Possible association of dose rate and the development of late visual toxicity for patients with intracranial tumours treated with pencil beam scanned proton therapy.

BACKGROUND AND PURPOSE: Rare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at unusually low dose levels and are thus difficult to understand considering dose metrics only. When transitioning from double scattering to pencil beam scanning, little consideration was given to increased dose rates observed with the latter delivery paradigm. We explored if dose rate related metrics could provide additional predicting factors for the development of late visual toxicities. MATERIALS AND METHODS: Radiation-induced intracranial visual pathway lesions were delineated on MRI for all index cases. Voxel-wise maximum dose rate (MDR) was calculated for 2 patients with observed optic nerve toxicities (CTCAE grade 3 and 4), and 6 similar control cases. Additionally, linear energy transfer (LET) related dose enhancing metrics were investigated. RESULTS: For the index cases, which developed toxicities at low dose levels (mean, 50 GyRBE), some dose was delivered at higher instantaneous dose rates. While optic structures of non-toxicity cases were exposed to dose rates of up to 1 to 3.2 GyRBE/s, the pre-chiasmatic optic nerves of the 2 toxicity cases were exposed to dose rates above 3.7 GyRBE/s. LET-related metrics were not substantially different between the index and non-toxicity cases. CONCLUSIONS: Our observations reveal large variations in instantaneous dose rates experienced by different volumes within our patient cohort, even when considering the same indications and beam arrangement. High dose rate regions are spatially overlapping with the radiation induced toxicity areas in the follow up images. At this point, it is not feasible to establish causality between exposure to high dose rates and the development of late optic apparatus toxicities due to the low incidence of injury.

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.

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.

Pencil Beam Scanning Proton Therapy for Adolescents and Young Adults with Head and Neck Sarcomas.

Purpose: To assess clinical outcomes of adolescents and young adults (AYAs) with head and neck sarcomas (HNSs) treated with pencil beam scanning proton therapy (PBSPT) and to report quality of life (QoL). Materials and Methods: Twenty-eight AYAs (aged 15 to 39 years) with HNS treated between January 2001 and July 2022 at our institution were included. The median age was 21.6 years. Rhabdomyosarcoma (39.3%), Ewing sarcoma (17.9%), chondrosarcoma (14.3%), and osteosarcoma (14.3%) were the most frequent diagnoses. Three (10.7%) patients were metastatic before PBSPT and 13 (46.4%) patients had a tumor with intracranial extension. The median total radiation dose was 63 GyRBE (range, 45 to 74 GyRBE). Thirteen (46.4%) patients received concomitant chemotherapy. Toxicity was reported according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (US National Institutes of Health, Bethesda, Maryland). Survival was estimated using the Kaplan-Meier method. QoL was assessed using a PEDQOL (Pediatric Quality of Life Questionnaire) questionnaire. Self-reported outcomes were assessed using institutional questionnaires. Results: With a median follow-up of 57 months (range, 3.7 to 243 months), 5 patients (17.8%) had local failure (LF) only, 2 (7.1%) experienced distant failure (DF) only, and 2 (7.1%) had LF and DF. The estimated 5-year local control (LC) and distant control (DC) rates were 71.8% and 80.5%, respectively. The median times to LF and DF were 13.4 and 22.2 months, respectively. Four (14.3%) patients died, all but one from their HNS. Estimated 5-year overall survival was 90.7%. Six (21.4%) patients developed nonocular grade ≥3 toxicity, which consisted of otitis media (n = 2), hearing impairment (n = 2), osteoradionecrosis (n = 1), and sinusitis (n = 1). Four (14.3%) patients developed cataracts that required surgery. The 5-year freedom from nonocular grade 3 toxicity was 91.1%. No grade 4 or higher toxicity was observed. Adolescents rated their quality of life before treatment worse than their parents did. Conclusion: Excellent outcomes with acceptable late-toxicity rates were observed for AYAs with HNS after PBSPT.

Multi-camera optical tracking and fringe pattern analysis for eye surface profilometry in ocular proton therapy.

