Liposomal Doxorubicin

Summary

Abstract

Liposomal doxorubicin (Myocet™) has been developed with the aim of improving the therapeutic index of the anthracycline doxorubicin by reducing the drug’s cardiotoxicity, but maintaining its antitumor efficacy. Liposomal doxorubicin plus cyclophosphamide is no less effective than conventional doxorubicin or epirubicin plus cyclophosphamide in the first-line treatment of women with metastatic breast cancer. In addition, the drug is significantly less cardiotoxic than conventional doxorubicin. The median cumulative dose to the first cardiac event for liposomal doxorubicin is higher than that for conventional doxorubicin; the potential to use doxorubicin for a longer period of time may benefit a number of patients. Liposomal doxorubicin has also shown potential as part of a chemotherapy regimen in patients with non-Hodgkin lymphoma (NHL). Thus, liposomal doxorubicin represents an important advance in terms of offering reduced cardiotoxicity compared with conventional doxorubicin, and can be used in preference to conventional doxorubicin in a combination regimen with cyclophosphamide in the first-line treatment of patients with metastatic breast cancer.

Pharmacologic Properties

The rationale used as the basis for the design of intravenous liposomal doxorubicin is that the liposomes cannot exit the circulation in healthy tissues, but can exit through leaky tumor-associated vessels. In animal models, liposomal doxorubicin is less cardiotoxic than conventional doxorubicin, and reduces mammary tumor growth to a significantly greater extent than conventional doxorubicin.

Encapsulation of doxorubicin markedly alters the pharmacokinetic properties of the drug. In patients with metastatic breast cancer, the area under the plasma concentration-time curve and maximum plasma concentration values for total doxorubicin were higher in liposomal doxorubicin recipients than conventional doxorubicin recipients, while the volume of distribution and clearance of total doxorubicin were lower with liposomal doxorubicin.

In an animal model, liposomal doxorubicin was still delivered effectively to tumors; however, compared with conventional doxorubicin, the peak distribution to the heart and gastrointestinal mucosa was reduced.

Metabolism and elimination of doxorubicin occur via the hepatobiliary route. The main metabolite is doxorubicinol. The pharmacokinetic properties of this metabolite following the administration of liposomal doxorubicin suggest that the drug is metabolized in a similar manner to, but at a slower rate than, conventional doxorubicin.

Therapeutic Efficacy

The efficacy of liposomal doxorubicin, as monotherapy or in combination with cyclophosphamide, has been assessed as first-line therapy in three fully-published, randomized, multicenter trials (all n ≥160) in women with metastatic breast cancer.

Liposomal doxorubicin was no less effective than conventional doxorubicin as monotherapy in terms of objective tumor response rates (both 26%), median time to disease progression (TTP), or median time to treatment failure (TTF).

Likewise, in terms of objective response rates, liposomal doxorubicin plus cyclophosphamide was no less effective than comparator combination regimens of conventional doxorubicin plus cyclophosphamide (43% vs 43%) or epirubicin plus cyclophosphamide (46% vs 39%). The median TTP and TTF with liposomal doxorubicin plus cyclophosphamide were non-inferior to those with conventional doxorubicin plus cyclophosphamide and significantly longer than those for epirubicin plus cyclophosphamide. In a subgroup of patients who had received prior adjuvant doxorubicin, the response rate and median TTF, but not median TTP or overall survival duration, were significantly greater for patients who received liposomal doxorubicin than conventional doxorubicin (both as monotherapy or in combination with cyclophosphamide).

Additionally, in small phase I/II and II trials in patients with locally advanced or metastatic breast cancer, liposomal doxorubicin has shown anti-tumor activity in combination with trastuzumab, paclitaxel and trastuzumab, gemcitabine and docetaxel, and cyclophosphamide and fluorouracil.

Liposomal doxorubicin shows potential as a replacement for conventional doxorubicin as part of commonly used chemotherapy regimens in patients with NHL; in three phase I/II or II trials, the overall response rate was >80%.

Tolerability

Liposomal doxorubicin was generally at least as well tolerated as conventional doxorubicin (both as monotherapy or in combination with cyclophosphamide) or epirubicin (in combination with cyclophosphamide) in three trials in patients with metastatic breast cancer. Neutropenia (absolute neutrophil count of <500 cells/μL) was the most common hematologic toxicity in both treatment arms of all trials (50–87%). The incidence of neutropenia with liposomal doxorubicin plus cyclophosphamide was lower than that with conventional doxorubicin plus cyclophosphamide but greater than that with epirubicin plus cyclophosphamide. Anemia was also common (14–27% of patients) in all arms of all trials.

Nausea/vomiting was the most common severe non-hematologic adverse event in all trials (13–24%); however, the incidence of this event did not differ significantly between treatment arms. In one trial, grade 3 stomatitis/mucositis was more frequent with liposomal doxorubicin plus cyclophosphamide than with epirubicin plus cyclophosphamide, while injection site toxicity was less common in liposomal doxorubicin plus cyclophosphamide recipients. Severe palmar-plantar erythrodysesthesia, which is a dose-limiting toxicity with pegylated liposomal doxorubicin, was not observed in any liposomal doxorubicin recipients.

Liposomal doxorubicin was significantly less cardiotoxic than conventional doxorubicin (both as monotherapy or in combination with cyclophosphamide). The incidence of congestive heart failure or protocol-defined cardiotoxicity compared with basal resting left ventricular ejection fraction was reduced >2-fold with liposomal doxorubicin monotherapy and >3-fold with liposomal doxorubicin plus cyclophosphamide.