Shireen Parsai, Jacob A. Miller, Aditya Juloori, Samuel T. Chao, Rupesh Kotecha, Alireza M. Mohammadi, Manmeet S. Ahluwalia, Erin S. Murphy, Gene H. Barnett, Michael A. Vogelbaum, Lilyana Angelov, David M. Peereboom and John H. Suh
With increasing survival for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer in the trastuzumab era, there is an increased risk of brain metastasis. Therefore, there is interest in optimizing intracranial disease control. Lapatinib is a small-molecule dual HER2/epidermal growth factor receptor inhibitor that has demonstrated intracranial activity against HER2+ breast cancer brain metastases. The objective of this study was to investigate the impact of lapatinib combined with stereotactic radiosurgery (SRS) on local control of brain metastases.
Patients with HER2+ breast cancer brain metastases who underwent SRS from 1997–2015 were included. The primary outcome was the cumulative incidence of local failure following SRS. Secondary outcomes included the cumulative incidence of radiation necrosis and overall survival.
One hundred twenty-six patients with HER2+ breast cancer who underwent SRS to 479 brain metastases (median 5 lesions per patient) were included. Among these, 75 patients had luminal B subtype (hormone receptor-positive, HER2+) and 51 patients had HER2-enriched histology (hormone receptor-negative, HER2+). Forty-seven patients received lapatinib during the course of their disease, of whom 24 received concurrent lapatinib with SRS. The median radiographic follow-up among all patients was 17.1 months. Concurrent lapatinib was associated with reduction in local failure at 12 months (5.7% vs 15.1%, p < 0.01). For lesions in the ≤ 75th percentile by volume, concurrent lapatinib significantly decreased local failure. However, for lesions in the > 75th percentile (> 1.10 cm3), concurrent lapatinib did not significantly improve local failure. Any use of lapatinib after development of brain metastasis improved median survival compared to SRS without lapatinib (27.3 vs 19.5 months, p = 0.03). The 12-month risk of radiation necrosis was consistently lower in the lapatinib cohort compared to the SRS-alone cohort (1.3% vs 6.3%, p < 0.01), despite extended survival.
For patients with HER2+ breast cancer brain metastases, the use of lapatinib concurrently with SRS improved local control of brain metastases, without an increased rate of radiation necrosis. Concurrent lapatinib best augments the efficacy of SRS for lesions ≤ 1.10 cm3 in volume. In patients who underwent SRS for HER2+ breast cancer brain metastases, the use of lapatinib at any time point in the therapy course was associated with a survival benefit. The use of lapatinib combined with radiosurgery warrants further prospective evaluation.
Aditya Juloori, Jacob A. Miller, Shireen Parsai, Rupesh Kotecha, Manmeet S. Ahluwalia, Alireza M. Mohammadi, Erin S. Murphy, John H. Suh, Gene H. Barnett, Jennifer S. Yu, Michael A. Vogelbaum, Brian Rini, Jorge Garcia, Glen H. Stevens, Lilyana Angelov and Samuel T. Chao
The object of this retrospective study was to investigate the impact of targeted therapies on overall survival (OS), distant intracranial failure, local failure, and radiation necrosis among patients treated with radiation therapy for renal cell carcinoma (RCC) metastases to the brain.
All patients diagnosed with RCC brain metastasis (BM) between 1998 and 2015 at a single institution were included in this study. The primary outcome was OS, and secondary outcomes included local failure, distant intracranial failure, and radiation necrosis. The timing of targeted therapies was recorded. Multivariate Cox proportional-hazards regression was used to model OS, while multivariate competing-risks regression was used to model local failure, distant intracranial failure, and radiation necrosis, with death as a competing risk.
Three hundred seventy-six patients presented with 912 RCC BMs. Median OS was 9.7 months. Consistent with the previously validated diagnosis-specific graded prognostic assessment (DS-GPA) for RCC BM, Karnofsky Performance Status (KPS) and number of BMs were the only factors prognostic for OS. One hundred forty-seven patients (39%) received vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Median OS was significantly greater among patients receiving TKIs (16.8 vs 7.3 months, p < 0.001). Following multivariate analysis, KPS, number of metastases, and TKI use remained significantly associated with OS.
The crude incidence of local failure was 14.9%, with a 12-month cumulative incidence of 13.4%. TKIs did not significantly decrease the 12-month cumulative incidence of local failure (11.4% vs 14.5%, p = 0.11). Following multivariate analysis, age, number of BMs, and lesion size remained associated with local failure. The 12-month cumulative incidence of radiation necrosis was 8.0%. Use of TKIs within 30 days of SRS was associated with a significantly increased 12-month cumulative incidence of radiation necrosis (10.9% vs 6.4%, p = 0.04).
Use of targeted therapies in patients with RCC BM treated with intracranial SRS was associated with improved OS. However, the use of TKIs within 30 days of SRS increases the rate of radiation necrosis without improving local control or reducing distant intracranial failure. Prospective studies are warranted to determine the optimal timing to reduce the rate of necrosis without detracting from survival.