Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy.
BACKGROUND
To assess feasibility, acute toxicity, and efficacy of intraventricular methotrexate administered as part of the primary therapy in medulloblastoma.


METHODS
From 2001 to 2007, 240 patients < 22 years from 61 treatment centres were registered. Patients received 2-3 cycles of intraventricular methotrexate with systemic chemotherapy in three different treatment arms of the prospective multicentre trial HIT2000 (150 children > 4 years with metastatic, 59 < 4 years with non-metastatic, 31 < 4 years with metastatic medulloblastoma).


RESULTS
211 patients received an intraventricular access device with a subcutaneous reservoir for the application of chemotherapy. Reservoir-associated complications were documented in 57 (27%) patients, mostly due to infection (n = 32) and reservoir malfunction (n = 19), requiring removal in 39 (18%) patients. Acute neurotoxicity likely associated with intraventricular MTX was observed in 9/202 documented patients. Toxicity was usually mild, apart from one therapy-associated death due to toxic oedema followed by seizures. Of 519 treatment cycles including intraventricular methotrexate, 226 (43%) were reduced or omitted, most frequently due to the absence of an intraventricular device. Survival rates were higher in patients receiving ⩾ 75% of the scheduled intraventricular methotrexate dose compared to those receiving < 75% in both univariate and multivariate models (event-free survival (EFS), 61.5 versus 46.2%, p = 0.004; OS, 75.5% versus 60.4%, p = 0.015; hazard ratio: EFS 1.723, p = 0.016; OS 1.648, p = 0.051).


CONCLUSIONS
Intraventricular methotrexate therapy was feasible and mostly well tolerated. Infections were the most frequent complication. A higher cumulative dose of intraventricular methotrexate was associated with better survival. Further evaluation of efficacy and late effects is warranted.
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.
Raisa S
RS
Pompe
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Germany.
André O
AO
von Bueren
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.
Martin
M
Mynarek
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.
Katja
K
von Hoff
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany; Division of Pediatric Oncology, Hematology and Hemostaseology, Department of Woman's and Children's Health, University Hospital Leipzig, Leipzig, Germany.
Carsten
C
Friedrich
Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany.
Robert
R
Kwiecien
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.
Wiebke
W
Treulieb
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.
Christine
C
Lindow
Department of Pediatric Oncology, University of Wuerzburg, Germany.
Frank
F
Deinlein
Pediatrics III, University Hospital of Essen, Germany.
Gudrun
G
Fleischhack
Department of Pediatric Oncology, University of Wuerzburg, Germany.
Joachim
J
Kuehl
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: s.rutkowski@uke.de.
Stefan
S
Rutkowski
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002528:Cerebellar Neoplasms / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007223:Infant; D007239:Infections / Q000209:etiology; D007276:Injections, Intraventricular; D008297:Male; D008527:Medulloblastoma / Q000628:therapy*; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D016016:Proportional Hazards Models; D011446:Prospective Studies; D055815:Young Adult
D008727:Methotrexate
Brain tumours; Chemotherapy; Intraventricular; Medulloblastoma; Methotrexate; Treatment