Use Of Whole Brain Radiotherapy Research Articles

Patient reported outcomes following whole brain radiotherapy in patients with brain metastases in NSIA-LUTH Cancer Center

BackgroundBrain metastases (BM) are a common complication in advanced cancer patients, and extremely challenging to treat. Consequently, whole brain radiotherapy (WBRT) remains the standard palliative intervention for patients with BM. The present study set to evaluate the clinical benefits of WBRT by assessing the quality of life (QoL) in WBRT-treated patients with BM, in Nigeria.MethodsThis was a prospective, longitudinal, hospital-based single-centre study. Consecutive sampling methodology was used to recruit 52 patients with BM undergoing WBRT. Patients were followed up on days 7, 30, 90 and 180 after WBRT. The EORTC QLQ-C15-PAL and EORTC QLQ-BN20 were employed to report patients’ responses. The likert scale responses were linearly converted into 0 – 100 scores, and the descriptive analysis was conducted using IBM SPSS Statistics 29.0, at 95% confidence interval, using the two-tailed t-test for continuous variables or the chi-square test for categorical values. The overall survival was calculated with the Kaplan Maier method and the difference tested with Log-rank method, considering the interval from the baseline until death or end of the study.ResultsThe study cohort was predominantly females (82.7%), and accordingly, 65.4% of the respondents had a breast primary tumor. A goodness-of-fit test yielded non-significant Chi square Pearson (p = 0.325) and Deviance (p = 1.000) residuals, indicating the best fit. The median overall survival was 180 days (~ 6 months). A total of 20 patients (38%) that survived up to 180 days reported alleviated symptoms and better functioning. A significant improvement in physical functioning (p < 0.001) and emotional functioning (p = 0.031) was reported at 180 days post WBRT, compared to baseline.ConclusionsWBRT is an effective palliative intervention in patients with BM, resulting in improved QoL. More than 50% of patients that survived ~ 3 months reported alleviation of pain, and 38% of patients that survived for ~ 6 months reported a significantly improved functioning. This demonstrated the clinical benefits of WBRT in palliative care and will add to the body of data on the use of WBRT, from Africa.

Selected-Lesion Stereotactic Radiosurgery (SL-SRS) as a Novel Strategy in the Treatment of Patients With Multiple Brain Metastases.

With the diminishing use of whole-brain radiotherapy (WBRT), there is increasing debate regarding the maximum number of brain metastases that should be treated with stereotactic radiosurgery (SRS). In patients with >10-15 lesions, some groups are proposing a new approach - selected-lesion SRS (SL-SRS) - where only a subset of intracranial lesions are chosen for irradiation. This study is an initial look into this practice. This is a cross-sectional exploratory survey study. A survey of 19 questions was created by the International Radiosurgery Research Foundation (IRRF) using open-ended and multiple-choice style questions on SL-SRS practices and indications with the goal of qualitatively understanding how SL-SRS is being implemented worldwide. The survey was distributed to physiciansin the United States (US) and internationally who are members of the IRRFand who perform SRS frequently.Ten out of 50 IRRF institutions provided responses reflecting the practices of 16 physicians. SL-SRS is being performed at 8/10 institutions. The most common reasons for using SL-SRS included patients with prior WBRT, patients with progressing systemic disease with central nervous system (CNS)-penetrating or immunotherapies available, specific requests from medical oncology, and cooperative studies using this approach. Lesion size was cited as the most important factor when choosing to irradiate any single lesion. The majority of respondents reported 30 mm and 40 mm as size cutoffs (by largest dimension) for treatment of a lesion in eloquent and non-eloquent locations, respectively. Eloquence of lesion location and attributable symptoms were also considered important. Progression of untreated lesions was the most common reason reported for bringing patients back for additional treatment. The responses to this survey show that SL-SRS is being used, allowing for small/asymptomatic brain metastases to be left safely unirradiated. It is currently used in patients who have >10-15 lesions with prior WBRT, those with progression of extracranial disease but with acceptable systemic treatment options, and those with poor functional status. The incorporation of this new approach into clinical trials should be considered for the safe study of the efficacy of new CNS-penetrating systemic therapies.

Neurotoxicity from Old and New Radiation Treatments for Brain Tumors.

Research regarding the mechanisms of brain damage following radiation treatments for brain tumors has increased over the years, thus providing a deeper insight into the pathobiological mechanisms and suggesting new approaches to minimize this damage. This review has discussed the different factors that are known to influence the risk of damage to the brain (mainly cognitive disturbances) from radiation. These include patient and tumor characteristics, the use of whole-brain radiotherapy versus particle therapy (protons, carbon ions), and stereotactic radiotherapy in various modalities. Additionally, biological mechanisms behind neuroprotection have been elucidated.

PRO: Do We Still Need Whole-Brain Irradiation for Brain Metastases?

