Early outcome after craniospinal irradiation with pencil beam scanning proton therapy for children, adolescents and young adults with brain tumors.

Central nervous system (CNS) tumors are the most common solid malignancies in children and adolescents and young adults (C-AYAs). Craniospinal irradiation (CSI) is an essential treatment component for some malignancies, but it can also lead to important toxicity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk and, thus, potentially reduced acute and late toxicity. This study aims to report the clinical outcomes and toxicity rates after CSI for C-AYAs treated with PBSPT. Seventy-one C-AYAs (median age: 7.4 years) with CNS tumors were treated with CSI between 2004 and 2021. Medulloblastoma (n = 42: 59%) and ependymoma (n = 8; 11%) were the most common histologies. Median prescribed total PBSPT dose was 54 GyRBE (range: 18-60.4), and median prescribed craniospinal dose was 24 GyRBE (range: 18-36.8). Acute and late toxicities were coded according to Common Terminology Criteria for Adverse Events. After a median follow-up of 24.5 months, the estimated 2-year local control, distant control, and overall survival were 86.3%, 80.5%, and 84.7%, respectively. Late grade ≥3 toxicity-free rate was 92.6% at 2 years. Recurrent and metastatic tumors were associated with worse outcome. In conclusion, excellent tumor control with low toxicity rates was observed in C-AYAs with brain tumors treated with CSI using PBSPT.

Pencil beam scanned protons for the treatment of patients with Ewing sarcoma.

BACKGROUND: Few data exist regarding the clinical outcome of patients with Ewing sarcoma (EWS) treated with pencil beam scanning proton therapy (PT). We report the outcome of children, adolescents and young adults (AYA) treated with PT at the Paul Scherrer Institute. MATERIALS: Thirty-eight patients (median age, 9.9 years) received a median dose of 54.9 Gy(RBE) (where RBE is relative biologic effectiveness). Size of the tumor ranged from 1.7 to 24 cm. Most common primary site was axial/pelvic (n = 27; 71%). Four patients (11%) presented with metastases at diagnosis. Twenty (53%) patients had chemo-PT only. Median follow-up was 49.6 months (range, 9.2-131.7). RESULTS: The 5-year actuarial rate of local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were 81.5%, 76.4%, and 83.0%, respectively. All local recurrences occurred in field and in patients with nonextremity primaries. Six patients died, all of tumor progression. Age < 10 years was a favorable factor of borderline significance for LC (P = 0.05) and OS (P = 0.05), but was significant for DMFS (P = 0.003). Tumor volume <200 ml was a significant prognostic factors for DMFS (P = 0.03), but not for OS (P = 0.07). Metastasis at diagnosis was a strong predictor of local failure (P = 0.003). Only two grade 3 late toxicities were observed. The 5-year actuarial rate of grade 3 toxicity-free survival was 90.9%. CONCLUSIONS: These preliminary data suggest that the outcomes of children and AYA with EWS are good and PT was well tolerated with few late adverse events. The local and distant tumor control for older patients with large pre-PT tumor volumes remains problematic.

Pencil beam scanning proton therapy for pediatric intracranial ependymoma.

To assess the clinical outcome and late side effect profile of pencil beam scanning proton therapy (PT) delivered to children with intracranial ependymoma. Between July-2004 and March-2013, 50 patients with intracranial ependymoma (n = 46, grade 3) received involved-field PT at Paul Scherrer Institute (PSI). Median age at time of PT was 2.6 years (range 1.1-15.2). Thirty-six patients had infratentorial and 14 supratentorial ependymomas. Seventeen patients presented with macroscopic residual disease after subtotal resection before starting PT (8 with ≤1.5 cc and 9 with >1.5 cc residual tumor respectively). Forty-three (86 %) patients received post-operative chemotherapy before PT according to protocols; 44 (88 %) patients younger than 5 years required general anesthesia. Median prescribed dose was 59.4 Gy (RBE) (range 54-60) delivered in 1.8-2 Gy (RBE) per fraction. Late toxicity was assessed according to CTCAE v4.0. With a mean follow-up time of 43.4 months (range 8.5-113.7) seven patients experienced local failure (6 with infratentorial tumors and 1 with supratentorial tumor); four of the local failures were in patients with residual disease ≥1.5 cc at the time of PT and 3 without residual macroscopic disease. Five patients died from tumor progression. Actuarial 5-year Local Control rates were 78 ± 7.5 % and 5-year OS rates were 84 ± 6.8 %. Three patients developed grade ≥3 toxicity: 2 developed unilateral deafness (infratentorial tumors infiltrating into the internal acoustic canal), one patient developed a fatal brainstem necrosis. Repeated general anesthesia in children younger than 5 years was delivered without complications. Our data indicate the safety and the effectiveness of PT for pediatric ependymomas. Local control and survival rates are encouraging considering the high grade histology in 92 % of the patients and the number of patients with residual tumor ≥1.5 cc. The rates of late effects compare favorably with published photon-treated cohorts.

