Passive Scattering Proton Therapy Research Articles

The Low-Dose Bath Paradox: Do Spatial Irradiation Patterns Play a Role in the Incidence of Radiation Pneumonitis Following PSPT or IMRT?

Radiation pneumonitis (RP) is a common side effect of thoracic irradiation, whose incidence has been associated with several dose-volume histogram (DVH) predictors, including the lung volume receiving at least 20 Gy (V20), the mean lung dose and V5 [Pinnix et al. IJROBP 2015; 92(1):175]. Nonetheless, a randomized trial of IMRT vs passively scattered proton therapy (PSPT) for non-small cell lung cancer (NSCLC) [Liao et al. J Clin Oncol 2018; 36(18):1813] did not show any difference in RP incidence, despite PSPT significantly spared healthy lung tissues, with a p-value of the null hypothesis on V5 of 10-10. Following the recent findings on regional dose-sensitivity of the lungs [Palma et al. IJROBP 2016; 96(1):127], this study aims to explore whether the spatial location of dose delivery in PSPT and IMRT patients could account for the observed mismatch between DVH predictors and RP outcome in the trial. We analyzed 178 patients prospectively treated with PSPT (64) or IMRT (114) for NSCLC to a prescribed dose of 66 or 74 Gy(RBE) in conventional daily fractionation with concurrent chemotherapy. 32 (28%) of IMRT patients and 23 (36%) of PSPT patients developed any CTCAE-grade RP, while 22 (19%) of IMRT patients and 18 (28%) of PSPT patients developed clinically symptomatic RP. A Voxel-Based Analysis (VBA) of local dose differences in healthy tissues was performed according to a non-parametric permutation test accounting for multiple comparisons and possible non-dosimetric confounding factors. From the obtained 3D significance maps, we derived the clusters of voxels that exhibit significant dose differences between groups. The VBA highlighted that:1.significant dose differences between patients with and without RP are found in the lower part of the lungs and in the heart, independently from the RP severity threshold used for patients’ grouping;2.PSPT significantly reduced dose to healthy tissue in the medial-anterior and upper parts of the thorax;3.the regions spared by PSPT and the clusters with doses significantly correlated to RP development are disjoint. In particular, the mean dose differences between PSPT and IMRT in the clusters of voxel associated with the RP development are not significant (p=0.39 and p=0.51 for clusters derived for any CTCAE-grade RP and symptomatic RP, respectively). The analyzed trial data provided a valuable opportunity to substantiate previously reported hypotheses on the prominent role of the lower parts of the lungs in the development of RP. Most importantly, the VBA of dose distribution associated to treatment modality showed that the tissues significantly spared by PSPT seemed not strongly sensitive for RP development. This could solve the seeming inconsistency between V5 distribution and RP incidence in the studied trial. The relationship between RP and thoracic regional radio-sensitivity should be considered in clinical practice and in the design of future trials.

Phase II Trial of Intensity-Modulated Photon or Scanning Beam Proton Therapy Both with Simultaneous Integrated Boost Dose Escalation to the Gross Tumor Volume with Concurrent Chemotherapy for Stage II/III Non-Small Cell Lung Cancer - Interim Analysis

Multiple studies have shown that high doses, with a biologic effective dose (BED) >100Gy, are required to control tumors in lung tissue. However, delivering high doses is difficult given the location and surrounding tissues at risk such as esophagus, heart and brachial plexus. One way to avoid toxicity is to deliver higher doses to the gross tumor volume (GTV) while keep the PTV dose at standard of 60Gy during the same fraction by using a simultaneous integrated boost (SIB) technique. Intensity modulated photon-based radiation therapy (IMRT) or intensity modulated and energy modulated proton beam therapy (IMPT) techniques allow us to deliver this. We conducted a phase II randomized study to compare IMRT vs. IMPT with concurrent chemotherapy in stage II-IIIB NSCLC patients. Patients with stage II-IIIB NSCLC were randomized to either receiving IMRT or IMPT with an SIB and concurrent chemotherapy. The PTV dose was 60 Gy in 2Gy Relative Biological Effectiveness (RBE) per fraction and the SIB dose was 66-72 Gy (RBE) in 2.2-2.4 Gy (RBE) per fraction. Primary endpoints include assessing and comparing grade III acute toxicity and local progression-free survival (LPFS), calculated from the first day of concurrent chemotherapy. Additionally, we also compared rates of acute toxicity to our prior randomized study data using IMRT and passive scattering proton therapy (PSPT) to 74 Gy in 34 fractions. Statistical analysis included descriptive statistics, Cox regression, and Kaplan-Meier survival. A total of 37 patients received IMRT SIB and 19 patients received IMPT SIB. Grade ≥3 radiation related toxicities (esophagitis, pneumonitis, dermatitis) were observed in 8% (n=3) in IMRT SIB and 0% (n=0) in IMPT SIB patients (p=0.001), which compared favorably with prior randomized trial results of IMRT (any Grade ≥3 toxicity: 21%) vs. PSPT (any Grade ≥3 toxicity: 26%). Specifically, the Grade ≥3 pneumonitis (RP) was 3% and 0% after IMRT SIB and IMPT SIB, respectively (p=0.519). The RP rates compared favorably with our prior trial results, Grade ≥3 RP was 6.5% (p=0.10) and 10.5% (p=0.33) after IMRT and PSPT, respectively. The rates of any Grade ≥3 hematologic toxicities were 8% and 16% after IMRT SIB and IMPT SIB, respectively (p<0.001). This also compared favorably to 79% and 65% after IMRT and PSPT from prior trial data (p<0.001), respectively. Local failure rates at 3 years were 26.5% and 11.1% after IMRT SIB and IMPT SIB, respectively (p=0.472). Median LPFS was 69.77 months for IMRT patients and 67.60 months for IMPT patients (p=0.816). Interim analysis shows that locally advanced NSCLC patients treated in a randomized fashion in this phase II trial had significantly improved acute toxicities compared to our historic data.

