Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer.
OBJECTIVE
To determine the efficacy and pharmacokinetics of intraventricular cytosine arabinoside (Ara-C) as front-line treatment for leptomeningeal metastases from breast cancer.


METHODS
Ten patients newly diagnosed with leptomeningeal metastases (LMM) from breast cancer were treated with 100 mg intraventricular cytosine arabinoside (IVT Ara-C) via an Ommaya reservoir. Treatment was administered three times a week for 2 weeks, then once a week for 4 weeks, and then once every 6 weeks for four cycles to responding patients. Nine patients were evaluable clinically, and seven patients underwent testing to determine the pharmacokinetic profile of Ara-C in the cerebrospinal fluid (CSF).


RESULTS
Two patients had partial responses lasting 9 and 40 weeks, respectively. Two other patients had stable disease. The median survival duration was 30 weeks (range: 5-58 weeks). Seven patients died from LMM. Acute toxic effects associated with IVT Ara-C included meningismus, nausea, vomiting, and myelosuppression. The median peak Ara-C level in CSF was 16.69+/-6.30 mM (SD). The half life for elimination was 1.45+/-0.61 h (SD) There was no drug accumulation between courses. Neuropsychological evaluations were completed in eight patients, six (75%) of whom had preexisting cognitive deficits. Their condition generally improved over the course of treatment until the LMM progressed. No neurotoxic side effects of IVT Ara-C were observed in the two patients who had normal baseline cognitive assessments.


CONCLUSIONS
IVT Ara-C at this dose and schedule has minimal activity as initial treatment for LMM from breast cancer despite achievement of high peak levels of the drug in the cerebrospinal fluid. A liposomal Ara-C formulation is currently under investigation.
Esteva
F J
FJ
Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030-4095, USA.
Soh
L T
LT
Holmes
F A
FA
Plunkett
W
W
Meyers
C A
CA
Forman
A D
AD
Hortobagyi
G N
GN
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000473:pathology*; D003071:Cognition / Q000502:physiology; D003561:Cytarabine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D008875:Middle Aged; D016019:Survival Analysis; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine