Liposome‐encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first‐line therapy of metastatic breast carcinoma

Abstract

BACKGROUND The objective of this study was to compare the efficacy and toxicity of the liposome‐encapsulated doxorubicin, TLC D‐99 (Myocet, Elan Pharmaceuticals, Princeton, NJ), and conventional doxorubicin in first‐line treatment of metastatic breast carcinoma (MBC). METHODS Two hundred twenty‐four patients with MBC and no prior therapy for metastatic disease were randomized to receive either TLC D‐99 (75 mg/m2) or doxorubicin (75 mg/m2) every 3 weeks, in the absence of disease progression or unacceptable toxicity. The primary efficacy endpoint was response rate. Responses were assessed using World Health Organization criteria and were required to be of at least 6 weeks' duration. The primary safety endpoint was cardiotoxicity. Cardiac function was monitored by multiple‐gated radionuclide cardioangiography scan, and the left ventricular ejection fraction (LVEF) was scored at a central laboratory. Patients were removed from study if LVEF declined 20 or more EF units from baseline to a final value of greater than or equal to 50%, or by 10 or more units to a final value of less than 50%, or onset of clinical congestive heart failure (CHF). RESULTS Median age was 54 years in both treatment groups. All relevant prog nostic factors were balanced, with the exception that there were significantly more progesterone receptor positive patients in the doxorubicin‐treated group. Protocol‐defined cardiotoxicity was observed in 13% of TLC D‐99 patients (including 2 cases of CHF) compared to 29% of doxorubicin patients (including 9 cases of CHF). Median cumulative doxorubicin dose at onset of cardiotoxicity was 785 mg/m2 for TLC D‐99 versus 570 mg/m2 for doxorubicin (P = 0.0001; hazard ratio, 3.56). The overall response rate was 26% in both treatment groups. The median TTP was 2.9 months on TLC D‐99 versus 3.1 months on doxorubicin. Median survival was 16 versus 20 months with a nonsignificant trend in favor of doxorubicin (P = 0.09). Clinical toxicities, commonly associated with doxorubicin, appeared less common with TLC D‐99, although the difference was not statistically significant. There was only one report of palmar‐plantar erythrodysesthesia (Grade 2) with this liposomal formulation of doxorubicin. CONCLUSIONS Single‐agent TLC D‐99 produces less cardiotoxicity than doxorubicin, while providing comparable antitumor activity. Cancer 2002;94:25–36. © 2002 American Cancer Society.

Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx™) in human osteosarcoma xenografts

“…In normal tissue, the intact liposomes are confined to the intravascular space, as normal blood vessels are not fenestrated to the same degree as in tumour tissue. Hence, the toxicity to normal tissue is reduced considerably, especially cardiotoxicity (Harris et al, 2002). Although liposomal delivery of doxorubicin improves the tumour uptake compared to free doxorubicin, the drug distribution within the tumour tissue is still heterogeneous (Vaage et al, 1997;Davies et al, 2004).…”

In vivo administration of liposomal vincristine sensitizes drug‐resistant human solid tumors

“…14 The benefits associated with liposomal anthracyclines in breast tumors have been mainly associated with reduced cardio-toxicity rather than with a significant improvement in the outcome of patients. 15 Clinical studies using VCR encapsulated in distearoylphospatidylcholine/cholesterol (DSPC/Chol) demonstrated that liposomal VCR can be administered at higher doses than free drug and it is effective in relapsed non-Hodgkin's lymphomas (NHL). 16,17 A modification of DSPC/Chol liposomes has been introduced generating the sphingomyelin/cholesterol (SM/Chol) liposomes.…”

Pegylated liposomal doxorubicin and trastuzumab as 1st and 2nd line therapy in her2/neu positive metastatic breast cancer: a multicenter phase II trial

“…Irreversible damage to the myocytes by free radicals, so called Type I myocardial damage, is presumed to be the cause of anthracycline-induced cardiomyopathy [22,23]. The development of encapsulated conventional anthracyclines, such as PLD have led to a reduction of the incidence and severity of cumulative dose-related cardiomyopathy while preserving antitumor activity [24][25][26][27]. Thus, PLD may offer patients the benefit of receiving higher cumulative doses (compared with conventional doxorubicin) over a longer period of time, ultimately resulting in greater drug exposure.…”