Passive Scattering Proton Therapy Research Articles

Letter to the editor on "The cochlear dose and the age at radiotherapy predict severe hearing loss after passive scattering proton therapy and cisplatin in children with medulloblastoma".

Letter to the editor on "The cochlear dose and the age at radiotherapy predict severe hearing loss after passive scattering proton therapy and cisplatin in children with medulloblastoma".

The cochlear dose and the age at radiotherapy predict severe hearing loss after passive scattering proton therapy and cisplatin in children with medulloblastoma.

Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin. We identified patients aged 3-21 years who were treated at our centers between 2007 and 2022. Audiograms were graded using the International Society of Pediatric Oncology (SIOP) Boston scale. Time to grades 3-4 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios and 95% confidence intervals (CI). Seventy-nine patients were treated with PSPT at a median age of 7.5 years (range: 3.1-21.1). The mean cochlear dose (Dmc) (±SD) was 31.5 ± 8.5 Gy, and the cumulative cisplatin dose was 295 ± 50 mg/m2. Fifty-nine patients (75%) received amifostine. Patients completed a median of 9 audiograms (range: 4-22) with a median audiogram follow-up of 49 months (range: 6-177). Twenty-seven patients (34%) had grades 3-4 HL. In adjusted Cox models, only higher Dmc (HR = 1.12, 95% CI:1.06-1.18) was associated with grades 3-4 HL. The predicted 3-year incidence of grades 3-4 HL was 40.0% (95% CI: 21.3-66.3) and 66.7% (95% CI: 35.4-93.7) for children with Dmc ≥36 Gy and age at radiotherapy ≥7 and <7 years, respectively (P = .042). It was 8.9% (95% CI: 2.3-31.6) and 15.6% (95% CI: 5.3-41.1) for children with Dmc <36 Gy and age at radiotherapy ≥7 and <7 years, respectively (P = .78). Children <7 years at radiotherapy with a Dmc ≥36 Gy are at higher risk for HL.

Prediction of radiation pneumonitis using the effective α/β of lungs and heart in NSCLC patients treated with proton beam therapy

PurposeRadiation pneumonitis (RP) remains a major complication in non-small cell lung cancer (NSCLC) patients undergoing radiochemotherapy (RCHT). Traditionally, the mean lung dose (MLD) and the volume of the total lung receiving at least 20 Gy (V20Gy) are used to predict RP in patients treated with normo-fractionated photon therapy.However, other models, including the actual dose-distribution in the lungs using the effective α/β model or a combination of radiation doses to the lungs and heart, have been proposed for predicting RP. Moreover, the models established for photons may not hold for patients treated with passively-scattered proton therapy (PSPT). Therefore, we here tested and validated novel predictive parameters for RP in NSCLC patient treated with PSPT. MethodsData on the occurrence of RP, structure files and dose-volume histogram parameters for lungs and heart of 96 NSCLC patients, treated with PSPT and concurrent chemotherapy, was retrospectively retrieved from prospective clinical studies of two international centers. Data was randomly split into a training set (64 patients) and a validation set (32 patients). Statistical analyses were performed using binomial logistic regression. ResultsThe biologically effective dose (BED) of the’lungs - GTV’ significantly predicted RP ≥ grade 2 in the training-set using both a univariate model (p = 0.019, AUCtrain = 0.72) and a multivariate model in combination with the effective α/β parameter of the heart (pBED = 0.006, pα/βeff = 0.043, AUCtrain = 0.74). However, these results did not hold in the validation-set (AUCval = 0.52 andAUCval = 0.50, respectively). Moreover, these models were found to neither outperform a model built with the MLD (p = 0.015, AUCtrain = 0.73, AUCval = 0.51), nor a multivariate model additionally including the V20Gy of the heart (pMLD = 0.039, pV20Gy,heart = 0.58, AUCtrain = 0.74, AUCval = 0.53). ConclusionUsing the effective α/β parameter of the lungs and heart we achieved similar performance to commonly used models built for photon therapy, such as MLD, in predicting RP ≥ grade 2. Therefore, prediction models developed for photon RCHT still hold for patients treated with PSPT.

Proton Therapy in the Treatment of Men with Breast Cancer

PurposeMale breast cancer treatment involves multimodality therapy, including radiation therapy; nevertheless, few men have received proton therapy (PT) for it. Further, heart disease is an established leading cause of death in men, and radiation therapy heart dose correlates with cardiac toxicity, highlighting the need for cardiac-sparing radiation techniques. Thus, we provide a descriptive analysis of PT in a male breast cancer cohort. Patients and MethodsMen who received PT for localized breast cancer between 2012 and 2022 were identified from a prospective database. Toxicities were prospectively recorded by using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. ResultsFive male patients were identified. All had estrogen receptor (ER)–positive, Her2neu-negative disease and received adjuvant endocrine therapy. One had genetic testing positive for BRCA2, one had a variant of unknown significance (VUS) in the APC gene, and one had a VUS in MSH2. Median age was 73 years (range, 41–80). Baseline comorbidities included obesity (n = 1), diabetes (n = 1), hypertension (n = 4), history of deep vein thrombosis (n = 1), personal history of myocardial infarction (n = 3; 1 with a pacemaker), and a history of lung cancer (n = 1). All received PT to the left chest wall and comprehensive regional lymphatics. One received passive-scattering PT, and 4 received pencil beam scanning. One patient received a boost to the mastectomy incision via electrons. Median heart dose was 1 GyRBE (range, 0–1.0), median 0.1-cm3 dose to the left anterior descending artery was 7.5 GyRBE (range, 0–14.2), and median follow-up was 2 years (range, 0.75–6.5); no patient experienced a new cardiac event, and all remain free from breast cancer recurrence and progression. ConclusionIn a small case series for a rare diagnosis, PT to the chest wall and regional lymphatics, including internal mammary nodes, resulted in low cardiac exposure, high local regional disease control rates, and minimal toxicity. Proton therapy should be considered for treating men with breast cancer to achieve cardiac sparing.

