Target coverage and cardiopulmonary sparing with the updated ESTRO-ACROP contouring guidelines for postmastectomy radiation therapy after breast reconstruction: a treatment planning study using VMAT and proton PBS techniques.

BACKGROUND: The European Society for Therapeutic Radiology and Oncology Advisory Committee in Radiation Oncology Practice (ESTRO-ACROP) recently released new contouring guidelines for postmastectomy radiation therapy (PMRT) after implant-based reconstruction (IBR). As compared to prior ESTRO guidelines, the new guidelines primarily redefined the chest wall (CW) target to exclude the breast prosthesis. In this study, we assessed the impact of these changes on treatment planning and dosimetric outcomes using volumetric-modulated arc therapy (VMAT) and proton pencil-beam scanning (PBS) therapy. METHODS: We performed a treatment planning study of 10 women with left-sided breast cancer who underwent PMRT after IBR. All target structures were delineated first using standard (ESTRO) breast contouring guidelines and then separately using the new (ESTRO-ACROP) guidelines. Standard organs-at-risk (OARs) and cardiac substructures were contoured. Four sets of plans were generated: (1) VMAT using standard ESTRO contours, (2) VMAT using new ESTRO-ACROP contours, (3) PBS using standard contours, and (4) PBS using new contours. RESULTS: VMAT plans using the new ESTRO-ACROP guidelines resulted in modest sparing of the left anterior descending coronary artery (LAD) (mean dose: 6.99 Gy standard ESTRO vs. 6.08 Gy new ESTRO-ACROP, p = 0.010) and ipsilateral lung (V20: 21.66% vs 19.45%, p = 0.017), but similar exposure to the heart (mean dose: 4.6 Gy vs. 4.3 Gy, p = 0.513), with a trend toward higher contralateral lung (V5: 31.0% vs 35.3%, p = 0.331) and CW doses (V5: 31.9% vs 35.4%, p = 0.599). PBS plans using the new guidelines resulted in further sparing of the heart (mean dose: 1.05 Gy(RBE) vs. 0.54 Gy(RBE), p < 0.001), nearly all cardiac substructures (LAD mean dose: 2.01 Gy(RBE) vs. 0.66 Gy(RBE), p < 0.001), and ipsilateral lung (V20: 16.22% vs 6.02%, p < 0.001). CONCLUSIONS: PMRT after IBR using the new ESTRO-ACROP contouring guidelines with both VMAT and PBS therapy is associated with significant changes in exposure to several cardiopulmonary structures.

Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas.

BACKGROUND: Negative surgical margins are uncommon for spine sarcomas; hence, adjuvant radiotherapy (RT) may be recommended but tumor dose may be constrained by spinal cord, nerve, and viscera tolerance. METHODS: Prospective Phase II clinical trial incorporating high dose RT. Eligible patients had primary or locally recurrent thoracic, lumbar, and/or sacral spine/paraspinal chordomas or sarcomas. Treatment included pre- and/or post-operative photon/proton RT ± radical resection. RESULTS: Fifty patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). RT dose was ≤72.0 GyRBE in 25 patients and 76.6-77.4 GyRBE in 25 patients. With 7.3-year median follow-up, the 5 and 8-year actuarial local control (LC) rates were 94% and 85% for primary tumors and 81% and 74% for the entire group. Local recurrence was less common for primary tumors, 4/36 (11%) versus 7/14 (50%) for recurrent tumors, P = 0.002. The 8-year actuarial risk of grade 3-4 late RT morbidity was 13%. No myelopathies were seen. No late neurologic toxicities noted with radiation doses ≤72.0 GyRBE while three sacral neuropathies appeared after doses of 76.6-77.4 GyRBE. CONCLUSIONS: LC with this treatment is high in patients with primary tumors. Late morbidity appears to be acceptable.

A reference-point-method-based online proton treatment plan re-optimization strategy and a novel solution to planning constraint infeasibility problem.

