Phase I-II study of pegylated liposomal doxorubicin combined with weekly paclitaxel as first-line treatment in patients with metastatic breast cancer.
OBJECTIVE
Pegylated liposomal doxorubicin (PLD) appears to be as active as doxorubicin in first-line metastatic breast cancer (MBC) patients, with lower cardiac toxicity. This phase I-II trial aimed to determine the dose limiting toxicity (DLT) and recommended dose (RD) of a first-line combination of PLD and weekly paclitaxel.


METHODS
MBC patients received PLD on day 1, administered over 60 minutes IV. (starting dose 30 mg/m2, escalation by 5 mg/m2 increments), and paclitaxel on days 1, 8, and 15. Initially (schedule A), paclitaxel was administered over 60 minutes (starting dose 80 mg/m2, 10 mg/m2 increments), then (schedule B) over 24 hours on day 1 (at a dose of 70 mg/m2, 10 mg/m2 increments), and in a 60 minute IV infusion at a fixed dose of 90 mg/m2 on days 8 and 15. Pharmacokinetics were assessed during cycle 1 in schedule B.


RESULTS
Thirty patients were treated (schedules A = 9; B = 21). Because of cutaneomucous toxicities in all patients in schedule A with discontinuation in 5 patients, schedule B was explored. Two DLTs (febrile neutropenia) occurred, with PLD 35 mg/m2 with paclitaxel 80 mg/m2 day 1 and 90 mg/m2 days 8 and 15 identified as recommended dose. Pharmacokinetic evaluation revealed an interaction, with increased levels of free doxorubicin and PLD during the paclitaxel infusion.


CONCLUSIONS
This combination according to schedule and dosages results in cutaneomucous and hematological toxicity, probably because of a pharmacokinetic interaction, which is poorly compatible with a good quality of life for MBC patients.
Bourgeois
Hugues
H
CHU de Poitiers, Poitiers, France.
Ferru
Aurélie
A
Lortholary
Alain
A
Delozier
Thierry
T
Boisdron-Celle
Michèle
M
Abadie-Lacourtoisie
Sophie
S
Joly
Florence
F
Chieze
Stéphanie
S
Chabrun
Virginie
V
Gamelin
Erick
E
Tourani
Jean-Marc
JM
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D004317:Doxorubicin / Q000008:administration & dosage; D004347:Drug Interactions; D005260:Female; D006321:Heart / Q000187:drug effects; D049691:History, Medieval; D006801:Humans; D007262:Infusions, Intravenous; D008081:Liposomes; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D016896:Treatment Outcome
D008081:Liposomes; D004317:Doxorubicin; D017239:Paclitaxel