This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Batist, G. Articles by Lee, L. W. Search for Related Content PubMed PubMed Citation Articles by Batist, G. Articles by Lee, L. W. Social Bookmarking                            What's this?

Reduced Cardiotoxicity and Preserved Antitumor Efficacy of Liposome-Encapsulated Doxorubicin and Cyclophosphamide Compared With Conventional Doxorubicin and Cyclophosphamide in a Randomized, Multicenter Trial of Metastatic Breast Cancer

From Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Tata Memorial Hospital, Mumbai; MNJ Institute of Oncology, Hyderabad; Cancer Institute, Madras; The Gujarat Cancer and Research Institute, Ahmedabad; Regional Cancer Centre, Trivandrum, India; Sidney Kimmel Cancer Center, San Diego, CA; University Medical Center, Jacksonville, FL; Columbia Comprehensive Cancer Clinic, Columbia, MO; Springfield Clinic, Springfield, IL; University of Maryland Cancer Center, Ellicott City, MD; and The Liposome Company, Princeton, NJ.

Address reprint requests to Gerald Batist, MD, Jewish General Hospital, 3755 Cote St Catherine, Montreal, PQ H3T 1E2, Canada; email: gbatist{at}onc.jgh.mcgill.ca

PURPOSE: To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC).

PATIENTS AND METHODS: Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m² of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m² of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival.

RESULTS: Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P = .0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m² for MC versus 480 mg/m² for AC (P = .0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months.

CONCLUSION: Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.

Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. Beslija, J. Bonneterre, H. J. Burstein, V. Cocquyt, M. Gnant, V. Heinemann, J. Jassem, W. J. Kostler, M. Krainer, S. Menard, et al. Third consensus on medical treatment of metastatic breast cancer Ann. Onc., November 1, 2009; 20(11): 1771 - 1785. [Abstract] [Full Text] [PDF]

				T.-H. CHOW, Y.-Y. LIN, J.-J. HWANG, H.-E. WANG, Y.-L. TSENG, S.-J. WANG, R.-S. LIU, W.-J. LIN, C.-S. YANG, and G. TING Improvement of Biodistribution and Therapeutic Index via Increase of Polyethylene Glycol on Drug-carrying Liposomes in an HT-29/luc Xenografted Mouse Model Anticancer Res, June 1, 2009; 29(6): 2111 - 2120. [Abstract] [Full Text] [PDF]

				A. Moreno-Aspitia and E. A. Perez Treatment Options for Breast Cancer Resistant to Anthracycline and Taxane Mayo Clin. Proc., June 1, 2009; 84(6): 533 - 545. [Abstract] [Full Text] [PDF]

				P. J. Barrett-Lee, J. M. Dixon, C. Farrell, A. Jones, R. Leonard, N. Murray, C. Palmieri, C. J. Plummer, A. Stanley, and M. W. Verrill Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk Ann. Onc., May 1, 2009; 20(5): 816 - 827. [Abstract] [Full Text] [PDF]

				A. Anton, A. Ruiz, M. A. Segui, L. Calvo, M. Munoz, J. Lao, F. Sancho, and L. Fernandez Phase I clinical trial of liposomal-encapsulated doxorubicin citrate and docetaxel, associated with trastuzumab, as neo-adjuvant treatment in stages II and IIIA, HER2-overexpressing breast cancer patients. GEICAM 2003-03 study Ann. Onc., March 1, 2009; 20(3): 454 - 459. [Abstract] [Full Text] [PDF]

				J. Cortes, S. Di Cosimo, M. A. Climent, H. Cortes-Funes, A. Lluch, P. Gascon, J. I. Mayordomo, M. Gil, M. Benavides, L. Cirera, et al. Nonpegylated Liposomal Doxorubicin (TLC-D99), Paclitaxel, and Trastuzumab in HER-2-Overexpressing Breast Cancer: A Multicenter Phase I/II Study Clin. Cancer Res., January 1, 2009; 15(1): 307 - 314. [Abstract] [Full Text] [PDF]

