Photon and Proton irradiation in Patient-derived, Three-Dimensional Soft Tissue Sarcoma Models.

BACKGROUND: Despite their heterogeneity, the current standard preoperative radiotherapy regimen for localized high-grade soft tissue sarcoma (STS) follows a one fits all approach for all STS subtypes. Sarcoma patient-derived three-dimensional cell culture models represent an innovative tool to overcome challenges in clinical research enabling reproducible subtype-specific research on STS. In this pilot study, we present our methodology and preliminary results using STS patient-derived 3D cell cultures that were exposed to different doses of photon and proton radiation. Our aim was: (i) to establish a reproducible method for irradiation of STS patient-derived 3D cell cultures and (ii) to explore the differences in tumor cell viability of two different STS subtypes exposed to increasing doses of photon and proton radiation at different time points. METHODS: Two patient-derived cell cultures of untreated localized high-grade STS (an undifferentiated pleomorphic sarcoma (UPS) and a pleomorphic liposarcoma (PLS)) were exposed to a single fraction of photon or proton irradiation using doses of 0 Gy (sham irradiation), 2 Gy, 4 Gy, 8 Gy and 16 Gy. Cell viability was measured and compared to sham irradiation at two different time points (four and eight days after irradiation). RESULTS: The proportion of viable tumor cells four days after photon irradiation for UPS vs. PLS were significantly different with 85% vs. 65% (4 Gy), 80% vs. 50% (8 Gy) and 70% vs. 35% (16 Gy). Proton irradiation led to similar diverging viability curves between UPS vs. PLS four days after irradiation with 90% vs. 75% (4 Gy), 85% vs. 45% (8 Gy) and 80% vs. 35% (16 Gy). Photon and proton radiation displayed only minor differences in cell-killing properties within each cell culture (UPS and PLS). The cell-killing effect of radiation sustained at eight days after irradiation in both cell cultures. CONCLUSIONS: Pronounced differences in radiosensitivity are evident among UPS and PLS 3D patient-derived sarcoma cell cultures which may reflect the clinical heterogeneity. Photon and proton radiation showed similar dose-dependent cell-killing effectiveness in both 3D cell cultures. Patient-derived 3D STS cell cultures may represent a valuable tool to enable translational studies towards individualized subtype-specific radiotherapy in patients with STS.

Outcome Measures of New Technologies in Uveal Melanoma: Review from the European Vision Institute Special Interest Focus Group Meeting.

Uveal Melanoma (UM) is the most common primary intra-ocular tumor in adults. New diagnostic procedures and basic science discoveries continue to change our patient management paradigms. A recent meeting of the European Vision Institute (EVI) special interest focus group was held on "Outcome Measures of New Technologies in Uveal Melanoma", addressing the latest advances in UM, starting with genetic developments, then moving on to imaging and treatment of the primary tumor, as well as to investigating the most recent developments in treating metastases, and eventually taking care of the patient's wellbeing. This review highlights the meeting's presentations in the context of the published literature.

Side effects of proton beam therapy of choroidal melanoma in dependence of the dose to the optic disc and the irradiated length of the optic nerve.

PURPOSE: To analyze the impact of the dose to the optic disc and the irradiated length of the optic nerve on radiation-induced optic neuropathy, radiation-induced retinopathy, iris neovascularization, secondary glaucoma, enucleation, and local tumor control after proton beam therapy (PBT) of choroidal melanoma. METHOD: Retrospective analysis of 1129 patients, who received primary PBT for the treatment of choroidal melanoma with a dose of 60 cobalt gray equivalents (CGE) between 1998 and 2013 at the Helmholtz-Zentrum Berlin, Germany. Kaplan-Meier curves and logrank test have been used for time-to-event analyses. Adjustment for potential confounders was done using multiple Cox regression models with forward and backward selection. RESULTS: We found a significant correlation between the irradiated length of the optic nerve and the dose to the optic disc (correlation coefficient, 0.93). Multivariate Cox regression revealed the dose to the optic disc as an independent predictive risk factor for the development of radiation-induced optic neuropathy (p < 0.001, HR 1.023, 95 CI 1.016-1.029), iris neovascularization (p < 0.001, HR 1.013, 95% CI 1.008-1.019), secondary glaucoma (p < 0.001, HR 1.017, 95% CI: 1.011-1.023) and enucleation (p < 0.001, HR 1.037, 95% CI 1.020-1.053). The irradiated length of the optic nerve was not a statistically independent predictive risk factor in multivariate analysis. CONCLUSION: Our data implicate the predominance of the dose to the optic disc over the irradiated length of the optic nerve regarding radiation-induced optic neuropathy, iris neovascularization, secondary glaucoma, and enucleation.

