Clinical Investigation
Association Between Radiation Necrosis and Tumor Biology After Stereotactic Radiosurgery for Brain Metastasis

https://doi.org/10.1016/j.ijrobp.2016.08.039Get rights and content

Background

The primary dose-limiting toxicity of stereotactic radiosurgery (SRS) is radiation necrosis (RN), which occurs after approximately 5% to 10% of treatments. This adverse event may worsen neurologic deficits, increase the frequency and cost of imaging, and necessitate prolonged treatment with steroids or antiangiogenic agents. Previous investigations have primarily identified lesion size and dosimetric constraints as risk factors for RN in small populations. We hypothesized that disease histology, receptor status, and mutational status are associated with RN.

Methods and Materials

All patients presenting with brain metastasis between 1997 and 2015 who underwent SRS and subsequent radiographic follow-up at a single tertiary-care institution were eligible for inclusion. The primary outcome was the cumulative incidence of radiographic RN. Multivariate competing risks regression was used to identify biological risk factors for RN.

Results

1939 patients (5747 lesions) were eligible for inclusion; 285 patients (15%) experienced radiographic RN after the treatment of 427 (7%) lesions. After SRS, the median time to RN was 7.6 months. After multivariate analysis, graded prognostic assessment, renal pathology, lesion diameter, and the heterogeneity index remained independently predictive of RN in the pooled cohort. In subset analyses of individual pathologies, HER2-amplified status (hazard ratio [HR] 2.05, P=.02), BRAF V600+ mutational status (HR 0.33, P=.04), lung adenocarcinoma histology (HR 1.89, P=.04), and ALK rearrangement (HR 6.36, P<.01) were also associated with RN.

Conclusions

In the present investigation constituting the largest series of RN, several novel risk factors were identified, including renal histology, lung adenocarcinoma histology, HER2 amplification, and ALK/BRAF mutational status. These risk factors may be used to guide clinical trial design incorporating biological risk stratification or dose escalation. Future studies determining the optimal timing of targeted therapies are warranted to further define the risk of RN.

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

References (32)

  • D. Boothe et al.

    Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery

    Neuro Oncol

    (2013)
  • K.L. Johung et al.

    Extended survival and prognostic factors for patients with ALK-rearranged non–small-cell lung cancer and brain metastasis

    J Clin Oncol

    (2016)
  • S.M. Shin et al.

    Survival but not brain metastasis response relates to lung cancer mutation status after radiosurgery

    J Neurooncol

    (2016)
  • G. Minniti et al.

    Stereotactic radiosurgery for brain metastases: Analysis of outcome and risk of brain radionecrosis

    Radiat Oncol

    (2011)
  • P.K. Sneed et al.

    Adverse radiation effect after stereotactic radiosurgery for brain metastases: Incidence, time course, and risk factors

    J Neurosurg

    (2015)
  • A.M. Mohammadi et al.

    Impact of radiosurgery prescription dose on the local control of small (≤2 cm) brain metastases

    J Neurosurg

    (2016)
  • Cited by (98)

    View all citing articles on Scopus

    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.

    View full text