Preliminary Report of Secondary Malignant Neoplasm Incidence in Pediatric Patients Receiving Proton versus Photon Craniospinal Irradiation for Medulloblastoma

Modeling studies have predicted fewer secondary malignant neoplasms (SMN) following treatment with proton beam therapy (PBT) compared to photon radiotherapy (XRT). However, there are concerns regarding secondary neutron production and possible associated excess SMN with passive scatter proton therapy (PSPT) compared to pencil beam proton therapy. We reviewed our multi-institutional experience treating pediatric medulloblastoma (MB) patients with craniospinal irradiation (CSI) using either XRT or PBT. We hypothesized that excess SMN would not be observed among patients treated with PBT. From 1996 to 2014, 166 patients with MB received CSI followed by tumor bed boost using either PSPT (n = 103) or XRT (n = 63). For the proton cohort, all patients received PSPT for the CSI portion and 93.9% received PSPT for the boost. For XRT patients, all received 3-D conformal RT CSI followed by an IMRT tumor bed boost. Median age was 8.0 years at time of radiotherapy (RT), (8.0 years PBT, 8.1 years XRT). A majority of patients were male (112/166, 67.5%) and a majority had standard-risk MB (102/166, 61.4%). Median follow-up was 78.5 months for the PBT cohort and 153.2 months for the XRT cohort (p < 0.001). The 5- and 10-year overall survival rates were 82.6% and 81.2% for standard-risk and 69.8% and 64.0% for high-risk patients, respectively. No OS difference was identified by RT modality (p=0.49). The 5- and 10-year actuarial SMN rate was 2.3% and 8.1% for the entire study population (N=166). By modality, 5- and 10-year SMN rates were 2.6% and 6.0% for PBT patients, and 0.0% and 8.0% for XRT patients (p=0.71). There was no difference in incidence of SMN according to age (p=0.99), gender (p=0.50) or CSI dose (p=0.61). There were a total of 8 SMN identified in total (4 in each cohort by RT modality), with a median time from RT completion to SMN diagnosis of 71.2 months (range: 5.8 - 145.6 months). Breaking down SMNs by histology, there were 3 sarcomas, 2 malignant gliomas, 1 papillary thyroid cancer, 1 parotid mucoepidermoid carcinoma, and 1 cerebellar malignant glioneuronal tumor. All 4 SMNs in the PBT cohort occurred either within the previously-irradiated target (n=2), or in the entrance dose region (n=2). For XRT patients, 3 SMN occurred in regions receiving exit dose while 1 was within the target. Our preliminary analysis demonstrates no difference in the rate of SMN between PBT-treated and XRT-treated patients up to 10 years following RT. Given the shorter follow-up time for PBT patients, longer-term follow-up remains necessary to understand differential SMN patterns across RT modalities better. It is notable that XRT-treated patients developed a higher rate of SMNs in regions of exit dose than in the target volume.