Breakdown of the blood-eye barrier in choroidal melanoma after proton beam radiotherapy.

PURPOSE: Irradiation of choroidal melanoma is a safe and globe preserving procedure. Chronic inflammatory processes and ischemia are the main reasons for secondary enucleation in the long run. The aim of this study was to determine whether intraocular inflammation and especially inflammatory response after proton beam therapy (PBT) is related to primary tumor characteristics such as height, tumor volume, and initial flare values. METHODS: Twenty-six patients treated for uveal melanoma using PBT were included. All patients were examined for signs of inflammation using laser flare photometry (LFP). Each examination included assessment of the melanoma and fellow eye (which acted as the control) and imaging of the melanoma. RESULTS: Significant differences of flare values between melanoma eyes and control group were found both at baseline (median 17.65 ph/ms (min 4, max 37.10), 7.45 ph/ms (min 0.80, max 16.40), respectively) and during follow-up (median 21.45 ph/ms (min 4.5, max 70.90); 6.05 ph/ms (min 2.40, max 16.40), respectively) (p < 0.001, Wilcoxon test). Flare values in melanoma eyes increased significantly after PBT (p = 0.005, Wilcoxon test) and after a follow-up of 94 days (median, 7-420 days). Flare values of the control group did not change (p = 0.946, Wilcoxon test). The increase of flare values correlated significantly with maximum tumor height and volume (Spearman-Rho 0.633, p = 0.001 and 0.519, p = 0.007, respectively). CONCLUSION: LFP has proven to show significantly higher flare values in melanoma eyes as compared with the control group and provides data on the course of the inflammatory response after treatment. It may ease treatment planning both at baseline and during follow-up.

Quantification of radiation retinopathy after beam proton irradiation in centrally located choroidal melanoma.

PURPOSE: To localize and quantify ischemic changes induced by proton beam irradiation of central choroidal melanoma and to identify baseline predictors correlated with the extent of ischemic changes. METHODS: Retrospective chart review of patients with central choroidal melanoma treated by proton beam irradiation and conducted widefield fluorescein angiography (≥ 20 months after radiation therapy). Quantification and location of ischemic areas and correlation to baseline predictors. Multiple linear regression model was performed for analyses. RESULTS: Twenty-five eyes from 25 patients were included in final analysis. Mean largest basal tumor area was 56.6 ± 40.0 mm2 and mean maximal tumor prominence 2.5 ± 1.4 mm. Mean total radiated area was 339.1 ± 68.3 mm2. All patients showed ischemic changes. Mean ischemic area was 387.6 ± 123.3 mm2 and mean ischemic index (ischemic area/total visible area) was 0.53 ± 0.23. Twenty-two patients (88%) presented ischemic changes outside of the irradiation field, which comprised of 23% of total ischemic area. Mean angular distance between lateral border of irradiation field and ischemic area outside of the radiated area was 44.8 ± 36.5°. Multivariable analysis revealed a positive correlation of total ischemic area with total radiated area (p = 0.02) and initial sonographic tumor prominence (p = 0.02). CONCLUSIONS: Ischemic changes induced by proton beam irradiation of central choroidal melanoma were localized and quantified. Ischemic changes exceed the tumor area distinctly and are found also outside of the irradiation field in the majority of patients. Size of irradiation area and tumor prominence are positively correlated with extent of ischemic area.

Salvage proton beam therapy for recurrent iris melanoma: outcome and side effects.

PURPOSE: This study aims to analyze the effect of salvage proton beam therapy for the treatment of recurrent iris melanoma. METHOD: In this clinical case series, we retrospectively analyzed the data of eight patients who underwent proton beam therapy of the whole anterior segment as salvage therapy between 2000 and 2016 for recurrent iris melanoma after resection, ruthenium brachytherapy, or sector proton beam therapy. Two patients received salvage proton beam therapy for repeated tumor relapse. All patients were observed and prepared for proton beam therapy at the Charité and irradiated at the Helmholtz-Zentrum Berlin where they received 50 cobalt Gray equivalents (CGE) in four daily fractions. We investigated survival rates and ocular outcome. RESULTS: Median follow-up after salvage proton beam therapy was 39 months. No local recurrence was detected during follow-up. One patient died from hepatic metastases 5.5 years after salvage therapy. Secondary glaucoma occurred in seven out of eight patients during follow-up. Two patients had chronic corneal erosion and two other patients presented with corneal decompensation, necessitating Descemet membrane endothelial keratoplasty (DMEK), and perforating keratoplasty. Median visual acuity was 0.2 logMAR before salvage proton beam therapy and 0.7 logMAR at the end of follow-up. CONCLUSION: Whole anterior segment salvage proton beam therapy has effectively controlled recurrent iris melanoma in our patients, but has been associated with a high incidence of radiation-induced corneal impairment and secondary glaucoma requiring extensive secondary treatment.

