Corticosteroids + Bevacizumab vs. Corticosteroids + Placebo (BEST) for Radionecrosis After Radiosurgery for Brain Metastases
Radionecrosis, Brain Metastases
About this trial
This is an interventional supportive care trial for Radionecrosis
Eligibility Criteria
Pre-Registration Eligibility Criteria:
- Patients who present with symptomatic brain radionecrosis after they have received radiosurgery for brain metastases from primary solid tumor including but not limited to lung, breast, colorectal cancer but excluding melanoma, choriocarcinoma, renal cell carcinoma or gliomas
- Patients at institutions that elect to utilize central imaging review to confirm eligibility must be pre-registered prior to submission of these images; images should be submitted as soon as possible after the pre-registration magnetic resonance imaging (MRI) is obtained; turnaround time for this review will be =< 72 business hours after receipt of images by the Imaging and Radiation Oncology Core (IROC)
- Patients at institutions that elect to confirm eligibility locally may be pre-registered at the same time as they are randomized
Registration/Randomization Eligibility Criteria:
A diagnosis of radionecrosis will be based on a clinical onset of symptoms and radiological findings of radionecrosis at 3-24 months following radiosurgery, with or without pathological confirmation.
1.1 'Symptomatic' brain radionecrosis to at least one lesion following radiosurgery treatment for brain metastases where 'symptomatic' is defined as:
1.1.1 New or increasing headache associated with mass effect, sensory or motor abnormality, cognitive changes, speech difficulty, balance or coordination difficulty, cranial nerve deficits
1.1.2 Symptoms are persistent or worsening despite administration of at least dexamethasone 4 mg (or equivalent corticosteroid) daily for 1 week
1.2 Clinical eligibility supported by central imaging real-time review. The presence of at least the following conventional MR image characteristic:
1.2.1 Conventional MR - Lesion quotient of < 0.3, where lesion quotient is defined as the proportional value of the maximum axial cross-sectional area of the T2-weighted defined lesion over the maximum axial cross-sectional area of the contrast-enhancing lesion on the T1-weighted post-gadolinium sequence on a comparable axial slice. If the conventional MR findings are not seen, the following dynamic susceptibility-contrast (DSC) MR characteristics may be used to meet eligibility for this study.
1.2.2 DSC MR - The cut-offs below will be based on GRE EPI DSC perfusion images, acquired without using a gadolinium pre-load:
1.2.2.1 Relative cerebral blood volume (rCBV) <1.5 in the enhancing- lesion relative to normal-appearing white matter (NAWM)
1.2.2.2. Percentage of signal recovery (PSR) > 76%, where PSR is determined by comparing the lower signal intensity during passage of the contrast bolus with the post-contrast signal intensity on the signal intensity-time curve
1.2.3 Centers that standardly use PET or MRS to determine a diagnosis of radionecrosis are permitted to use these modalities to assist in their patient selection; however the criteria described for conventional MR and/or DSC should also be met for study eligibility. Both PET and MRS are not mandatory for study eligibility.
Prior to start of treatment
2.1 Must have been taking a stable dose of corticosteroids for symptom management for at least 1 week before baseline MRI.
2.2 No systemic therapy within 2 weeks prior to registration or plan for systemic therapy within the first 8 weeks after study registration. The protocol provides a list of 'approved systemic' therapies that are allowed for concurrent use with bevacizumab.
2.3 No bevacizumab ≤ 3 months of study registration.
2.4 Central imaging real-time review (72 hour turn around) to confirm eligibility.
- Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done ≤ 14 days prior to registration and confirmation they are not nursing is required.
- Age ≥ 18 years
- Karnofsky Performance Status ≥ 60%
Required Initial Laboratory Values ≤14 days of registration:
6.1 Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3
6.2 Platelet Count ≥ 100,000/mm3
6.3 Hemoglobin ≥ 10 g/dL*
6.3.1 allowing transfusion or other intervention to achieve this minimum hemoglobin
6.4 BUN < 30 mg/dL
6.5 Creatinine < 1.7 mg/dL
6.6 Bilirubin ≤ 2.0 mg/dL
6.7 ALT ≤ 3.0 x upper limits of normal (ULN)
6.8 AST ≤ 3.0 x ULN
6.9 INR <1.5 x ULN**
6.9.1 unless patients are receiving anti-coagulation therapy. Patients receiving anti-coagulation therapy with an agent such warfarin or heparin are allowed to participate if INR ≤ 3.0.**
6.10 UPC Ratio <0.5 or if ≥ 0.5
6.10.1 24-hour urine protein must be <1000 mg
Able to participate in patient-report outcomes (MDASI-BT, DSQ-C, LASA) questionnaires.
