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Background: Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor., Methods: We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3-4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811., Findings: Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7-14·2), the median progression-free survival was 8·8 months (95% CI 5·7-16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2)., Interpretation: Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting., Funding: Pfizer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Real-world data are critical to demonstrate the reproducibility of evidence and external generalizability of randomized clinical trials. Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 that has been shown to improve progression-free survival (PFS) when combined with letrozole or fulvestrant in phase 3 clinical trials. We evaluated real-world outcomes in metastatic breast cancer patients who received palbociclib in combination with endocrine therapy in routine clinical practice., Methods: Records of patients with advanced hormone receptor (HR)-positive breast cancer treated with palbociclib at the Cleveland Clinic health system from February, 2015 to December, 2017 were retrospectively reviewed. The primary end point was PFS., Results: In this cohort, 411 women were included. The median age and follow-up times were 53.5 years and 10.2 months, respectively. The median PFS for palbociclib plus letrozole was 15.1 months for patients treated in first line, 10.5 months in second line, and 4.2 months in third line and beyond. For patients who received fulvestrant plus palbociclib, the median PFS in first, second, and third line and beyond were 11.6, 12.3, and 6.4 months, respectively. The most common adverse events were hematologic, with grade 3-4 neutropenia occurring in 58% of patients. Thirty-one (8%) patients permanently discontinued palbociclib due to adverse events., Conclusions: Among patients with HR-positive advanced breast cancer, the estimated PFS in patients treated with fulvestrant and palbociclib was comparable to a previously reported phase 3 trial. However, the median PFS with letrozole and palbociclib was shorter than previously reported data from phase 2 and 3 trials. Palbociclib toxicity was very manageable, with a low drug discontinuation rate.

Objective: Current management of gliomas involves a multidisciplinary approach, including a combination of maximal safe resection, radiotherapy, and chemotherapy. The use of intraoperative MRI (iMRI) helps to maximize extent of resection (EOR), and use of awake functional mapping supports preservation of eloquent areas of the brain. This study reports on the combined use of these surgical adjuncts., Methods: The authors performed a retrospective review of patients with gliomas who underwent minimal access craniotomy in their iMRI suite (IMRIS) with awake functional mapping between 2010 and 2017. Patient demographics, tumor characteristics, intraoperative and postoperative adverse events, and treatment details were obtained. Volumetric analysis of preoperative tumor volume as well as intraoperative and postoperative residual volumes was performed., Results: A total of 61 patients requiring 62 tumor resections met the inclusion criteria. Of the tumors resected, 45.9% were WHO grade I or II and 54.1% were WHO grade III or IV. Intraoperative neurophysiological monitoring modalities included speech alone in 23 cases (37.1%), motor alone in 24 (38.7%), and both speech and motor in 15 (24.2%). Intraoperative MRI demonstrated residual tumor in 48 cases (77.4%), 41 (85.4%) of whom underwent further resection. Median EOR on iMRI and postoperative MRI was 86.0% and 98.5%, respectively, with a mean difference of 10% and a median difference of 10.5% (p < 0.001). Seventeen of 62 cases achieved an increased EOR > 15% related to use of iMRI. Seventeen (60.7%) of 28 low-grade gliomas and 10 (30.3%) of 33 high-grade gliomas achieved complete resection. Significant intraoperative events included at least temporary new or worsened speech alteration in 7 of 38 cases who underwent speech mapping (18.4%), new or worsened weakness in 7 of 39 cases who underwent motor mapping (18.0%), numbness in 2 cases (3.2%), agitation in 2 (3.2%), and seizures in 2 (3.2%). Among the patients with new intraoperative deficits, 2 had residual speech difficulty, and 2 had weakness postoperatively, which improved to baseline strength by 6 months., Conclusions: In this retrospective case series, the combined use of iMRI and awake functional mapping was demonstrated to be safe and feasible. This combined approach allows one to achieve the dual goals of maximal tumor removal and minimal functional consequences in patients undergoing glioma resection.

Background: Nivolumab is approved for the treatment of refractory metastatic renal cell carcinoma. Patterns and predictors of progressive disease (PD) on nivolumab, and outcomes in such patients are lacking., Methods: A retrospective analysis of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) who received nivolumab at Cleveland Clinic (2015-2017) was performed. PD was defined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or clinical progression as per treating physician. Univariate analyses (UVA) and multivariate analyses (MVA) were used to identify clinical and laboratory markers as potential predictors of progression-free survival (PFS)., Results: Ninety patients with mean age of 65, 74% men, and 83% good or intermediate International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group were included. Median number of prior systemic treatments was 2 (range, 1-6). Median overall survival (OS) and PFS were 15.8 and 4.4 months, respectively. Fifty-seven patients (63%) had PD and 44% of patients with radiographic PD had new organ sites of metastases with brain (8/23, 35%) being the most common. Twelve patients received treatment beyond progression (TBP), and among 6 patients with available data, 3 (50%) had any tumor shrinkage (2 pts. with 17% shrinkage, one pt. with 29% shrinkage). Of 57 patients with PD, 28 patients (49%) were able to initiate subsequent treatment, mainly with axitinib and cabozantinib, while 40% of patients were transitioned to hospice after PD. In MVA, a higher baseline Neutrophil-to-Lymphocyte ratio (NLR) (HR, 1.86; 95% CI, 1.05-3.29; p = 0.033) was associated with an increased risk of progression, whereas higher (> 0.1 k/uL) baseline eosinophil count was associated with a lower risk of progression (HR, 0.54; 95% CI, 0.30-0.98; p = 0.042)., Conclusion: Brain was the most common site of PD in patients treated with nivolumab, and only half of patients progressing on nivolumab were able to initiate subsequent treatment. The risk of PD increased with a higher baseline NLR and reduced with a higher baseline eosinophil count.