(1) Background: In recent decades, the use of whole-brain radiation therapy (WBRT) in the treatment of brain metastases has significantly decreased, with clinicians fearing adverse neurocognitive events and data showing limited efficacy regarding local tumor control and overall survival. The present study thus aimed to reassess the role that WBRT holds in the treatment of brain metastases. (2) Methods: This review summarizes the available evidence from 1990 until today supporting the use of WBRT, as well as new developments in WBRT and their clinical implications. (3) Results: While one to four brain metastases should be exclusively treated with radiosurgery, WBRT does remain an option for patients with multiple metastases. In particular, hippocampus-avoidance WBRT, WBRT with dose escalation to the metastases, and their combination have shown promising results and offer valid alternatives to local stereotactic radiotherapy. Ongoing and published prospective trials on the efficacy and toxicity of these new methods are presented. (4) Conclusions: Unlike conventional WBRT, which has limited indications, modern WBRT techniques continue to have a significant role to play in the treatment of multiple brain metastases. In which situations radiosurgery or WBRT should be the first option should be investigated in further studies. Until then, the therapeutic decision must be made individually depending on the oncological context.

Feasibility of linac-based fractionated stereotactic radiotherapy and stereotactic radiosurgery for patients with up to ten brain metastases

BackgroundLinac-based fractionated stereotactic radiotherapy (fSRT) and stereotactic radiosurgery (SRS) are increasingly being used to manage patients with multiple metastases. This retrospective cohort study aimed to compare the outcomes after linac-based fSRT and SRS between three patient groups classified based on the number of brain metastases (BMs): 1 BM, 2–4 BM, 5–10 BM.MethodsThe data of consecutive patients with 1–10 BMs treated with fSRT or SRS between July 2016 and June 2018 at a single institution were collected. Patients with previous whole-brain radiotherapy (WBRT), concurrent use of WBRT, or surgical resection were excluded from the analysis. A total of 176 patients were classified into three groups according to the number of BMs: 78, 67, and 31 patients in 1 BM, 2–4 BM, and 5–10 BM, respectively. The Kaplan–Meier method was used to estimate overall survival (OS) curves, and the cumulative incidence with competing risks was used to estimate local control (LC), distant intracranial failure (DIF), and radiation necrosis (RN).ResultsMedian OS was 19.8 months (95% confidence interval [CI] 10.2–27.5), 7.3 months (4.9–11.1), and 5.1 months (4.0–9.0) in 1 BM, 2–4 BM, and 5–10 BM, respectively. Compared to 2–4 BM, 1 BM had significantly better OS (hazard ratio [HR] 0.59, 95% CI 0.40–0.87; p = 0.0075); however, 5–10 BM had comparable OS (HR 1.36, 95% CI 0.85–2.19; p = 0.199). There was no significant difference in LC, DIF, and RN between tumor number groups, but DIF was lower in 1 BM. RN of grade 2 or higher occurred in 21 patients (13.5%); grade 4 and 5 RN were not observed.ConclusionsThe linac-based fSRT and SRS for patients with 5–10 BMs is comparable to that for patients with 2–4 BMs in OS, LC, DIF, and RN. It seems reasonable to use linac-based fSRT and SRS in patients with 5–10 BMs.

Radiation Dose, Technique and Use of Brain Radiation on Overall Survival in Patients with Limited-Stage Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> The standard of care for limited-stage small cell lung cancer (LS-SCLC) currently involves concurrent chemoradiation +/- prophylactic cranial irradiation (PCI). Previous research has presented conflicting data regarding the optimal radiation therapy (RT) technique, RT dosage, and impact of brain RT on long term overall survival (OS). This study aimed to explore prognostic factors of OS in LS-SCLC cancer patients using a population-based cohort. <h3>Materials/Methods</h3> Data on all patients diagnosed with LS-SCLC in Ontario, Canada from 2005-2017 was obtained using the Institute for Clinical Evaluative Sciences (IC/ES) Data and Analytic Services. Eligible patients received curative intent chemoradiation, and OS was estimated from a landmark date of 6 months post-diagnosis to avoid survivor bias. Kaplan-Meier methods and Cox regression were used to estimate OS and explore differences between RT dose (40-49, 50-59, 60+ Gy), RT technique (3DCRT, IMRT, VMAT), and use of brain RT (PCI – 25 Gy, whole brain RT – 20 or 30 Gy, other brain RT, no brain RT). Multivariate analyses adjusted for sex, age, income quintile, Charlson comorbidity index, disease stage, prior history of cardiac disease, brain RT dose, and laterality. <h3>Results</h3> A total of 1360 LS-SCLC patients who received chemoradiation were included. Median OS (95% CI) was 18.1 months (16.6-19.4). Higher RT dose had significantly improved OS when compared to 40-49 Gy on univariate analysis (HR=0.83, 0.71-0.95, 60+ Gy), however, this did not persist when adjusting for other prognostic factors on multivariate analysis (HR=0.90, 0.77-1.06, 60+ Gy). The use of whole brain RT was associated with worse OS on both univariate (HR=1.47, 1.24-1.74) and multivariate (HR=1.42, 1.18-1.70) analyses. OS (95% CI) at 5-years for RT dose were 40-49 Gy: 16% (13-19%), 50-59 Gy: 23% (18-29), and 60+ Gy: 20% (16-25). For RT technique, OS (95% CI) at 5-years were 3DCRT: 19% (13-22), IMRT: 18% (13-23), and VMAT: 12% (4-25). Multivariate analyses demonstrated that male sex (HR=1.36, 1.20-1.55), more advanced stage disease (HR=1.35/1.94/3.08/1.67 for stage 2/3/4/Unknown vs 1), and older age were prognostic for worse OS. <h3>Conclusion</h3> Analyses of population-based data demonstrated that male sex, older age, and more advanced disease stage were notable predictors of OS in LS-SCLC. RT dose, when adjusting for other important prognostic variables did not predict for improved OS. However, use of whole brain RT (versus PCI or no PCI) was associated with worse OS. Use of PCI versus no PCI did not influence survival in this cohort, nor did RT technique.

