Pediatric Central Nervous System Embryonal Tumors: Presentation, Diagnosis, Therapeutic Strategies, and Survivorship-A Review.

Central nervous system (CNS) embryonal tumors represent a diverse group of neoplasms and have a peak incidence in early childhood. These tumors can be located anywhere within the CNS, and presenting symptoms typically represent tumor location. These tumors display distinctive findings on neuroimaging and are staged using magnetic resonance imaging of the brain and spine as well as evaluation of cerebrospinal fluid. Diagnosis is made based on an integrated analysis of histologic and molecular features via tissue sampling. Risk stratification is based on integration of clinical staging and extent of resection with histologic and molecular risk factors. The therapeutic approach for these tumors is multimodal and includes surgery, chemotherapy, and radiation, tailored to the individual patient factors (including age) and specific tumor type. Comprehensive supportive care including management of nausea, nutrition support, pain, fertility preservation, and mitigation of therapy-related morbidity (including hearing protection) is imperative through treatment of CNS embryonal tumors. Despite advances in therapy and supportive care, the long-term consequences of current treatment strategies are substantial. Integration of less toxic, molecularly targeted therapies and a comprehensive, multidisciplinary approach to survivorship care are essential to improving survival and the overall quality of life for survivors.

Evolution of Proton Radiation Therapy Brainstem Constraints on the Pediatric Proton/Photon Consortium Registry.

PURPOSE: Increasing concern that brainstem toxicity incidence after proton radiation therapy might be higher than with photons led to a 2014 University of Florida (UF) landmark paper identifying its risk factors and proposing more conservative dose constraints. We evaluated how practice patterns changed among the Pediatric Proton/Photon Consortium Registry (PPCR). MATERIAL AND METHODS: This prospective multicenter cohort study gathered data from patients under the age of 22 years enrolled on the PPCR, treated between 2002 and 2019 for primary posterior fossa brain tumors. After standardizing brainstem contours, we garnered dosimetry data and correlated those meeting the 2014 proton-specific brainstem constraint guidelines by treatment era, histology, and extent of surgical resection. RESULTS: A total of 467 patients with evaluable proton radiation therapy plans were reviewed. Median age was 7.1 years (range: <1-21.9), 63.0% (n = 296) were men, 76.0% (n = 357) were White, and predominant histology was medulloblastoma (55.0%, n = 256), followed by ependymoma (27.0%, n = 125). Extent of resection was mainly gross total resection (GTR) (67.0%, n = 312), followed by subtotal resection (STR) or biopsy (20.0%, n = 92), and near total resection (NTR) (9.2%, n = 43). The UF brainstem constraint metrics most often exceeded were the goal D50% of 52.4 gray relative biological equivalents (43.3%, n = 202) and maximal D50% of 54 gray relative biological equivalents (12.6%, n = 59). The compliance rate increased after the new guidelines (2002-2014: 64.0% vs 2015-2019: 74.6%, P = .02), except for ependymoma (46.3% pre- vs 50.0% post-guidelines, P = .86), presenting lower compliance (48.8%) in comparison to medulloblastoma/ primitive neuroectodermal tumors/pineoblastoma (77.7%), glioma (89.1%), and atypical teratoid/rhabdoid tumors (90.9%) (P < .001). Degree of surgical resection did not affect compliance rates (GTR/NTR 71.0% vs STR/biopsy 72.8%, P = .45), even within the ependymoma subset (GTR/NTR 50.5% vs STR/biopsy 38.1%, P = .82). CONCLUSION: Since the publication of the UF guidelines, the pediatric proton community has implemented more conservative brainstem constraints in all patients except those with ependymoma, irrespective of residual disease after surgery. Future work will evaluate if this change in practice is associated with decreased rates of brainstem toxicity.

Consolidative Proton Radiotherapy for Pediatric Extramedullary Ocular Acute Myeloid Leukemia.

Purpose: Pediatric acute myeloid leukemia (AML) often involves extramedullary sites, which can be resistant to standard induction chemotherapy. Consolidative radiation therapy can be used in select cases to improve local control rates and help bridge patients to curative stem cell transplants. However, there is no previously published data to support the use of proton radiotherapy (PT) in this setting. We present radiographic findings and pathologic outcomes of the first reported patient with extramedullary ocular AML to be treated with PT. Patients and Methods: Details regarding diagnostic evaluation and treatment were obtained from the electronic medical records at the University of Florida Proton Therapy Institute, Nemours Children's Health, and St. Joseph's Children's Hospital. Results: This 7-month-old patient presented with biopsy-proven relapsed AML in the bilateral anterior chambers of the eyes, which did not resolve with induction chemotherapy. The patient then received PT to a dose of 24 cobalt gray equivalent to both eyes and was found to have no evidence of disease following treatment. Conclusion: This case provides further evidence that consolidative radiotherapy may be considered for select patients with extramedullary AML who have limited response to induction chemotherapy. Given the increased prevalence of extramedullary AML in pediatric patients, it is worth considering the utilization of PT to mitigate damage to nearby organs and the risk of secondary malignancies.

