Proton Craniospinal Irradiation Research Articles

Geometric target margin strategy of proton craniospinal irradiation for pediatric medulloblastoma.

In proton craniospinal irradiation (CSI) for skeletally immature pediatric patients, a treatment plan should be developed to ensure that the dose is uniformly delivered to all vertebrae, considering the effects on bone growth balance. The technical (t) clinical target volume (CTV) is conventionally set by manually expanding the CTV from the entire intracranial space and thecal sac, based on the physician's experience. However, there are differences in contouring methods among physicians. Therefore, we aimed to propose a new geometric target margin strategy. Nine pediatric patients with medulloblastoma who underwent proton CSI were enrolled. We measured the following water equivalent lengths for each vertebra in each patient: body surface to the dorsal spinal canal, vertebral limbus, ventral spinal canal and spinous processes. A simulated tCTV (stCTV) was created by assigning geometric margins to the spinal canal using the measurement results such that the vertebral limb and dose distribution coincided with a margin assigned to account for the uncertainty of the proton beam range. The stCTV with a growth factor (correlation between body surface area and age) and tCTV were compared and evaluated. The median values of each index for cervical, thoracic and lumber spine were: the Hausdorff distance, 9.14, 9.84 and 9.77mm; mean distance-to-agreement, 3.26, 2.65 and 2.64mm; Dice coefficient, 0.84, 0.81 and 0.82 and Jaccard coefficient, 0.50, 0.60 and 0.62, respectively. The geometric target margin setting method used in this study was useful for creating an stCTV to ensure consistent and uniform planning.

Radiotherapy and Systemic Treatment for Leptomeningeal Disease.

Leptomeningeal disease (LMD) is a devastating sequelae of metastatic spread that affects approximately 5% of cancer patients. The incidence of LMD is increasing due to advancements in systemic therapy and enhanced detection methods. The purpose of this review is to provide a detailed overview of the evidence in the detection, prognostication, and treatment of LMD. A comprehensive literature search of PUBMED was conducted to identify articles reporting on LMD including existing data and ongoing clinical trials. We found a wide array of treatment options available for LMD including chemotherapy, targeted agents, and immunotherapy as well as several choices for radiotherapy including whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and craniospinal irradiation (CSI). Despite treatment, the prognosis for patients with LMD is dismal, typically 2-4 months on average. Novel therapies and combination approaches are actively under investigation with the aim of improving outcomes and quality of life for patients with LMD. Recent prospective data on the use of proton CSI for patients with LMD have demonstrated its potential survival benefit with follow-up investigations underway. There is a need for validated metrics to predict prognosis and improve patient selection for patients with LMD in order to optimize treatment approaches.

LMIC-13. ENCOURAGING EXPERIENCE OF CONCURRENT CARBOPLATIN DURING CRANIOSPINAL IRRADIATION USING IMAGE GUIDED INTENSITY MODULATED PROTON BEAM (IMPT) IN HIGH-RISK EMBRYONAL TUMORS: FIRST REPORT FROM A LOW MIDDLE-INCOME COUNTRY

Abstract BACKGROUND Concurrent carboplatin during craniospinal irradiation (CSI) using photon radiotherapy in High risk (HR) embryonal tumors has been shown to improve the event free survival in select subgroup of patients. Experience of using concurrent carboplatin during CSI using proton therapy is limited. METHOD A retrospective audit was done in Children <18 years from January 2018 to December 2023 diagnosed with HR embryonal tumors who received image guided pencil beam intensity modulated proton beam therapy-based CSI (35Gy/21#) along with concurrent carboplatin 35mg/m2 at least for 15 fractions. The patient demographics, pathological diagnosis, treatment related toxicities and date of follow-up were recorded in predesigned proforma using electronic medical record. RESULTS Twenty children with HR embryonal tumors with median age at diagnosis 5 years (Range: 1-15 years) with M: F ratio of 3:1 were included in the study. Fifteen (75%) of the patients had HR medulloblastoma defined by spinal metastases or HR molecular subtype of which 5 patients had group 3 medulloblastoma (3- leptomeningeal disease at baseline, 2- MYC amplification) while rest had embryonal tumors (3-NOS, 1-Pinealoblastoma and 1-ETMR). Carboplatin was well tolerated, however 12 (60%) patients developed neutropenia requiring daily G-CSF for an average of 5 days. Average time to complete radiotherapy was 45 days with median interruption of 4 days (Range 1-7). Radiotherapy induced toxicities included Grade 3 skin toxicity in 6 (30%) and grade 2 weight loss in 3 (15%). At a median follow up of 14 months (Range: 4-58), the PFS was 80% in the whole cohort while in the Group 3 Medulloblastoma the PFS was only 20% which was statistically significant(p=0.004). CONCLUSIONS Carboplatin along with proton CSI is well tolerated in children with HR embryonal tumors without significant adversities. Experience is encouraging especially in non-group 3 medulloblastoma patients in our cohort of children with HR embryonal tumors.

