Craniospinal Irradiation Research Articles

Craniospinal Reirradiation Using Proton Beam Radiotherapy in the Treatment of Pediatric Recurrent Medulloblastoma

<h3>Purpose/Objective(s)</h3> Craniospinal irradiation (CSI) is an essential part of medulloblastoma treatment even without any evidence of leptomeningeal metastasis. In case of recurrence, it is important to assess several factors to consider reirradiation course. These factors include prior radiation doses, time interval between radiotherapy courses and cumulative dose. In cases of leptomeningeal dissemination reirradiation of the entire craniospinal axis is needed, but may be accompanied by severe toxicity. Proton therapy may reduce toxicity without reducing treatment doses. <h3>Materials/Methods</h3> Proton beam craniospinal reirradiation (CSRI) course was conducted to 18 patients with recurrent medulloblastoma. Median dose to craniospinal axis during primary treatment was 30.6 Gy (24-36). Sixteen patients had additional local boost to recurrent and metastatic sites. In all cases we've made a dose gradient in the border zone to avoid irradiation of vertebral bodies. Eight patients had High Dose Chemotherapy (HDCT) before CSRI. The minimal interval between HDCT and CSRI was 2 months. Median dose at primary CSI was 23.7 Gy (23.4-36). Seven patients had reirradiation previously, two of them had CSRI with total dose of 18 Gy. <h3>Results</h3> Median time between two CSI courses was 33 months (19-126). Median follow-up period was 9 months (2-18). Six patients had disease progression, five of them died because of progression during the next 1.5 years after CSRI. Average time to progression was 13.3 ± 1.6 months (95% CI 10.1-16.4). During treatment we observed strong evidence of progressing thrombocytopenia (avg = 95 * 10⁹) with minimal values occurring during third week (p < 0.001). There was a non-significant decrease of hemoglobin and neutrophiles level (p_hemoglobin=0.4, p_neutrophiles=0.07). One patient had severe bone marrow hypoplasia during the treatment which required blood and platelet transfusion and neutrophil stimulation. The rest of the patients' hematological toxicity resolved without medical intervention. Only one patient had interruption during treatment because of COVID-19 infection. All the patients except one received chemotherapy after CSRI. None of them had any evidence of radiation necrosis or other radiological changes during the whole follow-up period. <h3>Conclusion</h3> CSRI is mostly used for medulloblastoma patients with refractory disease and leptomeningeal progression. Proton therapy may help to deliver curative doses with limited hematological toxicity and to minimize or completely avoid gastrointestinal toxicity. Probably it may lead to long-term disease control for such group of patients.

A Scalp Dose Cutoff That Prevents Permanent Alopecia in Scalp-Avoidance Whole-Brain Volumetric-Modulated Arc Radiotherapy for Pediatric Patients with Medulloblastomas

<h3>Purpose/Objective(s)</h3> Permanent alopecia significantly impacts the quality-of-life. We perform scalp-avoidance volumetric-modulated whole brain radiotherapy (SA-WBRT) as a component of craniospinal irradiation (CSI). However, the scalp cutoff dose that prevents permanent alopecia remains unknown. Here, we estimate the optimal cutoff dose for patients undergoing the St. Jude Medulloblastoma-96 protocol. <h3>Materials/Methods</h3> Eight pediatric patients (median age 8 years 0 months, range 4 years 8 months to 12 years 10 months) with medulloblastoma treated from May 2011 to August 2018 were enrolled. All patients underwent CSI and boost radiotherapy followed by four cycles of dose-intensive chemotherapy. Four patients were treated with conventional WBRT and the others with SA-WBRT. We defined permanent alopecia as hair loss persisting for 1 year after radiotherapy completion, graded by two reviewers for each patient using the SALT score; grades 3 and 4 alopecia were considered severe. We divided the scalp into top, back, left, and right areas and calculated the equivalent doses in 2-Gy fractions (assuming α/β = 2) to 50% of these areas (EQD50%); we compared these values to the alopecia grades. We drew receiver operating characteristic curves to determine the predictive performances of the EQD50% <i>in terms of</i> severe permanent alopecia and derived EQD50% cutoffs for the four scalp areas. <h3>Results</h3> The median follow-up period was 71 months (range 50.8-109.0 months) from start of radiotherapy. No patient experienced disease progression in the 5 years after radiotherapy, and no severe side effect was observed in patients undergoing SA-WBRT. Such patients tended to have less severe permanent alopecia than those who underwent conventional WBRT (4 vs. 10 regions, P = 0.07). The scalp EQD50% of SA-WBRT was significantly lower than that of conventional WBRT (16.6 ± 3.6 vs. 20.2 ± 5.5 Gy, P = 0.038). The optimal EQD50% cutoff for severe permanent alopecia was 21.2 Gy (area under the curve 83%; 83% sensitivity; 78% specificity). The severe alopecia area was markedly reduced when 21.2 Gy served as the cutoff (27.2 vs. 80.0%, P = 0.008). <h3>Conclusion</h3> SA-WBRT significantly reduced the scalp EQD50% and prevented severe permanent alopecia compared to conventional WBRT. The optimal cutoff dose was 21.2 Gy.

