Journal of Neurosurgery
Lilyana Angelov, Alireza M. Mohammadi, Elizabeth E. Bennett, Mahmoud Abbassy, Paul Elson, Samuel T. Chao, Joshua S. Montgomery, Ghaith Habboub, Michael A. Vogelbaum, John H. Suh, Erin S. Murphy, Manmeet S. Ahluwalia, Sean J. Nagel and Gene H. Barnett
Stereotactic radiosurgery (SRS) is the primary modality for treating brain metastases. However, effective radiosurgical control of brain metastases ≥ 2 cm in maximum diameter remains challenging and is associated with suboptimal local control (LC) rates of 37%–62% and an increased risk of treatment-related toxicity. To enhance LC while limiting adverse effects (AEs) of radiation in these patients, a dose-dense treatment regimen using 2-staged SRS (2-SSRS) was used. The objective of this study was to evaluate the efficacy and toxicity of this treatment strategy.
Fifty-four patients (with 63 brain metastases ≥ 2 cm) treated with 2-SSRS were evaluated as part of an institutional review board–approved retrospective review. Volumetric measurements at first-stage stereotactic radiosurgery (first SSRS) and second-stage SRS (second SSRS) treatments and on follow-up imaging studies were determined. In addition to patient demographic data and tumor characteristics, the study evaluated 3 primary outcomes: 1) response at first follow-up MRI, 2) time to local progression (TTP), and 3) overall survival (OS) with 2-SSRS. Response was analyzed using methods for binary data, TTP was analyzed using competing-risks methods to account for patients who died without disease progression, and OS was analyzed using conventional time-to-event methods. When needed, analyses accounted for multiple lesions in the same patient.
Among 54 patients, 46 (85%) had 1 brain metastasis treated with 2-SSRS, 7 patients (13%) had 2 brain metastases concurrently treated with 2-SSRS, and 1 patient underwent 2-SSRS for 3 concurrent brain metastases ≥ 2 cm. The median age was 63 years (range 23–83 years), 23 patients (43%) had non–small cell lung cancer, and 14 patients (26%) had radioresistant tumors (renal or melanoma). The median doses at first and second SSRS were 15 Gy (range 12–18 Gy) and 15 Gy (range 12–15 Gy), respectively. The median duration between stages was 34 days, and median tumor volumes at the first and second SSRS were 10.5 cm3 (range 2.4–31.3 cm3) and 7.0 cm3 (range 1.0–29.7 cm3). Three-month follow-up imaging results were available for 43 lesions; the median volume was 4.0 cm3 (range 0.1–23.1 cm3). The median change in volume compared with baseline was a decrease of 54.9% (range −98.2% to 66.1%; p < 0.001). Overall, 9 lesions (14.3%) demonstrated local progression, with a median of 5.2 months (range 1.3–7.4 months), and 7 (11.1%) demonstrated AEs (6.4% Grade 1 and 2 toxicity; 4.8% Grade 3). The estimated cumulative incidence of local progression at 6 months was 12% ± 4%, corresponding to an LC rate of 88%. Shorter TTP was associated with greater tumor volume at baseline (p = 0.01) and smaller absolute (p = 0.006) and relative (p = 0.05) decreases in tumor volume from baseline to second SSRS. Estimated OS rates at 6 and 12 months were 65% ± 7% and 49% ± 8%, respectively.
2-SSRS is an effective treatment modality that resulted in significant reduction of brain metastases ≥ 2 cm, with excellent 3-month (95%) and 6-month (88%) LC rates and an overall AE rate of 11%. Prospective studies with larger cohorts and longer follow-up are necessary to assess the durability and toxicities of 2-SSRS.
Rupesh Kotecha, Lilyana Angelov, Gene H. Barnett, Chandana A. Reddy, John H. Suh, Erin S. Murphy, Gennady Neyman and Samuel T. Chao
Traditionally, the treatment of choice for patients with metastases to the calvaria or skull base has been conventional radiation therapy. Because patients with systemic malignancies are also at risk for intracranial metastases, the utility of Gamma Knife surgery (GKS) for these patients has been explored to reduce excess radiation exposure to the perilesional brain parenchyma. The purpose of this study was to report the efficacy of GKS for the treatment of calvarial metastases and skull base lesions.
