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For treating peripheral brain lesions--where proton therapy would be expected to have the greatest depth-dose advantage over photon therapy--the lateral penumbra strongly impacts the SS plan quality relative to photon techniques: proton beamlet sigma at patient surface must be small (<7.1 mm for three-beam single-field optimized SS plans) in order to achieve comparable or smaller brain necrosis NTCP relative to photon radiosurgery techniques. Achieving such small in-air sigma values at low energy (<70 MeV) is a major technological challenge in commercially available proton therapy systems.

Purpose: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH À ) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH À to standard RT/TMZ therapy.Patients and Methods: This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH À ) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH À phase). Eight P-AscH À dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (!20 mmol/L). In the ADJ phase, P-AscH À doses were escalated in each subject at each cycle until plasma concentrations were !20 mmol/L. P-AscH À was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03).Results: Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n ¼ 8), median PFS was 10 months and median OS was 23 months.Conclusions: P-AscH À /RT/TMZ is safe with promising clinical outcomes warranting further investigation.

Background Delays in postoperative radiotherapy (PORT) for head and neck cancer (HNC) increase the risk for recurrence and mortality. The multifactorial nature of delays calls for an in‐depth understanding of potential contributors from the patient's and provider's perspectives. We sought to identify causes of delays in adjuvant radiotherapy initiation for HNC. Methods We performed a mixed‐methods study including patients with HNC care team members. Forty in‐depth interviews were performed (26 patients; 14 care team members). Timing and demographic data were collected from medical records. Results Median time from surgery to radiotherapy initiation was 45 days; 15 participants began after 42 days. Process delays and failure to communicate the urgency and significance of PORT initiation contributes to delays. Patients with a strong social support system experience less delays. Conclusions Achieving reductions in PORT initiation requires efficient care coordination, improved communication between interdisciplinary teams, and strengthening social support systems for patients with HNC.

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