Tumor control and QoL outcomes of very young children with atypical teratoid/rhabdoid tumor treated with focal only chemo-radiation therapy using pencil beam scanning proton therapy.

The aim of this analysis was to assess the early clinical results of pencil beam scanning proton therapy (PT) in the treatment of young children with non-metastatic atypical teratoid/rhabdoid tumor (ATRT) of the CNS. Fifteen children (male, n = 8, 53 %) were treated with PT between May 2008 and January 2013. Mean age at diagnosis was 17.4 ± 7.0 months. The localization was infratentorial in 9 (60 %) patients. Gross total resection of the primary tumors was achieved in 7 (47 %) patients. The dose administered focally under sedation was 54 Gy (RBE). After a median follow-up of 33.4 months (range 9.7-69.2), 3 (20 %), 4 (27 %) and 2 (13 %) patients presented with local failure (LF), distant brain failure (DBF) and spinal failure (SF), respectively. Six patients died, all of tumor progression. The 2-year overall- and progression-free survival was 64.6 and 66.0 %. Tumor location (supratentorial) and the extent of surgical resection (non-gross total resection) were negative prognostic factors for both OS and PFS. PT was well tolerated. No grade >2 acute toxicity was observed. The estimated 2-year toxicity-free survival was 90 %. As assessed by the PedsQoL proxy, no decrease in QoL was observed after PT. We conclude that PBS PT is an effective treatment for young children with ATRT. After PT, with or without concomitant chemotherapy, two third of the patients survived >2 years. Acute toxicity was manageable. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and treatment-induced toxicity.

Craniospinal irradiation using pencil beam Scanning: The PSI experience.

INTRODUCTION: We present the dosimetric evaluation of craniospinal irradiation (CSI) treatments delivered with protons at Paul Scherrer Institute (PSI), with special focus on local recurrences and late toxicity outcome. METHODS: This study included 71 children, adolescents and young adults (c-AYA), who received or intended to receive (3 patients, pts) CSI using PBS-PT at PSI between 2004 and January 2021. The most frequent primary tumours were: medulloblastoma (42 pts), ependymoma (8 pts) and germ cell tumors (6 pts). The patients were treated prone on Gantry1 (G1; 22 pts) up to 2017, and afterwards supine on Gantry2 (G2; 49 pts). Accuracy of prone vs. supine setup was evaluated. Nine patients received CSI for local failure (LF) after a first course of local fractionated radiation therapy (RT). For 59/71 patients (excluding three patients not receiving PBS-PT CSI and nine preirradiated) CSI plans were compared considering gantry and planning technique. Detailed analysis of the full treatment (CSI and boost series) was performed for 8 patients presenting with LFs (4 of them presented also distal failure) and for selected patients presenting with late toxicity (G2 to G4) or asymptomatic radiation-induced radiological findings. RESULTS: Supine positioning resulted in lower systematic and random errors as compared to prone (0.25 mm and 0.4 mm systematic errors respectively for supine and prone; random errors in PA direction reduced from 1.8 mm for prone to 1.4 mm for supine). CONCLUSIONS: LFs were not correlated with potential dose inaccuracies or lack of robustness and no correlation of toxicities to enhanced LET have been observed.

Patterns of practice of image guided particle therapy for cranio-spinal irradiation: A site specific multi-institutional survey of European Particle Therapy Network.

