Faculty Bibliography

BACKGROUND:The majority of chemoradiation (CRT) trials for locally advanced head and neck squamous cell carcinoma (HNSCC) have relied on platinum-based chemotherapy regimens administered every-3-weeks. However, given the increased utilization of weekly platinum regimens, it remains unclear how different chemotherapy schedules compare regarding efficacy and toxicity. METHODS:We retrospectively identified 212 patients with HNSCC who were treated at a single academic medical center with concurrent platinum-based CRT given weekly (N = 68) or every-three-weeks (N = 144). JMP version 10 (SAS Institute) was used for statistical analysis. Discrete variables were compared with the chi-square test and differences in the medians were assessed using the Wilcoxon test. Survival curves were constructed using the Kaplan-Meier method and significance was assessed using the log rank test. For univariate analysis and multivariate analysis, we used Cox proportional hazard or logistic regression models to compare differences in survival or differences in categorical variables, respectively. RESULTS:Patients receiving weekly platinum regimens were more likely to be older (median age 61.4 vs. 55.5 y; P < .001), have high or very high Charlson comorbidity index (45.6% vs. 27.8%; P = .01), and receive carboplatin-based chemotherapy (6.3% vs. 76.5%; P < .001). Weekly and every-3-week platinum regimens had similar locoregional control (HR 1.10; 95% CI 0.63-1.88; P = .72), progression-free survival (HR 1.13; 95% CI 0.75-1.69; P = .55), and overall survival (HR 1.11; 95% CI 0.64-1.86; P = .71). Every-3-weeks platinum regimens were associated with increased days of hospitalization (median: 3 days vs. 0 days; P = .03) and acute kidney injury (AKI) during radiotherapy (50.0% vs. 22.1%; P < .001). On multivariate analysis, AKI was significantly associated with every-3-weeks regimens (OR: 24.38; 95% CI 3.00-198.03; P = .003) and high comorbidity scores (OR: 2.74; 95% CI 2.15-5.99; P = .01). CONCLUSIONS:Our results suggest that every-3-weeks and weekly platinum-containing CRT regimens have similar disease control but weekly platinum regimens are associated with less acute toxicity.

H3K27 downregulates gene transcription. When H3K27 is trimethylated, it is tightly associated with inactive gene promoters. In malignant gliomas, the loss of histone H3K27 trimethylation is strongly associated with underlying K27M mutation; however the role of H3K27 in meningiomas has not been completely elucidated. Atypical and anaplastic meningiomas (WHO Grade II and III) are associated with higher risk of recurrence following gross total resection; however the molecular biology of anaplastic progression is not completely understood. We performed histological and molecular analysis of 14 WHO Grade II and III meningiomas and compared them with 6 locally invasive WHO Grade I meningiomas. Grade and atypical features were correlated with expression of histone H3K27 trimethylation by immunohistochemistry. Staining intensity (none, weak, moderate, strong) and extent of staining (0-100% of the tumor) were evaluated semi-quantitatively. We also tested the tumors for K27M mutation by mutation specific antibody. Out of 14 high grade meningiomas, 10 showed a complete loss of K27 trimethyl staining and 4 tumors showed small foci of preserved trimethyl staining, mostly in areas close to the dura; however staining intensity was weak. In contrary, all 6 (100%) WHO Grade I tumors showed preserved multifocal trimethyl mark expression in 25-50% of the tumor cells, with moderate (5) or strong (1) staining intensity. All tumors were negative for histone H3K27M mutation by immunohistochemistry. Atypical and anaplastic meningiomas show almost uniform loss of histone H3K27 trimethylation staining. However this loss of trimethylation is not caused by histone H3K27M mutation. Loss of histone H3K27 trimethylation leads to dysregulation of the PRC2 complex, which is involved in repression of non-cell-type specific promoters and may contribute to aggressive behavior. Clinically, loss of histone H3K27 trimethylation can be used as a diagnostic marker for a high grade meningiomaswhen histological features are inconclusive

The aim of this study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. We prospectively collected treatment parameters and outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). Univariate and multivariate analyses were performed to identify predictors of overall survival. The median overall survival from first SRS procedure was 6.7, 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54 % at 6 months and 41 % at 12 months from the time of SRS. In contrast, BRAF-WT had overall survival rates of 28 % at 6 months and 19 % at 12 months. Overall survival was extended for patients on a BRAF inhibitor at or after the first SRS. The median time to intracranial progression was 3.9 months on a BRAF inhibitor and 1.7 months without. The local control rate for all treated tumors was 92.5 %, with no difference based on BRAF status. Patients with higher KPS, fewer treated intracranial metastases, controlled systemic disease, RPA Class 1 and BRAF-M patients had extended overall survival. Overall, patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival from the time of SRS. As patients live longer as a result of more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.

We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012-2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7 %, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.