Trial of Preoperative Radiosurgery Versus Postoperative Stereotactic Radiotherapy for Resectable Brain Metastases

Study Overview
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Brief Summary
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The research question is whether a single fraction of preoperative radiosurgery can reduce the incidence of leptomeningeal disease 12 months following resection of a brain metastasis (BM) as compared with 5 fractions of postoperative stereotactic radiotherapy.

Detailed Description
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Neurosurgical resection of a brain metastasis in patients with a diagnosis of cancer may be indicated however the recurrence rate approximates 50% and adjuvant radiotherapy is standard. Single fraction postoperative stereotactic radiosurgery (SRS) has been widely adopted as a standard therapy as it achieves equivalent survival and prevents loss of neurocognitive function as compared with whole brain radiotherapy and improves cavity local control rates as compared with observation. Hypofractionated stereotactic radiotherapy in 3 to 5 fractions (hfSRT) is also used in the postoperative setting. Nodular leptomeningeal disease (nLMD) is a recognised pattern of failure after postoperative SRS and hfSRT. A 16.9% incidence of nodular LMD was seen after surgery and a similar incidence of 11%-28%is reported following postoperative SRS in retrospective series. These data suggest that postoperative SRS/hfSRT have no significant effect on the development of LMD following surgery. The incidence of LMD following single fraction preoperative SRS is only 6.1% according to the largest retrospective series. Preoperative SRS takes advantage of the easier delineation of an intact BM and sterilizes tumor cells disseminated at surgery. Side effects are minimized by a smaller planning margin, a dose reduction and resection of the irradiated volume. In addition, there is no delay to systemic therapy due to wound healing/complications. Furthermore, a single fraction offers patient convenience. This trial will randomise and compare intracranial outcomes between single fraction preoperative SRS and 5 fraction postoperative hFSRT.

Official Title
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A Multicenter Prospective, Interventional, Randomized Trial of Preoperative Radiosurgery Compared With Postoperative Stereotactic Radiotherapy for Resectable Brain Metastases

Conditions
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Brain Metastases, Adult

Intervention / Treatment
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* Radiation: preoperative radiosurgery
* Radiation: postoperative hypofractionated stereotactic radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Age ≥18 Karnofsky performance status ≥60 Histological diagnosis of a malignant primary or metastatic tumour Ability to take steroids No contraindication to magnetic resonance imaging (MRI) MRI-diagnosis of a clearly demarcated contrast-enhancing brain metastasis up to 4.0 cm diameter indicated for neurosurgical resection (tumorboard decision). Up to 3 other brain metastases suitable for primary radiosurgery/ stereotactic radiotherapy Survival estimated by primary clinician > 12 months Platelet count > 100/ml, INR < 1.3, Hb > 7.5 g/dL Exclusion Criteria: Radiosensitive histology: germ cell tumour, lymphoma, multiple myeloma >10 mm midline shift, effacement of the 4th ventricle or other sign of raised intracranial pressure requiring urgent decompressive surgery More than 4 brain metastases or the diameter of the metastasis for resection >4.0 cm. More than 1 metastasis requiring resection Leptomeningeal disease in the CSF or on MRI (unless localized and can be irradiated then resected with the metastasis) Prior radiation to the brain (SRS/SRT to lesion to be resected and /or WBRT) Prior resection of a primary or secondary brain tumor Prior diagnosis of a non-meningioma brain tumor Prior radionuclide therapy within 30 days Prior anti-VEGF therapy within 6 weeks Unable to tolerate radiosurgery immobilization and treatment Inability to give informed consent Pregnancy or lactation Females of reproductive potential not willing to use effective contraception for at least 6 months after radiotherapy Males of reproductive potential not effective contraception for 3 months after radiotherapy Lack of likely compliance with protocol and follow-up

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: Preoperative radiosurgery<br>The interventional arm is single fraction preoperative radiosurgery to a brain metastasis identified for neurosurgical resection. | Radiation: preoperative radiosurgery<br>* single fraction radiosurgery<br>|
| Active Comparator: Postoperative hypofractionated stereotactic radiotherapy<br>The active comparator arm is the standard of care of postoperative hypofractionated stereotactic radiotherapy to the surgical cavity in 5 fractions following resection of the brain metastasis. | Radiation: postoperative hypofractionated stereotactic radiotherapy<br>* 5 fraction stereotactic radiotherapy /fractionated radiosurgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leptomeningeal disease | Incidence (%) | 12 months after intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local control of the surgical cavity | No evidence of tumour recurrence on contrsat-enhanced MRI | 12 months after intervention | 
| Distant brain failure | New brain metastases | 12 months after intervention | 
| Radionecrosis | Adverse radiation effects | 12 months after intervention | 
| Quality of life assessment | EORTC questionnaire core questionnaire QLQ30, EORTC questionnaire brain module BN 20 (1-4, low scores reflect better QoL) | 3,6,12 months after intervention |