Treatment-planning approaches to intensity modulated proton therapy and the impact on dose-weighted linear energy transfer.

PURPOSE: We quantified the effect of various forward-based treatment-planning strategies in proton therapy on dose-weighted linear energy transfer (LETd). By maintaining the dosimetric quality at a clinically acceptable level, we aimed to evaluate the differences in LETd among various treatment-planning approaches and their practicality in minimizing biologic uncertainties associated with LETd. METHOD: Eight treatment-planning strategies that are achievable in commercial treatment-planning systems were applied on a cylindrical water phantom and four pediatric brain tumor cases. Each planning strategy was compared to either an opposed lateral plan (phantom study) or original clinical plan (patient study). Deviations in mean and maximum LETd from clinically acceptable dose distributions were compared. RESULTS: In the phantom study, using a range shifter and altering the robust scenarios during optimization had the largest effect on the mean clinical target volume LETd, which was reduced from 4.5 to 3.9 keV/µm in both cases. Variations in the intersection angle between beams had the largest effect on LETd in a ring defined 3 to 5 mm outside the target. When beam intersection angles were reduced from opposed laterals (180°) to 120°, 90°, and 60°, corresponding maximum LETd increased from 7.9 to 8.9, 10.9, and 12.2 keV/µm, respectively. A clear trend in mean and maximum LETd variations in the clinical cases could not be established, though spatial distribution of LETd suggested a strong dependence on patient anatomy and treatment geometry. CONCLUSION: Changes in LETd from treatment-plan setup follow intuitive trends in a controlled phantom experiment. Anatomical and other patient-specific considerations, however, can preclude generalizable strategies in clinical cases. For pediatric cranial radiation therapy, we recommend using opposed lateral treatment fields to treat midline targets.

Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning.

PURPOSE: To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03. PATIENTS AND METHODS: Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline. RESULTS: One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all P < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all P < .05). Median brain substructure dose-volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively. CONCLUSION: Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure-informed RT planning may mitigate neurocognitive impairment.

Cardiac-Sparing and Breast-Sparing Whole Lung Irradiation Using Intensity-Modulated Proton Therapy.

PURPOSE: Whole lung irradiation (WLI) is indicated for certain pediatric patients with lung metastases. This study investigated whether WLI delivered as intensity-modulated proton therapy (IMPT) could significantly spare the heart and breasts when compared with conventional WLI delivered with anteroposterior/posteroanterior photon fields and with intensity-modulated photon therapy (IMRT) WLI. MATERIALS AND METHODS: Conventional, IMRT, and IMPT plans were generated for 5 patients (aged 5-22 years). The prescription dose was 16.5 GyRBE in 1.5-GyRBE fractions. Conventional plans used 6-MV photons prescribed to the midline and a field-in-field technique to cover the planning target volume (the internal target volume [ITV] + 1 cm). IMRT plans used 6-MV photons with a 7-beam arrangement with dose prescribed to the planning target volume. IMPT plans used scenario-based optimization with 5% range uncertainty and 5-mm positional uncertainty to cover the ITV robustly. Monte Carlo dose calculation was used for all IMPT plans. Doses were compared with paired Student t test. RESULTS: The ITV Dmean was similar for the IMPT, conventional, and IMRT plans, but the IMPT plans had a lower Dmin and a higher Dmax at tissue interfaces than conventional plans (Dmean ratio: 0.96, P > .05; Dmin ratio: 0.9, P < .001; Dmax ratio: 1.1, P = .014). Dmeans for breast and heart substructures were lower with IMPT plans than with conventional/IMRT plans (heart ratios, 0.63:0.73; left ventricle ratios, 0.61:0.72; right ventricle ratios, 0.45:0.57; left atrium ratios, 0.79:0.85; right atrium ratios, 0.81:0.86; left breast ratios, 0.40:0.51; right breast ratio, 0.46:0.52; all P < .05). CONCLUSIONS: IMPT resulted in comparable ITV coverage and lower mean doses to the heart and breasts when compared with other techniques. Whole lung irradiation delivered as IMPT warrants prospective evaluation in pediatric patients.

Adaptive Proton Therapy for Pediatric Patients: Improving the Quality of the Delivered Plan With On-Treatment MRI.