Brain Metastases in Stage IV Esophageal Cancer: Incidence, Risk Factors and Radiation Utilization

<h3>Purpose/Objective(s)</h3> Limited studies indicate that brain metastases from esophageal cancer are uncommon and associated with poor prognosis. This National Cancer Database (NCDB) study investigated the incidence and risk factors associated with brain metastases at diagnosis for Stage IV esophageal cancer patients, as well as radiation utilization and outcomes. <h3>Materials/Methods</h3> The NCDB was used to identify newly diagnosed Stage IV esophageal cancer patients with brain metastases between 2010-2017. A multivariate logistic regression model was used to calculate the adjusted odds ratio (aOR) and 95% confidence interval (95% CI) for brain metastases at diagnosis. Survival analysis was performed using the Kaplan-Meier method and Cox regression modeling. The multivariate model included age, gender, race, insurance status, income, facility type, Charlson-Deyo comorbidity score, histology, and tumor location. <h3>Results</h3> Of 23,930 patients diagnosed with Stage IV esophageal cancer, 1,532 (6.4%) patients had brain metastases. There was no significant change in the incidence of brain metastases over time with 6.1% in 2010 to 6.6% in 2017 (range: 5.7-7.4%; p=0.27). Patients who were older (aOR 0.98 [95% CI 0.98-0.99]; p<0.0001), female (aOR 0.81 [0.69-0.96]; p=0.015), or Black (aOR 0.77 [0.60-0.99]; p=0.045) were less likely to present with brain metastases. Mid esophageal tumors had higher probability of brain metastases vs. lower esophageal location (aOR 1.55 [1.27-1.89]; p<0.0001). Adenocarcinoma histology was strongly associated with increased risk of brain metastases vs. squamous cell carcinoma (aOR 2.41 [1.97-2.95]; p<0.0001). Of 679 patients with brain metastases who received brain radiotherapy as part of their primary treatment, 504 (74.2%) received whole-brain radiotherapy (WBRT) and 175 (25.8%) received stereotactic radiosurgery (SRS). The use of WBRT decreased over time from 86.4% in 2010 to 72.7% in 2017, while the use of SRS increased from 13.6% in 2010 to 27.3% in 2017 (p=0.035). For patients who received brain radiotherapy, median follow-up was 5.1 months and median survival was 5.2 months. Median survival for patients who received WBRT was 4.5 months vs. 7.8 months for SRS patients (p=0.0001). On multivariate analysis, SRS was associated with improved survival vs. WBRT (hazard ratio [HR] 0.72 [0.59-0.89]; p=0.002). <h3>Conclusion</h3> Approximately 6% of patients with Stage IV esophageal cancer present with brain metastases, with no change in incidence from 2010 to 2017. Older, female, or Black patients were less likely to present with brain metastases, while adenocarcinoma histology and mid esophagus location were significant risk factors for synchronous brain metastases. While survival rates remain dismal, SRS is associated with improved survival vs. WBRT, and its utilization in this population is increasing over time.

Review of Current Principles of the Diagnosis and Management of Brain Metastases.

Brain metastases are the most common intracranial tumors and are increasing in incidence as overall cancer survival improves. Diagnosis of brain metastases involves both clinical examination and magnetic resonance imaging. Treatment may involve a combination of surgery, radiotherapy, and systemic medical therapy depending on the patient’s neurologic status, performance status, and overall oncologic burden. Advances in these domains have substantially impacted the management of brain metastases and improved performance status and survival for some patients. Indications for surgery have expanded with improved patient selection, imaging, and intraoperative monitoring. Robust evidence supports the use of whole brain radiotherapy and stereotactic radiosurgery, for both standalone and adjuvant indications, in almost all patients. Lastly, while systemic medical therapy has historically provided little benefit, modern immunotherapeutic agents have demonstrated promise. Current investigation seeks to determine the utility of neoadjuvant radiotherapy and laser interstitial thermal therapy, which have shown benefit in limited studies to date. This article provides a review of the epidemiology, pathology, diagnosis, and treatment of brain metastases and the corresponding supporting evidence.

Therapeutic role of memantine for the prevention of cognitive decline in cancer patients with brain metastasis receiving whole-brain radiotherapy: a narrative review.

