Phase II study of reduced‐dose craniospinal irradiation and combination chemotherapy for children with newly diagnosed medulloblastoma: A report from the Japanese Pediatric Brain Tumor Consortium

Abstract

Background: Standard doses of craniospinal irradiation (CSI) are 23.4 Gy for patients with average-risk and 36 Gy for those with high-risk medulloblastoma (MB). We investigated whether intensified chemotherapy including intrathecal chemotherapy with simultaneous irradiation is able to reduce CSI dose to 18 Gy. Methods: Newly diagnosed average-risk patients aged 3-11 years and high-risk patients aged 3-18 years were eligible. Patients with Stage M1-4 disease were classified as high-risk MB and the others, including M0 patients with >1.5 cm 2 postoperative residual tumor, were classified as average-risk MB. Patients received chemotherapy consisting of cyclophosphamide, etoposide, cisplatin, and vincristine. Radiotherapy was started concomitantly with the second course of chemotherapy. Radiation doses were 50 Gy to the primary site and 18 Gy to the craniospinal axis. Averagerisk patients received five courses of chemotherapy. High-risk patients received highdose chemotherapy consisting of thiotepa and melphalan following four courses of chemotherapy. All patients received intrathecal methotrexate. Results: From 2006 to 2014, 48 patients (35 average and 13 high risk) who met the eligibility/exclusion criteria were enrolled. The 3-year progression-free survival (PFS) and 3-year overall survival (OS) were 90.5% (standard error 5.2%) and 93.9% (4.2%), respectively, for average-risk patients, and 100% and 100%, respectively, for highrisk patients. There was no leukoencephalopathy or treatment-related deaths. Two patients experienced secondary cancer. Conclusions: These results suggest that CSI 18 Gy is adequate at least in a proportion of patients with MB treated with intensified chemotherapy including intrathecal methotrexate and simultaneous irradiation, though the results in high-risk patients were only exploratory.

High-dose thiotepa, in conjunction with melphalan, followed by autologous hematopoietic stem cell transplantation in patients with pediatric solid tumors, including brain tumors

“…Although radiotherapy is commonly administered to adult patients, irradiation for pediatric CNS tumors comes with an increased risk of later developmental adverse events [ 37 – 39 ]. A recent focus of research has been the use of HDT in combination with radiotherapy to reduce the irradiation exposure necessary for an adequate antitumor effect [ 40 , 41 ]; the outcomes observed with such combination regimens have been positive. However, HDT agents which are able to transition into the CNS, such as thiotepa, are likely to provide more clinical benefit in this regard.…”

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study

“…The majority of patients (29 out of 38 patients) received intrathecal chemotherapy involving six doses of methotrexate. Regarding the chemotherapeutic regimen, 92% (35 out of 38 patients) received treatment as per the Japan Pediatric Brain Tumor Consortium protocol [ 8 ], which includes four courses of cyclophosphamide, cisplatin, vincristine, and etoposide (Additional file 1 : Table). In this protocol, radiation therapy was concurrently administered during the second and third courses of chemotherapy, and HR patients underwent high-dose chemotherapy.…”

“…In Japan, LD-CSI has been performed for patients with medulloblastoma in clinical trials or at discretion of physicians since the 2010s, and the majority of patients have been in remission for a certain period [ 8 , 9 ]. We recently reported a long-term survivor case series of metastatic medulloblastoma treated with 24 gray (Gy) of CSI that demonstrated the potential prognostic significance of novel subtyping in Group 3/4 [ 9 ].…”

Questions and answers in the management of children with medulloblastoma over the time. How did we get here? A systematic review

“…In the San Francisco-Houston ( 27 ) phase II study (1984-1992), the reduction of CSI dose to 24 Gy resulted in decreased survival ( 27 ). Conversely, the Japanese Pediatric Brain Tumor Consortium ( 51 , 66 ) (1997-2006 and 2006-2014) despite administering a reduced neuraxis dose of 18 Gy, obtained optimal survival rates [5-year PFS of 82.1% ( 51 )] ( Table 4 ).…”