Beam Scanning Proton Therapy Research Articles

Incidence of alopecia in brain tumour patients treated with pencil scanning proton therapy and validation of existing NTCP models

Background and purposeRadiation-induced alopecia (RIA) is one of the most frequent and upsetting cosmetic side effects after radiotherapy (RT) for brain cancer. We report the incidence of RIA in a cohort of brain tumours patients treated with Proton Therapy (PT) and externally validate published NTCP models of grade 2 (G2) RIA for their implementation in clinical practice. MethodsData for patients treated for brain tumours with scanning beam PT between 2018 and 2022 were extracted. Acute, late and permanent RIA events were evaluated according to CTCAE 5.0. Lyman-Kutcher-Burman (LKB) and multivariable logistic regression (MLR) published models were computed from the relative dose-surface histogram of the scalp. External validity of models was assessed in terms of discrimination and calibration. ResultsIn the 264 patients analysed, rates of any grade acute (≤90 days after PT completion), late (>90 days) and permanent RIA (persisting for> 12 months) were 61.8 %, 24.7 % and 14.4 %, respectively. In our independent cohort, LKB- and MLR-NTCP showed a good discrimination for G2 RIA (0.71≤ROC-AUC≤0.83) while model calibration was unsatisfactory possibly due to a different outcome evaluation between training and validation cohorts, as well as differences in clinical and treatment related variables between the two groups. ConclusionsDespite the reasonable sensitivity and specificity of the NTCP models for RIA in the validation cohort, our study emphasizes the significance of differences between the cohorts utilized for model development and validation. Specifically, variations in the reporting of clinical outcomes inevitably jeopardize the validation of NTCP models. A standardize and objective RIA scoring system is essential.

Impact of Dosimetric Compromises on Early Outcomes of Chordomas and Chondrosarcomas Treated With Image-guided Pencil Beam Scanning Proton Beam Therapy

PurposeTo critically review the clinical factors, dosimetry, and their correlation with early outcomes in patients with chordomas and chondrosarcomas treated with pencil beam scanning proton beam therapy (PBS-PBT). MethodsConsecutive 64 patients diagnosed with chordoma, or chondrosarcoma treated at our centre were studied. Patient, tumor and treatment-related factors including dosimetry were captured. Early and late toxicities and early outcomes were evaluated and correlated with clinical and dosimetric factors using standard statistical tools. ResultsThe median age of patients was 39(4-74 years) and most common site was skullbase (47%) followed by sacrum(31%) and mobile spine(22%). The median prescription dose to the high-risk CTV for chordoma and chondrosarcoma was 70.4CGE(Cobalt Gray equivalent) and 66CGE at 2.2CGE per fraction respectively. At presentation to our centre, 55% presented after a recurrence/progression of which 17% received prior radiation and 32% had a significant neural compression. At the time of PBT, 25% of patients had suboptimal neural separation. Three-fourths of patients had at least an acceptable target coverage. While 11% had a tier-1 compromise (GTVD98<90%), 14% had a tier-2 compromise (GTVD98<59CGE). With a median follow-up of 27.5 months, 2-year local control and PFS was 86.7% and 81.8% for chordomas and 87.5% and 77.1% for chondrosarcomas respectively. Residual GTV>25cc and a tier-2 compromise were associated with inferior local control (HR-0.19,p=0.019; HR-0.061,p=0.022 respectively) and progression-free survival (HR-0.128,p=0.014; HR-0.194,p=0.025 respectively) on multivariate analysis. Despite multiple surgeries, a majority with recurrent disease and prior radiations, grade-3 acute and late toxicities were limited and comparable to others in the literature. ConclusionDespite multiple surgeries, adequate neural separation was challenging to achieve. Severe dosimetric compromise(GTVD98<59CGE) led to inferior early outcomes. Adequate neural separation is key to avoiding dosimetric compromise and achieving optimal local control.

Assessing alimentary tract radiation in liver cancer treatment with proton beam therapy: a PET/CT imaging study.

Proton beams deposit energy along their path, abruptly stopping and generating various radioactive particles, including positrons, along their trajectory. In comparison with traditional proton beam therapy, scanning proton beam therapy is effective in delivering proton beams to irregularly shaped tumors, reducing excessive radiation exposure to the alimentary tract during the treatment of liver cancer. In this study, we utilized positron emission tomography/computed tomography (PET/CT) imaging to assess the total amount of radiation to the alimentary tract during liver cancer treatment with proton beam therapy, involving the administration of complex irradiation in 13 patients. This approach resulted in the prevention of excess radiation. The planned radiation restraint doses for the colon exhibited a significant correlation with the PET values of the colon (correlation coefficient 0.8384, P=.0003). Likewise, the scheduled radiation restraint doses for the gastroduodenum were correlated with the PET values of the gastroduodenum (correlation coefficient 0.5397, P=.0569). PET/CT conducted after proton beam therapy is useful for evaluating excess radiation in the alimentary tract. Proton beam therapy in liver cancer, assessed via PET/CT, effectively reduced alimentary tract radiation, which is vital for optimizing treatments and preventing excess exposure.

