Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial

Robinson, Giles; Rudneva, Vasilisa A.; Buchhalter, Ivo; Billups, Catherine A.; Waszak, Sebastian M.; Smith, Kyle; Bowers, Daniel C.; Bendel, Anne; Fisher, Paul G.; Partap, Sonia; Crawford, John R.; Hassall, Tim; Indelicato, Daniel J.; Boop, Frederick A.; Klimo, Paul; Sabin, Noah D.; Patay, Zoltán; Merchant, Thomas E.; Stewart, Clinton F.; Orr, Brent A.; Korbel, Jan O.; Jones, David; Sharma, Tanvi; Lichter, Peter; Kool, Marcel; Korshunov, Andrey; Pfister, Stefan M.; Gilbertson, Richard J.; Sanders, Richard D.; Onar‐Thomas, Arzu; Ellison, David W.; Gajjar, Amar; Northcott, Paul A.

doi:10.1016/s1470-2045(18)30204-3

Cited by 171 publications

(217 citation statements)

References 33 publications

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“…Molecular subgroup classifications were included in SJYC07, in which young children with medulloblastoma were prescribed distinct consolidation regimens based off risk group . Risk groups were determined by tumor histology, extent of resection, disease stage, and age.…”

Section: Discussionsupporting

confidence: 75%

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Tumor bed proton irradiation in young children with localized medulloblastoma

Grewal

Fisher

et al. 2019

Pediatric Blood & Cancer

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Background Radiotherapy is often deferred in very young children with medulloblastoma, in favor of more intense chemotherapy and stem cell rescue; however, posterior fossa radiation has been shown to improve overall survival (OS) and event‐free survival compared with adjuvant chemotherapy alone. This study was performed to assess the OS, recurrence‐free survival (RFS), patterns of failure, and clinical toxicity for children aged five and under who received focal proton radiation to the tumor bed alone. Procedure From 2010 to 2017, 14 patients with newly diagnosed medulloblastoma at one institution received tumor bed irradiation following surgery and chemotherapy. The median age of the patients was 40 months (range, 10.9‐62.9 months). Results With a median follow‐up of 54 months, four patients relapsed: three within the central nervous system (CNS) outside of the posterior fossa, and one within the tumor bed after subtotal resection. All relapses occurred within 28 months after the completion of radiation therapy. Five‐year OS and RFS for this cohort of patients were 84% (95% CI, 48%‐96%) and 70% (95% CI, 38%‐88%), respectively. One patient experienced significant tumor regrowth soon after completion of radiation, autopsy showed viable tumor and necrosis near and within the brainstem, with relation to radiation unknown; however, no other acute clinical toxicities greater than grade 2 were observed in this group of patients. In the nine patients with available performance status follow‐up, no significant changes in Lansky performance status were observed. Conclusions Five‐year OS and RFS following tumor bed irradiation in young children with medulloblastoma appear to be improved compared with other studies that forego the use of radiation therapy in this patient population. This approach should be further investigated in young children with medulloblastoma.

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Section: Discussionsupporting

confidence: 75%

“…Findings from recently published trials suggest a five‐year progression‐free survival for younger children treated with radiation‐sparing approaching 30 to 60%, compared with 70% for older children . Similarly, overall survival (OS) at five years is 30% to 60% for younger children compared with 60% to 80% for older children …”

Section: Introductionmentioning

confidence: 99%

Tumor bed proton irradiation in young children with localized medulloblastoma

Grewal

Fisher

et al. 2019

Pediatric Blood & Cancer

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“…15 Furthermore, new evidence has demonstrated that methylation profiling of infant SHH MB can detect low-risk and high-risk groups within infants in this tumor subgroup. 37,52 Akin to the intertumoral heterogeneity observed within SHH MB, similar observations have been described among group 3 and group 4 MB. Definitively distinguishing group 3 from group 4 MB represents a challenge because of the now accepted inherent molecular overlap between the 2 groups that precludes complete separation.…”

Section: Dna Methylation Profilingsupporting

confidence: 75%

“…) . Furthermore, new evidence has demonstrated that methylation profiling of infant SHH MB can detect low‐risk and high‐risk groups within infants in this tumor subgroup …”

Section: Introductionmentioning

confidence: 99%

Advances in the classification of pediatric brain tumors through DNA methylation profiling: From research tool to frontline diagnostic

Kumar

Liu

Orr

et al. 2018

Cancer

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Despite significant improvements in pediatric brain tumor therapy and outcome, too many children still die from disease, and too many survivors suffer significant sequelae as a result of conventional therapies. Molecular characterization of pediatric brain tumors has afforded tremendous insight into the basic biology and clinical management of these deadly childhood diseases. Genomic, epigenomic, and transcriptional profiling have facilitated the identification of significant heterogeneity among previously uniform disease entities. In particular, DNA methylation profiling has emerged as a robust tool for identifying key disease-specific subgroups that can exhibit distinct clinical outcomes. These approaches, which also complement classical histologic techniques, can suggest key mechanistic underpinnings of tumorigenesis and open the door for better informed and more tailored therapy. By leveraging the results of large-scale classifications of disease cohorts, novel driver mutations and pathways can be uncovered, enabling generation of faithful animal models, promoting targeted drug design, informing development biology, and ultimately translating to improved clinical management. In this review, the progress in epigenetic classification of common malignant pediatric brain tumors – medulloblastoma, ependymoma, high-grade glioma, atypical teratoid/rhabdoid tumor, and CNS embryonal tumors – will be discussed, and the potential role of DNA methylation profiling as a frontline diagnostic modality will be emphasized.

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“…Only patients enrolled at St. Jude were included in this analysis. The details of this clinical trial, published elsewhere, will be summarized here . Patients enrolled received no systemic prior therapy other than corticosteroids, and upon entry onto the study were stratified into 1 of 3 risk groups (low, intermediate or high) depending on diagnosis, evidence of metastasis, and degree of tumour resection.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic basis for dosing high‐dose methotrexate in infants and young children with malignant brain tumours

Panetta

Roberts

Huang

et al. 2020

Brit J Clinical Pharma

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Aims No population pharmacokinetic studies of high‐dose methotrexate (HDMTX) have been conducted in infants with brain tumours, which are a vulnerable population. The aim of this study was to evaluate HDMTX disposition in these children to provide a rational basis for MTX dosing. Methods Patients received 4 monthly courses of HDMTX (5 g/m2 or 2.5 g/m2 for infants aged ≤31 days) as a 24‐h infusion. Serial samples were analysed for MTX by an enzyme immunoassay method. Pharmacokinetic parameters were estimated using nonlinear mixed effects population modelling. Demographics, concomitant medications and genetic polymorphisms were considered as pharmacokinetic covariates while MTX exposure and patient age were considered as covariates for Grade 3 and 4 toxicities. Results The population pharmacokinetics of HDMTX were estimated in 178 patients (age range 0.02–4.7 years) in 648 courses. The population clearance and volume were 90 mL/min/m2 and 14.4 L/m2, respectively. Significant covariates on body surface area adjusted MTX clearance included estimated glomerular filtration rate and co‐treatment with dexamethasone or vancomycin. No significant association was observed between MTX toxicity and MTX exposure, patient age, leucovorin dosage or duration. MTX clearance in infants ≤31 days at enrolment was 44% lower than in older infants, but their incidence of toxicity was not higher since they also received a lower MTX dosage. Conclusions By aggressively following institutional clinical guidelines, HDMTX‐related toxicities were low, and using covariates from the population pharmacokinetic model enabled the calculation of a rational dosage for this patient population for future clinical trials.

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Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial

Abstract: American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, NCI Cancer Center, Alexander and Margaret Stewart Trust, Sontag Foundation, and American Association for Cancer Research.

Cited by 171 publications

References 33 publications

Tumor bed proton irradiation in young children with localized medulloblastoma

Tumor bed proton irradiation in young children with localized medulloblastoma

Advances in the classification of pediatric brain tumors through DNA methylation profiling: From research tool to frontline diagnostic

Pharmacokinetic basis for dosing high‐dose methotrexate in infants and young children with malignant brain tumours

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