PURPOSE: To investigate the current practice patterns in image-guided particle therapy (IGPT) for cranio-spinal irradiation (CSI). METHODS: A multi-institutional survey was distributed to European particle therapy centres to analyse all aspects of IGPT. Based on the survey results, a Delphi consensus analysis was developed to define minimum requirements and optimal workflow for clinical practice. The centres participating in the institutional survey were invited to join the Delphi process. RESULTS: Eleven centres participated in the survey. Imaging for treatment planning was rather similar among the centres with Computed Tomography (CT) being the main modality. For positioning verification, 2D IGPT was more commonly used than 3D IGPT. Two centres performed routinely imaging for plan adaptation, by the rest ad hoc. Eight centres participated in the Delphi consensus analysis. The full consensus was reached on the use of CT imaging without contrast for treatment planning and the role of magnetic resonance imaging (MRI) in target and organs-at-risk delineation. There was an agreement on the necessity to perform patient position verification and correction before each isocentre. The most important outcome was the clear need for standardization and harmonization of the workflow. CONCLUSION: There were differences in CSI IGPT clinical practice among the European particle therapy centres. Moreover, the optimal workflow as identified by experts was not yet reached. There is a strong need for consensus guidelines. The state-of-the-art imaging technology and protocols need to be implemented into clinical practice to improve the quality of IGPT for CSI.

First clinical implementation of a highly efficient daily online adapted proton therapy (DAPT) workflow.

OBJECTIVE: This study presents the first clinical implementation of an efficient online daily adaptive proton therapy workflow (DAPT). Approach: The DAPT workflow includes a pre-treatment phase, where a template and a fallback plan are optimized on the planning CT. In the online phase, the adapted plan is re-optimized on daily images from an in-room CT. Daily structures are rigidly propagated from the planning CT. Automated quality assurance (QA) involves geometric, sanity checks and an independent dose calculation from the machine files. Differences from the template plan are analyzed field-by-field, and clinical plan is assessed by reviewing the achieved clinical goals using a traffic light protocol. If the daily adapted plan fails any QA or clinical goals, the fallback plan is used. In the offline phase the delivered dose is recalculated from log-files onto the daily CT, and a gamma analysis is performed (3%/3mm). The DAPT workflow has been applied to selected adult patients treated in rigid anatomy for the last serie of the treatment between October 2023 and April 2024. Main Results: DAPT treatment sessions averaged around 23 minutes [range: 15-30 min] and did not exceed the typical 30-minute time slot. Treatment adaptation, including QA and clinical plan assessment, averaged just under 7 minutes [range: 3:30-16 min] per fraction. All plans passed the online QAs steps. In the offline phase a good agreement with the log-files reconstructed dose was achieved (minimum gamma pass rate of 97.5 %). The online adapted plan was delivered for > 85% of the fractions. In 92% of total fractions, adapted plans exhibited improved individual dose metrics to the targets and/or organs at risk. Significance: This study demonstrates the successful implementation of an online daily DAPT workflow. Notably, the duration of a DAPT session did not exceed the time slot typically allocated for non-DAPT treatment. As far as we are aware, this is a first clinical implementation of daily online adaptive proton therapy. .

Clinical practice in European centres treating paediatric posterior fossa tumours with pencil beam scanning proton therapy.

BACKGROUND AND PURPOSE: As no guidelines for pencil beam scanning (PBS) proton therapy (PT) of paediatric posterior fossa (PF) tumours exist to date, this study investigated planning techniques across European PT centres, with special considerations for brainstem and spinal cord sparing. MATERIALS AND METHODS: A survey and a treatment planning comparison were initiated across nineteen European PBS-PT centres treating paediatric patients. The survey assessed all aspects of the treatment chain, including but not limited to delineations, dose constraints and treatment planning. Each centre planned two PF tumour cases for focal irradiation, according to their own clinical practice but based on common delineations. The prescription dose was 54 Gy(RBE) for Case 1 and 59.4 Gy(RBE) for Case 2. For both cases, planning strategies and relevant dose metrics were compared. RESULTS: Seventeen (89 %) centres answered the survey, and sixteen (80 %) participated in the treatment planning comparison. In the survey, thirteen (68 %) centres reported using the European Particle Therapy Network definition for brainstem delineation. In the treatment planning study, while most centres used three beam directions, their configurations varied widely across centres. Large variations were also seen in brainstem doses, with a brainstem near maximum dose (D2%) ranging from 52.7 Gy(RBE) to 55.7 Gy(RBE) (Case 1), and from 56.8 Gy(RBE) to 60.9 Gy(RBE) (Case 2). CONCLUSION: This study assessed the European PBS-PT planning of paediatric PF tumours. Agreement was achieved in e.g. delineation-practice, while wider variations were observed in planning approach and consequently dose to organs at risk. Collaboration between centres is still ongoing, striving towards common guidelines.

