Radiation-induced optic neuropathy (RION) is a rare side effect following radiation therapy involving the optic structures whose onset is, due to the low amount of available data, challenging to predict. We have analyzed a multi-institutional cohort including 289 skull-base cancer patients treated with proton therapy who all received >45 Gy_RBE to the optic apparatus. An overall incidence rate of 4.2% (12) was observed, with chordoma patients being at higher risk (5.8%) than chondrosarcoma patients (3.2%). Older age and arterial hypertension, tumor involvement, and repeated surgeries (>3) were found to be associated with RION. Based on bootstrapping and cross-validation, a NTCP model based on age and hypertension was determined to be the most robust, showing good classification ability (AUC-ROC 0.77) and calibration on our dataset. We suggest the application of this model with a threshold of 6% to segment patients into low and high-risk groups before treatment planning. However, further data and external validation are warranted before clinical application.

Background: Hypoxia is known to be prevalent in solid tumors such as non-small cell lung cancer (NSCLC) and reportedly correlates with poor prognostic clinical outcome. PET imaging can provide in-vivo hypoxia measurements to support targeted radiotherapy treatment planning. We explore the potential of proton therapy in performing patient-specific dose escalation and compare it with photon volumetric modulated arc therapy (VMAT). Methods: Dose escalation has been calibrated to the patient specific tumor response of ten stage IIb-IIIb NSCLC patients by combining HX4-PET imaging and radiobiological modelling of oxygen enhancement ratio (OER) to target variable tumor hypoxia. In a dose-escalation-by-contour approach, escalated dose levels were simulated to the most hypoxic region of the primary target and its effectiveness in improving loco-regional tumor control was assessed. Furthermore, the impact on normal tissue of proton treatments including dose escalation was evaluated in comparison to the normal tissue complication probability (NTCP) of conventional VMAT plans. Results: Ignoring regions of tumor hypoxia can cause overestimation of TCP values by up to 10%, which can effectively be recovered on average to within 0.9% of the nominal TCP, using patient-specific dose escalations of up to 22% of the prescribed dose to PET defined hypoxic regions. Despite such dose escalations, the use of protons could also simultaneously reduce mean doses to the heart (− 14.3 Gy_RBE), lung (− 8.3 Gy_RBE), esophagus (− 6.9 Gy_RBE) and spinal cord (− 3.8 Gy) compared to non-escalated VMAT plans. These reductions are predicted to lead to clinically relevant decreases in NTCP for radiation-induced pneumonitis (− 11.3%), high grade heart toxicity (− 7.4%) and esophagitis (− 7.5%). Conclusions: This study suggests that the administration of proton therapy for dose escalation to patient specific regions of tumor hypoxia in the treatment of NSCLC can mitigate TCP reduction due to hypoxia-induced radio resistance, while simultaneously reducing NTCP levels even when compared to non-escalated treatments delivered with state-of-the-art photon techniques.

Background and Purpose: To investigate the impact of organ motion on hypoxia-guided proton therapy treatments for non-small cell lung cancer (NSCLC) patients. Materials and Methods: Hypoxia PET and 4D imaging data of six NSCLC patients were used to simulate hypoxia-guided proton therapy with different motion mitigation strategies including rescanning, breath-hold, respiratory gating and tumour tracking. Motion-induced dose degradation was estimated for treatment plans with dose painting of hypoxic tumour sub-volumes at escalated dose levels. Tumour control probability (TCP) and dosimetry indices were assessed to weigh the clinical benefit of dose escalation and motion mitigation. In addition, the difference in normal tissue complication proba-bility (NTCP) between escalated proton and photon VMAT treatments has been assessed. Results: Motion-induced dose degradation was found for target coverage (CTV V95% up to-4%) and qual-ity of the dose-escalation-by-contour (QRMS up to 6%) as a function of motion amplitude and amount of dose escalation. The TCP benefit coming from dose escalation (+4-13%) outweighs the motion-induced losses (< 2%). Significant average NTCP reductions of dose-escalated proton plans were found for lungs (-14%), oesophagus (-10%) and heart (-16%) compared to conventional VMAT plans. The best plan dosimetry was obtained with breath hold and respiratory gating with rescanning. Conclusion: NSCLC affected by hypoxia appears to be a prime target for proton therapy which, by dose -escalation, allows to mitigate hypoxia-induced radio-resistance despite the sensitivity to organ motion. Furthermore, substantial reduction in normal tissue toxicity can be expected compared to conventional VMAT. Accessibility and standardization of hypoxia imaging and clinical trials are necessary to confirm these findings in a clinical setting. (C) 2022 The Author(s). Published by Elsevier B.V.

Objectives: The purpose of this study is to report the oncological outcome, observed toxicities and normal tissue complication probability (NTCP) calculation for pencil beam scanning (PBS) PT delivered to salivary gland tumour (SGT) patients. Methods: We retrospectively reviewed 26 SGT patients treated with PBSPT (median dose, 67.5 Gy(RBE)) between 2005 and 2020 at our institute. Toxicities were recorded according to CTCAEv.4.1. Overall survival (OS), local control (LC), locoregional control (LRC) and distant control (DC) were estimated. For all patients, a photon plan was re-calculated in order to assess the photon/proton NTCP. Results: With a median follow-up time of 46 months (range, 3–118), 5 (19%), 2 (8%), 3 (12%) and 2 (8%) patients presented after PT with distant, local, locoregional failures and death, respectively. The estimated 4 year OS, LC, LCR and DC were 90%, 90%, 87 and 77%, respectively. Grade 3 late toxicity was observed in 2 (8%) patients. The estimated 4 year late high-grade (≥3) toxicity-free survival was 78.4%. The calculated mean difference of NTCP-values after PBSPT and VMAT plans for developing Grade 2 or 3 xerostomia were 3.8 and 2.9%, respectively. For Grade 2–3 dysphagia, the grade corresponding percentages were 8.6 and 1.9%. Not using an up-front model-based approach to select patients for PT, only 40% of our patients met the Dutch eligibility criteria. Conclusion: Our data suggest excellent oncological outcome and low late toxicity rates for patients with SGT treated with PBSPT. NTCP calculation showed a substantial risk reduction for Grade 2 or 3 xerostomia and dysphagia in some SGT patients, while for others, no clear benefit was seen with protons, suggesting that comparative planning should be performed routinely for these patients. Advances in knowledge: We have reported that the clinical outcome of SGT patients treated with PT and compared IMPT to VMAT for the treatment of salivary gland tumour and have observed that protons delivered significantly less dose to organs at risks and were associated with less NTCP for xerostomia and dysphagia. Noteworthy, not using an up-front model-based approach, only 40% of our patients met the Dutch eligibility criteria.