Neo-Adjuvant vs. Post-Operative Stereotactic Radiosurgery for Operative Metastatic Brain Tumors

PRIMARY OBJECTIVES:

I. To determine for patients with brain metastases meeting the inclusion criteria, whether
there is an increase in the time to a composite endpoint of adverse outcomes including the
first occurrence of either: local recurrence, leptomeningeal disease, or symptomatic
radiation brain necrosis in patients who receive SRS prior to surgery as compared to patients
who receive surgery prior to SRS.

SECONDARY OBJECTIVES:

I. To determine for patients with brain metastases whether there is improved overall survival
for patients who receive SRS prior to surgery as compared to patients who receive SRS after
surgery.

II. To determine for patients with brain metastases whether there are improved patient
reported outcomes including quality of life for patients who receive SRS prior to surgery as
compared to patients who receive SRS after surgery.

III. To determine if preoperative SRS increases rates of surgical morbidity including
postoperative complications such as wound infection, need for longer hospital stays, or
readmission compared to a surgery first approach for resectable brain metastases.

IV. To determine for patients with brain metastases whether there is a higher rate of
completion of planned therapies for patients who receive SRS prior to surgery as compared to
patients who receive surgery prior to SRS.

V. To determine for patients with brain metastases whether there is a shorter time to
initiation or re-initiation of systemic therapy with pre-operative versus post-operative SRS.

VI. To determine for patients treated with pre-operative SRS whether there is a longer
interval to regional progression, any central nervous system (CNS) progression or need for
subsequent intracranial treatment compared to patients receiving post-operative SRS.

VII. To determine for patients with pre-operative as compared to post-operative radiation
whether there is a decreased rate of radiation necrosis, including asymptomatic and
symptomatic radiation necrosis.

VIII. To determine for patients with pre-operative as compared to post-operative radiation
whether there is a decreased rate of local recurrence.

IX. To determine for patients with pre-operative as compared to post-operative radiation
whether there is a decreased rate of leptomeningeal disease.

CORRELATIVE RESEARCH OBJECTIVES:

I. To determine the genetic and molecular alterations of brain metastases seen after
radiation versus in the setting of resection alone, including early radiobiologic changes in
tissue treated with SRS 24 to 48 hours prior, and to investigate detection rate of
corresponding circulating deoxyribonucleic acid (DNA) and/or inflammatory markers in
peripheral specimens.

II. To investigate the usefulness of biomarkers and response to radiation in predicting local
control and outcomes.

III. To look at cell capture of tumor cells as well as cell free DNA in cerebrospinal fluid
(CSF) sampled at the time of surgery, comparing patients receiving neoadjuvant treatment to
those that have not.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients undergo stereotactic radiosurgery on day 1. Within 4 weeks, patients undergo
surgery.

ARM B: Patients undergo surgery on day 1. Within 2 weeks, patients undergo stereotactic
radiosurgery.

After completion of study treatment, patients are followed up at 2 weeks, every 3-4 months
for up to 2 years and then periodically for up to 3 years.

Inclusion Criteria:

- Histological or cytological confirmation of solid tumor malignancy and/or clinical
history of known or suspected metastatic disease with an intraparenchymal brain tumor
consistent with brain metastasis based on clinical and radiologic findings

- Clinical indication for surgical resection of one brain metastasis based on
neurosurgery recommendation and patient deemed a surgical candidate

- Clinical indication and plan for stereotactic radiosurgery to all known brain lesions
requiring treatment (=< 10 metastases)

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2

- Negative pregnancy test done =< 7 days prior to registration, for persons of
childbearing potential only

- Provide written informed consent

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study) or agreement to complete pre-specified magnetic resonance imaging
(MRI) series and follow-up visits according to the study timeline mailing in digital
copies of images as well as clinical notes

Exclusion Criteria:

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy. * NOTE: Patients known to be
HIV, but without clinical evidence of an immunocompromised state, are eligible for
this trial

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Prior open neurosurgery for malignancy

- Primary germ cell tumor, small cell carcinoma, or lymphoma

- History of whole brain radiation therapy (WBRT)

- 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

- Leptomeningeal metastasis/disease

- A brain metastasis that is located =< 5 mm of the optic chiasm

- Any brain metastasis > 5 cm in size

- > 10 brain metastases

- Indication for surgical resection of >= 2 brain metastases

- Indication for long-term (anticipated greater than 4 weeks) 4 mg dexamethasone
equivalent of steroids or bevacizumab