Background and purpose: An optical tracking system for high-precision measurement of eye position and orientation during proton irradiation of intraocular tumors was designed. The system performed three-dimensional (3D) topography of the anterior eye segment using fringe pattern analysis based on Fourier Transform Method (FTM). Materials and methods: The system consisted of four optical cameras and two projectors. The design and modifications to the FTM pipeline were optimized for the realization of a reliable measurement system. Of note, phase-to-physical coordinate mapping was achieved through the combination of stereo triangulation and fringe pattern analysis. A comprehensive pre-clinical validation was carried out. Then, the system was set to acquire the eye surface of patients undergoing proton therapy. Topographies of the eye were compared to manual contouring on MRI. Results: Pre-clinical results demonstrated that 3D topography could achieve sub-millimetric accuracy (median:0.58 mm) and precision (RMSE:0.61 mm) in the clinical setup. The absolute median discrepancy between MRI and FTM-based anterior eye segment surface reconstruction was 0.43 mm (IQR:0.65 mm). Conclusions: The system complied with the requirement of precision and accuracy for image guidance in ocular proton therapy radiation and is expected to be clinically tested soon to evaluate its performance against the current standard.

Quality of Life, Clinical, and Patient-Reported Outcomes after Pencil Beam Scanning Proton Therapy Delivered for Intracranial Grade WHO 1-2 Meningioma in Children and Adolescents.

PURPOSE: The purpose of this study was to report the clinical and patient-reported outcomes of children and adolescents with intracranial meningioma treated with pencil beam scanning proton therapy (PBS-PT). MATERIAL AND METHODS: Out of a total cohort of 207 intracranial meningioma patients treated with PBS-PT between 1999 and 2022, 10 (4.8%) were children or adolescents aged < 18 years. Median age was 13.9 years (range, 3.2-17.2). Six (60%) children were treated as primary treatment (postoperative PT, n = 4; exclusive PT, n = 2) and four (40%) at the time of tumor recurrence. Acute and late toxicities were registered according to Common Terminology Criteria of Adverse Events (CTCAE). Quality of life (QoL) before PBS-PT was assessed using PEDQOL questionnaires. Educational, functional, and social aspects after PT were assessed through our in-house developed follow-up surveys. Median follow-up time was 71.1 months (range, 2.5-249.7), and median time to last questionnaire available was 37.6 months (range, 5.75-112.6). RESULTS: Five (50%) children developed local failure (LF) at a median time of 32.4 months (range, 17.7-55.4) after PBS-PT and four (80%) were considered in-field. One patient died of T-cell lymphoma 127.1 months after PBS-PT. Estimated 5-year local control (LC) and overall survival (OS) rates were 19.4% and 100.0%, respectively. Except for one patient who developed a cataract requiring surgery, no grade ≥3 late toxicities were reported. Before PT, patients rated their QoL lower than their parents in most domains. During the first year after PT, one child required educational support, one needed to attend to a special school, one had social problems and another three children required assistance for daily basic activities (DBA). Three years after PT, only one child required assistance for DBA. CONCLUSIONS: The outcome of children with intracranial meningioma treated with PBS-PT is in line with other centers who have reported results of radiation therapy delivered to this particular patient group. This therapy provides acceptable functional status profiles with no high-grade adverse radiation-induced events.

Clinical Outcomes in AYAs (Adolescents and Young Adults) Treated with Proton Therapy for Uveal Melanoma: A Comparative Matching Study with Elder Adults.

OBJECTIVE: The aim of this study was to compare the clinical outcomes of adolescents and young adults (AYAs) with those of elder adult patients treated with proton therapy (PT) for uveal melanoma (UM). MATERIAL AND METHODS: A retrospective, comparative study was conducted in UM patients who underwent PT at the Ocular Oncology Unit of the Jules-Gonin Eye Hospital (University of Lausanne, Lausanne, Switzerland) and the Paul Scherrer Institute (PSI); (Villigen, Switzerland) between January 1997 and December 2007. Propensity score matching (PSM) was used to select for each AYA (between 15-39 years old) an elder adult patient (≥40 years) with similar characteristics. We assessed ocular follow-up, local tumor control, metastasis incidence, and overall and relative survival (OS and RS). Non-terminal outcomes were then compared between the two groups using competing risk survival analysis. RESULTS: Out of a total of 2261 consecutive UM patients, after excluding 4 children (<15 years) and 6 patients who were metastatic at presentation, we identified 272 AYA patients and matched 270 of them with 270 elder adult patients. Before PSM, the AYA patients had a higher incidence of primary iris melanoma (4.0% vs. 1.4%; p = 0.005), while the elder patients were more likely to have other neoplastic diseases at presentation (9% vs. 3.7%; p = 0.004). Ocular outcomes and local tumor control were similar in both groups. Cumulative metastasis incidence for the AYA and elder adult groups was 13% and 7.9% at 5 years and 19.7% and 12.7% at 10 years, respectively, which was not significantly different between the groups (p = 0.214). The OS was similar in the two groups (p = 0.602), with estimates in the AYA and elder adult groups of 95.5% and 96.6% at 5 years and 94.6% and 91.4% at 10 years, respectively. However, the relative survival (RS) estimation was worse in the AYA group than the elder group (p = 0.036). CONCLUSION: While AYAs treated with PT for UM have similar ocular outcomes and present the same metastasis incidence and OS as elder adults, their RS is worse than that in elder adults, when compared with the population in general.

