This clinical trial studies the side effects of stereotactic radiosurgery and how well it works with or without vertebroplasty, separation surgery, or immunotherapy in patients with cancer that is radiation resistant and has spread to the spine (spinal metastases). Spinal metastases are rapidly progressive, have poor prognosis, are extremely difficult to treat, and can effect patient quality of life and overall health. Immunotherapy is a type of standard of care therapy to boost or restore the ability of the immune system to fight cancer. Stereotactic radiosurgery is a type of external radiation therapy that uses special equipment to position the patient and precisely give a single large dose of radiation to a tumor. A vertebroplasty is a procedure used to repair a bone in the spine that has a break caused by cancer, osteoporosis, or trauma. The purpose of this trial is to test different combinations of immunotherapy, stereotactic radiosurgery, and surgery to improve overall survival and quality of life in patients with spinal metastases.

PRIMARY OBJECTIVE:

I. To determine the overall efficacy and safety of stereotactic radiosurgery (SRS) with or without vertebroplasty or separation surgery in patients with radiation resistant histologies metastatic to the spine with or without concurrent immunotherapy with PD1 blockade.

SECONDARY OBJECTIVES:

I. To assess 6 month vertebral compression fracture (VCF) rate. II. To assess local control (LC) and distant disease control rates. III. To assess the progression free survival (PFS). IV. To assess the overall survival (OS). V. To assess potential vertebral compression fracture (VCF) risk in cancer patients with spinal metastases (SM).

VI. To assess changes in pain from baseline with patient reported measures, medication changes, and quality of life (QoL) measures.

EXPLORATORY OBJECTIVES:

I. To assess changes in immune-stimulatory effect via Trex1 relative to radiation dose.

II. To evaluate whether changes in Trex1 correlates with PD-L1 expression. III. To validate known molecular signatures predicting metastatic potential and molecular mechanisms that have previously been documented.

IV. To develop novel molecular biomarker signatures that predict local spinal metastasis control.

V. To evaluate molecular signatures at the time of spinal metastasis, and potentially define the "molecular evolution" of a tumor after treatment.

OUTLINE:

INDETERMINATE COHORT: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo vertebroplasty 2-4 weeks later, undergo SRS over 1-3 fractions depending upon the number of affected vertebral bodies in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo SRS over 1-3 fractions depending upon the number of affected vertebral bodies in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Inclusion Criteria:

• At least 18 years of age and older with indeterminate Spine Metastasis.
• All patients with histology that requires stereotactic RT as a part of their treatment.
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Disease visualized by CT or MRI
• Prior radiation therapy will be allowed at the discretion of the Radiation Oncologist based on current standard operating procedures.
• Tumor tissue from the core biopsy or resected site of disease will be collected, if available for biomarker analyses.
• Four or less consecutive spinal segments involved by tumor. Or four or less separate spinal tumor targets with a minimum of one vertebral body separation
• Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaire in either English or Spanish. The baseline assessment must be completed within required timelines. Inability (illiteracy in English or Spanish, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible

Exclusion Criteria:

• Patients < 18 years of age
• Inability to get a standard MRI or CT myelogram for radiation treatment target delineation
• Patients with prior radiation to the spinal segment to be treated may be included if the radiation dose can be delivered safely, per the treating radiation oncologist.
• Patients with symptomatic spinal cord compression requiring emergent surgery
• Pregnant or lactating women
• Systemic therapy or immunosuppressive medications, excluding immunotherapy, within 3-14 days of radiation treatment, at the discretion of the treating radiation oncologist .
• Patients with stable or unstable lesions based on SINS criteria