Outcome of Patients with Central Nervous System Multiple Myeloma (CNS-MM) Treated with CNS-Directed Radiation Therapy

<h3>Purpose/Objective(s)</h3> Extramedullary spread of multiple myeloma into the central nervous system (CNS-MM) is rare and confers a poor prognosis, with reported overall survival (OS) of 2-7 months. Outside of case reports, there is an undefined role of CNS-directed radiation therapy (RT) in managing CNS-MM. Here, we report our institutional outcomes in a cohort of patients with CNS-MM treated with CNS-directed RT. <h3>Materials/Methods</h3> We retrospectively identified patients with CNS-MM (established by CSF cytology, flow cytometry, or MRI brain/spine), treated with CNS-directed RT from 2015-2020. CNS-MM was defined as having leptomeningeal disease (LMD), parenchymal disease, or CSF involvement. Complete response (CR) was defined as having no cells in CSF or resolution of radiographic disease on MRI. Otherwise, patients were recorded as having partial response (PR) or stable disease (SD). The Kaplan-Meier method was used to estimate OS. <h3>Results</h3> Sixteen patients met inclusion criteria. CNS-MM was confirmed in 11 patients (69%) by CSF and MRI, 3 patients (19%) by CSF alone, and 2 patients (12%) by MRI alone. At CNS-MM diagnosis, 7 patients (43.8%) had received ≥3 prior lines of therapy, 7 (43.8%) were in 1^st/2^nd relapse, and 2 were newly diagnosed. The median time to CNS-MM from initial MM diagnosis was 40.3 mos (range: 0-105). Nine patients (56.3%) had high-risk disease as defined by plasmablastic morphology, cytogenetic features, or LDH elevation. Time to RT from CNS-MM diagnosis was 27 days (range: 9-264). Ten patients (62.5%) underwent craniospinal irradiation (CSI), four (25%) received brain RT (3 focal, 1 whole brain), and 2 (12.5%) received spine RT. The median dose was 23.4 Gy (3.6-30 Gy) in 12 fractions (2-15). Eight patients (50%) also received intrathecal therapy with cytarabine following CNS-MM diagnosis. Two patients (12.5%) underwent SCT post-RT. For the entire cohort (n=16), median OS was 46.6 mos (range: 11-125) from MM diagnosis, 4.2 mos (0.7-60.6) post-diagnosis of CNS-MM, and 3.9 mos (0.43-52) from start of RT. Fifteen patients completed the intended RT and 9 patients (60%) were evaluable post-RT with adequate follow-up consisting of CSF analysis and/or MRI imaging. For the 9 evaluable patients, the median OS from the start of RT was 7.23 mos (range: 3.1-52.1), with CR following RT in 6 patients (66.7%), PR in 2 patients (22.2%) by imaging, and SD in 1 patient (11.1%) by imaging and CSF cytology. Among the 6 patients that completely responded to RT, local relapse occurred in 2 patients at 3 mos and 1 patient at 24 mos post-RT. For the 6 patients with CR after RT, the median OS was 7.27 mos (3.2-52.1) from the start of RT, and 9.2 mos (3.8-60.6) from CNS-MM diagnosis. <h3>Conclusion</h3> Multiple myeloma patients with CNS involvement represent a high-risk patient population. Aggressive multimodality therapy may induce durable CNS control in a small subset of patients. CNS-directed RT may be an effective treatment strategy in selected patients and may increasingly be important to consider in the era of CAR T-cell therapy.

Second Neoplasms in Children Following Radiotherapy in the Modern Era: A Bicentric Report from the University of Florida and Memorial Sloan Kettering Cancer Center

