Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulating factor in metastatic breast cancer

Purpose: To estimate the toxicity and response rate of high-dose liposome-e ncapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company Inc, Prince ton, NJ) in patients with advanced breast cancer. Patients and Methods: Fifty-two breast cancer patients with bidimensionally measurable metastatic disease and no prior chemotherapy for metastatic dis ease received a 135 mg/m(2) intravenous (IV) bolus of TLC D-99 with 5 mu g/ kg of granulocyte colony-stimulating factor via subcutaneous injection ever y 21 days. Results: The median number of treatment cycles of TLC D-99 was three (range , one to 10 cycles), and the median total cumulative dose of TLC D-99 was 4 05 mg/m2 (range, 135 to 1,065 mg/m(2)). Grade IV neutropenia, thrombocytope nia, and mucositis were experienced by 48 (92%), 46 (88%), and 10 (19%) pat ients, respectively. Twenty (38%) of patients experienced cardiac toxicity: four (8%) experienced a decrease of 20% or more in left ventricular ejecti on fraction (LVEF) to a final value greater than or equal to 50%, nine (17% ) experienced a decrease of 10% or more in LVEF to a final value less than 50%, and seven (13%) developed symptomatic congestive heart failure (CHF), including one patient who died of cardiomyopathy after receiving a total do se of 1,035 mg/m(2), In a stepwise logistic regression model, the significa nt risk factors for the development of CHF were the cumulative dose of prio r adjuvant doxorubicin (P =.007) and the total cumulative dose of TLC D-99 (P =.032). The overall response rate was 46% (95% confidence interval [CI], 32% to 61%) on an intent-to-treat basis. The median duration of response w as 7.4 months (95% CI, 6.1 to 19.6 months) and the median progression-free survival was 6.1 months (95% CI, 5.4 to 7.5 months), Conclusion: There was no added therapeutic benefit to the dose escalation o f TLC D-99 in this study. A high rate of cardiotoxicity was also observed, especially among patients who had received prior adjuvant doxorubicin. This was probably attributable to the dose and schedule of TLC D-99 used in thi s trial, as well as the patient's lifetime cumulative doxorubicin dose. Adm inistration of high-dose TLC D-99 at 135 mg/m(2) every 3 weeks by IV bolus infusion does not warrant further investigation. J Clin Oncol 17:1435-1441, (C) 1999 by American Society of Clinical Oncology.