Objective. Propose a highly automated treatment plan re-optimization strategy suitable for online adaptive proton therapy. The strategy includes a rapid re-optimization method that generates quality replans and a novel solution that efficiently addresses the planning constraint infeasibility issue that can significantly prolong the re-optimization process.Approach. We propose a systematic reference point method (RPM) model that minimizes the l-infinity norm from the initial treatment plan in the daily objective space for online re-optimization. This model minimizes the largest objective value deviation among the objectives of the daily replan from their reference values, leading to a daily replan similar to the initial plan. Whether a set of planning constraints is feasible with respect to the daily anatomy cannot be known before solving the corresponding optimization problem. The conventional trial-and-error-based relaxation process can cost a significant amount of time. To that end, we propose an optimization problem that first estimates the magnitude of daily violation of each planning constraint. Guided by the violation magnitude and clinical importance of the constraints, the constraints are then iteratively converted into objectives based on their priority until the infeasibility issue is solved.Main results.The proposed RPM-based strategy generated replans similar to the offline manual replans within the online time requirement for six head and neck and four breast patients. The average targetD95and relevant organ at risk sparing parameter differences between the RPM replans and clinical offline replans were -0.23, -1.62 Gy for head and neck cases and 0.29, -0.39 Gy for breast cases. The proposed constraint relaxation solution made the RPM problem feasible after one round of relaxation for all four patients who encountered the infeasibility issue.Significance. We proposed a novel RPM-based re-optimization strategy and demonstrated its effectiveness on complex cases, regardless of whether constraint infeasibility is encountered.

Radiation Therapy for Stage IIA/B Seminoma: Modeling Secondary Cancer Risk for Protons and VMAT versus 3D Photons.

Radiation therapy (RT) is an effective treatment for stage IIA and select stage IIB seminomas. However, given the long life expectancy of seminoma patients, there are concerns about the risk of secondary cancers from RT. This study assessed differences in secondary cancer risk for stage II seminoma patients following proton pencil-beam scanning (PBS) and photon VMAT, compared to 3D conformal photon RT. Ten seminoma patients, five with a IIA staging who received 30 GyRBE and five with a IIB staging who received 36 GyRBE, had three RT plans generated. Doses to organs at risk (OAR) were evaluated, and secondary cancer risks were calculated as the Excess Absolute Risk (EAR) and Lifetime Attributable Risk (LAR). PBS reduced the mean OAR dose by 60% on average compared to 3D, and reduced the EAR and LAR for all OAR, with the greatest reductions seen for the bowel, liver, and stomach. VMAT reduced high doses but increased the low-dose bath, leading to an increased EAR and LAR for some OAR. PBS provided superior dosimetric sparing of OAR compared to 3D and VMAT in stage II seminoma cases, with models demonstrating that this may reduce secondary cancer risk. Therefore, proton therapy shows the potential to reduce acute and late side effects of RT for this population.

Evaluation of Carbon Fiber and Titanium Surgical Implants for Proton and Photon Therapy.

PURPOSE: Impending and actual pathologic fractures secondary to metastatic bone disease, lymphoma, or multiple myeloma often require intramedullary fixation followed by radiation therapy. Because of carbon's low atomic number, there are reduced computed tomography (CT) imaging artifacts and dose perturbation when planning postoperative radiation for carbon fiber (CF) rods. Herein, we characterize the dosimetric properties of CF implants compared with titanium alloy (TA) for proton and photon. METHODS AND MATERIALS: TA and CF samples were acquired from an implant manufacturer. Material characteristics were evaluated by CT scans with and without metal artifact reduction (MAR). Relative stopping power (RSP) was determined from the range pull-back of each sample in a 20-cm range proton beam. Photon transmission measurements were made in a solid water phantom and compared with the modeled dosimetry from the RayStation planning system. RESULTS: CF caused no visible CT artifacts, and MAR was not necessary for Hounsfield unit (HU) determination (median, 364 HU) or contouring, whereas TA (median, 3071 HU) caused substantial artifacts, which were improved, but not eliminated by MAR. The proton RSP was measured as 3.204 for TA and 1.414 for CF. For 6 MV photons, the measured transmission was 89.3% for TA and 98% for CF. CF RSP calculation and transmission from CT HU showed a physical density overestimate compared with measurements, which would cause a slight, but acceptable, dose uncertainty (<10% proton range or 1% photon transmission). CONCLUSIONS: With a density similar to bone, CF implants did not cause imaging artifacts and minimal dose perturbation compared with TA. Although the CF proton RSP is underestimated and the photon attenuation is overestimated by the HU, both effects are relatively small and may be most easily accounted for by planning with a 2-mm expansion around organs at risk beyond or in close proximity to the implant.

Late Radiation-Induced Carotid Artery Stenosis and Stroke in Pediatric Patient Treated With Proton Radiation Therapy for Skull-Base Chordoma.

