Evaluation of piroxantrone in women with metastatic breast cancer and failure on nonanthracycline chemotherapy.
BACKGROUND
Doxorubicin generally is considered to be the most effective single chemotherapeutic agent for the treatment of breast cancer. The major cumulative dose-limiting toxicity is cardiac toxicity, which may be related to the formation of free radicals with subsequent lipid peroxidation, leading to membrane damage. The anthrapyrazoles, of which piroxantrone is a member, were synthesized in an attempt to eliminate this toxicity.


METHODS
A Phase II clinical trial was conducted in 30 women with metastatic breast cancer in whom piroxantrone was administered at a dose of 160 mg/m2 by 1-hour infusion. The planned cycle length for retreatment was 3 weeks. Measurable metastatic disease and failure on one prior chemotherapy regimen, but no prior anthracycline exposure, were required for response evaluation.


RESULTS
Twenty-nine patients were evaluable for response, and 6 (21% and 95% confidence intervals: 10-43%) achieved an objective response (1 complete, 5 partial responses), with a median response duration of 244 days. The median time-to-disease progression for all patients was 124 days. Eight patients received cumulative doses of piroxantrone approaching or exceeding 1000 mg/m2, and all had reductions in the resting left ventricular ejection fraction (LVEF). The estimated median decrease in LVEF at 1000 mg/m2 was 16%, with a range of 10-28%. Clinical findings of congestive heart failure developed in two patients.


CONCLUSIONS
Piroxantrone had definite antitumor activity in women who had metastatic breast cancer and failure on prior chemotherapy that did not include an anthracycline. The 95% confidence interval for response probability was broad, but the level of activity observed was relatively low. The clear association with cardiac toxicity combined with the relatively low efficacy led to the conclusion that piroxantrone cannot be recommended for further development as therapy for women with breast cancer. Further study of other anthrapyrazoles is necessary to determine if the promise of this new class of agents can be fulfilled.
Ingle
J N
JN
Mayo Clinic, Rochester, MN 55905.
Kuross
S A
SA
Mailliard
J A
JA
Loprinzi
C L
CL
Jung
S H
SH
Nelimark
R A
RA
Krook
J E
JE
Long
H J
HJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000880:Anthraquinones / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects
D000880:Anthraquinones; D000970:Antineoplastic Agents; D011720:Pyrazoles; C046659:piroxantrone