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.

Quality-of-life evaluations in children and adolescents with Ewing sarcoma treated with pencil-beam-scanning proton therapy.

BACKGROUND: With improved survival rates for children with cancer, quality-of-life (QoL) issues have increasingly become the focus of attention. We report the QoL of children with Ewing sarcoma (EWS) treated with pencil-beam-scanning proton therapy (PT). METHODS: A PEDQOL (QoL questionnaire for children 4-18 years) self/proxy questionnaire was used to prospectively assess the QoL of 23 children <18 years with EWS treated with PT. This questionnaire evaluates eight different domains. Children (self-rating) and parents (proxy-rating) filled out the questionnaire at the start of PT (E1), 2 months after treatment (E2), and thereafter once yearly (E≥3). RESULTS: Compared with healthy controls, parents rated the QoL of their children at E1 significantly worse in all but two (cognition and social functioning-family) domains. At E4, significant differences between the two groups only remained in three of eight domains. At E1, children self-rated their QoL significantly worse in the domain Physical functioning (p = .004) and significantly better in the domain Body image (p = .044) compared to healthy controls, whereas no significant differences were observed at E4. For the longitudinal comparison E1 versus E4, according to parents, Emotional functioning, Cognition and Social functioning-peers were slightly decreased 2 years after PT. The children rated Emotional functioning and Body image poorly 2 years after PT. CONCLUSIONS: Children with EWS usually recovered seemingly well to normal QoL levels 2 years after the end of PT. They tended to rate their QoL substantially higher than their parents. However, in the longitudinal analysis at 2 years, children rated their Emotional functioning and Body image scores poorly.

Hearing Loss in Cancer Patients with Skull Base Tumors Undergoing Pencil Beam Scanning Proton Therapy: A Retrospective Cohort Study.

To assess the incidence and severity of changes in hearing threshold in patients undergoing high-dose pencil-beam-scanning proton therapy (PBS-PT). This retrospective cohort study included fifty-one patients (median 50 years (range, 13-68)) treated with PBS-PT for skull base tumors. No chemotherapy was delivered. Pure tone averages (PTAs)were determined before (baseline) and after PBS-PT as the average hearing thresholds at frequencies of 0.5, 1, 2, and 4 kHz. Hearing changes were calculated as PTA differences between pre-and post-PBS-PT. A linear mixed-effects model was used to assess the relationship between the PTA at the follow-up and the baseline, the cochlea radiation dose intensity, the increased age, and the years after PBS-PT. Included patients were treated for chordoma (n = 24), chondrosarcoma (n = 9), head and neck tumors (n = 9), or meningioma (n = 3), with a mean tumor dose of 71.1 Gy (RBE) (range, 52.0-77.8), and a mean dose of 37 Gy (RBE) (range, 0.0-72.7) was delivered to the cochleas. The median time to the first follow-up was 11 months (IQR, 5.5-33.7). The PTA increased from a median of 15 dB (IQR 10.0-25) at the baseline to 23.8 (IQR 11.3-46.3) at the first follow-up. In the linear mixed-effect model, the baseline PTA (estimate 0.80, 95%CI 0.64 to 0.96, p ≤ 0.001), patient's age (0.30, 0.03 to 0.57, p = 0.029), follow-up time (2.07, 0.92 to 3.23, p ≤ 0.001), and mean cochlear dose in Gy (RBE) (0.34, 0.21 to 0.46, p ≤ 0.001) were all significantly associated with an increase in PTA at follow-up. The applied cochlear dose and baseline PTA, age, and time after treatment were significantly associated with hearing loss after proton therapy.

MRI and FUNDUS image fusion for improved ocular biometry in Ocular Proton Therapy.