Hemoglobin Level during Radiotherapy Predicts Survival Outcomes after Radiochemotherapy for Stage III Non-Small Cell Lung Cancer

Low hemoglobin (Hgb) levels have been linked with poor prognosis in various malignancies including non-small cell lung cancer (NSCLC). Here we tested the hypothesis that low Hgb levels during radiochemotherapy for stage III NSCLC are associated with lower rates of overall survival (OS), disease-free survival (DFS), and distant metastasis(DM). We retrospectively reviewed Hgb levels before and during definitive radiochemotherapy (radiation dose ≥60 Gy) in 189 patients with inoperable stage III NSCLC. Seventy-nine (42%) patients were treated with 3D conformal radiotherapy (3DCRT), 85 (45%) with intensity-modulated radiotherapy (IMRT), and 24 (13%) with passive scattering proton therapy (PSPT), 1 patient received PSPT and IMRT sequentially. Eighty-one patients (43%) received induction chemotherapy. We calculated Hgb means before and during treatment and analyzed the changes in these values. Potential associations between mean Hgb levels during treatment and rates of OS, DM, and DFS were analyzed with Cox proportional hazards models. Mean Hgb levels before and during treatment for all patients were 13.2 g/dL (range 8.2−17.4) and 11.5 g/dL (range 8.6−14.7). Hgb decreased in most patients during treatment (mean difference 2.1 g/dL [range 0.5−6.9]). The median follow-up time was 21.3 months (range 2.8–121.4). In univariate analyses, mean Hgb levels were found to be associated with OS (hazard ratio [HR] 0.856, 95% confidence interval [CI] 0.750–0.977, P=0.021), DFS (HR 0.818, 95% CI 0.711–0.941,P=0.005), and DM (HR 0.786, 95% CI 0.668–0.924, P=0.004). Gross tumor volume (GTV) and tumor histology were also associated with survival outcomes and applied in multivariate analysis. Mean Hgb level was still significantly associated with OS (HR 0.871, 95% CI 0.763–0.994, P=0.041), DFS (HR 0.853, 95% CI 0.739–0.985,P=0.03), and DM (HR 0.837, 95% CI 0.709–0.988, P=0.035) after adjustment for GTV and histology. Hgb decreased during radiotherapy. Low Hgb levels during treatment predicted poorer OS, DFS, and DM in patients with stage III NSCLC. Monitoring Hgb levels during radiotherapy in large multi-center studies is recommended to validate the role of Hgb and to select threshold values.

Applying a variable relative biological effectiveness (RBE) might affect the analysis of clinical trials comparing photon and proton therapy for prostate cancer

The purpose of this study was the evaluation of the impact of a variable relative biological effectiveness (RBE) compared to a constant RBE value of 1.1 in proton therapy prostate trials due to uncertainties in α/β ratio.Twenty patients receiving passive scattered proton therapy (PSPT) and fifteen patients receiving intensity modulated proton therapy (IMPT) were compared to twenty patients treated with 7-field intensity modulated photon therapy (IMRT). For proton beam therapy (PBT), the RBE was estimated using two different RBE models. Tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP) were assessed.For one of the RBE models, dosimetric indices assuming a low α/β were ~10%–11% larger compared to using a fixed RBE. A different model resulted in 1%–3% lower values independent of α/β. Comparing PBT with IMRT revealed a negligible difference in TCP for a fixed RBE. Applying a variable RBE revealed an increase in TCP by 6% for PBT compared to IMRT for one model but a decrease of 2% for the other. Variable RBE values in PSPT resulted in an increase in NTCP for rectum from 7% to 11% for a fixed RBE with one model but a decrease to 6% for another. For IMPT, NTCP increased from 5% to 9% for a fixed RBE for one model but decreased to 3% using the other. The NTCP for bladder increased for PSPT for both models, from 11% to 19% and 14%, respectively. For IMPT, the NTCP increased from 12% to 17% using one model but decreased to 11% with the other.In radiation therapy for prostate cancer, disregarding variable RBE may lead to either underestimation or overestimation of the expected TCP and NTCP, depending on the RBE model and α/β. This should be considered when estimating uncertainties when comparing PBT and IMRT outcomes in clinical trials.

Hydrogel Spacer Reduces Rectal Dose during Proton Therapy for Prostate Cancer: A Dosimetric Analysis.