Clinical features and outcomes of patients with breast cancer with leptomeningeal carcinomatosis.

e13162 Background: Leptomeningeal carcinomatosis (LMC) is a rare, but deadly complication in breast cancer, with prior studies showing median overall survival (OS) of 15 weeks. There is a paucity of data on histologic and receptor subtype-specific survival, and there is no standard of care currently for treatment of LMC in breast cancer. We reviewed the outcomes of a contemporary cohort of breast cancer patients (pts) with LMC. Methods: This is a single-institution retrospective analysis of 38 female breast cancer pts diagnosed with LMC between 2016-2023, based on radiographic features and/or positive cerebrospinal fluid (CSF) cytology or CSF circulating tumor cells (CTCs). Patients consented to share information with a research biorepository, and we conducted a chart review of their clinical features and OS with LMC. Results: 25 pts (65.8%) had invasive ductal carcinoma (IDC), 7 pts (18.4%) had invasive lobular carcinoma (ILC), 4 (10.5%) had metaplastic carcinoma, and 2 (5.3%) had mixed IDC/ILC. 22 pts (57.9%) had triple-negative breast cancer (TNBC), 12 (31.6%) had estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-), and 4 (10.5%) had HER2+ disease. Median age at LMC diagnosis was 50 years. Median time between Stage IV and LMC diagnosis was 11 months. Pts received a median of 2 lines of systemic therapy for metastatic disease prior to LMC diagnosis. 11 pts (28.9%) had parenchymal brain metastasis prior to LMC diagnosis. 32 pts (84.2%) had signs of LMC on Magnetic Resonance Imaging of the brain and/or spine at diagnosis. 25 pts underwent CSF cytology and 13 pts underwent CSF CTC evaluation at LMC diagnosis; 14/25 pts (56%) had positive CSF cytology and 10/13 pts (76.9%) had detectable CSF CTCs. 21 pts (55.3%) underwent whole-brain radiotherapy, and 2 pts (5.3%) received proton craniospinal irradiation. 21 pts (55.3%) received IT therapy. 27 pts (71.1%) received at least 1 line of systemic therapy post-LMC diagnosis. Median OS between LMC diagnosis and death or last oncology follow up for the entire cohort was 5 months (range 0-57 months, 95% CI 3.0-8.0). There was a significant difference in median OS with LMC by receptor subtype: TNBC 3.5 months, ER+/HER2- 8 months, and HER2+ 23 months (p=0.0047). Two HER2+ pts survived ≥ 3 years post-LMC diagnosis with anti-HER2 antibody-drug conjugates and tyrosine kinase inhibitors +/- stereotactic radiosurgery (SRS) to parenchymal brain metastases. Amongst 9 pts with ER+/HER2-low disease, longer survival with LMC (≥ 16 months) was observed with trastuzumab deruxtecan, IT topotecan +/- IT trastuzumab, and SRS to parenchymal brain metastases. Conclusions: This study highlights heterogeneity in outcomes amongst breast cancer pts with LMC by receptor subtype, as well as improvement in outcomes for selected pts treated with novel therapeutics and a multidisciplinary approach. Larger prospective studies are needed to inform treatment paradigms for LMC.

Proton Craniospinal Irradiation for Treatment of Leptomeningeal Metastasis in Patients with Solid Malignancy: The MD Anderson Cancer Center Experience (S27.006)

Proton Craniospinal Irradiation for Treatment of Leptomeningeal Metastasis in Patients with Solid Malignancy: The MD Anderson Cancer Center Experience (S27.006)

Phantosmia during proton radiation and differences in frequency of phantosmia rates based on proton craniospinal irradiation technique for pediatric brain tumor patients.

Unusual olfactory perception, often referred to as "phantosmia" or "cacosmia" has been reported during brain radiotherapy (RT), but is infrequent and does not typically interfere with the ability to deliver treatment. We seek to determine the rate of phantosmia for patients treated with proton craniospinal irradiation (CSI) and identify any potential clinical or treatment-related associations. We performed a retrospective review of 127 pediatric patients treated with CSI, followed by a boost to the brain for primary brain tumors in a single institution between 2016 and 2021. Proton CSI was delivered with passive scattering (PS) proton technique (n=53) or pencil beam scanning technique (PBS) (n=74). Within the PBS group, treatment delivery to the CSI utilized a single posterior (PA) field (n=24) or two posterior oblique fields (n=50). We collected data on phantom smell, nausea/vomiting, and the use of medical intervention. Our cohort included 80 males and 47 females. The median age of patients was 10years (range: 3-21). Seventy-one patients (56%) received concurrent chemotherapy. During RT, 104 patients (82%) developed worsening nausea, while 63 patients (50%) reported episodes of emesis. Of those patients who were awake during CSI (n=59), 17 (29%) reported phantosmia. In the non-sedated group, we found a higher rate of phantosmia in patients treated with PBS (n=16, 42%) than PS (n=1, 4.7%) (p=.002). Seventy-eight patients (61%) required medical intervention after developing nausea/vomiting or phantosmia during RT. Two patients required sedation due to the malodorous smell during CSI. We did not find any significant difference in nausea/vomiting based on treatment technique. Proton technique significantly influenced olfactory perception with greater rates of phantosmia with PBS compared to PS. Prospective studies should be performed to determine the cause of these findings and determine techniques to minimize phantosmia during radiation therapy.

