Gy RBE Research Articles

Dosimetric evaluation of intensity modulated photon versus proton reirradiation of head and neck cancer

BackgroundReirradiation of head and neck cancer (HNC) became more accessible in the last decade, owing to modern irradiation techniques which offer a reduction in treatment related toxicities. The aim of this paper was to comparatively evaluate the dosimetric aspects derived from intensity modulated photon vs. proton treatment planning in reirradiated HNC patients. MethodsSix recurrent HNC patients were enrolled in this retrospective study. For each patient two treatment plans were created: one IMRT/VMAT and one IMPT plan. The prescribed dose for the second irradiation was between 50 and 70 Gy RBE. The study comparatively analyzed the CTV coverage, doses to organs at risk (OARs) and low doses received by the healthy tissue (other than OAR). ResultsSimilar CTV coverage was achieved for photon vs proton plans, with the latter presenting better homogeneity in four cases. Maximum dose to CTV was generally higher for photon plans, with differences ranging from 0.3 to 1.9%. For parotid glands and body, the mean dose was lower for proton plans. A notable reduction of low dose to healthy tissue (other than OARs) could be achieved with protons, with an average of 60% and 64% for D10% and Dmean, respectively. ConclusionThe dosimetric comparison between photon and proton reirradiation of HNC showed a great need for treatment individualization, concluding that protons should be considered for reirradiation on an individual basis.

Dose and DNA damage modelling of diffusing alpha-emitters radiation therapy using Geant4

Purpose:Diffusing alpha-emitters radiation therapy (DaRT) is a brachytherapy technique using α-particles to treat solid tumours. The high linear energy transfer (LET) and short range of α-particles make them good candidates for the targeted treatment of cancer. Treatment planning of DaRT requires a good understanding of the dose from α-particles and the other particles released in the 224Ra decay chain. Methods:The Geant4 Monte Carlo toolkit has been used to simulate a DaRT seed to better understand the dose contribution from all particles and simulate the DNA damage due to this treatment. Results:Close to the seed α-particles deliver the majority of dose, however at radial distances greater than 4 mm, the contribution of β-particles is greater. The RBE has been estimated as a function of number of double strand breaks (DSBs) and complex DSBs. A maximum seed spacing of 5.5 mm and 6.5 mm was found to deliver at least 20 Gy RBE weighted dose between the seeds for RBEDSB and RBEcDSB respectively. Conclusions:The DNA damage changes with radial distance from the seed and has been found to become less complex with distance, which is potentially easier for the cell to repair. Close to the seed α-particles contribute the majority of dose, however the contribution from other particles cannot be neglected and may influence the choice of seed spacing.

Prognostic analysis of radiation-induced liver damage following carbon-ion radiotherapy for hepatocellular carcinoma

BackgroundRadiation-induced liver damage (RILD) occasionally occurs following carbon-ion radiotherapy (CIRT) for liver tumors, such as hepatocellular carcinoma (HCC), in patients with impaired liver function disease. However, the associated risk factors remain unknown. The present study aimed to determine the risk factors of RILD after CIRT.MethodsWe retrospectively analyzed 108 patients with HCC treated with CIRT at the Osaka Heavy Ion Therapy Center between December 2018 and December 2022. RILD was defined as a worsening of two or more points in the Child–Pugh score within 12 months following CIRT. The median age of the patients was 76 years (range 47–95 years), and the median tumor diameter was 41 mm (range 5–160 mm). Based on the pretreatment liver function, 98 and 10 patients were categorized as Child–Pugh class A and B, respectively. We analyzed patients who received a radiation dose of 60 Gy (relative biological effectiveness [RBE]) in four fractions. The median follow-up period was 9.7 months (range 2.3–41.1 months), and RILD was observed in 11 patients (10.1%).ResultsMultivariate analysis showed that pretreatment Child–Pugh score B (p = 0.003, hazard ratio [HR] = 6.90) and normal liver volume spared from < 30 Gy RBE (VS30 < 739 cm3) (p = 0.009, HR = 5.22) were significant risk factors for RILD. The one-year cumulative incidences of RILD stratified by Child–Pugh class A or B and VS30 < 739 cm3 or ≥ 739 cm3 were 10.3% or 51.8% and 39.6% or 9.2%, respectively.ConclusionIn conclusion, the pretreatment Child–Pugh score and VS30 of the liver are significant risk factors for RILD following CIRT for HCC.

Prospective Analysis of Radiation-Induced Contrast Enhancement and Health-Related Quality of Life After Proton Therapy for Central Nervous System and Skull Base Tumors

Intracerebral radiation-induced contrast enhancement (RICE) can occur after photon as well as proton beam therapy (PBT). This study evaluated the incidence, characteristics, and risk factors of RICE after PBT delivered to, or in direct proximity to, the brain and its effect on health-related quality of life (HRQoL). Four hundred twenty-one patients treated with pencil beam scanning PBT between 2017 and 2021 were included. Follow-up included clinical evaluation and contrast-enhanced magnetic resonance imaging at 3, 6, and 12 months after treatment completion and annually thereafter. RICE was graded according to Common Terminology Criteria for Adverse Events version 4, and HRQoL parameters were assessed via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaires. The median follow-up was 24 months (range, 6-54), and median dose to 1% relative volume of noninvolved central nervous system (D1%CNS) was 54.3 Gy relative biologic effectiveness (RBE; range, 30-76 Gy RBE). The cumulative RICE incidence was 15% (n = 63), of which 10.5% (n = 44) were grade 1, 3.1% (n = 13) were grade 2, and 1.4% (n = 6) were grade 3. No grade 4 or 5 events were observed. Twenty-six of 63 RICE (41.3%) had resolved at the latest follow-up. The median onset after PBT and duration of RICE in patients in whom the lesions resolved were 11.8 and 9.0 months, respectively. On multivariable analysis, D1%CNS > 57.6 Gy RBE, previous in-field radiation, and diabetes mellitus were identified as significant risk factors for RICE development. Previous radiation was the only factor influencing the risk of symptomatic RICE. After PBT, general HRQoL parameters were not compromised. In a matched cohort analysis of 54/50 patients with and without RICE, no differences in global health score or functional and symptom scales were seen. The overall incidence of clinically relevant RICE after PBT is very low and has no significant negative effect on long-term patient QoL.

Treatment of Thymoma and Thymic Carcinoma with Proton Beam Therapy: Outcomes from the Proton Collaborative Group Prospective Registry

Given the generally long natural history of thymic malignancies, proton beam therapy (PBT) is advocated to minimize the risk of long-term toxicities to mediastinal organs. Adverse events (AE) and long-term clinical outcomes for this population have not been well-characterized. The Proton Collaborative Group registry (NCT01255748), a multi-institutional prospective database of academic and community proton centers in the US, was queried for patients with thymomas and thymic carcinomas treated with PBT. Patients with recurrent/metastatic disease, non-thymic histology, received either prior or palliative radiotherapy (dose < 40 Gy RBE) were excluded. Overall survival (OS) and local control (LC) were estimated using Kaplan-Meier methods. A total of 97 patients were identified in the PCG registry. After applying relevant exclusion criteria, 70 patients from 12 proton centers treated from 2011-2021 were included for analysis. Median follow-up length was 16 months. Median age was 58.5 years (IQR 46-63), and 60% were female. 81.4% had a diagnosis of thymoma, and 18.6% thymic carcinoma. 59 patients underwent surgical resection. 11 were treated with definitive PBT, of which 5 received concurrent chemotherapy. Median dose was 54 Gy RBE (range 41.4 - 70 Gy RBE), median number of fractions was 30 (range 21 - 38). 73.4% received pencil beam scanning and 23% uniform scanning PBT. Treatment was overall well-tolerated: a single patient developed grade 4 pneumonitis. Grade 3 AEs were seen in 3 patients - dyspnea, anorexia, and heart failure. Highest grade toxicity experienced was grade 2 for 47.1% and grade 1 for 42.9% of patients. 3-year overall survival (OS) was 82.6% for the entire cohort. 3-year OS was 94% for resected/adjuvant cohort and 35.6% in the non-surgical/definitive cohort. 3-year local control (LC) was 91.7% for the entire cohort. By surgery/margin status, 3-year LC was 96.8% in patients with close or negative margins (a single failure in a patient with close margins), whereas 3-year LC was 55.1% for patients with positive margins/unresectable disease. Thymic malignancies treated with PBT appear to have favorable outcomes, especially in the adjuvant setting, in this cohort representing the largest series of such patients.

Efficacy of Protontherapy in Atypical Meningiomas

To assess the efficacy and safety of complementary radiotherapy (RT) [by proton beams alone (PT) or in combination with photon beams (Ph)] to surgery in the local treatment of atypical meningiomas. One hundred one consecutive patients with atypical (WHO grade II) meningiomas were treated with PT +/- Ph at our institution between Nov 1996 to Sep 2022. The total median dose was 59.4 Gy RBE (range 59.4- 68.4) with Proton component alone (n = 76) or PT + Ph (n = 25). The median age at RT was 57.2 years old (range 22.0-79.6). Localization was supratentorial in 62 patients (61.4%), skull base in 29 patients (28.7%), and infratentorial in 10 patients (9.9%). Gross tumor resection was reported in 20 cases (19.8%) and subtotal in 81 (80.2%), 34 patients underwent multiples (2-4) surgeries before RT. Overall survival (OS), meningioma related survival (MRS), Progression Free Survival (PFS), Time to Local progression (TLP), and 3, 5 and 10-year survival rates were evaluated using Kaplan-Meier method. All post-PT clinical toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v 5.0). During follow-up after PT (median 47.8 months), local progression was reported in 26 patients (25.7%) and 24 patients died (including 13 meningioma-related deaths). Median TLP was 34.3 months (IC 95% 1.9-128.1), OS was 163 months (IC95% 93.9-232.2), MRS was 34.3 (IC 95% 1.9-128.1) and PFS was 41.4 (IC 95% 1.5-217.8). Actuarial 3, 5 and 9-year OS was 83%, 78% and 66%, while MRS was 89%, 83% and 71% respectively. Patients treated with PT alone presented better OS with 9 deaths (6 meningioma-related deaths) and median of 163.0 months [IC95% (93.9-232.2)], 3y-95%, 5y-93%, 10y-65%, respectively. However, the Patients treated with PT+Ph presented 15 deaths (7 meningioma-related deaths) and median of 51.9 months [IC 95% (7.0-96.8); 2y-75%, 5y-50%, 10y-50%) (p = 0.018). Median TLR was 36.4 months (26.6-46.2) after PT alone and 11.9 months (10.3-13.5) after PT+Ph. However, well-controlled radionecrosis ≤ Grade2 was more frequent after PT alone 20 cases vs 3 cases after PT+Ph. Long-term symptoms was observed during the last visit in 45 patients (44.6%) treated with PT vs. 8 (38.1%) treated with PT+Ph. PT alone or PT+Ph were effective and well-tolerated treatment in WHO grade II meningioma and PT alone appeared to be better for the local control and survival.