T cell infiltration in tumors has been investigated as a biomarker of response to checkpoint inhibitors. Neo-adjuvant studies in renal cell carcinoma (RCC) may provide a unique opportunity to compare T cell infiltration in a pretreatment renal mass biopsy to a posttreatment nephrectomy specimen, and thus evaluate the effects of immune checkpoint inhibitors. However, there are no data regarding the association of T cell infiltration in matched biopsy and nephrectomy samples without intervening treatment. Understanding this association will inform investigation of this potential biomarker in future studies.Matched biopsy and nephrectomy samples (without intervening systemic therapy) were identified from patients with nonmetastatic RCC. Selected tissue sections from biopsy and nephrectomy samples were reviewed and marked for intratumoral lymphocytes by a pathologist. Immunohistochemistry (IHC) was utilized to stain for T cell markers (CD3, CD4, and CD8). Intratumoral staining was then quantified in the tissue sections as counts per total tumor area surveyed. Spearman correlation (r) was used to measure associations.Thirty matched pairs were investigated. The median interval between biopsy and nephrectomy was 2.8 (0.2-87.7) months. Clear cell was the most common histology (29/30; 97%). There was a statistically significant positive correlation between the frequency of CD3 and CD8 T cells between matched biopsy and nephrectomy samples (r = 0.39; P = .036 and r = 0.38; P = .041, respectively).The frequencies of CD8+ T cells in matched biopsy and nephrectomy samples in RCC in the absence of intervening treatment have been characterized and show a positive correlation between matched biopsy and nephrectomy samples.

Background: There is limited information on O 6 -methylguanine DNA methyltransferase (MGMT) status, extent of surgical resection, and its impact on overall outcomes in patients with glioblastoma (GBM)., Methods: After institutional review board approval, 233 newly diagnosed patients with GBM with known MGMT status (2009-2015) were included in our analysis. Clinical, imaging, and follow-up data were collected from the database. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary end points, respectively., Results: Of patients, 51.9% were younger than 65 years and 44.2% were noted to have promoter methylation of MGMT. Median residual tumor volume was 1.1 cm 3 and extent of complete resection of enhancing tumor on imaging was 96%. Estimated median OS and PFS were 10.9 months and 5.4 months, respectively. MGMT status was an independent predictor of PFS (hazard ratio [HR], 0.52; P = 0.005) but only marginally associated with OS (P = 0.059). In MGMT methylated patients, extent of resection (≥86%) and good performance status (Karnofsky Performance Status ≥70) were independently associated with PFS and OS, respectively (PFS: HR, 0.21; P = 0.015; OS: HR, 0.05; P = 0.002). In MGMT promoter unmethylated patients, extent of resection (≥86%) was independently associated with OS (P = 0.039). Concurrent chemoradiotherapy was associated with OS/PFS irrespective of age and MGMT status., Conclusions: Greater extent of resection of enhancing tumor was associated with improved PFS in MGMT promoter methylated patients, OS regardless of MGMT status. Elderly patients with methylated MGMT promoter were found to have improved PFS whereas younger patients had improved OS with MGMT promoter methylated status., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: The incidence, risk factors, and outcomes of low-grade glioma patients who undergo malignant transformation (MT) in the era of temozolomide are not well known. This study evaluates these factors in a large group of World Health Organization grade 2 glioma patients treated at a tertiary-care institution., Methods and Materials: Patient, tumor, and treatment factors were analyzed using an institutional review board-approved low-grade glioma database. Characteristics were compared using χ 2 and Wilcoxon signed rank tests. Time to event was summarized using proportional hazards models. Univariate and multivariate survival analyses were performed., Results: Of a total of 599 patients, 124 underwent MT; 76 (61.3%) had biopsy-proven MT. The MT incidence was 21%, and the median time to MT was 56.4 months. The 5- and 10-year progression-free survival rates were 30.6% ± 4.2% and 4.8% ± 1.9%, respectively, for MT patients and 60% ± 2.4% and 38% ± 2.7%, respectively, for non-MT patients. The 5- and 10-year overall survival rates were 75% ± 4.0% and 46% ± 5.0%, respectively, for MT patients and 87% ± 1.7% and 78% ± 2.3%, respectively, for non-MT patients. On multivariate analysis, older age (P = .001), male sex (P = .004), multiple tumor locations (P = .004), chemotherapy alone (P = .012), and extent of resection (P = .045) remained significant predictors of MT., Conclusions: MT affects survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our finding that initial interventions could affect the rate of MT is provocative, but these data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT., (Copyright © 2017. Published by Elsevier Inc.)