Assistance by research personnel is acceptable if participant has disabilities that make reading or writing difficult.
- No evidence of recent hemorrhage at pre-registration MRI of the brain, however the following are permitted: presence of hemosiderin, resolving hemorrhagic changes related to surgery, and presence of punctate hemorrhage in the tumor.
No excess risk of bleeding (any of the following):
9.1 Bleeding diathesis or coagulopathy
9.2 Thrombocytopenia
9.3 Major surgical procedure, open biopsy, or significant traumatic injury within the past 28 days or anticipation of need for major surgical procedure during the course of the study.
9.4 Minor surgical procedures, stereotactic biopsy, fine needle aspiration, or core biopsy within the past 7 days.
No clinically significant cardiovascular disease.
10.1 No uncontrolled hypertension (systolic blood pressure ≤ 160 mm Hg or diastolic ≤ 100 mm Hg). Patients with hypertension must be adequately controlled with appropriate anti-hypertensive therapy or diet.
10.2 No history of arterial thrombotic events within the past 6 months, including:
10.2.1 transient ischemic attack (TIA)
10.2.2 cerebrovascular accident (CVA)
10.2.3 peripheral arterial thrombus
10.2.4 unstable angina or angina requiring surgical or medial intervention
10.2.5 myocardial infarction (MI)
10.2.6 significant peripheral artery disease (i.e., claudication on less than one block)
10.2.7 significant vascular disease (i.e., aortic aneurysm, history of aortic dissection)
10.3 Patients who have had a deep vein thrombosis or pulmonary embolus within the past 6 months are eligible if they are on stable therapeutic anticoagulation.
10.4 No current New York Heart Association classification II, III, or IV congestive heart failure.
- No history of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within past 12 months.
- No central lung metastases with excessive active bleeding.
No uncontrolled intercurrent illness including, but not limited to any of the following:
ongoing or active infection requiring IV antibiotics, cardiac arrhythmia, or psychiatric illness and/or social situations that would limit compliance with study requirements.
- No history of serious non-healing wound, ulcer, or bone fractures.
Sites / Locations
- Anchorage Associates in Radiation Medicine
- Anchorage Radiation Therapy Center
- Alaska Breast Care and Surgery LLC
- Alaska Oncology and Hematology LLC
- Alaska Women's Cancer Care
- Anchorage Oncology Centre
- Katmai Oncology Group
- Providence Alaska Medical Center
- PCR Oncology
- Providence Saint Joseph Medical Center/Disney Family Cancer Center
- UC San Diego Moores Cancer Center
- Beebe Medical Center
- Delaware Clinical and Laboratory Physicians PA
- Helen F Graham Cancer Center
- Medical Oncology Hematology Consultants PA
- Regional Hematology and Oncology PA
- Christiana Care Health System-Christiana Hospital
- Beebe Health Campus
- Nanticoke Memorial Hospital
- Christiana Care Health System-Wilmington Hospital
- Boca Raton Regional Hospital
- Halifax Health Medical Center-Centers for Oncology
- Baptist MD Anderson Cancer Center
- Mayo Clinic in Florida
- Moffitt Cancer Center
- University Cancer and Blood Center LLC
- Emory University Hospital/Winship Cancer Institute
- Memorial Health University Medical Center
- Summit Cancer Care-Memorial
- Low Country Cancer Care Associates PC
- Summit Cancer Care-Candler
- Saint Alphonsus Cancer Care Center-Boise
- Saint Luke's Mountain States Tumor Institute
- Saint Alphonsus Cancer Care Center-Caldwell
- Kootenai Medical Center
- Walter Knox Memorial Hospital
- Saint Luke's Mountain States Tumor Institute - Fruitland
- Idaho Urologic Institute-Meridian
- Saint Luke's Mountain States Tumor Institute - Meridian
- Saint Alphonsus Medical Center-Nampa
- Saint Luke's Mountain States Tumor Institute - Nampa
- Kootenai Cancer Center
- Kootenai Cancer Clinic
- Saint Luke's Mountain States Tumor Institute-Twin Falls
- Rush - Copley Medical Center
- Rush University Medical Center
- University of Illinois
- Carle on Vermilion
- Carle Physician Group-Effingham
- Carle Physician Group-Mattoon/Charleston