Proton Craniospinal Irradiation with Immunotherapy in Two Patients with Leptomeningeal Disease from Melanoma.

Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Proton versus photon craniospinal irradiation for adult medulloblastoma: A dosimetric, toxicity, and exploratory cost analysis.

This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18-66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all P < .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, P = .044) and decreased median weight loss during radiation (+1.0 versus -2.8kg, P = .011). Weight loss was associated with acute hospitalization (P = .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Volumetric Modulated Arc Therapy Craniospinal Irradiation Utilizing a Vertebral Body Sparing Approach: An Alternative Approach to Improve Access and Minimize Toxicity

Introduction: Craniospinal irradiation (CSI) is indicated for adult patients diagnosed with leptomeningeal disease (LMD). Proton-based vertebral-body-sparing (VBS) CSI has been explored with pediatric patients to minimize hematologic toxicity; however, utilization of VBS in an adult population is limited. A recent phase II trial has shown efficacy of proton-based CSI to treat non-small cell lung and breast cancer with LMD. We hypothesize that VBS-CSI utilizing volumetric modulated arc therapy (VMAT) could also effectively reduce dose to vertebral bodies and surrounding organs-at-risk (OARs), minimizing toxicity for adult patients with LMD and comparing favorably to proton-based CSI.Methods: Consecutive patients with leptomeningeal disease received VMAT VBS-CSI, 30 Gy in 10 fractions, as a part of a prospective registry. Full VMAT arcs for the brain fields matched to two spine isocenters for the upper and lower spine were created utilizing limited posterior arcs. To further decrease the vertebral body dose, an avoid entry and exit contour was created. Acute toxicity data were collected using Common Terminology Criteria for Adverse Events (CTCAE) v5.Results: Ten adult patients were treated in this cohort. One patient experienced Grade 2 neutropenia with the remaining nine experiencing Grade 1 hematologic toxicity. Three patients experienced Grade 2 gastrointestinal toxicity with the remaining seven experiencing Grade 1 nausea. No patient experienced Grade 3+ toxicities in this cohort. One patient experienced a 5-day delay in systemic therapy initiation due to neutropenia; otherwise, all patients planned for systemic therapy started without delay.Conclusions: In this study, VMAT VBS-CSI led to acceptable toxicity compared to patients treated with proton CSI on a phase 2 clinical trial. Given its promising early results, future prospective evaluation of the technique is warranted.

RADT-18. PROTON CRANIOSPINAL IRRADIATION WITH CHECKPOINT INHIBITOR THERAPY FOR PATIENTS WITH LEPTOMENINGEAL DISEASE FROM SOLID TUMORS – A SINGLE INSTITUTION CASE SERIES

Abstract BACKGROUND Leptomeningeal disease (LMD) is a devastating complication of cancer with median overall survival (OS) of 3-6 months following diagnosis. Proton craniospinal irradiation (pCSI) is a novel treatment option for LMD, permitting whole neuroaxis treatment with tolerable toxicity and improved efficacy compared to conventional photon whole brain radiation therapy and as needed focal spine radiotherapy. Despite this, patients experience progression and succumb to LMD. Addition of systemic therapy to pCSI may improve outcomes. METHODS In this single institution retrospective case series, we report feasibility of combination treatment with pCSI and immune checkpoint inhibitor (ICI) in patients with LMD from solid tumors. RESULTS Three patients were treated with pCSI (30 Gy in 10 fractions) and ICI. The first patient developed LMD related to large cell neuroendocrine carcinoma of lung primary, diagnosed by imaging and cytology, having previously undergone resection and stereotactic radiosurgery for brain metastases. Clinical and radiographic improvement was noted following pCSI, bevacizumab, and pembrolizumab therapy. Patient experienced disease progression and passed away only after ICI was held due to hypophysitis, with 6-month OS. The second patient developed LMD related to BRAF V600E mutant melanoma, diagnosed by imaging and cytology, having previously undergone ICI and BRAF-targeted therapy. Following pCSI, relatlimab, nivolumab, and BRAF-targeted therapy, the patient remains alive 7 months after LMD diagnosis despite radiographic progression treated with carboplatin, paclitaxel, intrathecal IL-2, ipilimumab, and bevacizumab. The third developed LMD related to BRAF-wildtype melanoma, diagnosed by imaging, having previously received ICI. Patient underwent pCSI followed by ipilimumab and nivolumab, progression-free 5 months after LMD diagnosis. CONCLUSION Addition of systemic therapy to pCSI is feasible for patients with LMD. Combination of ICI and pCSI may confer additional survival benefit, even among patients with prior exposure to ICI. These initial promising results warrant prospective evaluation.