[Multimodal Imaging of the Choroidal Melanoma, with Differential Diagnosis, Therapy (Radiation Planning) and Follow-up]. / Multimodale Bildgebung des Aderhautmelanoms mit seinen Differenzialdiagnosen, Therapie (Bestrahlungsplanung) und Verlaufskontrolle.

Imaging of intraocular tumors is multimodal, multi-purpose, and in continuous development. Therefore, imaging is indispensable for the detection, diagnosis, therapy and monitoring of intraocular tumours. A broad spectrum of imaging procedures is available for diagnostic testing and follow-up. This includes colour image acquisition, infrared imaging, autofluorescence imaging, fluorescence and indocyanine green angiography, optical coherence tomography (OCT) and sonography (US). In this article, the various investigations and their benefits are described using individual examples for the differential diagnosis of choroidal melanoma and retinal vascular tumours located in the fundus periphery.

Magnetic resonance safety and compatibility of tantalum markers used in proton beam therapy for intraocular tumors: A 7.0 Tesla study.

PURPOSE: Proton radiation therapy (PRT) is a standard treatment of uveal melanoma. PRT patients undergo implantation of ocular tantalum markers (OTMs) for treatment planning. Ultra-high-field MRI is a promising technique for 3D tumor visualization and PRT planning. This work examines MR safety and compatibility of OTMs at 7.0 Tesla. METHODS: MR safety assessment included deflection angle measurements (DAMs), electromagnetic field (EMF) simulations for specific absorption rate (SAR) estimation, and temperature simulations for examining radiofrequency heating using a bow-tie dipole antenna for transmission. MR compatibility was assessed by susceptibility artifacts in agarose, ex vivo pig eyes, and in an ex vivo tumor eye using gradient echo and fast spin-echo imaging. RESULTS: DAM (α < 1 °) demonstrated no risk attributed to magnetically induced OTM deflection. EMF simulations showed that an OTM can be approximated by a disk, demonstrated the need for averaging masses of mave = 0.01 g to accommodate the OTM, and provided SAR0.01g,maximum = 2.64 W/kg (Pin = 1W) in OTM presence. A transfer function was derived, enabling SAR0.01g estimation for individual patient scenarios without the OTM being integrated. Thermal simulations revealed minor OTM-related temperature increase (δT < 15 mK). Susceptibility artifact size (<8 mm) and location suggest no restrictions for MRI of the nervus opticus. CONCLUSION: OTMs are not a per se contraindication for MRI. Magn Reson Med 78:1533-1546, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Proton therapy of iris melanoma with 50 CGE : Influence of target volume on clinical outcome.

PURPOSE: The aim of this study was to evaluate local tumour control, incidence of radiation-induced glaucoma and associated interventions of sector-based and whole anterior segment proton beam therapy (PBT) for the treatment of iris melanoma. PATIENTS AND METHODS: We retrospectively analysed the data of 77 patients with iris melanoma who underwent PBT applied as 50 CGE in four daily fractions. Of the patients, 47 received PBT with a circular-shaped collimator and 30 with a conformal sector-shaped target volume. Local control, eye preservation and secondary glaucoma were evaluated. RESULTS: Median follow-up time was 54.9 months. Local tumour control was 100% in patients receiving whole anterior segment irradiation. Two patients developed pigment dispersion in the non-irradiated area after sector-based PBT and received whole anterior segment salvage PBT. The mean volume of ciliary body irradiated was 89.0% and 34.9% for whole anterior segment and lesion-based irradiation, respectively. At the end of follow-up, secondary glaucoma was found in 74.3% of the patients with whole anterior segment irradiation and in 19.2% with sector-based irradiation. Patients with sector-based PBT had a stable visual acuity of logMAR 0.1, while it declined from logMAR 0.1 to 0.4 after whole anterior segment irradiation. CONCLUSION: We found a significant reduction in radiation-induced secondary glaucoma and glaucoma-associated surgical interventions and stable visual acuity after sector-based irradiation compared with whole anterior segment irradiation. Sector-based irradiation revealed a higher risk for local recurrence, but selected patients with well-circumscribed iris melanoma benefit from applying a lesion-based target volume when treated with sector-based PBT.

