Pegylated liposomal doxorubicin is currently approved in the U.S. for the treatment of platinum-refractory metastatic ovarian cancer and AIDS-related Kaposi’s sarcoma.DOXIL (doxorubicin hcl liposome injection) in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy. It is also has been evaluated in several other tumor types, including breast cancer, non-Hodgkin’s lymphoma, and gynecologic malignancies. When compared with other liposomal anthracycline formulations, pegylated liposomal doxorubicin is the most extensively studied in patients with metastatic breast cancer(MBC). Pegylated liposomal doxorubicin has demonstrated antitumor activity and safety in patients with MBC, leading to its recent approval in the European Union as monotherapy for MBC in patients who have greater cardiac risks, in addition to its compendial listing in the U.S. for patients with MBC. The efficacy and safety of pegylated liposomal doxorubicin as single-agent therapy for MBC have been investigated in two phase II trials . In the first study, a total of 71 patients with stage IV breast cancer received pegylated liposomal doxorubicin at doses of 45-60 mg/m2 every 3-4 weeks for a maximum of six cycles; all patients had received prior nonanthracycline-based chemotherapy . The overall response rate was 31%, and treatment was generally well tolerated. Grade 3 or 4 neutropenia and mucositis were noted in 27% and 32% of patients, respectively; alopecia, cardiotoxicity, and nausea and vomiting were uncommon. Although skin toxicity occurred in 25% of cycles in patients receiving 60 mg/m2 every 3 weeks, the incidence was much lower at doses of 45 mg/m2 every 4 weeks, with only 5% of treatment cycles affected. Two phase III studies have compared the efficacy and safety of pegylated liposomal doxorubicin with those of other treatment regimens. Wigler and colleagues compared the efficacy and safety of pegylated liposomal doxorubicin with those of conventional doxorubicin as first-line therapy in patients with advanced MBC. A total of 509 women received 1-hour infusions of either pegylated liposomal doxorubicin, 50 mg/m2 once every 4 weeks, or conventional doxorubicin, 60 mg/m2 once every 3 weeks. Primary end points were progression-free survival and cardiac safety, while secondary end points included overall survival, response rate, and safety. The median progression-free survival was similar in both treatment groups: 6.9 months in patients receiving pegylated liposomal doxorubicin versus 7.8 months in patients receiving conventional doxorubicin (p = 0.99). Likewise, overall survival was 20.1 months for patients receiving pegylated liposomal doxorubicin, compared with 22.0 months in those receiving the conventional formulation. The incidences of alopecia, myelosuppression, and nausea and vomiting were lower in patients treated with pegylated liposomal doxorubicin than in patients treated with conventional doxorubicin. Perhaps most notably, pegylated liposomal doxorubicin was associated with a significantly lower incidence of cardiotoxicity, even at higher cumulative doses (p < 0.001). In another phase III study involving 301 patients with advanced MBC who had failed a prior taxane-containing regimen, Keller and colleagues compared pegylated liposomal doxorubicin, 50 mg/m2 every 4 weeks, with the European standard of treatment, either vinorelbine, 30 mg/m2 once weekly, or mitomycin C, 10 mg/m2 on days 1 and 28, plus vinblastine, 5 mg/m2 on days 1, 14, 28, and 42 every 6-8 weeks. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxicity.
In that study, pegylated liposomal doxorubicin demonstrated efficacy similar to that of the comparator regimens.
A 2013 reveiw concluded: “In patients with metastatic breast cancer, liposomal anthracyclines have proven to be as effective and less toxic when compared face to face with conventional anthracyclines, allowing a longer period of treatment and a higher cumulative dose of the anthracyclines. The combined analysis of available data indicates an overall reduction in risk for both cardiotoxicity (RR = 0.38, ) and clinical heart failure (RR = 0.20, ). The safety of liposomal anthracyclines endorsed its use in patients with some cardiac risk factors.
In HER2-positive breast cancer, the addition of trastuzumab to chemotherapy significantly increased response rate, progression-free survival, and overall survival. Initial studies demonstrated synergy when trastuzumab was combined with anthracyclines, but their excessive cardiac toxicity limited their use and nonanthracycline therapeutic strategies were designed.
Liposomal anthracyclines have proven to be effective and safe when combined with trastuzumab both in advanced and early breast cancer. Of particular interest is the use of the combination of liposomal anthracyclines plus trastuzumab in patients with early and HER2-overexpressing breast cancer, as this is probably the subgroup that would benefit most from a treatment with anthracyclines. The potential clinical benefit of anthracyclines in this setting should be investigated in a clinical trial comparing a regimen with liposomal anthracyclines versus a nonanthracyclines combination. ”
Juan Lao et al, Liposomal Doxorubicin in the Treatment of Breast Cancer Patients: A Review, Journal of Drug Delivery
Volume 2013 (2013), Journal of Drug Delivery
, Article ID 456409, 12 pages
Edgardo Rivera Liposomal Anthracyclines in Metastatic Breast Cancer: Clinical Update The Oncologist, Vol. 8, Suppl 2, 3–9, August 2003
Wigler N, O’Brien M, Rosso R et al. Reduced cardiac toxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin (CAELYXTM/Doxil) vs. doxorubicin for first-line treatment of metastatic breast cancer. Poster presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, Florida, May 18-21, 2002.