A critical appraisal of the four systematic reviews and meta-analysis on stereotactic body radiation therapy versus external beam radiotherapy for painful bone metastases and where we go from here.

Radiotherapy is an important treatment modality for pain control in patients with bone metastases. Stereotactic body radiation therapy (SBRT), which allows delivering a much higher dose per fraction while sparing critical structures compared to conventional external beam radiotherapy (cEBRT), has become more widely used, especially in the oligometastatic setting. Randomized controlled trials (RCTs) comparing the pain response rate of SBRT and cEBRT for bone metastases have shown conflicting results, as have four recent systematic reviews with meta-analyses of these trials. Possible reasons for the different outcomes between these reviews include differences in methodology, which trials were included, and the endpoints examined and how they were defined. We suggest ways to improve analysis of these RCTs, particularly performing an individual patient-level meta-analysis since the trials included heterogeneous populations. The results of such studies will help guide future investigations needed to validate patient selection criteria, optimize SBRT dose schedules, include additional endpoints (such as the time to onset of pain response, durability of pain response, quality of life (QOL), and side effects of SBRT), and better assess the cost-effectiveness and trade-offs of SBRT compared to cEBRT. An international Delphi consensus to guide selection of optimal candidates for SBRT is warranted before more prospective data is available.

Nivolumab and Stereotactic Radiosurgery for Patients With Breast Cancer Brain Metastases: A Nonrandomized, Open-Label Phase 1b Study.

PURPOSE: We hypothesize treatment with nivolumab and stereotactic radiosurgery (SRS) will be feasible and well tolerated, and may improve intracranial tumor control rates compared with SRS alone. METHODS AND MATERIALS: The study was designed as a prospective, single-arm, nonrandomized, open-label, phase 1b trial of nivolumab and SRS among patients with metastatic breast cancer brain metastases. Key eligibility criteria included patients with breast cancer brain metastases of all subtypes, age ≥18, Eastern Cooperative Oncology Group Performance Status ≤2 with ≤10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg intravenously) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT03807765. RESULTS: Between February 2019 and July 2020, a total of 12 patients were treated to 17 lesions. No dose limiting toxicities were noted in our patient population. The most common neurologic adverse events included grade 1 to 2 headaches and dizziness occurring in 5 (42%) of patients. Median intracranial control was 6.2 months (95% confidence interval, 3-14 months) with 6- and 12-month control rates of 55% and 22%, respectively. A total of 4 patients had systemic progression during the study. Median time to systemic progression free survival has not been reached with 6- and-12 month rates of 63% and 51%, respectively. CONCLUSIONS: Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. Preliminary data reveals activity in certain breast cancer patients to study therapy.

Patient-reported outcomes regarding radiation therapy in patients with multiple myeloma.

Background: Radiation therapy (RT) has been widely used for palliation in multiple myeloma. However, no data exist on symptom assessment and patient-reported outcomes regarding the efficacy of RT in this disease process. This study aims to demonstrate the impact of palliative RT on patient-reported symptoms in patients with multiple myeloma.Materials and Methods: Our Radiation Oncology and Supportive Care Medicine clinics established the use of a modified Edmonton Symptom Assessment Scale (ESAS) in 2015 assessing 12 symptom domains. All had ESAS data available from each encounter. Demographic and clinical data were retrospectively collected from an institutional data warehouse. We examined total and component survey scores for correlated data of patients during radiation treatment and patients not treated with radiation.Results: Clinic records of 30 patients with multiple myeloma seen in the Radiation Oncology and Supportive Care clinics from 2015 to 2018 were retrieved. A total of 91 discrete surveys were collected (1183 data points). Twenty of these were collected from weekly visits from 12 patients receiving RT; the remainder were from new patient or follow up encounters. Odds ratios were lower with radiation therapy for total scores (OR 4.86, p = .007), as well as several component scores.Conclusions: The use of palliative RT was associated with 5 times lower total symptom scores compared with nonuse. Similar beneficial results were found for several component scores. These patient-reported outcomes strongly suggest that providers should consider palliative radiation for symptomatic multiple myeloma patients. These data should be prospectively validated in a larger cohort of myeloma patients.

CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases.

