Strategy to minimize radiation burden in infants and high‐risk medulloblastoma using intrathecal methotrexate and high‐dose chemotherapy: A prospective registry study in Japan

Abstract

Background Most childhood medulloblastoma (MB) cases are curable using multimodal treatment, including craniospinal irradiation (CSI). However, late effects are a serious problem for survivors. This prospective registry study evaluated Japanese patients to determine whether a reduced radiation dose was feasible. Patients and Methods Patients with MB were classified as an infant group (<3 years old) and a high‐risk (HR) group (≥3 years old with metastasis). The HR group received intrathecal methotrexate (IT‐MTX) and high‐dose chemotherapy (HDC) using thiotepa and melphalan, as well as concomitant radiotherapy with a recommended CSI dose of 18 Gy and a total local dose of 50 Gy. Radiotherapy was only considered for infants if residual tumors were present after the HDC. Results Between 1997 and 2006, we identified 28 HR patients (M1: 9, M2/3: 19) and 17 infant patients (M0: 11, M1: 3, M2/3: 3). During the median follow‐up of 9.4 years for the entire HR group, the 5‐year progression‐free survival (PFS) rate was 82.1 ± 7.2% and the 5‐year overall survival (OS) rate was 85.7 ± 6.6%. Subanalyses of the patients who received the recommended treatment revealed that the 5‐year PFS and OS rates were both 90.5 ± 6.4%. In the infant group, the 5‐year PFS rate was 52.9 ± 12.1% and the 5‐year OS rate was 51.8 ± 12.4%. There were no serious adverse events associated with the IT‐MTX and HDC treatments. Conclusion Intensified chemotherapy using HDC and IT‐MTX might allow for a reduced prophylactic radiation dose in patients with MB with metastases. Further studies are needed to validate these findings.

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

“…However, it still gave promising results since there were no disease recurrences during a long‐term follow up. We have previously reported that HDC consisting of thiotepa and melphalan demonstrated antitumor activity against several types of tumors including MB, 7,9 and the registry data previously reported by us showed excellent results (5‐year PFS 82.1 ± 7.2% and 5‐year OS 85.7 ± 6.6%) in 28 high‐risk MB patients. Taken together, this strongly suggests that HDC not only allows the radiation dose to be reduced to 18 Gy but also significantly improves survival.…”

“…The results of this study of reduced‐dose CSI 18 Gy for children with newly diagnosed MB, which was based on a previous phase II trial prospective registry study, 7 showed a promising 5‐year PFS rate of 83.9 ± 6.7% for average‐risk patients. Simultaneous radiotherapy with the second and third courses of chemotherapy may raise the antitumor effect of treatment.…”

“…We have treated MB patients using CSI 18 Gy since 1997. Our group has performed a prospective registry study that showed promising results with intensified chemotherapy including high‐dose chemotherapy (HDC) and intrathecal methotrexate plus simultaneous irradiation, which might permit CSI dose reduction to 18 Gy in high‐risk MB patients 7 . Based on that result, we planned a phase II clinical trial to investigate whether multidrug‐intensified chemotherapy including intrathecal chemotherapy plus simultaneous irradiation, without HDC, is able to reduce the dose of CSI to 18 Gy in average‐risk MB patients.…”

“…Average‐risk patients ≥ 12 years were excluded because the degree of their cognitive decline after cranial irradiation was small and their benefit from dose reduction was limited. We also included high‐risk MB patients following the strategy of our previous registry study 7 …”

Thiotepa–melphalan myeloablative therapy for high‐risk neuroblastoma

“…(2019) reported toxicity profiles of this regimen in a further cohort 9 . Recently, a promising result of this regimen for high‐risk medulloblastoma was published 10 . By contrast, few studies have investigated this regimen for high‐risk neuroblastoma 11 .…”