Radiation vasculopathy is a well-recognized late complication of radiation therapy. We present a case of a stroke 29 years after high-dose proton radiation therapy for skull-base chordoma due to occlusion of bilateral internal carotid arteries.

Pencil beam scanning dose calibration at reduced source-to-axis distance.

BACKGROUND: Pencil beam scanning (PBS) monitoring chambers use an ionization control signal, monitor units (MUs), or gigaprotons (Gp) to irradiate a pencil beam and normalize dose calculations. The nozzle deflects the beam from the nozzle axis by an angle subtended at the source-to-axis distance (τ) from the isocenter. If the angle is not correctly considered in calibrations or calculations, it can lead to systematic errors. PURPOSE: Aspects to consider for machines of various τs are fourfold. First, for the machine, there is a pathlength change of proton tracks in the monitor chamber. Second, for measurements, a uniform-square irradiation over a plane, with constant Gp per spot, does not deliver uniform dose in a measurement plane. Third, for Monte Carlo (MC) simulations, Gp (and not MU) is proportional to simulating a number of protons. Fourth, for pencil beam algorithms (PBA), MU or Gp may be used for pencil beam weight, but usage needs to be consistent. Another consideration is the beam shape change from circular to oval in the projection onto voxels. METHODS: Coordinate systems for PBS delivery are described. RESULTS: Users of intermediate-τ machines, corresponding to the onset of 1% pathlength corrections within the scanned field size, must not assume that MUs are proportional to the number of particles in MC simulations, and the PBA may need pathlength corrections. For a field size of 24 × 24 cm2 , intermediate-τ machines correspond to 59 cm ≤ τ < 120 cm. For a field size of 40 × 40 cm2 , intermediate-τ machines correspond to 98 cm ≤ τ < 200 cm. Small-τ machines correspond to τ < 59 and 98 cm at these field sizes, respectively, which require corrections in projecting the beam shape onto voxels. CONCLUSIONS: Identifying corrections due to the pencil beam angle and their onset are important for reducing the outer diameter of proton therapy gantries. The use of Gp (or the number of protons) meterset standardizes data interchange and helps to reduce systematic errors due to the angle of the beam.

Proton Radiotherapy for Patients With Oligometastatic Breast Cancer Involving the Sternum.

INTRODUCTION: A subset of metastatic breast cancer patients present with oligometastatic disease involving the sternum. Given the proximity to traditional target structures, a proton radiation field can be expanded to include this region, providing definitive therapy for patients who are otherwise metastatic. We evaluated the feasibility and outcomes of a small series of patients who received comprehensive nodal irradiation inclusive of an isolated sternal metastasis using proton pencil beam scanning. MATERIALS AND METHODS: Four patients with a diagnosis of metastatic breast cancer with an isolated metastasis to the sternum received multimodality therapy with curative intent and then underwent adjuvant pencil beam scanning with definitive treatment to the sternum. Dosimetric parameters and treatment outcomes were evaluated. RESULTS: With respect to treatment coverage, proton therapy was able to deliver comprehensive target structure coverage while maintaining modest doses to the organs at risk compared with photon techniques. At a median follow-up of 28 months from diagnosis, none of the patients have experienced relapse within the radiation portal or developed additional sites of metastatic disease. CONCLUSION: Pencil beam scanning for oligometastatic breast cancer with isolated sternal lesions appears feasible without undue normal tissue exposure. Current treatment outcomes appear promising.

A deep LSTM autoencoder-based framework for predictive maintenance of a proton radiotherapy delivery system.