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors are becoming increasingly utilized in the setting of advanced, hormone receptor (HR+) positive breast cancer. Pre-clinical data suggests a potential synergy between radiation therapy (RT) and CDK4/6 inhibitors. We assessed clinical outcomes of patients treated at our institution with the use of CDK4/6 inhibitors and stereotactic radiation in the management of HR+ breast brain metastases. METHODS: A retrospective analysis of patients who received stereotactic radiotherapy for HR+ brain metastases within 6 months of CDK4/6 inhibitor administration was performed. The primary endpoint was neurotoxicity during or after stereotactic radiation. Secondary endpoints were local brain control, distant brain control, and overall survival (OS). RESULTS: A total of 42 lesions treated with stereotactic radiation in 15 patients were identified. Patients received either palbociclib (n = 10; 67%) or abemaciclib (n = 5; 33%). RT was delivered concurrently, before, or after CDK4/6 inhibitors in 18 (43%), 9 (21%), and 15 (36%) lesions, respectively. Median follow-up following stereotactic radiation was 9 months. Two lesions (5%) developed radionecrosis, both of which received four prior RT courses to the affected lesion prior to onset of radionecrosis and subsequently managed with steroids and bevacizumab. Six- and 12-month local control of treated lesions was 88% and 88%, while 6- and 12-month distant brain control was 61% and 39%, respectively. Median OS was 36.7 months from the date of brain metastases diagnosis. CONCLUSIONS: Stereotactic radiation to breast brain metastases was well tolerated alongside CDK4/6 inhibitors. Compared to historical data, brain metastases control rates are similar whereas survival appears prolonged.

Clinical outcomes of breast leptomeningeal disease treated with intrathecal trastuzumab, intrathecal chemotherapy, or whole brain radiation therapy.

PURPOSE: Leptomeningeal disease is a rare presentation of advanced metastatic breast cancer. The purpose of this study was to evaluate craniospinal progression between intrathecal (IT) trastuzumab, IT chemotherapy, and whole brain radiation therapy (WBRT) in leptomeningeal disease. METHODS: A total of 56 patients were identified with breast cancer leptomeningeal disease at our institution treated with IT trastuzumab (n = 18; 32%), single-agent IT chemotherapy (methotrexate n = 14 or thiotepa n = 1; 27%), or WBRT alone (n = 23; 41%). Patients were treated beginning November 2012 and followed until November 2018. RESULTS: Median time from breast cancer diagnosis to development of leptomeningeal disease was 4.3 years. There were no significant differences noted between IT trastuzumab, IT chemotherapy, or WBRT groups in age (p = 0.4), Karnofsky Performance Status (KPS) (p = 0.07), or receipt of systemic therapy at time of leptomeningeal disease treatment (p = 0.47). Median follow-up of patients from leptomeningeal diagnosis was 5 months (range 0.2-81.1 months). Significant differences were noted in Kaplan-Meier (KM) craniospinal progression-free survival (CS-PFS) with 6-month rates of 44%, 18%, and 26% (p = 0.04) between IT trastuzumab, IT chemotherapy, and WBRT, respectively. Craniospinal control > 10 months was achieved in four patients treated with IT trastuzumab. Twelve-month KM OS rates were 54%, 10%, and 19% (p = 0.01) between IT trastuzumab, IT chemotherapy, and WBRT groups, respectively. IT therapy was adequately tolerated with three patients undergoing treatment-related hospitalizations. CONCLUSIONS: In our institutional series, significant differences were noted in CS-PFS and OS by treatment modality. IT trastuzumab should be considered in the management HER2+ breast leptomeningeal disease.

Association of MGMT Promoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide: An Analysis From the NRG Oncology/RTOG 0424 Trial.

Importance: The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial-evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes-was not previously reported. Objective: To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes. Design, Setting, and Participants: Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses. Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS). Results: Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P < .001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P < .001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P = .045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P = .02). Conclusions and Relevance: In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status. Trial Registration: ClinicalTrials.gov Identifier: NCT00114140.

Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma.

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with bevacizumab and CPT-11 and was escalated using a standard 3 + 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. Correlative science involving proteomic profiling of serial patient plasma samples was performed. Nineteen patients were treated. The MTD of vorinostat was established at 400 mg on days 1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. Although the MTD was established, CPT-11 dose reductions were common early in therapy. High-dose vorinostat had an improved progression-free survival and overall survival when compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for the combination of vorinostat with bevacizumab and CPT-11 has been established, although it has poor long-term tolerability. With the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial.