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Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma

  1. Lyndsay Harris M.D.1,2,†,*,
  2. Gerald Batist M.D.3,
  3. Robert Belt M.D.4,
  4. Douglas Rovira M.D.5,
  5. Rudolph Navari M.D.6,
  6. Nozar Azarnia Ph.D.7,‡,
  7. Lauri Welles M.D.8,§,
  8. Eric Winer M.D.1,2,¶,
  9. TLC D-99 Study Group ‖

Article first published online: 28 DEC 2001

DOI: 10.1002/cncr.10201

Issue

Cancer

Cancer

Volume 94, Issue 1, pages 25–36, 1 January 2002

Additional Information

How to Cite

Harris, L., Batist, G., Belt, R., Rovira, D., Navari, R., Azarnia, N., Welles, L., Winer, E. and TLC D-99 Study Group (2002), Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer, 94: 25–36. doi: 10.1002/cncr.10201

Author Information

  1. 1

    Duke University Medical Center, Durham, North Carolina

  2. 2

    Dana-Farber Cancer Institute, Boston, Massachusetts

  3. 3

    McGill University, Montreal, Quebec, Canada

  4. 4

    St. Luke's Hospital, Kansas City, Missouri

  5. 5

    University of Colorado, Denver, Colorado

  6. 6

    Simon Williamson Clinic, Birmingham, Alabama

  7. 7

    Columbia Presbyterian Medical Center, New York, New York

  8. 8

    Elan Pharmaceuticals, Princeton, New Jersey

  1. †

    Fax: (617) 632-3709

  2. ‡

    Dr. Nozar Azarnia is a consultant for Elan Corporation.

  3. §

    Lauri Welles is an employee of Elan Pharmaceuticals.

  4. Eric Winer was a consultant to the Liposome Company in 1999 during the course of their submission of TLD to the FDA.

  5. ‖

    The following investigators and their institutions also participated in the study: Thomas Garrett, Columbia-Presbyterian Medical Center, New York, NY; Douglas Blayney, Lewis Cancer Care Center, Pomona, CA; Laurence Elias, UNM Cancer Center, Albuquerque, NM; Joanne Mortimer, Barnard Cancer Center, St. Louis, MO; Burton Needles, Saint John's Mercy Medical Center, St. Louis, MO; Timothy Webb, Central Arkansas Oncology Clinic, Hot Springs, AR; Joshua Atiba, UC Irvine Medical Center, Orange, CA; John Bickers, LSU Medical Center, New Orleans, LA; Thomas Godfrey, Loma Linda University Medical Center, Loma Linda, CA; Richard Love, University of Wisconsin Hospital, Madison, WI; Dustan Osborn, Western Washington Cancer Center, Olympia, WA; Joseph Aisner, University of Maryland Cancer Center, Baltimore, MD; Tom Anderson, Froedtert Memorial Lutheran Hosp, Milwaukee, WI; Dean Butler, Dial Research Associates, Nashville, TN; Paul Calabresi, Rhode Island Hospital, Providence, RI; Lawrence Feldman, Mount Sinai Hospital, Chicago, IL; Robert Kerr, Southwest Regional Cancer Centers, Austin, TX; Hans Nevinny, Memorial Medical Center, Tulsa, OK; Craig Reynolds, Ocala Oncology Center, Ocala, FL; Andrew Schneider, Hematology and Medical Oncology, Lauderhill, FL; Charles Tweedy, Amos Community Cancer Center, Columbus, GA; William Whaley, West Paces Ferry Clinic, Atlanta, GA; Michael DeMattia, Mount Clemons Hospital, Mount Clemons, MI; Gregory Harper, Lehigh Valley Hospital, Allentown, PA; Rebecca Moroose, Walt Disney Memorial Cancer Institute, Orlando, FL; Harry Staszewski, Winthrop University Hospital, Mineola, NY; Albert Begas, Boca Raton Community Hospital, Boca Raton, FL; Janice Dutcher, Montefiore Medical Center, Bronx, NY; Robert Ellis, Madigan Army Medical Center, Tacoma, WA; Gini Fleming, University of Chicago Medical Center, Chicago, IL; Michael Garcia, Norwood Clinic Research Center, Birmingham, AL; Joel Granick, Midwestern Regional Medical Center, Zion, IL; Jonathan Kloss, Lourdes Hospital Cancer Center, Binghamton, NY; Michael Roberts, Hematology and Oncology Associates, Phoenix, AZ; Federico Sanchez, Cancer Care Center, Menomonee Falls, WI; Richard Silver, New York Hospital–Cornell Medical Center, New York; Harvey Taylor, Hodges Cancer Center, Lubbock, TX.

*Dana-Farber Cancer Institute, Room D1210, 44 Binney Street, Boston, MA 02115

  1. †

    Fax: (617) 632-3709

  2. ‡

    Dr. Nozar Azarnia is a consultant for Elan Corporation.

  3. §

    Lauri Welles is an employee of Elan Pharmaceuticals.