Effectiveness of CT-image guidance in proton therapy for liver cancer and the importance of daily dose monitoring for tumors and organs at risk.

It is important to have precise image guidance throughout proton therapy in order to take advantage of the therapy's physical selectivity. We evaluated the effectiveness of computed tomography (CT)-image guidance in proton therapy for patients with hepatocellular carcinoma (HCC) by assessing daily proton dose distributions. The importance of daily CT image-guided registration and daily proton dose monitoring for tumors and organs at risk (OARs) was investigated. A retrospective analysis was conducted using 570 sets of daily CT (dCT) images throughout whole treatment fractions for 38 HCC patients who underwent passive scattering proton therapy with either a 66 cobalt gray equivalent (GyE)/10 fractions (n=19) or 76 GyE/20 fractions (n=19) protocol. The actual daily delivered dose distributions were estimated by forward calculation using the dCT sets, their corresponding treatment plans, and the recorded daily couch correction information. We then evaluated the daily changes of the dose indices D99% , V30GyE , and Dmax for the tumor volumes, non-tumorous liver, and other OARs, that is, stomach, esophagus, duodenum, colon, respectively. Contours were created for all dCT sets. We validated the efficacy of the dCT-based tumor registrations (hereafter, "tumor registration") by comparing them with the bone registration and diaphragm registration as a simulation of the treatment based on the positioning using the conventional kV X-ray imaging. The dose distributions and the indices of three registrations were obtained by simulation using the same dCT sets. In the 66 GyE/10 fractions, the daily D99% value in both the tumor and diaphragm registrations agreed with the planned value with 3%-6% (SD), and the V30GyE value for the liver agreed within ±3%; the indices in the bone registration showed greater deterioration. Nevertheless, tumor-dose deterioration occurred in all registration methods for two cases due to daily changes of body shape and respiratory condition. In the 76 GyE/20 fractions, in particular for such a treatment that the dose constraints for the OARs have to be cared in the original planning, the daily D99% in the tumor registration was superior to that in the other registration (p<0.001), indicating the effectiveness of the tumor registration. The dose constraints, set in the plan as the maximum dose for OARs (i.e., duodenum, stomach, colon, and esophagus) were maintained for 16 patients including seven treated with re-planning. For three patients, the daily Dmax increased gradually or changed randomly, resulting in an inter-fractional averaged Dmax higher than the constraints. The dose distribution would have been improved if re-planning had been conducted. The results of these retrospective analyses indicate the importance of daily dose monitoring followed by adaptive re-planning when needed. The tumor registration in proton treatment for HCC was effective to maintain the daily dose to the tumor and the dose constraints of OARs, particularly in the treatment where the maintenance for the dose constraints needs to be considered throughout the treatment. Nevertheless daily proton dose monitoring with daily CT imaging is important for more reliable and safer treatment.

Abstract P1-10-08: Incidence of rib fracture following treatment with proton therapy for breast cancer

Abstract Purpose: To determine the rate of rib fracture in a cohort of patients with breast cancer treated with proton therapy and enrolled on a prospective registry. In series investigating photon therapy for breast cancer, the rib fracture rate ranges from 0.3-13% Methods: From a prospective database, we identified patients treated with proton therapy for breast cancer at our institution between January 1, 2012 and December 31, 2020. Clinical and dosimetric data was extracted from the electronic medical record. The cumulative incidence method assessed rib fracture rate; the Fine-Gray test statistic assessed prognostic significance select variables. Results: 225 patients were identified, 223 women and 2 men. Median age at the time of radiation was 57.8 years (range, 25 – 87). 26% of patients were black, 69% white and 5% were other races or race not disclosed. 5% were Hispanic. 74% of patients had left-sided breast cancer, 5% bilateral, and 21% right-sided. DEXA scan was normal in 20%, showed osteopenia in 34%, osteoporosis in 6%, and not performed in 40%. 57% of patients received antiendocrine therapy with an aromatase inhibitor. For 16% of patients, the breast +/- internal mammary nodes (IMN) were treated, while 32% underwent proton therapy to treat the breast and comprehensive regional lymphatics. 1% of patients had chest wall +/- IMN treated, while 51% underwent proton therapy to treat the chest wall and comprehensive regional lymphatics. 41% of patients were treated with passive scatter proton therapy (n=92); 52% of these had mastectomy. 58% of patients received treatment with pencil beam scanning (PBS) proton therapy (n=131); 53% of these had mastectomy. A combination of passive scatter and PBS was used for 2 patients (1%). 85% of patients received a boost. Median follow-up was 3.1 years (range, 0.2 – 9.1). 97% of patients had &amp;gt; 12 months of follow-up. The 3 year cumulative incidence of in-field rib fracture was 3.7% (95%CI: 1.6%-7.1%). In total, 8 patients developed in-field rib fractures, one symptomatic and 7 identified incidentally on surveillance imaging, for a 0.4% rate of symptomatic rib fracture. Median time from completion of radiation to identification of rib fracture was 1.8 years (range, 0.4-7.4 years). Rib fractures occurred within 2.2 years from radiotherapy completion for seven of the eight patients who experienced this side effect. Three patients developed rib fractures outside of the radiation field, for a cumulative incidence of out-of-field rib fracture of 0.9% (95%CI: 0.2-3.0%). No variables were associated with rib fracture on univariate analysis. Of those with in-field rib fractures, 3 had low and 3 had normal bone density while 2 had not undergone testing; of those with out-of-field rib fractures, 2 had osteopenia and 1 did not have testing. Conclusions: Although a proton beam has higher biological dose deposition at end-of-range than the assumed constant RBE=1.1, the 3 year rate of any in-field rib fractures in our series remains low at 3.7%, with a 0.4% rate of symptomatic rib fracture. Contouring ribs as an OAR and establishing a dose constraint warrants further investigation as a means to maintaining a low rate of rib fracture with proton therapy. Citation Format: Julie Bradley, Xiaoying Liang, Raymond Mailhot Vega, Chunbo Liu, Eric Brooks, Teena Burchianti, Emma Viviers, Roi Dagan, Oluwadamilola Oladeru, Christopher Morris, Nancy Mendenhall. Incidence of rib fracture following treatment with proton therapy for breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-08.