Long Term Outcome and Quality of Life of Intracranial Meningioma Patients Treated with Pencil Beam Scanning Proton Therapy.

The aim of this study was to assess the clinical outcome, including QoL, of patients with intracranial meningiomas WHO grade 1-3 who were treated with Pencil Beam Scanning Proton Therapy (PBS PT) between 1997 and 2022. Two hundred patients (median age 50.4 years, 70% WHO grade 1) were analyzed. Acute and late side effects were classified according to CTCAE version 5.0. Time to event data were calculated. QoL was assessed descriptively by the EORTC-QLQ-C30 and BN20 questionnaires. With a median follow-up of 65 months (range: 3.8-260.8 months) the 5 year OS was 95.7% and 81.8% for WHO grade 1 and grade 2/3, respectively (p < 0.001). Twenty (10%) local failures were observed. Failures occurred significantly (p < 0.001) more frequent in WHO grade 2 or 3 meningioma (WHO grade 1: n = 7, WHO grade 2/3: n = 13), in patients with multiple meningiomas (p = 0.005), in male patients (p = 0.005), and when PT was initiated not as upfront therapy (p = 0.011). There were no high-grade toxicities in the majority (n = 176; 88%) of patients. QoL was assessed for 83 (41.5%) patients and for those patients PT did not impacted QoL negatively during the follow-up. In summary, we observed very few local recurrences of meningiomas after PBS PT, a stable QoL, and a low rate of high-grade toxicity.

A bi-directional beam-line energy ramping for efficient patient treatment with scanned proton therapy.

Objective.The treatment of mobile tumours using Pencil Beam Scanning (PBS) has become more prevalent in the last decade. However, to achieve the same beam delivery quality as for static tumours, treatments have to be combined with motion mitigation techniques, not limited but including, breath hold, gating and re-scanning, which typically prolong treatment time. In this article we present a novel method of bi-directional energy modulation and demonstrate our initial experience in improvement of treatment efficiency. Approach.At Paul Scherrer Institute Gantry 2 mobile tumours are treated by combining PBS with gating and volumetric re-scanning (VR), where the target volume is irradiated multiple times. Initial implementation of VR used only descending beam energies, creating a substantial dead time due to the beam-line initialization (ramping) before each re-scan. In 2019 we commissioned an energy meandering strategy that allows us to avoid beam line ramping in-between energy series while maintaining beam delivery quality.Main results.The measured beam parameters difference for both energy sequence are in the order of the typical daily variations: 0.2 mm in beam position and 0.2 mm in range. Using machine log files, we performed point-to-point dose difference calculations between original and new applications where we observed dose differences of less than 2%. After three years of operation employing bi-directional energy modulation, we have analysed the individual beam delivery time for 181 patients and have compared this to simulations of the timing behaviour assuming uni-directional energy sequence application. Depending on treatment complexity, we obtained plan delivery time reductions of up to 55%, with a median time gain of 17% for all types of treatments.Significance. Bi-directional energy modulation can help improving patient treatment efficiency by reducing delivery times especially for complex and specialised irradiations. It could be implemented in many existing facilities without significant additional hardware upgrades.

A survey of practice patterns for adaptive particle therapy for interfractional changes.

Background and purpose: Anatomical changes may compromise the planned target coverage and organs-at-risk dose in particle therapy. This study reports on the practice patterns for adaptive particle therapy (APT) to evaluate current clinical practice and wishes and barriers to further implementation. Materials and methods: An institutional questionnaire was distributed to PT centres worldwide (7/2020-6/2021) asking which type of APT was used, details of the workflow, and what the wishes and barriers to implementation were. Seventy centres from 17 countries participated. A three-round Delphi consensus analysis (10/2022) among the authors followed to define recommendations on required actions and future vision. Results: Out of the 68 clinically operational centres, 84% were users of APT for at least one treatment site with head and neck being most common. APT was mostly performed offline with only two online APT users (plan-library). No centre used online daily re-planning. Daily 3D imaging was used for APT by 19% of users. Sixty-eight percent of users had plans to increase their use or change their technique for APT. The main barrier was "lack of integrated and efficient workflows". Automation and speed, reliable dose deformation for dose accumulation and higher quality of in-room volumetric imaging were identified as the most urgent task for clinical implementation of online daily APT. Conclusion: Offline APT was implemented by the majority of PT centres. Joint efforts between industry research and clinics are needed to translate innovations into efficient and clinically feasible workflows for broad-scale implementation of online APT.

