Faculty Bibliography

AIM/OBJECTIVE:Anterior-oblique (AO) proton beams can form an attractive option for prostate patients receiving external beam radiotherapy (EBRT) as they avoid the femoral heads. For a cohort with hydrogel prostate-rectum spacers, we asked whether it was possible to generate AO proton plans robust to end-of-range elevations in linear energy transfer (LET) and modeled relative biological effectiveness (RBE). Additionally we considered how rectal spacers influenced planned dose distributions for AO and standard bilateral (SB) proton beams versus intensity-modulated radiotherapy (IMRT). MATERIAL AND METHODS/METHODS:We studied three treatment strategies for 10 patients with rectal spacers: (A) AO proton beams, (B) SB proton beams and (C) IMRT. For strategy (A) dose and LET distributions were simulated (using the TOPAS Monte Carlo platform) and the McNamara model was used to calculate proton RBE as a function of LET, dose per fraction, and photon α/β. All calculations were performed on pretreatment scans: inter- and intra-fractional changes in anatomy/set-up were not considered. RESULTS:For 9/10 patients, rectal spacers enabled generation of AO proton plans robust to modeled RBE elevations: rectal dose constraints were fulfilled even when the variable RBE model was applied with a conservative α/β = 2 Gy. Amongst a subset of patients the proton rectal doses for the planning target volume plans were remarkably low: for 2/10 SB plans and 4/10 AO plans, ≤10% of the rectum received ≥20 Gy. AO proton plans delivered integral doses a factor of approximately three lower than IMRT and spared the femoral heads almost entirely. CONCLUSION/CONCLUSIONS:Typically, rectal spacers enabled the generation of anterior beam proton plans that appeared robust to modeled variation in RBE. However, further analysis of day-to-day robustness would be required prior to a clinical implementation of AO proton beams. Such beams offer almost complete femoral head sparing, but their broader value relative to IMRT and SB protons remains unclear.

A 33-year-old man with symptomatic, unresectable osteosarcoma of the neck experienced disease progression despite treatment with multiple systemic agents. Given the tumor location, adjacent to the spinal cord and encasing the brachial plexus, proton beam therapy was recommended instead of conventional photon radiation therapy. The treatment was delivered in 3 weekly 10 cobalt-gray equivalents fractions, and there was minimal associated toxicity. There has been significant improvement in the patient's presenting symptoms as well as radiologically stable disease at 1 year. A photon intensity-modulated radiation therapy plan was created retrospectively for dosimetric comparison and demonstrated noninferiority, thereby highlighting the need for judicious use of proton therapy in certain cases.

A 29-year-old woman underwent resection of a left anterior mediastinal thymoma and pleurectomy. Postsurgical FDG PET/CT scan demonstrated FDG avidity in the right neck and upper thoracic fat but relatively absent FDG-avid fat in the left neck and upper thorax. Bilateral FDG-avid fat was also apparent in the lower chest and upper abdomen. After surgery, the patient demonstrated Horner syndrome, with left-sided ptosis, miosis, and facial anhidrosis. It is hypothesized that left-sided sympathetic nerves were compromised during surgery, leading to Horner syndrome and denervation of ipsilateral brown fat. The unilateral FDG avidity should not be mistaken for malignancy.

BACKGROUND:We evaluated the dosimetric differences between proton beam therapy (PBT) and intensity modulated radiation therapy (IMRT) for resected thymoma. We simultaneously report our early clinical experience with PBT in this cohort. PATIENTS AND METHODS:We identified 4 patients with thymoma or thymic carcinoma treated at our center from 2012 to 2014 who completed adjuvant PBT to a median dose of 57.0 cobalt Gy equivalents (CGE; range, 50.4-66.6 CGE) after definitive resection. Adjuvant radiation was indicated for positive (n = 3) or close margin (n = 1). Median age was 45 (range, 32-70) years. Stages included II (n = 2), III (n = 1), and IVA (n = 1). Analogous IMRT plans were generated for each patient for comparison, and preset dosimetric endpoints were evaluated. Early toxicities were assessed according to retrospective chart review. RESULTS:Compared with IMRT, PBT was associated with lower mean doses to the lung (4.6 vs. 8.1 Gy; P = .02), esophagus (5.4 vs. 20.6 Gy; P = .003), and heart (6.0 vs. 10.4 Gy; P = .007). Percentages of lung, esophagus, and heart receiving radiation were consistently lower in the PBT plans over a wide range of radiation doses. There was no difference in mean breast dose (2.68 vs. 3.01 Gy; P = .37). Of the 4 patients treated with PBT, 3 patients experienced Grade 1 radiation dermatitis, and 1 patient experienced Grade 2 dermatitis, which resolved after treatment. With a median follow-up of 5.5 months, there were no additional Grade ≥ 2 acute or subacute toxicities, including radiation pneumonitis. CONCLUSION:PBT is clinically well tolerated after surgical resection of thymoma, and is associated with a significant reduction in dose to critical structures without compromising coverage of the target volume. Prospective evaluation and longer follow-up is needed to assess clinical outcomes and late toxicities.