Brain metastases are the most common central nervous system tumors. The mainstay treatment for this tumor in low to middle income countries is whole brain radiation therapy. Irreversible cognitive decline is associated with the use of whole brain radiotherapy. Several pharmacologic and nonpharmacologic options have been employed in studies focusing on the prevention of cognitive decline following whole-brain radiation therapy. Memantine use has been shown to provide some benefit in reducing the rate of decline in cognitive function and time to cognitive failure. The objective of this review article is to provide a summary on available primary literature on the therapeutic role of memantine for the prevention of cognitive decline in cancer patients with brain metastasis receiving whole brain radiotherapy.

Radiotherapy for HER 2 Positive Brain Metastases: Urgent Need for a Paradigm Shift.

Simple SummaryBrain metastases (BMs) are common among patients with advanced HER2 breast cancer. The recent introduction of systemic therapy with central nervous system activity as well as the wider use of brain stereotactic radiotherapy (SRT) are contributing to improving the outcomes for these patients. In this review, we discuss a modified approach to the treatment of HER2-positive BMs from a radiation oncologist point of view, taking into consideration new advances in multimodal therapy and combinations of the most commonly used systemic treatments and brain radiation therapy (RT).Brain metastases (BMs) are common among patients affected by HER2+ metastatic breast cancer (>30%). The management of BMs is usually multimodal, including surgery, radiotherapy, systemic therapy and palliative care. Standard brain radiotherapy (RT) includes the use of stereotactic radiotherapy (SRT) for limited disease and whole brain radiotherapy (WBRT) for extensive disease. The latter is an effective palliative treatment but has a reduced effect on brain local control and BM overall survival, as it is also associated with severe neurocognitive sequelae. Recent advances both in radiation therapy and systemic treatment may change the paradigm in this subset of patients who can experience long survival notwithstanding BMs. In fact, in recent studies, SRT for multiple BM sites (>4) has shown similar efficacy when compared to irradiation of a limited number of lesions (one to three) without increasing toxicity. These findings, in addition to the introduction of new drugs with recognized intracranial activity, may further limit the use of WBRT in favor of SRT, which should be employed for treatment of both multiple-site BMs and for oligo-progressive brain disease. This review summarizes the supporting literature and highlights the need for optimizing combinations of the available treatments in this setting, with a particular focus on radiation therapy.

Clinical outcomes for pediatric patients receiving radiotherapy for solid tumor central nervous system metastases.

Central nervous system (CNS) metastases are rare, but devastating complications of pediatric solid tumors. Radiotherapy alone or postresection serves as an important treatment; however, data on the use of whole-brain radiotherapy (WBRT) versus focal radiotherapy, including stereotactic radiosurgery or stereotactic radiotherapy, for these indications are limited. We report a single institution experience of 26 pediatric patients treated with radiotherapy for solid tumor CNS metastases without leptomeningeal disease. Focal radiotherapy (n=10) was well tolerated and survival outcomes did not differ between patients treated with WBRT (n=16) versus focal radiation, suggesting that focal radiotherapy may be considered for patients with limited CNS metastases.

Multidisciplinary Management of Brain Metastases from Non-Small Cell Lung Cancer in the Era of Immunotherapy.

Brain metastases from non-small cell lung cancer often cause neurologic symptoms which lead to initial diagnosis or identification of recurrence. In other patients, they are identified on surveillance imaging or when a patient undergoing treatment develops neurological symptoms. Patients with symptomatic lesions should be started on dexamethasone and evaluated by a neurosurgeon as soon as possible. If feasible, surgery should be offered to decrease intracranial pressure, alleviate symptoms, and prevent irreversible neurological damage. Postoperative stereotactic radiosurgery (SRS) to the resection cavity and any additional brain metastases should follow within 4 weeks of surgery, as early as 2 weeks post-op. Tissue from surgery is used to confirm the diagnosis and test for targetable oncogenic driver mutations. Treatment response and surveillance for development of additional lesions is assessed with MRI of the brain 1 month after SRS and every 3 months thereafter. Patients who are not surgical candidates or who have small, asymptomatic brain metastases should proceed with SRS, the preferred treatment, or sometimes whole-brain radiation therapy (WBRT) if multifocal disease requires more extensive treatment, such as for leptomeningeal spread of disease. The number of brain metastases that warrants use of WBRT over SRS is controversial and a topic of ongoing investigation, and is discussed in this review. When possible, SRS is preferred over WBRT due to reduce morbidity and cognitive side effects. When patients are already on systemic therapy at time of brain metastases diagnosis, systemic therapy should continue, with radiation therapy occurring between cycles. Regarding systemic therapy for new diagnosis at time of brain metastases presentation, molecular testing will guide treatment choice, when available. If there is no neurosurgical intervention, biopsy of another site of disease may provide tissue for molecular testing. If there are no targetable oncogenic driver mutations, concurrent immune checkpoint blockade (ICB) and chemotherapy is preferable for patients who can tolerate it. Single-agent ICB is an alternative option for patients who cannot tolerate chemotherapy. Systemic therapy should start as soon as possible. In some patients with poor performance status, best supportive care may be the most appropriate choice. Treatment decisions should always incorporate patients' goals of care and in many cases should be discussed in a multidisciplinary setting.

