Glioblastoma (GBM) is a lethal and aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. Molecularly targeted agents hold great promise in treating these genetically heterogeneous tumors, yet have produced disappointing results. One reason for the clinical failure of these novel therapies can be the inability of the drugs to achieve effective concentrations in the invasive regions beyond the bulk tumor. In this review, we describe the influence of the blood-brain barrier on the distribution of anticancer drugs to both the tumor core and infiltrative regions of GBM. We further describe potential strategies to overcome these drug delivery limitations. Understanding the key factors that limit drug delivery into brain tumors will guide future development of approaches for enhanced delivery of effective drugs to GBM.

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Background Esophageal carcinoma is the eighth most common cancer in the world. Volumetric‐modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small‐spot intensity‐modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small‐spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects. Methods 35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small‐spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase‐averaged 4D‐CT's. The dose‐volume‐histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank‐sum test. For fair comparison, all the treatment plans were normalized to have the same CTVhigh D95% in the nominal scenario relative to the prescription dose. Results In the nominal scenario, small‐spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE], lung Dmean, heart Dmean compared with VMAT. CTVhigh dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE], liver V30Gy[RBE], stomach V45Gy[RBE], lung Dmean, V5Gy[RBE], and V20Gy[RBE], cord Dmax and D0.03boldcboldm3, liver Dmean, heart V20Gy[RBE], and V30Gy[RBE], but IMPT was significantly worse for CTVhigh D95%, D2boldcboldm3, and D5%‐D95%, CTVlow D95%, heart Dmean, and V40Gy[RBE], requiring careful and experienced adjustments during the planning process and robustness considerations. The small‐spot IMPT plans still met the standard clinical requirements after interplay effects were considered. Conclusions Small‐spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small‐spot IMPT for the treatment of distal esophageal carcinoma.

PurposeTo compare dosimetric performance of volumetric‐modulated arc therapy (VMAT) and small‐spot intensity‐modulated proton therapy for stage III non‐small‐cell lung cancer (NSCLC).Methods and MaterialsA total of 24 NSCLC patients were retrospectively reviewed; 12 patients received intensity‐modulated proton therapy (IMPT) and the remaining 12 received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTV) on averaged 4D‐CTs. The dose‐volume‐histograms (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases of each field per fraction. DVH indices were compared using Wilcoxon rank sum test.ResultsCompared with VMAT, IMPT delivered significantly lower cord Dmax, heart Dmean, and lung V5 Gy[ RBE ] with comparable CTV dose homogeneity, and protection of other OARs. In terms of plan robustness, the IMPT plans were statistically better than VMAT plans in heart Dmean, but were statistically worse in CTV dose coverage, cord Dmax, lung Dmean, and V5 Gy[ RBE ]. Other DVH indices were comparable. The IMPT plans still met the standard clinical requirements with interplay effects considered.ConclusionsSmall‐spot IMPT improves cord, heart, and lung sparing compared to VMAT and achieves clinically acceptable plan robustness at least for the patients included in this study with motion amplitude less than 11 mm. Our study supports the usage of IMPT to treat some lung cancer patients.

In recent years, there has been rapid adaption of proton beam radiotherapy (RT) for treatment of various malignancies in the gastrointestinal (GI) tract, with increasing number of institutions implementing intensity modulated proton therapy (IMPT). We review the progress and existing literature regarding the technical aspects of RT planning for IMPT, and the existing tools that can help with the management of uncertainties which may impact the daily delivery of proton therapy. We provide an in-depth discussion regarding range uncertainties, dose calculations, image guidance requirements, organ and body cavity filling consideration, implanted devices and hardware, use of fiducials, breathing motion evaluations and both active and passive motion management methods, interplay effect, general IMPT treatment planning considerations including robustness plan evaluation and optimization, and finally plan monitoring and adaptation. These advances have improved confidence in delivery of IMPT for patients with GI malignancies under various scenarios.

Purpose Intensity modulated proton beam radiation therapy (IMPT) has a clinically significant dosimetric advantage over intensity modulated photon radiation therapy (IMRT) for the treatment of patients with esophageal cancer, particularly for sparing the heart and lungs. We compared acute radiation therapy–related toxicities and short-term clinical outcomes of patients with esophageal cancer who received treatment with IMPT or IMRT. Methods and Materials We retrospectively reviewed the electronic health records of consecutive adult patients with esophageal cancer who underwent concurrent chemoradiotherapy with IMPT or IMRT in the definitive or neoadjuvant setting from January 1, 2014, through June 30, 2018, with additional follow-up data collected through January 31, 2019. Treatment-related toxicities were evaluated per the Common Terminology Criteria for Adverse Events, version 4. Survival outcomes were estimated with the Kaplan-Meier method. Results A total of 64 patients (32 per group) were included (median follow-up time: 10 months for IMPT patients vs 14 months for IMRT patients). The most common radiation therapy regimen was 45 Gy in 25 fractions, and 80% of patients received a simultaneous integrated boost to a median cumulative dose of 50 Gy. Similar numbers of IMPT patients (n = 15; 47%) and IMRT patients (n = 18; 56%) underwent surgery ( P = .07), with no difference in pathologic complete response rates (IMPT: n = 5; 33% vs IMRT: n = 7; 39%; P = .14). At 1 year, the clinical outcomes also were similar for IMPT and IMRT patients, respectively. Local control was 92% versus 84% ( P = .87), locoregional control 92% versus 80% ( P = .76), distant metastasis–free survival 87% versus 65% ( P = .08), progression-free survival 71% versus 45% ( P = .15), and overall survival 74% versus 71% ( P = .62). The rate of acute treatment–related grade 3 toxicity was similar between the groups ( P = .71). Conclusions In our early experience, IMPT is a safe and effective treatment when administered as part of definitive or trimodality therapy. Longer follow-up is required to evaluate the effectiveness of IMPT.

