Design and validation of a synchrotron proton beam line for FLASH radiotherapy preclinical research experiments.

PURPOSE: The main purpose of this work was to generate and validate the dosimetric accuracy of proton beams of dimensions that are appropriate for in vivo small animal and in vitro ultrahigh dose rate (FLASH) radiotherapy experiments using a synchrotron-based treatment delivery system. This study was performed to enable future investigations of the relevance of a spread-out Bragg peak (SOBP) under FLASH conditions. METHODS: The spill characteristics of the small field fixed horizontal beam line were modified to deliver accelerated protons in times as short as 2 ms and to control the dose delivered. A Gaussian-like transverse beam profile was transformed into a square uniform one at FLASH dose rates, while avoiding low-dose regions, a crucial requirement to protect normal tissue during FLASH irradiation. Novel beam-shaping devices were designed using Monte Carlo techniques to produce up to about 6 cm3 of uniform dose in SOBPs while maximizing the dose rate. These included a scattering foil, a conical flattening filter to maximize the flux of protons into the region of interest, energy filters, range compensators, and collimators. The shapes, sizes, and positions of the components were varied to provide the required field sizes and SOBPs. RESULTS: The designed and fabricated devices were used to produce 10-, 15-, and 20-mm diameter, circular field sizes and 10-, 15-, and 20-mm SOBP modulation widths at uniform physical dose rates of up to 375 Gy/s at the center of the SOBP and a minimum dose rate of about 255 Gy/s at the entrance, respectively, in cylindrical volumes. The flatness of lateral dose profiles at the center could be adjusted to within ±1.5% at the center of the SOBP. Assessment of systematic uncertainties, such as impact of misalignments and positioning uncertainties, was performed using simulations, and the results were used to provide appropriate adjustments to ensure high-accuracy FLASH beam delivery for both in vitro and in vivo preclinical experiments. CONCLUSIONS: It is feasible to use synchrotron-generated proton beams of sufficient dimensions for FLASH radiobiology experiments. We expect to use the system we developed to acquire in vitro and in vivo small animal FLASH radiobiology data as a function of dose, dose rate, oxygen content, and linear energy transfer to help us understand the underlying mechanisms of the FLASH phenomenon.

Intensity-modulated proton therapy and osteoradionecrosis in oropharyngeal cancer.

PURPOSE: We compared mandibular doses and osteoradionecrosis in patients with oropharyngeal cancer after intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT). METHODS AND MATERIALS: We identified 584 patients who received definitive radiotherapy for oropharyngeal cancer from January 2011 through June 2014 at MD Anderson Cancer Center (534 IMRT and 50 IMPT). The dosimetric variables and osteoradionecrosis were compared with Chi-square test or Fisher's exact test. RESULTS: Median follow-up time for all patients (534 IMRT and IMPT) was 33.8months (33.8months IMRT vs. 34.6months IMPT, P=0.854), and median time to osteoradionecrosis was 11.4months (range 6.74-16.1months). Mandibular doses were lower for patients treated with IMPT (minimum 0.8 vs. 7.3Gy; mean 25.6 vs. 41.2Gy; P<0.001), and osteoradionecrosis rates were lower as well: 2% IMPT (1 grade 1), 7.7% IMRT (12 grade 4, 5 grade 3, 1 grade 2 and 23 grade 1). Osteoradionecrosis location depended on the primary tumor site and high-dose field in the mandible. CONCLUSIONS: Osteoradionecrosis events were significantly associated with higher dose irradiation to mandibular. Use of IMPT minimized excess irradiation of the mandible and consequently reduced the risk of osteoradionecrosis for oropharyngeal cancer.

Perturbation of water-equivalent thickness as a surrogate for respiratory motion in proton therapy.

Respiratory motion is traditionally assessed using tumor motion magnitude. In proton therapy, respiratory motion causes density variations along the beam path that result in uncertainties of proton range. This work has investigated the use of water-equivalent thickness (WET) to quantitatively assess the effects of respiratory motion on calculated dose in passively scattered proton therapy (PSPT). A cohort of 29 locally advanced non-small cell lung cancer patients treated with 87 PSPT treatment fields were selected for analysis. The variation in WET (ΔWET) along each field was calculated between exhale and inhale phases of the simulation four-dimensional computed tomography. The change in calculated dose (ΔDose) between full-inhale and full-exhale phase was quantified for each field using dose differences, 3D gamma analysis, and differential area under the curve (ΔAUC) analysis. Pearson correlation coefficients were calculated between ΔDose and ΔWET. Three PSPT plans were redesigned using field angles to minimize variations in ΔWET and compared to the original plans. The median ΔWET over 87 treatment fields ranged from 1-9 mm, while the ΔWET 95th percentile value ranged up to 42 mm. The ΔWET was significantly correlated (p < 0.001) to the ΔDose for all metrics analyzed. The patient plans that were redesigned using ΔWET analysis to select field angles were more robust to the effects of respiratory motion, as ΔAUC values were reduced by more than 60% in all three cases. The tumor motion magnitude alone does not capture the potential dosimetric error due to respiratory motion because the proton range is sensitive to the motion of all patient anatomy. The use of ΔWET has been demonstrated to identify situations where respiratory motion can impact the calculated dose. Angular analysis of ΔWET may be capable of designing radiotherapy plans that are more robust to the effects of respiratory motion.

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.

Quality of life and toxicity from passively scattered and spot-scanning proton beam therapy for localized prostate cancer.