Encouraging Experience with Image-Guided Pencil Beam Scanning Proton Therapy in Craniopharyngioma—First Case Series From India

PurposeTo report our early clinical experience with image-guided, pencil beam scanning proton beam therapy(PBS-PBT) for residual or recurrent craniopharyngiomas. Material and MethodsBetween September 2019 and January 2023, nineteen consecutive patients with residual, or recurrent craniopharyngioma, suitable for radiation and treated with image-guided PBS-PBT were analyzed. We documented detailed dosimetric data, acute toxicities, early outcomes and imaging response on follow-up MRI scans. ResultsA total of nineteen patients (11-males, 8-females) with residual or recurrent craniopharyngioma were treated in the given period. Median age of cohort was 14 years(range:3-33), majority constituting adamantinomatous histology(95%). Most common clinical presentation(prior to PBT) and endocrine deficit was visual disturbance(79%) and hypocortisolism(74%), respectively. Among 19, thirteen had recurrent craniopharyngioma and five of them had received radiation previously. 26% of patients(5) underwent surgery at least thrice or more before proton therapy. Median dose delivered was 54GyE. Most common acute toxicity was grade-1 alopecia(63%). None had grade-3 or above acute toxicities. With a median follow-up of 18 months(3-40 months), twelve patients showed shrinkage of residual tumor/cyst, of which, four showed dramatic cyst reduction at 3-9 months on follow-up. Two-patients had reduction in both solid and cystic components, and the remaining had reduction in cystic component only. The remaining eight patients had stable disease on MRI, with 100% disease control rate and overall survival. Visual functions remained stable post treatment. ConclusionOur preliminary experience with modern PBS-PBT and image guidance for craniopharyngioma is encouraging. Proton therapy in our cohort is well tolerated resulting in limited toxicities and promising early outcomes.

Disease and toxicity outcomes for a modern cohort of patients with squamous cell carcinoma of cutaneous origin involving the parotid gland: Comparison of volumetric modulated arc therapy and pencil beam scanning proton therapy

ObjectivesWe sought to describe outcomes for locally advanced cutaneous squamous cell carcinoma (SCC) involving the parotid treated with volumetric modulated arc therapy (VMAT) versus pencil beam scanning proton beam therapy (PBT). Materials and MethodsPatients were gathered from 2016 to 2022 from 5 sites of a large academic RT department; included patients were treated with RT and had parotid involvement by: direct extension of a cutaneous primary, parotid regional spread from a previously or contemporaneously resected but geographically separate cutaneous primary, or else primary parotid SCC (with a cutaneous primary ostensibly occult). Acute toxicities were provider-reported (CTCAE v5.0) and graded at each on treatment visit. Statistical analyses were conducted. ResultsMedian follow-up was 12.9 months (1.3 – 72.8); 67 patients were included. Positive margins/extranodal extension were present in 34 cases; gross disease in 17. RT types: 39 (58.2 %) VMAT and 28 (41.8 %) PBT. Concurrent systemic therapy was delivered in 10 (14.9 %) patients. There were 17 treatment failures (25.4 %), median time of 168 days. Pathologically positive neck nodes were associated with locoregional recurrence (p = 0.015). Oral cavity, pharyngeal constrictor, and contralateral parotid doses were all significantly lower for PBT. Median weight change was −3.8 kg (-14.1 – 5.1) for VMAT and −3 kg (-16.8 – 3) for PBT (p = 0.013). Lower rates of ≥ grade 1 xerostomia (p = 0.002) and ≥ grade 1 dysguesia (p < 0.001) were demonstrated with PBT. ConclusionsCutaneous SCC involving the parotid can be an aggressive clinical entity despite modern multimodal therapy. PBT offers significantly lower dose to organs at risk compared to VMAT, which seemingly yields diminished acute toxicities.

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.

Oncologic Outcomes of Conventionally Fractionated, Hypofractionated, and Stereotactic Body Spot-Scanned Proton Radiation Therapy for Prostate Cancer: The Mayo Clinic Experience.