  4. Eric Winer was a consultant to the Liposome Company in 1999 during the course of their submission of TLD to the FDA.

  5. ‖

    The following investigators and their institutions also participated in the study: Thomas Garrett, Columbia-Presbyterian Medical Center, New York, NY; Douglas Blayney, Lewis Cancer Care Center, Pomona, CA; Laurence Elias, UNM Cancer Center, Albuquerque, NM; Joanne Mortimer, Barnard Cancer Center, St. Louis, MO; Burton Needles, Saint John's Mercy Medical Center, St. Louis, MO; Timothy Webb, Central Arkansas Oncology Clinic, Hot Springs, AR; Joshua Atiba, UC Irvine Medical Center, Orange, CA; John Bickers, LSU Medical Center, New Orleans, LA; Thomas Godfrey, Loma Linda University Medical Center, Loma Linda, CA; Richard Love, University of Wisconsin Hospital, Madison, WI; Dustan Osborn, Western Washington Cancer Center, Olympia, WA; Joseph Aisner, University of Maryland Cancer Center, Baltimore, MD; Tom Anderson, Froedtert Memorial Lutheran Hosp, Milwaukee, WI; Dean Butler, Dial Research Associates, Nashville, TN; Paul Calabresi, Rhode Island Hospital, Providence, RI; Lawrence Feldman, Mount Sinai Hospital, Chicago, IL; Robert Kerr, Southwest Regional Cancer Centers, Austin, TX; Hans Nevinny, Memorial Medical Center, Tulsa, OK; Craig Reynolds, Ocala Oncology Center, Ocala, FL; Andrew Schneider, Hematology and Medical Oncology, Lauderhill, FL; Charles Tweedy, Amos Community Cancer Center, Columbus, GA; William Whaley, West Paces Ferry Clinic, Atlanta, GA; Michael DeMattia, Mount Clemons Hospital, Mount Clemons, MI; Gregory Harper, Lehigh Valley Hospital, Allentown, PA; Rebecca Moroose, Walt Disney Memorial Cancer Institute, Orlando, FL; Harry Staszewski, Winthrop University Hospital, Mineola, NY; Albert Begas, Boca Raton Community Hospital, Boca Raton, FL; Janice Dutcher, Montefiore Medical Center, Bronx, NY; Robert Ellis, Madigan Army Medical Center, Tacoma, WA; Gini Fleming, University of Chicago Medical Center, Chicago, IL; Michael Garcia, Norwood Clinic Research Center, Birmingham, AL; Joel Granick, Midwestern Regional Medical Center, Zion, IL; Jonathan Kloss, Lourdes Hospital Cancer Center, Binghamton, NY; Michael Roberts, Hematology and Oncology Associates, Phoenix, AZ; Federico Sanchez, Cancer Care Center, Menomonee Falls, WI; Richard Silver, New York Hospital–Cornell Medical Center, New York; Harvey Taylor, Hodges Cancer Center, Lubbock, TX.

Publication History

  1. Issue published online: 28 DEC 2001
  2. Article first published online: 28 DEC 2001
  3. Manuscript Accepted: 17 AUG 2001
  4. Manuscript Received: 1 JUN 2001

Funded by

  • Elan Pharmaceuticals, Princeton, New Jersey

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Keywords:

  • doxorubicin;
  • anthracyclines;
  • TLC D-99;
  • breast carcinoma;
  • liposomal chemotherapy

Abstract

BACKGROUND

The objective of this study was to compare the efficacy and toxicity of the liposome-encapsulated doxorubicin, TLC D-99 (Myocet, Elan Pharmaceuticals, Princeton, NJ), and conventional doxorubicin in first-line treatment of metastatic breast carcinoma (MBC).

METHODS

Two hundred twenty-four patients with MBC and no prior therapy for metastatic disease were randomized to receive either TLC D-99 (75 mg/m2) or doxorubicin (75 mg/m2) every 3 weeks, in the absence of disease progression or unacceptable toxicity. The primary efficacy endpoint was response rate. Responses were assessed using World Health Organization criteria and were required to be of at least 6 weeks' duration. The primary safety endpoint was cardiotoxicity. Cardiac function was monitored by multiple-gated radionuclide cardioangiography scan, and the left ventricular ejection fraction (LVEF) was scored at a central laboratory. Patients were removed from study if LVEF declined 20 or more EF units from baseline to a final value of greater than or equal to 50%, or by 10 or more units to a final value of less than 50%, or onset of clinical congestive heart failure (CHF).

RESULTS

Median age was 54 years in both treatment groups. All relevant prog nostic factors were balanced, with the exception that there were significantly more progesterone receptor positive patients in the doxorubicin-treated group. Protocol-defined cardiotoxicity was observed in 13% of TLC D-99 patients (including 2 cases of CHF) compared to 29% of doxorubicin patients (including 9 cases of CHF). Median cumulative doxorubicin dose at onset of cardiotoxicity was 785 mg/m2 for TLC D-99 versus 570 mg/m2 for doxorubicin (P = 0.0001; hazard ratio, 3.56). The overall response rate was 26% in both treatment groups. The median TTP was 2.9 months on TLC D-99 versus 3.1 months on doxorubicin. Median survival was 16 versus 20 months with a nonsignificant trend in favor of doxorubicin (P = 0.09). Clinical toxicities, commonly associated with doxorubicin, appeared less common with TLC D-99, although the difference was not statistically significant. There was only one report of palmar-plantar erythrodysesthesia (Grade 2) with this liposomal formulation of doxorubicin.

CONCLUSIONS

Single-agent TLC D-99 produces less cardiotoxicity than doxorubicin, while providing comparable antitumor activity. Cancer 2002;94:25–36. © 2002 American Cancer Society.

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