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

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.

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