A comparison of two methodologies for radiotherapy treatment plan optimization and QA for clinical trials.

BACKGROUND AND PURPOSE: The efficacy of clinical trials and the outcome of patient treatment are dependent on the quality assurance (QA) of radiation therapy (RT) plans. There are two widely utilized approaches that include plan optimization guidance created based on patient-specific anatomy. This study examined these two techniques for dose-volume histogram predictions, RT plan optimizations, and prospective QA processes, namely the knowledge-based planning (KBP) technique and another first principle (FP) technique. METHODS: This analysis included 60, 44, and 10 RT plans from three Radiation Therapy Oncology Group (RTOG) multi-institutional trials: RTOG 0631 (Spine SRS), RTOG 1308 (NSCLC), and RTOG 0522 (H&N), respectively. Both approaches were compared in terms of dose prediction and plan optimization. The dose predictions were also compared to the original plan submitted to the trials for the QA procedure. RESULTS: For the RTOG 0631 (Spine SRS) and RTOG 0522 (H&N) plans, the dose predictions from both techniques have correlation coefficients of >0.9. The RT plans that were re-optimized based on the predictions from both techniques showed similar quality, with no statistically significant differences in target coverage or organ-at-risk sparing. The predictions of mean lung and heart doses from both methods for RTOG1308 patients, on the other hand, have a discrepancy of up to 14 Gy. CONCLUSIONS: Both methods are valuable tools for optimization guidance of RT plans for Spine SRS and Head and Neck cases, as well as for QA purposes. On the other hand, the findings suggest that KBP may be more feasible in the case of inoperable lung cancer patients who are treated with IMRT plans that have spatially unevenly distributed beam angles.

Monte Carlo Simulations of Neutron Ambient Dose Equivalent in a Novel Proton Therapy Facility Design.

PURPOSE: The neutron shielding properties of the concrete structures of a proposed proton therapy facility were evaluated with help of the Monte Carlo technique. The planned facility's design omits the typical maze-structured entrances to the treatment rooms to facilitate more efficient access and, instead, proposes the use of massive concrete/steel doors. Furthermore, straight conduits in the treatment room walls were used in the design of the facility, necessitating a detailed investigation of the neutron radiation outside the rooms to determine if the design can be applied without violating existing radiation protection regulations. This study was performed to investigate whether the operation of a proton therapy unit using such a facility design will be in compliance with radiation protection requirements. METHODS: A detailed model of the planned proton therapy expansion project of the University of Texas, M. D. Anderson Cancer Center in Houston, Texas, was produced to simulate secondary neutron production from clinical proton beams using the MCNPX Monte Carlo radiation transport code. Neutron spectral fluences were collected at locations of interest and converted to ambient dose equivalents using an in-house code based on fluence to dose-conversion factors provided by the International Commission on Radiological Protection. RESULTS AND CONCLUSIONS: At all investigated locations of interest, the ambient dose equivalent values were below the occupational dose limits and the dose limits for individual members of the public. The impact of straight conduits was negligible because their location and orientation were such that no line of sight to the neutron sources (ie, the isocenter locations) was established. Finally, the treatment room doors were specially designed to provide spatial efficiency and, compared with traditional maze designs, showed that while it would be possible to achieve a lower neutron ambient dose equivalent with a maze, the increased spatial (and financial) requirements may offset this advantage.

Evaluation of the high definition field of view option of a large-bore computed tomography scanner for radiation therapy simulation.

BACKGROUND AND PURPOSE: Computed tomography (CT) scanning is the basis for radiation treatment planning, but the 50-cm standard scanning field of view (sFOV) may be too small for imaging larger patients. We evaluated the 65-cm high-definition (HD) FOV of a large-bore CT scanner for CT number accuracy, geometric distortion, image quality degradation, and dosimetric accuracy of photon treatment plans. MATERIALS AND METHODS: CT number accuracy was tested by placing two 16-cm acrylic phantoms on either side of a 40-cm phantom to simulate a large patient extending beyond the 50-cm-diameter standard scanning FOV. Dosimetric accuracy was tested using anthropomorphic pelvis and thorax phantoms, with additional acrylic body parts on either side of the phantoms. Two volumetric modulated arc therapy beams (a 15-MV and a 6-MV) were used to cover the planning target volumes. Two-dimensional dose distributions were evaluated with GAFChromic film and point dose accuracy was checked with multiple thermoluminescent dosimeter (TLD) capsules placed in the phantoms. Image quality was tested by placing an American College of Radiology accreditation phantom inside the 40-cm phantom. RESULTS: The HD FOV showed substantial changes in CT numbers, with differences of 314 HU-725 HU at different density levels. The volume of the body parts extending into the HD FOV was distorted. However, TLD-reported doses for all PTVs agreed within ± 3%. Dose agreement in organs at risk were within the passing criteria, and the gamma index pass rate was >97%. Image quality was degraded. CONCLUSIONS: The HD FOV option is adequate for RT simulation and met accreditation standards, although care should be taken during contouring because of reduced image quality.