EPID-04. EVOLVING SURVIVAL IN PATIENTS WITH LEPTOMENINGEAL METASTASES FROM SOLID TUMORS

Abstract BACKGROUND The prognosis for patients with leptomeningeal metastases (LM) has been historically bleak, with an average survival &amp;lt; 4 months and limited treatment options. As modern therapeutics prolong the lives of cancer patients, the life expectancy of those with LM may also improve. This study aims to demonstrate survival trends in patients with LM over a 20-year time span. METHODS This is a single-institution retrospective analysis of patients diagnosed with solid tumor LM, excluding primary brain tumors, between 2002-2022. LM diagnosis was determined via unequivocal radiographic enhancement, CSF cytology, and CSF circulating tumor cell enumeration (CSF-CTC, cells/3mL). Patient characteristics, CSF-CTC enumeration at diagnosis, and therapeutic interventions post-LM were collected. Median overall survival (OS) with IQRs were calculated. RESULTS A total of 626 patients with LM were identified. The median age at LM diagnosis was 59 years (range, 13-86) with a female predominance (72.5%). Primary malignancy consisted of lung (45.2%), breast (35.7%), melanoma (4.0%), and other (15.1%). The 20-year median OS in patients with lung cancer was 4.8 months (1.9-13.0), breast cancer was 6.1 months (2.0-13.7), and melanoma was 7.1 months (2.8-14.5). Median OS was prolonged in patients with a CSF-CTC count ≤ 50 versus &amp;gt; 50 (8.9 vs 3.4 months, p&amp;lt; 0.0001). Patients who received LM-directed proton craniospinal irradiation (17.1%), photon involved-field radiation (45.5%), and no radiation (37.4%) had a median OS of 8.7 months (4.3-20.2), 4.3 months (1.5-9.1), and 3.4 months (1.2-12.5), respectively. Patients diagnosed with LM between 2017-2022 trended towards superior median OS (6.2 months, 2.2-14.0) compared to those diagnosed between 2002-2016 (5.3 months, 2.2-12.2). CONCLUSION In this largest known series of patients with LM, outcomes show signs of improvement. Superior survival trends emerge based on primary malignancy, early detection, and modern treatment modalities. Further analyses will define survival trends by patient characteristics, cancer subtypes, and systemic therapies.

Early Outcomes from Proton Craniospinal Irradiation (pCSI) for Leptomeningeal Disease from Solid Tumors

Prospective data suggest that proton craniospinal irradiation (pCSI) improves overall survival (OS) in patients with leptomeningeal disease (LMD) from solid tumors, compared to the historical standard of involved field radiation. To evaluate outcomes of this novel approach in a real-world setting, our institutional experience with treating adults with pCSI for LMD from solid malignancies was evaluated. On an IRB-approved protocol, medical records of adults with LMD from solid tumors treated with pCSI were retrospectively reviewed for patient, disease and treatment characteristics and outcomes. CNS-PFS and OS were calculated from the last day of pCSI, and survival was modeled using Kaplan-Meier analysis. From December 2021 to November 2022, 17 patients with median age 51y (range 22-71y) were treated with pCSI for LMD from solid tumors. Thirteen patients (76%) were female. Ten had ECOG PS of 0-1, and seven had PS 2-3. Nine patients (53%) had breast cancer, 3 (18%) had non-small cell lung cancer (NSCLC), 2 (12%) had melanoma, 1 (6%) had colorectal adenocarcinoma, 1 (6%) had endocervical adenocarcinoma, and 1 (6%) had two synchronous primaries (adenocarcinoma of the gastro-esophageal junction and neuroendocrine carcinoma of the lung). All patients had prior radiation; ten had prior radiation to the brain, one had prior radiation to the spine, and six had other sites previously radiated. Fourteen patients (82%) were treated to 30 Gy in 10 fractions and 3 (18%) were treated to 25 Gy in 10 fractions due to overlap with prior radiation fields. Median follow-up was 4 months (range, 1-13 months). Among 15 evaluable patients, median CNS-PFS and median OS were 3.6 months and 4.7 months, respectively. For patients with breast cancer or NSCLC, 62% were alive at 6 months; median OS has not been reached. Treatment was well tolerated with no grade 3-4 non-hematologic adverse events. pCSI is a novel method for treatment of LMD from solid tumors that has been rapidly adopted. Based on our preliminary review, it is safe and well-tolerated; patient selection is critical. As these patients are often heavily pretreated, prior radiation fields must be considered in pCSI planning.

