The role of the liposomal anthracyclines and other systemic therapies in the management of advanced breast cancer

Hebrew University of Jerusalem, Yerushalayim, Jerusalem, Israel
Seminars in Oncology (Impact Factor: 3.9). 01/2005; 31(6 Suppl 13):106-46. DOI: 10.1053/j.seminoncol.2004.09.018
Source: PubMed


For patients whose breast cancers are not responsive to endocrine therapy, there are a large number of cytotoxic drugs that will induce a response. In spite of the introduction of new, very active drugs such as the taxanes, vinorelbine, capecitabine, gemcitabine, and trastuzumab, the anthracyclines are still as active as any--and more active than most--drugs used to treat breast cancer. Their inclusion in combinations to treat early and advanced disease prolongs survival. However, they cause nausea, vomiting, alopecia, myelosuppression, mucositis, and cardiomyopathies. There is no evidence that increasing the dose of conventional anthracyclines or any other of the cytotoxics beyond standard doses will improve outcomes. Schedule may be more important than dose in determining the benefit of cytotoxics used to treat breast cancer. Weekly schedules and continuous infusions of 5-fluorouracil and doxorubicin may have some advantages over more intermittent schedules. Liposomal formations of doxorubicin reduce toxicity, including cardiotoxicity; theoretically they should also be more effective because of better targeting of tumor over normal tissues. Both pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) and liposomal doxorubicin (Myocet [NPLD]) appeared to be as effective as conventional doxorubicin and much less toxic in multiple phase II and phase III studies. PLD has been evaluated in combinations with cyclophosphamide, the taxanes, vinorelbine, gemcitabine, and trastuzumab, and NPLD has been evaluated in combination with cyclophosphamide and trastuzumab. Both liposomal anthracyclines are less cardiotoxic than conventional doxorubicin. The optimal dose of PLD is lower than that of conventional doxorubicin or NPLD. Patients treated with PLD have almost no alopecia, nausea, or vomiting, but its use is associated with stomatitis and hand-foot syndrome, which can be avoided or minimized with the use of proper dose-schedules. In contrast, the optimal dose-schedule of NPLD is nearly identical to that of conventional doxorubicin. The toxicity profile of NPLD is similar to that of conventional doxorubicin, but toxicities are less severe and NPLD is better tolerated than conventional doxorubicin at higher doses.

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    • "In order to minimize cardiotoxicity, doxorubicin was initially encapsulated in anionic liposomes giving anionic doxorubicin-AB nanoparticles that enabled improved drug accumulation in tumours and increased antitumour activity while diminishing side effects of cardiotoxicity [33, 34]. Such drug formulations have been used efficiently in clinic for the treatment of ovarian and breast cancer [35, 36]. Thereafter, Doxil was devised corresponding to a drug-ABC nanoparticle system (PEGylated drug nanoparticle system), comprising PEGylated liposomes with encapsulated doxorubicin. "
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    07/2013; 2013(2):165981. DOI:10.1155/2013/165981
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    • "As previously described, colloidal vesicles can attenuate the biopharmaceutical properties of bioactive agents, allowing an increase in their pharmacological effects as well as modulation of their pharmacokinetic parameters (eg, plasma half-life) as a consequence of being protected from metabolic pathways.18,61 For example, encapsulation of the anthracycline, doxorubicin, approved and commercialized as Doxil and Caelyx, reduced its side effects, in particular its cardiotoxicity and myelotoxicity.62,63 "
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    ABSTRACT: This review describes the strategies used in recent years to improve the biopharmaceutical properties of gemcitabine, a nucleoside analog deoxycytidine antimetabolite characterized by activity against many kinds of tumors, by means of liposomal devices. The main limitation of using this active compound is the rapid inactivation of deoxycytidine deaminase following administration in vivo. Consequently, different strategies based on its encapsulation/complexation in innovative vesicular colloidal carriers have been investigated, with interesting results in terms of increased pharmacological activity, plasma half-life, and tumor localization, in addition to decreased side effects. This review focuses on the specific approaches used, based on the encapsulation of gemcitabine in liposomes, with particular attention to the results obtained during the last 5 years. These approaches represent a valid starting point in the attempt to obtain a novel, commercializable drug formulation as already achieved for liposomal doxorubicin (Doxil(®), Caelyx(®)).
    International Journal of Nanomedicine 11/2012; 7:5423-36. DOI:10.2147/IJN.S34025 · 4.38 Impact Factor
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    • "Among the drugs or drug combinations currently proposed for recurrent/metastatic breast cancer, anthracyclines and taxanes are considered the most effective ones, with rates of overall response between 46 and 88% (Mavroudis et al, 2000; Morales et al, 2004; Gamucci et al, 2007; Von Minckwitz, 2007); however, the use of anthracyclines in clinical practice is limited by drug-associated toxicity, particularly myelosuppression and cardiotoxicity (Robert et al, 2004). Indeed, the replacement of doxorubicin with epirubicin or pegylated liposomal doxorubicin (PLD) has strongly improved the pattern and severity of adverse effects (Robert et al, 2004; O'Brien, 2008); moreover, also the proper use of growth factor support (Morales et al, 2004) or the adoption of weekly schedules for combinations of anthracyclines/taxanes (Gamucci et al, 2007) has been proposed to overcome haematological toxicity. Besides PLD, whose activity as a single agent in recurrent/ metastatic breast cancer has been documented in several phase II studies (response rate ¼ 31 – 38%) (Ranson et al, 1997; Lyass et al, "
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    ABSTRACT: This multicentre phase II study was aimed at investigating the activity and safety of pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) as front-line therapy in a large series of chemotherapy-naïve recurrent/metastatic breast cancer patients. From June 2003 to December 2006, a total of 71 recurrent/metastatic breast cancer patients were enrolled. Median age was 63 years (range=37-79), and 31 patients (43.7%) were > or =65 years old. Patients received PLD, 25 mg m(-2), day 1, followed by GEM, 800 mg m(-2), days 1 and 8, q21. Response was evaluable in 64 cases. Eight complete (12.5%) and 17 partial responses (26.6%) were registered, with an overall response rate of 39.1%. Thirty patients (46.9%) experienced stable disease, with an overall clinical benefit of 85.9%. Median time to progression (TTP) was 11 months, whereas median overall survival (OS) was not reached. The rate of 1- and 2-year OS was 79 and 61%, respectively. A total of 443 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients (20.3%) and 3 patients (4.3%), respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases (7.2%) and one case (1.4%), whereas grade 3 and 4 mucositis occurred in six cases (8.7%) and two cases (2.9%), respectively. Grade 2 cardiac toxicity was observed in only one case. Interestingly enough, there was no difference in the percentage and severity of either haematological or non-haematological toxicity according to the age of the patients (<65 vs > or =65 years). We confirmed in a large, very homogenous study sample of chemotherapy-naïve recurrent/metastatic breast cancer patients the efficacy and safety of PLD/GEM combination, providing response rates, median TTP and OS values comparable with those achieved with more toxic combinations.
    British Journal of Cancer 06/2008; 98(12):1916-21. DOI:10.1038/sj.bjc.6604409 · 4.84 Impact Factor
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