International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationAssociation Between Radiation Necrosis and Tumor Biology After Stereotactic Radiosurgery for Brain Metastasis
Introduction
Approximately 170,000 new cases of brain metastasis are diagnosed annually in the United States, with a median life expectancy of less than 10 months 1, 2. Modern multidisciplinary care incorporates resection, systemic therapy, whole brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Unfortunately, limited intracranial penetration of systemic agents necessitates aggressive local therapy. The chief dose-limiting toxicity of SRS is radiation necrosis (RN), which occurs after approximately 5% to 10% of treatments 3, 4. This adverse event may worsen neurologic deficits, increase the frequency and cost of imaging, and necessitate prolonged treatment with steroids or antiangiogenic agents 4, 5, 6.
Although SRS generally offers robust local control, 12-month local failure approaches 20% for larger metastases, with limited capacity to dose-escalate secondary to RN (7). As survival increases with improvements in systemic therapies, intracranial control becomes increasingly imperative, and thus strategic dose escalation is desirable. Over the past decade, there has been tremendous interest in biological risk stratification and precision medicine 8, 9, 10. Although dosimetric parameters have been associated with RN, no investigations have identified associations between RN and histology, receptor status, or mutational status 3, 11, 12, 13, 14. Accordingly, the rate of RN has not significantly decreased, representing a significant source of treatment-related morbidity and cost (3). We hypothesized that disease histology, receptor status, and mutational status are associated with the rate of RN.
Section snippets
Patient selection and data collection
An institutional review board (IRB)-approved retrospective cohort study was conducted. All patients presenting with brain metastasis between 1997 and 2015 who underwent SRS at a single tertiary-care institution were eligible for inclusion. Patients treated with surgery, WBRT, or both alone were excluded. Lesions without radiographic follow-up were excluded.
The following data were retrospectively collected in an IRB-approved registry: age, sex, primary pathology, Karnofsky performance status
Patient characteristics
In all, 1939 patients (5747 lesions) were eligible for inclusion; 2246 patients with brain metastasis did not undergo SRS and were excluded, and 182 patients did not undergo follow-up imaging after SRS and were excluded. Patients without radiographic follow-up were of comparable age, sex, extracranial disease burden, and intracranial disease burden. Median KPS (80 vs 80, P<.01) and GPA (median, 2 vs 2, P<.01) were statistically but not clinically significantly poorer. A greater proportion of
Discussion
We report the largest series evaluating RN, and the first to specifically identify associations between tumor biology and this dose-limiting adverse event. In support of our hypothesis, we observed distinct populations at increased risk for RN, including patients with renal cell carcinoma, HER2-amplified breast cancers, ALK+ lung cancers, and V600 wild-type melanoma. As the prevalence of brain metastasis increases, incorporation of biological characteristics into predictive models may permit
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Conflict of interest: S.T. Chao receives honoraria from Varian Medical Systems. M.A. Vogelbaum holds equity in, receives royalties from, and is a company founder and officer of Infuseon Therapeutics, Inc; receives honoraria for scientific advisory meeting from Pharmicokinesis, Inc; and receives honoraria for DSMB membership from Neuralstem, Inc. M.S. Ahluwalia is a consultant for and receives grant support from Elekta; receives grant support from Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Spectrum Pharmaceuticals, Tracon Pharmaceuticals, and Novocure; and is a consultant for Merck, Genentech/Roche, Incyte, Caris Lifesciences, Monteris Medical, and MRI Interventions Inc. J.H. Suh receives travel support from Elekta and research support from Varian Medical Systems. The other authors report no conflict of interest.