation: MRgSBRT (Magnetic Resonance-guided Stereotactic Body Radiotherapy)<br>* MRgSBRT (Magnetic Resonance-guided Stereotactic Body Radiotherapy)<br>|
| Experimental: B<br>ITV (Internal target volume)-based Stereotactic Body Radiotherapy (ITV-SBRT), if a biologically effective dose (BED) of ≥ 100 Gy is achievable using an ITV | Radiation: ITV (Internal target volume)-based Stereotactic Body Radiotherapy (ITV-SBRT)<br>* ITV (Internal target volume)-based Stereotactic Body Radiotherapy (ITV-SBRT)<br>|
| Experimental: C<br>Magnetic Resonance-guided Stereotactic Body Radiotherapy (MRgSBRT). If a BED of ≥ 100 Gy cannot be achieved using an ITV concept (e.g. due to OAR constraints), patients will be treated in arm C using MRgSBRT with the highest achievable dose as deemed appropriate by the treating radiation oncologist | Radiation: MRgSBRT (Magnetic Resonance-guided Stereotactic Body Radiotherapy)<br>* MRgSBRT (Magnetic Resonance-guided Stereotactic Body Radiotherapy)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related Toxicity | occurrence of treatment-related gastrointestinal or hepatobiliary CTCAE V5.0 toxicity of grade III or higher | within the first year after radiation treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related Toxicity | assesment of toxicity according to CTCAE V5.0 in all three treatment groups | within 24 months after radiation treatment | 
| Treatment related Quality of life | Changes in quality of life according to EORTC QLQ C-30 | within 24 months after radiation treatment | 
| Treatment related Quality of life | Changes in quality of life according to EORTC QLQ LMC-21 | within 24 months after radiation treatment | 
| local Tumor Control | Change of local Tumor size at one specific site | within 24 months after radiation treatment | 
| locoregional control | Change of local Tumor size within a defined local region | within 24 months after radiation treatment | 
| distant tumor control | apparence of distant Tumor leasions | within 24 months after radiation treatment | 
| progression-free survival (PFS) | time of suvival without Tumor progression | 24 months after radiation treatment | 
| overall survival (OS) | time of Survival of studypopulation | 24 months after radiation treatment | 
| Changes in applied biological effective doses (BED) to the target Volumen (Tumor) | BED increase and OAR doses with MRgSBRT compared to initial ITV-based planning in arms A and C | through study completion, an average of 1 year | 
| Evaluation of potential prognostic biomarkers | Changes in blood Levels of blood Parameters compared to reference samples | within 24 months after radiation treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Magentic Resonance-guided Adaptive Stereotactic Body Radiotherapy