Prospective Feasibility Trial of Vertebral Body Sparing Pencil Beam Scanning Proton Craniospinal Irradiation in Growing Children

Advanced proton therapy techniques now allow for delivery of craniospinal irradiation (CSI) to the entire brain and thecal sac while sparing many of the anterior vertebral bodies from doses expected to inhibit growth, though this technique has not been prospectively studied. The purpose of this trial is to test the feasibility and robustness of vertebral body sparing (VBS) CSI in children with standard image guidance, to assess the dosimetric and toxicity benefits of this approach, and to report early clinical outcomes. Children 3-18 years old requiring CSI treatment were eligible for this IRB approved prospective clinical trial. The CSI clinical target volume (CTV) included the brain, entire thecal sac and neural foramina with no expansion. Select anterior vertebral bodies (AVB) could be included at the physician's discretion. The spinal portion of the CTV was treated with PA beam(s) with robust optimization (+/-3.5% range, 5mm positional uncertainty). Daily image guidance included kV/kV imaging. Cone beam CT (CBCT) was acquired weekly after final positioning and a virtual CT (vCT) was created for quality assurance (QA) analysis. Acute toxicity was prospectively assessed weekly during treatment and 1 month after per CTCAE v5.0. Ten children with a median patient age and CSI dose of 9 years (range 3-16) and 36 Gy (RBE) (range 15-36 Gy (RBE)) were enrolled. Common diagnoses were medulloblastoma (n = 4) and non-germinomatous germ cell tumor (n = 3). Seven patients received prior chemotherapy; 2 patients were treated with palliative intent. Dose statistics for the anterior vertebral body varied according to age, CSI dose and portion of the spine, with the greatest sparing in the lower thoracic and lumbar vertebrae for all patients. Nine patients completed all QA CTs; one patient required a replan due to weight gain. For all remaining patients the treatment was highly robust: CTV V95 reduction at the C-spine, T-spine, and L-spine was 0.0±0.1%, 0.6±1.3%, and 0.8±1.1%, respectively. The highest grade non-hematologic acute toxicity was grade 2 alopecia (n = 9) and grade 2 nausea/vomiting (n = 5). One patient reported transient grade 1 esophagitis during treatment. Hematologic toxicity included >/ = grade 3 lymphopenia in 7 patients, >/ = grade 3 leukopenia in 1 patient, >/ = grade 2 anemia in 6 patients, and >/ = grade 1 thrombocytopenia in 3 patients. Median follow-up is 16.6 months (range 10-36 months). Three patients experience intracranial disease progression: 2 local and 1 distant intracranial failure. There were no failures within the spine. Proton vertebral body sparing CSI targeting the thecal sac only is a highly robust treatment technique and is well tolerated. Weekly CBCT to assess changes in soft tissue posterior to the spine is recommended. Further follow-up is required to assess long-term growth outcomes.

Volumetric Modulated Arc Therapy Craniospinal Irradiation Utilizing a Vertebral Body Sparing Approach: A Toxicity Analysis

Craniospinal irradiation (CSI) is indicated for adult patients diagnosed with leptomeningeal disease (LMD). Proton-based vertebral-body-sparing (VBS) CSI has been explored with pediatric patients to minimize hematologic toxicity; however, utilization of VBS in an adult population is limited. A recent phase II trial (Yang et al, JCO 2022) has shown efficacy of proton-based CSI to treat non-small cell lung and breast cancer with LMD. We hypothesize that VBS-CSI utilizing volumetric modulated arc therapy (VMAT) could also effectively reduce dose to vertebral bodies and surrounding organs-at-risk (OARs), minimizing toxicity for adult patients with LMD and comparing favorably to proton-based CSI. Consecutive patients with leptomeningeal disease received VMAT VBS-CSI, 30 Gy in 10 fractions, as a part of a prospective registry. Full VMAT arcs for the brain fields matched to two spine isocenters for the upper and lower spine were created utilizing limited posterior arcs. The PTV was created with margins of 3mm uniformly around the brain contour and 7mm around the spinal canal. To further decrease the vertebral body dose, an avoid entry and exit contour was created. This structure was a margin on the PTV anteriorly designed to carve dose out of the vertebral bodies while still maintaining coverage to the PTV. Acute toxicity data were collected using Common Terminology Criteria for Adverse Events (CTCAE) v5 and was defined as toxicity occurring within 30 days of treatment conclusion. Ten adult patients were treated in this cohort. All patients completed radiation treatment. One patient experienced Grade 2 neutropenia with the remaining nine experiencing Grade 1 hematologic toxicity (three Grade 1 pancytopenia, six Grade 1 thrombocytopenia). Three patients experienced Grade 2 gastrointestinal toxicity (Grade 2 nausea, Grade 2 esophagitis, Grade 2 esophagitis/Grade 2 diverticulitis) with the remaining seven experiencing Grade 1 nausea. No patient experienced Grade 3+ toxicities in this cohort. One patient experienced a 5-day delay in systemic therapy initiation due to neutropenia; otherwise, all patients planned for systemic therapy started without delay. VMAT VBS-CSI is an effective technique to reduce dose to surrounding OARs and vertebral bodies. In this study, VMAT VBS-CSI led to acceptable toxicity compared to patients treated with proton CSI on a phase 2 clinical trial. An NRG phase 3 clinical trial may be developed to evaluate the efficacy of proton-based CSI for patients with LMD. However, these data show how VMAT VBS-CSI may be an acceptable alternative for centers without proton therapy capabilities. Given its promising early results, future prospective evaluation of the technique is warranted.