INTRODUCTION: Ocular biometry in Ocular Proton Therapy (OPT) currently relies on a generic geometrical eye model built by referencing surgically implanted markers. An alternative approach based on image fusion of volumetric Magnetic Resonance Imaging (MRI) and panoramic fundus photography was investigated. MATERIALS AND METHODS: Eighteen non-consecutive uveal melanoma (UM) patients, who consented for an MRI and had their tumour base visible on panoramic fundus photography, were included in this comparative analysis. Through generating digitally-reconstructed projections from MRI images using the Lambert azimuthal equal-area projection, 2D-3D image fusion between fundus photography and an eye model delineated on MRI scans was achieved and allowed for a novel definition of the target base (MRI + FCTV). MRI + FCTV was compared with MRI-only delineation (MRIGTV) and the conventional (EyePlan) target definition (EPCTV). RESULTS: The combined use of fundus photography and MRI to define tumour volumes reduced the average discrepancies by almost 65% with respect to the MRI only tumour definitions when comparing with the conventionally planned EPCTV. With the proposed method, shallow sub-retinal tumour infiltration, otherwise invisible on MRI, can be included in the target volume definition. Moreover, a novel definition of the fovea location improves the accuracy and personalisation of the 3D eye model. CONCLUSION: MRI and fundus image fusion overcomes some of the limitations of ophthalmological MRI for tumour volume definition in OPT. This novel eye tumour modelling method might improve treatment planning personalisation, allowing to better anticipate which patients could benefit from prophylactic treatment protocols for radiation induced maculopathy.

Clinical Outcome After Pencil Beam Scanning Proton Therapy of Patients With Non-Metastatic Malignant and Benign Peripheral Nerve Sheath Tumors.

Objective: Peripheral nerve sheath tumors (PNSTs) commonly arise from peripheral nerve roots and grow locally invasive. Malignant PNSTs (mPNSTs) represent aggressive sarcomas of neural origin that can originate from PNSTs. Radiation therapy is commonly used as part of the required multimodal treatment. However, both entities tend to occur early in life and are associated with the genetic disorder neurofibromatosis type 1 (NF-1), which is known to cause increased radiosensitivity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of the dose delivered to organs at risk and the integral dose and, thus, potentially also a reduction of radiation-induced adverse events. We report the clinical outcome and toxicity rates of patients with (m)PNSTs treated with PBSPT. Methods: We retrospectively reviewed 36 patients who received PBSPT (median dose, 64 GyRBE) with curative intent for (m)PNSTs between 1999 and 2020 at our institute. Twenty-eight (78%) and 8 (22%) patients were treated at diagnosis and for tumor recurrence/progression, respectively. The median age was 32 years (range, 3-75), and 25 (69%) patients were male. mPNST and PNST were diagnosed in 31 (86%) and 5 (14%) patients, respectively. Underlying NF-1 disease was found in 8 (22%) patients. Acute and late toxicities were recorded according to Common Terminology Criteria for Adverse Events, version 4.1 (CTCAE v4.1). Overall survival (OS), local control (LC), and distant control (DC) were estimated using the Kaplan-Meier method. Results: With a median follow-up time of 31 months (range, 4-194), 13 (36%) patients died from a progressive disease, 8 (22%) experienced local failure, and 14 (39%) experienced distant failure after PBSPT. Estimated 2-year OS, LC, and DC were 75.5%, 73.5%, and 61.2%, respectively. Acute grade 3 toxicity (dermatitis, mucositis, and pain) was observed in 5 (14%) patients. Late grade 3 cataract and osteonecrosis were both observed in 1 (3%) patient at 34 and 194 months after PBSPT, respectively. There was no late grade >3 toxicity or radiation-induced secondary cancer. Conclusion: To our knowledge, this is the first study to analyze the outcome of (m)PNSTs treated with proton therapy using a PBS delivery paradigm. In our cohort, consisting mainly of patients with mPNSTs, we report reasonable oncological outcomes and low toxicity rates after PBSPT.

Clinical Outcomes after International Referral of Uveal Melanoma Patients for Proton Therapy.