Incidence of Rib Fracture following Treatment with Proton Therapy for Breast Cancer.

To determine the rib fracture rate in a cohort of patients with breast cancer treated with proton therapy. From a prospective database, we identified 225 patients treated with proton therapy between 2012 and 2020 (223 women; 2 men). Clinical and dosimetric data were extracted, the cumulative incidence method assessed rib fracture rate, and Fine-Gray tests assessed prognostic significance of select variables. In-field rib fracture was defined as a fracture that occurred in a rib located within the 10% isodose line. Out-of-field rib fracture was defined as a fracture occurring in a rib location outside of the 10% isodose line. Of the patients, 74% had left-sided breast cancer; 5%, bilateral; and 21%, right-sided. Dual-energy x-ray absorptiometry scans showed normality in 20%, osteopenia in 34%, and osteoporosis in 6% (test not performed in 40%). Additionally, 57% received an aromatase inhibitor. Target volumes were breast ± internal mammary nodes (IMNs) (16%), breast and comprehensive regional lymphatics (32%), chest wall ± IMNs (1%), and chest wall/comprehensive regional lymphatics (51%). Passive-scattered proton therapy was used for 41% of patients, 58% underwent pencil-beam scanning (PBS), and 1% underwent a combination (passive scattering/PBS), with 85% of patients receiving a boost. Median follow-up was 3.1 years, with 97% having >12-month follow-up. The 3-year cumulative in-field rib fracture incidence was 3.7%. Eight patients developed in-field rib fractures (1 symptomatic, 7 imaging identified) for a 0.4% symptomatic rib fracture rate. Median time from radiation completion to rib fracture identification was 1.8 years (fractures were identified within 2.2 years for 7 of 8 patients). No variables were associated with rib fracture on univariate analysis. Three fractures developed outside the radiation field (0.9% cumulative incidence of out-of-field rib fracture). In this series of patients with breast cancer treated with proton therapy, the 3-year rib fracture rates remain low (in-field 3.7%; symptomatic 0.4%). As in photon therapy, the asymptomatic rate may be underestimated owing to a lack of routine surveillance imaging. However, patients experiencing symptomatic rib fractures after proton therapy for breast cancer are rare.

Analysis of Early Outcomes of Pencil Beam Proton Therapy Compared with Passive Scattering Proton Therapy for Clival Chordoma

To assess the early outcomes of the following 2 types of proton therapy: passive scattering proton therapy (PSPT) and pencil beam proton therapy (PBPT). The consecutive patients who had surgery in our facility were retrospectively reviewed. Thirty-two patients were identified (PBPT 22 patients [69%]). The mean (±standard deviation [SD]) tumor size was 3.8±1.8cm, and the most common location was the upper clivus (41%). Four cases (13%) were revision surgeries referred from elsewhere, and 2 cases underwent additional surgery elsewhere to achieve near-total resection before radiation. The cerebrospinal fluid leak occurred in 3 patients (9%). The mean (±SD) prescribed dose of PSPT and PBPT was 74±3Gy and 72±3Gy, respectively (P= 0.07). The mean (±SD) fractionation of PSPT and PBPT was 39±2 and 36±2, respectively (P= 0.001). Radiation toxicities were recorded in endocrine (11 patients [34%]), ophthalmic (3 patients [9%]), otologic (7 patients [22%]), and radiation necrosis (4 patients [13%]). PSPT was associated with endocrinopathy (odds ratio [OR], 10.5; 95% confidence interval, 1.86-59.4, P= 0.008), and radiation dose was associated with otologic toxicity (OR 1.57; 95% confidence interval, 1.02-2.44; P= 0.04). The gross-near total resection group had better progression-free survival than the subtotal resection group regardless of radiation therapy (P= 0.01). Overall, 3-year progression-free survival was 73%, and 5-year overall survival was 93%. The PBPT group showed comparable outcome to the PSPT group. The degree of resection was more important than the modality of proton therapy. Further follow-up and cases are necessary to evaluate the benefit of PBPT.