Consensus guide on CT-based prediction of stopping-power ratio using a Hounsfield look-up table for proton therapy.

BACKGROUND AND PURPOSE: Studies have shown large variations in stopping-power ratio (SPR) prediction from computed tomography (CT) across European proton centres. To standardise this process, a step-by-step guide on specifying a Hounsfield look-up table (HLUT) is presented here. MATERIALS AND METHODS: The HLUT specification process is divided into six steps: Phantom setup, CT acquisition, CT number extraction, SPR determination, HLUT specification, and HLUT validation. Appropriate CT phantoms have a head- and body-sized part, with tissue-equivalent inserts in regard to X-ray and proton interactions. CT numbers are extracted from a region-of-interest covering the inner 70% of each insert in-plane and several axial CT slices in scan direction. For optimal HLUT specification, the SPR of phantom inserts is measured in a proton beam and the SPR of tabulated human tissues is computed stoichiometrically at 100 MeV. Including both phantom inserts and tabulated human tissues increases HLUT stability. Piecewise linear regressions are performed between CT numbers and SPRs for four tissue groups (lung, adipose, soft tissue, and bone) and then connected with straight lines. Finally, a thorough but simple validation is performed. RESULTS: The best practices and individual challenges are explained comprehensively for each step. A well-defined strategy for specifying the connection points between the individual line segments of the HLUT is presented. The guide was tested exemplarily on three CT scanners from different vendors, proving its feasibility. CONCLUSION: The presented step-by-step guide for CT-based HLUT specification with recommendations and examples can contribute to reduce inter-centre variations in SPR prediction.

Influence of Radiation Dose, Photon Energy, and Reconstruction Kernel on rho/z Analysis in Spectral Computer Tomography: A Phantom Study.

BACKGROUND/AIM: The effective atomic number (Zeff) and electron density relative to water (ρe or Rho) of elements can be derived in dual-energy computed tomography (DECT). The aim of this phantom study was to investigate the effect of different photon energies, radiation doses, and reconstruction kernels on Zeff and Rho measured in DECT. MATERIALS AND METHODS: An anthropomorphic head phantom including five probes of known composition was scanned under three tube-voltage combinations in DECT: Sn140/100 kV, 140/80 kV and Sn140/80 kV with incremented radiation doses. Raw data were reconstructed with four reconstruction kernels (I30, I40, I50, and I70). Rho and Zeff were measured for each probe for all possible combinations of scan and reconstruction parameters. RESULTS: DECT-based Rho and Zeff closely approached the reference values with a mean and maximum error of 1.7% and 6.8%, respectively. Rho was lower for 140/80 kV compared with Sn140/100 kV and Sn140/80 kV with differences being 0.009. Zeff differed among all tube voltages with the most prominent difference being 0.28 between 140/80 kV and Sn140/100 kV. Zeff was lower in I70 compared with those of I30 and I40 with a difference of 0.07. Varying radiation dose yielded a variation of 0.0002 in Rho and 0.03 in Z, both considered negligible in practice. CONCLUSION: DECT comprises a feasible method for the extraction of material-specific information. Slight variations should be taken into account when different radiation doses, photon energies, and kernels are applied; however, they are considered small and in practice not crucial for an effective tissue differentiation.

Commissioning and quality assurance of a novel solution for respiratory-gated PBS proton therapy based on optical tracking of surface markers.