Predictive risk factors for radiation retinopathy and optic neuropathy after proton beam therapy for uveal melanoma.

PURPOSE: This study was performed in order to evaluate the incidence of radiation retinopathy and optic neuropathy occurring after proton beam therapy for uveal melanoma. METHODS: Included in this study were all patients who had been treated with primary proton beam therapy for uveal melanoma at the oncology service between May 1998 and June 2014 with a minimum follow-up of 12 months. Excluded were all patients who underwent re-irradiation, or vitrectomy due to exudative retinal detachment or for tumor-resection. RESULTS: During this period, 1127 patients matched the inclusion criteria, of whom 768 (68.1 %) and 463 (41.0 %) developed radiation retinopathy and optic neuropathy after a median time of 18.9 months (2.0-99.84 months) and 19.8 months (0.2-170.4 months), respectively. Mean follow-up was 53.4 months (12-170.4 months). Included were 558 men (49.5 %) and 569 women (50.5 %). Mean age was 61 years (16-89 years). Visual acuity slightly decreased from initial levels of 0.3 logMAR-0.4 logMAR in patients without developing any radiation-induced complication but severely decreased to 1.0 logMAR or 1.5 logMAR in the case of developing radiation retinopathy only or optic neuropathy, respectively. Independent risk factors for radiation retinopathy were a centrally (<2.5 mm from sensitive structures) located tumor or a thick tumor located more than 2.5 mm from sensitive structures, while those for radiation optic neuropathy comprised a short distance and applied dose to the optic disk. CONCLUSION: The risk for radiation retinopathy is higher in central uveal melanoma. Mid-/peripheral tumors are at high risk for radiation retinopathy and maculopathy if presenting with increased thickness.

Trabeculectomy in patients with uveal melanoma after proton beam therapy.

BACKGROUND: Retrospective evaluation of intraocular pressure, use of topical and systemic anti-glaucoma medication, secondary complications, local tumor control and survival in patients treated with trabeculectomy for the regulation of the intraocular pressure (IOP) after proton beam therapy for uveal melanoma. METHODS: In this retrospective clinical case series we evaluated the follow-up of 15 patients receiving a trabeculectomy as surgical treatment if the IOP could not be lowered adequately by medications or laser surgery. All patients had received proton beam therapy for uveal melanoma at the Helmholtz-Zentrum Berlin between 1998 and 2010. RESULTS: The median IOP decreased significantly from 35 mmHg ± 8.8 before TE to 16 mmHg ± 8.2 (=52.3 %) six months after TE (Wilcoxon-Mann-Whitney-U Test, p<0.01). None of the patients needed any glaucoma medication six months after trabeculectomy. Two patients developed local recurrence during follow-up, which were independent of the trabeculectomy. One patient had to be enucleated due to intractable pain and suspected remaining tumor activity. One patient died due to metastasis. CONCLUSIONS: Trabeculectomy is an option in intractable glaucoma in patients with uveal melanoma after proton beam therapy in single cases. Secondary interventions are common. Inoculation metastases are possible. Secure local tumor control must be a prerequisite for filtrating operations.

Cataract development in patients treated with proton beam therapy for uveal melanoma.

PURPOSE: To evaluate the incidence, risk factors, and dosages of proton beam therapy associated with cataract development, and long-term visual outcomes after treatment of uveal melanoma. METHODS: All patients receiving primary proton beam therapy for uveal melanoma between 1998 and 2008 with no signs of cataract before irradiation were included. A minimum follow-up of 12 months was determined. Exclusion criteria included all applied adjuvant therapies such as intravitreal injections, laser photocoagulation, tumor resections, or re-irradiation. For subgroup analysis, we included all patients who underwent brachytherapy between 1998 and 2008 for uveal melanoma, considering the above mentioned inclusion and exclusion criteria. RESULTS: Two hundred and fifty-eight patients matched our inclusion criteria. Median follow-up was 72.6 months (12.0-167.4 months). Of these 258 patients, 71 patients (66.3 %) presented with cataract after 31.3 months (0.7-142.4 months), of whom 35 (20.4 %) required surgery after 24.2 (0.7-111.1 months) to ensure funduscopic tumor control. Kaplan-Meier estimates calculated a risk for cataract of 74.3 % after 5 years. There was no increase in metastasis or local recurrence in these patients. Patient's age was the sole independent statistically significant risk factor for cataract development. The probability of cataract occurrence significantly increased with doses to lens exceeding 15-20 CGE. Neither the appearance of cataract nor cataract surgery influenced long-term visual outcome. CONCLUSION: Cataract formation is the most frequent complication after irradiation. There is no benefit vis-a-vis brachytherapy with regard to cataract development. Data indicate a dose-effect threshold of 0.5 CGE for cataractogenesis, with significantly increasing risk above a dose of 15 CGE. Furthermore, cataract surgery can be performed without an increased risk for metastasis.