INTRODUCTION: Unscheduled machine downtime can cause treatment interruptions and adversely impact patient treatment outcomes. Conventional Quality Assurance (QA) programs of a proton Pencil Beam Scanning (PBS) system ensure its operational performance by keeping the beam parameters within clinical tolerances but often do not reveal the underlying issues of the device prior to a machine malfunction event. In this study, we propose a Predictive Maintenance (PdM) approach that leverages an advanced analytical tool built on a deep neural network to detect treatment delivery machine issues early. METHODS: Beam delivery log file data from daily QA performed at the Burr Proton Center of Massachusetts General Hospital were collected. A novel PdM framework consisting of long short-term memory-based autoencoder (LSTM-AE) modeling of the proton PBS delivery system and a Mahalanobis distance-based error metric evaluation was constructed to detect rare anomalous machine events. These included QA beam pauses, clinical operational issues, and treatment interruptions. The model was trained in an unsupervised fashion on the QA data of normal sessions so that the model learned characteristics of normal machine operation. The anomaly is quantified as the multivariate deviation between the model predicted data and the measured data of the day using Mahalanobis distance (M-Score). Two-layer and three-layer Long short-term memory-based stacked autoencoder (LSTM-SAE) models were optimized for exploring model performance improvement. Model validation was performed with two clinical datasets and was analyzed using the area under the precision-recall curve (AUPRC) and the area under the receiver operating characteristic (AUROC). RESULTS: LSTM-SAE models showed strong performance in predicting QA beam pauses for both clinical validation datasets. Despite severe skew in the dataset, the model achieved AUPRC of 0.60 and 0.82 and AUROC of 0.75 and 0.92 in the respective 2018 and 2020 datasets. Moreover, these amount to 2.8-fold and 10.7-fold enhancement compared to the respective baseline event rates. In addition, in terms of treatment interruption events, model prediction enabled 3.88-fold and 51.2-fold detection improvement, while the detection improvement for clinical operational issues was 1.04-fold and 1.37-fold, respectively, in the 2018 and 2020 datasets. CONCLUSION: Our novel deep LSTM-SAE-based framework allows for highly discriminative prediction of anomalous machine events and demonstrates great promise for enabling PdM for proton PBS beam delivery.

Technical note: Does the greater power of pencil beam scanning reduce the need for a proton gantry? A study of head-and-neck and brain tumors.

PURPOSE: Proton therapy systems without a gantry can be more compact and less expensive in terms of capital cost and therefore more available to a larger patient population. Would the advances in pencil beam scanning (PBS) and robotics make gantry-less treatment possible? In this study, we explore if the high-quality treatment plans can be obtained without a gantry. METHODS AND MATERIALS: We recently showed that proton treatments with the patient in an upright position may be feasible with a new soft robotic immobilization device and imaging which enables multiple possible patient orientations during a treatment. In this study, we evaluate if this new treatment geometry could enable high quality treatment plans without a gantry. We created PBS treatment plans for seven patients with head-and-neck or brain tumors. Each patient was planned with two scenarios: one with a gantry with the patient in supine position and the other with a gantry-less fixed horizontal beam-line with the patient sitting upright. For the treatment plans, dose-volume-histograms (DVHs), target homogeneity index (HI), mean dose, D 2 ${D_2}$ , and D 98 ${D_{98}}$ are reported. A robustness analysis of one plan was performed with ± $ \pm $ 2.5-mm setup errors and ± $ \pm $ 3.5% range uncertainties with nine scenarios. RESULTS: Most of the PBS-gantry-less plans had similar target HI and organs-at-risk mean dose as compared to PBS-gantry plans and similar robustness with respect to range uncertainties and setup errors. CONCLUSIONS: PBS provides sufficient power to deliver high quality treatment plans without requiring a gantry for head-and-neck or brain tumors. In combination with the development of the new positioning and immobilization methods required to support this treatment geometry, this work suggests the feasibility of further development of a compact proton therapy system with a fixed horizontal beam-line to treat patients in sitting and reclined positions.

A dynamic blood flow model to compute absorbed dose to circulating blood and lymphocytes in liver external beam radiotherapy.

We have developed a novel 4D dynamic liver blood flow model, capable of accurate dose estimation to circulating blood cells during liver-directed external beam radiotherapy, accounting for blood recirculation and radiation delivery time structure. Adult male and adult female liver computational phantoms with detailed vascular trees were developed to include the hepatic arterial, hepatic portal venous, and hepatic venous trees. A discrete time Markov Chain approach was applied to determine the spatiotemporal distribution of 105blood particles (BP) in the human body based on reference values for cardiac output and organ blood volumes. For BPs entering the liver, an explicit Monte Carlo simulation was implemented to track their propagation along ∼2000 distinct vascular pathways through the liver. The model tracks accumulated absorbed dose from time-dependent radiation fields with a 0.1 s time resolution. The computational model was then evaluated for 3 male and 3 female patients receiving photon (VMAT and IMRT) and proton (passive SOBP and active PBS) treatments. The dosimetric impact of treatment modality, delivery time, and fractionation on circulating blood cells was investigated and quantified using the mean dose (µdose,b),V>0Gy,V>0.125Gy,andD2%. Average reductions inµdose,b,V>0Gy,V>0.125GyandD2%of 45%, 6%, 53%, 19% respectively, were observed for proton treatments as compared to photon treatments. Our simulation also showed thatV>0Gy,V>0.125Gy, andD2%were highly sensitive to the beam-on time. BothV>0GyandV>0.125Gyincreased with beam-on time, whereasD2%decreased with increasing beam-on time, demonstrating the tradeoff between low dose to a large fraction of blood cells and high dose to a small fraction of blood cells. Consequently, proton treatments are not necessarily advantageous in terms of dose to the blood simply based on integral dose considerations. Instead, both integral dose and beam-on time can substantially impact relevant dosimetric indices.