PURPOSE: To report quality of life (QOL)/toxicity in men treated with proton beam therapy for localized prostate cancer and to compare outcomes between passively scattered proton therapy (PSPT) and spot-scanning proton therapy (SSPT). METHODS AND MATERIALS: Men with localized prostate cancer enrolled on a prospective QOL protocol with a minimum of 2 years' follow-up were reviewed. Comparative groups were defined by technique (PSPT vs SSPT). Patients completed Expanded Prostate Cancer Index Composite questionnaires at baseline and every 3-6 months after proton beam therapy. Clinically meaningful differences in QOL were defined as ≥0.5 × baseline standard deviation. The cumulative incidence of modified Radiation Therapy Oncology Group grade ≥2 gastrointestinal (GI) or genitourinary (GU) toxicity and argon plasma coagulation were determined by the Kaplan-Meier method. RESULTS: A total of 226 men received PSPT, and 65 received SSPT. Both PSPT and SSPT resulted in statistically significant changes in sexual, urinary, and bowel Expanded Prostate Cancer Index Composite summary scores. Only bowel summary, function, and bother resulted in clinically meaningful decrements beyond treatment completion. The decrement in bowel QOL persisted through 24-month follow-up. Cumulative grade ≥2 GU and GI toxicity at 24 months were 13.4% and 9.6%, respectively. There was 1 grade 3 GI toxicity (PSPT group) and no other grade ≥3 GI or GU toxicity. Argon plasma coagulation application was infrequent (PSPT 4.4% vs SSPT 1.5%; P=.21). No statistically significant differences were appreciated between PSPT and SSPT regarding toxicity or QOL. CONCLUSION: Both PSPT and SSPT confer low rates of grade ≥2 GI or GU toxicity, with preservation of meaningful sexual and urinary QOL at 24 months. A modest, yet clinically meaningful, decrement in bowel QOL was seen throughout follow-up. No toxicity or QOL differences between PSPT and SSPT were identified. Long-term comparative results in a larger patient cohort are warranted.

An MCNPX Monte Carlo model of a discrete spot scanning proton beam therapy nozzle.

PURPOSE: The purposes of this study were to validate a discrete spot scanning proton beam nozzle using the Monte Carlo (MC) code MCNPX and use the MC validated model to investigate the effects of a low-dose envelope, which surrounds the beam's central axis, on measurements of integral depth dose (IDD) profiles. METHODS: An accurate model of the discrete spot scanning beam nozzle from The University of Texas M. D. Anderson Cancer Center (Houston, Texas) was developed on the basis of blueprints provided by the manufacturer of the nozzle. The authors performed simulations of single proton pencil beams of various energies using the standard multiple Coulomb scattering (MCS) algorithm within the MCNPX source code and a new MCS algorithm, which was implemented in the MCNPX source code. The MC models were validated by comparing calculated in-air and in-water lateral profiles and percentage depth dose profiles for single pencil beams with their corresponding measured values. The models were then further tested by comparing the calculated and measured three-dimensional (3-D) dose distributions. Finally, an IDD profile was calculated with different scoring radii to determine the limitations on the use of commercially available plane-parallel ionization chambers to measure IDD. RESULTS: The distance to agreement, defined as the distance between the nearest positions of two equivalent distributions with the same value of dose, between measured and simulated ranges was within 0.13 cm for both MCS algorithms. For low and intermediate pencil beam energies, the MC simulations using the standard MCS algorithm were in better agreement with measurements. Conversely, the new MCS algorithm produced better results for high-energy single pencil beams. The IDD profile calculated with cylindrical tallies with an area equivalent to the area of the largest commercially available ionization chamber showed up to 7.8% underestimation of the integral dose in certain depths of the IDD profile. CONCLUSIONS: The authors conclude that a combination of MCS algorithms is required to accurately reproduce experimental data of single pencil beams and 3-D dose distributions for the scanning beam nozzle. In addition, the MC simulations showed that because of the low-dose envelope, ionization chambers with radii as large as 4.08 cm are insufficient to accurately measure IDD profiles for a 221.8 MeV pencil beam in the scanning beam nozzle.

Spot scanning proton beam therapy for prostate cancer: treatment planning technique and analysis of consequences of rotational and translational alignment errors.

PURPOSE: Conventional proton therapy with passively scattered beams is used to treat a number of tumor sites, including prostate cancer. Spot scanning proton therapy is a treatment delivery means that improves conformal coverage of the clinical target volume (CTV). Placement of individual spots within a target is dependent on traversed tissue density. Errors in patient alignment perturb dose distributions. Moreover, there is a need for a rational planning approach that can mitigate the dosimetric effect of random alignment errors. We propose a treatment planning approach and then analyze the consequences of various simulated alignment errors on prostate treatments. METHODS AND MATERIALS: Ten control patients with localized prostate cancer underwent treatment planning for spot scanning proton therapy. After delineation of the clinical target volume, a scanning target volume (STV) was created to guide dose coverage. Errors in patient alignment in two axes (rotational and yaw) as well as translational errors in the anteroposterior direction were then simulated, and dose to the CTV and normal tissues were reanalyzed. RESULTS: Coverage of the CTV remained high even in the setting of extreme rotational and yaw misalignments. Changes in the rectum and bladder V45 and V70 were similarly minimal, except in the case of translational errors, where, as a result of opposed lateral beam arrangements, much larger dosimetric perturbations were observed. CONCLUSIONS: The concept of the STV as applied to spot scanning radiation therapy and as presented in this report leads to robust coverage of the CTV even in the setting of extreme patient misalignments.