The authors performed a retrospective chart review of 21 patients with at least 1 calvarial or skull base metastatic lesion treated with GKS during 2001–2013. For 7 calvarial lesions, a novel technique, in which a bolus was placed over the treatment site, was used. For determination of local control or disease progression, radiation therapy data were examined and posttreatment MR images and oncology records were reviewed. Survival times from the date of procedure were estimated by using Kaplan-Meier analyses.
The median patient age at treatment was 57 years (range 29–84 years). A total of 19 (90%) patients received treatment for single lesions, 1 patient received treatment for 3 lesions, and 1 patient received treatment for 4 lesions. The most common primary tumor was breast cancer (24% of patients). Per lesion, the median clinical and radiographic follow-up times were 10.3 months (range 0–71.9 months) and 7.1 months (range 0–61.3 months), respectively. Of the 26 lesions analyzed, 14 (54%) were located in calvarial bones and 12 (46%) were located in the skull base. The median lesion volume was 5.3 cm3 (range 0.3–55.6 cm3), and the median prescription margin dose was 15 Gy (range 13–24 Gy). The median overall survival time for all patients was 35.9 months, and the 1-year local control rate was 88.9% (95% CI 74.4%–100%). Local control rates did not differ between lesions treated with the bolus technique and those treated with traditional methods or between calvarial lesions and skull base lesions (p > 0.05). Of the 3 patients for whom local treatment failed, 1 patient received no further treatment and 2 patients responded to salvage chemotherapy. Subsequent brain parenchymal metastases developed in 2 patients, who then underwent GKS.
GKS is an effective treatment modality for patients with metastases to the calvarial bones or skull base. For patients with superficial calvarial lesions, a novel approach with bolus application resulted in excellent rates of local control. GKS provides an effective therapeutic alternative to conventional radiation therapy and should be considered for patients at risk for calvarial metastases and brain parenchymal metastases.
Matthew M. Grabowski, Pablo F. Recinos, Amy S. Nowacki, Jason L. Schroeder, Lilyana Angelov, Gene H. Barnett and Michael A. Vogelbaum
The impact of extent of resection (EOR) on survival for patients with glioblastoma (GBM) continues to be a point of debate despite multiple studies demonstrating that increasing EOR likely extends survival for these patients. In addition, contrast-enhancing residual tumor volume (CE-RTV) alone has rarely been analyzed quantitatively to determine if it is a predictor of outcome. The purpose of this study was to evaluate the effect of CE-RTV and T2/FLAIR residual volume (T2/F-RV) on overall survival.
A retrospective review of 128 patients who underwent primary resection of supratentorial GBM followed by standard radiation/chemotherapy was undertaken utilizing quantitative, volumetric analysis of pre- and postoperative MR images. The results were compared with clinical data obtained from the patients' medical records.
At analysis, 8% of patients were alive, and no patients were lost to follow-up. The overall median survival was 13.8 months, with a median Karnofsky Performance Scale (KPS) score of 90 at presentation. The median contrast-enhancing preoperative tumor volume (CE-PTV) was 29.0 cm3, and CE-RTV was 1.2 cm3, equating to a 95.8% median EOR. The median T2/F-RV was 36.8 cm3. CE-PTV, CE-RTV, T2/F-RV, and EOR were all statistically significant predictors of survival when controlling for age and KPS score. A statistically significant benefit in survival was seen with a CE-RTV less than 2 cm3 or an EOR greater than 98%. Evaluation of the volumetric analysis methodology was performed by observers of varying degrees of experience—an attending neurosurgeon, a fellow, and a medical student. Both the medical student and fellow recorded correlation coefficients of 0.98 when compared with the attending surgeon's measured volumes of CE-PTV, while for CE-RTV, correlation coefficients of 0.67 and 0.71 (medical student and fellow, respectively) were obtained.
