Brain metastases are a very common manifestation of cancer that have historically been approached as a single disease entity given the uniform association with poor clinical outcomes. Fortunately, ...our understanding of the biology and molecular underpinnings of brain metastases has greatly improved, resulting in more sophisticated prognostic models and multiple patient-related and disease-specific treatment paradigms. In addition, the therapeutic armamentarium has expanded from whole-brain radiotherapy and surgery to include stereotactic radiosurgery, targeted therapies and immunotherapies, which are often used sequentially or in combination. Advances in neuroimaging have provided additional opportunities to accurately screen for intracranial disease at initial cancer diagnosis, target intracranial lesions with precision during treatment and help differentiate the effects of treatment from disease progression by incorporating functional imaging. Given the numerous available treatment options for patients with brain metastases, a multidisciplinary approach is strongly recommended to personalize the treatment of each patient in an effort to improve the therapeutic ratio. Given the ongoing controversies regarding the optimal sequencing of the available and expanding treatment options for patients with brain metastases, enrolment in clinical trials is essential to advance our understanding of this complex and common disease. In this Review, we describe the key features of diagnosis, risk stratification and modern paradigms in the treatment and management of patients with brain metastases and provide speculation on future research directions.
Abstract
BACKGROUND
Guidelines regarding stereotactic radiosurgery (SRS) for brain metastases are missing recently published evidence.
OBJECTIVE
To conduct a systematic review and provide an ...objective summary of publications regarding SRS in managing patients with 1 to 4 brain metastases.
METHODS
Using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was conducted using PubMed and Medline up to November 2016. A separate search was conducted for SRS for larger brain metastases.
RESULTS
Twenty-seven prospective studies, critical reviews, meta-analyses, and published consensus guidelines were reviewed. Four key points came from these studies. First, there is no detriment to survival by withholding whole brain radiation (WBRT) in the upfront management of brain metastases with SRS. Second, while SRS on its own provides a high rate of local control (LC), WBRT may provide further increase in LC. Next, WBRT does provide distant brain control with less need for salvage therapy. Finally, the addition of WBRT does affect neurocognitive function and quality of life more than SRS alone.
For larger brain metastases, surgical resection should be considered, especially when factoring lower LC with single-session radiosurgery. There is emerging data showing good LC and/or decreased toxicity with multisession radiosurgery.
CONCLUSION
A number of well-conducted prospective and meta-analyses studies demonstrate good LC, without compromising survival, using SRS alone for patients with a limited number of brain metastases. Some also demonstrated less impact on neurocognitive function with SRS alone. Practice guidelines were developed using these data with International Stereotactic Radiosurgery Society consensus.
Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create ...diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians.
A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis.
Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined.
Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.
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.
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.
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.
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.
To develop consensus contouring guidelines for postoperative stereotactic body radiation therapy (SBRT) for spinal metastases.
Ten spine SBRT specialists representing 10 international centers ...independently contoured the clinical target volume (CTV), planning target volume (PTV), spinal cord, and spinal cord planning organ at risk volume (PRV) for 10 representative clinical scenarios in postoperative spine SBRT for metastatic solid tumor malignancies. Contours were imported into the Computational Environment for Radiotherapy Research. Agreement between physicians was calculated with an expectation minimization algorithm using simultaneous truth and performance level estimation with κ statistics. Target volume definition guidelines were established by finding optimized confidence level consensus contours using histogram agreement analyses.
Nine expert radiation oncologists and 1 neurosurgeon completed contours for all 10 cases. The mean sensitivity and specificity were 0.79 (range, 0.71-0.89) and 0.94 (range, 0.90-0.99) for the CTV and 0.79 (range, 0.70-0.95) and 0.92 (range, 0.87-0.99) for the PTV), respectively. Mean κ agreement, which demonstrates the probability that contours agree by chance alone, was 0.58 (range, 0.43-0.70) for CTV and 0.58 (range, 0.37-0.76) for PTV (P<.001 for all cases). Optimized consensus contours were established for all patients with 80% confidence interval. Recommendations for CTV include treatment of the entire preoperative extent of bony and epidural disease, plus immediately adjacent bony anatomic compartments at risk of microscopic disease extension. In particular, a "donut-shaped" CTV was consistently applied in cases of preoperative circumferential epidural extension, regardless of extent of residual epidural extension. Otherwise more conformal anatomic-based CTVs were determined and described. Spinal instrumentation was consistently excluded from the CTV.
We provide consensus contouring guidelines for common scenarios in postoperative SBRT for spinal metastases. These consensus guidelines are subject to clinical validation.