P07.10.A CLINICAL OUTCOMES OF SPOT-SCANNING PROTON BEAM THERAPY FOR IDH-MUTANT CNS WHO GRADE 2 AND 3 GLIOMA

Abstract BACKGROUND The latest WHO brain tumour classification puts utmost emphasis on prognostic significance of isocitrate dehydrogenase (IDH) mutation. IDH-wildtype tumours are now automatically considered CNS WHO grade 4 and associated with poor prognosis. On the contrary, patients with IDH1/2-mutant tumours have a favourable outcome. A high chance of long-term survival justifies the use of proton beam therapy (PBT) in these patients as it reduces unnecessary dose to unaffected brain and, consequently, late side effects. The data on outcomes specific for IDH-mutant tumours, in particular CNS WHO grade 3, remains limited. In this study we analysed the results of PBT in patients with IDH-mutant glioma of both CNS WHO grade 2 and 3 treated at our institution. MATERIAL AND METHODS The analysis included 30 patients enrolled in MedAustron prospective registry study (NCT03049072), who were diagnosed with CNS WHO Grade 2 and 3 glioma with IDH1/2 mutation. The median patient age was 38.8 years (range: 20.3 - 77.9) and male to female ratio was 16:14. The median time from last surgery to PBT was 91 days. CNS WHO grade 2 tumours (n =17) were treated with 54-54.04 Gy RBE total dose in 27-30 fractions and CNS WHO grade 3 tumours (n = 13) received 59.6-60 Gy RBE in 30-33 fractions. Fifteen (50%) and 24 (80%) of patients received temozolomide-based concomitant and adjuvant chemotherapy, respectively. Follow-up including MRI was obtained at 3, 6 and 12 months post PBT completion and then annually. RESULTS The median follow-up was 46.1 months (range: 13-69). Actuarial 3-year PFS of the whole cohort was 84.7% (95%CI: 64.1%-94%) and OS was 95.8% (95%CI: 73.9%-99.4%). At latest follow-up, 14 out of 17 patients with CNS WHO grade 2 (82.4%) and 8 out of 13 CNS WHO grade 3 tumours (61.5%) remained progression-free. Two patients died due to disease progression. This corresponded to actuarial 3-year PFS and OS of 86.8% (95%CI: 56.6%-96.6%) and 91.7% (95%CI: 53.9%-98.8%) for CNS WHO grade 2 and 83.3% (95%CI: 48.2%-95.5%) and 100% for CNS WHO grade 3 tumours, respectively. No risk factors of death and disease progression could be identified. Specifically, no significant differences were observed between CNS WHO grade 2 and 3 tumours for neither OS nor PFS (p = 1.0 and p = 0.32, respectively). The average time to progression in patients with treatment failure was 35.3 months. Only one patient (3.3%) developed grade ≥ 3 toxicity (G3 transient seizures). Radiation-induced brain lesions (RIBL) were identified in 11 patients (36.7%), out of which 10 (90.9%) remained asymptomatic. The median time to RIBL onset was 11.48 months and median duration in patients in whom RIBL eventually resolved was 14.8 months. CONCLUSION Our clinical data demonstrate that PBT is a safe and effective treatment of IDH-mutant glioma. Due to favourable and comparable outcomes of both grade 2 and 3 IDH-mutant tumours it is a valuable therapeutic option for both patient groups.

Proton or Carbon Ion Therapy for Skull Base Chordoma: Rationale and First Analysis of a Mono-Institutional Experience

Skull base chordomas are radio-resistant tumors that require high-dose, high-precision radiotherapy, as can be delivered by particle therapy (protons and carbon ions). We performed a first clinical outcome analysis of particle therapy based on the initial 4-years of operation. Between August 2017 and October 2021, 44 patients were treated with proton (89%) or carbon ion therapy (11%). Prior gross total resection had been performed in 21% of lesions, subtotal resection in 57%, biopsy in 12% and decompression in 10%. The average prescription dose was 75.2 Gy RBE in 37 fractions for protons and 66 Gy RBE in 22 fractions for carbon ions. At a median follow-up of 34.3 months (range: 1-55), 2-, and 3-year actuarial local control rates were 95.5% and 90.9%, respectively. The 2-, and 3-year overall and progression-free survival rates were 97.7%, 93.2%, 95.5% and 90.9%, respectively. The tumor volume at the time of particle therapy was highly predictive of local failure (p < 0.01), and currently, there is 100% local control in patients with tumors < 49 cc. No grade ≥3 toxicities were observed. There was no significant difference in outcome or side effect profile seen for proton versus carbon ion therapy. Five patients (11.4%) experienced transient grade ≤2 radiation-induced brain changes. The first analysis suggests the safety and efficacy of proton and carbon ion therapy at our center. The excellent control of small to mid-size chordomas underlines the effectiveness of particle therapy and importance of upfront maximum debulking of large lesions.