Proton therapy for prostate cancer may reduce bowel dose and risk of bowel symptoms relative to photon-based methods. Here, we determined the effect of using a biodegradable, injectable hydrogel spacer on rectal dose on plans for treating prostate cancer with intensity-modulated proton therapy (IMPT) or passive scattering proton therapy (PSPT). Pairs of IMPT and PSPT plans for 9 patients were created from fused computed tomography/magnetic resonance imaging scans obtained before and after spacer injection. Calculated values of rectal V40, V60, V70, V80, and maximum dose (Dmax) were compared with Wilcoxon signed rank tests. Displacements at the base (BP), midgland (MP), and apex (AP) of the prostate relative to the anterior rectal wall with the spacer in place were averaged for each patient and correlated with V70 by using linear regression models. The presence of a spacer reduced all dosimetric parameters for both PSPT and IMPT, with the greatest difference in V70, which was 81.1% lower for PSPT-with-spacer than for IMPT-without-spacer. Median displacements at BP, MP, and AP were 12 mm (range 7-19), 2 mm (range 0-4), and 1 mm (range 0-5) without the spacer and 19 mm (range 12-23), 10 mm (range 8-16), and 7 mm (range 2-12) with the spacer. Modest linear trends were noted between rectal V70 and displacement for IMPT-with-spacer and PSPT-with-spacer. When displacement was ≥8 mm, V70 was ≤5.1% for IMPT-with-spacer and PSPT-with-spacer. Use of biodegradable hydrogel spacers for prostate cancer treatment provides a significant reduction of radiation dose to the rectum with proton therapy. Significant reductions in rectal dose occurred in both PSPT and IMPT plans, with the greatest reduction for IMPT-with-spacer relative to PSPT alone. Prospective studies are ongoing to assess the clinical impact of reducing rectal dose with hydrogel spacers.

Spatial Dose Patterns Associated With Radiation Pneumonitis in a Randomized Trial Comparing Intensity-Modulated Photon Therapy With Passive Scattering Proton Therapy for Locally Advanced Non-Small Cell Lung Cancer

Radiation pneumonitis (RP) is commonly associated with thoracic radiation therapy, and its incidence is related to dose and volume of the normal lung in the path of radiation. Our aim was to investigate dose patterns associated with RP in patients enrolled in a randomized trial of intensity modulated radiation therapy (IMRT) versus passive scattering proton therapy (PSPT) for locally advanced non-small cell lung cancer. We analyzed 178 patients prospectively treated with PSPT or IMRT for non-small cell lung cancer to a prescribed dose of 66 or 74Gy in conventional daily fractionation with concurrent chemotherapy. Forty patients (22%) developed clinically symptomatic RP. Voxel-based analysis of local dose differences was done with a nonparametric permutation test accounting for multiple comparisons. From the obtained 3-dimensional significance maps, we derived clusters of voxels that exhibited dose differences between groups at a statistical significance level of 0.05. The voxel-based analysis highlighted that (1) significant dose differences between patients with and without RP were found in the lower part of the lungs and in the heart and (2) the anatomic regions significantly spared by PSPT and the clusters in which doses were significantly correlated with RP development were disjoint. The analyzed trial data provide an unprecedented opportunity to substantiate previous hypotheses regarding the role of the heart and the lower lungs in the development of RP. Knowledge of this relationship between RP and thoracic regional radiosensitivity should be considered in clinical practice and in the design of future trials.

Serum Testosterone 60 Months after Passive-Scatter Proton Therapy for Localized Prostate Cancer

Studies demonstrate a decline of ∼10% in serum testosterone (ST) level after X-ray radiotherapy for prostate cancer. We evaluated changes in ST for patients with low- and intermediate-risk prostate cancer receiving 70-82Gy(RBE) using passive-scatter proton therapy (PT). ST was checked at baseline (n = 358) and at 60+ months after PT (n = 166). The median baseline ST was 363.3 ng/dl (range, 82.0–974.0). The median ST 5 years after PT was 391.5 ng/dl (range, 108.0–1061.0). The difference was not statistically significant (p = 0.9341). Passive-scatter PT was not associated with testosterone suppression at 5 years, suggesting that protons may cause less out-of-field scatter radiation than X-rays.

Influence and Countermeasure of Respiratory Motion on Matchline Profile of Field Matching Technique in Passive Scattering Proton Therapy for Esophageal Cancer

This study aimed to evaluate the influence of change in respiratory motion on matchline (ML) and reduction of the effect by increasing ML levels of field matching technique in passive scattering proton therapy for esophageal cancer. To evaluate the influence of respiratory motion in terms of stability, we measured relative dose around ML using a respiratory motion phantom. The relative error was -0.5% when the respiratory motion phantom worked stable, whereas there was obvious change that the relative error was -25.5% when the difference of amplitude between upper field and lower field was one side 3 mm on each cranially and caudally direction. In clinical case of the seven esophageal cancer patients simulated by the treatment planning system, assuming the difference of amplitude was 3 mm, the relative error of maximum (minimum) dose in clinical target volume around ML against the original treatment plan were 5.8±1.2% (-6.0±2.7%), 3.3±0.9% (-3.8±1.0%), and 2.4±0.5% (2.6±0.8%) on average (±SD) when ML levels were 2, 4, and 6, respectively. Increasing ML levels can reduce the influence of respiratory motion.

Effect of anatomical change on dose distribution during radiotherapy for maxillary sinus carcinoma: passive scattering proton therapy versus volumetric-modulated arc therapy.