				C. Riganti, S. Doublier, C. Costamagna, E. Aldieri, G. Pescarmona, D. Ghigo, and A. Bosia Activation of Nuclear Factor-{kappa}B Pathway by Simvastatin and RhoA Silencing Increases Doxorubicin Cytotoxicity in Human Colon Cancer HT29 Cells Mol. Pharmacol., August 1, 2008; 74(2): 476 - 484. [Abstract] [Full Text] [PDF]

				B. L. Frei and S. A. Soefje A Review of the Cardiovascular Effects of Oncology Agents Journal of Pharmacy Practice, April 1, 2008; 21(2): 146 - 158. [Abstract] [PDF]

				A. Morabito, M. C. Piccirillo, K. Monaco, C. Pacilio, F. Nuzzo, P. Chiodini, C. Gallo, A. de Matteis, F. Perrone, and NCI Naples Breast Cancer Group First-Line Chemotherapy for HER-2 Negative Metastatic Breast Cancer Patients Who Received Anthracyclines as Adjuvant Treatment Oncologist, November 1, 2007; 12(11): 1288 - 1298. [Abstract] [Full Text] [PDF]

				M. Colozza, E. de Azambuja, N. Personeni, F. Lebrun, M. J. Piccart, and F. Cardoso Achievements in Systemic Therapies in the Pregenomic Era in Metastatic Breast Cancer Oncologist, March 1, 2007; 12(3): 253 - 270. [Abstract] [Full Text] [PDF]

				J. Woodley-Cook, L. Y.Y. Shin, L. Swystun, S. Caruso, S. Beaudin, and P. C. Liaw Effects of the chemotherapeutic agent doxorubicin on the protein C anticoagulant pathway Mol. Cancer Ther., December 1, 2006; 5(12): 3303 - 3311. [Abstract] [Full Text] [PDF]

				Z.-p. Yuan, L.-j. Chen, L.-y. Fan, M.-h. Tang, G.-l. Yang, H.-s. Yang, X.-b. Du, G.-q. Wang, W.-x. Yao, Q.-m. Zhao, et al. Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clin. Cancer Res., May 15, 2006; 12(10): 3193 - 3199. [Abstract] [Full Text] [PDF]

				J. D. Floyd, D. T. Nguyen, R. L. Lobins, Q. Bashir, D. C. Doll, and M. C. Perry Cardiotoxicity of Cancer Therapy J. Clin. Oncol., October 20, 2005; 23(30): 7685 - 7696. [Abstract] [Full Text] [PDF]

				P. Schmid, J. Krocker, C. Jehn, K. Michniewicz, S. Lehenbauer-Dehm, H. Eggemann, V. Heilmann, S. Kummel, C. O. Schulz, A. Dieing, et al. Primary chemotherapy with gemcitabine as prolonged infusion, non-pegylated liposomal doxorubicin and docetaxel in patients with early breast cancer: final results of a phase II trial Ann. Onc., October 1, 2005; 16(10): 1624 - 1631. [Abstract] [Full Text] [PDF]

				E. Mrozek, C. A. Rhoades, J. Allen, E. M. Hade, and C. L. Shapiro Phase I trial of liposomal encapsulated doxorubicin (MyocetTM; D-99) and weekly docetaxel in advanced breast cancer patients Ann. Onc., July 1, 2005; 16(7): 1087 - 1093. [Abstract] [Full Text] [PDF]

				T. M. Allen, D. R. Mumbengegwi, and G. J.R. Charrois Anti-CD19-Targeted Liposomal Doxorubicin Improves the Therapeutic Efficacy in Murine B-Cell Lymphoma and Ameliorates the Toxicity of Liposomes with Varying Drug Release Rates Clin. Cancer Res., May 1, 2005; 11(9): 3567 - 3573. [Abstract] [Full Text] [PDF]

				J-H Chen, R Ling, Q Yao, Y Li, T Chen, Z Wang, and K-Z Li Effect of small-sized liposomal Adriamycin administered by various routes on a metastatic breast cancer model Endocr. Relat. Cancer, March 1, 2005; 12(1): 93 - 100. [Abstract] [Full Text] [PDF]

