Stereotactic Radiosurgery or Hippocampus Avoidance Whole-Brain Radiation Therapy with Memantine in Treating Patients with 5-15 Brain Metastases

This phase III trial studies stereotactic radiosurgery to see how well it works compared to hippocampus avoidance whole-brain radiation therapy with memantine in treating patients with 5-15 brain tumors that have spread from other places in the body. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Hippocampus avoidance whole-brain radiation therapy delivers radiation to the entire brain except for the hippocampus. The hippocampus is a brain structure that is important for memory. Hippocampus avoidance during whole-brain radiation therapy decreases the amount of radiation that is delivered to this area. Memantine is often given with whole brain radiation therapy and may decrease the risk of cognitive side effects after radiation therapy to the brain. It is not yet known whether stereotactic radiosurgery or whole-brain radiation therapy works better in treating patients with 5-15 brain metastases.

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 * The total tumor volume must be 30 cm^3 or less; lesion volume will be approximated by measuring the lesion’s three perpendicular diameters on contrast-enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g. xyz/2); alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumor volume
• Center must have the ability to treat patients with either a Gamma Knife, Cyberknife, or a linear accelerator-based radiosurgery system, or access to a center at which the trial is open which can treat with using one of these systems
• 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; the baseline assessment must be completed within required timelines, prior to randomization * Patient must also be able and willing to complete the neurocognitive testing without assistance from family and companions; patients must be fluent in English or French, and fully testable in one of those languages * A patient that is able but unwilling to complete the questionnaires will be considered ineligible
• 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
• The enrolling facility is credentialed by Imaging and Radiation Oncology Core (IROC) to perform SRS and HA-WBRT - or have access to a center where these treatments are credentialed and the study is open; the treating center must have completed stereotactic radiosurgery credentialing of the specific system(s) to be used in study patients; the treating center must have completed intensity-modulated radiation therapy (IMRT) credentialing of the specific IMRT system(s) 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 enrollment 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 Canadian Cancer Trials Group (CCTG) policy, protocol treatment is to begin within 14 days of patient enrollment
• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method; a woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy / vasectomized partner; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures * Women of childbearing potential will have a pregnancy test to determine eligibility as part of the pre-study evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected; for example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumor production of human chorionic gonadotropin (hCG), as seen with some cancers; patient will be considered eligible if an ultrasound is negative for pregnancy

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 tumor, 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 tumor 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^3 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, or hypersensitivity to any excipients of memantine
• Current alcohol or drug abuse
• Current use of N-methyl-D-aspartate (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)
• Clinically significant untreated or uncontrolled cardiovascular conditions, and/or symptomatic cardiac dysfunction (i.e. unstable angina, congestive heart failure, myocardial infarction within the previous year, cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects, uncontrolled hypertension)
• Current active or uncontrolled urinary tract infections (UTI)
• History of epilepsy or seizures, and not currently taking anti-epileptic medication
• Any other serious intercurrent illness or medical condition judged by the local investigator to compromise the patient's safety, preclude safe administration of the planned protocol treatment, or would not permit the patient to be managed according to the protocol guidelines
• Patients with architectural distortion of lateral ventricular systems which, in the opinion of the local investigator, makes hippocampal delineation challenging

PRIMARY OBJECTIVES:

I. To compare the overall survival in patients with five to fifteen brain metastases who receive stereotactic radiosurgery (SRS) compared to patients who receive hippocampal-avoidant whole-brain radiation therapy (HA-WBRT) plus memantine hydrochloride (memantine).

II. 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 plus memantine.

SECONDARY OBJECTIVES:

I. To compare time to central nervous system (CNS) failure (local, distant, and leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT plus memantine.

II. To evaluate if there is any difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive HA-WBRT plus memantine.

III. To evaluate number of salvage procedures following SRS in comparison to HA-WBRT plus memantine.

IV. To evaluate the individual cognitive test results following SRS in comparison to HA-WBRT plus memantine.

V. To tabulate and descriptively compare the post-treatment adverse events associated with the interventions.

VI. To evaluate the time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT plus memantine.

VII. To prospectively validate a predictive nomogram for distant brain failure.

VIII. To compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT plus memantine.

IX. To evaluate patient’s quality of life, as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) + Brain Cancer Module (BN20), European Quality of Life-5-Dimensional (EQ-5D), Eastern Cooperative Oncology Group (ECOG) performance status, for those who receive SRS compared to those who receive HA-WBRT plus memantine.

X. Collect plasma to evaluate whether detectable somatic mutations in liquid biopsy can enhance prediction of the overall survival and development of new brain metastases.

XI. 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.

XII. Collect whole-brain dosimetry on all patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis (hippocampal dosimetry will be retrospectively assessed).

XIII. Collect imaging parameters and workflow details relating to the radiosurgery planning MRIs (including timing of MR prior to radiosurgery, magnet field strength, contrast type/dose/timing, use of image post-processing, and formal reviewed by radiology) to be prospectively correlated with tumor control outcomes (local control, intracranial control).

XIV. Evaluate serial changes in imaging features found in routine magnetic resonance imaging (MRI) images (T2w changes, morphometry) that may predict tumor control and/or neurocognitive outcomes

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM I: Patients receive memantine hydrochloride orally (PO) twice daily (BID) for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo 10 fractions of HA-WBRT daily for up to 3 weeks.

ARM II: Patients undergo 1 fraction of SRS.

After completion of study treatment, patients are followed up at 8 weeks, 4, 6, 9, 12, 16, and 24 months, then annually afterwards.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Canadian Cancer Trials Group

Principal Investigator
David Roberge

• Primary ID CCTG CE.7
• Secondary IDs NCI-2018-00395, CE.7
• Clinicaltrials.gov ID NCT03550391