PREDICTORS OF TREATMENT RESPONSE OF VASOPROLIFERATIVE RETINAL TUMORS TO RUTHENIUM-106 BRACHYTHERAPY.

PURPOSE: To identify predictors of treatment response by evaluating long-term outcomes of vasoproliferative retinal tumors after ruthenium-106 brachytherapy. METHODS: In a retrospective case series, 39 eyes of 38 patients with vasoproliferative retinal tumors received ruthenium-106 brachytherapy between 2001 and 2013. Baseline clinical and morphologic parameters were analyzed regarding posttreatment tumor activity status. RESULTS: Within a median follow-up period of 2.9 ± 2.9 years, overall, a tumor inactivation was achieved in 72% of cases and visual acuity remained stable in 69%. The mean apex dose was 90 ± 23 Gy (range, 51-140 Gy). Mean tumor thickness decreased significantly, from 2.9 ± 0.9 mm to 1.5 ± 1.0 mm (P < 0.001; paired t-test). Persistence or recurrence of tumor activity occurred in 28% of cases, requiring secondary intervention with intravitreal drug injections, vitrectomy, cryotherapy, or repeated brachytherapy. Comparison of inactive and active vasoproliferative retinal tumors revealed significant correlation between both initial basal tumour diameter and area and subsequent tumour activity status. In particular, a diameter >7.5 mm was associated with an 8-fold risk of persistent or recurrent activity, whereas basal area >40 mm demonstrated a 6-fold risk (P = 0.009 and 0.021, respectively; Fisher's exact-test). In contrast, tumor thickness was not found to be of prognostic relevance. CONCLUSION: Ruthenium-106 brachytherapy is an effective and safe therapeutic option for vasoproliferative retinal tumors. Additionally, tumor diameter and area are efficient predictors of persistence or recurrence of tumor activity.

Proton Therapy for 166 Patients with Iris Melanoma: Side Effects and Oncologic Outcomes.

OBJECTIVE: To investigate the oncologic and functional outcomes of a large cohort of patients with a favorable stage of circumscribed and diffuse iris melanoma who underwent primary proton treatment and the risk factors related to initial tumor characteristics and the treatment field architecture. DESIGN: Retrospective, single-center, case study. PARTICIPANTS: We reviewed 225 patients with iris melanoma who were consecutively treated with proton beam therapy at our institution between 1998 and 2020. METHODS: We performed Kaplan-Meier time-to-event analyses and multivariate Cox proportional hazard analyses to identify the impacts of tumor characteristics and target volumes on oncologic and functional outcomes. MAIN OUTCOME MEASURES: We measured local tumor control, eye preservation rates, metastasis-free survival, cataract and glaucoma-directed surgery, intraocular pressure, and changes in visual acuity. RESULTS: Of the 192 patients with tumors confined to the iris (T1a-c) who underwent proton therapy as primary treatment, a total of 166 patients (mean age, 58.4 years; 88 women) with a minimum follow-up of 6 months were included. Multifocal or diffuse tumor spread was present in 77 (46.4%) patients. The median follow-up time was 54.0 (interquartile range, 27.4-91.8 months) months. Local recurrence occurred in 2 patients (1.2%) with circumscribed iris melanoma. Enucleation was a rare event (n = 5, 3%) and no patient developed metastatic disease. A large-treatment field (full aperture, involving > 10 clock hours) was identified as a risk factor for the development of secondary glaucoma (hazard ratio [HR], 6.3; P < 0.001) and subsequent surgical interventions (HR, 10.85; P < 0.001). The large-treatment field group showed a significant decline in visual acuity (logarithm of the minimum angle of resolution > 0.3; log-rank P < 0.0001), which was associated with secondary glaucoma (HR, 3.40; P = 0.002). CONCLUSIONS: Proton therapy provides an effective, noninvasive treatment option for patients with a favorable stage of iris melanoma. Irradiation of the anterior segment for up to 10 clock hours is associated with a low risk of the development of secondary glaucoma and vision loss. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Commissioning and validation of a novel commercial TPS for ocular proton therapy.