<h3>Purpose/Objective(s)</h3> Over the past two decades, eliminating secondary radiation-induced neoplasms has been a primary aim of our field. This study quantifies the results of that effort with a focus on children who received intensity-modulated radiotherapy (IMRT) and proton therapy (PT). <h3>Materials/Methods</h3> A total of 1880 pediatric patients with > 2 years follow-up received radiotherapy between 1999 and 2019, including 348 treated with IMRT and 1532 treated with PT (97% passive-scatter). The median age was 9.2 years old, including 623 patients ≤5 years old. Overall, 31 patients had a known genetic tumor predisposition syndrome, most commonly neurofibromatosis (n=15); 1044 had central nervous system tumors; 191 patients were treated with large volume-radiation, including craniospinal irradiation (CSI) in 135; and 988 patients received alkylating chemotherapy. Patients treated with IMRT were more likely to receive alkylating chemotherapy (76.4% vs 47.1%, p <0.001), but received a lower median radiation dose (50.4 vs 54 Gy, p <0.001) and were marginally less likely to have a tumor predisposition syndrome (0.6% vs 1.9%, p = 0.10). Cumulative incidence method provided estimates of secondary neoplasms including benign and malignant solid tumors as well as leukemia. Multiple variables were assessed using proportional hazard regression for competing risks. The median follow-up duration was 6.5 years (range, 2-21.9) and included 296 and 773 patients with >5 years follow-up in the IMRT and proton cohorts, respectively. <h3>Results</h3> The 5-year local control rate was similar between the 2 cohorts at 90.7% following PT vs 91.4% following IMRT. For all patients, the 5- and 10-year rates of developing a second neoplasm were 1.2% and 3.3%, respectively. On multivariate analysis, the presence of a tumor predisposition syndrome (10.1% vs 1.1%), the use of alkylating chemotherapy (2.1% vs 0.3%), and the use of IMRT (2% vs 1%) were significantly associated with the development of a second neoplasm 5 years after treatment (all p < 0.05). When patients with tumor predisposition syndromes were excluded from the analysis, the use of alkylating chemotherapy (1.9% vs 0.2%) and the use of IMRT (2.0% vs 0.8%) independently retained a significant association with second neoplasms (both p < 0.05). The difference in secondary malignant solid tumors was non-significant; however, 4/14 (29%) malignant solid tumors occurred outside the target region in the patients treated with PT compared to 5/10 (50%) in patients treated with IMRT. <h3>Conclusion</h3> Compared to IMRT, early data reveal a significant reduction in second neoplasms among children treated with PT, most pronounced in those who do not have underlying tumor predisposition syndromes. This could be due to a reduction in leukemia and malignant solid tumors developing in tissue exposed to low-dose radiation outside the target region.

Review of 20 years of Adult Medulloblastoma Treatment at a High-Volume Center – Chemotherapy Prescription Trends and Survival

<h3>Purpose/Objective(s)</h3> Medulloblastomas are WHO grade 4 tumors and represent less than 1% of adult brain malignancies. Standard of care is maximal safe resection follow by craniospinal and primary site radiation – the role for chemotherapy has been unclear. The objective of this study was to review 20-year chemotherapy prescribing trends in adult medulloblastoma patients at a high-volume center, with secondary objectives assessing overall and progression free-survival. We hypothesized that primary chemotherapy (concurrent or adjuvant) would be associated with prolonged survival and that patients treated in the most recent decade would have received chemotherapy more often. <h3>Materials/Methods</h3> A retrospective review was performed of adult medulloblastoma patients at a high-volume center from 1999-01-01–2020-12-31. Eligible patients were 18 years and older with a pathologic diagnosis of medulloblastoma – those with supratentorial primitive neuroectodermal tumors were excluded. Descriptive statistics were used to present population data and Kaplan–Meier estimators for survival analysis. <h3>Results</h3> Forty-nine patients were eligible; median age was 30 and male: female ratio was 2:1. Desmoplastic and classical histologies were the most common. Molecular subgroup was available for 6 patients, with SHH predominating. Of all patients, 47% (23/49 were classified as high risk – most commonly due to large cell/anaplastic histology or large residual. Only 10 (20%) received primary chemotherapy, 70% of which had high risk disease. Of the patients who received primary chemotherapy, 30% went on to receive chemotherapy for recurrence or metastases; of the entire population, this was only 39%. Primary regimens were mainly cisplatin/lomustine/vincristine, while recurrence regimens were often cisplatin/etoposide. The majority who received primary chemotherapy were treated from 2010–2020. Median overall survival was 7.8 years (95% CI 5.7–∞), with 1-, 5-, and 10-year survival 95.8%, 67.5% and 42.2% respectively. Overall survival was marginally better for those who did not receive primary chemotherapy (8.5 years) vs those who did (7.4 years) <i>but this was non-significant</i>. The main chemotherapy toxicity was hematologic and neuropathy - 90% of primary chemotherapy patients experienced toxicity <h3>Conclusion</h3> This study reviewed 20 years of treatment trends for a group of adult medulloblastoma patients at a high-volume center. We found only a small proportion of patients received chemotherapy as their primary treatment with surgery and radiation. Patients who received primary chemotherapy had marginally worse overall survival, but this was non-significant – perhaps due to baseline worse clinical status not captured by the definition of high vs. intermediate risk disease. Despite calls for adjuvant chemotherapy for all adult medulloblastoma patients, there is clinical equipoise and future randomized trials are needed.

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.

Phase II Randomized Trial Comparing Proton Craniospinal Irradiation with Photon Involved-Field Radiotherapy for Patients with Solid Tumor Leptomeningeal Metastasis

<h3>Purpose/Objective(s)</h3> Solid tumor leptomeningeal metastasis (LM) is associated with limited survival and treatments. Photon involved-field radiotherapy (IFRT) is the standard of care radiotherapy (RT) but lacks durability in disease and symptom control. We hypothesized that proton craniospinal irradiation (pCSI) encompassing the central nervous system (CNS) would result in superior disease control. <h3>Materials/Methods</h3> We conducted a randomized phase 2 study comparing pCSI vs. IFRT in patients with non-small cell lung cancer (NSCLC) or breast cancer LM. Eligibility criteria included radiographic and/or cytologic LM and Karnofsky performance status (KPS)≥ 60. Patients were stratified by histology and systemic disease (active vs. stable) and were randomized in a 2:1 ratio favoring pCSI. For all other solid tumor histologies, patients were enrolled on an exploratory cohort and all received pCSI. RT was 3Gy x 10 fractions for all patients. The primary objective is CNS progression-free survival (CNS PFS), defined as time from randomization to CNS progression (POD); the secondary objectives include overall survival (OS) and treatment-related adverse events (TAEs). A target of 81 patients to compare pCSI and IFRT was designed with a one-sided alpha of 0.025 and power of 0.8 based on stratified log-rank test. Analysis is based on intent-to-treat. <h3>Results</h3> From 4/2020-10/2021, 42 and 21 patients were randomized to pCSI and IFRT, respectively. Baseline factors were not different: median age was 56 vs. 61 years (p=0.5), both cohorts included 57% NSCLC and 52% patients with active systemic disease. At median follow up of 7.1 months, 25 patients had CNS POD and 28 died. At planned interim analysis, significant benefit in CNS PFS was observed with pCSI (median=7.5 months, 95% CI: 6.6-NA) vs. IFRT (median=2.0. 95% CI: 1.0-5.1, p<0.001). As a result, the Data and Safety Monitoring Committee recommended early discontinuation of the trial. In addition, OS benefit with pCSI (median= 8.2 months, 95% CI: 7.4-NA) vs. IFRT (median= 4.9 months, 95% CI: 3.1-NA, p=0.04) was observed. In a multivariable analysis including age, KPS and stratification factors, pCSI remained significantly associated with improved CNS PFS (HR=13, 95% CI: 5-33, p<0.001) and OS (HR=2, 95% CI: 1-5, p=0.04). Grade 3 non-heme TAEs occurred in 3 patients with pCSI and 5 with IFRT. The only Grade 4 TAE was lymphopenia (4 patients in each cohort). For the exploratory pCSI cohort, 35 patients enrolled, the median age was 61, 20 (57%) had active systemic disease and ovarian (7 [20%]) was the most common histology. At median follow up of 9.6 months, 7 (20%) had CNS POD and 20 (57%) died. Median CNS PFS was 5.4 months (95% CI: 4.8-9.1), OS was 6.6 months (95% CI: 5.4-12.1), 4 patients had Grade 3 non-heme TAEs and 4 had Grade 4 lymphopenia. <h3>Conclusion</h3> In this pre-planned interim analysis of the first randomized trial of RT for LM, we demonstrated improved CNS PFS of pCSI compared to IFRT, meeting the primary endpoint. pCSI also had a significant OS benefit. Toxicities were comparable.

The Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA can Predict Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastasis

<h3>Purpose/Objective(s)</h3> Solid tumor leptomeningeal metastasis (LM) is a devastating disease with poor survival. Proton craniospinal irradiation (pCSI) is a promising treatment for LM, and there is a need for biomarkers for patient selection. Understanding the genetic variation of LM pre- and post-pCSI can elucidate differences in response to radiotherapy. We analyzed the observed mutations in cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) of LM patients treated with pCSI and explored whether the variant allele fraction (VAF) can predict survival. <h3>Materials/Methods</h3> We examined 14 patients from a phase I trial pCSI for solid tumor LM (NCT03281889) with pre- and post-pCSI ctDNA assessment. Mutations were identified using an institutional targeted-sequencing panel, MSK-IMPACT, and allele specific copy number variation was used to determine mutation clonality. Primary tumors or solid tumor metastases, and ctDNA in the plasma was also analyzed. VAF and cancer cell fraction (CCF) were calculated. An independent clinical sequencing cohort of 50 LM patients who did not receive pCSI was used for comparison. Kaplan Meier analysis was used to associate mutation measures and survival outcomes. <h3>Results</h3> The median overall survival for the cohort was 9 months (IQR: 5-21 months). The median number of mutations observed in the CSF ctDNA pre- pCSI was 10 (range:0-25) and post-pCSI was 9 (range:0-42). We observed the clonal evolution between solid tissue and ctDNA of the CSF and plasma, and we identified mutations that are unique by compartment, with more mutations seen in the CSF compared to plasma. A higher VAF pre-pCSI (VAF_pre) was associated with worse OS (8 months for VAF_pre≥0.32 [median] vs 21 months for VAF_pre<0.32, p=0.05). Patients with increased VAF after pCSI had significantly worse survival (6 months vs 18 months, p=0.008). The CCF of novel subclonal mutations after pCSI showed that higher values were associated with worse OS (8 months vs 17 months, p=0.05). In the comparison cohort, VAF≥0.37 [median] was associated with worse OS after CNS-directed RT (8 months vs 9 months, p=0.05). <h3>Conclusion</h3> In LM patients undergoing pCSI, there are unique baseline mutation profiles and distinct responses to pCSI that may be able to predict survival after radiotherapy. Analysis of the ctDNA of LM patients before and after pCSI shows that improved outcomes are associated with lower frequency of mutations. The quantification of these mutations has important implications for patient stratification in CNS-directed radiotherapy and escalation of therapy after pCSI.