Spot/pencil beam scanned proton therapy is a relatively new technology with fundamental differences from double scattered or IMRT. We aimed to report the long-term oncologic outcomes of a contemporary prospective series of patients treated with spot-scanned proton therapy (SSPT). An IRB-approved prospective registry identified patients with prostate cancer treated with proton therapy between January 2016 and December 2018. Descriptive statistics were calculated for all patients. Clinical, demographic, and treatment characteristics were gathered and analyzed. Kaplan-Meier curves were generated to estimate survival and recurrence rates. Outcomes assessed included 5-year overall survival (OS), 5-year local control (LC), biochemical failure (BF), regional and distant failures, and physician-reported adverse events (AEs). Biochemical failure was defined as rise in PSA ≥ 2.0 ng/mL above nadir PSA. Acute and chronic gastrointestinal (GI) and genitourinary (GU) grade 2+ and grade 3+ baseline-adjusted AEs were assigned using CTCAE v5.0. All failures were re-staged with PET C-11 or PSMA. With a median follow up of 4.4 years (IQR 3.7 - 5), two hundred and eighty-six prostate cancer patients with a median age of 72 (IQR 67.5 - 77) were treated with spot-scanned proton radiation. The median Gleason grade group was 3 (IQR 2 - 4). The median pre-RT PSA was 6.9 ng/mL (IQR 4.3 - 10.5). Median T-stage was T1c. Nearly 64% of all patients were on androgen deprivation therapy at the time of initiating radiation treatment. The median total radiation dose was 79.2 Gy delivered over 44 fractions, 70 Gy over 28 fractions, and 38 Gy over 5 fractions for CF, HF, and SBRT regimens, respectively. The BF rate for all patients was 8.4%. The 5-year LC rates for CF, HF, and SBRT were 100% (95% CI: 100 - 100), 100% (95% CI: 100 - 100), and 97.3% (95% CI: 92.2 - 100), respectively (p = 0.07). Regional recurrences occurred in 12 (4.2%) patients: 8 (5.6%) treated with CF, 2 (2.1%) with HF, and 2 (4.3%) with SBRT (p = 0.62). Distant metastatic failures occurred in 12 patients (4.2%): 5 (3.5%) treated with CF, 7 (7.4%) with HF, and none with SBRT (0%) (p = 0.052). The 5-year OS for patients treated with CF, HF, and SBRT SSPT were 88.2% (95% CI: 81.8 - 95), 86.2% (95% CI: 77.6 - 95.6), and 97.2% (95% CI: 92 - 100), respectively (p = 0.1). Acute and chronic grade 2+ GI baseline-adjusted AEs occurred in 8 (2.8%) and 51 (17.8%) patients, respectively. Acute and chronic grade 3+ GI baseline-adjusted AEs occurred in 3 (1%) and 4 (1.4%) patients, respectively. Acute and chronic grade 2+ GU-related AEs were observed in 72 (25.2%) and 63 (22%) patients, respectively. Acute and chronic grade 3+ GU toxicity was observed in 3 (1%) and 6 (2.1%) patients, respectively. Spot-scanned proton radiation therapy provides high local control rates and excellent oncologic outcomes across different fractionation schedules with low long-term AE rates.

CT-on-Rails Utilization for Image Guidance and Plan Adaptation at a Single-Room Proton Therapy Center.

In-room CT-on-rails is a relatively rare imaging modality in proton therapy. This work evaluated the utilization of CT-on-rails (CTOR) for image guidance and plan adaptation at a single-room proton therapy center. All patients treated from the proton center beginning treatment to the current date were evaluated (May 2021 - January 2023). Patients were treated using a Mevion S250i scanning beam proton therapy system with an in-room Definition Edge CTOR. The image guidance technique utilized for each patient was evaluated (CTOR, orthogonal planar kV imaging, or both). For patients who required a new CT for plan adaptation, the use of CT images from CTOR or a new simulation CT was assessed. Of the 132 patients treated over the evaluated time period, 56.0% utilized CTOR for image guidance at some point during their treatment. 21.2% utilized CTOR as the only image guidance technique, while 34.8% utilized CTOR in combination with kV planar imaging. For 43.9% of patients, only orthogonal planar kV imaging was utilized. Head and neck treatment sites most often utilized CTOR alone as an image guidance technique, while central nervous system sites most often utilized kV planar imaging alone. Of the patients who required new CT imaging for plan adaptation, 75.0% utilized CTOR images. Some reasons for patients not being able to utilize CTOR imaging for re-planning were the need for 4DCT imaging (which was not available on the CTOR) or the need to re-make immobilization devices (such as thermoplastic masks due to becoming loose). CTOR was shown to be utilized for image guidance in the majority of patients receiving proton therapy at a single-room proton therapy center. CTOR was able to be used for plan adaptation in a large majority of patients, eliminating the need to schedule additional CT simulation appointments for these patients.