Modeling Variable Proton Relative Biological Effectiveness (RBE) Using Voxel-Level Image Density Change for Non-Small Cell Lung Cancer (NSCLC) Patients Treated with Passive Scattering Proton Therapy (PSPT) or Intensity Modulated Photon Therapy (IMRT)

<h3>Purpose/Objective(s)</h3> To test the hypothesis that radiation damage measured via lung image density change is a function of variable RBE for protons with a coefficient of determination (R²) greater than 0.8. <h3>Materials/Methods</h3> Data from 61 NSCLC patients previously treated on a prospective clinical trial with PSPT (N = 24) or IMRT (N = 37) to 74 Gy(RBE) (proton RBE of 1.1) were acquired. Patients with noticeable atelectasis or pleural effusion were excluded. For each patient, a ∼5-month post-treatment PETCT was obtained to assess response and was deformed to the planning exhale phase of the 4DCT (exCT) via a biomechanical model-based image registration algorithm. Subsequently, voxel-level image density change (IDC) within the normal ipsilateral lung was obtained by subtracting the exCT from the deformed PETCT, as a signal of biological damage. IMRT dose (D_x) was recalculated on the exCT using a commercial treatment planning system while the PSPT dose (D_p) and dose-averaged linear energy transfer (LET_d) were recalculated on the exCT using a commissioned track-repeating Monte-Carlo system. The fitted variable RBE models included a linear model (RBE = 1 + λ•LET_d) and a linear-quadratic (LQ) model (RBE = 1/(2D_p)•{√[(α/β)² + 4D_p(α/β)(p₀+(p₁•LET_d)/(α/β) + 4D_p²(p₂ + p₃•√(α/β)•LET_d)] - α/β}) with α/β = 3 Gy for lung tissue. <b>RBE was modeled against the ratio between D_x and D_p at given IDC levels.</b> We adapted Lyman-Kutcher-Burman normal tissue complication probability (NTCP) model to fit the dose-IDC relationship for each cohort by averaging the dose and IDC of voxels in 5-Gy dose intervals (adaptations: n = 1, effective dose = voxel dose, and complication probability = IDC normalized against global min and max IDC). LET_d corresponding to each D_p was approximated by averaging the LET_d of voxels that received D_p with a margin of 0.001Gy. All NTCP and RBE models were fitted using non-linear least squares with the Python SciPy package. <h3>Results</h3> For NTCP fitting, min and max IDC were 2.7 HU and 136.3 HU, respectively, and TD₅₀ and m were fitted to be 31.5 Gy and 0.51 for PSPT (R² = 0.99) and 44.4 Gy and 0.40 for IMRT (R² = 0.98). The table shows the IDC levels, the corresponding LET_d (SD), and the fitted D_x and D_p. The linear model resulted in λ = 0.154 µm/keV (R² = 0.27), and the LQ model resulted in p₀ = -0.72, p₁ = 10.02, p₂ = 1.51, and p₃ = -0.08 (R² = 0.999). <h3>Conclusion</h3> The study demonstrates that voxel-level radiation damage and image changes for proton therapy are functions of dose and LET and, thus, variable RBE.

CNS Necrosis after Proton Therapy for Sinonasal Carcinoma

<h3>Purpose/Objective(s)</h3> Sinonasal cancers (SC) are a rare, diverse disease group with a relatively poor prognosis. Local control (LC) has improved with advances in imaging, surgery, and radiotherapy including proton therapy (PT), albeit with increased risk of toxicity such as central nervous system (CNS) necrosis. Our objective was to assess CNS necrosis risk in patients who receive PT for SC and evaluate prognostic factors and DVH metrics. <h3>Materials/Methods</h3> We reviewed 173 patients (age 18+ yrs) treated with PT (+/- chemo) for SC (excluding melanoma, lymphoma, sarcoma, distant metastasis, ≤ 6 mos follow-up, and reirradiation) at a single institution. We assessed CNS necrosis using CTCAEv5 and censored events at last primary site imaging, local recurrence, distant metastasis, or death. We estimated survival, disease control, and CNS necrosis rates using the cumulative incidence method. We used a Fine-Gray test to correlate prognostic univariate factors, competing risks proportional hazards regression for multivariate analysis, and correlated select whole-brain DVH parameters (V40-80, 5 GyE intervals, Dmax, and Dmean) with CNS necrosis using univariate logistic regression on 93 patients with >1-yr imaging follow-up and no competing events. <h3>Results</h3> Median age was 60 years (range, 18-86) with a median follow-up of 5 yrs among survivors (range, 0.5 – 13.5), most had T3-4 tumors (91%) and naso-ethmoid tumors (77%); 42% had intracranial and 34% had cranial nerve invasion. Most (80%) had surgery before PT; 69% received chemo. Most received passive-scatter PT (84%) at 1.2 GyE/fraction twice-daily (85%) to ≥70 GyE (79%; median, 73.2; range, 54 – 74.4). 5-yr LC (95% CI), disease-free, and overall survival rates were 84% (78-89%), 63% (56-71%), and 59% (51-77%). After gross-total resection, the 5-yr LC rate was 92% (95% CI, 86-96%). There were 72 (40%) CNS necrosis events at a median 2.6 yrs from end of PT (range, 1.1 – 9.1) with 14 (8%) grade 3+ events and 3 deaths. Most events (53%) were asymptomatic (grade 1). Freedom from CNS necrosis (grade 1+, 2+, and 3+ [95% CI]) at 5 years was 78% (72-85), 90% (85-94), and 92% (87-95). T3/4 disease, intracranial invasion, biopsy alone, total dose, and chemotherapy were negatively correlated prognostic factors. Nearly all DVH metrics showed strong correlation with CNS necrosis risk except Dmean. The receiver-operator curve characteristics for V65 showed the strongest correlation (AUC 0.83 grade 2+, AUC 0.78 grade 3+) and the model provided candidate DVH goals (V65 < 1mL, 5% risk of grade 3) with an acceptable deviation (V65 < 17mL, 15% risk of grade 3+) for those with gross skull base/intracranial tumor. <h3>Conclusion</h3> PT +/- chemo in the primary and adjuvant settings yields high rates of LC for locally advanced SC. CNS toxicity is a significant risk, but most events are asymptomatic and self-limited. We intend to decrease treatment intensity after gross total resection given the favorable LC in this subset. These data provide updated DVH goals to decrease the risk of CNS toxicity.