Clinical Outcomes of Medulloblastoma Patients Treated with Proton Radiotherapy: A Systematic Review

<h3>Purpose/Objective(s)</h3> The aim of this study was to comprehensively review all studies examining clinical outcomes of proton therapy for craniospinal irradiation of medulloblastoma, to determine whether theoretical dosimetric advantages of proton therapy have translated into superior clinical outcomes, including survival and toxicities. <h3>Materials/Methods</h3> We performed a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, using the PubMed (Medline), EMBASE, and Cochrane Library databases (inception to December 2021). The study was registered with PROSPERO, CRD42022302455. Articles in the English language reporting on clinical outcomes of pediatric and/or adult medulloblastoma patients treated with proton therapy were included. Two independent authors screened all titles/abstracts, reviewed full texts and extracted relevant data, with discrepancies resolved by consensus. Individual study quality was scored using Newcastle Ottawa Scale and overall evidence base by GRADE scale. <h3>Results</h3> Thirty-five studies were included, representing 629 unique patients. Publication dates ranged from 2011 to 2021, with the majority (n=32) from the United States. None of the studies were randomized, 12 were comparative, 9 were prospective, 3 mixed and 22 retrospective. Average mean/median follow up was 5.0 years (range = 4 weeks to 12.6 years). The majority of studies (n=19) reported on treatment with passive scatter proton beams exclusively. Average study quality score was 6.08 out of 9 (SD 0.688, median 5). Seven studies scored ≥8/9 on the Newcastle Ottawa Scale; an overall "moderate" GRADE score was assigned. Well-designed comparative cohort studies with adequate follow-up demonstrate superior neurocognitive outcomes, lower incidence of hypothyroidism (23% vs 69%) and reduced acute toxicities (including myelosuppression, esophagitis, diarrhea, weight loss and nausea/vomiting) in patients treated with protons compared to photons. The 10-year cumulative incidence of secondary malignancy is also lower for proton cohorts (2.1-4.9% vs 8%), but did not reach statistical significance in any individual study. Overall survival (10-yr) (85.3-86.9% for standard-risk disease), progression-free survival (10-yr), patterns of failure, and other endocrine outcomes such as incidence of GH deficiency, adrenal insufficiency and precocious puberty were similar to those reported for photon therapy. Quality of life, ototoxicity and incidence of CNS injury were also found to be comparable between proton and photon cohorts, albeit with lower quality of evidence. Overall, quality of evidence was most robust in the domains of intellectual outcomes, endocrinopathies and acute toxicity. <h3>Conclusion</h3> Moderate grade evidence supports proton beam therapy as a preferred treatment for craniospinal irradiation of medulloblastoma based on equivalent disease outcomes and comparable-to-improved toxicity versus photon beam radiotherapy.

Results of the treatment of pineal tumors in children: the Lyon experience.

Pineal tumors are rare and their incidence is of 1% among all pediatric tumors of the central nervoussystem. Patient survival depends on the histology, the extension of the surgical removal, and the efficacy of thecomplementary treatment (chemotherapy and cranio-spinal irradiation), as well as the age of the patient. In this study, we analyzed 151 pediatric patients treated for pineal tumors from 1997 to2020 in Lyon, France. All patients were recorded in the French Register of Pineal tumors, which has beencentralized and maintained in Lyon since 2010. Our analysis shows that benign tumors have an overall positive prognosis with total surgical removal.Concerning pineal parenchymal tumors, pinealoblastomas have a poor prognosis , especially in children less thanthree years old. A new pathological classification system allows for a better stratification of patient risk withindifferent groups of patients with pineal tumors. It is also important to note that the identification of DICER 1syndrome in families with pinealoblastomas warrant further medical investigation. Patients with Germ Cell Tumors have more favorable outcomes, with a global survival rate of 87 % and a puregerminoma survival rate of almost 97%. When analyzing the prognosis of pineal gland gliomas, otherwise knownas tectal plate gliomas, pilocytic astrocytomas had a promising prognosis. Otherwise, prognosis of other tectal plategliomas are related to the grade of malignancy and the efficacy of complementary treatment. Lastly, papillarytumors need a complete removal for the best chance of survival, and Atypical teratoid/ rabdoid tumors (AT/TR)still have a bad prognosis, regardless of surgical resection. Our results show that, with regards to pediatric pineal region tumors, there are still areas inprognostic indicators that need to be improved. Similarly, these pathologies need to be treated via amultidisciplinary approach to improve a patient's survival rate and their quality of life.