We present the commissioning and quality assurance of our clinical protocol for respiratory gating in pencil beam scanning proton therapy for cancer patients with moving targets. In a novel approach, optical tracking has been integrated in the therapy workflow and used to monitor respiratory motion from multiple surrogates, applied on the patients' chest. The gating system was tested under a variety of experimental conditions, specific to proton therapy, to evaluate reaction time and reproducibility of dose delivery control. The system proved to be precise in the application of beam gating and allowed the mitigation of dose distortions even for large (1.4cm) motion amplitudes, provided that adequate treatment windows were selected. The total delivered dose was not affected by the use of gating, with measured integral error within 0.15cGy. Analysing high-resolution images of proton transmission, we observed negligible discrepancies in the geometric location of the dose as a function of the treatment window, with gamma pass rate greater than 95% (2%/2mm) compared to stationary conditions. Similarly, pass rate for the latter metric at the 3%/3mm level was observed above 97% for clinical treatment fields, limiting residual movement to 3mm at end-exhale. These results were confirmed in realistic clinical conditions using an anthropomorphic breathing phantom, reporting a similarly high 3%/3mm pass rate, above 98% and 94%, for regular and irregular breathing, respectively. Finally, early results from periodic QA tests of the optical tracker have shown a reliable system, with small variance observed in static and dynamic measurements.

Effects of deep inspiration breath hold on prone photon or proton irradiation of breast and regional lymph nodes.

We report on a comparative dosimetrical study between deep inspiration breath hold (DIBH) and shallow breathing (SB) in prone crawl position for photon and proton radiotherapy of whole breast (WB) and locoregional lymph node regions, including the internal mammary chain (LN_MI). We investigate the dosimetrical effects of DIBH in prone crawl position on organs-at-risk for both photon and proton plans. For each modality, we further estimate the effects of lung and heart doses on the mortality risks of different risk profiles of patients. Thirty-one patients with invasive carcinoma of the left breast and pathologically confirmed positive lymph node status were included in this study. DIBH significantly decreased dose to heart for photon and proton radiotherapy. DIBH also decreased lung doses for photons, while increased lung doses were observed using protons because the retracting heart is displaced by low-density lung tissue. For other organs-at-risk, DIBH resulted in significant dose reductions using photons while minor differences in dose deposition between DIBH and SB were observed using protons. In patients with high risks for cardiac and lung cancer mortality, average thirty-year mortality rates from radiotherapy-related cardiac injury and lung cancer were estimated at 3.12% (photon DIBH), 4.03% (photon SB), 1.80% (proton DIBH) and 1.66% (proton SB). The radiation-related mortality risk could not outweigh the ~ 8% disease-specific survival benefit of WB + LN_MI radiotherapy in any of the assessed treatments.

Proton Therapy for Intracranial Meningioma for the Treatment of Primary/Recurrent Disease Including Re-Irradiation.

Meningeal tumors represent approximately 10-25% of primary brain tumors and occur usually in elderly female patients. Most meningiomas are benign (80-85%) and for symptomatic and/or large tumors, surgery, with or without radiation therapy (RT), has been long established as an effective means of local tumor control. RT can be delivered to inoperable lesions or to those with non-benign histology and for Simpson I-III and IV-V resection. RT can be delivered with photons or particles (protons or carbon ions) in stereotactic or non-stereotactic conditions. Particle therapy delivered for these tumors uses the physical properties of charged carbon ions or protons to spare normal brain tissue (i.e. Bragg peak), with or without or a dose-escalation paradigm for non-benign lesions. PT can substantially decrease the dose delivered to the non-target brain tissues, including but not limited to the hippocampi, optic apparatus or cochlea. Only a limited number of meningioma patients have been treated with PT in the adjuvant or recurrent setting, as well as for inoperable lesions with pencil beam scanning and with protons only. Approximately 500 patients with image-defined or WHO grade I meningioma have been treated with protons. The reported outcome, usually 5-year local tumor control, ranges from 85 to 99% (median, 96%). For WHO grade II or III patients, the outcome of only 97 patients has been published, reporting a median tumor local control rate of 52% (range, 38-71.1). Only 24 recurring patients treated previously with photon radiotherapy and re-treated with PT were reported. The clinical outcome of these challenging patients seems interesting, provided that they presented initially with benign tumors, are not in the elderly category and have been treated previously with conventional radiation dose of photons. Overall, the number of meningioma patients treated or-re-irradiated with this treatment modality is small and the clinical evidence level is somewhat low (i.e. 3b-5). In this review, we detail the results of upfront PT delivered to patients with meningioma in the adjuvant setting and for inoperable tumors. The outcome of meningioma patients treated with this radiation modality for recurrent tumors, with or without previous RT, will also be reviewed.

