|
|
A phase I study of
capecitabine and concurrent radiotherapy (RT) for patients with newly diagnosed
glioblastoma multiforme (GBM)
A. J. Newman, J. Fiveash, S. Rosenfeld, M. Johnson, R. Diasio, W. Wang, A.
Cockrell-Donohue, L. B. Nabors
University of Alabama at
Birmingham, Birmingham, AL
Background. Capecitabine, an oral fluoropyrimidine, has efficacy in many
solid tumors, and has proven to be safe and effective when combined with RT for
rectal cancer.
Studies suggest correlation of response with tumor thymidine phosphorylase (TP)
and dihydropyrimidine dehydrogenase (DPD) expression (TP/DPD ratio).
TP/DPD is increased in GBM and RT improves this ratio.
Methods. Patients were enrolled in 2
cohorts based on anti-convulsant (AED) use (P450 inducing or non-P450) and
received 60 Gy RT in 30 fractions over 6 weeks and concurrent BID capecitabine
starting at 625 mg/m2 BID (1250 mg/m2/day).
Capecitabine was escalated by 25% in consecutive groups of 3 pts per
cohort.
Pts received daily capecitabine during RT and for 4 weeks after
(induction).
After a 1-week break, pts received maintenance capecitabine: 1250 mg/m2 BID
(2500 mg/m2/day), days 1-14 every 3 weeks until progression or unacceptable
toxicity.
Primary endpoint: maximum tolerated dose (MTD) of capecitabine during
induction.
Secondary endpoints: safety, disease free and overall survival.
Laboratory correlates: tumor TP/DPD by Q-RT-PCR, correlation of
toxicity/efficacy with DPD promoter polymorphisms, and effects of P450 inducing
AEDs on capecitabine pharmacokinetics.
Results.
From March to December 2003, 15
evaluable pts were enrolled [13 male, 2 female; mean age 52.1 years (range
19-70); mean KPS 88.67% (range 60-100%)].
A dose limiting toxicity (DLT) occurred in both arms at dose level 1 resulting
in expansion to 6 pts.
No further DLTs occurred.
The non-P450 AED arm at level 2 (750mg/m2 BID) had 2 DLTs (diarrhea) in the
first 3 pts.
The MTD for this arm was defined as 625mg/m2 BID.
Enrollment continues for dose level 2 P450 AED arm.
Conclusions.
Capecitabine and concurrent
RT for newly diagnosed GBM appears safe and well tolerated without unexpected
toxicities.
This combination is an exciting new approach to the treatment of GBM and merits
further evaluation.
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_19-001732,00.asp
|