Craniospinal irradiation for CNS leukemia: rates of response and durability of CNS control.

PURPOSE: Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited. METHODS: We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated. RESULTS: Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18 Gy to the brain and 12 Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12 Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI. CONCLUSION: CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space.

Little patients, big impacts: a narrative review of palliative and emergent radiotherapy for pediatric cancers.

BACKGROUND AND OBJECTIVE: The use of radiotherapy (RT) in the palliative and emergent settings for pediatric cancers is an under-utilized resource. Our objective was to provide an evidence-based review of the data to increase awareness of the benefit for this population along with providing guidance on pediatric specific treatment considerations for palliative care physicians, pediatric oncologists, and radiation oncologists. METHODS: A narrative review was performed querying PubMed, MEDLINE, ClinicalTrials.gov databases, and supplemented with review articles, survey studies, current and recent clinical trials. When limited data existed, well-designed retrospective and prospective studies in the adult setting were evaluated and expert opinion was provided from pediatric oncologists. KEY CONTENT AND FINDINGS: Pediatric specific treatment considerations include the use of anesthesia, impact of treatment on the developing child, and logistical challenges of RT. Treatment modality and dose selection are driven by histology and symptomatic site of pain, where we discuss detailed recommendations for hematologic, central nervous system, and solid tumors. For palliative RT, an underlying principle of searching for the lowest effective dose to balance response rate with minimal acute and late treatment related morbidity and logistical hardships is of paramount importance when caring for a pediatric patient. Lastly, we outline how to effectively communicate this option to patients and their caregivers. CONCLUSIONS: Palliative RT can be of valuable benefit in most settings for patients with pediatric cancer. There is an unmet need for prospective data to inform on dose-fractionation along with patient and caregiver reported outcomes.

Somatic Versus Germline: A Case Series of Three Children With ATM-Mutated Medulloblastoma.

Somatic versus Germline-A Case Series of Three Children with ATM- mutated Medulloblastoma.

Adolescent and Young Adult (AYA) Oncology, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on considerations for the comprehensive care of AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

Radiotherapy for Atypical Teratoid/Rhabdoid Tumor (ATRT) on the Pediatric Proton/Photon Consortium Registry (PPCR).

PURPOSE: Atypical teratoid/rhabdoid tumors (ATRT) of the central nervous system (CNS) are rare tumors with a poor prognosis and variable use of either focal or craniospinal (CSI) radiotherapy (RT). Outcomes on the prospective Pediatric Proton/Photon Consortium Registry (PPCR) were evaluated according to RT delivered. METHODS: Pediatric patients receiving RT were prospectively enrolled on PPCR to collect initial patient, disease, and treatment factors as well as provide follow-up for patient outcomes. All ATRT patients with evaluable data were included. Kaplan-Meier analyses with log-rank p-values and cox proportional hazards regression were performed. RESULTS: The PPCR ATRT cohort includes 68 evaluable ATRT patients (median age 2.6 years, range 0.71-15.40) from 2012 to 2021. Median follow-up was 40.8 months (range 3.4-107.7). Treatment included surgery (65% initial gross total resection or GTR), chemotherapy (60% with myeloablative therapy including stem cell rescue) and RT. For patients with M0 stage (n = 60), 50 (83%) had focal RT and 10 (17%) had CSI. Among patients with M + stage (n = 8), 3 had focal RT and 5 had CSI. Four-year overall survival (OS, n = 68) was 56% with no differences observed between M0 and M + stage patients (p = 0.848). Local Control (LC) at 4 years did not show a difference for lower primary dose (50-53.9 Gy) compared to ≥ 54 Gy (73.3% vs 74.7%, p = 0.83). For patients with M0 disease, four-year OS for focal RT was 54.6% and for CSI was 60% (Hazard Ratio 1.04, p = 0.95. Four-year event free survival (EFS) among M0 patients for focal RT was 45.6% and for CSI was 60% (Hazard Ratio 0.71, p = 0.519). For all patients, the 4-year OS comparing focal RT with CSI was 54.4% vs 60% respectively (p = 0.944), and the 4-year EFS for focal RT or CSI was 42.8% vs 51.4% respectively (p = 0.610). CONCLUSION: The PPCR ATRT cohort found no differences in outcomes according to receipt of either higher primary dose or larger RT field (CSI). However, most patients were M0 and received focal RT. A lower primary dose (50.4 Gy), regardless of patient age, is appealing for further study as part of multi-modality therapy.

