Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5 or More Brain Metastases
- Conditions
- Brain Metastases
- Interventions
- Procedure: Stereotactic Radiosurgery (SRS)Radiation: Hippocampal-avoidant (HA-WBRT) Radiotherapy
- Registration Number
- NCT03550391
- Lead Sponsor
- Canadian Cancer Trials Group
- 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).
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 206
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Stereotactic Radiosurgery (SRS) Stereotactic Radiosurgery (SRS) SRS 18-20 or 22Gy in single fraction Hippocampal-avoidant (HA-WBRT) plus Memantine Hippocampal-avoidant (HA-WBRT) Radiotherapy WBRT 30Gy in 10 fractions + memantine Hippocampal-avoidant (HA-WBRT) plus Memantine Memantine WBRT 30Gy in 10 fractions + memantine
- Primary Outcome Measures
Name Time Method Overall Survival 4.5 years To compare the overall survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive HA-WBRT + memantine
Neurocognitive progression-free survival 4.5 years 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
- Secondary Outcome Measures
Name Time Method 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 Prospectively validate a predictive nomogram for distant brain failure in patients who receive SRS 4.5 years a predictive nomogram as a clinically useful tool to determine the likelihood of distant brain failure (DBF) at different time points after radiosurgery
Quality of life, as assessed by EQ-5D-5L 4.5 years Quality of life assessed by ECOG performance status 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 Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis 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 Time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to HA-WBRT + memantine 4.5 years Compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive HA-WBRT + memantine. 4.5 years Comparison based on payer rates (Medicare for US / provincial heath authorities in Canadian jurisdictions with activity-based funding)
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 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 4.5 years 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)
Tabulate and descriptively compare the post-treatment adverse events associated with the interventions. 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 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
Trial Locations
- Locations (85)
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
University of Arizona Cancer Center-Orange Grove Campus
🇺🇸Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
🇺🇸Tucson, Arizona, United States
City of Hope Corona
🇺🇸Corona, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States
City of Hope at Irvine Lennar
🇺🇸Irvine, California, United States
UC San Diego Moores Cancer Center
🇺🇸La Jolla, California, United States
City of Hope Antelope Valley
🇺🇸Lancaster, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
🇺🇸Orange, California, United States
Kaiser Permanente-Rancho Cordova Cancer Center
🇺🇸Rancho Cordova, California, United States
Rohnert Park Cancer Center
🇺🇸Rohnert Park, California, United States
The Permanente Medical Group-Roseville Radiation Oncology
🇺🇸Roseville, California, United States
South Sacramento Cancer Center
🇺🇸Sacramento, California, United States
Kaiser Permanente Medical Center - Santa Clara
🇺🇸Santa Clara, California, United States
City of Hope South Pasadena
🇺🇸South Pasadena, California, United States
Kaiser Permanente Cancer Treatment Center
🇺🇸South San Francisco, California, United States
CSSS Champlain-Charles Le Moyne
🇨🇦Greenfield Park, Quebec, Canada
City of Hope South Bay
🇺🇸Torrance, California, United States
City of Hope Upland
🇺🇸Upland, California, United States
Boca Raton Regional Hospital
🇺🇸Boca Raton, Florida, United States
UM Sylvester Comprehensive Cancer Center at Coral Gables
🇺🇸Coral Gables, Florida, United States
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
🇺🇸Deerfield Beach, Florida, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
🇺🇸Hollywood, Florida, United States
Mayo Clinic in Florida
🇺🇸Jacksonville, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸Miami, Florida, United States
Memorial Hospital West
🇺🇸Pembroke Pines, Florida, United States
UM Sylvester Comprehensive Cancer Center at Plantation
🇺🇸Plantation, Florida, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Piedmont Hospital
🇺🇸Atlanta, Georgia, United States
Emory University Hospital/Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States
Emory Saint Joseph's Hospital
🇺🇸Atlanta, Georgia, United States
Saint Alphonsus Cancer Care Center-Boise
🇺🇸Boise, Idaho, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Decatur Memorial Hospital
🇺🇸Decatur, Illinois, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
HSHS Saint Elizabeth's Hospital
🇺🇸O'Fallon, Illinois, United States
Methodist Medical Center of Illinois
🇺🇸Peoria, Illinois, United States
OSF Saint Francis Medical Center
🇺🇸Peoria, Illinois, United States
Northwestern Medicine Cancer Center Warrenville
🇺🇸Warrenville, Illinois, United States
Community Cancer Center North
🇺🇸Indianapolis, Indiana, United States
Iowa Methodist Medical Center
🇺🇸Des Moines, Iowa, United States
Luminis Health Anne Arundel Medical Center
🇺🇸Annapolis, Maryland, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
University of Michigan Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States
Regions Hospital
🇺🇸Saint Paul, Minnesota, United States
Saint Francis Medical Center
🇺🇸Cape Girardeau, Missouri, United States
Siteman Cancer Center at West County Hospital
🇺🇸Creve Coeur, Missouri, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center-South County
🇺🇸Saint Louis, Missouri, United States
Missouri Baptist Medical Center
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center at Saint Peters Hospital
🇺🇸Saint Peters, Missouri, United States
Billings Clinic Cancer Center
🇺🇸Billings, Montana, United States
Benefis Sletten Cancer Institute
🇺🇸Great Falls, Montana, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸Lebanon, New Hampshire, United States
AtlantiCare Surgery Center
🇺🇸Egg Harbor Township, New Jersey, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
SUNY Upstate Medical Center-Community Campus
🇺🇸Syracuse, New York, United States
Mission Hospital
🇺🇸Asheville, North Carolina, United States
Cone Health Cancer Center
🇺🇸Greensboro, North Carolina, United States
East Carolina University
🇺🇸Greenville, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Sanford Bismarck Medical Center
🇺🇸Bismarck, North Dakota, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Legacy Good Samaritan Hospital and Medical Center
🇺🇸Portland, Oregon, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Fox Chase Cancer Center Buckingham
🇺🇸Furlong, Pennsylvania, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Geisinger Wyoming Valley/Henry Cancer Center
🇺🇸Wilkes-Barre, Pennsylvania, United States
Self Regional Healthcare
🇺🇸Greenwood, South Carolina, United States
Huntsman Cancer Institute/University of Utah
🇺🇸Salt Lake City, Utah, United States
Dartmouth Cancer Center - North
🇺🇸Saint Johnsbury, Vermont, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Arthur J E Child Comprehensive Cancer Centre
🇨🇦Calgary, Alberta, Canada
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
BCCA-Vancouver Cancer Centre
🇨🇦Vancouver, British Columbia, Canada
QEII Health Sciences Centre/Nova Scotia Health Authority
🇨🇦Halifax, Nova Scotia, Canada
Juravinski Cancer Centre at Hamilton Health Sciences
🇨🇦Hamilton, Ontario, Canada
London Regional Cancer Program
🇨🇦London, Ontario, Canada
University Health Network-Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
CHUM - Centre Hospitalier de l'Universite de Montreal
🇨🇦Montreal, Quebec, Canada
The Research Institute of the McGill University Health Centre (MUHC)
🇨🇦Montreal, Quebec, Canada
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ)
🇨🇦Quebec City, Quebec, Canada
Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
🇨🇦Sherbrooke, Quebec, Canada