A case-control study of linear energy transfer and relative biological effectiveness related to symptomatic brainstem toxicity following pediatric proton therapy

A fixed relative biological effectiveness (RBE) of 1.1 (RBE1.1) is used clinically in proton therapy even though the RBE varies with properties such as dose level and linear energy transfer (LET). We therefore investigated if symptomatic brainstem toxicity in pediatric brain tumor patients treated with proton therapy could be associated with a variable LET and RBE. 36 patients treated with passive scattering proton therapy were selected for a case-control study from a cohort of 954 pediatric brain tumor patients. Nine children with symptomatic brainstem toxicity were each matched to three controls based on age, diagnosis, adjuvant therapy, and brainstem RBE1.1 dose characteristics. Differences across cases and controls related to the dose-averaged LET (LETd) and variable RBE-weighted dose from two RBE models were analyzed in the high-dose region. LETd metrics were marginally higher for cases vs. controls for the majority of dose levels and brainstem substructures. Considering areas with doses above 54Gy(RBE1.1), we found a moderate trend of 13% higher median LETd in the brainstem for cases compared to controls (P=.08), while the difference in the median variable RBE-weighted dose for the same structure was only 2% (P=.6). Trends towards higher LETd for cases compared to controls were noticeable across structures and LETd metrics for this patient cohort. While case-control differences were minor, an association with the observed symptomatic brainstem toxicity cannot be ruled out.

Comparative assessment of passive scattering and active scanning proton therapy techniques using Monte Carlo simulations

Background: in this study, two proton beam delivery designs, i.e. passive scattering proton therapy (PSPT) and pencil beam scanning (PBS), were quantitatively compared in terms of dosimetric indices. The GATE Monte Carlo (MC) particle transport code was used to simulate the proton beam system; and the developed simulation engines were benchmarked with respect to the experimental measurements. Method: a water phantom was used to simulate system energy parameters using a set of depth-dose data in the energy range of 120–235 MeV. To compare the performance of PSPT against PBS, multiple dosimetric parameters including Bragg peak width (BP W50), peak position, range, peak-to-entrance dose ratio, penumbra(90-10)%, penumbra(80-20)%, M 95% and dose volume histogram have been analyzed under the same conditions. Furthermore, the clinical test cases introduced by AAPM TG-119 were simulated in both beam delivery modes to compare the relevant clinical values obtained from Dose Volume Histogram (DVH) analysis. Results: the parametric comparison in the water phantom between the two techniques revealed that the value of peak-to-entrance dose ratio in PSPT is considerably higher than that from PBS by a factor of 8%. In addition, the BP_W50, penumbra(90-10)%, penumbra(80-20)%, and M 95% in PSPT was increased by a factor of 7, 51, 37, and 2.7%, respectively compared to the corresponding value obtained from PBS model. TG-119 phantom simulations showed that the difference of PTV mean dose between PBS and PSPT techniques are up to 1.8% while the difference of max dose to organ at risks (OARs) exceeds 50%. Conclusion: the results of this simulation show that although the passive scattering design method has a slightly higher ability to adjust the dose in target volume, but the active scanning proton therapy systems was superior in dose painting, and lower out-of-field dose compared to passive scattering design.

Predictive performance of different NTCP techniques for radiation-induced esophagitis in NSCLC patients receiving proton radiotherapy

This study aimed to compare the predictive performance of different modeling methods in developing normal tissue complication probability (NTCP) models for predicting radiation-induced esophagitis (RE) in non–small cell lung cancer (NSCLC) patients receiving proton radiotherapy. The dataset was composed of 328 NSCLC patients receiving passive-scattering proton therapy and 41.6% of the patients experienced ≥ grade 2 RE. Five modeling methods were used to build NTCP models: standard Lyman–Kutcher–Burman (sLKB), generalized LKB (gLKB), multivariable logistic regression using two variable selection procedures-stepwise forward selection (Stepwise-MLR), and least absolute shrinkage and selection operator (LASSO-MLR), and support vector machines (SVM). Predictive performance was internally validated by a bootstrap approach for each modeling method. The overall performance, discriminative ability, and calibration were assessed using the Negelkerke R2, area under the receiver operator curve (AUC), and Hosmer–Lemeshow test, respectively. The LASSO-MLR model showed the best discriminative ability with an AUC value of 0.799 (95% confidence interval (CI): 0.763–0.854), and the best overall performance with a Negelkerke R2 value of 0.332 (95% CI: 0.266–0.486). Both of the optimism-corrected Negelkerke R2 values of the SVM and sLKB models were 0.301. The optimism-corrected AUC of the gLKB model (0.796) was higher than that of the SVM model (0.784). The sLKB model had the smallest optimism in the model variation and discriminative ability. In the context of classification and probability estimation for predicting the NTCP for radiation-induced esophagitis, the MLR model developed with LASSO provided the best predictive results. The simplest LKB modeling had similar or even better predictive performance than the most complex SVM modeling, and it was least likely to overfit the training data. The advanced machine learning approach might have limited applicability in clinical settings with a relatively small amount of data.