Outcomes Following Proton Therapy for Non-Metastatic Central Nervous System Germinoma in Children and Adolescents

Radiation is a key component in the treatment of central nervous system pure germinoma (PG) in children and adolescents. Compared to photons, proton therapy (PT) improves normal tissue sparing and potentially reduces adverse effects, but there are sparse data on long-term patient outcomes. Herein, we present the largest reported single institution experience utilizing PT for the management of PG. We performed an IRB-approved retrospective review of a prospective database containing 35 patients with non-metastatic PG treated with PT between July 2007 and September 2021. The median age at treatment was 13 years. All patients had > 6 months of follow up. Two patients were diagnosed based on cerebral spinal fluid B-HCG levels and the remaining 33 patients through histopathology. Eleven patients had bifocal or multifocal intracranial disease. Most patients (n = 31, 88.6%) received induction chemotherapy with carboplatin + etoposide (n = 25, 80.6%) with all demonstrating a radiographic response to neoadjuvant therapy. Twenty-nine were treated with whole ventricular irradiation (WVI) with an involved field (IF) boost, 2 with craniospinal irradiation + WVI + IF, 2 with IF, 1 with CSI + IF, and 1 with whole brain + IF. Among this subgroup, the most common total dose was 30 GyRBE (n = 18, 51.4%). Of the 4 patients that did not receive chemotherapy, 3 received WVI + IF and 1 was treated with CSI + WVI + IF. The total dose in the patients not receiving chemotherapy was 45 GyRBE. Twenty-nine patients were treated with double scattered PT (DS) and 6 patients with pencil beam scanning PT (PBS). We utilized the cumulative incidence method to estimate local control (LC), freedom from distant metastases (FFDM), freedom from progression (FFP), and overall survival (OS). Treatment related toxicity was assessed according to the CTCAEv5. Median follow up was 6.2 years (Range: 0.9-15.2 years). The 10-year KM estimates for LC, FFDM, FFP, and OS were 100%, 100%, 100%, and 97% respectively. One patient developed acute lymphocytic leukemia 8 months after treatment and died. The sole ³ grade 3 radiation-related toxicity was a cavernoma with hemorrhage 3.6 years post treatment requiring surgical resection. The most common adverse events were hearing impairment requiring hearing aids (n = 3), hypersomnia requiring medication (n = 3), and new onset endocrinopathy (n = 1). Of the 22 evaluable patients ³18 years old at last follow up, 7 were high school graduates/in college, 8 college graduates, and 5 others gainfully employed. The use of proton therapy in the multi-modality approach to non-metastatic PG does not compromise local control. Although serious side effects are rare and treatment has minimal impact on survivors' early educational/career trajectory, the 100% cure rate supports further investigation into selective radiation dose and volume de-escalation.

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.

Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer

Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. This was a phase 2, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to 12 weeks after completion of 60 to 70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 toxicity. Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range, 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n = 5; 2 were pembrolizumab-related), disease progression (n = 4), and completion of 1 year (n = 3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI, 4.2-23.7) and 22.8 months (95% CI, 6.9-not reached), respectively. There was only one isolated in-field failure after reRT. Grade ≥3 toxicities occurred in 10 patients (45%); 2 were pembrolizumab-related. There were 2 grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2 of 22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.

Proton beam therapy in repeat irradiation of recurrent head and neck tumors: analysis of short-term results

Introduction. Recurrence of head and neck tumors occurs in 50 % of cases and usually has locoregional character. Due to the characteristics of dose distribution, proton beam therapy is a promising treatment option for patients with recurrences of tumors in this location who previously underwent radiation therapy.Aim. To evaluate the effectiveness and tolerability of repeat irradiation using active scanning proton beam therapy in patients with recurrent head and neck tumors who previously underwent radiation therapy.Materials and methods. Between November of 2015 and December of 2020, 40 patients with locoregional recurrence of head and neck tumors underwent treatment using active scanning proton beam therapy at the A. F . Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center. Median cumulative dose of primary irradiation was 64.5 Gy. Median time between primary and repeat irradiation was 35.7 months, mean irradiated volume of the repeat course was 94.5 cm3. Proton beam therapy was performed using standard mode (2 isoGy) and accelerated hypofractionation (2.4 isoGy / 3 isoGy) with mean equivalent cumulative dose of 56.4 Gy (α / β = 10). Radiation toxicity was evaluated using the Radiation Therapy Oncology Group European (RTOG) / Organization for Research and Treatment of Cancer (EORTC) scale.Results. Treatment response was achieved in 34 (85 %) patients: in 17 (42.5 %) patients, stable disease was observed; in 10 (25 %) patients, partial response was observed; and in 7 (17.5 %) patients, complete response was observed. In 6 (15 %) cases, disease progression was diagnosed at first follow-up examination. One- and two-year locoregional control, progression-free survival and overall survival were 58.4 / 19.8; 44.5 / 19.8 and 82.3 / 38.8 % respectively with median follow-up duration of 14.2 months. Median survival was 19.5 months. Grade III and above early radiation toxicity was observed in 3 (7.5 %) patients. In total, 6 (15 %) cases of grade III complications and 2 (5 %) episodes of carotid artery rupture leading to death were observed. Overall frequency of complications of grade III and higher was 20 %.Conclusion. Repeat irradiation using proton beam therapy can be considered an effective and safe treatment method for patients with recurrent head and neck tumors. Dosimetric and radiobiological benefits of proton beams allow to achieve balance between high doses and radiation exposure in previously irradiated tissues.

