Trial Information

A Phase III Trial of Post-Surgical Stereotactic Radiosurgery (SRS) Compared With Whole Brain Radiotherapy (WBRT) for Resected Metastatic Brain Disease

OBJECTIVES:

Primary

- To ascertain in patients with one to four brain metastases whether there is improved
overall survival in patients who receive stereotactic radiosurgery (SRS) to the
surgical bed compared to patients who receive whole-brain radiotherapy (WBRT).

- To ascertain in patients with one to four brain metastases whether there is less
neurocognitive progression at 6 months post-radiation in patients who receive SRS to
the surgical bed compared to patients who receive WBRT.

Secondary

- To ascertain in patients with resected brain metastases whether there is improved
quality-of-life (QOL) in patients who receive SRS to the surgical bed compared to
patients who receive WBRT.

- To ascertain in patients with one to four brain metastases whether there is equal
longer time to central nervous system (CNS) failure (brain) in patients who receive SRS
to the surgical bed compared to patients who receive WBRT.

- To ascertain 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.

- To ascertain 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.

- To tabulate and descriptively compare the post-treatment adverse events associated with
the interventions.

- To evaluate local tumor bed recurrence at 6 months with post-surgical SRS to the
surgical bed in comparison to WBRT.

- To evaluate time to local recurrence with post-surgical SRS to the surgical bed in
comparison to WBRT.

- 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.

Exploratory

- To evaluate radiation changes in the limbic system that may correlate with
neurotoxicity using brain MRI scans.

- To determine whether Apo E (i.e., Apo E2, Apo E3, and Apo E4) genotyping may prove to
be a predictor of radiation-induced neurocognitive decline (or neuroprotection).

- To determine whether inflammatory markers (i.e., IL-1, IL-6, and TNF-α) may prove to be
predictors of radiation-induced neurocognitive decline.

- To determine whether oxidative stress biomarkers (i.e., protein carbonyl content, lipid
hydroperoxides, and isoprostane levels) may prove to be predictors of radiation-induced
neurocognitive decline.

- To determine whether hormone and growth factors [i.e., glucocorticoids (e.g.,
cortisol), gonadal steroids (e.g., estradiol, testosterone, progesterone), growth
hormone, human chorionic gonadotropin (hCG), insulin-like growth factor-1 (IGF-1), and
neuronal growth factor (NGF)] may prove to be a predictor of radiation-induced
neurocognitive decline.

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). 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.

Serum, whole blood, and urine samples are collected at baseline and periodically during
study for genetic markers, inflammatory markers, oxidative stress biomarkers, and hormone
and growth factor studies by ELISA and other assays.

Patients complete the Functional Assessment of Cancer Therapy-Brain (FACT-BR), the
activities of daily living (ADLs), the Fatigue/Uniscale Assessment, and the Linear Analog
Self Assessment (LASA) quality-of-life questionnaires at baseline and periodically during
study. Neurocognitive functions, such as memory, verbal fluency, visual attention, executive
function, and delayed memory, are also assessed.

After completion of study therapy, patients are followed up periodically for 5 years.