Dosimetric analysis of local failures in skull-base chordoma and chondrosarcoma following pencil beam scanning proton therapy.

BACKGROUND: Despite combined modality treatment involving surgery and radiotherapy, a relevant proportion of skull-base chordoma and chondrosarcoma patients develop a local recurrence (LR). This study aims to analyze patterns of recurrence and correlate LR with a detailed dosimetric analysis. METHODS: 222 patients were treated with proton radiotherapy for chordoma (n = 151) and chondrosarcoma (n = 71) at the PSI between 1998 and 2012. All patients underwent surgery, followed by pencil-beam scanning proton therapy to a mean dose of 72.5 ± 2.2GyRBE. A retrospective patterns of recurrence analysis was performed: LR were contoured on follow-up MRI, registered with planning-imaging and the overlap with initial target structures (GTV, PTVhigh-dose, PTVlow-dose) was calculated. DVH parameters of planning structures and recurrences were calculated and correlated with LR using univariate and multivariate cox regression. RESULTS: After a median follow-up of 50 months, 35 (16%) LR were observed. Follow-up MRI imaging was available for 27 (77%) of these recurring patients. Only one (3.7%) recurrence was located completely outside the initial PTV (surgical pathway recurrence). The mean proportions of LR covered by the initial target structures were 48% (range 0-86%) for the GTV, 70% (range 0-100%) for PTVhigh and 83% (range 0-100%) for PTVlow. In the univariate analysis, the following DVH parameters were significantly associated with LR: GTV(V < 66GyRBE, p = 0.01), GTV(volume, p = 0.02), PTVhigh(max, p = 0.02), PTVhigh(V < 66GyRBE, p = 0.03), PTVhigh(V < 59GyRBE, p = 0.02), PTVhigh(volume, p = 0.01) and GTV(D95, p = 0.05). In the multivariate analysis, only histology (chordoma vs. chondrosarcoma, p = 0.01), PTVhigh(volume, p = 0.05) and GTV(V < 66GyRBE, p = 0.02) were independent prognostic factors for LR. CONCLUSION: This study identified DVH parameters, which are associated with the risk of local recurrence after proton therapy using pencil-beam scanning for patients with skull-base chordoma and chondrosarcoma.

Prognostic factors for spinal chordomas and chondrosarcomas treated with postoperative pencil-beam scanning proton therapy: a large, single-institution experience.

OBJECTIVE: The aim of this paper was to evaluate the prognostic factors in surgical and adjuvant care for spinal chordomas and chondrosarcomas after surgery followed by high-dose pencil-beam scanning proton therapy (PBS-PT). METHODS: From 1997 to 2016, 155 patients (61 female patients; median age 55 years) with spinal (cervical, n = 61; thoracic, n = 29; lumbar, n = 13; sacral, n = 46; pelvic, n = 6) classic chordomas (n = 116) and chondrosarcomas (n = 39; most were low grade) were treated with maximal safe resection followed by PBS-PT (median dose prescribed: 74 Gy [relative biological effectiveness], range 48.6-77 Gy). The majority of patients (n = 153, 98.7%) had undergone at least 1 resection prior to PBS-PT (median 1, range 0-5; biopsy only, n = 2). Fewer than half (45.1%) of the surgeries were rated as gross-total resections (GTRs) prior to PBS-PT. Surgical stabilization (SS) was present in 39% of all patients (n = 60). Ninety-one patients (59%) presented with macroscopic tumor at the start of PBS-PT. The median follow-up duration was 64.7 months (range 12.2-204.8 months). RESULTS: The 5-year local tumor control, disease-free survival (DFS), and overall survival were 64.9% (95% CI 56.3%-73.5%), 59.4% (95% CI 50.6%-68.2%), and 77.9% (95% CI 70.6%-85.2%), respectively. In total, 63 patients (40.6%) experienced failure during the follow-up period: local only in 32 (20.6%), distal only in 7 (4.5%), local + distal in 19 (12.3%), surgical pathway failure (SPF) only in 2 (1.3%), local + SPF in 2 (1.3%), and distal + SPF in 1 (< 1%). Univariate analysis identified gross residual disease, the presence of SS, and treatment era prior to 2008 as highly significant for worse outcome, with all 3 remaining significant on multivariate analysis. The type of surgery (GTR or subtotal resection/biopsy) and whether GTR was achieved by en bloc or curettage did not show a significant prognostic effect. Surgical complications prior to PBS-PT were present in 42.5% of all surgically treated patients and were seen more commonly in patients with multiple surgical interventions (p = 0.005) and those operated on with the intent of en bloc resection (p = 0.006). CONCLUSIONS: The extent of resection and metallic stabilization substantially influenced clinical outcomes for patients with spinal chordoma or chondrosarcoma despite high-dose adjuvant PBS-PT. Optimal upfront surgical management of these tumors continues to include GTR, as possible, with prompt adjuvant proton therapy.

