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

Tracking Information

• First Submitted Date: June 11, 2011
• First Posted Date: June 14, 2011
• Results First Submitted Date: September 27, 2017
• Results First Posted Date: July 26, 2018
• Last Update Posted Date: September 16, 2022
• Actual Study Start Date: July 2011
• Actual Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 26, 2018)

• 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.
• 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.

Original Primary Outcome Measures (submitted: June 11, 2011)

• Neurocognitive progression at 6 months post-radiation in patients who received SRS compared to patients who received WBRT
• Overall survival

Current Secondary Outcome Measures (submitted: June 26, 2018)

• 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.
• Time to CNS Failure in These Patients [ Time Frame: Up to 5 years post radiation ]
• 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.

Original Secondary Outcome Measures (submitted: June 11, 2011)

• Local control of the surgical bed
• Time to CNS failure in these patients
• Quality-of-life at 6 months of these patients

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Stereotactic Radiosurgery or Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases That Have Been Removed By Surgery
• Official Title: A Phase III Trial of Post-Surgical Stereotactic Radiosurgery (SRS) Compared With Whole Brain Radiotherapy (WBRT) for Resected Metastatic Brain Disease

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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Cognitive/Functional Effects
• Metastatic Cancer
• Neurotoxicity
• Radiation Toxicity
• Unspecified Adult Solid Tumor, Protocol Specific

Intervention

• Radiation: stereotactic radiosurgery
  Undergo RT
• Radiation: whole-brain radiation therapy
  Undergo radiotherapy (RT)

Study Arms

• 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.
  Intervention: Radiation: whole-brain radiation therapy
• 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.
  Intervention: Radiation: stereotactic radiosurgery

Publications *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 26, 2018): 194
• Original Estimated Enrollment (submitted: June 11, 2011): 192
• Actual Study Completion Date: December 15, 2019
• Actual Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States
• Removed Location Countries: Canada

Administrative Information

• NCT Number: 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) )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Alliance for Clinical Trials in Oncology
• Original Responsible Party: Paul D. Brown, M. D. Anderson Cancer Center at University of Texas
• Current Study Sponsor: Alliance for Clinical Trials in Oncology
• Original Study Sponsor: North Central Cancer Treatment Group
• Collaborators: National Cancer Institute (NCI)

Investigators

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

• PRS Account: Alliance for Clinical Trials in Oncology
• Verification Date: September 2022