Results of the NRG Oncology/RTOG 0848 Adjuvant Chemotherapy Question-Erlotinib+Gemcitabine for Resected Cancer of the Pancreatic Head: A Phase II Randomized Clinical Trial.

PURPOSE: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. METHODS: Eligibility-within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9<180. Gemcitabine arm-6 cycles of gemcitabine. Gemcitabine+erlotinib arm-gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α=0.15) to detect the hypothesized OS signal (hazard ratio=0.72) in favor of the arm 2. RESULTS: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥3 and arm 2: 28%, (P=0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P=0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). CONCLUSIONS: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.

Statistical evaluation of worst-case robust optimization intensity-modulated proton therapy plans using an exhaustive sampling approach.

PURPOSE: To assess the worst-case robust optimization IMPT plans with setup and range uncertainties and to test the hypothesis that the worst-case robust optimization strategies could cover most possible setup and range uncertainties in the real scenarios. METHODS: We analyzed the nominal and worst-case robust optimization IMPT plans of seven patients with head and neck cancer patients. To take uncertainties into account for the dose calculation, we performed a comprehensive simulation in which the dose was recalculated 625 times per given plan using Gaussian systematic setup and proton range uncertainties. Subsequently, based on the simulation results, we calculated the target coverage in all perturbation scenarios, as well as the ratios of target coverage located within the threshold of eight worst-case scenarios. We set the criteria for the optimized plan to be the ratios of 1) the dose delivered to 95% (D95%) of clinical target volumes 1 and 2 (CTV1 and CTV2) above 95% of the prescribed dose, and 2) the D95% of clinical target volume 3 (CTV3) above 90% of the prescribed dose in worst-case situations. RESULTS: The probability that the perturbed-dose indices of the CTVs in each scenario were within the worst-case scenario limits ranged from 89.51 to 91.22% for both the nominal and worst-case robust optimization IMPT plans. A quartile analysis showed that the selective robust optimization IMPT plans all had higher D95% values for CTV1, CTV2, and CTV3 than did the nominal IMPT plans. CONCLUSIONS: The worst-case strategy for robust optimization is adequately models and covers most of the setup and range uncertainties for the IMPT treatment of head and neck patients in our center.

Proton versus photon radiation-induced cell death in head and neck cancer cells.

BACKGROUND: Photon (X-ray) radiotherapy (XRT) kills cells via DNA damage, however, how proton radiotherapy (PRT) causes cell death in head and neck squamous cell carcinoma (HNSCC) is unclear. We investigated mechanisms of HNSCC cell death after XRT versus PRT. METHODS: We assessed type of death in 2 human papillomavirus (HPV)-positive and two HPV-negative cell lines: necrosis and apoptosis (Annexin-V fluorescein isothiocyanate [FITC]); senescence (ß-galactosidase); and mitotic catastrophe (γ-tubulin and diamidino-phenylindole [DAPI]). RESULTS: The XRT-induced or PRT-induced cellular senescence and mitotic catastrophe in all cell lines studied suggested that PRT caused cell death to a greater extent than XRT. After PRT, mitotic catastrophe peaked in HPV-negative and HPV-positive cells at 48 and 72 hours, respectively. No obvious differences were noted in the extent of cell necrosis or apoptosis after XRT versus PRT. CONCLUSION: Under the conditions and in the cell lines reported here, mitotic catastrophe and senescence were the major types of cell death induced by XRT and PRT, and PRT may be more effective.

