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      Gemcitabine and taxanes in metastatic breast cancer: a systematic review

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          Abstract

          Incremental advances over the last two decades in the treatment of stage IV metastatic breast cancer (MBC) have resulted in significantly prolonging the average life expectancy. In 2008, the estimated 5-year relative survival rate for MBC is 27% which compares favorably to rates in stage IV lung (3%) and pancreatic cancers (1%). Despite these advances, MBC remains an incurable disease, often associated with many symptoms and a decreased quality of life (QoL). Therefore, therapy goals in the treatment of MBC include prolonging both progression-free survival and overall survival rates, while at the same time improving QoL by palliation of symptoms. Therefore, systemic chemotherapy ideally should not induce unnecessary toxicities. Once chemotherapy is indicated, a number of drugs and regimens are available but only a few offer both palliation of symptoms (responses to therapy) and overall survival benefit. The addition of novel biologic compounds to chemotherapy has been shown in phase III trials to improve all the above mentioned clinical outcomes in MBC. This review will discuss data supporting the use of gemcitabine/taxane combinations in the treatment of MBC.

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          Most cited references 31

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          Cancer Statistics, 2008

           A. Jemal,  R. Siegel,  E. Ward (2008)
          Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,437,180 new cancer cases and 565,650 deaths from cancer are projected to occur in the United States in 2008. Notable trends in cancer incidence and mortality include stabilization of incidence rates for all cancer sites combined in men from 1995 through 2004 and in women from 1999 through 2004 and a continued decrease in the cancer death rate since 1990 in men and since 1991 in women. Overall cancer death rates in 2004 compared with 1990 in men and 1991 in women decreased by 18.4% and 10.5%, respectively, resulting in the avoidance of over a half million deaths from cancer during this time interval. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. Although much progress has been made in reducing mortality rates, stabilizing incidence rates, and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.
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            Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results.

            Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC. Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to docetaxel 100 mg/m(2) on day 1 (n = 256). Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P =.0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P =.0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P =.006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination). The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2), with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2). Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.
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              Gemcitabine: metabolism, mechanisms of action, and self-potentiation.

              Gemcitabine (dFdC) is a new anticancer nucleoside that is an analog of deoxycytidine. It is a pro-drug and, once transported into the cell, must be phosphorylated by deoxycytidine kinase to an active form. Both gemcitabine diphosphate (dFdCTP) and gemcitabine triphosphate (dFdCTP) inhibit processes required for DNA synthesis. Incorporation of dFdCTP into DNA is most likely the major mechanism by which gemcitabine causes cell death. After incorporation of gemcitabine nucleotide on the end of the elongating DNA strand, one more deoxynucleotide is added and thereafter, the DNA polymerases are unable to proceed. This action ("masked termination") apparently locks the drug into DNA as the proofreading enzymes are unable to remove gemcitabine from this position. Furthermore, the unique actions that gemcitabine metabolites exert on cellular regulatory processes serve to enhance the overall inhibitory activities on cell growth. This interaction is termed "self-potentiation" and is evidenced in very few other anticancer drugs.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                December 2008
                December 2008
                : 4
                : 6
                : 1157-1164
                Affiliations
                Division of Hematology/Oncology, Braman Family Breast Cancer Institute, UMSylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA
                Author notes
                Correspondence: Stefan Glück, Division of Hematology/Oncology, Braman Family Breast Cancer Institute, UMSylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, 1475 NW 12th Ave., Suite 3510, Miami FL 33136, USA, Tel +1 305 243 4909, Fax +1 305 243 4047, Email sgluck@ 123456med.miami.edu
                Article
                tcrm-4-1157
                2643097
                19337423
                © 2008 Dove Medical Press Limited. All rights reserved
                Categories
                Review

                Medicine

                taxanes, gemcitabine, metastatic breast cancer

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