Pharmacokinetic study of cisplatin and infusional etoposide phosphate in advanced breast cancer with correlation of response to topoisomerase IIalpha expression.
OBJECTIVE
There is substantial interpatient variability in etoposide pharmacokinetics. Pharmacokinetic adjustment to specific plasma concentrations may make it possible to define a therapeutic plasma concentration and relate drug target expression in the tumor to response. This study evaluated the combination of cisplatin with a prolonged infusion of etoposide phosphate (EP) in advanced breast cancer and correlated response to topoisomerase II expression.


METHODS
Eligible patients, previously treated with an anthracycline, received 60 mg/m(2) cisplatin, followed by a 5-day infusion of EP. Plasma etoposide levels were measured on days 2 and 4 of each cycle with adjustment of the infusion rate to achieve an initial target etoposide concentration of 2 micro g/ml or 1.5 micro g/ml. Primary tumor blocks were stained by immunohistochemistry for topoisomerase IIalpha and beta.


RESULTS
Thirty-six patients, treated in three consecutive cohorts, received 145 cycles of chemotherapy. Targeting plasma etoposide concentration reduced interpatient pharmacokinetic variability (32% and 62% of patients, respectively, within 10% of target concentration on days 2 and 4; cycle 1). Significant hematological toxicity (89% of patients with at least one episode of grade III/IV neutropenia, 64% of patients with at least one episode of grade III/IV thrombocytopenia) was observed. Thirty-nine percent of patients achieved a partial response, and 19% had stable disease for at least 3 months. The median time to tumor progression was 4 months, with a median survival of 11 months. Topoisomerase IIalpha expression was significantly higher (P < 0.001) in responding patients compared with those with stable or progressive disease. There was no difference in topoisomerase IIbeta expression between groups.


CONCLUSIONS
Cisplatin and infusional EP is an active, but intensive, schedule in heavily pretreated patients with breast cancer. Clinical response correlates with tumor topoisomerase IIalpha expression.
Cancer Research UK Medical Oncology Unit, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom.
Jeremy P
JP
Braybrooke
Nicola C
NC
Levitt
Simon
S
Joel
Theresa
T
Davis
Srinivasan
S
Madhusudan
Helen
H
Turley
Sue
S
Wilner
Adrian L
AL
Harris
Denis C
DC
Talbot
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000493:pharmacokinetics*; D015331:Cohort Studies; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis*; D004268:DNA-Binding Proteins; D018450:Disease Progression; D005047:Etoposide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D011960:Receptors, Estrogen / Q000378:metabolism; D013997:Time Factors
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009943:Organophosphorus Compounds; D011960:Receptors, Estrogen; C061400:etoposide phosphate; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D002945:Cisplatin