Characterization of a new physical phantom for testing rigid and deformable image registration.

The purpose of this study was to describe a new user-friendly, low-cost phantom that was developed to test the accuracy of rigid and deformable image registration (DIR) systems and to demonstrate the functional efficacy of the new phantom. The phantom was constructed out of acrylic and includes a variety of inserts that simulate different tissue shapes and properties. It can simulate deformations and location changes in patient anatomy by changing the rotations of both the phantom and the inserts. CT scans of this phantom were obtained and used to test the rigid and deformable registration accuracy of the Velocity software. Eight rotation and translation scenarios were used to test the rigid registration accuracy, and 11 deformation scenarios were used to test the DIR accuracy. The mean rotation accuracies in the X-Y (axial) and X-Z (coronal) planes were 0.50° and 0.13°, respectively. The mean translation accuracy was 1 mm in both the X and Y direction and was tested in soft tissue and bone. The DIR accuracies for soft tissue and bone were 0.93 (mean Dice similarity coefficient), 8.3 and 4.5 mm (mean Hausdouff distance), 0.95 and 0.79 mm (mean distance), and 1.13 and 1.12 (mean volume ratio) for soft tissue content (DTE oil) and bone, respectively. The new phantom has a simple design and can be constructed at a low cost. This phantom will allow DIR systems to be effectively and efficiently verified to ensure system performance.

3D treatment planning system-Varian Eclipse for proton therapy planning.

The capabilities of the Eclipse treatment planning system (TPS) (Varian Medical Systems, Palo Alto, CA) for proton therapy treatment planning are described. Various steps involved in the planning process to produce a 3-dimensional (3D) dose distribution both for the passive scattering and pencil beam scanning proton beam therapy are outlined. Mitigation of range and setup uncertainties through robust optimization is discussed. Use of verification plans for patient treatment field dosimetry quality assurance (QA) is presented. Limitations of the Eclipse TPS and future developments are discussed.

Reirradiation of thoracic cancers with intensity modulated proton therapy.

PURPOSE: Reirradiation of thoracic malignancies is a treatment challenge, with concerns for toxicity and the inability to deliver definitive doses. Intensity modulated proton therapy (IMPT) may allow safe delivery of a higher dose of radiation to the tumor while minimizing toxicities. METHODS AND MATERIALS: Between 2011 and 2016, 27 patients who received IMPT for reirradiation of thoracic malignancies with definitive intent were retrospectively analyzed. Patients were included if they received a prior thoracic radiation course. All doses were recalculated to an equivalent dose in 2-Gy fractions (EQD2). Patients received IMPT to a median dose of 66 EQD2 Gy (range, 43.2-84 Gy) for recurrence of thoracic cancer (93%) or sequentially after a course of thoracic stereotactic ablative radiation therapy (7%). RESULTS: Twenty-two patients (81%) were treated for non-small cell lung cancer. The median time to reirradiation was 29.5 months. At a median follow-up for all patients of 11.2 months (25.9 surviving patients), the median overall survival was 18.0 months, with a 1-year overall survival of 54%. Four patients (15%) experienced an in-field local failure (LF), with a 1-year freedom from LF rate of 78%. The 1-year freedom from locoregional failure and 1-year progression-free survival rates were 61% and 51%, respectively. Patients who received 66 EQD2 Gy or higher had improved 1-year freedom from LF (100% vs 49%; P = .013), 1-year freedom from locoregional failure (84% vs 23%; P = .035), and 1-year progression-free survival (76% vs 14%; P = .050). Reirradiation was well tolerated, with only 2 patients (7%) experiencing late grade 3 pulmonary toxicity, and none with grade 3 or higher esophagitis. There were no grade 4-5 toxicities. CONCLUSIONS: These data represent the largest series of patients treated with IMPT for definitive reirradiation of thoracic cancers. They demonstrate that IMPT provided durable local control with minimal toxicity and suggest that higher doses may improve outcomes.

Synchrotron-Based Pencil Beam Scanning Nozzle with an Integrated Mini-Ridge Filter: A Dosimetric Study to Optimize Treatment Delivery.

