Stereotactic Radiosurgery or Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases That Have Been Removed By Surgery

• ClinicalTrials.gov Identifier: NCT01372774
• Recruitment Status: Completed
• First Posted: June 14, 2011
• Results First Posted: July 26, 2018
• Last Update Posted: September 16, 2022
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Study Description

Brief Summary:

RATIONALE: Stereotactic radiosurgery may be able to send x-rays directly to the tumor and cause less damage to normal tissue. Radiation therapy uses high-energy x rays to kill tumor cells. It is not yet known whether stereotactic radiosurgery is more effective than whole-brain radiation therapy in treating patients with brain metastases that have been removed by surgery.

PURPOSE: This randomized phase III trial studies how well stereotactic radiosurgery works compared to whole-brain radiation therapy in treating patients with brain metastases that have been removed by surgery.

Condition or disease	Intervention/treatment	Phase
Cognitive/Functional Effects; Metastatic Cancer; Neurotoxicity; Radiation Toxicity; Unspecified Adult Solid Tumor, Protocol Specific	Radiation: stereotactic radiosurgery; Radiation: whole-brain radiation therapy	Phase 3

Detailed Description:

Primary Goals

1. Overall Survival - To determine in patients with one to four brain metastases whether there is improved overall survival in patients who receive SRS to the surgical bed compared to patients who receive WBRT.
2. Neurocognitive Progression - To determine in patients with one to four brain metastases whether there is less neurocognitive progression post-randomization in patients who receive SRS to the surgical bed compared to patients who receive WBRT.

Secondary Goals

1. Quality of Life (QOL) - To determine in patients with resected brain metastases whether there is improved QOL in patients who receive SRS to the surgical bed compared to patients who receive WBRT.
2. Central Nervous System Failure - To determine in patients with one to four brain metastases whether there is equal or longer time to central nervous system (CNS) failure (brain) in patients who receive SRS to the surgical bed compared to patients who receive WBRT.
3. Functional Independence - To determine in patients with one to four brain metastases whether there is longer duration of functional independence in patients who receive SRS to the surgical bed compared to patients who receive WBRT.
4. Long-Term Neurocognitive Status - To determine in patients with one to four brain metastases whether there is better long-term neurocognitive status in patients who receive SRS to the surgical bed compared to patients who receive WBRT.
5. Adverse Events - To tabulate and descriptively compare the post-treatment adverse events associated with the interventions.
6. Local Tumor Bed Recurrence - To evaluate local tumor bed recurrence at 6 months with post-surgical SRS to the surgical bed in comparison to WBRT.
7. Local Recurrence - To evaluate time to local recurrence with post-surgical SRS to the surgical bed in comparison to WBRT.
8. CNS Failure Patterns - To evaluate if there is any difference in CNS failure patterns (local, distant, leptomeningeal) in patients who receive SRS to the surgical bed compared to patients who receive WBRT.

OUTLINE: This is a multicenter study. Patients are stratified according to age in years (< 60 vs ≥ 60), extracranial disease controlled (≤ 3 months vs > 3 months), number of pre-operative brain metastases (1 vs 2-4), histology (lung vs radioresistant [brain metastases from a sarcoma, melanoma, or renal cell carcinoma histology] vs other), and resection cavity maximal diameter (≤ 3 cm vs > 3 cm). Patient must complete baseline QOL and neurocognitive tests prior to registration/randomization. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo whole-brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks.
• Arm II: Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure.