This review will focus on the indications, clinical experience, and technical considerations of proton beam radiation therapy in the treatment of patients with breast cancer. For patients with early stage disease, proton therapy delivers less dose to non-target breast tissue for patients receiving partial breast irradiation (PBI) therapy, which may result in improved cosmesis but requires further investigation. For patients with locally advanced breast cancer requiring treatment to the regional lymph nodes, proton therapy allows for an improved dosimetric profile compared with conventional photon and electron techniques. Early clinical results demonstrate acceptable toxicity. The possible reduction in cardiopulmonary events as a result of reduced dose to organs at risk will be tested in a randomized control trial of protons vs. photons.

PURPOSE/OBJECTIVE:Reirradiation therapy (re-RT) is the only potentially curative treatment option for patients with locally recurrent head and neck cancer (HNC). Given the significant morbidity with head and neck re-RT, interest in proton beam radiation therapy (PBRT) has increased. We report the first multi-institutional clinical experience using curative-intent PBRT for re-RT in recurrent HNC. METHODS AND MATERIALS/METHODS:A retrospective analysis of ongoing prospective data registries from 2 hybrid community practice and academic proton centers was conducted. Patients with recurrent HNC who underwent at least 1 prior course of definitive-intent external beam radiation therapy (RT) were included. Acute and late toxicities were assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and the Radiation Therapy Oncology Group late radiation morbidity scoring system, respectively. The cumulative incidence of locoregional failure was calculated with death as a competing risk. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were calculated with the Kaplan-Meier method. RESULTS:Ninety-two consecutive patients were treated with curative-intent re-RT with PBRT between 2011 and 2014. Median follow-up among surviving patients was 13.3 months and among all patients was 10.4 months. The median time between last RT and PBRT was 34.4 months. There were 76 patients with 1 prior RT course and 16 with 2 or more courses. The median PBRT dose was 60.6 Gy (relative biological effectiveness, [RBE]). Eighty-five percent of patients underwent prior HNC RT for an oropharynx primary, and 39% underwent salvage surgery before re-RT. The cumulative incidence of locoregional failure at 12 months, with death as a competing risk, was 25.1%. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were 84.0% and 65.2%, respectively. Acute toxicities of grade 3 or greater included mucositis (9.9%), dysphagia (9.1%), esophagitis (9.1%), and dermatitis (3.3%). There was 1 death during PBRT due to disease progression. Grade 3 or greater late skin and dysphagia toxicities were noted in 6 patients (8.7%) and 4 patients (7.1%), respectively. Two patients had grade 5 toxicity due to treatment-related bleeding. CONCLUSIONS:Proton beam re-RT of the head and neck can provide effective tumor control with acceptable acute and late toxicity profiles likely because of the decreased dose to the surrounding normal, albeit previously irradiated, tissue, although longer follow-up is needed to confirm these findings.

PURPOSE/OBJECTIVE:To quantify the relative biological effectiveness (RBE) of the distal edge of the proton Bragg peak, using an in vitro assay of DNA double-strand breaks (DSBs). METHODS AND MATERIALS/METHODS:U2OS cells were irradiated within the plateau of a spread-out Bragg peak and at each millimeter position along the distal edge using a custom slide holder, allowing for simultaneous measurement of physical dose. A reference radiation signal was generated using photons. The DNA DSBs at 3 hours (to assess for early damage) and at 24 hours (to assess for residual damage and repair) after irradiation were measured using the γH2AX assay and quantified via flow cytometry. Results were confirmed with clonogenic survival assays. A detailed map of the RBE as a function of depth along the Bragg peak was generated using γH2AX measurements as a biological endpoint. RESULTS:At 3 hours after irradiation, DNA DSBs were higher with protons at every point along the distal edge compared with samples irradiated with photons to similar doses. This effect was even more pronounced after 24 hours, indicating that the impact of DNA repair is less after proton irradiation relative to photons. The RBE demonstrated an exponential increase as a function of depth and was measured to be as high as 4.0 after 3 hours and as high as 6.0 after 24 hours. When the RBE-corrected dose was plotted as a function of depth, the peak effective dose was extended 2-3 mm beyond what would be expected with physical measurement. CONCLUSIONS:We generated a highly comprehensive map of the RBE of the distal edge of the Bragg peak, using a direct assay of DNA DSBs in vitro. Our data show that the RBE of the distal edge increases with depth and is significantly higher than previously reported estimates.