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Concomitant and
adjuvant temozolomide (TMZ) and radiotherapy (RT) for newly diagnosed
glioblastoma multiforme (GBM).
Conclusive results of a randomized phase III
trial by the EORTC Brain & RT Groups and NCIC Clinical Trials Group
R. Stupp, W. P. Mason, M. J. Van Den Bent, M. Weller, B. Fisher, M. Taphoorn,
A. A. Brandes, G. Cairncross, D. Lacombe, R. O. Mirimanoff
University Hospital (CHUV), Lausanne, Switzerland; Princess
Margaret Hospital, Toronto, ON, Canada; University Hospital/Rotterdam Cancer
Center, Rotterdam, Netherlands; University of Tübingen Medical School, Tübingen,
Germany; University of Western Ontario, London, ON, Canada; University Medical
Center, Utrecht, Netherlands; Azienda Ospedale-Università, Ospedale Busonera,
Padova, Italy; University of Calgary, Calgary, AB, Canada; EORTC Data Center,
Brussels, Belgium
Background. Standard therapy of GBM
after biopsy or resection is RT.
TMZ, a novel methylating agent demonstrated some activity against recurrent
glioma.
In a phase II trial we observed a potential survival advantage by adding TMZ
concomitantly and adjuvant to RT (Stupp et al. JCO 2002).
In this randomized trial we tested this novel regimen against RT.
Methods. Patients (pts) age 18-70 years
with histologically proven newly diagnosed GBM (WHO grade IV) were
eligible.
Pts were randomized between standard RT (60 Gy in 30 daily fractions of 2 Gy)
versus the same RT and concomitant (TMZ 75 mg/m2/d, daily up to 42 days)
followed by up to 6 cycles of adjuvant TMZ (150-200 mg/m2, daily x 5d, q28
d).
Survival (intent to treat) was the primary endpoint aiming at a 30% improvement
(log-rank).
Pathology was centrally reviewed.
Results. Five hundred and seventy-three
pts from 85 centers were randomized.
Median follow-up is 2 years, 436 patients have died.
Median time between histological diagnosis and treatment start was 5
weeks.
RT was delivered as prescribed in 93% of pts.
Concomitant TMZ was administered without interruption in 76%, temporarily
interrupted in 11% and prematurely discontinued in 12%.
Adjuvant TMZ was given to 76% of pts, 36% completed all 6 cycles for a total of
924 cycles.
The increase in median survival is 3 months.
The log-rank test is significant with a p-value of < .0001.
The hazard ratio is 0.62 (95% c.i. 0.51-0.75).
Grade 3/4 hematotoxicity was observed in 7% of pts during concomitant TMZ/RT
treatment, and in 16% (5.2% of cycles) of the adjuvant TMZ.
Patients continue to be followed to evaluate long term effects of treatment.
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RT (n=286)
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RT/TMZ (n=287)
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p-value
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Age, median (range) [years]
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56.6 (23.1-70.8)
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55.7 (19-70.5)
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NS
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Tumor resection
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70%
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68%
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NS
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WHO PS : 0 / 1 / 2
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39% / 49% / 12%
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39% / 48% / 13%
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NS
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Steroids at baseline
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75%
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67%
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p=0.041
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Progr.-free surv. (95% c.i.)
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5.0 mo (4.2-5.5)
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7.2 mo (5.8-8.3)
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p< .0001
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Median survival (95% c.i.)
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12 mo (11.2-13.2)
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15 mo (13.6-16.8)
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p< .0001
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2-year survival (95% c.i.)
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8% (4-12%)
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26% (20-32%)
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p< .0001
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Conclusions. Concomitant and adjuvant
TMZ chemotherapy significantly improves PFS and overall survival in GBM
pts. [BrainLife]
This treatment is safe and well tolerated.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-001655,00.asp
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