Objective:Maxillary sinus carcinomas are anatomically situated next to many organs at risk (OARs), and anatomical change is often observed during radiotherapy. We analyzed the effect of anatomical change on dose distribution of passive scattering proton therapy (PSPT) and volumetric-modulated arc therapy (VMAT) for 20 patients.Methods:The first plans were generated based on the first CT images. The second CT images were acquired after 3 weeks, and the second plans were generated by copying the first plans to the second CT images. The effect of anatomical change was estimated by comparing both plans.Results:Target volume change was observed in all cases, however, the influence on dose coverage of clinical target volume tended to be small. Alternatively, the doses to almost all OARs were increased. In particular, the increase in the dose to brainstem (p < 0.001) and optic chiasm (p < 0.001) was significantly higher in the second PSPT plan than in the first PSPT plan. Although PSPT is sensitive to anatomical change, the dose to OARs remained significantly lower in PSPT plans than that in VMAT plans.Conclusion:PSPT was confirmed to be more effective than VMAT even the effect of anatomical change was taken into account. Therefore, it is expected that the contralateral vision can be preserved reliably while optimal target coverage is provided.Advances in knowledge:PSPT allowed significant sparing of OARs even in the result of the second plans affected by the anatomical change. PSPT offers benefits over VMAT in reducing dose to several OARs.

Validation of Effective Dose as a Better Predictor of Radiation Pneumonitis Risk Than Mean Lung Dose: Secondary Analysis of a Randomized Trial

To confirm the superiority of effective dose (Deff) over mean lung dose (MLD) for predicting risk of radiation pneumonitis (RP), using data from patients on a randomized trial of intensity modulated radiation therapy (IMRT) versus passively scattered proton therapy (PSPT). The prescribed target dose for the 203 evaluated patients was 66 to 74Gy (relative biological effectiveness) in 33 to 37 fractions with concurrent carboplatin/paclitaxel. Time to grade ≥2 RP was computed from the start of radiation therapy, with disease recurrence or death considered censoring events. Generalized Lyman models of censored time to RP were constructed with MLD or Deff as the dosimetric parameter. Smoking status (current, former, never) was also analyzed. Of the 203 patients, 46 experienced grade ≥2 RP (crude incidence 23%) at a median 3.7months (range, 0.6-12.6months). The volume parameter estimated for the Deff model was n=0.5, confirming estimates from earlier studies. Compared with MLD (in which n=1), the dosimetric parameter Deff, computed using n=0.5, resulted in a better fit of the Lyman model to the clinical data (P=.010). Using Deff, the model describes RP risk for IMRT and PSPT data combined because no further improvement was found from separate fits (P=.558). Based on Deff, predicted RP risk per patient ranged from 24 percentage points lower to 19 percentage points higher than predictions based on MLD. For patients with similar MLD, Deff predicted higher risk, on average, for PSPT over IMRT. Current smokers had a lower risk of RP compared with former smokers and nonsmokers (P=.021). We used data from a randomized trial to validate our previous finding that Deff with n=0.5 (corresponding to root mean squared dose) is a better predictor of RP than is MLD. Differences between Deff and MLD indicate that delivering higher doses to smaller lung volumes (vs lower doses to larger volumes) increases RP risk. We further corroborated that current smoking is associated with decreased RP risk.

Investigation on Patient/Compensator Scatter Factor for Monitor Unit Calculation in Proton Therapy.

Purpose:It is the goal of this study to use both Monte Carlo (MC) simulation and the pencil beam dose algorithm (PBA) in the treatment planning system to investigate Patient scatter factor (PSF) and Compensator scatter factor (CSF) for calibrating the dose per monitor unit (DMU) for a passive scattering proton therapy system.Materials and Methods: PSFs and CSFs for brain, lung, pancreas, and prostate treatment sites were calculated by using MC simulation and PBA from the treatment planning software to evaluate the agreement between the two.Results:This study shows that the CSF values are always greater than 1, with some reaching nearly 4% above unity, and depending strongly on the shape of the compensator. Monte Carlo and PBA-calculated CSF factors agree very well, with average differences below 1%. PSF values calculated in this study ranged from 0.919 to 1.023 and are largely dependent on the type of tissue heterogeneities in the treatment field. Monte Carlo and PBA-calculated PSF factors show differences, with the largest discrepancies seen in lung cases, with an average difference of 1.9%. It is also shown that dense bone will drive a PSF to values greater than unity, while large quantities of air decrease the PSF to below unity.Conclusion:We have showed that the compensator and patient anatomy can have a significant impact on clinical proton dose distribution. It is recommended that both Monte Carlo and treatment planning system should be used to take these factors into account in the final DMU calculation.

