Evaluation of piroxantrone in women with metastatic breast cancer and failure on nonanthracycline chemotherapy

J. N. Ingle, S. A. Kuross, J. A. Mailliard, Charles Lawrence Loprinzi, S. H. Jung, R. A. Nelimark, J. E. Krook, H. J. Long

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1733-1738
Number of pages6
JournalCancer
Volume74
Issue number6
DOIs
StatePublished - 1994

Fingerprint

piroxantrone
Breast Neoplasms
Drug Therapy
Anthracyclines
Stroke Volume
Confidence Intervals
Phase II Clinical Trials
Retreatment
Doxorubicin
Lipid Peroxidation
Free Radicals
Disease Progression
Heart Failure
Membranes

Keywords

  • anthrapyrazole
  • cardiac toxicity
  • chemotherapy
  • metastatic breast cancer
  • Phase II clinical trial

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Evaluation of piroxantrone in women with metastatic breast cancer and failure on nonanthracycline chemotherapy. / Ingle, J. N.; Kuross, S. A.; Mailliard, J. A.; Loprinzi, Charles Lawrence; Jung, S. H.; Nelimark, R. A.; Krook, J. E.; Long, H. J.

In: Cancer, Vol. 74, No. 6, 1994, p. 1733-1738.

Research output: Contribution to journalArticle

Ingle, J. N. ; Kuross, S. A. ; Mailliard, J. A. ; Loprinzi, Charles Lawrence ; Jung, S. H. ; Nelimark, R. A. ; Krook, J. E. ; Long, H. J. / Evaluation of piroxantrone in women with metastatic breast cancer and failure on nonanthracycline chemotherapy. In: Cancer. 1994 ; Vol. 74, No. 6. pp. 1733-1738.
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title = "Evaluation of piroxantrone in women with metastatic breast cancer and failure on nonanthracycline chemotherapy",
abstract = "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.",
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T1 - Evaluation of piroxantrone in women with metastatic breast cancer and failure on nonanthracycline chemotherapy

AU - Ingle, J. N.

AU - Kuross, S. A.

AU - Mailliard, J. A.

AU - Loprinzi, Charles Lawrence

AU - Jung, S. H.

AU - Nelimark, R. A.

AU - Krook, J. E.

AU - Long, H. J.

PY - 1994

Y1 - 1994

N2 - 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.

AB - 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.

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