New brain metastases after whole-brain radiotherapy of initial brain metastases in breast cancer patients: the significance of molecular subtypes (KROG 16-12).

To identify the risk factors leading to new brain metastases (BM) following brain-directed treatment for initial BM resulting from breast cancer (BC). In this multi-institutional study, 538BC patients with available follow-up imaging after brain-directed treatment for initial BM were analyzed. Tumor molecular subtypes were classified as follows: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-, n = 136), HER2-positive (HER2+, n = 253), or triple-negative BC (TNBC, n = 149). In 37.4% of patients, new BM emerged at a median of 10.5months after brain-directed treatment for initial BM. The 1-year actuarial rate of new BM for HR+/HER2-, HER2+, and TNBC were 51.9%, 44.0%, and 69.6%, respectively (p = 0.008). Initial whole-brain radiotherapy (WBRT) reduced new BM rates (22.5% reduction at 1year, p < 0.001) according to molecular subtype (HR+/HER2-, 42% reduction at 1year, p < 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis revealed an increased risk of new BM for the following factors: shorter intervals between primary BC diagnoses and BM (p = 0.031); TNBC (relative to HR+/HER2-) (p = 0.016); presence of extracranial metastases (p = 0.019); number of BM (>4) (p < 0.001); and BM in both tentorial regions (p = 0.045). Anti-HER2 therapy in HER2+ patients (p = 0.013) and initial use of WBRT (p < 0.001) significantly lowered new BM development. Tumor molecular subtypes were associated with both rates of new BM development and the effectiveness of initial WBRT. Anti-HER2 therapy in HER2+ patients significantly lowered new BM occurrence.

Association of Innovations in Radiotherapy and Systemic Treatments With Clinical Outcomes in Patients With Melanoma Brain Metastasis From 2007 to 2016

Treatments for melanoma brain metastasis changed between 2007 and 2016 with the advent of new radiotherapy techniques, targeted therapeutic agents, and immunotherapy. Changes in clinical outcomes over time have not been systematically investigated in large population-based studies. To investigate the association of innovations in radiotherapy techniques and systemic therapies with clinical outcomes among patients with melanoma brain metastasis. This population-based cohort study included all patients who received radiotherapy and/or surgery for the treatment of melanoma brain metastasis in Ontario, Canada, between January 1, 2007, and June 30, 2016. Brain treatment patterns and clinical outcomes were described by period (2007-2009, 2010-2012, and 2013-2016). Provincial administrative records were used to obtain data on surgery, radiotherapy, and drugs. Follow-up data were censored on August 31, 2016. A Kaplan-Meier analysis and multivariable Cox regression analyses were performed. Data were analyzed between November 8, 2017 and May 13, 2020. Overall survival, whole-brain radiotherapy-free survival, and time to subsequent brain treatment. A total of 1096 patients (mean [SD] age, 61.7 [14.0] years; 751 men [68.5%]) with melanoma brain metastasis received treatment in Ontario between January 1, 2007, and June 30, 2016. Of those, 326 patients received treatment from 2007 to 2009 (period 1), 310 patients received treatment from 2010 to 2012 (period 2), and 460 patients received treatment from 2013 to 2016 (period 3). Patient age, other sociodemographic characteristics, and disease factors were similar between periods. Whole-brain radiotherapy was the first local brain-directed treatment used in 246 patients (75.5%; 95% CI, 70.8%-80.1%) in period 1, decreasing to 239 patients (52.0%; 95% CI, 47.4%-56.5%) in period 3. The use of partial-brain radiotherapy techniques as the first treatment increased from 11 patients (3.4%; 95% CI, 1.4%-5.3%) in period 1 to 98 patients (21.3%; 95% CI, 17.6%-25.0%) in period 3. After the first treatment for melanoma brain metastasis, the use of BRAF and MEK inhibitors and immunotherapy increased from less than 6 patients (<1.8%; 95% CI, <0.4% to <3.3%) in period 1 to 188 patients (40.9%; 95% CI, 36.4%-45.4%) in period 3. Overall survival was greater in period 3 (1-year survival, 21.8% [95% CI, 17.9%-25.9%] and 2-year survival, 13.8% [95% CI, 10.4%-17.8%]; Wilcoxon P = .001) compared with period 1 (1-year survival, 12.3% [95% CI, 9.0%-16.1%] and 2-year survival, 6.4% [95% CI, 4.1%-9.5%]), with an adjusted hazard ratio (aHR) of 0.65 (95% CI, 0.56-0.77). The findings were unchanged after accounting for the variation in imaging practice between periods. Between period 1 and period 3, the use of whole-brain radiotherapy decreased (aHR, 0.32; 95% CI, 0.22-0.46), and the use of multiple brain-directed treatments increased (aHR, 2.16; 95% CI, 1.48-3.14). These findings suggest that innovations in systemic therapy and radiotherapy are associated with improvements in clinical outcomes among patients with melanoma brain metastasis, even in population-wide routine practice. Overall survival improved over time, and the use of whole-brain radiotherapy decreased. However, many patients continued to receive whole-brain radiotherapy in the last period (2013-2016) examined.