Multi-Institutional Phase I Feasibility Trial of Vertebral Body Sparing CSI for Pediatric Brain Tumors

Craniospinal irradiation (CSI) is an essential part of curative treatment for several pediatric brain tumors. Proton CSI allows for sparing of the organs anterior to the vertebral bodies (VBs), but this technique still includes the entire VB in the target for growing children. providing no advantage in marrow sparing or adverse effects on growth. Advances in proton therapy including Proton Beam Scanning (PBS) allow for delivery of proton CSI with substantial vertebral body sparing (VBS). We sought to determine the feasibility of VBS CSI using PBS based on the effects on tumor control and growth, and the occurrence of grade III/IV hematologic toxicity. Clinical and treatment characteristics were recorded for 20 pediatric patients with medulloblastoma (n = 14) or germ cell tumor (GCT) (n = 6) who received proton VBS CSI without concurrent chemotherapy or with concurrent single-agent vincristine in a multi-institutional clinical trial. The following standard variables were extracted for each patient: age, histology, radiation dose, chemotherapy regimen, and growth hormone replacement status. Complete blood counts (CBC) with differential and data on height/weight were recorded at baseline pre-RT, weekly during RT, and after completion of cancer treatment. Hematologic toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 (CTCAE v4). Median age of 13 male and 7 female patients receiving proton VBS CSI was 10 years (range: 5.1 - 15.1). All GCT patients (n = 6, 30%) received pre-RT chemo. Median CSI dose was 23.4 Gy (range: 21.0 - 37.8), and total dose to tumor bed was 54 Gy in 18 patients (90%) while 2 patients with pure germinoma received a total dose of 36 and 37.5 Gy, respectively. 11 patients (55%) did not receive concurrent vincristine. At a median follow up of 26.4 months (range: 12.5 - 56.3) from the start of RT, no patients relapsed. 17 patients (85%) developed grade ≥3 hematologic toxicity including grade 3 lymphopenia (n = 16), leukopenia (n = 9), neutropenia (n = 8), anemia (n = 1), and grade 4 neutropenia (n = 1). The patient who developed grade 4 neutropenia had low white blood counts prior to RT. 14 patients (70%) received post-RT chemo. No patients required platelet transfusion during RT. Those findings are similar to historical controls. 4 patients started growth hormone replacement therapy after RT. No patients developed spine deformities after the completion of treatment. Proton VBS CSI is a feasible and well tolerated treatment for children with brain tumors. Longer follow up is needed to assess for late effects on tumor control. It is too early to assess for height in this cohort but for the patients that had longer follow up, normal height was achieved.

JS01.4.A CENTRALIZED CRANIOSPINAL PROTON THERAPY FOR MEDULLOBLASTOMA PATIENTS; AN EVALUATION OF THE CARE INFRASTRUCTURE IN THE NETHERLANDS