A mini-ridge filter is often used to widen the Bragg peak in the longitudinal direction at low energies but not high energies. To facilitate the clinical use of a mini-ridge filter, we performed a planning study for the feasibility of a mini-ridge filter as an integral part of the synchrotron nozzle (IMRF). Dose models with and without IMRF were commissioned in a commercial Treatment planning system (TPS). Dosimetric characteristics in a homogenous water phantom were compared between plans with and without IMRF for a fixed spread-out Bragg peak width of 4 cm with distal ranges varying from 8 to 30 g/cm². Six clinical cases were then used to compare the plan quality between plans. The delivery efficiency was also compared between plans in both the phantom and the clinical cases. The Bragg peak width was increased by 0.18 cm at the lowest energy and by only about 0.04 cm at the highest energy. The IMRF increased the spot size (σ) by up to 0.1 cm at the lowest energy and by only 0.02 cm at the highest energy. For the phantom, the IMRF negligibly affected dose at high energies but increased the lateral penumbra by up to 0.12 cm and the distal penumbra by up to 0.06 cm at low energies. For the clinical cases, the IMRF slightly increased dose to the organs at risk. However, the beam delivery time was reduced from 18.5% to 47.1% for the lung, brain, scalp, and head and neck cases, and dose uniformities of target were improved up to 2.9% for these cases owing to the reduced minimum monitor unit effect. In conclusion, integrating a mini-ridge filter into a synchrotron nozzle is feasible for improving treatment efficiency without significantly sacrificing the plan quality.

Technical Note: Dosimetric characteristics of the ocular beam line and commissioning data for an ocular proton therapy planning system at the Proton Therapy Center Houston.

PURPOSE: To systematically analyze and present the properties of a small-field, double-scattering proton beam line intended to be used for the treatment of ocular cancer, and to provide configuration data for commission of the Eclipse Ocular Proton Planning System. METHODS: Measurements were made using ionization chambers, diodes, and films to determine dose profiles and output factors of the proton beams of the beam line at the Proton Therapy Center Houston. In parallel, Monte Carlo simulations were performed to validate the measured data and to provide additional insight into detailed beam parameters that are hard to measure, such as field size factors and a comparison of output factors as a function of circular and rectangular fields. RESULTS: The presented data comprise depth dose profiles, including distal and proximal profiles used to configure the Eclipse Ocular Proton Planning system, distal fall-off widths, lateral profiles and penumbrae sizes, as well as output factors as a function of field size, SOBP width, range shifter thickness, snout position, and source-to-surface distance. CONCLUSIONS: We have completed a comprehensive characterization of the beam line. The data will be useful to characterize proton beams in clinical and experimental small-field applications.

Long-term outcome of phase I/II prospective study of dose-escalated proton therapy for early-stage non-small cell lung cancer.

PURPOSE: The aim of this phase I/II study was to assess the long-term clinical benefits and toxicities of proton beam therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From June 2006 to September 2011, 35 patients with medically inoperable T1N0M0 (central or superior location, 12 patients) or T2-3N0M0 (any location, 23 patients) NSCLC were treated with 87.5Gy at 2.5Gy/fraction of proton therapy. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The median follow-up time was 83.1months (95% CI: 69.2-97.1months). For all 35 patients, the 1, 3, and 5-year overall survival rates were 85.7%, 42.9%, and 28.1%, respectively. The 5-year local recurrence-free, regional recurrence-free, and distant metastasis-free survival rates were 85.0%, 89.2%, and 54.4%, respectively. Different T stages had no effect on local and regional recurrence (p=0.499, p=1.00). However, with the increase in T stages, the distant metastasis rate increased significantly (p=0.006). The most common adverse effects were dermatitis (grade 2, 51.4%; grade 3, 2.9%) and radiation pneumonitis (grade 2, 11.4%; grade 3, 2.9%). Other grade 2 toxicities included esophagitis (2.9%), rib fracture (2.9%), heart toxicities (5.7%), and chest wall pain (2.9%). CONCLUSIONS: According to our long-term follow-up data, proton therapy with ablative doses is well tolerated and effective in medically inoperable early-stage NSCLC. Systemic therapy should be considered to reduce the rate of distant metastasis in cases of T2 and T3 lesions.

Human papillomavirus status and the relative biological effectiveness of proton radiotherapy in head and neck cancer cells.

BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal carcinomas response better to X-ray therapy (XRT) than HPV-negative disease. Whether HPV status influences the sensitivity of head and neck cancer cells to proton therapy or the relative biological effectiveness (RBE) of protons versus XRT is unknown. METHODS: Clonogenic survival was used to calculate the RBE; immunocytochemical analysis and neutral comet assay were used to evaluate unrepaired DNA double-strand breaks. RESULTS: HPV-positive cells were more sensitive to protons and the unrepaired double-strand breaks were more numerous in HPV-positive cells than in HPV-negative cells (p < .001). Protons killed more cells than did XRT at all fraction sizes (all RBEs > 1.06). Cell line type and radiation fraction size influenced the RBE. CONCLUSION: HPV-positive cells were more sensitive to protons than HPV-negative cells maybe through the effects of HPV on DNA damage and repair. The RBE for protons depends more on cell type and fraction size than on HPV status. © 2016 Wiley Periodicals, Inc. Head Neck 39: 708-715, 2017.

Intensity-Modulated Proton Therapy Adaptive Planning for Patients with Oropharyngeal Cancer.

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.

Spot scanning proton therapy minimizes neutron dose in the setting of radiation therapy administered during pregnancy.

This is a real case study to minimize the neutron dose equivalent (H) to a fetus using spot scanning proton beams with favorable beam energies and angles. Minimum neutron dose exposure to the fetus was achieved with iterative planning under the guidance of neutron H measurement. Two highly conformal treatment plans, each with three spot scanning beams, were planned to treat a 25-year-old pregnant female with aggressive recurrent chordoma of the base of skull who elected not to proceed with termination. Each plan was scheduled for delivery every other day for robust target coverage. Neutron H to the fetus was measured using a REM500 neutron survey meter placed at the fetus position of a patient simulating phantom. 4.1 and 44.1 µSv/fraction were measured for the two initial plans. A vertex beam with higher energy and the fetal position closer to its central axis was the cause for the plan that produced an order higher neutron H. Replacing the vertex beam with a lateral beam reduced neutron H to be comparable with the other plan. For a prescription of 70 Gy in 35 fractions, the total neutron H to the fetus was estimated to be 0.35 mSv based on final measurement in single fraction. In comparison, the passive scattering proton plan and photon plan had an estimation of 26 and 70 mSv, respectively, for this case. While radiation therapy in pregnant patients should be avoided if at all possible, our work demonstrated spot scanning beam limited the total neutron H to the fetus an order lower than the suggested 5 mSv regulation threshold. It is far superior than passive scattering beam and careful beam selection with lower energy and keeping fetus further away from beam axis are essential in minimizing the fetus neutron exposure.

Quantitative analysis of treatment process time and throughput capacity for spot scanning proton therapy.

PURPOSE: To determine the patient throughput and the overall efficiency of the spot scanning system by analyzing treatment time, equipment availability, and maximum daily capacity for the current spot scanning port at Proton Therapy Center Houston and to assess the daily throughput capacity for a hypothetical spot scanning proton therapy center. METHODS: At their proton therapy center, the authors have been recording in an electronic medical record system all treatment data, including disease site, number of fields, number of fractions, delivered dose, energy, range, number of spots, and number of layers for every treatment field. The authors analyzed delivery system downtimes that had been recorded for every equipment failure and associated incidents. These data were used to evaluate the patient census, patient distribution as a function of the number of fields and total target volume, and equipment clinical availability. The duration of each treatment session from patient walk-in to patient walk-out of the spot scanning treatment room was measured for 64 patients with head and neck, central nervous system, thoracic, and genitourinary cancers. The authors retrieved data for total target volume and the numbers of layers and spots for all fields from treatment plans for a total of 271 patients (including the above 64 patients). A sensitivity analysis of daily throughput capacity was performed by varying seven parameters in a throughput capacity model. RESULTS: The mean monthly equipment clinical availability for the spot scanning port in April 2012-March 2015 was 98.5%. Approximately 1500 patients had received spot scanning proton therapy as of March 2015. The major disease sites treated in September 2012-August 2014 were the genitourinary system (34%), head and neck (30%), central nervous system (21%), and thorax (14%), with other sites accounting for the remaining 1%. Spot scanning beam delivery time increased with total target volume and accounted for approximately 30%-40% of total treatment time for the total target volumes exceeding 200 cm(3), which was the case for more than 80% of the patients in this study. When total treatment time was modeled as a function of the number of fields and total target volume, the model overestimated total treatment time by 12% on average, with a standard deviation of 32%. A sensitivity analysis of throughput capacity for a hypothetical four-room spot scanning proton therapy center identified several priority items for improvements in throughput capacity, including operation time, beam delivery time, and patient immobilization and setup time. CONCLUSIONS: The spot scanning port at our proton therapy center has operated at a high performance level and has been used to treat a large number of complex cases. Further improvements in efficiency may be feasible in the areas of facility operation, beam delivery, patient immobilization and setup, and optimization of treatment scheduling.