Proof of principle study of the use of a CMOS active pixel sensor for proton radiography.

PURPOSE: Proof of principle study of the use of a CMOS active pixel sensor (APS) in producing proton radiographic images using the proton beam at the Massachusetts General Hospital (MGH). METHODS: A CMOS APS, previously tested for use in s-ray radiation therapy applications, was used for proton beam radiographic imaging at the MGH. Two different setups were used as a proof of principle that CMOS can be used as proton imaging device: (i) a pen with two metal screws to assess spatial resolution of the CMOS and (ii) a phantom with lung tissue, bone tissue, and water to assess tissue contrast of the CMOS. The sensor was then traversed by a double scattered monoenergetic proton beam at 117 MeV, and the energy deposition inside the detector was recorded to assess its energy response. Conventional x-ray images with similar setup at voltages of 70 kVp and proton images using commercial Gafchromic EBT 2 and Kodak X-Omat V films were also taken for comparison purposes. RESULTS: Images were successfully acquired and compared to x-ray kVp and proton EBT2/X-Omat film images. The spatial resolution of the CMOS detector image is subjectively comparable to the EBT2 and Kodak X-Omat V film images obtained at the same object-detector distance. X-rays have apparent higher spatial resolution than the CMOS. However, further studies with different commercial films using proton beam irradiation demonstrate that the distance of the detector to the object is important to the amount of proton scatter contributing to the proton image. Proton images obtained with films at different distances from the source indicate that proton scatter significantly affects the CMOS image quality. CONCLUSION: Proton radiographic images were successfully acquired at MGH using a CMOS active pixel sensor detector. The CMOS demonstrated spatial resolution subjectively comparable to films at the same object-detector distance. Further work will be done in order to establish the spatial and energy resolution of the CMOS detector for protons. The development and use of CMOS in proton radiography could allow in vivo proton range checks, patient setup QA, and real-time tumor tracking.

The impact of variable relative biological effectiveness in proton therapy for left-sided breast cancer when estimating normal tissue complications in the heart and lung.

The aim of this study was to evaluate the clinical impact of relative biological effectiveness (RBE) variations in proton beam scanning treatment (PBS) for left-sided breast cancer versus the assumption of a fixed RBE of 1.1, particularly in the context of comparisons with photon-based three-dimensional conformal radiotherapy (3DCRT) and volumetric modulated arc therapy (VMAT). Ten patients receiving radiation treatment to the whole breast/chest wall and regional lymph nodes were selected for each modality. For PBS, the dose distributions were re-calculated with both a fixed RBE and a variable RBE using an empirical RBE model. Dosimetric indices based on dose-volume histogram analysis were calculated for the entire heart wall, left anterior descending artery (LAD) and left lung. Furthermore, normal tissue toxicity probabilities for different endpoints were evaluated. The results show that applying a variable RBE significantly increases the RBE-weighted dose and consequently the calculated dosimetric indices increases for all organs compared to a fixed RBE. The mean dose to the heart and the maximum dose to the LAD and the left lung are significantly lower for PBS assuming a fixed RBE compared to 3DCRT. However, no statistically significant difference is seen when a variable RBE is applied. For a fixed RBE, lung toxicities are significantly lower compared to 3DCRT but when applying a variable RBE, no statistically significant differences are noted. A disadvantage is seen for VMAT over both PBS and 3DCRT. One-to-one plan comparison on 8 patients between PBS and 3DCRT shows similar results. We conclude that dosimetric analysis for all organs and toxicity estimation for the left lung might be underestimated when applying a fixed RBE for protons. Potential RBE variations should therefore be considered as uncertainty bands in outcome analysis.

Proton Radiation Therapy for Pediatric Craniopharyngioma.