Pencil beam scanning proton therapy for the treatment of craniopharyngioma complicated with radiation-induced cerebral vasculopathies: A dosimetric and linear energy transfer (LET) evaluation.

BACKGROUND AND PURPOSE: This study analyses the dosimetric and dose averaged Linear Energy transfer (LETd) correlation in paediatric craniopharyngioma (CP) patients with and without radiation-induced cerebral vasculopathies (RICVs) treated with pencil beam scanning (PBS) proton therapy (PT). MATERIAL AND METHODS: We reviewed a series of 16 CP patients treated with PT to a median dose of 54 Gy(RBE). Two (12.5%) index patients presented RICVs 14 and 24 months (median, 19) after PT. Organs at risks (OARs) as bilateral internal carotid arteries (ICAs) and circle of Willis were contoured based on CTs and MRIs pre- and post-PT. Dosimetry was reviewed and LETd distributions were calculated; LETd metric for PTVs and OARs were analysed. For a sub-cohort, dosimetric and LETd values robustness due to range uncertainties were computed. RESULTS: For the two index patients, no correlation was observed between RICVs and OARs doses. However for those patients mean(maximum) LETd values in the affected OARs were up to 4.0 ± 0.4 (7.8 ± 0.1)keV/µm; those LETd values were significantly higher (p = 0.02) than the mean(maximum) LETd values for the rest of the cohort (mean: 3.1 ± 0.3, maximum: 4.8 ± 1.0 keV/µm). This was due to asymmetric field arrangement, thus resulting in marked asymmetric LETd distributions. For such arrangement, maximum LETd values variations in vascular structures due to range uncertainties were up to 1.2 keV/µm, whilst for the symmetric one they were up to 0.7 keV/µm. CONCLUSIONS: For children with and without RICVs, quantitative analysis showed a significant correlation with LETd average/maximum values in vascular structures, whilst no correlation was found on dosimetric parameters.

Radiation-induced optic neuropathy after pencil beam scanning proton therapy for skull-base and head and neck tumours.

OBJECTIVE: To assess the radiation-induced optic neuropathy (RION) prevalence, following high dose pencil beam scanning proton therapy (PBSPT) to skull base and head and neck (H&N) tumours. METHODS: Between 1999 and 2014, 216 adult patients, median age 47 years (range, 18-77), were treated with PBS PT for skull base or H&N malignancies, delivering ≥45 GyRBE to the optic nerve(s) (ON) and/or optic chiasma (OC). The median administered dose to the planning target volume was 74.0 GyRBE (range, 54.0-77.4). The median follow-up was 5.3 years (range, 0.8-15.9). RESULTS: RION was observed in 14 (6.5%) patients at a median time of 13.2 months (range, 4.8-42.6) following PBSPT. Most (92.9%) of RION were symptomatic. Most affected patients (11/14; 79%) developed unilateral toxicity. Grade 4, 3, 2 and 1 toxicity was observed in 10, 2, 1 and 1 patients, respectively. On univariate analyses, age (<70 vs ≥70 years; p < 0.0001), hypertension (p = 0.0007) and tumour abutting the optic apparatus (p = 0.012) were associated with RION. OC's V60 GyRBE was of border line significance (p = 0.06). None of the other evaluated OC-ON dose/volume metrics (Dmax, Dmean, V40-60) were significantly associated with this complication. CONCLUSION: These data suggest that high-dose PBS PT for skull base and H&N tumours is associated with a low prevalence of RION. Caution should be however exercised when treating elderly/hypertensive patients with tumours abutting the optic apparatus. ADVANCES IN KNOWLEDGE: This is the first study reporting the risk of developing RION following proton therapy with PBS technique, demonstrating the safety of this treatment.