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Purpose Radiation-induced optic neuropathy (RION) is a rare, yet severe complication following radiation therapy for brain, head and neck, or skull-base tumors. Although several risk factors, such as age, metabolic syndrome, and delivered dose, have been identified, we aimed at expanding the understanding of the mechanisms of interplay regarding dosimetry and patient variables leading to the onset of RION with a focus on proton therapy. Methods and Materials In this retrospective study, we have investigated proton-specific risk factors by comparing common phenomenological normal tissue complication probability models with a multivariate analysis that includes clinical features on a cohort of patients with skull-base and head and neck cancer treated with pencil beam scanning. Results Although predictive power of the Lyman-Kutcher-Burman and Poisson models was limited for this data set, the addition of clinical variables such as age, tumor involvement, hypertension, or sex remarkably increased model performance. Conclusions Based on our assessment, the maximum dose in the optical apparatus is confirmed the most intuitive risk factor. However, above a certain dose threshold, clinical patient characteristics are the deciding factors for the onset of RION. We observed a tendency toward a volume effect that, if confirmed, would imply a benefit for high precision radiation therapy techniques such as proton therapy for the treatment of patients with high clinical risk for RION.

Purpose: The accuracy of analytical dose calculations (ADC) and dose uncertainties resulting from anatomical changes are both limiting factors in proton therapy. For the latter, rapid plan adaption is necessary; for the former, Monte Carlo (MC) approaches are increasingly recommended. These, however, are inherently slower than analytical approaches, potentially limiting the ability to rapidly adapt plans. Here, we compare the clinical relevance of uncertainties resulting from both. Methods and Materials: Five patients with non-small cell lung cancer with up to 9 computed tomography (CT) scans acquired during treatment and five paranasal (head and neck) patients with 10 simulated anatomical changes (sinus filling) were analyzed. On the initial planning CT scans, treatment plans were optimized and calculated using an ADC and then recalculated with MC. Additionally, all plans were recalculated (non-adapted) and reoptimized (adapted) on each repeated CT using the same ADC as for the initial plan, and the resulting dose distributions were compared. Results: When comparing analytical and MC calculations in the initial treatment plan and averaged over all patients, 94.2% (non-small cell lung cancer) and 98.5% (head and neck) of voxels had differences

Purpose To evaluate the efficacy and safety of high-dose pencil-beam scanning proton therapy (PBS-PT) in the adjuvant treatment of spinal chordomas. Methods and Materials Between 1997 and 2015, 100 patients with spinal chordomas (median age, 56 years; range, 25-81 years) were treated with adjuvant PBS-PT at the Paul Scherrer Institute: cervical (n = 46), thoracic (n = 4), lumbar (n = 12), and sacral (n = 38). The majority (88%) received PBS-PT alone rather than combined photon–proton therapy. The median radiation therapy dose prescribed was 74 Gy (relative biological effectiveness [RBE]) (range, 59.4-77 Gy [RBE]). Thirty-nine patients (39%) had undergone surgical stabilization, primarily with titanium hardware, before radiation therapy. Results With a median follow-up of 65 months (range, 13-175 months), 5-year local control, disease control, and overall survival rates were 63% (95% confidence interval [CI] 57.7-68.7%; median, 103 months), 57% (95% CI 50.9-62.1%; median, 82 months), and 81% (95% CI 76.8-85.6%; median, 157 months), respectively. On univariate and multivariate analyses, the presence of surgical stabilization was highly prognostic for worsened outcomes. Multivariate analysis also revealed the extent of treatment volumes and presence of gross residual disease to be important in predicting outcomes. High-grade (grade ≥3) toxicities were rare in both the acute (8%) and late (6%) settings. Conclusion For spinal chordomas, PBS-PT remains a highly effective and safe method for delivery of dose-escalated adjuvant radiation therapy. The presence of metallic surgical stabilization prognosticates for worsened outcomes. Further investigation is warranted to characterize ideal treatment volumes and effect of surgical stabilization on therapy for these challenging tumors.