Leptomeningeal disease after surgical resection and radiosurgery for brain metastases and neurologic death: A multi-institutional analysis.

2524 Background: Postoperative radiosurgery (SRS) has been associated with up to 30% risk of subsequent leptomeningeal disease (LMD). We previously demonstrated that radiographic pattern of LMD (classical “sugarcoating” [cLMD] vs. nodular [nLMD]) in this setting is prognostic. The association between radiographic pattern of LMD, type of salvage treatment (tx), and neurologic death (ND) has not been well described. Methods: The records of patients (pts) with brain metastases (BM), of which 1 was resected and treated with adjunctive SRS, and who subsequently developed LMD were combined from 7 tertiary care centers. Pts with classically radiosensitive tumors or prior or planned whole brain radiotherapy (WBRT) were excluded. ND was defined as symptomatic CNS progression around the time of death without life threatening systemic symptoms or progression. Salvage radiotherapy (RT) for LMD was categorized according to use of WBRT vs. focal cranial RT. Results: The study cohort consisted of 147 pts, of which 125 had died with known cause, 107 also received LMD salvage tx, and 82 also had cranial MRI follow-up. The ND rate in the 125 pts who died with known cause was 79%; the rate in pts who underwent LMD salvage tx (n = 107) was 76%. Univariate logistic regression demonstrated radiographic pattern of LMD (cLMD vs. nLMD, odds ratio [OR] 2.9, p = 0.04) and 2nd LMD failure after salvage tx (OR 3.9, p = 0.02) as significantly associated with ND. The ND rate was 86% for cLMD vs. 68% for nLMD pattern. WBRT was used in 95% of pts with cLMD vs. 52% of pts with nLMD. In the nLMD cohort (n = 58), there was no difference in ND rate based on type of salvage RT (WBRT: 67% vs. focal cranial RT: 68%, p = 0.92). Second LMD failure (vs. not) was associated with higher ND in the nLMD cohort (77% vs. 52%, p = 0.02). Of the 26 pts with nLMD who experienced 2nd LMD failure, 7 had classical 2nd LMD, of which 100% experienced ND, and 19 had nodular 2nd LMD, of which 68% experienced ND (p = 0.09). Conclusions: LMD after surgery and SRS for brain metastases is a clinically significant event with high rates of neurologic death. Classical LMD pattern (vs. nodular) and 2nd LMD failure after salvage tx were significantly associated with higher risk of neurologic death. In the nodular LMD cohort, radiographic pattern of 2nd LMD may be associated with risk of subsequent neurologic death. Pts with nodular LMD treated with salvage focal cranial RT or WBRT had similar risk of neurologic death. Methods to decrease LMD and the subsequent high risk of neurologic death in this setting warrant investigation.

Impact of brain metastasis velocity on neurologic death for brain metastasis patients experiencing distant brain failure after initial stereotactic radiosurgery

Patients with high rates of developing new brain metastases have an increased likelihood of dying of neurologic death. It is unclear, however, whether this risk is affected by treatment choice following failure of primary stereotactic radiosurgery (SRS). From July 2000 to March 2017, 440 patients with brain metastasis were treated with SRS and progressed to have a distant brain failure (DBF). Eighty-seven patients were treated within the immunotherapy era. Brain metastasis velocity (BMV) was calculated for each patient. In general, the institutional philosophy for use of salvage SRS vs whole brain radiotherapy (WBRT) was to postpone the use of WBRT for as long as possible and to treat with salvage SRS when feasible. No further treatment was reserved for patients with poor life expectancy and who were not expected to benefit from salvage treatment. Two hundred and eighty-five patients were treated with repeat SRS, 91 patients were treated with salvage WBRT, and 64 patients received no salvage radiation therapy. One-year cumulative incidence of neurologic death after salvage SRS vs WBRT was 15% vs 23% for the low- (p = 0.06), 30% vs 37% for the intermediate- (p <0.01), and 31% vs 48% (p <0.01) for the high-BMV group. Salvage WBRT was associated with increased incidence of neurologic death on multivariate analysis (HR 1.64, 95% CI 1.13-2.39, p = 0.01) when compared to repeat SRS. One-year cumulative incidence of neurologic death for patients treated within the immunotherapy era was 9%, 38%, and 38% for low-, intermediate-, and high-BMV groups, respectively (p = 0.01). Intermediate and high risk BMV groups are predictive of neurologic death. The association between BMV and neurologic death remains strong for patients treated within the immunotherapy era.

Neuro-Oncology Practice Clinical Debate: stereotactic radiosurgery or fractionated stereotactic radiotherapy following surgical resection for brain metastasis.