Establishing the feasibility of the dosimetric compliance criteria of RTOG 1308: phase III randomized trial comparing overall survival after photon versus proton radiochemotherapy for inoperable stage II-IIIB NSCLC.

BACKGROUND: To establish the feasibility of the dosimetric compliance criteria of the RTOG 1308 trial through testing against Intensity Modulation Radiation Therapy (IMRT) and Passive Scattering Proton Therapy (PSPT) plans. METHODS: Twenty-six lung IMRT and 26 proton PSPT plans were included in the study. Dose Volume Histograms (DVHs) for targets and normal structures were analyzed. The quality of IMRT plans was assessed using a knowledge-based engineering tool. RESULTS: Most of the RTOG 1308 dosimetric criteria were achieved. The deviation unacceptable rates were less than 10 % for most criteria; however, a deviation unacceptable rate of more than 20 % was computed for the planning target volume minimum dose compliance criterion. Dose parameters for the target volume were very close for the IMRT and PSPT plans. However, the PSPT plans led to lower dose values for normal structures. The dose parameters in which PSPT plans resulted in lower values than IMRT plans were: lung V5Gy (%) (34.4 in PSPT and 47.2 in IMRT); maximum spinal cord dose (31.7 Gy in PSPT and 43.5 Gy in IMRT); heart V5Gy (%) (19 in PSPT and 47 in IMRT); heart V30Gy (%) (11 in PSPT and 19 in IMRT); heart V45Gy (%) (7.8 in PSPT and 12.1 in IMRT); heart V50% (Gy) (7.1 in PSPT and 9.8 in IMRT) and mean heart dose (7.7 Gy in PSPT and 14.9 Gy in IMRT). CONCLUSIONS: The revised RTOG 1308 dosimetric compliance criteria are feasible and achievable.

Clinical Outcomes and Patterns of Disease Recurrence After Intensity Modulated Proton Therapy for Oropharyngeal Squamous Carcinoma.

PURPOSE: A single-institution prospective study was conducted to assess disease control and toxicity of proton therapy for patients with head and neck cancer. METHODS AND MATERIALS: Disease control, toxicity, functional outcomes, and patterns of failure for the initial cohort of patients with oropharyngeal squamous carcinoma (OPC) treated with intensity modulated proton therapy (IMPT) were prospectively collected in 2 registry studies at a single institution. Locoregional failures were analyzed by using deformable image registration. RESULTS: Fifty patients with OPC treated from March 3, 2011, to July 2014 formed the cohort. Eighty-four percent were male, 50% had never smoked, 98% had stage III/IV disease, 64% received concurrent therapy, and 35% received induction chemotherapy. Forty-four of 45 tumors (98%) tested for p16 were positive. All patients received IMPT (multifield optimization to n=46; single-field optimization to n=4). No Common Terminology Criteria for Adverse Events grade 4 or 5 toxicities were observed. The most common grade 3 toxicities were acute mucositis in 58% of patients and late dysphagia in 12%. Eleven patients had a gastrostomy (feeding) tube placed during therapy, but none had a feeding tube at last follow-up. At a median follow-up time of 29 months, 5 patients had disease recurrence: local in 1, local and regional in 1, regional in 2, and distant in 1. The 2-year actuarial overall and progression-free survival rates were 94.5% and 88.6%. CONCLUSIONS: The oncologic, toxicity, and functional outcomes after IMPT for OPC are encouraging and provide the basis for ongoing and future clinical studies.

Motion-robust intensity-modulated proton therapy for distal esophageal cancer.