- Good Samaritan Regional Health Center
- Carle Cancer Center
- The Carle Foundation Hospital
- Rush-Copley Healthcare Center
- Deaconess Clinic Downtown
- Community Cancer Center East
- Community Cancer Center South
- Community Cancer Center North
- Community Howard Regional Health
- Memorial Regional Cancer Center Day Road
- Chancellor Center for Oncology
- Reid Health
- Memorial Hospital of South Bend
- Iowa Methodist Medical Center
- Medical Oncology and Hematology Associates-Des Moines
- Broadlawns Medical Center
- Iowa Lutheran Hospital
- Trinity Regional Medical Center
- Methodist West Hospital
- Central Care Cancer Center - Garden City
- Central Care Cancer Center - Great Bend
- Kansas Institute of Medicine Cancer and Blood Center
- Minimally Invasive Surgery Hospital
- Menorah Medical Center
- Saint Luke's South Hospital
- Mercy Medical Center
- Saint Joseph Mercy Hospital
- University of Michigan Comprehensive Cancer Center
- IHA Hematology Oncology Consultants-Brighton
- Saint Joseph Mercy Brighton
- IHA Hematology Oncology Consultants-Canton
- Saint Joseph Mercy Canton
- Caro Cancer Center
- IHA Hematology Oncology Consultants-Chelsea
- Saint Joseph Mercy Chelsea
- Hematology Oncology Consultants-Clarkston
- Newland Medical Associates-Clarkston
- Beaumont Hospital-Dearborn
- Ascension Saint John Hospital
- Great Lakes Cancer Management Specialists-Doctors Park
- Beaumont Hospital - Farmington Hills
- Genesee Cancer and Blood Disease Treatment Center
- Genesee Hematology Oncology PC
- Genesys Hurley Cancer Institute
- Hurley Medical Center
- Great Lakes Cancer Management Specialists-Van Elslander Cancer Center
- Lymphoma Clinic of Michigan
- Michigan Breast Specialists-Grosse Pointe Woods
- William Beaumont Hospital-Grosse Point
- Allegiance Health
- Sparrow Hospital
- Hope Cancer Clinic
- Saint Mary Mercy Hospital
- Great Lakes Cancer Management Specialists-Macomb Medical Campus
- Michigan Breast Specialists-Macomb Township
- Saint Mary's Oncology/Hematology Associates of Marlette
- Ascension Providence Hospitals - Novi
- 21st Century Oncology-Pontiac
- Hope Cancer Center
- Newland Medical Associates-Pontiac
- Saint Joseph Mercy Oakland
- Huron Medical Center PC
- Lake Huron Medical Center
- Great Lakes Cancer Management Specialists-Rochester Hills
- Michigan Cancer Specialists
- Oakland Colon and Rectal Association
- Cancer Care Associates PC
- Comprehensive Medical Center PLLC
- Hematology Oncology Consultants PC
- Oakland Medical Group
- William Beaumont Hospital-Royal Oak
- Saint Mary's of Michigan
- Oncology Hematology Associates of Saginaw Valley PC
- Ascension Providence Hospitals - Southfield
- Bhadresh Nayak MD PC-Sterling Heights
- Premier Hematology Oncology Care
- Mitchell Folbe MD PC
- Saint Joseph Health System-Tawas City
- Michigan Institute of Urology-Town Center
- Claudia BR Herke MD PC
- William Beaumont Hospital - Troy
- Hematology Oncology Consultants PC-Troy
- Advanced Breast Care Center PLLC
- Bhadresh Nayak MD PC-Warren
- Great Lakes Cancer Management Specialists-Macomb Professional Building
- Macomb Hematology Oncology PC
- Michigan Breast Specialists-Warren
- Saint John Macomb-Oakland Hospital
- Saint Mary's Oncology/Hematology Associates of West Branch
- Huron Gastroenterology PC
- IHA Hematology Oncology Consultants-Ann Arbor
- Essentia Health Saint Joseph's Medical Center
- Essentia Health - Deer River Clinic
- Essentia Health Saint Mary's - Detroit Lakes Clinic
- Essentia Health Cancer Center
- Essentia Health Saint Mary's Medical Center
- Miller-Dwan Hospital
- Lake Region Healthcare Corporation-Cancer Care
- Essentia Health - Fosston
- Essentia Health Hibbing Clinic
- Essentia Health - Park Rapids
- Mayo Clinic
- Essentia Health Sandstone
- Essentia Health Virginia Clinic
- Saint Louis Cancer and Breast Institute-Ballwin
- Central Care Cancer Center - Bolivar
- Cox Cancer Center Branson
- Siteman Cancer Center at West County Hospital
- Centerpoint Medical Center LLC
- Freeman Health System
- Mercy Hospital Joplin
- Saint Luke's Hospital of Kansas City
- Research Medical Center
- Saint Luke's East - Lee's Summit
- Delbert Day Cancer Institute at PCRMC