The incidence of radiation necrosis has increased secondary to greater use of combined modality therapy for brain tumors and stereotactic radiosurgery. Given that its characteristics on standard ...imaging are no different that tumor recurrence, it is difficult to diagnose without use of more sophisticated imaging and nuclear medicine scans, although the accuracy of such scans is controversial. Historically, treatment had been limited to steroids, hyperbaric oxygen, anticoagulants, and surgical resection. A recent prospective randomized study has confirmed the efficacy of bevacizumab in treating radiation necrosis. Novel therapies include using focused interstitial laser thermal therapy. This article will review the diagnosis and treatment of radiation necrosis.
Controversy endures regarding the optimal treatment of patients with brain metastases (BMs). Debate persists, despite many randomized trials, perhaps because BM patients are a heterogeneous ...population. The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis-Specific Graded Prognostic Assessment DS-GPA).
A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. After exclusion of the patients with recurrent BMs or incomplete data, 4,259 patients with newly diagnosed BMs remained eligible for analysis. Univariate and multivariate analyses of the prognostic factors and outcomes by primary site and treatment were performed. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment.
The significant prognostic factors varied by diagnosis. For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. For melanoma and renal cell cancer, the significant prognostic factors were Karnofsky performance status and the number of BMs. For breast and gastrointestinal cancer, the only significant prognostic factor was the Karnofsky performance status. Two new DS-GPA indexes were thus designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma. The median survival by GPA score, diagnosis, and treatment were determined.
The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making.
OBJECTIVE 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. METHODS 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. RESULTS 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 cm
(range 2.4-31.3 cm
) and 7.0 cm
(range 1.0-29.7 cm
). Three-month follow-up imaging results were available for 43 lesions; the median volume was 4.0 cm
(range 0.1-23.1 cm
). 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. CONCLUSIONS 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.
Cranial radiation can impact the cerebral vasculature in many ways, with a wide range of clinical manifestations. The incidence of these late effects including cerebrovascular accidents (CVAs), ...lacunar lesions, vascular occlusive disease including moyamoya syndrome, vascular malformations, and hemorrhage is not well known. This article reviews the preclinical findings regarding the pathophysiology of late radiation-induced vascular damage, and discusses the clinical incidence and risk factors for each type of vasculopathy. The pathophysiology is complex and dependent on the targeted blood vessels, and upregulation of pro-inflammatory and hypoxia-related genes. The risk factors for adult CVAs are similar to those for patients not exposed to cranial radiotherapy. For children, risks for late vascular complications include young age at radiotherapy, radiotherapy dose, NF1, tumor location, chemotherapy, and endocrine abnormalities. The incidence of late vascular complications of radiotherapy may be impacted by improved technology, therapeutic interventions, and appropriate follow up.
•SBRT contouring recommendations for metastatic disease to the sacrum have been established.•High degree of agreement in target delineation among spine SBRT experts.•Critical first step to ...standardisation of target delineation practice in the sacrum.•The sacral classification system (SCS) guides the anatomic description of contours.•The SCS will help serve as a framework for future pattern of failure analyses.
To interrogate inter-observer variability in gross tumour volume (GTV) and clinical target volume (CTV) delineation specific to the treatment of sacral metastases with spinal stereotactic body radiation therapy (SBRT) and develop CTV consensus contouring recommendations.
Nine specialists with spinal SBRT expertise representing 9 international centres independently contoured the GTV and CTV for 10 clinical cases of metastatic disease within the sacrum. Agreement between physicians was calculated with an expectation minimisation algorithm using simultaneous truth and performance level estimation (STAPLE) and with kappa statistics. Optimised confidence level consensus contours were obtained using a voxel-wise maximum likelihood approach and the STAPLE contours for GTV and CTV were based on an 80% confidence level.
Mean GTV STAPLE agreement sensitivity and specificity was 0.70 (range, 0.54–0.87) and 1.00, respectively, and 0.55 (range, 0.44–0.64) and 1.00 for the CTV, respectively. Mean GTV and CTV kappa agreement was 0.73 (range, 0.59–0.83) and 0.59 (range, 0.41–0.70), respectively. Optimised confidence level consensus contours were identified by STAPLE analysis. Consensus recommendations for the CTV include treating the entire segment containing the disease in addition to the immediate adjacent bony anatomic segment at risk of microscopic extension.
Consensus recommendations for CTV target delineation specific to sacral metastases treated with SBRT were established using expert contours. This is a critical first step to achieving standardisation of target delineation practice in the sacrum and will serve as a baseline for meaningful pattern of failure analyses going forward.
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