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Phase II Trial of High-Dose Liposome-Encapsulated Doxorubicin With Granulocyte Colony-Stimulating Factor in Metastatic Breast Cancer

From the Breast Oncology Center, Dana-Farber Cancer Institute, Boston, MA; Ohio State University, Columbus, OH; Maine Center for Cancer Medicine, Portland, ME; The Liposome Company, Inc, Princeton, NJ; and the Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC.

Address reprint requests to Charles L. Shapiro, MD, Arthur James Cancer Hospital and Research Institute, Ohio State University, Starling-Loving Hall, 320 W 10th St, Columbus, OH 43210; email shapiro-1{at}medctr.osu.edu

PURPOSE: To estimate the toxicity and response rate of high-dose liposome-encapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company Inc, Princeton, 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 disease received a 135 mg/m² intravenous (IV) bolus of TLC D-99 with 5 µg/kg of granulocyte colony-stimulating factor via subcutaneous injection every 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 405 mg/m² (range, 135 to 1,065 mg/m²). Grade IV neutropenia, thrombocytopenia, and mucositis were experienced by 48 (92%), 46 (88%), and 10 (19%) patients, respectively. Twenty (38%) of patients experienced cardiac toxicity: four (8%) experienced a decrease of 20% or more in left ventricular ejection fraction (LVEF) to a final value 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 dose of 1,035 mg/m². In a stepwise logistic regression model, the significant risk factors for the development of CHF were the cumulative dose of prior 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 was 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 of 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 this trial, as well as the patient's lifetime cumulative doxorubicin dose. Administration of high-dose TLC D-99 at 135 mg/m² every 3 weeks by IV bolus infusion does not warrant further investigation.

Presented in part at the American Society of Clinical Oncology Meeting, Philadelphia, PA, May 18-21, 1996.

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