A Review of Proton Therapy - Current Status and Future Directions.

The original rationale for proton therapy was the highly conformal depth-dose distributions that protons are able to produce, compared to photons, which allow greater sparing of normal tissues and escalation of tumor doses, thus potentially improving outcomes. Additionally, recent research, which is still ongoing, has revealed previously unrecognized advantages of proton therapy. For instance, the higher relative biological effectiveness (RBE) near the end of the proton range can be exploited to increase the difference in biologically effective dose in tumors vs. normal tissues. Moreover, the smaller "dose bath", i.e., the compact nature of proton dose distributions has been found to reduce exposure of circulating lymphocytes and the immune organs at risk. There is emerging evidence that the resulting sparing of the immune system has the potential to improve outcomes. Protons, accelerated to therapeutic energies ranging from 70 to 250 MeV, are transported to the treatment room where they enter the treatment head mounted on a rotating gantry. The initially narrow beams of protons are spread laterally and longitudinally and shaped appropriately to deliver treatments. Spreading and shaping can be achieved by electro-mechanically for "passively-scattered proton therapy' (PSPT); or using magnetic scanning of thin "beamlets" of protons of a sequence of initial energies. The latter technique is used to treat patients with optimized intensity modulated proton therapy (IMPT), the most powerful proton therapy modality, which is rapidly supplanting PSPT. Treatment planning and plan evaluation for proton therapy require different techniques compared to photon therapy due, in part, to the greater vulnerability of protons to uncertainties, especially those introduced by inter- and intra-fractional variations in anatomy. In addition to anatomic variations, other sources of uncertainty in the treatments delivered include the approximations and assumptions of models used for computing dose distributions and the current practice of proton therapy of assuming the RBE to have a constant value of 1.1. In reality, the RBE is variable and a complex function of proton energy, dose per fraction, tissue and cell type, end point, etc. Despite the high theoretical potential of proton therapy, the clinical evidence supporting its broad use has so far been mixed. The uncertainties and approximations mentioned above, and the technological limitations of proton therapy may have diminished its true clinical potential. It is generally acknowledged that proton therapy is safe, effective and recommended for many types of pediatric cancers, ocular melanomas, chordomas and chondrosarcomas. Promising results have been and continue to be reported for many other types of cancers as well; however, they are based on small studies. At the same time, there have been reports of unforeseen toxicities. Furthermore, because of the high cost of establishing and operating proton therapy centers, questions are often raised about the value of proton therapy. The general consensus is that there is a need for continued improvement in the state of the art of proton therapy. There is also a need to conduct randomized trials and/or collect outcomes data in multi-institutional registries to generate high level evidence of the advantages of protons. Fortuitously, such efforts are taking currently place. Ongoing research is aimed at better understanding the biological and immunomodulatory effects of proton therapy and the consequences of the physical uncertainties on proton therapy and reducing them through image-guidance and adaptive radiotherapy. Since residual uncertainties will remain despite our best efforts, in order to increase the resilience of dose distributions in the face of uncertainties and improve our confidence in dose distributions seen on treatment plans, robust optimization techniques are being developed and implemented and continue to be perfected. Such research and continuing technological advancements in planning and delivery methods are likely to help demonstrate the superiority of protons.

Ultra-Hypofractionated Proton Therapy in Localized Prostate Cancer: Passive Scattering versus Intensity-Modulated Proton Therapy

Few studies have directly compared passive scattering (PS) to intensity-modulated proton therapy (IMPT) in the delivery of ultra-hypofractionated proton beams to the localized prostate cancer (PCa). In this preliminary study involving five patients previously treated with CyberKnife, treatment plans were created for PS and IMPT (36.25 CGE in five fractions with two opposing fields) to compare the dosimetric parameters to the planning target volume (PTV) and organs-at-risk (OAR: rectum, bladder, femoral heads). Both plans met the acceptance criteria. Significant differences were observed in the minimum and maximum doses to the PTV. The mean dose to the PTV was lower for PS (35.62 ± 0.26 vs. 37.18 ± 0.14; p = 0.002). Target coverage (D98%) was better for IMPT (96.79% vs. 99.10%; p = 0.004). IMPT resulted in significantly lower mean doses to the rectum (16.75 CGE vs. 6.88 CGE; p = 0.004) and bladder (17.69 CGE vs. 5.98 CGE p = 0.002). High dose to the rectum (V36.25 CGE) were lower with PS, but not significantly opposite to high dose to the bladder. No significant differences were observed in mean conformity index values, with a non-significant trend towards higher mean homogeneity index values for PS. Non-significant differences in the gamma index for both fields were observed. These findings suggest that both PS and IMPT ultra-hypofractionated proton therapy for PCa are highly precise, offering good target coverage and sparing of normal tissues and OARs.