BACKGROUND: Until today, the majority of ocular proton treatments worldwide were planned with the EYEPLAN treatment planning system (TPS). Recently, the commercial, computed tomography (CT)-based TPS for ocular proton therapy RayOcular was released, which follows the general concepts of model-based treatment planning approach in conjunction with a pencil-beam-type dose algorithm (PBA). PURPOSE: To validate RayOcular with respect to two main features: accurate geometrical representation of the eye model and accuracy of its dose calculation algorithm in combination with an Ion Beam Applications (IBA) eye treatment delivery system. METHODS: Different 3D-printed eye-ball-phantoms were fabricated to test the geometrical representation of the corresponding CT-based model, both in orthogonal 2D images for X-ray image overlay and in fundus view overlaid with a funduscopy. For the latter, the phantom was equipped with a lens matching refraction of the human eye. Funduscopy was acquired in a Zeiss Claus 500 camera. Tantalum clips and fiducials attached to the phantoms were localized in the TPS model, and residual deviations to the actual position in X-ray images for various orientations of the phantom were determined, after the nominal eye orientation was corrected in RayOcular to obtain a best overall fit. In the fundus view, deviations between known and displayed distances were measured. Dose calculation accuracy of the PBA on a 0.2 mm grid was investigated by comparing between measured lateral and depth-dose profiles in water for various combinations of range, modulation, and field-size. Ultimately, the modeling of dose distributions behind wedges was tested. A 1D gamma-test was applied, and the lateral and distal penumbra were further compared. RESULTS: Average residuals between model clips and visible clips/fiducials in orthogonal X-ray images were within 0.3 mm, including different orientations of the phantom. The differences between measured distances on the registered funduscopy image in the RayOcular fundus view and the known ground-truth were within 1 mm up to 10.5 mm distance from the posterior pole. No clear benefit projection of either polar mode or camera mode could be identified, the latter mimicking camera properties. Measured dose distributions were reproduced with gamma-test pass-rates of >95% with 2%/0.3 mm for depth and lateral profiles in the middle of spread-out Bragg-peaks. Distal falloff and lateral penumbra were within 0.2 mm for fields without a wedge. For shallow depths, the agreement was worse, reaching pass-rates down to 80% with 5%/0.3 mm when comparing lateral profiles in air. This is caused by low-energy protons from a scatter source in the IBA system not modeled by RayOcular. Dose distributions modified by wedges were reproduced, matching the wedge-induced broadening of the lateral penumbra to within 0.4 mm for the investigated cases and showing the excess dose within the field due to wedge scatter. CONCLUSION: RayOcular was validated for its use with an IBA single scattering delivery nozzle. Geometric modeling of the eye and representation of 2D projections fulfill clinical requirements. The PBA dose calculation reproduces measured distributions and allows explicit handling of wedges, overcoming approximations of simpler dose calculation algorithms used in other systems.

Technical note: Impact of beam properties for uveal melanoma proton therapy-An in silico planning study.

PURPOSE: To evaluate the impact of beam quality in terms of distal fall-off (DFO, 90%-10%) and lateral penumbra (LP, 80%-20%) of single beam ocular proton therapy (OPT) and to derive resulting ideal requirements for future systems. METHODS: Nine different beam models with DFO varying between 1 and 4 mm and LP between 1 and 4 mm were created. Beam models were incorporated into the RayStation with RayOcular treatment planning system version 10 B (RaySearch Laboratories, Stockholm, Sweden). Each beam model was applied for eight typical clinical cases, covering different sizes and locations of uveal melanoma. Plans with and without an additional wedge were created, resulting in 117 plans with a total prescribed median dose of 60 Gy(RBE) to the clinical target volume. Treatment plans were analyzed in terms of V20-V80 penumbra volume, D1 (dose to 1% of the volume) for optic disc and macula, optic nerve V30 (volume receiving 30 Gy(RBE), i.e., 50% of prescription), as well as average dose to lens and ciliary body. An LP-dependent aperture margin was based on estimated uncertainties, ranging from 1.7 to 4.0 mm. RESULTS: V20-V80 showed a strong influence by LP, while DFO was less relevant. The optic disc D1 reached an extra dose of up to 3000 cGy(RBE), comparing the defined technical limit of DFO = LP = 1 mm with DFO = 3 mm/LP = 4 mm. The latter may result from a pencil-beam scanning (PBS) system with static apertures. Plans employing a wedge showed an improvement for organs at risk sparing. CONCLUSION: Plan quality is strongly influenced by initial beam parameters. The impact of LP is more pronounced when compared to DFO. The latter becomes important in the treatment of posterior tumors near the macula, optic disc or optic nerve. The plan quality achieved by dedicated OPT nozzles in single- or double-scattering design might not be achievable with modified PBS systems.