Proton Beam Therapy for Early Breast Cancer: A Systematic Review and Meta-analysis of Clinical Outcomes

Adjuvant proton beam therapy (PBT) is increasingly available to patients with breast cancer. It achieves better planned dose distributions than standard photon radiation therapy and therefore may reduce the risks. However, clinical evidence is lacking. A systematic review of clinical outcomes from studies of adjuvant PBT for early breast cancer published in 2000 to 2022 was undertaken. Early breast cancer was defined as when all detected invasive cancer cells are in the breast or nearby lymph nodes and can be removed surgically. Adverse outcomes were summarized quantitatively, and the prevalence of the most common ones were estimated using meta-analysis. Thirty-two studies (1452 patients) reported clinical outcomes after adjuvant PBT for early breast cancer. Median follow-up ranged from 2 to 59 months. There were no published randomized trials comparing PBT with photon radiation therapy. Scattering PBT was delivered in 7 studies (258 patients) starting 2003 to 2015 and scanning PBT in 22 studies (1041 patients) starting 2000 to 2019. Two studies (123 patients) starting 2011 used both PBT types. For 1 study (30 patients), PBT type was unspecified. Adverse events were less severe after scanning than after scattering PBT. They also varied by clinical target. For partial breast PBT, 498 adverse events were reported (8 studies, 358 patients). None were categorized as severe after scanning PBT. For whole breast or chest wall ± regional lymph nodes PBT, 1344 adverse events were reported (19 studies, 933 patients). After scanning PBT, 4% (44/1026) of events were severe. The most prevalent severe outcome after scanning PBT was dermatitis, which occurred in 5.7% (95% confidence interval, 4.2-7.6) of patients. Other severe adverse outcomes included infection, pain, and pneumonitis (each ≤1%). Of the 141 reconstruction events reported (13 studies, 459 patients), the most prevalent after scanning PBT was prosthetic implant removal (34/181, 19%). This is a quantitative summary of all published clinical outcomes after adjuvant PBT for early breast cancer. Ongoing randomized trials will provide information on its longer-term safety compared with standard photon radiation therapy.

Individualised Estimation of Quality-adjusted Survival Benefit and Cost-effectiveness of Proton Beam Therapy in Intermediate-stage Hodgkin Lymphoma

AimsRadiotherapy for Hodgkin lymphoma leads to the irradiation of organs at risk (OAR), which may confer excess risks of late effects. Comparative dosimetry studies show that proton beam therapy (PBT) may reduce OAR irradiation compared with photon radiotherapy, but PBT is more expensive and treatment capacity is limited. The purpose of this study is to inform the appropriateness of PBT for intermediate-stage Hodgkin lymphoma (ISHL). Materials and methodsA microsimulation model simulating the course of ISHL, background mortality and late effects was used to estimate comparative quality-adjusted life years (QALYs) lived and healthcare costs after consolidative pencil beam scanning PBT or volumetric modulated arc therapy (VMAT), both in deep-inspiration breath-hold. Outcomes were compared for 606 illustrative patients covering a spectrum of clinical presentations, varying by two age strata (20 and 40 years), both sexes, three smoking statuses (never, former and current) and 61 pairs of OAR radiation doses from a comparative planning study. Both undiscounted and discounted outcomes at 3.5% yearly discount were estimated. The maximum excess cost of PBT that might be considered cost-effective by the UK's National Institute for Health and Care Excellence was calculated. ResultsOAR doses, smoking status and discount rate had large impacts on QALYs gained with PBT. Current smokers benefited the most, averaging 0.605 undiscounted QALYs (range –0.341 to 2.171) and 0.146 discounted QALYs (range –0.067 to 0.686), whereas never smokers benefited the least, averaging 0.074 undiscounted QALYs (range –0.196 to 0.491) and 0.017 discounted QALYs (range –0.030 to 0.086). For the gain in discounted QALYs to be considered cost-effective, PBT would have to cost at most £4812 more than VMAT for current smokers and £645 more for never smokers. This is below preliminary National Health Service cost estimates of PBT over photon radiotherapy. ConclusionIn a UK setting, PBT for ISHL may not be considered cost-effective. However, the degree of unquantifiable uncertainty is substantial.