The treatment of resected brain metastasis has shifted away from the historical use of whole-brain radiotherapy (WBRT) toward adjuvant radiosurgery (stereotactic radiosurgery [SRS]) based on a recent prospective clinical trial demonstrating less cognitive decline with the use of SRS alone and equivalent survival as compared with WBRT. Whereas all level 1 evidence to date concerns single-fraction SRS for postoperative brain metastasis, there is emerging evidence that fractionated stereotactic radiotherapy (FSRT) may improve local control at the resected tumor bed. The lack of direct comparative data for SRS vs FSRT results in a diversity in clinical practice. In this article, Greenspoon and Roberge defend the use of SRS as the standard of care for resected brain metastasis, whereas Palmer and Brown argue for FSRT.

Whole Brain Radiotherapy Practice Patterns in the Era of Stereotactic Radiosurgery

Increased access to stereotactic radiosurgery (SRS) to treat brain metastases (BM) has prompted reassessment of whole brain radiotherapy (WBRT) indications. A patterns of care analysis of various WBRT dose-fractionations for the U.S. in the era of SRS was performed. Adults in the National Cancer Database with BM at diagnosis of a lung, breast, skin, urogenital, gastrointestinal, or head/neck primary tumor between 2010-2015 and no prior malignancy were identified. WBRT was defined as 20-50 Gy to the brain in 4-44 fractions (fx) at 1.6-6 Gy/fx totaling 60-100 Gy2 biologically equivalent dose, administered in ≤60 days using a non-SRS external beam modality. SRS was defined as radiosurgery modality, 12-24 Gy/1 fx, 18-30 Gy/2 fx, 21-36 Gy/3 fx, 21-36 Gy/4 fx, or 25-40 Gy/5 fx to the brain. Short (ShWBRT), standard (StWBRT), and extended (ExWBRT) courses were defined as <10, 10-15, and >15 fx, respectively. Odds ratios (OR) of ShWBRT or ExWBRT receipt relative to StWBRT were calculated from multivariate logistic regression. Yearly utilization trends were analyzed with linear regression. 90388 subjects with BM at diagnosis were identified, the majority with primary lung cancer (83.0%). Of these, 24262 (26.8%) received WBRT and 11486 (12.7%) received SRS. 374 (0.4%) subjects received >10 fx and were reported to have received a radiosurgery modality, potentially reflecting combination WBRT and SRS, and were excluded from WBRT analysis. Annual use of WBRT decreased from 27.8% in 2010 to 23.5% in 2015, whereas annual use of SRS increased from 8.7% in 2010 to 17.9% in 2015. The most common WBRT dose-fractionations were 30 Gy/10 fx (56.8%), 37.5 Gy/15 fx (15.5%), and 35 Gy/14 fx (11.0%). 1020 (4.2%), 22356 (92.1%), and 886 (3.7%) received ShWBRT, StWBRT, and ExWBRT, respectively. StWBRT was the most frequently used fractionation for all primary sites. There was a significant reduction in use of ExWBRT (slope = -22.4%/yr, R2 = 0.97, p<0.01) between 2010-2015. No significant trends were identified for use of ShWBRT or StWBRT. On multivariate analysis, factors associated with significantly higher usage of ShWBRT were no chemotherapy receipt (OR 3.5, 95% CI 3.1-4.1, p<0.01), Medicaid compared to private insurance (OR 1.4, 95% CI 1.1-1.8, p<0.01), and treatment at academic centers (OR 1.3, 95% CI 1.1-1.6, p<0.01). On multivariate analysis, factors associated with significantly higher usage of ExWBRT were chemotherapy receipt (OR 1.2, 95% CI 1.0-1.4, p=0.03) and treatment at comprehensive community cancer centers (OR 1.7, 95% CI 1.4-2.0, p<0.01). WBRT utilization to treat BM at diagnosis in the U.S. has decreased, especially >15 fx regimens. Choosing Wisely’s recommendation in Sept 2014 to not add WBRT to SRS may have influenced the observed trends. WBRT in 10-15 fx was the most common regimen for all primary tumors analyzed. WBRT in <10 fx was used much more frequently in those who did not receive chemotherapy, likely due to poor performance status.

Multifraction Stereotactic Radiosurgery to Large Brain Metastases: Is This Scheme Effective and Safe?