Event monitoring occurs up to 5 years post registration/randomization.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 194 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Trial of Post-Surgical Stereotactic Radiosurgery (SRS) Compared With Whole Brain Radiotherapy (WBRT) for Resected Metastatic Brain Disease
• Actual Study Start Date: July 2011
• Actual Primary Completion Date: August 2016
• Actual Study Completion Date: December 15, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Arm I - WBRT; Patients undergo whole brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization.	Radiation: whole-brain radiation therapy; Undergo radiotherapy (RT)
Experimental: Arm II - SRS; Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization.	Radiation: stereotactic radiosurgery; Undergo RT

Outcome Measures

Primary Outcome Measures :

1. Cognitive Deterioration Free Survival Post-radiation in Patients Who Received SRS Compared to Patients Who Received WBRT [ Time Frame: from baseline up to 5 years post radiation ]
   To determine in patients with one to four brain metastases whether there is less nuerocognitive progression post-randomization in patients who receive SRS to the surgical bed compared to patients who receive WBRT. Neurocognitive progression is defined as a drop of at least one stanard deviation from baseline in one of the six neurocognitive tests at post-randomization evaluation.
2. Overall Survival [ Time Frame: from baseline up to 5 years post radiation ]
   To determine in patients with one to four brain metastases whether there is improved overall survival in patients who receive SRS to the surgical bed compared to patients who receive WBRT. Overall survival is defined as the time from randomization to death from any cause.

Secondary Outcome Measures :

1. Local Control of the Surgical Bed [ Time Frame: Up to 6 months post radiation ]
   Local control of the surgical bed means that tumor did not recur at the unresected metastases treated with stereotactic radiosurgery, SRS, or whole brain radiotherapy, WBRT. Intercranial Brain Control Rates estimated via 1-Cumulatice Incidence Rate from Competing Risk survival analysis of time to the specific recurrence type. Deaths without recurrence are censored at time of death.
2. Time to CNS Failure in These Patients [ Time Frame: Up to 5 years post radiation ]
3. Change in Quality-of-life at 6 Months [ Time Frame: Up to 6 months post randomization ]
   Clinically significant change in quality of life is defined as ten-point change on QOL scores (transformed to a 0 to 100 scale). As measured by the overall score from the FACT-Br. An improvement is defined as a change greater than or equal ten points.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Pre-registration Inclusion Criteria:

1. Number of Brain Metastases - Four or fewer brain metastases (as defined on the pre-operative MRI or CT brain scan) and status post resection of one of the lesions.
2. Non-CNS Primary Site - Pathology from the resected brain metastasis must be consistent with a non-central nervous system primary site. Note: Patients with or without active disease outside the nervous system are eligible (including patients with unknown primaries), as long as the pathology from the brain is consistent with a non-central nervous system primary site.
3. Size of Metastases - Any unresected lesions must measure < 3.0 cm in maximal extent on the contrasted MRI or CT brain scan obtained ≤ 35 days prior to pre-registration. The unresected lesions will be treated with SRS as outlined in the treatment section of the protocol. Note: The metastases size restriction does not apply to the resected brain metastasis; with resected brain metastases only surgical cavity size determines eligibility.

4. Size of Resection Cavity - Resection cavity must measure <5.0 cm in maximal extent on the post-operative MRI or CT brain scan obtained ≤35 days prior to pre-registration.

   Note: It is permissible for the resection of a dominant brain metastasis to include a smaller "satellite" metastasis as long as the single resection cavity is less than the maximum size requirements.

5. Tumor Staging Procedures - All standard tumor-staging procedures necessary to define baseline extra cranial disease status completed ≤42 days prior to pre-registration.
6. Treatment with Gamma Knife or Radiosurgery - Able to be treated with either a gamma knife or a linear accelerator-based radiosurgery system.
7. Age ≥ 18 years
8. Neurocognitive Testing - Willing and able to complete neurocognitive testing without assistance from family and companions. Note: Because neurocognitive testing is one of the primary goals of this study, patients must be able to utilize English language booklets (and/or French booklets if enrolled in Canada).
9. Quality of Life (QOL) Questionnaires - Willing and able to complete QOL by themselves or with assistance
10. ECOG Performance Status - ECOG Performance Status (PS) 0, 1, or 2.
11. SRS Credentialed by IROC Houston Quality Assurance - The site's SRS facility is IROC Houston Quality Assurance approved.
12. Neurocognitive Testing Credentialing - The site study team member performing neurocognitive testing of patients must have credentialing confirming completion of the neurocognitive testing training of the protocol.
13. Written Informed Consent - Provide written informed consent
14. Mandatory Samples for Correlative Tests - Willing to provide mandatory blood and urine samples for correlative research purposes.