BACKGROUND: Radiation therapy (RT) is used for pediatric craniopharyngioma in the definitive, adjuvant, or salvage settings. Proton RT may be useful owing to tumor proximity to eloquent anatomy. We report clinical outcomes for a large cohort treated with proton therapy. METHODS: We conducted a retrospective review of pediatric patients (≤21 years) treated with surgery and proton therapy for craniopharyngioma between August 2002 and October 2018. Clinical characteristics, treatment course, and outcomes were recorded. Acute toxicity was graded using Common Terminology Criteria for Adverse Events, version 5.0. Late toxicity was assessed using neuroendocrine, neuro-ophthalmologic, and neuropsychological testing. RESULTS: Among 77 patients, median age at diagnosis was 8.6 years (range, 1.3-20); median age at radiation was 9.6 years (range, 2.3-20.5). Most common presenting symptoms were headache (58%), visual impairment (55%), and endocrinopathy (40%). Patients underwent a median of 2 surgical interventions (range, 1-7) before protons. At initial surgery, 18% had gross total resection, 60% had subtotal resection, and 22% had biopsy/cyst decompression. Median RT dose was 52.2 Gy (relative biologic effectiveness). Common acute toxicities were headache (29%), fatigue (35%), and nausea/vomiting (12%). Only 4% developed any acute grade 3 toxicity. Nine patients experienced cyst growth requiring replanning or surgical decompression. At a median of 4.8 years from RT (range, 0.8-15.6), there were 6 local failures and 3 deaths, 2 related to disease progression. Effect of tumor and treatment contributed to late toxicity including Moyamoya syndrome (13%), visual impairment (40%), and endocrine deficiency requiring hormone replacement (94%). Subclinical decline in functional independence and adaptive skills in everyday life was detected at follow-up. CONCLUSIONS: Surgery and proton therapy results in excellent disease control for pediatric craniopharyngioma. Severe acute toxicity is rare. Late toxicities from tumor, surgery, and radiation remain prevalent. Endocrine and ophthalmology follow-up is necessary, and neuropsychological testing may identify patients at risk for treatment-related cognitive and adaptive functioning changes.

Assessment of out-of-field absorbed dose and equivalent dose in proton fields.

PURPOSE: In proton therapy, as in other forms of radiation therapy, scattered and secondary particles produce undesired dose outside the target volume that may increase the risk of radiation-induced secondary cancer and interact with electronic devices in the treatment room. The authors implement a Monte Carlo model of this dose deposited outside passively scattered fields and compare it to measurements, determine the out-of-field equivalent dose, and estimate the change in the dose if the same target volumes were treated with an active beam scanning technique. METHODS: Measurements are done with a thimble ionization chamber and the Wellhofer MatriXX detector inside a Lucite phantom with field configurations based on the treatment of prostate cancer and medulloblastoma. The authors use a GEANT4 Monte Carlo simulation, demonstrated to agree well with measurements inside the primary field, to simulate fields delivered in the measurements. The partial contributions to the dose are separated in the simulation by particle type and origin. RESULTS: The agreement between experiment and simulation in the out-of-field absorbed dose is within 30% at 10-20 cm from the field edge and 90% of the data agrees within 2 standard deviations. In passive scattering, the neutron contribution to the total dose dominates in the region downstream of the Bragg peak (65%-80% due to internally produced neutrons) and inside the phantom at distances more than 10-15 cm from the field edge. The equivalent doses using 10 for the neutron weighting factor at the entrance to the phantom and at 20 cm from the field edge are 2.2 and 2.6 mSv/Gy for the prostate cancer and cranial medulloblastoma fields, respectively. The equivalent dose at 15-20 cm from the field edge decreases with depth in passive scattering and increases with depth in active scanning. Therefore, active scanning has smaller out-of-field equivalent dose by factors of 30-45 in the entrance region and this factor decreases with depth. CONCLUSIONS: The dose deposited immediately downstream of the primary field, in these cases, is dominated by internally produced neutrons; therefore, scattered and scanned fields may have similar risk of second cancer in this region. The authors confirm that there is a reduction in the out-of-field dose in active scanning but the effect decreases with depth. GEANT4 is suitable for simulating the dose deposited outside the primary field. The agreement with measurements is comparable to or better than the agreement reported for other implementations of Monte Carlo models. Depending on the position, the absorbed dose outside the primary field is dominated by contributions from primary protons that may or may not have scattered in the brass collimating devices. This is noteworthy as the quality factor of the low LET protons is well known and the relative dose risk in this region can thus be assessed accurately.

