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Brain
tumours in children and
Temozolomide
Brain
tumours in children are the most common of the solid tumours and account
for about 16% of all pediatric malignancy, being second only to leukaemia.
The treatment of brain tumours embraces a multidisciplinary approach
involving surgery, radiotherapy and chemotherapy. To date, we are lacking
in drugs being efficacious without severe side effects, therefore more
active and less toxic compounds are urgently needed. Temozolomide
belongs to the imidazotetrazine class and it is a DNA-methylating agent.
TMZ is a pro-drug, spontaneously converted into its active form at
physiological pH, thus not requires enzymatic activation in the liver. It
has almost 100% oral bioavailability, with some limited influence of the
fasting state, and is able to cross the blood brain barrier, showing a
good activity against gliomas in adults. On the basis of the results
obtained in adult malignant gliomas, phase I and II clinical trials were
performed to evaluate the efficacy and the safety of the use of this novel
drug in pediatric cancer too, but pediatric brain gliomas do not appear to
be sensitive to this compound, at least alone, and even though, Verschuur
et al. observed a mild response in children with oligodendrogliomas, this
kind of tumour is very rare in children. The
dose limiting toxicity is a reversible and non-cumulative myelosuppression:
neutropenia and, especially, thrombocytopenia are more frequent with the
use of the 5-day schedule, occurring about 21 days after the first dose of
the cycle and recovering within 7-14 days.
Another significant aspect of TMZ toxicity profile is the
lymphocytopenia and low CD4+ cell counts, that occur with all extended
schedule of administration both in adults and children. To
date, some aspects of the use of TMZ in children remain unknown, such as
the administration with other compounds (i.e. VP16 or Cisplatin) or its
use with extended schedule. So, phase II clinical trial are necessary to
clarify the real efficacy of TMZ in children. However,
in their multicentric study, Cefalo et al. showed the good antitumour
activity of TMZ against refractory or recurrent Medulloblastoma/PNET.
Although this study is still
ongoing, these data are very interesting because TMZ may become the first
line drug for the treatment of this kind of tumour. In
conclusion, even though TMZ alone did not show the expected efficacy, new
phase II clinical trials should be performed to prove its efficacy in
combination with other drug or using new schedules, especially against
Medulloblastoma /PNET.
Bibliographical reference: Barone G et al.: "Role of temozolomide in pediatric brain tumors", Childs Nerv Syst. 2006 Mar 25
Giuseppe Barone Division of Pediatric Oncology, Catholic University of Rome, Largo A. Gemelli, 8, Rome, Italy
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