High dose methotrexate for pediatric high grade glioma: results of the HIT-GBM-D Pilot study

Abstract

We conducted a phase II study to test methotrexate (5 g/m(2)), as a single agent prior to radiochemotherapy for pediatric high-grade glioma and diffuse intrinsic pontine glioma. Thirty patients (19 male, median age 10.8) were enrolled. Tumors were located as follows: cortex 10, pons 7, other 13. Tumor resection was classified as gross total in 6, subtotal in 6, partial in 4, biopsy in 11 and not performed in 3. WHO grading of the histology was: IV: 11, III: 12 and II: 3. Patients received methotrexate 5 g/m(2) in 24-hour infusions on days 1 and 15. Subsequently 54 Gy radiation was administered with simultaneous chemotherapy including cisplatin, etoposide, vincristine and ifosfamide as previously described. Eight 6-weeks cycles of maintenance chemotherapy consisted of vincristine 1.5 mg/m(2) on days 1, 8 and 15; lomustine 100 mg/m(2) on day 2 and prednisone 40 mg/kg on days 1-17. Event-free survival rates in the whole group of 30 patients were: 43, 20, and 13% after 1, 2 and 5 years, respectively. The response evaluation after methotrexate was available in 19 of the 24 patients who started treatment with measurable disease: CR: 0, PR: 1, SD 18, PD: 0. After radiochemotherapy the response of 24 patients with measurable disease was CR: 1, PR 10, SD 12, PD 1. Both response and event-free survival were superior to the control group of 330 patients treated in various protocols of the same cooperative group. In subgroup analyses the use of dexamethasone during early treatment was linked to poor event free survival. Giving two cycles of high-dose methotrexate prior to radiochemotherapy was feasible, and the approach was taken forward to a randomized phase III trial.

Management of high-grade gliomas in the pediatric patient: Past, present, and future

“…19 HIT-GBM-B -treated participants with RT and concurrent chemotherapy (cisplatin/etoposide in the first cycle and cisplatin/ etoposide/ifosfamide in the second cycle) followed by interferon-g and/or low-dose cyclophosphamide maintenance therapy 20 ; HIT-GBM-C involved administration of intensive chemotherapy (vincristine, cisplatin, ifosfamide, and etoposide) both during and after RT followed by oral valproic acid as maintenance therapy (a histone deacetylase/HDAC inhibitor) 1 ; and HIT-GBM-D, a pilot phase II study, evaluated the efficacy of single-agent methotrexate (MTX) prior to RT and chemotherapy. 22 In this pilot study, 2 doses of MTX (5 gm/m 2 ) were given prior to RT followed by simultaneous chemotherapy-RT and subsequent maintenance chemotherapy as per the HIT-GBM-C protocol. The toxicity profile was acceptable, with no deaths related to drug toxicity.…”

“…Data from this study suggested that the HIT-GBM-D protocol is favorable for treating pHGG patients with a GTR. 22 The approach of giving 2 cycles of high-dose MTX prior to radiochemotherapy will be assessed in a phase III RCT, and results from the randomized study are pending. The German Society for Pediatric Oncology Vanan and Eisenstat: "Management of pediatric high-grade gliomas" conducted a randomized clinical trial to evaluate the efficacy of pre-RT intensive chemotherapy in pHGGs in 1991.…”

The Effect of ABCG2 and ABCC4 on the Pharmacokinetics of Methotrexate in the Brain

“…MTX is a folate antagonist with limited uptake in the brain, which likely contributes to the need for high-dose therapy (Nierenberg et al, 1991;Wolff et al, 2011). Studies in rodents (Devineni et al, 1996) and patients (Blakeley et al, 2009) that used brain microdialysis to measure the brain interstitial fluid MTX concentrations attest to its limited distribution in the normal brain, with a brain-to-plasma ratio 0.051 6 0.032 and 0.032 6 0.094 in rodents and humans, respectively.…”

Treatment of high-grade glioma in children

“…Hiçbiri YDG olgularına anlamlı bir yarar getirmemiştir. [14][15][16] Fransa Pediatrik Onkoloji Grubu da, 1990-1996 arasında RT öncesi verilen karmustin (BCNU), sisplatin ve etoposid (VP-16) (BCV) tedavisinin etkinliğini araştırmış ancak pulmoner toksisitesi çok fazla görülen bu KT seçeneği önerilmemiştir. [17] Erişkin GBM'li hastalarda Temozolomide'nin (TMZ) etkinliği gösterildikten sonra, birçok pediatrik çalışma bu tedavi protokolünü denemiş ancak benzer yaşam sürelerini gösterememiştir.…”