Quality of life and treatment-related burden during ocular proton therapy: a prospective trial of 131 patients with uveal melanoma.

BACKGROUND: Proton beam therapy is a well-established treatment option for patients with uveal melanoma (UM). The treatment procedure, in general, includes placing radiopaque clips to ensure exact eye-positioning during radiotherapy, followed by the delivery of proton irradiation. The short-term burden associated with proton therapy in patients with UM has rarely been addressed. In this prospective study, we investigated the physiological and psychological aspects of proton therapy that might affect the well-being of patients during the different stages of treatment. METHODS: During the treatment procedure, we conducted longitudinal assessments of the Quality of life (QOL), organ-specific symptoms, and psychological aspects in patients with UM with three questionnaires (EORTC QLQ-C30, EORTC QLQ-OPT30, and GAD-7). Patients completed questionnaires before clip surgery (T0), before proton therapy (T1), after completing treatment (T2), and three months after treatment completion (T3). We also collected data on tumor characteristics and socio-demographics to identify potential risk factors associated with high treatment burdens. RESULTS: We prospectively included 131 consecutive patients. Questionnaire data showed a significant, temporary decline in global QOL and an increase in eye-related symptoms, as a result of the clip surgery (T0-T1). After treatment completion (T2), global QOL improved gradually, and none of the eye-related symptoms significantly deteriorated over the course of proton therapy. The global QOL returned to baseline levels three months after treatment (T3). We identified baseline anxiety as an independent risk factor for experiencing an acute treatment-related burden. Furthermore, we found interactions between GAD7 and patient sex showing that anxiety had a more pronounced effect on QOL outcome in female patients. CONCLUSION: The short-term treatment-related burden of ocular proton therapy appeared to be largely associated with the preceding clip surgery, rather than the irradiation procedure. We found that anxiety was strongly associated with experiencing QOL issues during the treatment procedure. Our findings could contribute to the development of future strategies for improving the treatment process and psycho-oncologic patient care.

FLASH proton irradiation setup with a modulator wheel for a single mouse eye.

PURPOSE: Recent studies indicate that FLASH irradiation, which involves ultra-high dose rates in a short time window (usually >40 Gy/s in <500 ms), might be equally efficient against tumors but less harmful to healthy tissues, compared to conventional irradiation with the same total dose. Aiming to verify the latter claim for ocular proton radiotherapy, in vivo experiments with mice are being carried out by Charité - Universitätsmedizin Berlin. This work presents the implemented setup for delivering FLASH proton radiation to a single eye of mice at the Helmholtz-Zentrum Berlin für Materialien und Energie (HZB). MATERIALS AND METHODS: The HZB cyclotron is tuned to provide a high-intensity 68 MeV focused proton beam. Outside the vacuum beamline, the protons hit a single scatterer, which also serves as range shifter, and a rotating modulator wheel, which produces a flat depth-dose distribution. Two transmission ionization chambers in between, read out by fast electronics, are used as dose monitors for triggering an in-vacuum beam shutter, which blocks the beam once the desired dose has been delivered. A collimating aperture shapes the radiation field at the isocenter, which is measured by a radioluminescent screen and a CCD camera. At the same position, a parallel-plate ionization chamber of type Advanced Markus® is used for absolute dosimetry and characterization of the spread-out Bragg peak inside a water phantom. A thin-foil mirror of adjustable tilt in the beam path assists the correct alignment of the target through side illumination. Radiochromic films of type EBT3 are used to supplement the dosimetry and assist the alignment. RESULTS: A dose rate of 75 Gy/s has been measured, delivering within 200 ms 15 Gy (RBE) with a reproducibility better than ±1%. A depth-dose curve with a range of 5.2 mm in water, 0.9 mm distal fall-off (90%-10%), and ±2.5% ripple has been demonstrated, with a PTV of 6.3 mm diameter, 1.7 mm lateral penumbra (90%-10%), 8% uniformity, and 3% symmetry. CONCLUSIONS: The implemented setup is able to accommodate ocular irradiation of narcotized mice with protons, targeting selectively the left or the right eye, under conventional and FLASH conditions. Switching between these two modes can be done within half an hour, including the calibration of the dose monitors and the verification of the dose delivery. Further upgrades are planned after the completion of the on-going experiment.

