title: Taxanes and gemcitabine doublets in the management of HER-2 negative metastatic breast cancer: towards optimization of association and schedule.
abstract: The management of human epidermal receptor-2 (HER-2) negative metastatic breast cancer (MBC) is usually problematic, since no standard therapy exists in this setting. For some patients, combination chemotherapy represents a valuable approach, although its use is often limited by the risks of increased toxicity as well as impairments in quality of life (QoL) that often outweigh the marginal efficacy benefit. Against this background, the use of taxanes, either paclitaxel or docetaxel, in combination with gemcitabine as first-line treatment of HER-2 negative MBC is supported by the evidence of the single-agent activity of these drugs, beneficial pharmacological interactions, different mechanisms of action and largely non superimposable toxicity profiles. A number of phase II studies have explored the activity of a taxane plus gemcitabine in both chemonaïve and pretreated MBC patients, all showing remarkably high response rates and exceptional tolerability. In randomized phase III trials, the paclitaxel and gemcitabine combination showed significant improvements in objective responses, time to progression and overall survival, as compared to paclitaxel monotherapy, whereas the docetaxel and gemcitabine doublet demonstrated equal efficacy and better tolerability, as compared to docetaxel plus capecitabine. In addition to standard threeweekly dosing regimens, alternative schedules of administration of taxanes and gemcitabine doublets (weekly, twoweekly) might deserve further investigation due to their potential usefulness in reducing pharmacological toxicity while maintaining or increasing dose-intensity and clinical efficacy. Furthermore, uncertainty exists on which taxane should be preferred in combination with gemcitabine, since no head-to-head comparison between paclitaxel-gemcitabine and docetaxel-gemcitabine has been performed so far. Ongoing trials will address these issues and future investigations will also include the evaluation of bevacizumab, the monoclonal antibody targeted against vascular endothelial growth factor (VEGF), in combination with taxanes and gemcitabine doublets.
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Metro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fabi
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Russillo
authors.forename: Paola
authors.initials: P
authors.lastname: Papaldo
authors.forename: Michelino
authors.initials: M
authors.lastname: De Laurentiis
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Ferretti
authors.forename: Domenica
authors.initials: D
authors.lastname: Pellegrini
authors.forename: Carmen
authors.initials: C
authors.lastname: Nuzzo
authors.forename: Vanessa
authors.initials: V
authors.lastname: Graziano
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vici
authors.forename: Marianna
authors.initials: M
authors.lastname: Introna
authors.forename: Alessandra
authors.initials: A
authors.lastname: Felici
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Carlini
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D017326:Clinical Trials, Phase III as Topic; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077143:Docetaxel; D004334:Drug Administration Schedule; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D000077143:Docetaxel; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000093542:Gemcitabine