Elsevier

European Journal of Cancer

Volume 51, Issue 17, November 2015, Pages 2634-2642
European Journal of Cancer

Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy

https://doi.org/10.1016/j.ejca.2015.08.009Get rights and content

Highlights

  • Infections were the majority of IVAD associated complications.

  • Toxicity seems to be rare and usually mild (6%) apart of one therapy associated death.

  • The total dose of i.ventr. MTX was determined as an independent risk-factor for survival.

Abstract

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).

Conclusion

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.

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)

  • S. Rutkowski et al.

    Treatment of early childhood medulloblastoma by postoperative chemotherapy alone

    N Engl J Med

    (2005)
  • M.D. Taylor et al.

    Molecular subgroups of medulloblastoma: the current consensus

    Acta Neuropathol

    (2012)
  • S. Rutkowski

    Current treatment approaches to early childhood medulloblastoma

    Expert Rev Neurother

    (2006)
  • R.J. Packer et al.

    Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma

    J Neurosurg

    (1991)
  • J. Kühl et al.

    Preradiation chemotherapy of children and young adults with malignant brain tumors: Results of the German pilot trial HIT‘88/‘89

    Klin Pädiatrie

    (1998)
  • S. Kellie

    Chemotherapy of central nervous system tumours in infants

    Child’s Nerv Syst

    (1999)
  • A. Kiltie et al.

    Survival and late effects in medulloblastoma patients treated with craniospinal irradiation under three years old

    Med Pediatr Oncol

    (1997)
  • A.O. Von Bueren et al.

    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

    (2011)
  • C. Kalifa et al.

    The therapy of infantile malignant brain tumors: current status?

    J Neurooncol

    (2005)
  • Cited by (0)

    Deceased.

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