- Mercy Clinic-Rolla-Cancer and Hematology
- Heartland Regional Medical Center
- Saint Louis Cancer and Breast Institute-South City
- Washington University School of Medicine
- Siteman Cancer Center at Saint Peters Hospital
- Mercy Hospital Springfield
- CoxHealth South Hospital
- Mercy Hospital Washington
- Community Hospital of Anaconda
- Billings Clinic Cancer Center
- Bozeman Deaconess Hospital
- Benefis Healthcare- Sletten Cancer Institute
- Great Falls Clinic
- Saint Peter's Community Hospital
- Kalispell Regional Medical Center
- Community Medical Hospital
- Carson Tahoe Regional Medical Center
- Cancer and Blood Specialists-Henderson
- Comprehensive Cancer Centers of Nevada - Henderson
- Comprehensive Cancer Centers of Nevada-Horizon Ridge
- Las Vegas Cancer Center-Henderson
- Nevada Cancer Specialists-Saint Rose
- 21st Century Oncology-Henderson
- Comprehensive Cancer Centers of Nevada-Southeast Henderson
- Desert West Surgery
- Nevada Cancer Specialists?Oakey
- University Medical Center of Southern Nevada
- Cancer and Blood Specialists-Shadow
- Radiation Oncology Centers of Nevada Central
- 21st Century Oncology
- HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway
- HealthCare Partners Medical Group Oncology/Hematology-San Martin
- Radiation Oncology Centers of Nevada Southeast
- Cancer Therapy and Integrative Medicine
- 21st Century Oncology-Vegas Tenaya
- Ann M Wierman MD LTD
- Cancer and Blood Specialists-Tenaya
- Comprehensive Cancer Centers of Nevada - Northwest
- HealthCare Partners Medical Group Oncology/Hematology-Tenaya
- Nevada Cancer Specialists-Tenaya
- Comprehensive Cancer Centers of Nevada-Summerlin
- Summerlin Hospital Medical Center
- Las Vegas Cancer Center-Medical Center
- 21st Century Oncology-Fort Apache
- Comprehensive Cancer Centers of Nevada
- Nevada Cancer Specialists-Fort Apache
- HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills
- Comprehensive Cancer Centers of Nevada - Central Valley
- University Cancer Center
- Hope Cancer Care of Nevada-Pahrump
- Renown Regional Medical Center
- Saint Mary's Regional Medical Center
- Radiation Oncology Associates
- New Hampshire Oncology Hematology PA-Concord
- New Hampshire Oncology Hematology PA-Hooksett
- Englewood Hospital and Medical Center
- Overlook Hospital
- Roswell Park Cancer Institute
- Laura and Isaac Perlmutter Cancer Center at NYU Langone
- University of Rochester
- Randolph Hospital
- Cone Health Cancer Center at Alamance Regional
- UNC Lineberger Comprehensive Cancer Center
- Carolinas Medical Center/Levine Cancer Institute
- Southeastern Medical Oncology Center-Clinton
- Southeastern Medical Oncology Center-Goldsboro
- Wayne Memorial Hospital
- Cone Health Cancer Center
- East Carolina University
- Onslow Memorial Hospital
- Southeastern Medical Oncology Center-Jacksonville
- Cone Heath Cancer Center at Mebane
- Annie Penn Memorial Hospital
- Southeastern Medical Oncology Center-Wilson
- Wake Forest University Health Sciences
- Essentia Health Cancer Center-South University Clinic
- Essentia Health - Jamestown Clinic
- Cleveland Clinic Akron General
- Indu and Raj Soin Medical Center
- Dayton Physicians LLC-Miami Valley South
- Miami Valley Hospital South
- Oncology Hematology Care Inc-Kenwood
- Good Samaritan Hospital - Dayton
- Miami Valley Hospital
- Dayton Physicians LLC-Samaritan North
- Miami Valley Hospital North
- Armes Family Cancer Center
- Blanchard Valley Hospital
- Orion Cancer Care
- Atrium Medical Center-Middletown Regional Hospital
- Dayton Physicians LLC-Atrium
- Dayton Physicians LLC-Wayne
- Wayne Hospital
- Greater Dayton Cancer Center
- First Dayton Cancer Care
- Kettering Medical Center
- Dayton Physicians LLC-Signal Point
- Dayton Physicians LLC-Wilson
- Springfield Regional Cancer Center
- Springfield Regional Medical Center
- Dayton Physicians LLC-Upper Valley
- Upper Valley Medical Center
- Mercy Hospital Oklahoma City
- Saint Alphonsus Medical Center-Baker City
- Saint Charles Health System
- Clackamas Radiation Oncology Center
- Providence Oncology and Hematology Care Southeast
- Bay Area Hospital
- Providence Newberg Medical Center