Patterns of Local-Regional Failure After Intensity Modulated Radiation Therapy or Passive Scattering Proton Therapy With Concurrent Chemotherapy for Non-Small Cell Lung Cancer

We compared differences in patterns of locoregional failure, and the influence of adaptive planning on those patterns, in patients who received passive scattering proton therapy (PSPT) versus intensity modulated photon therapy (IMRT) for non-small cell lung cancer. Treatment simulation computed tomography scans and dose distributions were registered with images depicting the recurrence. Local failure (LF) was defined as failure within the internal target volume (ITV); marginal failure (MF) as failure between the ITV and planning target volume (PTV) plus a 10-mm margin (PTV+10mm); and regional failure (RF) as outside the PTV+10mm. Weekly during-treatment 4-dimensional computed tomography simulation and verification plans were obtained for all patients. Adaptive plans were developed if the verification plan showed deviations in protocol-specified dose distribution, and failure locations were recorded for those patients as well. Of the 212 patients analyzed, most (152 [72%]) had no failure; of the 60 patients with failure, 27 (45%) had LF (within the ITV), 23 (38%) had MF (between the ITV and PTV+10mm), and 10 (17%) had RF (>10mm outside the PTV). MF rates were no different for IMRT patients (16 of 136 [12%]) or PSPT patients (7 of 76 [9%], log-rank P=.558). The only independent predictor of MF on Cox proportional hazards analysis was T3-4 status. Large tumors and use of PSPT independently predicted the need for adaptive planning. Although 5-year overall survival rates were poorer for patients with large tumors versus small tumors (P<.001), the rates were similar for patients with large tumors who received adaptive planning versus small tumors. No differences in LF, MF, or RF patterns were found for IMRT versus PSPT. Proton therapy more often required adaptive planning, and the techniques used for adaptive planning did not compromise tumor control. Response to chemoradiation by larger tumors predicted favorable survival.

Independent application of an analytical model for secondary neutron equivalent dose produced in a passive-scattering proton therapy treatment unit

The purpose of this study was to independently apply an analytical model for equivalent dose from neutrons produced in a passive-scattering proton therapy treatment unit, H. To accomplish this objective, we applied the previously-published model to treatment plans of two pediatric patients. Their model accounted for neutrons generated by mono-energetic proton beams stopping in a closed aperture. To implement their model to a clinical setting, we adjusted it to account for the area of a collimating aperture, energy modulation, air gap between the treatment unit and patient, and radiation weighting factor. We used the adjusted model to estimate H per prescribed proton absorbed dose, DRx, for the passive-scattering proton therapy beams of two children, a 9-year-old girl and 10-year-old boy, who each received intracranial boost fields as part of their treatment. In organs and tissues at risk for radiation-induced subsequent malignant neoplasms, T, we calculated the mass-averaged H, HT, per DRx. Finally, we compared HT/DRx values to those of previously-published Monte Carlo (MC) simulations of these patients’ fields. HT/DRx values of the adjusted model deviated from the MC result for each organ on average by 20.8 ± 10.0% and 44.2 ± 17.6% for the girl and boy, respectively. The adjusted model underestimated the MC result in all T of each patient, with the exception of the girl’s bladder, for which the adjusted model overestimated HT/DRx by 3.1%. The adjusted model provided a better estimate of HT/DRx than the unadjusted model. That is, between the two models, the adjusted model reduced the deviation from the MC result by approximately 37.0% and 46.7% for the girl and boy, respectively. We found that the previously-published analytical model, combined with adjustment factors to enhance its clinical applicability, predicted HT/DRx in out-of-field organs and tissues at risk for subsequent malignant neoplasms with acceptable accuracy. This independent application demonstrated that the analytical model may be useful broadly for clinicians and researchers to calculate equivalent dose from neutrons produced externally to the patient in passive-scattering proton therapy.

Pencil beam scanning versus passively scattered proton therapy for unresectable pancreatic cancer.