Development and Validation of a Spatial Dose Pattern Based Model Predicting Acute Pulmonary Toxicity in Patients Treated With Volumetric Arc-Therapy for Locally Advanced Lung Cancer

<h3>Purpose/Objective(s)</h3> (Chemo)-radiotherapy is the standard treatment for patients with locally advanced lung cancer (LALC) not accessible to surgery. Despite strict application of dose constraints, acute toxicities such as acute pulmonary toxicity (APT) remain frequent, and may impact treatment's compliance and patients' quality of life. Previously, on a population treated with intensity-modulated photon therapy or passive scattering proton therapy, spatial dose patterns associated with APT were identified in the lower lungs, especially in the lower right lung. In the present study, we aim to define these spatial dose patterns on a retrospective cohort treated by volumetric-arc therapy (VMAT) and to validate our findings prospectively. <h3>Materials/Methods</h3> For the training cohort, we retrospectively included all patients treated in our institution by VMAT for a LALC between 2015 and 2018. APT was scored according to the CTCAE v4.0 scale. All dose maps were registered to a thorax phantom using a segmentation-based elastic registration. Voxel-based analysis of local dose differences was performed with a non-parametric permutation test accounting for <i>n = 10.000</i> permutations, producing a 3-dimensional significance maps on which clusters of voxels that exhibited significant dose differences (<i>P < 0.05</i>) between the two toxicity groups (APT ≥ grade 2 vs APT < grade 2) were identified. A dose cut-off was defined by maximizing the Youden-Index derived from the Receiver Operative Curve. For the validation cohort, we applied the predefined spatial dose pattern and the dose cut-off to an observational prospective cohort. The model was evaluated using the Area under the curve (AUC) and the balanced accuracy (Bacc: mean of the sensitivity and specificity). <h3>Results</h3> 167 and 42 patients were included in the training and validation cohorts, with respective APT rates of 22.2% and 21.4%. In the training cohort, a cluster of voxels was identified in the lower right lung with a cut off of 30.3 Gy for the D_mean(mean-dose). This spatial-based model resulted in an AUC of 0.69 and a Bacc of 0.71. Using the same voxel cluster and the D_meancut-off on the validation cohort, the model resulted in an AUC of 0.74 and a Bacc of 0.69. <h3>Conclusion</h3> Our model corroborates previous findings regarding the possible role of the lower right lung regarding the development of APT and successfully evaluates its robustness in a prospective cohort treated by VMAT. Regional radiosensitivity should be considered in usual lung dose constraints.

Acute Toxicity Following Ipsilateral Head and Neck Radiation Therapy: Proton vs. Intensity-Modulated Photon Radiotherapy

Given its unique properties, proton beam radiation therapy has the ability to reduce dose to at-risk organs. Proton's Bragg peak gives sharp distal dose fall off, which results in little or no dose beyond this region. As such, ipsilateral head and neck radiation with protons can spare the contralateral side to a greater extent than photon-based radiation, potentially causing reduced acute toxicity.Eighty-six patients (59 protons and 27 intensity modulated radiation therapy [IMRT]) who received primary or adjuvant ipsilateral head and neck radiation were retrospectively reviewed. Patients received radiation to one side and this must have included at least the parotid region in the treatment field. Primary disease site was major salivary gland in 40, cutaneous in 23, tonsil in 19 and other in 4 patients. Passive scatter proton therapy was delivered with 1-3 fields daily. Median dose delivered was 66 cobalt gray equivalent with protons and 60 gray with IMRT.No grade 4 or greater acute mucositis was present in either group. Median acute mucositis was grade 1 for protons and 2 for IMRT. Grade 0, 1, 2 or 3 acute mucositis toxicity was present in 28 (47%), 11 (19%), 17 (29%) and 3 patients (5%) respectively with proton treatment and present in 7 (26%), 3 (11%), 12 (44%) and 5 patients (19%) respectively with IMRT (P = 0.053). Percutaneous endoscopic gastrostomy (PEG) tube was placed during radiation treatment for 1 patient (2%) with protons and 4 patients (15%) for IMRT (P = 0.032). Two patients in the proton group had a PEG tube placed prior to starting radiation and one patient in the IMRT group refused PEG tube placement despite treating physician recommendation. No grade 4 or greater acute radiation dermatitis was experienced by patients in either group. Median acute radiation dermatitis was grade 2 for protons and 2 for IMRT. Grade 0, 1, 2 or 3 toxicity was present in 0 (0%), 7 (12%), 47 (80%) and 4 patients (7%) respectively with proton treatment and present in 0 (0%), 5 (19%), 20 (74%) and 2 patients (7%) respectively with IMRT (P = 0.718). The majority of patients in both treatment groups completed treatment with ≤ 5 days of missed fractions (86.4% with protons, 85.1% with IMRT). Median number of missed treatment days was 2 in both groups.Ipsilateral radiation therapy is well tolerated with IMRT and proton based radiation therapy. Fewer patients underwent PEG tube placement in the proton cohort, however these results should be further validated with prospective patient-toxicity centered studies.

