Following the EAB for NCI Designation this study was identified as having no funding and not meeting enrollment goals. It was requested by the EAB that this study be closed due to inactivity.

This pilot study is a randomized, open-label, 2-arm active-controlled phase II clinical trial conducted at a single study site (UAMS). Subjects will be randomized to one of the 2 treatment arms and stratified by size of index lesion and number of brain metastases.

The investigators will prospectively compare preoperative (neoadjuvant) SRS/SRT to postoperative (adjuvant) SRS/SRT in patients undergoing surgical resection for brain metastases.

The investigators hypothesize that neoadjuvant SRS/SRT prior to surgical resection of brain metastases will result in improved freedom from Central Nervous System (CNS) events when compared to adjuvant SRS/SRT after surgical resection.

Inclusion Criteria:

• Patients with prior histopathological diagnosis of cancer other than small cell lung cancer, lymphoma, and germ cell histologies.
• MR imaging of the brain with findings strongly suggestive of metastatic tumor(s) as assessed by the radiologist.
• Seen by a neurosurgeon or radiation oncologist and judged to be appropriate for participation in this study, including the ability to tolerate both surgery and SRS/SRT, e.g., the ability to lie flat in a stereotactic soft head frame.
• ECOG ≤ 2
• 1-2 index lesion(s) appropriate for resection, not previously treated with SRS/SRT.

Index lesion(s) should be > 2 cm and < 5 cm in largest dimension, and require resection. Alternatively, patients with a diagnosis of melanoma and a lesion < 1.5cm in largest dimension may also be included. o All other brain lesions must be appropriate for SRS/SRT alone and treated according to physician preference. Prior neurosurgery and/or prior SRS/SRT at a non-overlapping location are permitted at the discretion of the treating physician.

- MRI confirmed 1-10 lesions, 1-2 of which are the index lesions undergoing surgery.

Each non-index lesion (up to 10) must measure ≤ 3.0 cm in maximal extent on contrasted MRI scan, and not otherwise require resection.

• Clinical indication and plan for stereotactic radiosurgery to all known brain lesions requiring treatment (≤ 10 metastases).
• Surgical resection able to be performed within 15 days of radiotherapy completion.
• Written informed consent obtained from subject, or a legally designated power of attorney and ability for subject to comply with the requirements of the study.
• Negative pregnancy test in women of childbearing potential (WOCBP) within 30 days of radiation. WOCBP is a female patient less than 50 years of age or who has menstruated within the last 12 months.
• Platelet count > 80 k/cumm, Hgb > 7.5 gm/dL, INR < 1.3, ANC > 1.5 k/cumm

Exclusion Criteria:

• Not a surgical candidate per neurosurgeon's discretion.

• Contraindication to general anesthesia.

• Not a radiosurgical candidate per radiation oncologist's discretion.

• Metastatic germ cell tumor, small cell carcinoma, leukemia, multiple myeloma or lymphoma or any primary brain tumor

• ECOG > 2

• < 3 months expected survival

• Radiologic documentation of hydrocephalus in addition to symptoms of hydrocephalus

• Radiographic or cytologic evidence of leptomeningeal disease.

• Imaging Findings:

  • Midline shift > 6mm
  • >10 lesions, one of which is the index lesion
  • Largest lesion > 5cm

• Pregnancy

• Known allergy to gadolinium, pacemaker, or other contraindication such as metal implant that is not safe for MRI. Patients with MRI-compatible implants are eligible.

• Patients who have local recurrence of previously treated brain metastasis.

• Patients who have received prior WBRT.

• Inherited radiation hypersensitivity syndromes

  o Ataxia Telangiectasia, Nijmegen Breakage Syndrome, Fanconi Anemia, DNA Ligase IV, Mre 11 deficiency, SCID, Bloom's syndrome

• Collagen vascular diseases

  o Active systemic lupus erythematous (SLE), scleroderma, mixed connective tissue disorder, polymyositis or dermatomyositis, CREST Syndrome

• Cytotoxic Chemotherapy within 7 days prior to SRS/SRT.

  o Molecularly targeted therapies, including immune-modulatory drugs, can be given within 7 days of SRS/SRT at the discretion of the treating physician.

• Patients who received anti-VEGF therapy within 6 weeks prior to enrollment, as there is increased risk of fatal brain hemorrhage with surgical resection.

• Treatment plan respecting normal tissue tolerances using dose fractionation specified within the protocol cannot be achieved.

1 year

Outcome measures not computed because study closed prior to completion of follow-up visits so there is nothing to analyze.