PURPOSE: To develop methods for evaluation and mitigation of dosimetric impact due to respiratory and diaphragmatic motion during free breathing in treatment of distal esophageal cancers using intensity-modulated proton therapy (IMPT). METHODS: This was a retrospective study on 11 patients with distal esophageal cancer. For each patient, four-dimensional computed tomography (4D CT) data were acquired, and a nominal dose was calculated on the average phase of the 4D CT. The changes of water equivalent thickness (ΔWET) to cover the treatment volume from the peak of inspiration to the valley of expiration were calculated for a full range of beam angle rotation. Two IMPT plans were calculated: one at beam angles corresponding to small ΔWET and one at beam angles corresponding to large ΔWET. Four patients were selected for the calculation of 4D-robustness-optimized IMPT plans due to large motion-induced dose errors generated in conventional IMPT. To quantitatively evaluate motion-induced dose deviation, the authors calculated the lowest dose received by 95% (D95) of the internal clinical target volume for the nominal dose, the D95 calculated on the maximum inhale and exhale phases of 4D CT DCT0 andDCT50 , the 4D composite dose, and the 4D dynamic dose for a single fraction. RESULTS: The dose deviation increased with the average ΔWET of the implemented beams, ΔWETave. When ΔWETave was less than 5 mm, the dose error was less than 1 cobalt gray equivalent based on DCT0 and DCT50 . The dose deviation determined on the basis of DCT0 and DCT50 was proportionally larger than that determined on the basis of the 4D composite dose. The 4D-robustness-optimized IMPT plans notably reduced the overall dose deviation of multiple fractions and the dose deviation caused by the interplay effect in a single fraction. CONCLUSIONS: In IMPT for distal esophageal cancer, ΔWET analysis can be used to select the beam angles that are least affected by respiratory and diaphragmatic motion. To further reduce dose deviation, the 4D-robustness optimization can be implemented for IMPT planning. Calculation of DCT0 and DCT50 is a conservative method to estimate the motion-induced dose errors.

Proton Beam Therapy for Localized Prostate Cancer: Results from a Prospective Quality-of-Life Trial.

PURPOSE: To report prostate cancer outcomes, toxicity, and quality of life (QOL) in men treated with proton beam therapy (PBT). PATIENTS AND METHODS: Patients were enrolled in a prospective trial. All participants received 75.6 to 78 Gy (RBE). Up to 6 months of luteinizing hormone-releasing hormone agonist therapy was allowed. The Phoenix definition defined biochemical failure. Modified Radiation Therapy Oncology Group criteria defined toxicity. Expanded Prostate Cancer Index Composite questionnaires objectified QOL. Clinically significant QOL decrement was defined as ≥0.5 × baseline standard deviation. RESULTS: In total, 423 men were analyzed. The National Comprehensive Cancer Network risk classification was used (low 43%; intermediate 56%; high 1%). At the 5.2-year median follow-up, overall and disease-specific survival rates were 99.8% and 100%, respectively. Cumulative biochemical failure rate was 5.2% (95% confidence interval [CI] = 3.0%-8.3%); acute grade 2 genitourinary (GU) toxicity was 46.3%; acute grade 2 gastrointestinal (GI) toxicity was 5.0% (95% CI = 3.1%-7.3%). There was no acute grade ≥3 GI or GU toxicity. Cumulative late grade 2 GU and GI toxicity was 15.9% (95% CI = 13%-20%) and 9.7% (95% CI = 6.5%-12%), respectively. There were 2 grade 3 late GI toxicities (rectal bleeding) and no late grade ≥3 GU toxicity. The 4-year mean Expanded Prostate Cancer Index Composite urinary, bowel, sexual, and hormonal summary scores (range; standard deviation) were 89.7 (43.8-100; 11), 91.3 (41.1-94.6; 10), 57.8 (0.0-96.2; 27.1), and 92.2 (25-95.5; 10.5), respectively. Compared with baseline, there was no clinically significant decrement in urinary, sexual, or hormonal QOL after treatment completion. A modest (<10 points), yet clinically significant, decrement in bowel QOL was appreciated throughout follow-up. CONCLUSION: Contemporary PBT resulted in excellent biochemical control, minimal risk of higher-grade toxicity, and modest QOL decrement. Further investigation comparing PBT with alternative prostate cancer treatment strategies are warranted.