Development and prospective validation of a spatial dose pattern based model predicting acute pulmonary toxicity in patients treated with volumetric arc-therapy for locally advanced lung cancer

Introduction(Chemo)-radiotherapy is the standard treatment for patients with locally advanced lung cancer (LALC) not accessible to surgery. Despite strict application of dose constraints, acute toxicities such as acute pulmonary toxicity (APT) remain frequent, and may impact treatment’s compliance and patients’ quality of life. Previously, on a population treated with intensity-modulated photon therapy or passive scattering proton therapy, spatial dose patterns associated with APT were identified in the lower lungs, especially in the posterior right lung. In the present study, we aim to define these spatial dose patterns on a retrospective cohort treated by volumetric-arctherapy (VMAT) and to validate our findings prospectively. MethodsFor the training cohort, we retrospectively included all patients treated in our institution by VMAT for a LALC between 2015 and 2018. APT was scored according to the CTCAE v4.0 scale. All dose maps were registered to a thorax phantom using a segmentation-based elastic registration. Voxel-based analysis of local dose differences was performed with a non-parametric permutation test accounting for n = 10.000 permutations, producing a 3-dimensional significance maps on which clusters of voxels that exhibited significant dose differences (p < 0.05) between the two toxicity groups (APT ≥ grade 2 vs APT < grade 2) were identified. A prediction model (Pmap-Model) was then built using a neural network approach and then applied to an observational prospective cohort for validation. The model was evaluated using the Area under the curve (AUC) and the balanced accuracy (Bacc: mean of the sensitivity and specificity). Results165 and 42 patients were included in the training and validation cohorts, with respective APT rates of 22.4% and 19.1%. In the training cohort, a cluster of voxels (Pmap-region) was identified in the posterior right lung. In the training cohort, the Pmap-Model combining 11 features among which the mean dose to the Pmap-region resulted in an AUC of 0.99 and a Bacc of 99.2 using an 8% probability threshold. Using the same voxel cluster on the validation cohort, the Pmap-model resulted in an AUC of 0.81 and a Bacc of 82.0. ConclusionOur APT-prediction model was successfully validated in a prospective cohort treated by VMAT. Regional radiosensitivity should be considered in usual lung dose constraints, opening the possibility of easily implementable adaptive dosimetry planning.

Long-term Outcomes from Proton Therapy for Sinonasal Cancers.

PurposeTo report long-term disease control, survival, and toxicity after proton therapy for sinonasal cancer.Patients and MethodsWe reviewed 143 cases of adults with nonmetastatic sinonasal cancers treated with primary (18%; n = 26) or adjuvant (82%; n = 117) proton therapy. The most common histologies were squamous cell carcinoma (29%; n = 42), olfactory neuroblastoma (23%; n = 33), and adenoid cystic carcinoma (16%; n = 23). Patients had predominantly advanced-stage disease (T3, 24%, n = 35; T4, 66%, n = 94) and high-grade histology (52%; n = 74). Surgery included endoscopic resection alone (50%) with craniotomy (10%) or open resection (40%), and 31% had gross disease present at radiotherapy. Most (91%) received high-dose (median, 73.6 Gy radiobiological equivalent [GyRBE]; 84% >70 GyRBE) passive-scatter proton therapy using accelerated hyperfractionation (1.2 GyRBE twice daily) and concurrent chemotherapy (70%). Univariate and multivariate models assessed prognostic factors. Grade 3+ toxicities were recorded per Common Terminology Criteria, version 4. Median follow-up was 3.4 years (range, 0.1–12.5 years) overall and 4.9 years (range, 0.9–12.5 years) for living patients.ResultsThe 5-year outcomes were as follows: local control (LC), 80%; neck control, 96%; local-regional control, 78%; freedom from distant metastases, 71%; and disease-free survival, 62%; cause-specific survival, 64%; and overall survival, 59%. Surgery improved LC, but only with gross total resection (5-year LC 87% versus subtotal resection 62.9%, and biopsy alone 55% (P < 0.001). Gross residual disease was the only significant prognostic factor for local-regional control on multivariate analysis. High-grade, T4, and local recurrence were associated with decreased overall survival. Late (G3+) toxicity occurred in 22% (32 of 143), including central nervous system necrosis and vision loss in 6% (9 of 143) and 3.5% (5 of 143), respectively.ConclusionProton therapy after gross-total resection provides excellent long-term LC in patients with locally advanced, high-grade sinonasal cancer. Moreover, LC remains strongly associated with long-term survival. With gross disease, about 60% of patients had long-term LC with proton therapy and induction or concurrent chemotherapy.

Evaluation of the dosimetric effect of scattered protons in clinical practice in passive scattering proton therapy

The present study verified and evaluated the dosimetric effects of protons scattered from a snout and an aperture in clinical practice, when a range compensator was included. The dose distribution calculated by a treatment planning system (TPS) was compared with the measured dose distribution and the dose distribution calculated by Monte Carlo simulation at several depths. The difference between the measured and calculated results was analyzed using Monte Carlo simulation with filtration of scattering in the snout and aperture. The dependence of the effects of scattered protons on snout size, beam range, and minimum thickness of the range compensator was also investigated using the Monte Carlo simulation. The simulated and measured results showed that the additional dose compared with the results calculated by the TPS at shallow depths was mainly due to protons scattered by the snout and aperture. This additional dose was filtered by the structure of the range compensator so that it was observed under the thin region of the range compensator. The maximum difference was measured at a depth of 16 mm (8.25%), with the difference decreasing with depth. Analysis of protons contributing to the additional dose showed that the contribution of protons scattered from the snout was greater than that of protons scattered from the aperture when a narrow snout was used. In the Monte Carlo simulation, this effect of scattered protons was reduced when wider snouts and longer‐range proton beams were used. This effect was also reduced when thicker range compensator bases were used, even with a narrow snout. This study verified the effect of scattered protons even when a range compensator was included and emphasized the importance of snout‐scattered protons when a narrow snout is used for small fields. It indicated that this additional dose can be reduced by wider snouts, longer range proton beams, and thicker range compensator bases. These results provide a better understanding of the additional dose from scattered protons in clinical practice.