Pre-registration Exclusion Criteria:

1. Pregnancy, Nursing and Contraception - pregnant women, nursing women and men or women of childbearing potential who are unwilling to employ adequate contraception throughout the study and for men for up to 3 months after completing treatment.
2. Prior Cranial Radiation Therapy
3. MRI or CT Scans - Inability to complete a MRI or CT scan with contrast of the head.
4. Gadolinium Allergy - Known allergy to gadolinium.
5. Cytotoxic Chemotherapy - Planned cytotoxic chemotherapy during the SRS or WBRT.
6. Other Tumor Types - Primary germ cell tumor, small cell carcinoma, or lymphoma
7. Leptomeningeal Metastasis - Widespread definitive leptomeningeal metastasis
8. Location of Brain Metastasis - A brain metastasis that is located ≤ 5 mm of the optic chiasm or within the brainstem.

Randomization Inclusion Criteria:

1. Number of Unresected Lesions - Post-operative MRI or CT scan confirmed zero, one, two or three unresected lesions.

   1.1 Each unresected lesion must measure ≤ 3.0 cm in maximal extent on the contrasted post-operative MRI or CT brain scan.

   1.2 Note: The pre-registration, post-operative, brain scan may be used for the randomization scan if obtained ≤ 28 days prior to randomization.

   1.3 Note: If there are no unresected brain metastases (i.e., all brain metastases have been resected), a post-operative CT brain scan may be used if obtained ≤ 28 days prior to randomization.

2. Size of Resection Cavity - Post-operative MRI or CT scan confirms resection cavity measures < 5.0 cm in maximal extent.

   2.1 Note: The pre-registration, post-operative brain scan may be used for the randomization scan if obtained ≤ 28 days prior to randomization.

   2.2 Note: If there are no unresected brain metastases (i.e., all brain metastases have been resected), a post-operative CT brain scan may be used if obtained ≤28 days prior to randomization.

3. Urine or Serum Pregnancy Test - Negative urine or serum pregnancy test done ≤ 7 days prior to randomization, for women of child bearing potential only.

