Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5 or More Brain Metastases

Study Overview
=================
Brief Summary
-----------------
Stereotactic radiosurgery (SRS) is a commonly used treatment for brain tumors. It is a one-day (or in some cases two day), out-patient procedure during which a high dose of radiation is delivered to small spots in the brain while excluding the surrounding normal brain. Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) is when radiation therapy is given to the whole brain, while trying to decrease the amount of radiation that is delivered to the area of the hippocampus. The hippocampus is a brain structure that is important for memory. Memantine is a drug that is given to help relieve symptoms that can be caused by WBRT, including problems with memory and other mental symptoms. Health Canada, the regulatory body that oversees the use of drugs in Canada, has not approved the sale or use of memantine in combination with WBRT to treat this kind of cancer, although they have allowed its use in this study.

Detailed Description
-----------------
The purpose of this research study is to compare the effects (good or bad) of receiving stereotactic radiosurgery (SRS) versus receiving hippocampal-avoidant whole brain radiotherapy (HA-WBRT) plus a drug called memantine, on brain metastases. Receiving SRS could control cancer that has spread to the brain. This study will allow the researchers to know whether this different approach is better, the same, or worse than the usual approach. To decide if it is better, the study doctors will be looking to see if the stereotactic radiosurgery (SRS) helps to either slow the growth of cancer or stop it from coming back, compared to the usual approach. Doctors will also look to see if this new approach increases the life span of patients with this type of cancer, and if it helps with quality of life and cancer related symptoms. The usual approach for patients who are not in a study is treatment with whole brain radiation therapy alone (WBRT).

Official Title
-----------------
A Phase III Trial of Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5 or More Brain Metastases

Conditions
-----------------
Brain Metastases

Intervention / Treatment
-----------------
* Drug: Memantine
* Radiation: Hippocampal-avoidant (HA-WBRT) Radiotherapy
* Procedure: Stereotactic Radiosurgery (SRS)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have 5 or more brain metastases as counted on a T1 contrast enhanced MRI obtained ≤ 30 days from randomization (maximum 15 brain metastases). Patients must have a pathological diagnosis (cytological or histological) of a non-hematopoietic malignancy. The largest brain metastasis must measure <2.5 cm in maximal diameter. Centre must have the ability to treat patients with either a Gamma Knife, Cyberknife, or a linear accelerator-based radiosurgery system. Patient must be > 18 years of age. Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French either alone or with assistance. ECOG performance status 0, 1, or 2. Creatinine clearance must be ≥ 30 ml/min within 28 days prior to registration. The Neurocognitive Testing examiner must have credentialing confirming completion of the neurocognitive testing training. Facility is credentialed by IROC to perform SRS and HA-WBRT. The treating centre must have completed stereotactic radiosurgery credentialing of the specific system(s) to be used in study patients. The treating centre must have completed IMRT credintialing of this specific IMRT systems to be used in study patients for the purposes of HA-WBRT. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate. A similar process must be followed for sites outside of Canada as per their respective cooperative group's procedures. Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up. In accordance with CCTG policy, protocol treatment is to begin within 14 days of patient enrolment. Women/men of childbearing potential must have agreed to use a highly effective contraceptive method. Exclusion Criteria: Pregnant or nursing women. Men or women of childbearing potential who are unwilling to employ adequate contraception. Inability to complete a brain MRI. Known allergy to gadolinium. Prior cranial radiation therapy. Planned cytotoxic chemotherapy within 48 hours prior or after the SRS or HA-WBRT. Primary germ cell tumour, small cell carcinoma, or lymphoma. Widespread definitive leptomeningeal metastasis. This includes cranial nerve palsy, leptomeningeal carcinomatosis, ependymal involvement, cranial nerve involvement on imaging, suspicious linear meningeal enhancement, or cerebrospinal fluid (CSF) positive for tumour cells. A brain metastasis that is located ≤ 5 mm of the optic chiasm or either optic nerve. Surgical resection of a brain metastasis (stereotactic biopsies will be allowed). More than 15 brain metastases on a volumetric T1 contrast MRI (voxels of 1mm or smaller) performed within the past 14 days, or more than 10 metastases in the case of a non-volumetric MRI. Prior allergic reaction to memantine. Current alcohol or drug abuse. Current use of NMDA antagonists, such as amantadine, ketamine, or dextromethorphan. Diagnosis of chronic liver disease/cirrhosis of the liver (e.g. Child-Pugh class B or C). Patients with architectural distortion of lateral ventricular systems, which, in the opinion of the local investigator, makes hippocampal delineation challenging

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an international multi-centre, open-label, randomized phase III trial comparing stereotactic radiosurgery compared with hippocampal-avoidant whole brain radiotherapy (HA-WBRT) plus memantine for 5-15 brain metastases
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hippocampal-avoidant (HA-WBRT) plus Memantine<br>WBRT 30Gy in 10 fractions + memantine | Drug: Memantine<br>* 20 mg (10 mg divided twice daily). Dose will be escalated by 5 mg per week. Memantine should start at 5 mg, and then increased in 5 mg increments at the following schedule, depending on the patient's response and tolerance:<br>Radiation: Hippocampal-avoidant (HA-WBRT) Radiotherapy<br>* 30Gy in 10 fractions<br>|
| Experimental: Stereotactic Radiosurgery (SRS)<br>SRS 18-20 or 22Gy in single fraction | Procedure: Stereotactic Radiosurgery (SRS)<br>* 18-20 or 22 Gy in single fraction<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | To compare the overall survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive HA-WBRT + memantine | 4.5 years | 
| Neurocognitive progression-free survival | To compare the neurocognitive progression-free survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive HA-WBRT + memantine | 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to central nervous system (CNS) failure (local, distant, and leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT + memantine |  | 4.5 years | 
| Difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT + memantine |  | 4.5 years | 
| Number of salvage procedures following SRS in comparison to HA-WBRT + memantine |  | 4.5 years | 
| Neurocognitive progression-free survival in patients who receive SRS compared to HA-WBRT + memantine | measured from date the patient is randomized to date at which there is a drop of at least 1.5 standard deviations from baseline in two of the six neurocognitive tests (all tests are standardized based on published norms) | 4.5 years | 
| Tabulate and descriptively compare the post-treatment adverse events associated with the interventions. |  | 4.5 years | 
| Time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT + memantine |  | 4.5 years | 
| Prospectively validate a predictive nomogram for distant brain failure in patients who receive SRS | a predictive nomogram as a clinically useful tool to determine the likelihood of distant brain failure (DBF) at different time points after radiosurgery | 4.5 years | 
| Compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT + memantine. | Comparison based on payer rates (Medicare for US / provincial heath authorities in Canadian jurisdictions with activity-based funding) | 4.5 years | 
| Quality of life, as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) with brain cancer module (BN20) |  | 4.5 years | 
| Quality of life assessed by ECOG performance status |  | 4.5 years | 
| Quality of life, as assessed by EQ-5D-5L |  | 4.5 years | 
| Collect plasma to evaluate whether detectable somatic mutations in liquid biopsy can enhance prediction of the overall survival and development of new brain metastases. |  | 4.5 years | 
| Analysis of serum samples for inflammatory biomarker C-reactive protein and brain-derived-neurotrophic factor (BDNF) to elucidate molecular/genomic mechanisms of neurocognitive decline and associated radiographic changes |  | 4.5 years | 
| Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis |  | 4.5 years | 
| Evaluate serial changes in imaging features found in routine MRI images (T2w changes, morphometry) that may predict tumour control and/or neurocognitive outcomes |  | 4.5 years |