Proton Therapy for Uveal Melanoma: A Single-Institution Experience

<h3>Purpose/Objective(s)</h3> Uveal melanoma (UM) is the most common intraocular malignancy in adults. Eye-preserving approaches like episcleral plaque brachytherapy are common but limited in patients (pts) with large tumors or those adjacent to the optic nerve. Proton therapy (PT) offers an alternative eye-preserving treatment option. We report a single-institution experience utilizing PT to treat UM. We hypothesized that PT would provide excellent local control (LC) and eye preservation (EP) with acceptable toxicity and visual outcomes across all patients, including those with large tumors in adverse locations. <h3>Materials/Methods</h3> We reviewed the records of treatment-naive pts who received PT for non-metastatic UM between June 2012 and December 2020. All pts had ≥ 6 months of follow-up. Treatment planning was performed in EyePlan (Clatterbridge, UK) based on eye/tumor measurements and 3-4 implanted scleral fiducial markers, registered fundus photographs, and confirmed by CT/MRI. Pts were set-up in a seated position with gaze fixation and real-time image guidance using a single en face beam to a total 50-60 Gy RBE in 4-5 consecutive daily fractions. We estimated disease control and survival, including LC, EP, distant metastasis-free survival (DMFS), cause-specific survival (CSS), overall survival (OS), and grade 3+ toxicity as defined by CTCAEv5 using the cumulative incidence method. Regression of multiple variables simultaneously was accomplished with competing-risks Cox regression. <h3>Results</h3> 120 pts met inclusion criteria; 33 had a biopsy of their lesion; 9.2% were class 2. Moreover, 47.5% had COMS medium while 35.8% had large tumors. Median tumor thickness was 5.0 mm (0.5 – 13.0) and median basal dimension was 13.0 mm (4.0 – 25.0). Median distance to the fovea and optic disc was 3.5 mm. 38% had retinal detachment with 47% having significantly impaired visual acuity at baseline (worse than Snellen 20/40). 98.3% received 60 Gy RBE over 4 daily fractions. Median follow-up was 31 months (6 – 104). The 2-year estimates (95% CI) for LC, EP, DMFS, CSS, and OS were 94% (88-97%), 95% (90-98%), 88% (81-93%), 94% (88-97%), and 90% (83-95%), respectively. 9 pts underwent enucleation following PT (5 for recurrent/persistent disease). Retinopathy (5%), neovascular glaucoma (3.3%), and optic nerve disorder (2.5%) were the most common severe toxicities. 60% of toxicity resolved during follow-up. 38% had functional vision (20/40 or better) at last follow-up. Pretreatment visual acuity had a substantial impact on post-treatment vision. Tumor size was an independent prognostic factor for OS (p=0.01), CSS (p<0.01), EP (p=0.02), and DMFS (p<0.01). No prognostic factor was associated with LC. <h3>Conclusion</h3> Our experience using PT for UM is consistent with previously reported outcomes demonstrating high rates of LC and EP with acceptable toxicity despite a significant percentage of patients with large tumors and/or adverse location near the optic nerve.

Patient-Reported and Dosimetric Determinants of Trismus after Chemoradiation with Proton Beam for Nasopharyngeal Carcinoma: A Prospective Study

<h3>Purpose/Objective(s)</h3> Trismus after radiation therapy for head and neck cancer is common. Yet, prospective efforts investigating patient reported outcomes with dosimetric predictors are lacking. <h3>Materials/Methods</h3> We conducted a prospective, phase II clinical trial of adult patients with biopsy proven, stage IIB-IVB nasopharyngeal cancer treated with concurrent proton-based chemoradiotherapy (cisplatin 100 mg/m2 q 3week), followed by adjuvant cisplatin and 5-fluorouracil. Trismus was assessed in a multifactorial fashion. Objective trismus was defined as a decrease in maximal inter-incisal distance (MID) of >20%, relative to baseline. Patient-reported trismus was assessed using trismus domain of the EORTC QLQ H&N35 questionnaire. The relationship between radiation dose to the muscles of mastication/temporomandibular joint (TMJ) and the development of trismus was evaluated using Cox regression. <h3>Results</h3> Between 2006-2011, 24 patients were enrolled. Median age was 48 years old. Median follow-up was 3.0 years. 63% of patients had stage III/IV disease. The mean doses to the lateral pterygoids, medial pterygoids, suprahyoids, infrahyoids, masseters, temporalis, and TMJs was 54, 51, 16, 46, 14, 12, and 32 Gy RBE, respectively. Eleven patients developed objective trismus. The median decrease in MID at 24 months was 6mm (range 1-19mm, IQR 5-11mm). Nine patients developed patient-reported trismus. Association of presence vs absence of patient-reported trismus and decline in 2y MID was seen (median 10mm vs 5mm, p=.03). Dose (per Gy increase) to the lateral pterygoids was associated with patient-reported trismus (HR 1.16, 95% CI 1.01-1.33, p=.04) and magnitude of decline in 2y MID (β=0.48mm, 95% CI 0.01-0.96mm, p=.045) but not objective trismus (HR 1.07, 95% CI 0.96-1.19, p=.25). Dose (per Gy increase) to TMJs was associated with patient-reported trismus (HR 1.14, 95% CI 1.02-1.26, p=.02), objective trismus (HR 1.12, 95% CI 1.01-1.25, p=.04) and magnitude of decline in 2y MID (β =0.53mm, 95% CI 0.12-0.95mm, p=.01). Patients with patient-reported trismus had higher mean dose to TMJ (36 vs 30 Gy, p=0.01) and lateral pterygoids (57 vs 52 Gy, p=0.03) than those who did not. <h3>Conclusion</h3> In this prospective study incorporating a homogeneous patient population and treatment regimen, the development of patient-reported trismus after chemoradiation with proton beam was associated with increase in mean dose to the lateral pterygoids and TMJ and decline in 2y MID. Delineation and avoidance of these structures seems prudent.

JS09.6.A Low incidence of radiation-induced brain lesions and stable QoL following proton irradiation for CNS and Skull Base tumors- results from the prospective MedAustron register REGI-MA-002015

