Revised clinical and molecular risk strata define the incidence and pattern of failure in Medulloblastoma following risk-adapted radiotherapy and dose-intensive chemotherapy: results from a phase III multi-institutional study

Author:

Lucas John T1,Tinkle Christopher L1ORCID,Huang Jie2,Onar-Thomas Arzu2,Srinivasan Sudharsan1,Tumlin Parker1,Becksfort Jared1,Klimo Paul3,Boop Frederick A3,Robinson Giles W4,Orr Brent A5,Harreld Julie H6,Krasin Matthew J1,Northcott Paul A7,Ellison David W5,Gajjar Amar4,Merchant Thomas E1

Affiliation:

1. Departments of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

2. Departments of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

3. Departments of Surgery, St. Jude Children’s Research Hospital, Memphis, TN, USA

4. Departments of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

5. Departments of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

6. Departments of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN, USA

7. Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Abstract

Abstract Background We characterize the patterns of progression across medulloblastoma (MB) clinical risk and molecular subgroups from SJMB03, a Phase III clinical trial. Methods 155 pediatric patients with newly diagnosed MB were treated on a prospective, multi-center phase III trial of adjuvant radiotherapy (RT) and dose-intense chemotherapy with autologous stem cell transplant. Craniospinal radiotherapy to 23.4 Gy (average risk, AR) or 36-39.6 Gy (high risk, HR) was followed by conformal RT with a 1 cm clinical target volume to a cumulative dose of 55.8 Gy. Subgroup was determined using 450K DNA methylation. Progression was classified anatomically (primary site failure (PSF) +/- distant failure (DF), or isolated DF), and dosimetrically. Results 32 patients have progressed (median follow-up 11.0 years (range, 0.3 – 16.5 y) for patients without progression). Anatomic failure pattern differed by clinical risk (P=0.0054) and methylation subgroup (P=0.0034). The 5-year cumulative incidence (CI) of PSF was 5.1% and 5.6% in AR and HR patients, respectively (P=0.92), and did not differ across subgroups (P=0.15). 5-year CI of DF was 7.1% vs. 28.1% for AR vs. HR (P=0.0003); and 0% for WNT, 15.3% for SHH, 32.9% for G3, and 9.7% for G4 (P=0.0024). Of 9 patients with PSF, 8 were within the primary site RT field and 4 represented SHH tumors. Conclusions The low incidence of PSF following conformal primary site RT is comparable to prior studies using larger primary site or posterior fossa boost volumes. Distinct anatomic failure patterns across MB subgroups suggest subgroup-specific treatment strategies should be considered.

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Neurology (clinical),Oncology

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