OBJECTIVE: To assess oncological and ophthalmological outcomes after international referral of uveal melanoma patients for proton therapy. MATERIALS AND METHODS: This is a retrospective study among Dutch uveal melanoma patients who were treated in Switzerland with 60.0 CGE proton therapy (in 4 fractions) from 1987 to 2019. All patients were ineligible for brachytherapy due to tumour size and/or proximity to the optic nerve. Time-to-event analyses were performed using Kaplan-Meier's methodology and Cox proportional hazards models. RESULTS: There were 103 patients (104 eyes) with a median largest tumour diameter of 19 mm (range 6-26 mm). Tumours were localised centrally (11%), mid-peripherally (65%) or peripherally (34%). Median follow-up was 7 years. Five-year local control, distant metastasis-free survival and eye preservation rates were 94%, 70% and 81% respectively. At five years, severe, moderate and mild visual impairment was observed in respectively 79%, 4% and 6% of the patients. Larger tumour volumes and more central tumour localisation were associated with severe visual impairment. After correction for these factors, dose to the macula, optic disc and retina, but not optic nerve was significantly associated with severe visual impairment. CONCLUSION: International referral for proton therapy yielded good tumour control and eye preservation rates, but risk of distant metastasis and severe visual impairment were substantial, possibly due to the selection of advanced tumour stages and/or central localisation. Dose to the macula may be more relevant than dose to the optic nerve for preservation of visual acuity, which is relevant for the treatment planning of proton therapy.

A Prospective Study on Health-Related Quality of Life and Patient-Reported Outcomes in Adult Brain Tumor Patients Treated with Pencil Beam Scanning Proton Therapy.

Proton therapy (PT) is delivered to complex brain tumors to obtain an optimal curative treatment with limited toxicity. Value-based oncological medicine is increasingly important, particularly when long-term survival is to be expected. This study aims to evaluate health-related quality of life (HRQOL) and patient reported outcomes (PROs) in patients treated with PT for brain tumors. Adult patients with brain tumors treated with PT filled out the EORTC-QLQ-C30 and BN20 questionnaires up to three years following PT. Toxicity was scored using the CTCAE v4.03. QoL and PRO were correlated to clinical factors. Three-year overall survival, distant brain control and local control rates were 98%, 97% and 84%, respectively. No ≥G3 acute toxicity was observed. Late PT-related ≥G3 severe toxicity occurred in seven patients (5.7%). Lower global QoL scores after PT were significantly correlated to low Karnofsky performance status (KPS) before PT (p = 0.001), surgical complications before PT (p = 0.04) and progressive disease (p = 0.017). A low QLQ-30 summary score at one year follow-up was correlated to sex (p = 0.015), low KPS before PT (p < 0.001), and central nervous system symptoms before PT (p = 0.018). Reported QLQ-BN20 neurological symptoms were correlated to lower KPS at baseline (p < 0.001) and surgical complications before PT (p = 0.03). PT-related toxicity only influenced reported symptoms directly following PT, but not QoL. Although global QoL temporarily decreased after treatment, it improved again from one year onwards. Global QoL and reported symptoms over time were not correlated with the proton therapy and were more related to preexisting symptoms and progressive disease. This study assists in improving patient support in patients with brain tumors receiving PT.

Non-invasive recognition of eye torsion through optical imaging of the iris pattern in ocular proton therapy.

The introduction of non-invasive imaging techniques such as MRI imaging for treatment planning and optical eye tracking for in-room eye localization would obviate the requirement of clips implantation for many patients undergoing ocular proton therapy. This study specifically addresses the issue of torsional eye movement detection during patient positioning. Non-invasive detection of eye torsion is performed by measuring the iris pattern rotations using a beams eye view optical camera. When handling images of patients to be treated using proton therapy, a number of additional challenges are encountered, such as changing eye position, pupil dilatation and illumination. A method is proposed to address these extra challenges while also compensating for the effect of cornea distortion in eye torsion computation. The accuracy of the proposed algorithm was evaluated against corresponding measurement of eye torsion using the clips configuration measured on x-ray images. This study involves twenty patients who received ocular proton therapy at Paul Scherrer Institute and it is covered by ethical approval (EKNZ 2019-01987).

Potential and pitfalls of 1.5T MRI imaging for target volume definition in ocular proton therapy.

INTRODUCTION: Ocular proton therapy (OPT) for the treatment of uveal melanoma has a long and remarkably successful history. This is despite that, for the majority of patients treated, the definition of the eye anatomy is based on a simplified geometrical model embedded in the treatment planning system EyePlan. In this study, differences in anatomical and tumor structures from EyePlan, and those based on 1.5T magnetic resonance imaging (MRI) are assessed. MATERIALS AND METHODS: Thirty-three uveal melanoma patients treated with OPT at our institution were subject to eye MRI. The target volumes were manually delineated on those images by two radiation oncologists. The resulting volumes were geometrically compared to the clinical standard. In addition, the dosimetric impact of using different models for treatment planning were evaluated. RESULTS: Two patients (6%) presented lesions too small to be visible on MRI. Target volumes identified on MRI scans were on average smaller than EyePlan with discrepancies arising mostly from the definition of the tumor base. Clip-to-tumor base distances measured on MRI models exhibited higher discrepancy to ophthalmological measurements than EyePlan. For 53% of cases, treatment plans optimized for lesions identified on MRI only, failed to achieve sufficient target coverage for EyePlan volumes. DISCUSSION: The analysis has shown that 1.5T MRI might be more susceptible to misses of flat tumor extension of the clinical target volume than the current clinical standard. Thus, a proper integration of ancillary imaging modalities, leading to a better characterization of the full lesion, is required.