Objectives: To identify risk factors associated with early distant radiographic progression in patients undergoing stereotactic radiosurgery (SRS) for brain metastases (BM)., Methods: Following Institutional Review Board approval, data of 1427 patients (4283 BM lesions) who were treated by SRS at the Cleveland Clinic for 2000-2012 were collected. Local tumor progression (LTP), distant tumor progression (DTP), and radiographic radiation necrosis (RN) were the primary endpoints. Patient, imaging, radiosurgery, and tumor variables and follow-up data were collected., Results: The median number of targets was 2 (range, 1-17); 45% of the patients had a single lesion. DTP was observed in 10% at 3 months and 19% at 6 months. Patients with 5-10 target lesions for SRS were more likely to develop new lesions at both 3 and 6 months compared to those with 2-4 lesions (odds ratio [OR], 0.83, 95% confidence interval [CI], 0.40-0.85 and OR, 0.85, 95% CI, 0.45-0.86 respectively; P < 0.05). Younger age (<65 years; P < 0.001), higher number of lesions (>1; P < 0.001), cumulative intracranial tumor volume (CITV) <2.75 cc (P = 0.023), type of SRS (upfront and salvage vs. boost; P < 0.001), and tumor pathology (radiosensitive; P < 0.001), were independent predictors of early distant tumor progression following SRS., Conclusions: The number of target lesions and low CITV are both independent predictors of early DTP following SRS for BM. Radiosensitive tumor histology, younger age (<65 years), and SRS without previous whole-brain radiation therapy (upfront or salvage) were also predictors of early DTP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Patients with single brain metastasis (SBM) have better outcomes after stereotactic radiosurgery (SRS). We analyzed our SRS database to evaluate possible prognostic factors in patients with SBM., Methods: A total of 584 patients with SBM were treated with SRS at our institution (2000-2012). Study end points were overall survival (OS), and distant and local intracranial progression-free survival (DPFS and LPFS, respectively). Multivariable analysis was performed to develop prognostic models., Results: Median OS was 10.8 months. A total of 196 patients (36.7%) had distant progression and 102 patients (19.2%) had local progression. New SBM prognostic indices (SPIs) were devised for OS, DPFS, and LPFS. Graded prognostic assessment, neurologic symptoms (P = 0.01), and tumor volume (P = 0.02) were independently associated with OS. The SPI for OS was defined: unfavorable (OS, 7.3 months), intermediate (OS, 10.6 months), and favorable (OS, 19.8 months). For DPFS, age (P = 0.0029), tumor volume (P = 0.0002), and previous whole-brain radiotherapy (P = 0.027) were prognostic and were used to define SPI for DPFS: favorable (6-month cumulative incidence failure [CIF], 10.9%), intermediate (6-month CIF, 16.7%), and unfavorable (6-month CIF, 26.0%) (P < 0.001). For LPFS, graded prognostic assessment (P = 0.0012) and tumor volume (P = 0.0004) were significant, and defined 2 groups in the LPFS SPI: unfavorable (6-month CIF, 12.3%) and favorable (6-month CIF, 6%) (P < 0.001)., Conclusions: This is the largest series of patients with SBM treated with SRS analyzed for OS, LPFS, and DPFS. SPI was devised for end points. Tumor volume had a significant association with all 3 end points. Neurologic symptoms, age, and previous whole-brain radiotherapy were also found to be prognostic., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Cardiac sarcomas are rare and have a poor prognosis. The median overall survival remains dismal and has been reported ranging from 6 months to a few years. Primary cardiac sarcoma is the most common malignant tumor comprising approximately 95% of all malignant tumors of the heart., Methods: We conducted a retrospective chart review in a single institution of patients diagnosed between March 1988 and April 2013. A total of 42 patients were identified. The following variables were studied: age at diagnosis, year of diagnosis, sex, stage, site of tumor involvement, tumor histology, grade, treatment modality, type of chemotherapy, and survival outcome. The overall median follow-up time was 49.5 months., Results: The most common histologic type was angiosarcoma. Overall estimated median survival (EMS) was 25 months. Tumors involving the left side of the heart and pericardium demonstrated better survival. Patients who received multimodality treatment (any combination of surgery, radiation therapy, and chemotherapy) had an EMS of 36.5 months compared with 14.1 months for patients treated with surgery, radiation therapy, or chemotherapy only (P=0.05)., Conclusions: Cardiac sarcoma is a lethal tumor with an EMS of 25 months. The tumor histology could be a possible predictor of better survival. Although selection bias may have been present, multimodality therapy (surgery, radiation therapy, and chemotherapy) was associated with improved survival.