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Phase I/II trial of IV
topotecan (TOPO) in combination with whole brain radiation therapy (WBXRT)
M. A. Spear, A. Mirmiran, E. McClay
UCSD, San Diego, CA; San Diego Cancer Research Institute, San
Diego, CA
Background.
Durable intracranial control of brain metastases remains an
issue subsequent to WBXRT.
Topotecan (TOPO) crosses the blood-brain barrier and has
been shown to exhibit synergistic cytotoxicity with XRT.
We thus conducted a phase I/II trial to determine the
toxicities and estimate efficacy TOPO and WBXRT.
Methods.
Eligible patients had radiologically detectable evidence of
brain metastases.
Patients received 30 Gy WBXRT given in 10 fractions.
TOPO was administered as a 30 min. IV infusion within 60
min prior to XRT.
In phase I, patients were treated in groups of 3 at each
TOPO dose level.
The dose of TOPO started at 0.4 mg/m2/day and
was escalated in increments of 0.1 mg/m2/day.
A total of 9 patients were studied at UCSD and the
outcomes of these patients reported below.
Results.
The dose-limiting toxicity proved to be Grade IV neutropenia at
0.6 mg/m2.
Thus, 0.5 m/m2 came to be established as the
MTD and was used in the phase II portion of the trial.
Two of the 9 patients experienced grade IV (22%), and 1
each had Grade III (11%), Grade II (11%), and Grade I (11%) neutropenia.
2 patients experienced Grade IV (22%),1 had Grade III
(11%), and 2 experienced Grade I (22%) thrombocytopenia.
5 patient sdemonstrated Grade I elevated liver enzymes
(56%), and 1 had Grade II (11%).
Other observed toxicities included nausea, vomiting,
constipation, and skin rash.
Alopecia and radiation dermatitis (Grade I) were seen
within the expected time frame and severity as for WBXRT alone.
Only Grade I neurologic events were observed in 2 patients
(22%) (headache and weakness).
1/9 patients showed a response to treatment, and that was
partial (OR 11%).
3 had Stable Disease (33%), and 4 experienced Progressive
Disease (44%).
Median Progression-Free Survival was 60 days; Median
Overall Survival was 102 days.
Conclusions.
TOPO concomitant to WBXRT is tolerable.
This regimen has the additional advantage of providing
systemic treatment while whole brain radiation is in progress.
Although response and survival outcomes in this small
study are not higher than expected from historical controls, efficacy was not a
primary end point, and thus larger studies would be useful investigate this
issue.
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_19-00108,00.asp
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