Comparing Ultra-hypofractionated Proton versus Photon Therapy in Extremity Soft Tissue Sarcoma.

Recent single institution, phase II evidence has demonstrated the feasibility and efficacy of ultra-hypofractionated, preoperative photon therapy in 5 fractions for the treatment of soft tissue sarcoma (STS). Our purpose was to evaluate the dosimetric benefits of modern scanning beam proton therapy compared with conventional photon radiation therapy (RT) for the neoadjuvant treatment of adult extremity STS. Existing proton and photon plans for 11 adult patients with STS of the lower extremities previously treated preoperatively with neoadjuvant RT at our center were used to create proton therapy plans using Raystation Treatment Planning System v10.A. Volumes were delineated, and doses reported consistent with International Commission on Radiation Units and Measurements reports 50, 62, and 78. Target volumes were optimized such that 100% clinical target volume (CTV) was covered by 99% of the prescription dose. The prescribed dose was 30 Gy for PT and RT delivered in 5 fractions. For proton therapy, doses are reported in GyRBE = 1.1 Gy. The constraints for adjacent organs at risk (OARs) within 1 cm of the CTV were the following: femur V30Gy ≤ 50%, joint V30Gy < 50%, femoral head V30Gy ≤ 5 cm3, strip V12 ≤ 10%, and skin V12 < 50%. Target coverage goals, OAR constraints, and integral dose were compared by Student t test with P < .05 significance. A minimum 99% CTV coverage was achieved for all plans. OAR dose constraints were achieved for all proton and photon plans; however, mean doses to the femur (10.7 ± 8.5 vs 16.1 ± 7.7 GyRBE), femoral head (2.0 ± 4.4 vs 3.6 ± 6.4 GyRBE), and proximal joint (1.8 ± 2.4 vs 3.5 ± 4.4 GyRBE) were all significantly lower with PT vs intensity-modulated radiation therapy (IMRT) (all P < .05). Integral dose was significantly reduced for proton vs photon plans. Conformity and heterogeneity indices were significantly better for proton therapy. Proton therapy maintained target coverage while significantly reducing integral and mean doses to the proximal organs at risk compared with RT. Further prospective investigation is warranted to validate these findings and potential benefit in the management of adult STS.

High-Risk Non-Small Cell Lung Cancer Treated With Active Scanning Proton Beam Radiation Therapy and Immunotherapy

PurposeNon-small cell lung cancer (NSCLC) is a deadly malignancy that is frequently diagnosed in patients with significant medical comorbidities. When delivering local and regional therapy, an exceedingly narrow therapeutic window is encountered, which often precludes patients from receiving aggressive curative therapy. Radiation therapy advances including particle therapy have been employed in an effort to expand this therapeutic window. Here we report outcomes with the use of proton therapy with curative intent and immunotherapy to treat patients diagnosed with high-risk NSCLC. Methods and MaterialsPatients were determined to be high risk if they had severe underlying cardiopulmonary dysfunction, history of prior thoracic radiation therapy, and/or large volume or unfavorable location of disease (eg, bilateral hilar involvement, supraclavicular involvement). As such, patients were determined to be ineligible for conventional x-ray–based radiation therapy and were treated with pencil beam scanning proton beam therapy (PBS-PBT). Patients who demonstrated excess respiratory motion (ie, greater than 1 cm in any dimension noted on the 4-dimensional computed tomography simulation scan) were deemed to be ineligible for PBT. Toxicity was reported using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Overall survival and progression-free survival were calculated using the Kaplan-Meier method. ResultsA total of 29 patients with high-risk NSCLC diagnoses were treated with PBS-PBT. The majority (55%) of patients were defined as high risk due to severe cardiopulmonary dysfunction. Most commonly, patients were treated definitively to a total dose of 6000 cGy (relative biological effectiveness) in 30 fractions with concurrent chemotherapy. Overall, there were a total of 6 acute grade 3 toxicities observed in our cohort. Acute high-grade toxicities included esophagitis (n = 4, 14%), dyspnea (n = 1, 3.5%), and cough (n = 1, 3.5%). No patients developed grade 4 or higher toxicity. The majority of patients went on to receive immunotherapy, and high-grade pneumonitis was rare. Two-year progression-free and overall survival was estimated to be 51% and 67%, respectively. COVID-19 was confirmed or suspected to be responsible for 2 patient deaths during the follow-up period. ConclusionsRadical PBS-PBT treatment delivered in a cohort of patients with high-risk lung cancer with immunotherapy is feasible with careful multidisciplinary evaluation and rigorous follow-up.