Characterization of the HollandPTC proton therapy beamline dedicated to uveal melanoma treatment and an interinstitutional comparison.

PURPOSE: Eye-dedicated proton therapy (PT) facilities are used to treat malignant intraocular lesions, especially uveal melanoma (UM). The first commercial ocular PT beamline from Varian was installed in the Netherlands. In this work, the conceptual design of the new eyeline is presented. In addition, a comprehensive comparison against five PT centers with dedicated ocular beamlines is performed, and the clinical impact of the identified differences is analyzed. MATERIAL/METHODS: The HollandPTC eyeline was characterized. Four centers in Europe and one in the United States joined the study. All centers use a cyclotron for proton beam generation and an eye-dedicated nozzle. Differences among the chosen ocular beamlines were in the design of the nozzle, nominal energy, and energy spectrum. The following parameters were collected for all centers: technical characteristics and a set of distal, proximal, and lateral region measurements. The measurements were performed with detectors available in-house at each institution. The institutions followed the International Atomic Energy Agency (IAEA) Technical Report Series (TRS)-398 Code of Practice for absolute dose measurement, and the IAEA TRS-398 Code of Practice, its modified version or International Commission on Radiation Units and Measurements Report No. 78 for spread-out Bragg peak normalization. Energy spreads of the pristine Bragg peaks were obtained with Monte Carlo simulations using Geant4. Seven tumor-specific case scenarios were simulated to evaluate the clinical impact among centers: small, medium, and large UM, located either anteriorly, at the equator, or posteriorly within the eye. Differences in the depth dose distributions were calculated. RESULTS: A pristine Bragg peak of HollandPTC eyeline corresponded to the constant energy of 75 MeV (maximal range 3.97 g/cm2 in water) with an energy spread of 1.10 MeV. The pristine Bragg peaks for the five participating centers varied from 62.50 to 104.50 MeV with an energy spread variation between 0.10 and 0.70 MeV. Differences in the average distal fall-offs and lateral penumbrae (LPs) (over the complete set of clinically available beam modulations) among all centers were up to 0.25 g/cm2 , and 0.80 mm, respectively. Average distal fall-offs of the HollandPTC eyeline were 0.20 g/cm2 , and LPs were between 1.50 and 2.15 mm from proximal to distal regions, respectively. Treatment time, around 60 s, was comparable among all centers. The virtual source-to-axis distance of 120 cm at HollandPTC was shorter than for the five participating centers (range: 165-350 cm). Simulated depth dose distributions demonstrated the impact of the different beamline characteristics among institutions. The largest difference was observed for a small UM located at the posterior pole, where a proximal dose between two extreme centers was up to 20%. CONCLUSIONS: HollandPTC eyeline specifications are in accordance with five other ocular PT beamlines. Similar clinical concepts can be applied to expect the same high local tumor control. Dosimetrical properties among the six institutions induce most likely differences in ocular radiation-related toxicities. This interinstitutional comparison could support further research on ocular post-PT complications. Finally, the findings reported in this study could be used to define dosimetrical guidelines for ocular PT to unify the concepts among institutions.

Practice Considerations for Proton Beam Radiation Therapy of Uveal Melanoma During the Coronavirus Disease Pandemic: Particle Therapy Co-Operative Group Ocular Experience.

Uveal melanoma (UM) is a rare but life-threatening cancer of the eye. In light of the coronavirus disease (COVID-19) pandemic, hospitals and proton eye therapy facilities must analyze several factors to ensure appropriate treatment protocols for patients and provider teams. Practice considerations to limit COVID-19 transmission in the proton ocular treatment setting for UM are necessary. The Particle Therapy Co-Operative Group is the largest international community of particle/proton therapy providers. Participating experts have current or former affiliation with the member institutions of the Particle Therapy Co-Operative Group Ocular subcommittee with long-standing high-volume proton ocular programs. The practices reviewed in this document must be taken in conjunction with local hospital procedures, multidisciplinary recommendations, and regional/national guidelines, as each community may have its unique needs, supplies, and protocols. Importantly, as the pandemic evolves, so will the strategies and recommendations. Given the unique circumstances for UM patients, along with indications of potential ophthalmologic transmission as a result of health care providers working in close proximity to patients and intrinsic infectious risk from eyelashes, tears, and hair, practice strategies may be adapted to reduce the risk of viral transmission. Certainly, providers and health care systems will continue to examine and provide as safe and effective care as possible for patients in the current environment.