A Case of Non-Germinomatous Germ Cell Tumors of the Frontal Lobe Arising From the Lateral Ventricle With a Synchronous Pineal Lesion

Non-germinomatous germ cell tumours (NGGCT) are rare intracranial tumours that account for 1% to 3% of cases. They are usually seen in the pineal and suprasellar regions. NGGCT of the frontal lobe arising from the lateral ventricle with a synchronous pineal lesion is uncommon. We present a case of NGGCT with multifocal lesions in the pineal gland, frontal lobe, and pons treated with chemotherapy followed by craniospinal irradiation (CSI).

Craniospinal Irradiation of Pediatric Medulloblastoma, Dosimetric Comparison between Helical Tomotherapy, and Conventional Radiation Therapy

Craniospinal Irradiation of Pediatric Medulloblastoma, Dosimetric Comparison between Helical Tomotherapy, and Conventional Radiation Therapy

An Analysis of Major Target Deviations in Craniospinal Irradiation Treatment Plans for Patients With Intermediate-Risk Medulloblastoma Within a Phase 3 Clinical Trial (Children's Oncology Group Study ACNS0331)

PurposeCraniospinal irradiation remains an essential and yet difficult part of the treatment of patients with medulloblastoma. Whereas technological advances offer promise of increased conformity, realiance on advanced technology is not without risk, and it remains critical to carefully delineate targets. We describe examples of target deviations (TDs) in craniospinal irradiation treatment plans for postoperative patients with medulloblastoma in a phase 3 clinical trial (ACNS 0331). Methods and MaterialsThe principal investigator independently performed a review of the treatment plans and portal films of enrolled patients and evaluated the plans for TDs. TDs of dose, dose uniformity, and volume were defined as major or minor deviations. Major TDs scored as protocol violations. The effect of major TDs on event-free survival (EFS) and overall survival (OS) was evaluated using the stratified Cox proportional hazards model. ResultsOf the 549 patients enrolled, 461 were available for this analysis. Thirty-two (7%) plans did not have data sufficient for TD evaluation. Major TDs were found in 32 of the 461 plans (7%). Of those, 21 were deviations of target volume alone, 7 were deviations of target dose alone, and 4 were deviations of both target volume and dose. The 25 patients with TDs of volume involved 29 sites. The most common major TDs of volume involved the brain (9 of 29) and the posterior fossa (9 of 29). On Cox proportional hazards modeling, the presence of a major TD did not statistically significantly affect EFS (hazard ratio, 0.98; 95% confidence interval, 0.45-2.11; P = .9541) or OS (hazard ratio, 1.10; 95% confidence interval, 0.51-2.38; P = .8113). ConclusionsAlthough intensity modulated radiation therapy and proton therapy are promising in improving conformity and sparing organs at risk, technology does not substitute for careful anatomic definition of target volumes. The study was not powered to evaluate the effect of TDs on EFS and OS; therefore, the statistical analysis presented in this study must be interpreted with caution.

Feasibility of treating pediatric intracranial germ cell tumors in a middle-income country: The Jordanian experience.

Pediatric intracranial germ cell tumors (iGCT) are rare, with limited data available from Arabic countries. We retrospectively reviewed the medical charts of children <18years diagnosed with iGCT at King Hussein Cancer Center/Jordan (January 2003 to December 2020) for clinical characteristics, treatment, and morbidities. Sixteen patients had germinoma; median age was 6.9years and median symptoms duration 8months. Nine tumors were suprasellar, five pineal, and two bifocal. Four were metastatic. Eight patients had slightly elevated beta subunit human chorionic gonadotropin and 11 patients had resection/biopsy. Fifteen patients received chemotherapy; mostly carboplatin (450mg/m2 )/etoposide, which had low toxicity. All patients received radiotherapy (different doses and fields). At median follow-up of 7.7years, one tumor recurred (progression-free survival: 91%±8%). Twelve patients who continued follow-up had stable visual and endocrine deficits to their initial presentation. Five finished or are finishing diploma and seven had poor school performance (four left school). Six patients were diagnosed with nongerminomatous germ cell tumor; median symptom duration was 1month. Three tumors were pineal, two suprasellar, and one at quadrigeminal plate. Three were metastatic. Five tested patients had high tumor markers and four had resection/biopsy. All patients received chemotherapy, and then five received craniospinal radiation. Two patients are alive, two died with tumor progression, one died in remission with electrolyte imbalance, and one developed leukemia and died with septic shock. We achieved excellent survival in treating germinoma using a feasible protocol for low middle-income countries. However, patients encountered significant morbidities exacerbated by delayed diagnosis and unnecessary surgical interventions despite abnormal tumor markers. Raising awareness on iGCT symptomatology and diagnosis may help limit these morbidities.

Review of 20 years of adult medulloblastoma treatment: Chemotherapy prescription trends and survival.