Arms positioning in post-mastectomy proton radiation: Feasibility and development of a new arms down contouring atlas.

BACKGROUND AND PURPOSE: Breast cancer patients receiving radiation are traditionally positioned with both arms up, but this may not be feasible or comfortable for all patients. We evaluated the treatment planning and positioning reproducibility differences between the arms up and arms down positions for patients receiving post-mastectomy radiation therapy (PMRT) using proton pencil beam scanning (PBS). MATERIALS AND METHODS: Ten PMRT patients who were scheduled to receive PBS underwent CT-based treatment planning in both an arms down and a standard arms up position. An arms down contouring atlas was developed for consistency in treatment planning. Treatment plans were performed on both scans. A Wilcoxon test was applied to compare arms up and arms down metrics across patients. Five patients received treatment in the arms-down position at our institution while others were treated with the arms up. Residual set-up errors were recorded for each patient's treatment fractions and compared between positions. RESULTS: Target structure coverage remained consistent between the arms up and arms down positions. In regard to the OAR, the heart mean and maximum doses were statistically significantly lower in the arms up position versus the arms down position, however, the absolute differences were modest. Patients demonstrated similar setup errors, less than 0.5 mm differences, in all directions. CONCLUSIONS: PBS for PMRT in the arms down position appeared stable and reproducible compared to the traditional arms up positioning. The degree of OAR sparing in the arms down group was minimally less robust but still far superior to conventional photon therapy.

MRI-based IMPT planning for prostate cancer.

PURPOSE: Treatment planning for proton therapy requires the relative proton stopping power ratio (RSP) information of the patient for accurate dose calculations. RSP are conventionally obtained after mapping of the Hounsfield units (HU) from a calibrated patient computed tomography (CT). One or multiple CT are needed for a given treatment which represents additional, undesired dose to the patient. For prostate cancer, magnetic resonance imaging (MRI) scans are the gold standard for segmentation while offering dose-less imaging. We here quantify the clinical applicability of converted MR images as a substitute for intensity modulated proton therapy (IMPT) treatment of the prostate. METHODS: MRCAT (Magnetic Resonance for Calculating ATtenuation) is a Philips-developed technology which produces a synthetic CT image consisting of five HU from a specific set of MRI acquisitions. MRCAT and original planning CT data sets were obtained for ten patients. An IMPT plan was generated on the MRCAT for each patient. Plans were produced such that they fulfill the prostate protocol in use at Massachusetts General Hospital (MGH). The plans were then recomputed onto the nominal planning CT for each patient. Robustness analyses (±5 mm setup shifts and ±3.5 % range uncertainties) were also performed. RESULTS: Comparison of MRCAT plans and their recomputation onto the planning CT plan showed excellent agreement. Likewise, dose perturbations due to setup shifts and range uncertainties were well within clinical acceptance demonstrating the clinical viability of the approach. CONCLUSIONS: This work demonstrate the clinical acceptability of substituting MR converted RSP images instead of CT for IMPT planning of prostate cancer. This further translates into higher contouring accuracy along with lesser imaging dose.

The risk for developing a secondary cancer after breast radiation therapy: Comparison of photon and proton techniques.

BACKGROUND AND PURPOSE: To compare secondary malignancy risks of modern proton and photon therapy techniques for locally advanced breast cancer. METHODS AND MATERIALS: We utilized dosimetric data from 34 [10 photon-VMAT, 10 photon-3DCRT, 14 pencil beam scanning proton (PBS)] breast cancer patients who received comprehensive nodal irradiation. Employing a model based on organ equivalent dose to account for both inhomogeneous organ dose distributions and non-linear functional dose relationships, we estimated excess absolute risk, excess relative risk, and lifetime attributable risk (LAR) for secondary malignancies. The model uses dose distribution, number of fractions, age at exposure, attained age, the linear-quadratic dose response relationship for cell survival, repopulation factor, as well as gender specific age dependencies, and initial slopes of dose response curves. RESULTS: The LAR for carcinoma at age 70 was estimated to be up to 3.64% for esophagus with an advantage of 3DCRT over PBS and VMAT. For the ipsilateral lung, risks were lowest for PBS (up to 5.56%), followed by 3DCRT (up to 6.54%) and VMAT (up to 7.7%). For the contralateral lung, there is a clear advantage of 3DCRT and PBS techniques (risk <0.86%) over VMAT (up to 4.4%). The risk for the contralateral breast is negligible for 3DCRT and PBS but was estimated as up to 1.2% for VMAT. Risks for the thyroid are overall negligible. Independently performed comparative treatment plans on 10 patients revealed that the risk for the contralateral lung and breast using VMAT can be more than an order of magnitude higher compared to PBS. Sarcoma risks were estimated as well showing similar trends but were overall lower compared to carcinoma. CONCLUSION: Conventional (3DCRT) techniques led to the lowest estimated risks of, thyroid and esophageal secondary cancers while PBS demonstrated a benefit for secondary lung and contralateral breast cancer risks, with the highest risks overall associated with VMAT techniques.