Abstract Background Irradiation of intracranial tumors may induce endothelial damage in the surrounding normal brain tissues, resulting in an increase of capillary permeability. These changes can be depicted on magnetic resonance imaging (MRI) as a new contrast medium uptake - not associated with tumor. Radiation-induced brain lesions (RIBL) occur after photon as well as proton irradiation. This study evaluated the incidence of RIBL after proton irradiation and their impact on Quality of Life (QoL). Material and Methods 421 patients treated between 01/2017 and 06/2021 were included. All patients participated in a prospective registry study (ClinicalTrials.gov Identifier: NCT03049072). Follow-up evaluations including MRIs were at 3,6,12 months after treatment completion and annually thereafter. QoL parameters were assessed by EORTC-CTC30 and BN20 questionnaires. Results 48.9% (n=206) patients received therapy for intracranial non-CNS tumors (meningioma, pituitary adenoma, and other), 26.8% (n=113) for head and neck cancer with skull base involvement, 14.5% (n=61) for primary CNS tumors and 9.7% (n=41) for skull base tumor. Median follow-up was 24 months (range 6-54 ), 352 (86%) patients had proton therapy as primary treatment, 59 (14%) had salvage treatment with proton re-irradiation (ReRT). Median prescribed dose was 58.5 Gy (RBE) (range 40-78 Gy (RBE)), median D1% of brain tissue was 54.3 Gy (RBE) (range 30-76 Gy RBE). Local control and overall survival were 91% and 95% at 2 years. The cumulative RIBL incidence was 15.0% (n=63), with significantly lower occurrence in the primary RT group vs. the ReRT group (12.9% vs. 27.1%; p&amp;lt;0.001). According to Grade, the distribution was 10.5% (n=44) Grade I (asymptomatic, MRT finding only), Grade II RIBL, 13 (3.1%) (moderate symptoms) (grade 2) and 1,4% (n=6) developed Grade 3 toxicity. Actuarial 2-year RIBL incidence was 18.2% (95%CI: 14.1-23.2) for the all Grades and the entire, 15.7% (95%CI: 11.6-21) following primary radiation and 34.2% (95%CI: 21.9-50.9) after ReRT. All RIBL developed outside the residual tumor, but inside the Planning Target Volume (PTV), median D1% was 60.3Gy (RBE) (range 46.1- 122.3 Gy(RBE)), median time to development was 11.8 months (range 2.7-37 months) in the total cohort, for primary RT 14.2mo (4.3mo -37.1mo) and 6.0mo (2.7mo -19.3mo) following ReRT. At the time of analysis 26 of the 63 RIBL had resolved (41.3%). General QoL was not compromised. In a matched-pair analysis of 54/50 patients with/without RIBL, only at the 12 month a significant difference in the global health score in favour of non-RIBL patients was observed. At 24 months the score for RIBL patients improved without difference between the groups. Conclusion Overall incidence of RIBL after proton radiotherapy is very low - even for skull base tumors requiring high total doses and it had no significant negative impact on long term QoL.

Radiation-induced contrast enhancement following proton radiotherapy for low-grade glioma depends on tumor characteristics and is rarer in children than adults

Background and purposeProton beam radiotherapy (PRT) is used in the treatment of low-grade glioma (LGG) to mitigate long-term sequelae. Following PRT, increased rates of radiation-induced contrast enhancements (RICE) are suspected but poorly understood. Materials and methodsWe analyzed consecutive 227 patients (42 children and 185 adults) treated with PRT (54 Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years. ResultsTumors were graded WHO 1 in a minority (n = 22, 12%) of adults, but a majority of children (n = 29, 69%). In contrast, tumors were graded WHO 2 in the majority (n = 160, 87%) of adults and a minority of children (n = 10, 24%). Five-year overall survival following PRT was 81% in adults and 91% in children. The risk of RICE was 5-fold more frequent in adults (25%) vs. children (5%; p = 0.0043). In children and adults, RICE were symptomatic in 50% and 55% (n = 1 and 26) of cases with CTCAE grade 0 in 47% (n = 23), grade 1 in 25% (n = 12), 0% grade 2 (n = 0) and 29% grade 3 (n = 14), respectively. In adults, RICE risk was associated to WHO grading (8% in WHO grade 1 vs. 24% in WHO grade 2, p = 0.026), independent of age (p = 0.44) and irradiation dose (p = 0.005), but not independent of IDH mutational status. ConclusionsThese data demonstrate effectiveness of PRT for LGG in both children and adults. The RICE risk is lower in children which are a main target group for PRT and differs with WHO grading.

Definitive high-dose, proton-based radiation for unresected mobile spine and sacral chordomas

Background/PurposeTreatment of spine and sacral chordoma generally involves surgical resection, usually in conjunction with radiation therapy.In certain locations, resection may result in significant neurological dysfunction, so definitive radiation has been used as an alternative to surgery. The purpose of this study is to report the results of high-dose, proton-based definitive radiotherapy for unresected spinal and sacral chordomas. Materials/MethodsRetrospective review of 67 patients with newly diagnosed, unresected spinal chordomas treated with high-dose definitive, proton-based radiotherapy at our center from 1975 to 2019. ResultsReasons for radiotherapy alone included medical inoperability and/or concern for neurological dysfunction based on spine level or patient choice. Tumor locations included cervical (n = 10), thoracic (n = 1), lumbar (n = 4) spine, and sacrum (n = 52). Median maximal tumor diameter was 7.4 cm (range 1.8–25 cm). Median total dose was 77.4 Gy (RBE) (range 73.8–85.9 Gy RBE). Analysis with median follow-up of 56.2 months (range, 4–171.7 months) showed overall survival of 83.5 % (95%CI: 69.4–91.5%) and 65.9% (95%CI: 47.3–79.3%), disease-free survival of 64% (95%CI: 49.3–75.4) and 44.1% (95%CI: 27.8–59.2%), local control of 81.8% (95%CI: 67.6–90.2%) and 63.6% (95%CI: 44.7–77.5%), and distant control of 77.4% (95%CI: 63.6–86.5%) and 72.5% (95%CI: 55.7–83.8%) at 5 and 8 years respectively. The most common late side effect was insufficiency fracture. ConclusionThese results continue to support the use of high-dose definitive radiotherapy for patients with medically inoperable or otherwise unresected mobile spine or sacrococcygeal chordomas. There is a trend towards better disease-free survival with doses > 78 Gy (RBE).