The historic standard of care for adult medulloblastoma has been considered surgery and radiation, while chemotherapy is increasingly being prescribed. This study reviewed 20-year chemotherapy trends at a high-volume center, as well as overall and progression free-survival. Adults with medulloblastoma treated at an academic center from January 1, 1999 to -December 31, 2020 were reviewed. Patient baseline data were summarized and Kaplan-Meier estimators were used for survival. Forty-nine patients were included; median age was 30 years and male: female ratio was 2:1. Desmoplastic and classical histologies were most common. Of all patients, 23 (47%) were high risk and 7 (14%) metastatic at diagnosis. Only 10 (20%) received initial chemotherapy, of which 70% were high risk and 30% metastatic, with most treated from 2010 to 2020. Forty percent of initial chemotherapy patients received salvage chemotherapy for recurrence or metastases (of all patients, 49% required salvage). Initial chemotherapy regimens were mainly cisplatin/lomustine/vincristine, and at recurrence cisplatin/etoposide. Median overall survival was 8.6 years (95% CI 7.5-∞), with 1-, 5-, and 10-year survival at 95.8%, 72%, and 46.7%. Median overall survival for those who did not receive initial chemotherapy was 12.4 years and 7.4 years for those who did (P-value .2). Twenty years of adult medulloblastoma treatment was reviewed. Initial chemotherapy patients, most of whom were high risk, trended towards worse survival, but this was nonsignificant. The ideal timing and choice of chemotherapy for adult medulloblastoma is unknown-challenges of administering chemotherapy following photon craniospinal irradiation may have prevented it from becoming routine.

Parent ratings of executive functioning in pediatric survivors of medulloblastoma and pilocytic astrocytoma

The present study compared parent-rated executive functioning in pediatric medulloblastoma (MB) and pilocytic astrocytoma (PA) survivors. Although standard care for both includes surgical resection, children with MB additionally receive chemotherapy and craniospinal irradiation. Given well-documented neurocognitive late effects associated with the latter, we anticipated poor parent-reported executive functioning in MB survivors. Parents/guardians of 36 MB survivors and 20 PA survivors completed the Behavior Rating Inventory of Executive Functioning (BRIEF). PA survivors were younger at diagnosis (t[51.97] = 3.07, p < .001, d = 0.86) and demonstrated higher IQ (t[54] = −3.51, p < .001, d = 0.95). However, relative to the MB group, the PA group was rated as having significantly more problems on all BRIEF scales (all p ≤ .05; d = 0.30 − 1.10), except the Shift scale. Additionally, all mean BRIEF scores for MB survivors were within normal limits, whereas for PA survivors, all mean BRIEF scores except for Organization of Materials were significantly discrepant from normative means. Overall, PA survivors were rated as demonstrating poorer executive function than MB survivors. Five theories are discussed as possible explanations for these surprising findings: two related to group differences, two related to potential sources of parental bias, and one related to the nature of questionnaire-based assessment. All these theories represent directions for future research. Parent questionnaires such as the BRIEF may have real-world implications for pediatric brain tumor survivors. Future research should explore factors affecting parent ratings of executive functioning in these populations, along with comparison to performance-based measures.

A Script-Based Automatic Intensity Modulated Radiation Therapy Planning Method With Robust Optimization for Craniospinal Irradiation

This report describes a script-based automatic planning method with robust optimization for craniospinal irradiation (CSI) to reduce sensitivity to field matching errors and increase planning efficiency. The data of 10 CSI patients with planning target volume (PTV) lengths between 49.8 and 85.0 cm were retrospectively studied. Robust intensity modulated radiation therapy plans with ±5-mm longitudinal position uncertainty were generated by the automatic planning script. A simple dose prediction model and a self-adjusting method were implied in the automatic plans. The plans’ robustness against setup errors was evaluated by deliberately shifting the middle beamset ±5 mm in the superior-inferior direction. Manual and nonrobust plans were also created to evaluate the automatic robust plans’ quality, efficiency, and robustness. There were no significant differences between the manual and automatic plans in terms of homogeneity index; conformity index; D1%, D2%, and D98% of PTV; and average doses of organs at risk. However, the D99% of the PTV in the automatic plans was slightly inferior to that in the manual plans. Compared with the manual plans, the automatic plans greatly increased efficiency, with a reduction in planning time of approximately 48%. When ±5-mm superior-inferior errors were introduced, the average deviations of the maximum dose D1% and minimum dose D99% to the spinal cord were 4.9% (±1.1%) and –3.4% (±1.3%), respectively. However, the corresponding values of the nonrobust plans were 20.0% (±5.4%) and –21.2 (±6.3%), respectively. The script-based automatic CSI planning method, combining robust optimization and a dose prediction model, efficiently created a good-quality plan that was robust to setup errors.

Three-Dimensional Dosimetry by Optical-CT and Radiochromic Gel Dosimeter of a Multiple Isocenter Craniospinal Radiation Therapy Procedure.