To assess the rate of radiation necrosis (RN) and white matter lesions (WMLs) in pediatric patients with primary brain tumors treated with pencil beam scanning (PBS) proton therapy (PT) with or without concomitant chemotherapy at the PSI.Between 1999 and 2015, 171 pediatric patients (age18 years) were treated with PT. Median age at diagnosis was 3.3 years (range, 0.3-17.0 years), and the median delivered dose was 54 Gy (relative biological effectiveness) (range, 40.0-74.1 Gy). Radiation necrosis and WMLs were defined as a new area of abnormal signal intensity on T2-weighted images or increased signal intensity on T2-weighted images, and contrast enhancement on T1 occurring in the brain parenchyma included in the radiation treatment field, which did not demonstrate any abnormality before PT. Radiation necrosis and WMLs were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up period for the surviving patients was 49.8 months (range, 5.9-194.7 months).Twenty-nine patients (17%) developed RN at a median time of 5 months (range, 1-26 months), most of them (n = 17; 59%) being asymptomatic (grade 1). Grade 2, 4, and 5 toxicities occurred in 8, 2, and 2 patients, respectively. Eighteen patients (11%) developed WMLs at a median time of 14.5 months (range, 2-62 months), most of them (n = 13; 72%) being asymptomatic (grade 1). White matter lesion grade 2 and 3 toxicities occurred in 4 and 1 patient(s), respectively. The 5-year RN-free and WML-free survival was 83% and 87%, respectively. In univariate analysis, neoadjuvant (P = .025) or any (P = .03) chemotherapy, hydrocephalus before PT (P = .035), and ependymoma (P = .026) histology were significant predictors of RN.Children treated with PT demonstrated a low prevalence of symptomatic RN (7%) or WML (3%) compared with similar cohorts treated with either proton or photon radiation therapy. Chemotherapy, ependymomal tumors and hydrocephalus as an initial symptom were significant risk factors for RN.

We evaluated the feasibility of treating patients with locally advanced non-small cell lung cancer (NSCLC) with pencil beam scanned intensity modulated proton therapy (IMPT) in breath-hold.Fifteen NSCLC patients who had previously received 66 Gy in 33 fractions with image guided photon radiation therapy were included in the present simulation study. In addition to a planning breath-hold computed tomography (CT) scan before the treatment start, a median of 6 (range 3-9) breath-hold CT scans per patient were acquired prospectively throughout the radiation therapy course. Three-field IMPT plans were constructed using the planning breath-hold CT scan, and the four-dimensional dose distributions were simulated, with consideration of both patient intra- and interfraction motion, in addition to dynamic treatment delivery.The median clinical target volume receiving 95% of the prescribed dose was 99.8% and 99.7% for the planned and simulated dose distributions, respectively. For 3 patients (20%), the dose degradation was5%, and plan adjustment was needed. Dose degradation correlated significantly with the change in water-equivalent path lengths (P.01) in terms of the percentage of voxels with 3-mm or more undershoot on repeat CT scans. The dose to the organs at risk was similar for the planned and simulated dose distributions. Three or fewer breath-holds per field would be required for 12 of the 15 patients, which was clinically feasible.For 9 of 15 NSCLC patients, IMPT in breath-hold was both dosimetrically robust and feasible to deliver regarding the treatment time. Three patients would have required plan adaption to meet the dosimetric criteria. The change in water-equivalent path length is an indicator of plan robustness and should be considered for the selection of patients for whom the plan would require adaptation.

Purpose To assess the radiation dose tolerance of the spinal cord by reviewing our institutional experience regarding the incidence of radiation-induced spinal cord toxicity after high-dose pencil beam scanning proton therapy (PBSPT). Methods and Materials Seventy-six patients (median age 53 years; range, 23-79 years) treated for spinal chordoma (n=55) or chondrosarcoma (n=21) met the following criteria and were retrospectively analyzed: PBSPT only, no reirradiation or concomitant chemotherapy, maximum dose (Dmax) to the spinal cord of ≥45 Gy(relative biological effectiveness [RBE]), ≥18 years of age, and follow-up of ≥12 months. The delivered dose was 59.4 to 75.2 Gy(RBE) [median 73.9 Gy(RBE)] delivered with conventional fractionation between 2000 and 2014. The Dmax, D2%, and V40-V60 of the surface (sSC) and center (cSC) of the spinal cord were recorded. Toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 4.03. Results Median follow-up was 65.5 months (range, 13-173 months). Patients received a mean Dmax and D2% to the sSC of 59.0 (median 58.7; range, 48.3-75.9) and 55.3 (median 52.7; range, 43.1-73.8) Gy(RBE), respectively. The corresponding values for the cSC were 52.3 (median 52.7; range, 32.3-73.3) and 51.1 (median 52.0; range, 25.3-73.1) Gy(RBE), respectively. Four patients (5%) developed acute radiation-induced neurotoxicity (grade [G] 1, n=1; G2, n=3). Twelve patients (16%) experienced late neurologic toxicities (G1, n=7; G2, n=4; G4, n=1). One patient with a history of pre-PBSPT symptomatic spinal cord compression redeveloped tetraplegia (G4) after receiving a Dmax of 57.8 Gy(RBE) to the sSC and 54.1 Gy(RBE) to the cSC. No significant correlation was found between sSC Dmax and D2%, cSC Dmax and D2%, or the length of CTV and toxicity. Conclusions High-dose conformal PBSPT may be delivered safely in close proximity to the spinal cord with minimal neurotoxicity. Dose constraints of 64 Gy(RBE) as D2% for the sSC and 54 Gy(RBE) for the cSC seem appropriate for clinical use.