Gemcitabine and mitoxantrone in metastatic breast cancer: a phase-I-study.
BACKGROUND
Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen.


METHODS
Patients with metastatic breast cancer were treated with gemcitabine (1000-1400 mg/m(2)) on days 1, 8 and 15 and mitoxantrone (10-14 mg/m(2)) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme.


RESULTS
Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m(2) gemcitabine and 14 mg/m(2) mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m(2) and mitoxantrone 12 mg/m(2) based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively.


CONCLUSIONS
In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m(2) and mitoxantrone 12 mg/m(2).
Schmid
Peter
P
Berlin Breast Cancer Research Group, Medizinische Klinik mit Schwerpunkt Onkologie und Hämatologie, Charité Campus Mitte, Humboldt Universität zu Berlin, Berlin, Germany. peter.schmid@charite.de
Flath
Bernd
B
Akrivakis
Konstantin
K
Heilmann
Volker
V
Mergenthaler
Hans-Günther
HG
Sezer
Orhan
O
Kreienberg
Rolf
R
Possinger
Kurt
K
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D009503:Neutropenia / Q000139:chemically induced; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D008942:Mitoxantrone; D000093542:Gemcitabine