Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy
Introduction
Medulloblastoma (MB) is the most common malignant brain tumour in childhood [1]. Young age, disseminated disease, residual tumour in patients without dissemination, and biological parameters are major prognostic factors [2], [3], [4], [5], [6], [7]. Survival rates have raised continuously over the last decades [8], [9], [10], [11]. Because of frequent dissemination via the cerebrospinal fluid (CSF), craniospinal radiotherapy (CSI) is important backbone of multimodal treatment. Due to the high vulnerability to radiotherapy-induced cognitive deficits, MB treatment in children younger than 3–5 years is particularly difficult [8], [12], [13]. To reduce these deficits, recent regimens tried to avoid or delay radiotherapy in young children by intensified postoperative chemotherapy [6], [14], [15], [16], [17], and/or addition of intraventricular chemotherapy to intravenous chemotherapy. In the HIT-SKK1992 trial of the Society of Pediatric Oncology and Hematology in Germany, Austria and Switzerland (GPOH) intraventricular methotrexate (i.vc. MTX) was introduced to substitute radiotherapy in children younger than 3 years with MB [6]. Neurocognitive outcome was better compared to the previous, CSI including trial HIT-SKK1987, and survival rates improved, particularly for desmoplastic MB [18]. These results were confirmed for non-disseminated MB under the age of 4 in the subsequent study HIT‘2000 [15].
When administered directly into the CSF via intraventricular access device (IVAD), sustained cytotoxic MTX CSF-levels can be achieved [19]. Compared to repeated lumbar punctures (LP), intraventricular therapy is convenient, painless, and relatively safe [20]. However, several complications have been reported, including infection, haemorrhage, oedema or technical problems (e.g. misplacement or malfunction) [20], [21], [22]. Infections may be associated with both implantation and treatment application and are usually caused by Staphylococcus epidermidis [20], [23]. Serious complications which require removal and reimplantation of the reservoir appear to be infrequent in previous studies analysing older patients [20], [23], but information on complications in younger children is rare [8], [15].
MTX can cause neurotoxic effects by direct toxicity to the central nervous system (CNS) and the influence on diverse biochemical pathways [24]. MTX-induced neurotoxicity is classified into acute (during or within hours), subacute (after days to weeks) and chronic (after months to years) forms. Acute neurotoxicity (seizures, confusion, somnolence and chemical arachnoiditis) is supposed to be related to peak MTX-CSF-levels and the total MTX dosage [24], [25]. Bleyer et al. [25] reported reduced acute neurotoxicity rates when MTX was given in a “concentration × time” regimen compared to higher, single injections of MTX. In addition, the “concentration × time” schedule achieved a longer therapeutically effective concentration of MTX in the CSF. Subacute neurotoxicity usually manifests as encephalopathy and myelopathy. Learning disabilities, a decrease in intelligence, and leukoencephalopathy are considered symptoms of chronic MTX-associated neurotoxicity [24].
Here, we evaluate the feasibility and acute toxicity of intraventricular MTX treatment in children and young adults with metastatic and non-metastatic MB treated within the prospective multicentre trial HIT‘2000. Explorative efficacy analyses assessing the effect of intraventricular MTX treatment on survival are reported.
Section snippets
Eligibility
The HIT2000 trial (NCT00303810) was approved by the ethics committee of the University of Wuerzburg. All patients or legal representatives gave their written informed consent before participation. Patients were included in this study if they had histologically confirmed primary MB and were stratified into a treatment arm including i.vc. MTX. All patients were younger than 22 years at diagnosis and were to have received the first postoperative treatment course according to schedule of the
Staging and patient’s characteristics
From January 2001 to December 2007, 240 children with newly diagnosed MB, treated in 61 centres in Germany, Austria and Switzerland were registered to one of the three different treatment arms of the HIT2000 trial. Of 90 patients under the age of four, 59 with non-disseminated disease were treated according to the HIT2000-BIS4 protocol and 31 with disseminated disease to the MET-HIT2000-BIS4 protocol. 150 patients older than 4 years with disseminated disease were treated according to the
Discussion
Based on our knowledge this report is the largest series published on i.vc. MTX chemotherapy in paediatric brain tumours.
Our data demonstrate that the application of i.vc. MTX is feasible in a true multicentre setting with acceptable toxicities and gives preliminary data on effectiveness. Complications of i.vc. MTX chemotherapy might be associated with the IVAD or with side effects of intra-CSF MTX.
In our cohort, the overall device-associated complication rate was 27%, leading to removal in
Funding
The HIT2000 trial office and the reference institutions are supported by the German Children’s Cancer Foundation (Deutsche Kinderkrebsstiftung).
Conflict of interest statement
None declared.
References (38)
- et al.
Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: reults of the German prospective randomized trial HIT’91
J Radiat Oncol Biol Phys
(2000) - et al.
Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children
Lancet Oncol
(2005) - et al.
Treatment of medulloblastoma in young children
Lancet Oncol
(2005) - et al.
“Concentration x time” methotrexate via a subcutaneous reservoir: a less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms
Blood
(1978) - et al.
Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial
Eur J Cancer
(2010) - et al.
Population-based epidemiologic data on brain tumors in German Children
Cancer
(2001) - et al.
Metastasis stage, adjuvant treatment and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children ’ s Cancer Group 921 randomized phase III study
J Clin Oncol
(1999) - et al.
The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine and prednisone
J Neurosurg
(1990) - et al.
Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy
J Neurosurg
(1994) - et al.
Medulloblastoma: present concepts of stratification into risk groups
Pediatr Neurosurg
(2003)
Treatment of early childhood medulloblastoma by postoperative chemotherapy alone
N Engl J Med
Molecular subgroups of medulloblastoma: the current consensus
Acta Neuropathol
Current treatment approaches to early childhood medulloblastoma
Expert Rev Neurother
Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma
J Neurosurg
Preradiation chemotherapy of children and young adults with malignant brain tumors: Results of the German pilot trial HIT‘88/‘89
Klin Pädiatrie
Chemotherapy of central nervous system tumours in infants
Child’s Nerv Syst
Survival and late effects in medulloblastoma patients treated with craniospinal irradiation under three years old
Med Pediatr Oncol
Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT‘2000 confirming the prognostic impact of histology
Neuro Oncol
The therapy of infantile malignant brain tumors: current status?
J Neurooncol
Cited by (0)
- †
Deceased.