P18.11.A Active beam scanning proton therapy for large skull base benign meningiomas: long-term results

Abstract Purpose To report long-term results of active beam scanning proton therapy (PT) for large skull base benign meningiomas Material and Methods Eighty-two patients (pts) with large skull base meningiomas were treated with PT between April 2015 and December 2021. Median age was 62 years (range, 48-82) while KPS ranged between 60 and 100 (median 90); 60 were female (73%), and 22 were male (27%). Thirty-two pts (39%) had histologically proven World Health Organization (WHO) Grade I tumors. In remaining pts diagnosis was based on the typical imaging appearance of benign meningioma. All patients received PT for residual, progressive or non-operable lesions. Newly diagnosed tumors received total dose of 50 GyRBE (RBE: relative biologic effectiveness) while progressing meningiomas 54 GyRBE. All the treatments were delivered at 2 GyRBE per fraction. All pts were treated with active beam scanning PT using 3 fields with single field optimization technique. Treatment planning was based on morphological magnetic resonance imaging (MRI) with contrast enhancement medium administration. All pts received also 68-Ga-DOTATOC-PET. Gross tumor volume ranged from 21 to 64 cc. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.0. Median follow-up time was 40 months (range, 3-83). Results All pts completed the treatment without breaks. Registered acute side effects include grade 1 (19%) and grade 2 (8%) skin erythema, grade 1 (5%) and grade 2 (5%) alopecia, grade 1 (40%) fatigue, grade 1 (5%) and grade 2 (10%) conjunctivitis, grade 1 (10%) pain, grade 1 (5%) blurred vision, grade 1 (10%) headache, and grade 2 (5%) skin hyperpigmentation. One pts (1%) experienced grade 3 pain. There were no further grade 3 or higher acute toxicities. Registered late side effects include grade 1 (2%) and grade 2 (5%) alopecia, grade 1 (21%) fatigue, grade 1 (5%) and grade 2 (5%) headache, grade 1 (6%) dizziness, grade 1 (3%) blurred vision, grade 1 (3%) and grade 2 (6%) pain, grade 1 (2%) dry eye, and grade 1 (5%) skin hyperpigmentation. Two pts (2%) experienced grade 3 pain. Two further pts (2%) experienced grade 3 optic neuropathy. There were no further grade 3 or higher late toxicities. During follow-up one pts (1%) with cavernous sinus meningioma experienced complete obstruction of intracavernous carotid artery with mild transient symptoms that resolved in few days and brain tissue ischemia detected at MRI (grade 2). Before irradiation this pts already had a meningioma-related near-complete obstruction of the intracavernous carotid artery and received a vascular surgery evaluation. Currently, absolute tumor control is 99%. Moreover, relief of symptoms recorded before irradiation occurred in 40% of pts. Conclusion PT is safe and effective treatment for pts with large skull base benign meningiomas.

EPEN-22. Molecularly aggressive ependymomas treated with Image guided pencil beam proton therapy: consecutive patient Indian experience

AIM: To assess the toxicities and early clinical outcomes in patients of primary and recurrent ependymomas treated with image guided pencil beam scanning proton beam therapy (PBS-PBT). MATERIALS AND METHODS: Between January 2019- December 2021, we analyzed consecutive patients of ependymomas treated with image guided PBS-PBT. They were also analyzed molecularly, and all recurrent/re-irradiated patients were considered for craniospinal irradiation (CSI). Acute toxicities were assessed based on NCI CTC v5.0, local control and radiological response by 3-monthly MRI post therapy. RESULTS: Seventeen consecutive patients with ependymoma (13 Grade III and 4 Grade II) (median age-9 years) were analyzed. 9 patients were primary, 7 were treated at first recurrence and 1 at second recurrence. Majority had posterior fossa (PF) tumors (12) followed by supratentorial (ST) (3) and spine (2). Among PF ependymomas, 10 had global loss of H3K27me3, whereas amongst ST, 1 had YAP1 fusion, 1 had L1CAM positivity and other, negative L1CAM and p65/RELA on immunohistochemistry. Gross/near-total resection was achieved in 87% patients. Primary ependymomas were treated with focal radiotherapy; and among recurrent cases, 7 received CSI followed by primary site boost to a total median dose of 55CGE (50.2-55.8CGE). Grade 2 dermatitis, grade 2 and 3 hematological toxicities (CSI) were noted in 3,2 and 2 patients respectively. Grade 2 fatigue noted in 53% of all and 71% receiving CSI. With a median follow-up of 10 months (2-24 months), local control (LC) and disease-free survival (DFS) was 87.5% (primary-100%, recurrent-75%) and overall survival (OS) was 94% (primary-100%, recurrent-88%). CONCLUSION: Our experience of treating patients of ependymoma with complete resection followed by PBS-PBT including CSI is encouraging with low acute toxicities. Recurrent/molecularly aggressive cases may be considered for CSI. Keywords: PT, proton beam therapy, ependymomas, primary and recurrent

Comparison of Estimated Late Toxicities between IMPT and IMRT Based on Multivariable NTCP Models for High-Risk Prostate Cancers Treated with Pelvic Nodal Radiation.