CE-RTV and EOR were found to be significant predictors of survival after GBM resection. CERTV was the more significant predictor of survival compared with EOR, suggesting that the volume of residual contrast-enhancing tumor may be a more accurate and meaningful reflection of the pathobiology of GBM.
Alireza Mohammad Mohammadi, Pablo F. Recinos, Gene H. Barnett, Robert J. Weil, Michael A. Vogelbaum, Samuel T. Chao, John H. Suh, Nicholas F. Marko, Paul Elson, Gennady Neyman and Lilyana Angelov
The authors evaluated overall survival and factors predicting outcome in patients with ≥ 5 brain metastases who were treated with Gamma Knife surgery (GKS).
Medical records from patients with ≥ 5 brain metastases treated with GKS between 1997 and 2010 at the Cleveland Clinic Gamma Knife Center were retrospectively reviewed. Patient demographics, tumor characteristics, treatment-related factors, and outcome data were evaluated.
One hundred seventy patients were identified, with a median age of 58 years. The female/male ratio was 1.2:1. Gamma Knife surgery was used as an upfront treatment in 35% of patients and as salvage treatment in 65% of patients with multiple brain metastases. The median overall survival after GKS was 6.7 months (95% CI 5.5–8.1). At the time of GKS, 128 patients (75%) had concurrent extracranial metastases, and in 69 patients (41%) multiple extracranial sites were involved. Ninety-two patients (54%) had a history of whole-brain radiation therapy, and 158 patients (93%) had a Karnofsky Performance Scale (KPS) score ≥ 70. The median total intracranial disease volume was 3.2 cm3 (range 0.2–37.2 cm3). A total intracranial tumor volume ≥ 10 cm3 was observed in 32 patients (19%). Lower KPS score at the time of treatment (p < 0.0001), patient age > 60 years (p = 0.004), multiple extracranial metastases (p = 0.0001), and greater intracranial burden of disease (p = 0.03) were prognostic factors for poor outcome in the univariate and multivariate analyses.
In this study, GKS was safe and effective for upfront and salvage treatment in patients with ≥ 5 brain metastases. Gamma Knife surgery should be considered as an additional treatment modality for these patients, especially in the subset of patients with favorable prognostic factors.
Michael A. Vogelbaum, Lilyana Angelov, Shih-Yuan Lee, Liang Li, Gene H. Barnett and John H. Suh
The maximal tolerated dose (MTD) for stereotactic radiosurgery (SRS) for brain tumors was established by the Radiation Therapy Oncology Group (RTOG) in protocol 90-05, which defined three dose groups based on the maximal tumor diameter. The goal in this retrospective study was to determine whether differences in doses to the margins of brain metastases affect the ability of SRS to achieve local control.
Between 1997 and 2003, 202 patients harboring 375 tumors that met study entry criteria underwent SRS for treatment of one or multiple brain metastases. The median overall follow-up duration was 10.7 months (range 3–83 months). A dose of 24 Gy to the tumor margin had a significantly lower risk of local failure than 15 or 18 Gy (p = 0.0005; hazard ratio 0.277, confidence interval [CI] 0.134–0.573), whereas the 15- and 18-Gy groups were not significantly different from each other (p = 0.82) in this regard. The 1-year local control rate was 85% (95% CI 78–92%) in tumors treated with 24 Gy, compared with 49% (CI 30–68%) in tumors treated with 18 Gy and 45% (CI 23–67%) in tumors treated with 15 Gy. Overall patient survival was independent of dose to the tumor margin.
Use of the RTOG 90-05 dosing scheme for brain metastases is associated with a variable local control rate. Tumors larger than 2 cm are less effectively controlled than smaller lesions, which can be safely treated with 24 Gy. Prospective evaluations of the relationship between dose to the tumor margin and local control should be performed to confirm these observations.