Intraoperative Radiotherapy in Patients With Brain Metastases

Study Overview
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Brief Summary
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Intraoperative radiotherapy (IORT) is a new alternative for local radiotherapy with the advantages of dose escalation, reduced overall treatment time, and enhanced patient convenience, however the degree of efficacy is unknown, as well as and which is the most efficient dose. The objective of this study is to evaluate the efficacy and safety of IORT in patients with surgical excision of brain metastases at a dose of 20 Gy is at least as effective and safe as other forms of radiation therapy in patients with resection of brain metastases.

Detailed Description
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INTRODUCTION Brain metastases occur in roughly 30% of all cancer patients during their course of disease. Their incidence is believed to rise due to the aging population that develops more cancer per se, an increase in overall survival due to more effective extracranial therapies but with only few (novel) substances crossing the blood-brain barrier and more broadly available and more advanced imaging techniques. Neurosurgical treatment remains a cornerstone in the management of brain metastasis, especially for lesions causing mass effects or neurological deficits or in case tissue is necessary to establish a diagnosis. As local recurrence rates are as high as 50-60% after surgical resection alone, adjuvant therapies to prevent such are necessary. Whole brain radiotherapy (WBRT) does not influence survival but rather impairs neurocognitive functions and, as histologic in-depth exams of cavity borders showed that most brain metastases infiltrate only 0.3-1.2 mm into the surrounding healthy brain tissue, therefore treatment is to date usually confined to the cavity margin. Thus, the currently recommended standard of care is post-operative stereotactic radiosurgery (SRS) to the resection cavity. One of the drawbacks of this modality is the incidence of radionecrosis, especially in large tumor volumes. As an alternative to radiosurgery, hypofractionated local radiotherapy is also used, reducing the risk of radionecrosis in large volumes. There are no prospective randomized studies comparing both techniques. The need to find a modality of radiotherapy that achieves al least the efficacy of radiosurgery or hypofractionated local radiotherapy, without the disadvantages thereof, makes IORT as a possible treatment alternative. The objective of this study is to evaluate the efficacy and safety of IORT in patients with surgical excision of brain metastases at a dose of 20 Gy is at least as effective and safe as other forms of radiation therapy in patients with resection of brain metastases. OBJECTIVES Primary Objective Median local progression free survival (lPFS), defined as time span (in months) between surgery and recurrence within a 0,5 cm margin around the resection cavity, assessed by serial MRI scans and RANO response assessment criteria for brain metastases . Radiation-related (acute / late) neurotoxicity, assessed by regular neurological examinations and serial MRI scans. Secondary objectives Median regional PFS (rPFS), resembling the time (in months) from surgery to any progression outside of the 0,5 cm margin around the resection cavity, assessed by serial MRI scans and RANO response assessment criteria for brain metastases . Global PFS (gPFS), defined as the time (in months) from surgery to any intra- and extracranial tumor progress. Median overall survival (OS), defined as the time (in months) from surgery of brain metastases to death from by any cause. DESIGN This trial is an open, single arm, single institution, prospective trial to determine the efficiency and safety of IORT with low-energy photons to the cavity after resection of brain metastases. A total of 25 patients will be included.

Official Title
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Intraoperative Radiotherapy in Patients With Brain Metastases

Conditions
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Brain Metastases

Intervention / Treatment
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* Radiation: Intraoperative radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Karnofsky Performance Status ≥ 70 Newly diagnosed cerebral or cerebellar lesion (contrast enhancing on a T1-weighted MRI scan) amenable to total resection with no dural attachment Frozen section confirming a metastasis of an extracranial ( Central Nervous System i.e. non-CNS) tumor Adequate distance to optic nerve(s), chiasm and brainstem (organs at risk for radiotherapy) Adequate birth control Exclusion Criteria: Leptomeningeal spread and dural attachment (assessed pre- and intraoperatively) Frozen section reveals primary CNS tumor, lymphoma, SCLC (Small-cell lung cancer) or germinoma More than one brain metastasis Psychiatric or social condition potentially interfering with compliance Contraindication against anesthesia, surgery, MRI and/or contrast agents Pregnant or breast-feeding women

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arms<br>To determine the efficiency and safety of IORT with low-energy photons to the cavity after resection of brain metastases | Radiation: Intraoperative radiotherapy<br>* Intraoperative radiotherapy application immediately following resection of brain metastases.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median local progression free survival (lPFS) | Recurrence within a 0.5 cm margin around the resection cavity, assessed by serial magnetic resonance imaging (MRI scans) and response assessment criteria in neuro-oncology (RANO) | 6 months from the date of surgery. | 
| Radiation-related acute neurotoxicity | Neurotoxicity related to radiotherapy evaluated according to the scale of the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Score from 0 to 5, with 5 being the worst toxicity - Acute toxicity: cerebral edema | 3 months from the date of surgery. | 
| Radiation-related late neurotoxicity | Neurotoxicity related to radiotherapy evaluated according to the scale of the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Score from 0 to 5, with 5 being the worst toxicity - Late toxicity: radionecrosis. | 6 months from the date of surgery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median regional PFS (rPFS) | To any progression outside of the 0.5 cm margin around the resection cavity, assessed by serial MRI scans and RANO response assessment in neuro-oncology . | 6 months from the date of surgery | 
| Global PFS (gPFS) | The time (in months) from surgery to any intra- and extracranial tumor progress | 6 months from the date of surgery | 
| Median overall survival (OS) | The time (in months) from surgery of brain metastases to death from by any cause. | 6 months from the date of surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain metastases, Intraoperative radiotherapy, Intrabeam