PurposeTo compare the late gastrointestinal (GI) and genitourinary toxicities (GU) estimated using multivariable normal tissue complication probability (NTCP) models, between pencil-beam scanning proton beam therapy (PBT) and helical tomotherapy (HT) in patients of high-risk prostate cancers requiring pelvic nodal irradiation (PNI) using moderately hypofractionated regimen.Materials and MethodsTwelve consecutive patients treated with PBT at our center were replanned with HT using the same planning goals. Six late GI and GU toxicity domains (stool frequency, rectal bleeding, fecal incontinence, dysuria, urinary incontinence, and hematuria) were estimated based on the published multivariable NTCP models. The ΔNTCP (difference in absolute NTCP between HT and PBT plans) for each of the toxicity domains was calculated. A one-sample Kolmogorov-Smirnov test was used to analyze distribution of data, and either a paired t test or a Wilcoxon matched-pair signed rank test was used to test statistical significance.ResultsProton beam therapy and HT plans achieved adequate target coverage. Proton beam therapy plans led to significantly better sparing of bladder, rectum, and bowel bag especially in the intermediate range of 15 to 40 Gy, whereas doses to penile bulb and femoral heads were higher with PBT plans. The average ΔNTCP for grade (G)2 rectal bleeding, fecal incontinence, stool frequency, dysuria, urinary incontinence, and G1 hematuria was 12.17%, 1.67%, 2%, 5.83%, 2.42%, and 3.91%, respectively, favoring PBT plans. The average cumulative ΔNTCP for GI and GU toxicities (ΣΔNTCP) was 16.58% and 11.41%, respectively, favoring PBT. Using a model-based selection threshold of any G2 ΔNTCP >10%, 67% (8 patients) would be eligible for PBT.ConclusionProton beam therapy plans led to superior sparing of organs at risk compared with HT, which translated to lower NTCP for late moderate GI and GU toxicities in patients of prostate cancer treated with PNI. For two-thirds of our patients, the difference in estimated absolute NTCP values between PBT and HT crossed the accepted threshold for minimal clinically important difference.

Redefine the Role of Spot-Scanning Proton Beam Therapy for the Single Brain Metastasis Stereotactic Radiosurgery.

PurposeTo explore the role of using Pencil Beam Scanning (PBS) proton beam therapy in single lesion brain stereotactic radiosurgery (SRS), we developed and validated a dosimetric in silico model to assist in the selection of an optimal treatment approach among the conventional Volumetric Modulated Arc Therapy (VMAT), Intensity Modulated Proton Therapy (IMPT) and Spot-scanning Proton Arc (SPArc).Material and MethodsA patient’s head CT data set was used as an in silico model. A series of targets (volume range from 0.3 cc to 33.03 cc) were inserted in the deep central and peripheral region, simulating targets with different sizes and locations. Three planning groups: IMPT, VMAT, and SPArc were created for dosimetric comparison purposes and a decision tree was built based on this in silico model. Nine patients with single brain metastases were retrospectively selected for validation. Multiple dosimetric metrics were analyzed to assess the plan quality, such as dose Conformity Index (CI) (ratio of the target volume to 100% prescription isodose volume); R50 (ratio of 50% prescription isodose volume to the target volume); V12Gy (volume of brain tissue minus GTV receiving 12 Gy), and mean dose of the normal brain. Normal tissue complication probability (NTCP) of brain radionecrosis (RN) was calculated using the Lyman-Kutcher-Burman (LKB) model and total treatment delivery time was calculated. Six physicians from different institutions participated in the blind survey to evaluate the plan quality and rank their choices.ResultsThe study showed that SPArc has a dosimetric advantage in the V12Gy and R50 with target volumes > 9.00 cc compared to VMAT and IMPT. A significant clinical benefit can be found in deep centrally located lesions larger than 20.00 cc using SPArc because of the superior dose conformity and mean dose reduction in healthy brain tissue. Nine retrospective clinical cases and the blind survey showed good agreement with the in silico dosimetric model and decision tree. Additionally, SPArc significantly reduced the treatment delivery time compared to VMAT (SPArc 184.46 ± 59.51s vs. VMAT: 1574.78 ± 213.65s).ConclusionThe study demonstrated the feasibility of using Proton beam therapy for single brain metastasis patients utilizing the SPArc technique. At the current stage of technological development, VMAT remains the current standard modality of choice for single lesion brain SRS. The in silico dosimetric model and decision tree presented here could be used as a practical clinical decision tool to assist the selection of the optimal treatment modality among VMAT, IMPT, and SPArc in centers that have both photon and proton capabilities.