Matching Protocol and Practice: The Challenge of Meeting Lung and Kidney Total Body Irradiation Constraints for Scleroderma.

PURPOSE: Total body irradiation (TBI), a form of immunomodulation, improves treatment outcomes for rapidly progressive scleroderma. The landmark Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial used strict 200-cGy lung and kidney dose restrictions to limit the likelihood of normal tissue toxicity. The protocol as written did not specify how or where the 200-cGy limit was to be measured, opening the door to variable techniques and outcomes. METHODS AND MATERIALS: Following the SCOT protocol, a validated 18-MV TBI beam model was used to evaluate lung and kidney doses with varying Cerrobend half-value layers (HVLs). Block margins were constructed per the SCOT protocol. RESULTS: Using the 2 HVL SCOT block guidelines, the average central point dose under the lung block center was 353 (±27) cGy, almost double the mandated 200 cGy. The mean lung dose was 629 (±30) cGy, triple the mandated 200 cGy. No block thickness could achieve the mandated 2 Gy due to contribution from unblocked peripheral lung tissue. With 2 HVLs, the average kidney dose was 267 (±7) cGy. Three HVLs were needed to reduce it <200 cGy, meeting the mandated SCOT limit. CONCLUSIONS: There is considerable ambiguity (and inaccuracy) in lung and kidney dose modulation for TBI. It is not possible to achieve the mandated lung doses using the protocol-specified block parameters. Future investigators are encouraged to take these findings into account to develop more explicit, achievable, reproducible, and accurate TBI methodology.

Survival of patients with orbital and eyelid rhabdomyosarcoma treated on Children's Oncology Group studies from 1997 to 2013: A report from the Children's Oncology Group.

BACKGROUND: Orbital rhabdomyosarcoma (ORMS) commonly presents as low-risk disease (stage 1, group I-III, embryonal RMS) with excellent outcome. Long-term follow-up of patients with low-risk ORMS and outcomes of less common subgroups of ORMS treated on recent Children's Oncology Group (COG) trials have not been reported. METHODS: Patients with ORMS enrolled on COG trials from 1997 to 2013 were identified. Demographic information and disease characteristics were collected. Outcomes were determined for the following subgroups: 1) low-risk ORMS, 2) resected (group I/II) low-risk ORMS, 3) non-low-risk ORMS, and 4) recurrent ORMS. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method. ResultsThe authors identified 218 patients with ORMS. Most tumors were embryonal/botryoid (n = 169; 77.5%), <5 cm (n = 213; 97.7%), group III (n = 170; 78.0%), and without lymph node involvement (N0; n = 215; 98.6%). For 192 patients with low-risk ORMS, the 10-year EFS and OS rates were 85.5% (95% confidence interval [CI], 77.0%-94.0%) and 95.6% (95% CI, 90.8%-100.0%), respectively. Those with group I/II low-risk ORMS (n = 5 in group I; n = 39 in group IIA) had 10-year EFS and OS rates of 88.0% (95% CI, 72.6%-100.0%) and 97.6% (95% CI, 90.0%-100.0%), respectively. Twenty-six patients with non-low-risk ORMS had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%-100.0%) and 95.8% (95% CI, 87.7%-100.0%), respectively. For patients with recurrent ORMS, the 10-year OS rate from the time of recurrence was 69.4% (95% CI, 50.0%-88.8%). CONCLUSIONS: Patients with ORMS had favorable long-term survival outcomes on COG studies from 1997 to 2013, including those who had both low-risk and non-low-risk disease. A significant proportion of patients with recurrent ORMS may achieve long-term survival.

Pediatric Central Nervous System Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Central nervous system (CNS) cancers account for approximately one quarter of all pediatric tumors and are the leading cause of cancer-related death in children. More than 4,000 brain and CNS tumors are diagnosed each year in children and teens, and the incidence rate has remained stagnant in recent years. The most common malignant pediatric CNS tumors are gliomas, embryonal tumors consisting of predominately medulloblastomas, and germ cell tumors. The inaugural version of the NCCN Guidelines for Pediatric Central Nervous System Cancers focuses on the diagnosis and management of patients with pediatric diffuse high-grade gliomas. The information contained in the NCCN Guidelines is designed to help clinicians navigate the complex management of pediatric patients with diffuse high-grade gliomas. The prognosis for these highly aggressive tumors is generally poor, with 5-year survival rates of <20% despite the use of combined modality therapies of surgery, radiation therapy and systemic therapy. Recent advances in molecular profiling has expanded the use of targeted therapies in patients whose tumors harbor certain alterations. However, enrollment in a clinical trial is the preferred treatment for eligible patients.