Randomization Exclusion Criteria: none

Contacts and Locations

Locations

United States, California

Mills - Peninsula Hospitals

Burlingame, California, United States, 94010

Los Angeles County-USC Medical Center

Los Angeles, California, United States, 90033

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States, 90033

United States, Delaware

Christiana Care Health System-Christiana Hospital

Newark, Delaware, United States, 19718

United States, Florida

Mount Sinai Medical Center

Miami Beach, Florida, United States, 33140

United States, Georgia

John B Amos Cancer Center

Columbus, Georgia, United States, 31904

United States, Illinois

NorthShore University HealthSystem-Evanston Hospital

Evanston, Illinois, United States, 60201

United States, Indiana

Memorial Hospital of South Bend

South Bend, Indiana, United States, 46601

United States, Massachusetts

Lowell General Hospital

Lowell, Massachusetts, United States, 01854

Saint Vincent Hospital/Reliant Medical Group

Worcester, Massachusetts, United States, 01608

United States, Michigan

West Michigan Cancer Center

Kalamazoo, Michigan, United States, 49007-3731

United States, Minnesota

Sanford Clinic North-Bemidji

Bemidji, Minnesota, United States, 56601

Mayo Clinic Cancer Center

Rochester, Minnesota, United States, 55905

Regions Hospital

Saint Paul, Minnesota, United States, 55101

United Hospital

Saint Paul, Minnesota, United States, 55102

United States, Nebraska

University of Nebraska Medical Center

Omaha, Nebraska, United States, 68198

United States, New Hampshire

Wentworth-Douglass Hospital

Dover, New Hampshire, United States, 03820

United States, New Jersey

Somerset Medical Center

Somerville, New Jersey, United States, 08876

United States, New York

State University of New York Upstate Medical University

Syracuse, New York, United States, 13210

United States, North Carolina

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States, 27599

Novant Health Presbyterian Medical Center

Charlotte, North Carolina, United States, 28233-3549

United States, North Dakota

Sanford Bismarck Medical Center

Bismarck, North Dakota, United States, 58501

Sanford Clinic North-Fargo

Fargo, North Dakota, United States, 58102

Sanford Roger Maris Cancer Center

Fargo, North Dakota, United States, 58122

United States, Ohio

Summa Akron City Hospital/Cooper Cancer Center

Akron, Ohio, United States, 44304

Case Western Reserve University

Cleveland, Ohio, United States, 44106

United States, Oregon

Legacy Good Samaritan Hospital and Medical Center

Portland, Oregon, United States, 97210

United States, Pennsylvania

Abington Memorial Hospital

Abington, Pennsylvania, United States, 19001

Saint Luke's University Hospital-Bethlehem Campus

Bethlehem, Pennsylvania, United States, 18015

Geisinger Medical Center

Danville, Pennsylvania, United States, 17822

Aria Health-Torresdale Campus

Philadelphia, Pennsylvania, United States, 19114

United States, South Dakota

Sanford Cancer Center Oncology Clinic

Sioux Falls, South Dakota, United States, 57104

Sanford USD Medical Center - Sioux Falls

Sioux Falls, South Dakota, United States, 57117

United States, Tennessee

Thompson Cancer Survival Center

Knoxville, Tennessee, United States, 37916

United States, Texas

University of Texas Medical Branch

Galveston, Texas, United States, 77555

United States, Wisconsin

Saint Vincent Hospital

Green Bay, Wisconsin, United States, 54301

Froedtert and the Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Alliance for Clinical Trials in Oncology

National Cancer Institute (NCI)

Investigators

• Study Chair: Paul D. Brown, MD; M.D. Anderson Cancer Center

More Information

Additional Information:

Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Palmer JD, Klamer BG, Ballman KV, Brown PD, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, Greenspoon J, Parney IF, Laack NNI, Ashman JB, Bahary JP, Hadjipanayis CG, Urbanic JJ, Barker FG 2nd, Farace E, Khuntia D, Giannini C, Buckner JC, Galanis E, Roberge D. Association of Long-term Outcomes With Stereotactic Radiosurgery vs Whole-Brain Radiotherapy for Resected Brain Metastasis: A Secondary Analysis of The N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group) Randomized Clinical Trial. JAMA Oncol. 2022 Dec 1;8(12):1809-1815. doi: 10.1001/jamaoncol.2022.5049.

Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, Greenspoon J, Parney IF, Laack NNI, Ashman JB, Bahary JP, Hadjipanayis CG, Urbanic JJ, Barker FG 2nd, Farace E, Khuntia D, Giannini C, Buckner JC, Galanis E, Roberge D. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1049-1060. doi: 10.1016/S1470-2045(17)30441-2. Epub 2017 Jul 4.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT01372774
• Other Study ID Numbers: N107C; NCCTG-N107C; CDR0000701474 ( Registry Identifier: PDQ (Physician Data Query) ); NCI-2011-02676 ( Registry Identifier: CTRP (Clinical Trials Reporting System) )
• First Posted: June 14, 2011
• Results First Posted: July 26, 2018
• Last Update Posted: September 16, 2022
• Last Verified: September 2022

Keywords provided by Alliance for Clinical Trials in Oncology:

neurotoxicity; radiation toxicity; cognitive/functional effects; tumors metastatic to brain; unspecified adult solid tumor, protocol specific

Additional relevant MeSH terms:

Neurotoxicity Syndromes; Nervous System Diseases; Poisoning; Chemically-Induced Disorders