Phase II Study of Proton Beam Radiation Therapy for Patients With Breast Cancer Requiring Regional Nodal Irradiation.

PURPOSE: To evaluate the safety and efficacy of proton beam radiation therapy (RT) for patients with breast cancer who require regional nodal irradiation. METHODS: Patients with nonmetastatic breast cancer who required postoperative RT to the breast/chest wall and regional lymphatics and who were considered suboptimal candidates for conventional RT were eligible. The primary end point was the incidence of grade 3 or higher radiation pneumonitis (RP) or any grade 4 toxicity within 3 months of RT. Secondary end points were 5-year locoregional failure, overall survival, and acute and late toxicities per Common Terminology Criteria for Adverse Events (version 4.0). Strain echocardiography and cardiac biomarkers were obtained before and after RT to assess early cardiac changes. RESULTS: Seventy patients completed RT between 2011 and 2016. Median follow-up was 55 months (range, 17 to 82 months). Of 69 evaluable patients, median age was 45 years (range, 24 to 70 years). Sixty-three patients (91%) had left-sided breast cancer, two had bilateral breast cancer, and five had right-sided breast cancer. Sixty-five (94%) had stage II to III breast cancer. Sixty-eight (99%) received systemic chemotherapy. Fifty (72%) underwent immediate reconstruction. Median dose to the chest wall/breast was 49.7 Gy (relative biological effectiveness) and to the internal mammary nodes, 48.8 Gy (relative biological effectiveness), which indicates comprehensive coverage. Among 62 surviving patients, the 5-year rates for locoregional failure and overall survival were 1.5% and 91%, respectively. One patient developed grade 2 RP, and none developed grade 3 RP. No grade 4 toxicities occurred. The unplanned surgical re-intervention rate at 5 years was 33%. No significant changes in echocardiography or cardiac biomarkers after RT were found. CONCLUSION: Proton beam RT for breast cancer has low toxicity rates and similar rates of disease control compared with historical data of conventional RT. No early cardiac changes were observed, which paves the way for randomized studies to compare proton beam RT with standard RT.

Reducing X-ray imaging for proton postmastectomy chest wall patients.

PURPOSE: Proton postmastectomy radiation therapy (PMRT) patients are positioned daily using surface imaging with additional x-ray imaging for confirmation. This study aims to investigate whether weekly x-ray imaging with daily surface imaging, as performed for photon treatment, is sufficient to maintain PMRT patient positioning fidelity. METHODS AND MATERIALS: Calculated radiographic corrections and surface imaging residual setup errors were analyzed at the treatment angle for 28 PMRT patients (with and without breast implant, left and right sided). The temporal repartition of radiographic translations >3 mm occurring after surface imaging positioning was studied as well as their impact on the final patient position, defined as the comparison between the treatment angle surface image and the planning computed tomography scan. To compare both sets of images, the traditional bony anatomy landmarks on the digitally reconstructed radiographs were replaced by 3 radiopaque markers placed over the patient's skin tattoos. The temporal variation of the distances between these skin markers was analyzed, as were the surface imaging statistics. RESULTS: Discrepancies between surface imaging and x-ray imaging were more frequent for patients without breast implants and among reconstructed patients with large implants. One-quarter of studied patients exhibited calculated radiographic translations >3 mm during the last week of treatment. In most circumstances, applying radiographic corrections did not affect patient position, which remained within 3 mm/2° robustness tolerances. One patient's implant shifted following computed tomography planning; this shift would not have been detected without x-ray imaging. CONCLUSION: Initial and weekly x-ray acquisition combined with daily surface imaging seems adequate both for routine PMRT positioning and to monitor potential changes in the treatment area. The limits of the surface imaging system, however, need to be better specified among patients without breast implants or in those with large implant reconstructions.