Craniospinal irradiation (CSI) is a complex radiation technique employed to treat patients with primitive neuroectodermal tumors such as medulloblastoma or germinative brain tumors with the risk of leptomeningeal spread. In adults, this technique poses a technically challenging planning process because of the complex shape and length of the target volume. Thus, it requires multiple fields and different isocenters to guarantee the primary-tumor dose delivery. Recently, some authors have proposed the use IMRT technique for this planning with the possibility of overlapping adjacent fields. The high-dose delivery complexity demands three-dimensional dosimetry (3DD) to verify this irradiation procedure and motivated this study. We used an optical CT and a radiochromic Fricke-xylenol-orange gel with the addition of formaldehyde (FXO-f) to evaluate the doses delivered at the field junction region of this treatment. We found 96.91% as the mean passing rate using the gamma analysis with 3%/2 mm criteria at the junction region. However, the concentration of fail points in a determined region called attention to this evaluation, indicating the advantages of employing a 3DD technique in complex dose-distribution verifications.

JS04.5.A Enhancing the activity of anti-CD47 antibody therapy with radiotherapy in preclinical models of medulloblastoma

Abstract Background Brain cancers are the most common solid cancer in children and the leading cause of cancer-related deaths in children. Medulloblastoma is the most common paediatric brain tumour. Treatment for medulloblastoma involves surgery, craniospinal irradiation (CSI) and chemotherapy. These therapies are extremely damaging to the developing brain and have not changed in decades, resulting in stagnation in the survival outcomes for children with medulloblastoma, and poor quality of life for children who survive their treatment. Immunotherapy has become a focus of novel treatment development. While there are multiple clinical trials aiming to increase immune recognition of medulloblastoma, none have been successful to date. Anti-CD47 is an immune-modulating therapeutic antibody which blocks the anti-phagocytic signal, CD47, expressed by brain cancer cells. Anti-CD47 has shown promising preliminary efficacy in brain cancer models. Material and Methods Using a small animal radiotherapy platform, we have developed a preclinical CSI protocol which mimics clinical radiotherapy. Using an orthotopic xenograft model of medulloblastoma, mice were treated with either anti-CD47 antibody therapy, CSI, or the combination of both anti-CD47 and CSI. Results CSI was found to deplete adaptive immune cells in the brain, while myeloid cells remained the dominant populations. Anti-CD47 antibody therapy was ineffective as a single agent against a patient derived xenograft model of Group 3 medulloblastoma, and CSI as a monotherapy resulted in temporary tumour regression. We found that the combination of anti-CD47 with CSI resulted in marked and persistent tumour regression. Conclusion This preclinical work has shown promising efficacy of anti-CD47 in combination with CSI, which we are currently testing in additional models. Our work is currently employing a range of techniques such as high dimensional flow cytometry and single cell sequencing to elucidate the mechanisms by which radiotherapy enhances the anti-tumour activity of myeloid cells. This work will enable the rational design and translation of optimal combination therapies for medulloblastoma clinical trials.

Biomarkers for risk-based treatment modifications for CNS germ cell tumors: Updates on biological underpinnings, clinical trials, and future directions.

CNS germ cell tumors (GCTs) preferentially occur in pediatric and adolescent patients. GCTs are located predominantly in the neurohypophysis and the pineal gland. Histopathologically, GCTs are broadly classified into germinomas and non-germinomatous GCTs (NGGCTs). In general, germinoma responds well to chemotherapy and radiation therapy, with a 10-year overall survival (OS) rate of approximately 90%. In contrast, NGGCTs have a less favorable prognosis, with a five-year OS of approximately 70%. Germinomas are typically treated with platinum-based chemotherapy and whole-ventricular radiation therapy, while mature teratomas can be surgically cured. Other NGGCTs require intensive chemotherapy with radiation therapy, including whole brain or craniospinal irradiation, depending on the dissemination status and protocols. Long-term treatment-related sequelae, including secondary neoplasms and cerebrovascular events, have been well recognized. These late effects have a tremendous impact in later life, especially since patients are mostly affected in childhood or young adults. Intending to minimize the treatment burden on patients, the identification of biomarkers for treatment stratification and evaluation of treatment response is of critical importance. Recently, tumor cell content in germinomas has been shown to be closely related to prognosis, suggesting that cases with low tumor cell content may be safely treated with a less intensive regimen. Among the copy number alterations, the 12p gain is the most prominent and has been shown to be a negative prognostic factor in NGGCTs. MicroRNA clusters (mir-371-373) were also revealed to be a hallmark of GCTs, demonstrating the potential for the application of liquid biopsy in the diagnosis and detection of recurrence. Recurrent mutations have been detected in the MAPK or PI3K pathways, most typically in KIT and MTOR and low genome-wide methylation has been demonstrated in germinoma; this most likely reflects the cell-of-origin primordial germ cells for this tumor type. These alterations can also be leveraged for liquid biopsies of cell-free DNA and may potentially be targeted for treatment in the future. Advancements in basic research will be translated into clinical practice and can directly impact patient management. Additional understanding of the biology and pathogenesis of GCTs will lead to the development of better-stratified clinical trials, ultimately resulting in improved treatment outcomes and a reduction in long-term treatment-related adverse effects.