PURPOSE: Pencil-beam scanning proton therapy is particularly sensitive to anatomic changes, which may affect the delivered dose distribution. This study examined whether offline adaptation using on-treatment magnetic resonance imaging (MRI) scan during proton therapy could improve plan quality for pediatric patients. METHODS AND MATERIALS: Pediatric patients with at least 1 MRI scan in the treatment position (MRItx) during proton therapy between January 2017 and July 2019 were retrospectively reviewed. Patients underwent MRI and computed tomography simulation. Cases were planned with scenario-based optimization with 3 mm/3% positional/range uncertainty. Patients demonstrating anatomic change on MRItx were recontoured. The original plans were applied to the anatomy-of-the-day for dose recalculation (delivered plans). Plans were subsequently reoptimized offline, using original beam angles and dose-volume constraints (adapted plans). Delivered plans were compared with adapted plans to detect significant changes in plan quality, defined as a ≥5% decrease in the clinical target volume (CTV) receiving 95% of the prescription dose (V95) or a ≥5% increase in the dose-volume parameter used as an organ-at-risk constraint. RESULTS: Seventy-three pediatric patients were eligible, with 303 MRI scans (73 simulation and 230 MRItx scans) available for analysis. The median MRItx scans per patient was 3 (range, 1-7). Twenty patients (27%) showed anatomic change, with 11 (55%) demonstrating a significant change in delivered plan quality. Significant changes were noted on MRItx from week 2 (n = 3) or week 3 (n = 8). Seven of these 11 patients (64%) had a significantly reduced CTV V95 (median decrease, 7.6%; range, 5%-16%). Four (36%) had a significantly increased dose to the brain stem, hippocampus, and/or optic apparatus. Eight had a suprasellar low-grade glioma or head and neck rhabdomyosarcoma. CONCLUSION: On-treatment MRI was useful in detecting anatomic changes during proton therapy. MRI-based offline adaptation improved plan quality for most patients with anatomic changes. Further studies should determine the clinical value of MRI-based adaptive therapy for pediatric patients.

Influence of Target Location, Size, and Patient Age on Normal Tissue Sparing- Proton and Photon Therapy in Paediatric Brain Tumour Patient-Specific Approach.

BACKGROUND: Proton radiotherapy produces superior dose distributions compared to photon radiotherapy, reducing side effects. Differences between the two modalities are not fully quantified in paediatric patients for various intracranial tumour sites or age. Understanding these differences may help clinicians estimate the benefit and improve referral across available centres. Our aim was to compare intensity-modulated proton therapy (IMPT) and intensity-modulated photon radiotherapy (IMRT) radiation doses for select paediatric intracranial tumours. METHODS: IMPT and IMRT dose distributions for gender-matched paediatric cranial CT-datasets (ages 5, 9 and 13 years) were retrospectively calculated to simulate irradiation of supratentorial (ependymoma) and infratentorial (medulloblastoma) target volumes diameters (1-3 cm) and position (central and 1-2 cm shifts). RESULTS: Clinical dosimetric objectives were achieved for all 216 treatment plans. Whilst infratentorial IMPT plans achieved greater maximum dose sparing to optic structures (4.8-12.6 Gy optic chiasm), brainstem sparing was limited (~0.5 Gy). Mean dose difference for optic chiasm was associated with medulloblastoma target position (p < 0.0197). Supratentorial IMPT plans demonstrated greater dose reduction for the youngest patients (pituitary gland p < 0.001). CONCLUSIONS: Normal tissue sparing was achieved regardless of patient age for infratentorial tumours. However, for supratentorial tumours, there was a dosimetric advantage of IMPT across 9 vs. 13-year-old patients.

Interplay Effect of Target Motion and Pencil-Beam Scanning in Proton Therapy for Pediatric Patients.

PURPOSE: To investigate the effect of interplay between spot-scanning proton beams and respiration-induced tumor motion on internal target volume coverage for pediatric patients. MATERIALS AND METHODS: Photon treatments for 10 children with representative tumor motions (1-13 mm superior-inferior) were replanned to simulate single-field uniform dose- optimized proton therapy. Static plans were designed by using average computed tomography (CT) data sets created from 4D CT data to obtain nominal dose distributions. The motion interplay effect was simulated by assigning each spot in the static plan delivery sequence to 1 of 10 respiratory-phase CTs, using the actual patient breathing trace and specifications of a synchrotron-based proton system. Dose distributions for individual phases were deformed onto the space of the average CT and summed to produce the accumulated dose distribution, whose dose-volume histogram was compared with the one from the static plan. RESULTS: Tumor motion had minimal impact on the internal target volume hot spot (D2), which deviated by <3% from the nominal values of the static plans. The cold spot (D98) was also minimally affected, except in 2 patients with diaphragmatic tumor motion exceeding 10 mm. The impact on tumor coverage was more pronounced with respect to the V99 rather than the V95. Decreases of 10% to 49% in the V99 occurred in multiple patients for whom the beam paths traversed the lung-diaphragm interface and were, therefore, more sensitive to respiration-induced changes in the water equivalent path length. Fractionation alone apparently did not mitigate the interplay effect beyond 6 fractions. CONCLUSION: The interplay effect is not a concern when delivering scanning proton beams to younger pediatric patients with tumors located in the retroperitoneal space and tumor motion of <5 mm. Children and adolescents with diaphragmatic tumor motion exceeding 10 mm require special attention, because significant declines in target coverage and dose homogeneity were seen in simulated treatments of such patients.