Toxicity and Survival Outcomes From Intensity Modulated Proton Therapy-Based Re-Irradiation in Patients With Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Cumulative radiation doses to organs-at-risk is the primary limiting factor when delivering thoracic reirradiation (reRT). Intensity-modulated proton therapy (IMPT) offers a unique dosimetric advantage allowing for dose-escalation while limiting normal tissue irradiation. Given the limited published data, we analyzed toxicity and survival outcomes of non-small cell lung cancer (NSCLC) patients with prior radiation history undergoing IMPT-based definitive reRT. <h3>Materials/Methods</h3> A single-institution retrospective IRB-approved analysis was conducted of 62 consecutive patients treated with IMPT-reRT between from 2016-2020. Median dose of prior RT was 60.2 Gy EQD2 (range 30-126 Gy EQD2). Median time between initial and reirradiation courses was 30 months (range 3.5 – 562 months). Median IMPT-reRT dose was 62.2 Gy (RBE) EQD2 (range 40.1 – 99.7 Gy RBE EQD2). Patients received conventionally fractioned (n=37), twice-daily (n=6), or hypofractionated (n=19) reirradiation. The majority had full overlap with the previous radiation field (N=49, 79%), were centrally located (N=42, 58%), and involved nodal irradiation (N=47, 76%). Concurrent chemotherapy was delivered in 27 (44%) patients. Treatment related toxicities were analyzed in relationship to re-RT dosimetric parameters in 30 patients whose initial RT plan was available. Kaplan-Meier method and Cox Proportional Hazard was used to estimate overall survival (OS) and freedom from local progression (FFLP) calculated from the start of reRT. <h3>Results</h3> Grade 3 acute toxicities were seen in 6 (9%) patients (pulmonary [N=3], esophageal/skin/fatigue [N=1 each]). With a median follow-up from the start of reirradiation of 12.5 months, 8 (13%) patients experienced a grade 3 late toxicity (esophageal [N=4], pulmonary [N=3] and cardiac [N=1]). Two (3%) grade 5 toxicities were observed. None of the analyzed dosimetric parameters (lung, heart, esophageal, target) correlated with grade 3 or more toxicity. CTV size greater than 150 cm³ exhibited a trend of association with grade 3+ toxicity HR = 3.2 (95% CI: 0.88 – 12.1; p=0.08). Median FFLP was not reached and median OS was 22.6 months (95% CI, 16.5 – 22.1 months). On univariate analysis variables associated with improved OS were higher reirradiation dose, cumulative radiation dose >135 Gy, and smaller CTV (< 150 cc). However, on MVA only CTV size retained statistical significance (HR = 3.56; 95% CI, 1.10 – 11.48; p=0.03). <h3>Conclusion</h3> This is the largest series to date reporting outcomes for NSCLC patients treated with IMPT-reRT which demonstrated acceptable risk (<15%) of grade 3 or higher late toxicity with durable local control and prolonged survival. In contrast to limited published literature, no specific dosimetric parameters were significantly correlated with risk of toxicity.

Effectiveness and Toxicity of Fractionated Proton Beam Radiotherapy for Cranial Nerve Schwannoma Unsuitable for Stereotactic Radiosurgery.

PurposeIn this benign tumor entity, preservation of cranial nerve function is of special importance. Due to its advantageous physical properties, proton beam radiotherapy (PRT) is a promising approach that spares healthy tissue. Could PRT go along with satisfactory preservation rates for cranial nerve function without compromising tumor control in patients with cranial nerve schwannoma unsuitable for stereotactic radiosurgery?MethodsWe analyzed 45 patients with cranial nerve schwannomas who underwent PRT between 2012 and 2020 at our institution. Response assessment was performed by MRI according to RECIST 1.1, and toxicity was graded following CTCAE 5.0.ResultsThe most common schwannoma origin was the vestibulocochlear nerve with 82.2%, followed by the trigeminal nerve with 8.9% and the glossopharyngeal nerve as well as the vagal nerve, both with each 4.4%. At radiotherapy start, 58% of cranial nerve schwannomas were progressive and 95.6% were symptomatic. Patients were treated with a median total dose of 54 Gy RBE in 1.8 Gy RBE per fraction. MRI during the median follow-up period of 42 months (IQR 26–61) revealed stable disease in 93.3% of the patients and partial regression in 6.7%. There was no case of progressive disease. New or worsening cranial nerve dysfunction was found in 20.0% of all patients, but always graded as CTCAE °I-II. In seven cases (16%), radiation-induced contrast enhancements (RICE) were detected after a median time of 14 months (range 2–26 months). RICE were asymptomatic (71%) or transient symptomatic (CTCAE °II; 29%). No CTCAE °III/IV toxicities were observed. Lesions regressed during the follow-up period in three of the seven cases, and no lesion progressed during the follow-up period.ConclusionThese data demonstrate excellent effectiveness with 100% local control in a median follow-up period of 3.6 years with a promising cranial nerve functional protection rate of 80%. RICE occurred in 16% of the patients after PRT and were not or only mildly symptomatic.

Incidence of Symptomatic Brain Injury Following Pencil Beam Scanning Proton Beam Therapy for Management of Central Nervous System Tumors

