Sabato 27 ottobre 2012 - Pacini Editore

RElaziONi
gery, followed by radiotherapy. In the last thirty years the
role of adjuvant therapy with chemotherapy has been long
investigated and discussed. Some cooperative clinical trials
studied the addition of various chemotherapy regimens to
radiotherapy but no randomized phase III clinical trials demonstrated
a benefit from the employment of adjuvant chemotherapy
based on nitrosourea. Furthermore, a meta-analysis
comprising 12 randomized studies suggested a little survival
benefit in those patients who were treated with chemotherapy.
Temozolomide, an oral alkylating agent of recent introduction,
has demonstrated antineoplastic activity as single
agent in the treatment of relapsing glioma. Temozolomide
fulfills its tumoricidal activity by altering DNA and by determining
consequently genetic damages that are incompatible
with cell life. Recent studies demonstrated a key role
of the enzyme O-6-methylguanine-DNA-methyltransferase
(MGMT) in the resistance mechanism to alkylating drugs. In
fact this enzyme removes the genetic alteration produced by
alkylating agents and protects therefore the neoplastic cell
from the lethal damages induced by these drugs. According
to the knowledge of MGMT-induced repair mechanisms and
with the intent to overcome the resistance to temozolomide
in GBM, some studies have developed new temozolomide
administration methods able to work on MGMT. In fact,
the administration of 75 mg/m 2 temozolomide for six weeks
demonstrated a reduction of MGMT enzyme activity. The
reduction of this enzyme activity is important because low
levels of MGMT in tumor tissue are associated with longer
survival in patients with glioblastoma treated with adjuvant
chemotherapy. Furthermore, if associated with radiotherapy,
it can improve its efficacy. On the basis of these assumptions
the EORTC (European Organization for Research and Treatment
of Cancer) and the NCIC (National Cancer Institute of
Canada) have planned and developed a broad randomized
phase III study that includes 573 patients, treated in 85
European and Canadian centers. This study has compared
efficacy and tolerability of radiotherapy alone compared to
the treatment with temozolomide, concomitant and adjuvant
to radiotherapy.
Methods. Patients with a new histological diagnosis of glioblastoma
have been randomized to receive only radiotherapy
(focal irradiation divided in daily fraction of 2 Gy administered
five days a week for six weeks, for a total administration
of 60 Gy) or radiotherapy with a daily continuous treatment
with temozolomide (75 mg/m 2 /die, seven days a week, from
the first to the last day of radiotherapy), followed by six cycles
of adjuvant treatment with temozolomide (from 150 to 200
mg/ m 2 /die, for five days every 28 days). The main objective
has been the survival assessment.
Results. 573 patients, coming from 85 European and Canadian
centers, have been randomized. The average age was 56
years old and 84 % of patients underwent debulking surgery.
To a median follow-up of 28 months, median survival was
of 14.6 months in patients treated with radiotherapy and te-
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mozolomide, and of 12.1 months in those patients who were
treated only with radiotherapy. Hazard ratio for death risk in
the radiotherapy-temozolomide set had been of 0.63 (95%
confidence interval, 0.52 - 0.75; p