Randomized Trial of Doxorubicin, Bisantrene, and Miltoxantrone in Advanced Breast Cancer: A Southwest Oncology Group Study

Abstract

Four hundred eleven women with metastatic breast cancer were randomly assigned to receive either 60 mg/m2 doxorubicin (130 patients), 320 mg/m2 bisantrene (146 patients), or 14 mg/m2 mitoxantrone (135 patients). The doses were given intravenously every 3 weeks with a cross-over design to determine their relative efficacy and toxicity. To be eligible, patients must have had one previous chemotherapy regimen, and patients who were estrogen receptor positive must have failed endocrine therapy. There were 365 patients assessable for response and 399 assessable for toxic effects. The median age was 57 years; 18% were premenopausal or perimenopausal. Visceral dominant disease was present in 66% of the patients. Ninety-seven percent of the patients had a disease-free interval from diagnosis to first recurrence of less than 1 year. The response rate was 28% with doxorubicin, 13% with bisantrene, and 14% with mitoxantrone (P = .004). Median time to treatment failure was 133 days with doxorubicin, 66 days with bisantrene, and 68 days with mitoxantrone (logrank P = .06). The median survival was 315 days for doxorubicin, 290 days for bisantrene, and 177 days for mitoxantrone (logrank P = .04), although survival at 2 years was similar for all three agents. There were five responses in the 66 patients crossed over to doxorubicin and one response each for patients crossed over to bisantrene (39 patients) or mitoxantrone (63 patients). Toxicity leading to discontinuance of therapy was more common with doxorubicin, and discontinuance of therapy was due primarily to patient's request or cardiotoxicity. The major dose-limiting toxic effect for all three agents was leukopenia. Nausea and vomiting, mucositis, and alopecia were more severe with doxorubicin. Congestive heart failure developed in nine patients treated with doxorubicin, zero patients treated with bisantrene, and two patients treated with mitoxantrone. A decrease in the left ventricular ejection fraction, as defined by moderate to severe Alexander grade changes, was more common in patients treated with doxorubicin (doxorubicin-treated patients = 20%, bisantrene-treated patients = 5%, and mitoxantrone-treated patients = 10%). This study demonstrates that bisantrene and mitoxantrone have only modest activity in metastatic breast carcinoma. The activity of doxorubicin is greater than that of the other two agents, but at a cost of increased toxicity.

Phase II Study of Single-Agent Pegylated Liposomal Doxorubicin HCl (PLD) in Metastatic Breast Cancer After First-Line Treatment Failure

“…The overall response rate reported here is also comparable to those obtained from other agents, including conventional doxorubicin, epirubicin, cyclophosphamide, etoposide, and docetaxel, used singly in the second-line treatment of metastatic breast cancer [16][17][18][19][20][21][22]. The overall response rates of these agents range from 26 to 58%, with myelosuppression as the main toxicity [16][17][18][19][20][21][22].…”

“…The overall response rates of these agents range from 26 to 58%, with myelosuppression as the main toxicity [16][17][18][19][20][21][22]. The toxicity profile of PLD reported in this study is distinctly different from these agents, including conventional doxorubicin and epirubicin.…”

Cardiotoxicity and Cardioprotection in Childhood Cancer

“…Other doxorubicin analogs, idarubicin and mitoxantrone, although they may reduce cardiac injury, do not completely eliminate the risk of cardiotoxicity [43,48]. Studies with use of these different analogs have so far been done only in adults with breast cancer [47,48].…”

“…Studies with use of these different analogs have so far been done only in adults with breast cancer [47,48]. To our knowledge, no studies have been conducted in adolescents that might justify the use of analogs in this group.…”

A Phase II Trial of Weekly High-Dose Folinic Acid and 5-Fluorouracil in Combination with Epirubicin as Salvage Chemotherapy in Advanced Breast Cancer

“…As no qualitative differences in mecha nism of action have been demonstrated between EPI and doxorubicin, cross-resistance is expected. Experiments in vitro and in vivo have confirmed the existence of com plete cross-resistance between these two drugs [18], Al though there are no substantial data available concerning cross-resistance between EPI and tetrahydropyranyldoxorubicin, there is some indication that cross-resis tance seems to be incomplete in the treatment of breast cancer [19], A lack of complete cross-resistance between EPI and mitoxantrone has been noted in preclinical [20] and clinical studies [21], Nevertheless, cross-resistance was reported to be marked and only occasional crossover response was demonstrated [22], However, it is very hard to say whether the effect of the investigated regimen in pretreated patients was mainly based either on the modulation of FU by HDFA or on the lack of absolute cross-resistance to the anthracycline ana logues applied with the investigated patients. The median duration of response of 6 months appears to be satisfacto ry, especially considering that the median time under treatment was 3.2 months only.…”