Although proton beam therapy (PBT) results in decreased dose to non-target tissue compared to modern photon therapy, there are concerns of rare CNS injury occurring following PBT due in part to RBE/LET uncertainties. Such uncertainties can be further exacerbated when delivering PBT using pencil beam scanning (PBS) technology. The primary objective of this study was to report the incidence of CNS toxicities in a large cohort of adult brain tumor patients treated with PBS at a single academic proton center. We hypothesized that PBS can be safely delivered for treatment of CNS tumors.A single-institution retrospective IRB-approved analysis was conducted of all patients with CNS tumors treated with PBT at our institution between February 2016 and April 2020. Patients were excluded if follow up was less than one month. Kaplan-Meier estimates of treatment toxicities were calculated, accounting for death and local recurrence as competing risks. Multivariate analysis (MVA) was performed using the Cox proportional hazard model to determine risk factors associated with symptomatic toxicity.A total of 283 consecutive patients with CNS toxicities (116 [41%] males, 167 [59%] females) completed a course of definitive-intent PBT; 116 patients had meningiomas/pituitary adenomas, 92 patients had gliomas/GBM, and 75 patients had other histologies (chordoma, paraganglioma, ependymoma, medulloblastoma, pineal tumor). Median age was 52 years old (range 18-91). Median dose of PBT was 51.3 Gy (RBE = 1.1, [range 20.4 - 78.8 Gy RBE]). Median dose per fraction was 1.8 Gy/fx (range 1.1-3.8 Gy/fx). Sixty patients [21%] had received some form of prior intracranial RT. Concurrent systemic therapy was delivered in 49 patients [17%]. Median follow-up time was 20 months. The 2-year incidence of symptomatic-treatment toxicity was 8.7%. Symptomatic radiation necrosis occurred in 13 patients including optic neuritis [N = 2], seizure [N = 3], neurologic deficit [N = 9], stroke [N = 1] and brainstem necrosis [N = 2]. Two patients had symptoms with no radiation-related imaging changes including stroke [N = 1] and seizure [N = 1]. MVA identified prior intracranial irradiation (HR 3.901, 95% CI 1.42, 10.73, P = 0.008) and increasing EQD2 of proton radiation (HR 1.077 per Gray, 95% CI 1.00, 1.15, P = 0.036) as predictive factors for increased incidence of adverse events including symptomatic toxicity and asymptomatic radiation necrosis. No PBT treatment planning parameters were found to correlate with toxicity risk.This is the largest series to date reporting outcomes for patients with CNS tumors treated with pencil beam scanning PBT. Our analysis indicates that pencil beam scanning PBT in this setting is well-tolerated with a toxicity profile similar to modern photon therapy. Future studies correlating toxicity-risk with LET are warranted.B. Savla: None. G.S. Alexander: None. K. Sun: None. S.M. Bentzen: Travel Expenses; University of Copenhagen. S. Mossahebi: None. Y. Kwok: None. W.F. Regine: None. M.V. Mishra: Employee; Orthofix. Research Grant; ASTRO, Keep Punching. Advisory Board; Patient Centers Outcomes Research Institute (PCORI. Travel Expenses; Patient Centers Outcomes Research Institute (PCORI.

NCOG-64. INCIDENCE OF EARLY OCULAR COMPLICATIONS AFTER PROTON RADIATION FOR CHILDHOOD BRAIN TUMORS

Abstract OBJECTIVES To determine the incidence, timing and risk factors of ocular complications after proton radiation (RT) in childhood brain tumor patients, to better inform screening for these complications. METHODS We performed a single-institution retrospective review of children treated with proton RT for brain tumors, with ophthalmology data available. Data abstracted included demographics, radiation details and ocular complications (cataract, dry eyes, retinal changes). RESULTS We treated 81 children with brain tumors, with protons, from 2010-18. Forty three patients with ophthalmology data available, were included in the study, with a median age of 8.3 years (y) (0.8 – 20.6y) (13 craniospinal irradiation/CSI, 27 involved-field radiation/IFRT, 3 whole ventricle). Median follow-up from end of radiation to last eye exam was 2.1y (0.2 – 7.2y). The incidence of ocular complications was 21% (9/43 patients) overall, and 62% (8/13) after CSI. Bilateral cataracts were detected at a median of 3.2y post-radiation, with incidence of 14% (6/43) overall and 38% (5/13) after CSI. Three patients underwent lens replacement. Dry eyes developed in 23% (3/13) of patients during or soon after CSI (0.04 and 0.7y post-RT). One patient with craniopharyngioma developed retinal scarring and cataracts, 2.2y and 3.5y, after IFRT. The median radiation dose to the lenses, for patients with cataract, was 26.02 Gy RBE (4 patients: 19.41 – 31.54). For 3 patients with dry eyes, the median dose (Gy RBE) was 27.93 (11.98 – 28.71) to lenses, 36.96 (25.12 – 47.49) to lacrimal glands and 30.78 (25.08 – 36.49) to corneas (mean doses to bilateral ocular structures). CONCLUSIONS Children are at risk for cataract and dry eyes after cranial protons, especially CSI, and need ophthalmology follow-up. Larger studies are needed to validate these findings and identify risk-mitigation strategies, with longer follow-up to determine the incidence of ocular complications, and functional outcomes, after cranial proton radiation.

Treatment Outcomes After Proton Therapy for Ewing Sarcoma of the Pelvis

Ewing sarcoma of the pelvis is associated with inferior local control compared with those arising from other primary sites. Despite its increased use, outcome data for treatment with proton therapy remain limited. We report 3-year disease control and toxicity in pediatric patients treated with proton therapy. Thirty-five patients aged ≤21 years (median, 14 years) with nonmetastatic pelvic Ewing sarcoma received proton therapy and chemotherapy between 2010 and 2018. Overall survival and tumor control rates were calculated using the Kaplan-Meier method. A log-rank test assessed significance between strata of prognostic factors. Significant toxicity was reported per the Common Terminology Criteria for Adverse Events, version 4.0. Most patients received definitive radiation (n = 26; median dose 55.8 Gy relative biological effectiveness [RBE]; range, 54.0-64.8), 7 received preoperative radiation (50.4 Gy RBE), and 2 received postoperative radiation (45 Gy RBE and 54 Gy RBE). The median primary tumor size was 10.5 cm. With a median follow-up of 3 years (range, 0.3-9.0 years), the 3-year overall survival, progression-free survival, and local control rates were 83% (95% confidence interval [CI], 65%-93%), 64% (95% CI, 45%-79%), and 92% (95% CI, 74%-98%), respectively. There was no association between local control, progression-free survival, or overall survival and tumor size, patient age, radiation dose, or definitive versus pre-/postoperative radiation therapy. Median time to progression was 1 year (range, 0.1-1.9 years). All patients with large tumors (≥8 cm) who underwent definitive proton therapy with a higher dose (≥59.4 Gy RBE) remained free from tumor recurrence (n = 5). Five patients experienced grade ≥2 subacute/late toxicity, all of whom were treated with combined surgery and radiation. Definitive proton therapy offers local control comparable to photon therapy in pediatric patients with pelvic Ewing sarcoma. These data lend preliminary support to radiation dose escalation without significant toxicity, which may contribute to the favorable outcomes. Combined surgery and radiation therapy, particularly preoperative radiation, is associated with postoperative complications, but not survival, compared with radiation alone.