Patterns of Care and Utilization Disparities in Proton Radiation Therapy for Pediatric Central Nervous System Malignancies.

Purpose: Proton radiation therapy (PR) is well established in the treatment of pediatric malignancies in the central nervous system (CNS) with dosimetric advantages that reduce late radiation therapy (RT) effects. In this analysis, we sought to evaluate the utilization of PR in children with primary CNS malignancies and characterize the clinical and sociodemographic factors predictive of receipt of PR. Methods and Materials: The National Cancer Database was queried to identify all pediatric patients with primary CNS malignancies treated with curative intent RT from 2004 to 2017. Clinical characteristics and demographics were analyzed using standard t and χ2 testing. Predictors of PR receipt were identified with univariable and multivariable logistic regression. Results: We identified 9126 patients ≤18 years of age treated with RT between 2004 and 2017, of which 1045 (11.5%) received PR. PR usage continued to increase significantly, from <1% in 2004 to 28% in 2017. The proportion of white and Asian patients receiving PR for nonhigh-grade glioma and nonmeningioma CNS malignancies during the study period rose from <1% for both to 35% and 44%, respectively, and in black patients the proportion rose from <1% to 26%. Multivariable predictors of receipt of PR include year of diagnosis, age <6 years, income level, distance from PR facility, and histology; multivariable predictors of receipt of photon RT include black race, rural residence, and Medicaid insurance. These factors remained significant when isolating the most recent 5 years of data. Conclusions: Proton radiation therapy usage for CNS malignancies increased significantly during the study period. Despite the potential clinical advantages of PR for pediatric primary CNS malignancies, there are notable socioeconomic, geographic, and racial disparities in the receipt of PR that persisted despite the increased availability and accessibility. Further study is warranted to identify how to address the disparities and better support these patients.

Wee1 kinase inhibitor adavosertib with radiation in newly diagnosed diffuse intrinsic pontine glioma: A Children's Oncology Group phase I consortium study.

Background: Children with diffuse intrinsic pontine gliomas (DIPG) have a dismal prognosis. Adavosertib (AZD1775) is an orally available, blood-brain barrier penetrant, Wee1 kinase inhibitor. Preclinical efficacy against DIPG is heightened by radiation induced replication stress. Methods: Using a rolling six design, 7 adavosertib dose levels (DLs) (50 mg/m2 alternating weeks, 50 mg/m2 alternating with weeks of every other day, 50 mg/m2, then 95, 130, 160, 200 mg/m2) were assessed. Adavosertib was only given on days of cranial radiation therapy (CRT).The duration of CRT (54 Gy over 30 fractions; 6 weeks) constituted the dose limiting toxicity (DLT) period. Endpoints included tolerability, pharmacokinetics, overall survival (OS) and peripheral blood γH2AX levels as a marker of DNA damage. Results: A total of 46 eligible patients with newly diagnosed DIPG [median (range) age 6 (3-21) years; 52% female] were enrolled. The recommend phase 2 dose (RP2D) of adavosertib was 200 mg/m2/d during days of CRT. Dose limiting toxicity included ALT elevation (n = 1, DL4) and neutropenia (n = 1, DL7). The mean Tmax, T1/2 and Clp on Day 1 were 2 h, 4.4 h, and 45.2 L/hr/m2, respectively. Modest accumulation of adavosertib was observed comparing day 5 versus day 1 AUC0-8h (accumulation ratio = 1.6). OS was 11.1 months (95% CI: 9.4, 12.5) and did not differ from historical control. Conclusion: Adavosertib in combination with CRT is well tolerated in children with newly diagnosed DIPG, however, compared to historical controls, did not improve OS. These results can inform future trial design in children with high-risk cancer.

Impact of lung block shape on cardiac dose for total body irradiation.

Evaluating cardiac dose during total body irradiation (TBI) is of increasing interest. A three-dimensional beam model for TBI was commissioned and lung shielding was simulated in a treatment planning system with the cardiac silhouette partially blocked and unblocked. When blocked, the median heart dose decreased by 6% (IQR = 6%) and the median cardiac V12Gy decreased by 27% (IQR = 17%). The median left anterior descending artery dose decreased 20% (IQR = 12%) for blocked cases. Because using partial heart shielding may result in considerable changes in dose to cardiac structures, TBI protocols should explicitly consider lung block design parameters and their potential effects.