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A Phase III Trial of Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5 or More Brain Metastases
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.
Eligibility Criteria
Inclusion Criteria
- 1Patients must have 5 or more brain metastases as counted on a T1 contrast enhanced MRI obtained ≤ 30 days from randomization (maximum 15 brain metastases).
- 2Patients must have a pathological diagnosis (cytological or histological) of a non-hematopoietic malignancy.
- 3The largest brain metastasis must measure \<2.5 cm in maximal diameter.
- 4Centre must have the ability to treat patients with either a Gamma Knife, Cyberknife, or a linear accelerator-based radiosurgery system.
- 5Patient must be \> 18 years of age.
- 6Patient 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.
- 7ECOG performance status 0, 1, or 2.
- 8Creatinine clearance must be ≥ 30 ml/min within 28 days prior to registration.
- 9The Neurocognitive Testing examiner must have credentialing confirming completion of the neurocognitive testing training.
- 10Facility 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.
- 11Patient 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.
- 12A similar process must be followed for sites outside of Canada as per their respective cooperative group's procedures.
- 13Patients 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.
- 14In accordance with CCTG policy, protocol treatment is to begin within 14 days of patient enrolment.
- 15Women/men of childbearing potential must have agreed to use a highly effective contraceptive method.
Exclusion Criteria
- 1Pregnant or nursing women.
- 2Men or women of childbearing potential who are unwilling to employ adequate contraception.
- 3Inability to complete a brain MRI.
- 4Known allergy to gadolinium.
- 5Prior cranial radiation therapy.
- 6Planned cytotoxic chemotherapy within 48 hours prior or after the SRS or HA-WBRT.
- 7Primary germ cell tumour, small cell carcinoma, or lymphoma.
- 8Widespread 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.
- 9A brain metastasis that is located ≤ 5 mm of the optic chiasm or either optic nerve.
- 10Surgical resection of a brain metastasis (stereotactic biopsies will be allowed).
- 11More 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.
- 12Prior allergic reaction to memantine.
- 13Current alcohol or drug abuse.
- 14Current use of NMDA antagonists, such as amantadine, ketamine, or dextromethorphan.
- 15Diagnosis of chronic liver disease/cirrhosis of the liver (e.g. Child-Pugh class B or C).
- 16Patients with architectural distortion of lateral ventricular systems, which, in the opinion of the local investigator, makes hippocampal delineation challenging
Locations
86 sites participating in this study
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia 30322
Emory Saint Joseph's Hospital
Atlanta, Georgia 30342
University of Arizona Cancer Center-Orange Grove Campus
Tucson, Arizona 85704
Baldassarre Stea