With an increasing number of proton centers capable of delivering pencil beam scanning (PBS), understanding the dosimetric differences in PBS compared to passively scattered proton therapy (PSPT) for pancreatic cancer is of interest. Optimized PBS plans were retrospectively generated for 11 patients with locally advanced pancreatic cancer previously treated with PSPT to 59.4 Gy on a prospective trial. The primary tumor was targeted without elective nodal coverage. The same treatment couch, target coverage and normal tissue dose objectives were used for all plans. A Wilcoxon t-test was performed to compare various dosimetric points between the two plans for each patient. All target volume coverage goals were met in all PBS and passive scattering (PS) plans, except for the planning target volume (PTV) coverage goal (V100% >95%) which was not met in one PS plan (range, 81.8-98.9%). PBS was associated with a lower median relative dose (102.4% vs. 103.8%) to 10% of the PTV (P=0.001). PBS plans had a lower median duodenal V59.4 Gy (37.4% vs. 40.4%; P=0.014), lower small bowel median V59.4 Gy (0.11% vs. 0.37%; P=0.012), lower stomach median V59.4 Gy (0.01% vs. 0.1%; P=0.023), and lower median dose to 0.1 cc of the spinal cord {35.0 vs. 38.7 Gy [relative biological effectiveness (RBE)]; P=0.001}. Liver dose was higher in PBS plans for median V5 Gy (24.1% vs. 20.2%; P=0.032), V20 Gy (3.2% vs. 2.8%; P=0.010), and V25 Gy (2.6% vs. 2.2%; P=0.019). There was no difference in kidney dose between PBS and PS plans. Proton therapy for locally advanced pancreatic cancer using PBS was not clearly associated with clinically meaningful reductions in normal tissue dose compared to PS. Some statistically significant improvements in PTV coverage were achieved using PBS. PBS may offer improved conformality for the treatment of irregular targets, and further evaluation of PBS and PS incorporating elective nodal irradiation should be considered.

Prognostic factors of radiation dermatitis following passive-scattering proton therapy for breast cancer

BackgroundTo identify prognostic factors for grade 3 radiation dermatitis following passive-scattering proton therapy for breast cancer.MethodsThis retrospective study included data on 23 (11 post-mastectomy and 12 post-lumpectomy) breast cancer patients who underwent proton therapy with the passive scattering technique in our institute from 2012 to 2016. Each patient received 50–50.4 cobalt Gy equivalent (CGE) at 1.8 or 2 CGE per daily fraction. Logistic regression analysis was performed to identify prognostic factors for grade 3 skin toxicity. Receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) were used to evaluate the performance of the models.Results43% of the studied patients developed grade 3 radiation dermatitis. The dose-volume histogram (DVH) parameters of V52.5CGE and D10cm3 to skin5mm were correlated with grade 3 radiation dermatitis in both univariate and multivariate logistic regression analyses. Univariate logistic regression analysis suggested that D10cm3 to skin5mm (AUC = 0.69) and V52.5CGE to skin5mm (AUC = 0.70) were prognostic for grade 3 skin toxicity. The models using the combination of D10cm3 to skin5mm or V52.5CGE to skin5mm with breast volume marginally increased the AUC to 0.72 and 0.73, respectively. Models using the combination of D10cm3 to skin5mm or V52.5CGE to skin5mm with history of smoking increased the AUC to 0.75 and 0.83, respectively.ConclusionIn the current study, we identified prognostic factors for grade 3 radiation dermatitis in patients treated with passive-scattering proton therapy for breast cancer. This study provides promising tool for identifying high risk patients for whom treatment plan adjustment could be done to reduce the risk of radiation-induced grade 3 skin toxicity.

Considerations when treating lung cancer with passive scatter or active scanning proton therapy.

Lung cancer, due to its poor clinical outcomes and significant toxicity associated with standard photon-based radiation, is a disease site that has the potential to greatly benefit from accurate treatment with proton radiation therapy. The potential of proton therapy is the ability to increase the radiation dose to the tumor while simultaneously decreasing the radiation dose to surrounding healthy tissues. For lung cancer treatment, this could mean significant sparing of the uninvolved healthy lung, which is difficult to achieve with external photon beam therapy, or decreasing the heart dose. In treating lung cancer with proton therapy, some additional considerations need to be made compared to treating patients with external photon beam radiation therapy. These include accounting for the finite range of protons in the patient, understanding temporal effects, potential dose discrepancies and choosing an appropriate treatment planning system for the task. One final consideration is differences between the different available proton therapy delivery systems-passive scattered proton therapy (PSPT) and active scanning proton therapy.

A machine learning approach to the accurate prediction of monitor units for a compact proton machine.