				S. Chan, N. Davidson, E. Juozaityte, F. Erdkamp, A. Pluzanska, N. Azarnia, and L. W. Lee Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer Ann. Onc., October 1, 2004; 15(10): 1527 - 1534. [Abstract] [Full Text] [PDF]

				E. Briasoulis, G. Pentheroudakis, V. Karavasilis, E. Tzamakou, D. Rammou, and N. Pavlidis Weekly paclitaxel combined with pegylated liposomal doxorubicin (CaelyxTM) given every 4 weeks: dose-finding and pharmacokinetic study in patients with advanced solid tumors Ann. Onc., October 1, 2004; 15(10): 1566 - 1573. [Abstract] [Full Text] [PDF]

				Q. Chen, S. Tong, M. W. Dewhirst, and F. Yuan Targeting tumor microvessels using doxorubicin encapsulated in a novel thermosensitive liposome Mol. Cancer Ther., October 1, 2004; 3(10): 1311 - 1317. [Abstract] [Full Text] [PDF]

				A. M. Levine, A. Tulpule, B. Espina, A. Sherrod, W. D. Boswell, R. D. Lieberman, B. N. Nathwani, and L. Welles Liposome-Encapsulated Doxorubicin in Combination With Standard Agents (cyclophosphamide, vincristine, prednisone) in Patients With Newly Diagnosed AIDS-Related Non-Hodgkin's Lymphoma: Results of Therapy and Correlates of Response J. Clin. Oncol., July 1, 2004; 22(13): 2662 - 2670. [Abstract] [Full Text] [PDF]

				G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, and L. Gianni Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity Pharmacol. Rev., June 1, 2004; 56(2): 185 - 229. [Abstract] [Full Text] [PDF]

				A. Iop, A. M. Manfredi, and S. Bonura Fatigue in cancer patients receiving chemotherapy: an analysis of published studies Ann. Onc., May 1, 2004; 15(5): 712 - 720. [Abstract] [Full Text] [PDF]

				T. M. Allen and P. R. Cullis Drug Delivery Systems: Entering the Mainstream Science, March 19, 2004; 303(5665): 1818 - 1822. [Abstract] [Full Text] [PDF]

				M. E. R. O'Brien, N. Wigler, M. Inbar, R. Rosso, E. Grischke, A. Santoro, R. Catane, D. G. Kieback, P. Tomczak, S. P. Ackland, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYXTM/Doxil(R)) versus conventional doxorubicin for first-line treatment of metastatic breast cancer Ann. Onc., March 1, 2004; 15(3): 440 - 449. [Abstract] [Full Text] [PDF]

				E. Rivera Liposomal Anthracyclines in Metastatic Breast Cancer: Clinical Update Oncologist, August 1, 2003; 8(90002): 3 - 9. [Abstract] [Full Text] [PDF]

				S. Campos Liposomal Anthracyclines: Adjuvant and Neoadjuvant Therapy for Breast Cancer Oncologist, August 1, 2003; 8(90002): 10 - 16. [Abstract] [Full Text] [PDF]

				T. Safra Cardiac Safety of Liposomal Anthracyclines Oncologist, August 1, 2003; 8(90002): 17 - 24. [Abstract] [Full Text] [PDF]

				S. Limat, K. Demesmay, L. Voillat, Y. Bernard, E. Deconinck, A. Brion, A. Sabbah, M. C. Woronoff-Lemsi, and J. Y. Cahn Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin's lymphoma Ann. Onc., February 1, 2003; 14(2): 277 - 281. [Abstract] [Full Text] [PDF]

				N. M. Marina, D. Cochrane, E. Harney, K. Zomorodi, S. Blaney, N. Winick, M. Bernstein, and M. P. Link Dose Escalation and Pharmacokinetics of Pegylated Liposomal Doxorubicin (Doxil) in Children with Solid Tumors: A Pediatric Oncology Group Study Clin. Cancer Res., February 1, 2002; 8(2): 413 - 418. [Abstract] [Full Text] [PDF]

				G. Williams, P. Cortazar, R. Pazdur, G. Batist, and L. Welles Developing Drugs to Decrease the Toxicity of Chemotherapy J. Clin. Oncol., July 15, 2001; 19(14): 3439 - 3441. [Full Text]