Radiation-Induced Brain Injury after Proton Radiotherapy Is Linked to Increased Distal Edge Linear Energy Transfer (LET) and Anatomically Variable Radiation Sensitivity

The incidence of radiation necrosis (RN) after proton beam therapy (PBT) has been discussed particularly in the context of a potentially enhanced biological effectiveness (RBE) towards the distal field edge. RN is commonly identified as radiation-induced contrast enhancing (RI-CE) lesions in magnetic resonance images (MRI), which need to be distinguished from post-operative changes and gliosis. We set out to (i) determine the safety of PBT by evaluating the incidence of RI-CE lesions and (ii) investigate the possibility of spatially variable radiation sensitivity, either caused by enhanced distal RBE or engrained in the anatomy of the brain. We reviewed 110 patients (median age 35 years) who had received actively scanned proton radiotherapy between 2010 and 2015 for histologically proven low grade glioma. Median dose was 54 Gy (RBE = 1.1) (range 50.4 – 60 Gy RBE). Every treatment plan was re-calculated with Monte Carlo (Fluka) to yield a dose and dose-averaged linear energy transfer (LETD) distribution. Regular follow-up amounted to more than 1200 MRI examinations (median follow up 39 months), on which RI-CE lesions were delineated. Every volume element of 1 mm3 in the brain receiving a dose of more than 40 Gy(RBE) was tagged with (i) the proximity to the ventricular system (PVS) and (ii) the LETD. The relative risks for RI-CE lesions were assessed by logistic regression with these parameters, without further biological model assumptions. To account for the growth dynamics of lesions between MRI scans, voxel weights were modified to avoid statistical bias of large lesions at the time of discovery. PBT for low grade glioma results in overall survival of 95 % after two years and 90 % after seven years. Median progression free survival has not yet been reached with surviving fractions of 85 % after two years and 54 % after seven years. The incidence of temporary or clinically silent radiation induced brain injury was significantly higher than previously assumed and was observed in 31 (28 %) patients with a median latency of 15 months. RI-CE lesions with clinical symptoms ≥ CTCAE °II were observed in seven (6.3 %) patients. Of all RI-CE lesions, 26 (51 %) were in a high LETD (LETD >= 5.0 keV/mum) volume and 32 (63 %) were in proximity to the ventricular system (distance voxel-ventricle <= 4mm). Consequentially, both high LETD: OR = 2.6 (95% CI: 1.4–4.8, p = 0.003) and PVS: OR = 8.7 (95% CI: 5.0–15.4, p < 0.001) are highly predictive risk factors. PBT is a safe and efficacious option for patients with low grade glioma. Clinically relevant and symptomatic radiation necrosis was as rare as known from conventional photon treatment. The spatial analysis of the lesion occurrence pattern hints at a moderately increased RBE at the distal edge of the proton beam. Surprisingly, a dose > 40 Gy(RBE) in proximity to the ventricles increases the risk of a lesion 3-fold more than LETD, which hints at a narrowly defined region of elevated radiation sensitivity.

Clinical results of proton therapy reirradiation for recurrent nasopharyngeal carcinoma

Background and purpose: Recurrent nasopharyngeal carcinoma (NPC) has limited curative treatment options. Reirradiation is the only potential definitive treatment in advanced stages at a cost of substantial severe and often life-threatening toxicity. Proton therapy (PT) reduces irradiated volume compared with X-ray radiotherapy and could be advantageous in terms of safety and efficacy in a population of heavily pretreated patients. We report the retrospective results of PT reirradiation in recurrent NPC patients treated at our InstitutionMethods: All recurrent NPC patients treated since the beginning of clinical activity entered the present analysis. Clinical target volume consisted of Gross Tumor volume plus a patient-specific margin depending on disease behavior, tumor location, proximity of organs at risk, previous radiation dose. No elective nodal irradiation was performed. Active scanning technique with the use of Single Field Optimization (SFO) or Multifield Optimization (MFO) was adopted. Cumulative X-ray -PT doses were calculated for all patients using a dose accumulation tool since 2016. Treatment toxicity was retrospectively collected.Results: Between February 2015, and October 2018, 17 recurrent NPC patients were treated. Median follow-up (FUP) was 10 months (range 2–41). Median PT reirradiation dose was 60 Gy RBE (range 30.6–66). The majority of patients (53%) underwent concomitant chemotherapy. Acute toxicity was low with no ≥ G3 adverse events. Late events ≥ G3 occurred in 23.5% of patients. Most frequent late toxicity was hearing impairment (17,6%). G2 soft tissue necrosis occurred in two patients. Fatal bleeding of uncertain cause (either tumor recurrence or G5 carotid blowout) occurred in one patient. Kaplan–Meier 18 months Overall Survival (OS) and Local control (LC) rates were 54.4% and 66.6%, respectively.Conclusions: Our initial results with the use of modern PT for reirradiation of recurrent NPC patients are encouraging. Favorable LC and OS rates were obtained at the cost of acceptable severe late toxicity.