Clinical treatment planning systems for proton therapy currently do not calculate monitor units (MUs) in passive scatter proton therapy due to the complexity of the beam delivery systems. Physical phantom measurements are commonly employed to determine the field-specific output factors (OFs) but are often subject to limited machine time, measurement uncertainties and intensive labor. In this study, a machine learning-based approach was developed to predict output (cGy/MU) and derive MUs, incorporating the dependencies on gantry angle and field size for a single-room proton therapy system. The goal of this study was to develop a secondary check tool for OF measurements and eventually eliminate patient-specific OF measurements. The OFs of 1754 fields previously measured in a water phantom with calibrated ionization chambers and electrometers for patient-specific fields with various range and modulation width combinations for 23 options were included in this study. The training data sets for machine learning models in three different methods (Random Forest, XGBoost and Cubist) included 1431 (~81%) OFs. Ten-fold cross-validation was used to prevent "overfitting" and to validate each model. The remaining 323 (~19%) OFs were used to test the trained models. The difference between the measured and predicted values from machine learning models was analyzed. Model prediction accuracy was also compared with that of the semi-empirical model developed by Kooy (Phys. Med. Biol. 50, 2005). Additionally, gantry angle dependence of OFs was measured for three groups of options categorized on the selection of the second scatters. Field size dependence of OFs was investigated for the measurements with and without patient-specific apertures. All three machine learning methods showed higher accuracy than the semi-empirical model which shows considerably large discrepancy of up to 7.7% for the treatment fields with full range and full modulation width. The Cubist-based solution outperformed all other models (P<0.001) with the mean absolute discrepancy of 0.62% and maximum discrepancy of 3.17% between the measured and predicted OFs. The OFs showed a small dependence on gantry angle for small and deep options while they were constant for large options. The OF decreased by 3%-4% as the field radius was reduced to 2.5cm. Machine learning methods can be used to predict OF for double-scatter proton machines with greater prediction accuracy than the most popular semi-empirical prediction model. By incorporating the gantry angle dependence and field size dependence, the machine learning-based methods can be used for a sanity check of OF measurements and bears the potential to eliminate the time-consuming patient-specific OF measurements.

Exradin W1 plastic scintillation detector for in vivo skin dosimetry in passive scattering proton therapy

In vivo skin dosimetry is desirable in passive scattering proton therapy because of the possibility of high entrance dose with a small number of fields. However, suitable detectors are needed to determine skin dose in proton therapy. Plastic scintillation detectors (PSDs) are particularly well suited for applications in proton therapy because of their water equivalence, small size, and ease of use. We investigated the utility of the Exradin W1, a commercially available PSD, for in vivo skin dosimetry during passive scattering proton therapy. We evaluated the accuracy of the Exradin W1 in six patients undergoing proton therapy for prostate cancer, as part of an Institutional Review Board-approved protocol. Over 22 weeks, we compared in vivo PSD measurements with in-phantom ionization chamber measurements and doses from the treatment planning system, resulting in 96 in vivo measurements. Temperature and ionization quenching correction factors were applied on the basis of the dose response of the PSD in a phantom. The calibrated PSD exhibited an average 7.8% under-response (±1% standard deviation) owing to ionization quenching. We observed 4% under-response at 37 °C relative to the calibration-temperature response. After temperature and quenching corrections were applied, the overall PSD dose response was within ±1% of the expected dose for all patients. The dose differences between the PSD and ionization chamber measurements for all treatment fields were within ±2% (standard deviation 0.67%). The PSD was highly accurate for in vivo skin dosimetry in passively scattered proton beams and could be useful in verifying proton therapy delivery.

Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer.

Purpose This randomized trial compared outcomes of passive scattering proton therapy (PSPT) versus intensity-modulated (photon) radiotherapy (IMRT), both with concurrent chemotherapy, for inoperable non-small-cell lung cancer (NSCLC). We hypothesized that PSPT exposes less lung tissue to radiation than IMRT and thereby reduces toxicity without compromising tumor control. The primary end points were grade ≥ 3 radiation pneumonitis (RP) and local failure (LF). Patients and Methods Eligible patients had stage IIB to IIIB NSCLC (or stage IV NSCLC with a single brain metastasis or recurrent lung or mediastinal disease after surgery) who were candidates for concurrent chemoradiation therapy. Pairs of treatment plans for IMRT and PSPT were created for each patient. Patients were eligible for random assignment only if both plans satisfied the same prespecified dose-volume constraints for at-risk organs at the same tumor dose. Results Compared with IMRT (n = 92), PSPT (n = 57) exposed less lung tissue to doses of 5 to 10 Gy(RBE), which is the absorbed Gy dose multiplied by the relative biologic effectiveness (RBE) factor for protons; exposed more lung tissue to ≥ 20 Gy(RBE), but exposed less heart tissue at all dose levels between 5 and 80 Gy(RBE). The grade ≥ 3 RP rate for all patients was 8.1% (IMRT, 6.5%; PSPT, 10.5%); corresponding LF rates were 10.7% (all), 10.9% (IMRT), and 10.5% (PSPT). The posterior probability of IMRT being better than PSPT was 0.54. Exploratory analysis showed that the RP and LF rates at 12 months for patients enrolled before versus after the trial midpoint were 21.1% (before) versus 18.2% (after) for the IMRT group (P = .047) and 31.0% (before) versus 13.1% (after) for the PSPT group (P = .027). Conclusion PSPT did not improve dose-volume indices for lung but did for heart. No benefit was noted in RP or LF after PSPT. Improvements in both end points were observed over the course of the trial.