Good long-term visual outcomes of parapapillary choroidal melanoma patients treated with proton therapy: a comparative study.

PURPOSE: To evaluate why small- and certain medium-sized parapapillary choroidal melanoma (pcM) patients treated with hypo-fractionated proton therapy (PT) retain excellent long-term visual acuity (VA) and assess the negative predictive factors for retaining good vision (≤ 0.2 logMAR (≥ 0.6 decimal) after 5 years. METHODS: This single-center, retrospective, comparative study recruited consecutive pcM patients that were treated with PT. Between 1984 and 2005, 609 patients received a total of 60 CGE, of whom 310 met the following inclusion criteria: posterior tumor border ≤ 2.5 mm from the optic disc, largest tumor diameter ≤ 17.9 mm, tumor thickness ≤ 5.2 mm and available follow-up data for at least 5 years. RESULTS: Mean follow-up was 120.8 ± 48.8 months (54.0-295.0). Out of 310 patients, 64 (21%) maintained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years following PT and were allocated to the "good visual outcome" (GVO) group, while the remaining 246 (79%) constituted the "poor visual outcome" (PVO) group, subdivided into 70 (22%) with a VA of 0.3-1.0 logMAR (0.1-0.5 decimal) and 157 (57%) patients with a VA > 1.0 logMAR (< 0.1 decimal). On multivariate analysis, older age (P = 0.04), tumor localization ≤ 0.5 mm to the fovea (P < 0.03), volume of the optic disc and macula receiving 50% of dose (30 CGE) (P = 0.02 and P < 0.001, respectively) were independent negative predictors of GVO. CONCLUSIONS: Of 310 small- to medium-sized pcM patients successfully treated with PT, 21% retained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years. Strongest negative predictive factor for retaining good long-term vision was the volume of the macula irradiated with at least 30 Gy.

Outcomes of adolescents and young adults treated for brain and skull base tumors with pencil beam scanning proton therapy.

BACKGROUND: The use of proton therapy (PT) in adolescents and young adults (AYAs) is becoming increasingly popular. This study aims to assess the outcomes and late toxicity consequences in AYAs (15-39 years) with brain/skull base tumors treated with pencil beam scanning proton therapy. METHODS: One hundred seventy six AYAs treated curatively at the Paul Scherrer Institute (PSI) were identified. Median age was 30 years (range 15-39) and median prescribed dose was 70.0 Gy (relative biological effectiveness [RBE]) (range 50.4-76.0). The most common tumors treated were chordomas/chondrosarcomas (61.4%), followed by gliomas (15.3%), and meningiomas (14.2%). RESULTS: After a median follow up of 66 months (range 12-236), 24 (13.6%) local only failures and one (0.6%) central nervous system (CNS) distant only failure were observed. The 6-year local control, distant progression-free survival, and overall survival were 83.2%, 97.4%, and 90.2%, respectively. The 6-year high-grade (≥grade [G] 3) PT-related late toxicity-free survival was 88.5%. Crude late toxicity rates were 26.2% G1, 37.8% G2, 12.2% G3, 0.6% G4, and 0.6% G5. The one G4 toxicity was a retinopathy and one G5 toxicity was a brainstem hemorrhage. The 6-year cumulative incidences for any late PT-related pituitary, ototoxicity, and neurotoxicity were 36.3%, 18.3%, and 25.6%; whilst high-grade (≥G3) ototoxicity and neurotoxicity were 3.4% and 2.9%, respectively. No secondary malignancies were observed. The rate of unemployment was 9.5% pre-PT, increasing to 23.8% post-PT. Sixty-two percent of survivors were working whilst 12.7% were in education post-PT. CONCLUSIONS: PT is an effective treatment for brain/skull base tumors in the AYA population with a reasonable late toxicity profile. Despite good clinical outcomes, around one in four AYA survivors are unemployed after treatment.