- Saint Alphonsus Medical Center-Ontario
- Providence Willamette Falls Medical Center
- Providence Portland Medical Center
- Providence Saint Vincent Medical Center
- Lehigh Valley Hospital-Cedar Crest
- Lehigh Valley Hospital - Muhlenberg
- Christiana Care Health System-Concord Health Center
- Roper Hospital
- Charleston Hematology Oncology Associates-Roper
- Lowcountry Hematology Oncology PA-North Charleston
- Bon Secours Saint Francis Hospital
- Charleston Hematology Oncology Associates PA-Saint Francis
- Lowcountry Hematology Oncology PA-West Ashley
- Greenville Health System Cancer Institute-Laurens
- Greenville Health System Cancer Institute-Easley
- Greenville Health System Cancer Institute-Butternut
- Greenville Health System Cancer Institute-Faris
- Greenville Memorial Hospital
- Greenville Health System Cancer Institute-Eastside
- Greenville Health System Cancer Institute-Greer
- Lowcountry Hematology Oncology PA-Mount Pleasant
- Greenville Health System Cancer Institute-Seneca
- Greenville Health System Cancer Institute-Spartanburg
- Vanderbilt-Ingram Cancer Center Cool Springs
- Vanderbilt Breast Center at One Hundred Oaks
- Vanderbilt University/Ingram Cancer Center
- M D Anderson Cancer Center
- Providence Regional Cancer System-Aberdeen
- Cancer Care Center at Island Hospital
- PeaceHealth Saint Joseph Medical Center
- Providence Regional Cancer System-Centralia
- Swedish Medical Center-Edmonds
- Providence Regional Cancer Partnership
- Swedish Cancer Institute-Issaquah
- Kadlec Clinic Hematology and Oncology
- Providence Regional Cancer System-Lacey
- PeaceHealth Saint John Medical Center
- Pacific Gynecology Specialists
- Swedish Medical Center-Ballard Campus
- Kaiser Permanente Washington
- Swedish Medical Center-First Hill
- Swedish Medical Center-Cherry Hill
- Providence Regional Cancer System-Shelton
- Rockwood Clinic Cancer Treatment Center-Valley
- Rockwood Cancer Treatment Center-DHEC-Downtown
- Rockwood North Cancer Treatment Center
- PeaceHealth Southwest Medical Center
- Providence Saint Mary Regional Cancer Center
- Providence Regional Cancer System-Yelm
- United Hospital Center
- WVUH-Berkely Medical Center
- West Virginia University Healthcare
- Camden Clark Medical Center
- Ashland Memorial Medical Center
- Duluth Clinic Ashland
- University of Wisconsin Hospital and Clinics
- Billings Clinic-Cody
- Welch Cancer Center
- BCCA-Vancouver Cancer Centre
- Juravinski Cancer Centre at Hamilton Health Sciences
- Ottawa Hospital and Cancer Center-General Campus
- Odette Cancer Centre- Sunnybrook Health Sciences Centre
- University Health Network-Princess Margaret Hospital
- CHUM - Hopital Notre-Dame
- CHUM - Centre Hospitalier de l'Universite de Montreal
- Jewish General Hospital
- Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
Arms of the Study
Arm 1
Arm 2
Experimental
Experimental
bevacizumab + corticosteroids
placebo + corticosteroids
The patient will receive bevacizumab 10 mg/kg IV given on days 1 and 15 of a 28 day cycle for 4 cycles. Once the patient has started the study treatment, the dose of corticosteroids will be tapered every 5 days (e.g., dexamethasone 2 mg or prednisone 15 mg per taper), as tolerated, under the management of the treating MD. If patients deteriorate while tapering, dexamethasone will be increased up to a maximum of 16 mg per day, as per treating MD, to manage symptoms. Patients who meet the criteria for clinical progression will be treated as per treating MD.
The patient will receive placebo 0.9% NaCl volume equal to bevacizumab volume added to 100 mL bag of 0.9% NaCl delivered IV given on days 1 and 15 of a 28-day cycle for 4 cycles. Once the patient has started the study treatment, the dose of corticosteroids will be tapered every 5 days (e.g., dexamethasone 2 mg or prednisone 15 mg per taper), as tolerated, under the management of the treating MD. If patients deteriorate while tapering, dexamethasone will be increased up to a maximum of 16 mg per day, as per treating MD, to manage symptoms. Patients who meet the criteria for clinical progression will be allowed to receive bevacizumab according to the protocol.