Many fractionation regimens have been described for the treatment of large brain metastases with stereotactic radiosurgery (SRS). The purpose of this analysis is to demonstrate the efficacy and the tolerance of multifraction stereotactic radiosurgery (mSRS), 3 fractions, in patients with large brain metastases. Were reviewed all patients with brain metastases treated with mSRS (3 fractions) at a single institution. Patients with large brain metastases were the majority population, but patients who were not appropriate candidates for single fraction SRS were treated with mSRS and included as well. Prognostic factors including Ds-GPA, Score Index for Radiosurgery (SIR), number of lesions, systemic disease status, primary site, PTV volume, dose (3 schemes were used due a constraint of the organ at risk - 7 Gy, 8 Gy or 9 Gy/fraction), use of whole brain radiotherapy (WBRT) either pre or post SRS, surgery and the use of systemic therapy were all evaluated. The toxicity was graded using the CTCAE V. 4.0. Kaplan- Mayer and Log-Rank test were used for survival curve calculations. Chi-square test was used for comparative analysis with a significance level of 0.05. Between March 2015 and November 2018, 86 patients were enrolled, of which 2 were excluded due to loss to follow-up and 144 lesions treated. The median follow-up was 9.0 months. The patient characteristics are shown in Table 1. The overall survival (OS) at 12 and 24 months was 43% and 21.6%, respectively, with a median overall survival of 10 months. Death due to neurological failure was 14.5%. Local control at 12 months was 81.3%, with 47.6% developing new lesions after the first mSRS. There wasn’t a correlation between local control and dose/fraction, PTV volume and the other factors. There were 4 patients with acute grade 3 toxicity (paresthesia), reversible with corticosteroids. The most common symptom was headache, grade 1 and 2, (23.5%). Eight patients had grade 1-2 seizures. The radionecrosis rate was 9.5%, and four patients had symptomatic radionecrosis. The PTV volume average was 20.87 cc (1-140 cc). In multivariate analysis, Ds-GPA, SIR, KPS, primary site (melanoma and breast were better) and systemic progression status had a statistically significant effect on OS. The dose/fraction and PTV volume did not correlate with toxicity or radionecrosis. This mSRS scheme of 3 fractions to large brain metastases showed good local control with low complication rates, in the studied population. In our retrospective analysis of 84 patients, we conclude that this 3 fraction mSRS is safe and effective. A prospective trial is warranted to compare and evaluate the best SRS regimens for this approach.Abstract 2160; Table 1Patients CharacteristicsAge (median)54.5 y (22-81)Numb. Lesions: 1 - 3; >3;91.6%/ 8.4%Ds-GPA 0-1; 1.5 - 2.5; >2.5;23.8%/ 29.8%/ 46.4%/Primary Lung; Breast; Melanoma; Others;39.3%/ 28.6%/ 8.3%/ 23.8%Fractionation 7 Gy x 3; 8 Gy x 3; 9 Gy x 3;8.3%/ 29.8%/ 61.9%/WBRT Pre mSRS; Pos mSRS; No;13.1%/ 23.8%/ 63.1%/ Open table in a new tab

Phase I Study of Trametinib in Combination with Whole-Brain Radiation Therapy for Brain Metastases

Trametinib is an oral reversible, highly selective inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and 2, and preclinical data suggests that trametinib can radiosensitize tumor cells. We performed a phase I study to determine the maximum tolerable dose (MTD) and safety of trametinib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases (BM). After confirmation of intracranial BM, patients were treated with trametinib and WBRT to a dose of 37.5 Gy in 15 fractions. Trametinib was given starting day -6 (7 total doses), followed by WBRT starting on day 1, and trametinib was given concurrently with radiation (7 days per week). The starting dose of trametinib was 1 mg and was escalated in a standard 3+3 fashion, to 1.5 mg and 2 mg. The primary endpoint was to determine the MTD of trametinib to be used in combination with WBRT. Secondary objectives included evaluation of tolerability and feasibility of WBRT + trametinib, objective response (RECIST criteria), neurologic progression-free survival (nPFS), and overall survival (OS). Characteristics of the 10 patients enrolled 2014-2016 were: mean age, 55 yrs; median BM, 5 (range 1 to >10); histologies were melanoma (n=5), breast (n=2), colorectal (n=1), esophageal adenocarcinoma (n=1) and eccrine carcinoma (n=1). Treatment involved WBRT 37.5 Gy in 10 fractions (n=9) and 30 Gy in 10 fractions (n=1). Dose level 1 was trametinib 1 mg (n=3), and level 2 was trametinib 1.5 mg (n=7). 1 patient withdrew consent in dose level 2. There were 39 Grade 1-2 toxicities and there were 13 Grade 3-4 toxicities. 1 patient experienced a grade 2 seizure during treatment, but no other reported neurotoxicities. 2 patients in dose level 2 experienced a DLT: grade 4 thrombocytopenia and grade 3 diarrhea. 1 patient experienced grade 4 elevation of hepatic enzymes, which was not a pre-defined DLT. 5 patients experienced ten grade 3 toxicities: lymphopenia, thrombocytopenia, diarrhea, fatigue, dehydration, nausea/vomiting, hyperglycemia, dyspnea, hyponatremia, and elevated troponin. The trial failed to accrue the 3 additional patients in dose level 1 and was closed early due to slow accrual. Median follow-up time from on treatment date to off-study date was 2.2 months. Median OS was 2.2 months. The median nPFS was 1.5 months. Objective response was measured in 6 patients as 4 did not live to complete follow up imaging. Of these 6, only 2 demonstrated a partial response to treatment. Trametinib failed to show a signal for response with concurrent WBRT, but survival in our cohort was worse than expected. The MTD is less than 1.5 mg. Concurrent use of WBRT with 1 mg of trametinib demonstrated safety in 3 patients; however, the trial was closed early due to slow accrual. Shifting patterns of practice contributed to slow accrual, particularly increased utilization of stereotactic radiosurgery (SRS). Future studies may attempt to ascertain the MTD in healthier individuals using SRS.