Purpose: The authors aimed to illustrate the potential dose differences to clinical target volumes (CTVs) and organs-at-risk (OARs) volumes after proton adaptive treatment planning was used. Patients and Methods: The records of 10 patients with oropharyngeal cancer were retrospectively reviewed. Each patient's treatment plan was generated by using the Eclipse treatment planning system. Verification computed tomography (CT) scan was performed during the fourth week of treatment. Deformable image registrations were performed between the 2 CT image sets, and the CTVs and major OARs were transferred to the verification CT images to generate the adaptive plan. We compared the accumulated doses to CTVs and OARs between the original and adaptive plans, as well as between the adaptive and verification plans to simulate doses that would have been delivered if the adaptive plans were not used. Results: Body contours were different on planning and week-4 verification CTs. Mean volumes of all CTVs were reduced by 4% to 8% (P .04), and the volumes of left and right parotid glands also decreased (by 11% to 12%, P .004). Brainstem and oral cavity volumes did not significantly differ (all P ! .14). All mean doses to the CTV were decreased for up to 7% (P .04), whereas mean doses to the right parotid and oral cavity increased from a range of 5% to 8% (P .03), respectively. Conclusion: Verification and adaptive planning should be recommended during the course of proton therapy for patients with head and neck cancer to ensure adequate dose deliveries to the planned CTVs, while safe doses to OARs can be respected.

Importance: Oral mucositis causes substantial morbidity during head-and-neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis–related pain. A common mouthwash comprising diphenhydramine-lidocaine-antacid is also widely used. Objective: To evaluate the effect of doxepin or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis–related pain. Design, Settings, and Participants: A multi-institutional, 3-group, randomized, double-blind, placebo-controlled phase III trial was conducted from November 1, 2014, to May 16, 2016, in 30 institutions in the United States; 275 patients undergoing definitive head-and-neck radiotherapy with oral mucositis pain rated ≥4 (scale, 0-10) were eligible and randomized. Patients were followed up for a maximum of 28 days after randomization. The last follow-up occurred in June 2016. Interventions: Patients were randomized to doxepin (25 mg/5 mL water), 92 patients; diphenhydramine-lidocaine-antacid mouthwash, 91 patients; and placebo, 92 patients. Main Outcome and Measures: Primary end point was total oral mucositis pain reduction (area under the curve, adjusting for baseline pain scale) over 4 hours after a single dose of doxepin or diphenhydramine-lidocaine-antacid, compared with a single dose of placebo. Minimal clinically important difference was 3.5-point change. Secondary end points included drowsiness, unpleasant taste, and stinging/burning. All scales ranged from 0 (best) to 10 (worst). Results: Among the 275 patients randomized (median age, 61 years; 58 [21%] women), 227 (83%) completed treatment per protocol. Mucositis pain over the first 4 hours decreased by 11.6 points in the doxepin group, by 11.7 points in the diphenhydramine-lidocaine-antacid group, and by 8.7 points in the placebo group, with between-group differences of 2.9 points (95% CI [0.2 to 6.0]; P=.021) for doxepin vs placebo and 3.0 points (95% CI [0.1 to 5.9]; P=.004) for diphenhydramine-lidocaine-antacid vs placebo. More drowsiness (2.6 points; 95% CI [−0.7 to 5.9]; P=.03), unpleasant taste (2.8 points; 95% CI [0.8 to 4.8]; P=.002), and stinging/burning (4.9 points; 95% CI [2.9 to 6.9]; P<.001) were reported with doxepin mouthwash vs placebo. Maximum grade 3 adverse events for the doxepin mouthwash, diphenhydramine-lidocaine-antacid mouthwash, and placebo groups occurred in 3 (4%), 3 (4%), and 2 (2%) patients, respectively. Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid group. Conclusions and Relevance: Among patients undergoing head-and-neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with placebo significantly reduced oral mucositis pain for the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes. Trial Registration: clinicaltrials.gov Ident...