Abstract BACKGROUND The introduction of proton radiotherapy in the Netherlands resulted in the centralization of proton craniospinal irradiation (pCSI) for patients with medulloblastoma (MB) to a single center. For optimal outcome of MB patients, timely start of pCSI and treatment without interruptions is important. However, national-scale referrals and the complexity of delivering pCSI pose a risk for treatment delays in these patients. Therefore, to aid in high quality care, integration of pCSI within the national pediatric oncology center and collaboration within the Dutch neuro oncology society - rare cancer working group was established. In this study, we evaluated the care infrastructure for pCSI for a nationwide defined MB patient cohort in the Netherlands. MATERIAL AND METHODS All Dutch MB patients referred for pCSI to our center were included in this analysis. The interval between surgery and start of pCSI was calculated, excluding patients who received neo-adjuvant chemotherapy. Overall treatment time, use of (back-up) photon fractions and plan adaptations were evaluated. Data regarding planned and additional multidisciplinary care during pCSI were extracted from the medical records. RESULTS Between February 2018 and December 2022, 79 MB patients, including 25 (32%) adult (&amp;gt;18 years) patients, were treated with pCSI. The median interval between surgery and start of pCSI for pediatric and adult patients was 32 days (IQR 30, 35) and 41 days (IQR 35, 55) respectively, and 91% and 47% started within 40 days from surgery. The median overall treatment time for all patients was 41 days (range 11). The longest treatment interruption was 3 days in one adult patient. Eight patients received a median of 9 photon fractions (IQR 2, 11); most often because of the need to start treatment quickly. In 30% of all patients a plan adaptation was needed, mostly because of changes in patient weight during treatment. In our center, it is considered standard of care to involve the (pediatric) medical oncologist and neurologist during pCSI. Clinical care (hospitalization) was required in 42% of the patients for a median of 10 days. Anesthesia was necessary predominantly for patients aged 8 years and younger. Other (para)medical disciplines involved during pCSI were neurosurgery (6%), neuropsychology (22%), speech therapy (25%), rehabilitation therapy (46%) and nutritional specialist (73%). CONCLUSION The Dutch pCSI infrastructure for MB patients facilitated a timely start of treatment in over 90% of pediatric patients and in nearly half of the adult patients. During pCSI treatment, a well-orchestrated interplay between several (para)medical disciplines is required to provide all potential necessary care. More disciplines were involved and more clinical care was required for pediatric patients. We were able to deliver pCSI treatment with less than 3 days interruption in 98% of patients.

Clinical Characterization of a Table Mounted Range Shifter Board for Synchrotron-Based Intensity Modulated Proton Therapy for Pediatric Craniospinal Irradiation.

Purpose: To report our design, manufacturing, commissioning and initial clinical experience with a table-mounted range shifter board (RSB) intended to replace the machine-mounted range shifter (MRS) in a synchrotron-based pencil beam scanning (PBS) system to reduce penumbra and normal tissue dose for image-guided pediatric craniospinal irradiation (CSI). Methods: A custom RSB was designed and manufactured from a 3.5 cm thick slab of polymethyl methacrylate (PMMA) to be placed directly under patients, on top of our existing couch top. The relative linear stopping power (RLSP) of the RSB was measured using a multi-layer ionization chamber, and output constancy was measured using an ion chamber. End-to-end tests were performed using the MRS and RSB approaches using an anthropomorphic phantom and radiochromic film measurements. Cone beam CT (CBCT) and 2D planar kV X-ray image quality were compared with and without the RSB present using image quality phantoms. CSI plans were produced using MRS and RSB approaches for two retrospective pediatric patients, and the resultant normal tissue doses were compared. Results: The RLSP of the RSB was found to be 1.163 and provided computed penumbra of 6.9 mm in the phantom compared to 11.8 mm using the MRS. Phantom measurements using the RSB demonstrated errors in output constancy, range, and penumbra of 0.3%, -0.8%, and 0.6 mm, respectively. The RSB reduced mean kidney and lung dose compared to the MRS by 57.7% and 46.3%, respectively. The RSB decreased mean CBCT image intensities by 86.8 HU but did not significantly impact CBCT or kV spatial resolution providing acceptable image quality for patient setup. Conclusions: A custom RSB for pediatric proton CSI was designed, manufactured, modeled in our TPS, and found to significantly reduce lateral proton beam penumbra compared to a standard MRS while maintaining CBCT and kV image-quality and is in routine use at our center.

Comparison of Craniospinal Irradiation Using Proton Beams According to Irradiation Method and Initial Experience Treating Pediatric Patients

This study compared craniospinal irradiation using proton beam therapy (PBT) according to irradiation method and investigated the initial effects. Twenty-four pediatric patients (1-24 years old) who received proton craniospinal irradiation were examined. Passive scattered PBT (PSPT) and intensity modulated PBT (IMPT) were used in 8 and 16 patients, respectively. The whole vertebral body technique was used for 13 patients <10 years old, and the vertebral body sparing (VBS) technique was used for the remaining 11 patients aged ≥10 years. The follow-up period was 17 to 44 (median, 27) months. Organ-at-risk and planning target volume (PTV) doses and other clinical data were examined. The maximum lens dose using IMPT was lower than that using PSPT (P=.008). The mean thyroid, lung, esophagus, and kidney doses were lower in patients treated using the VBS technique compared with the whole vertebral body technique (all P < .001). The minimum PTV dose of IMPT was higher than that of PSPT (P=.01). The inhomogeneity index of IMPT was lower than that of PSPT (P=.004). IMPT is better than PSPT at reducing the dose to the lens. The VBS technique can decrease the doses to neck-chest-abdomen organs. The PTV coverage of IMPT is superior to that of PSPT.

Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases.

Proton craniospinal irradiation (pCSI) is a promising treatment for patients with solid tumor leptomeningeal metastasis (LM). We hypothesize that genetic characteristics before and changes resulting after pCSI will reflect clinical response to pCSI. We analyzed the cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) from patients receiving pCSI for LM and explored genetic variations associated with response. We subjected CSF from 14 patients with LM before and after pCSI to cell-free DNA sequencing using a targeted-sequencing panel. In parallel, plasma ctDNA and primary tumors were subjected to targeted sequencing. Variant allele frequency (VAF) and cancer cell fraction (CCF) were calculated; clonality of observed mutations was determined. Kaplan-Meier analysis was used to associate genomic changes with survival. The median overall survival (OS) for the cohort was 9 months [interquartile range (IQR), 5-21 months]. We showed clonal evolution between tumor and ctDNA of the CSF and plasma with unique mutations identified by compartment. Higher CSF ctDNA mean VAF before pCSI (VAFpre) had worse OS (6 months for VAFpre ≥ 0.32 vs. 9 months for VAFpre < 0.32; P = 0.05). Similarly, increased VAF after pCSI portended worse survival (6 vs. 18 months; P = 0.008). Higher mean CCF of subclonal mutations appearing after pCSI was associated with worse OS (8 vs. 17 months; P = 0.05). In patients with solid tumor LM undergoing pCSI, we found unique genomic profiles associated with pCSI through CSF ctDNA analyses. Patients with reduced genomic diversity within the leptomeningeal compartment demonstrated improved OS after pCSI suggesting that CSF ctDNA analysis may have use in predicting pCSI response.

Dosimetric Predictors of Acute Lymphopenia during Proton Craniospinal Irradiation in Children

<h3>Purpose/Objective(s)</h3> Radiation-induced lymphopenia is well documented in craniospinal irradiation (CSI), and recent work suggests proton CSI (pCSI) decreases hematotoxicity associated with the technique. However, no studies have examined the relative contribution of CSI subvolumes on lymphopenia rates. The objective of this study was to evaluate the impact of brain, spine, and boost target volume (bPTV) dosimetry on acute lymphopenia in pediatric patients receiving pCSI. <h3>Materials/Methods</h3> This single-institution, retrospective study evaluated patients aged ≤25 receiving pCSI ± sequential boost as part of definitive therapy for CNS tumors. The absolute lymphocyte count (ALC) at nadir during RT was recorded. Baseline differences in patients stratified by grade of lymphopenia were tested with Mann-Whitney U and chi-square tests. Difference in median overall survival (OS) was evaluated using the log-rank test. Simple and multiple regression was used to identify dosimetric quantities associated with ALC employing stepwise variable selection with significance set at p ≤ 0.05. <h3>Results</h3> From 5/2014 - 1/2020, 53 patients were treated with pCSI with a median follow up of 4.5 years. Tumors included medulloblastoma (66%), dysgerminoma (17%), pineoblastoma (8%), ependymoma (4%), ATRT (2%), neuroblastoma (2%), and PNET (2%). Of these, 28%, 66%, and 74% received neoadjuvant, concurrent, and adjuvant chemotherapy, respectively. Grade 1, 2, 3, and 4 lymphopenia during RT was observed in 6%, 6%, 59%, and 30%, respectively. There was no significant difference in sex, age, craniospinal axis dose, boost dose, bPTV, performance status, pretreatment ALC, vertebral body sparing (VBS), or concurrent chemotherapy in those with and without G3/G4 lymphopenia. However, there was a significantly lower proportion of patients receiving neoadjuvant chemotherapy in the G3/G4 lymphopenia group (23% vs 67%, p=0.047). There was a nonsignificant trend for poorer OS in those experiencing G3/G4 lymphopenia during RT (median OS: 3.8 yrs vs 4.7 yrs). On simple regression, metrics describing dose to the brain, spine, and bPTV were significantly associated with ALC (<b>Table 1</b>). On multiple regression controlling for age and neoadjuvant chemotherapy, ALC was significantly associated with mean doses to the spine and bPTV. <h3>Conclusion</h3> Higher mean doses to the spine and bPTV were associated with lower ALC during pCSI in this pediatric population. This effect remained when controlling for age and neoadjuvant chemotherapy, factors known to be associated with lymphopenia during therapy. Larger studies are necessary to further elucidate the impact of pCSI subvolumes, particularly marrow-containing structures within the spine and pelvis, on acute lymphopenia rates in pCSI.