High Dose Therapy with Stem Cell Support for Breast Cancer: The Jury Is Still Out

  • Michael Crump
  • Kathleen Pritchard
Part of the Cancer Treatment and Research book series (CTAR, volume 103)


The treatment of breast cancer, both in the adjuvant and metastatic setting, has been a story of great success coupled with frustration. For primary breast cancer, a series of randomized controlled trials testing new concepts in the application of chemotherapy and hormonal therapy, in both node positive and node negative patients, has produced small but significant improvements in disease-free and overall survival.1–3 Individual trials reported recently have also indicated incremental benefit from the substitution of epirubicin for methotrexate4,5 and the addition of paclitaxel after doxorubicin, plus cyclophosphamide (AC) chemotherapy.6 Nonetheless, subgroups of patients, particularly those with large numbers of positive lymph nodes, appear to derive relatively limited benefit from currently available treatment and in these patients the diagnosis of breast cancer carries a high mortality.


Breast Cancer Clin Oncol Metastatic Breast Cancer Hematopoietic Stem Cell Transplantation Autologous Bone Marrow Transplantation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Early Breast Cancer Trialists Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 352: 930–942, 1998.CrossRefGoogle Scholar
  2. 2.
    Early Breast Cancer Trialists Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 351: 1451–1467, 1998.CrossRefGoogle Scholar
  3. 3.
    Early Breast Cancer Trialists Collaborative Group: Ovarian ablation for early breast cancer: An overview of the randomized trials. Lancet 348: 1189–1196, 1996.CrossRefGoogle Scholar
  4. 4.
    Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16 (8): 2651–2658, 1998.PubMedGoogle Scholar
  5. 5.
    Mouridsen HT, Andersen J, Andersson M, Dombernowsky P, et al: Adjuvant anthracycline in breast cancer. Improved outcome in premenopausal patients following substitution of methotrexate in the CMF combination with epirubicin. Proc Am Soc Clin Oncol 18: 68a, 1999.Google Scholar
  6. 6.
    Henderson IC, Berry D, Demetri G, et al: Improved disease-free and - overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer. Proc Am Soc Clin Oncol 17: 101a, 1998.Google Scholar
  7. 7.
    Henderson IC, Garber JE, Breitmeyer JB, Hayes DF, Harris JR: Comprehensive management of disseminated breast cancer. Cancer 66: 1439–1448, 1990.PubMedCrossRefGoogle Scholar
  8. 8.
    Fossati R, Confalonieri C, Torri V, Ghyislandi TE, Penna A, Pistotti V, Tinazzi A, Liberati A: Cytotoxic and hormonal treatment for metastatic breast cancer: A systematic review of published randomized trials involving 31,510 women. J Clin Oncol 16: 3439–3460, 1998.PubMedGoogle Scholar
  9. 9.
    Frei, III E, Canellos GP: Dose: A critical factor in cancer chemotherapy. Am J Med 69: 585–594, 1980.PubMedCrossRefGoogle Scholar
  10. 10.
    Hryniuk W, Bush H: The importance of dose intensity in cancer chemotherapy of metastatic breast cancer. J Clin Oncol 2: 1281–1288, 1984.PubMedGoogle Scholar
  11. 11.
    Hudis C, Seidman A, Beselga J, et al: Sequential dose-dense doxorubicin, paclitaxel and cyclophosphamide for resectable high-risk breast cancer: Feasibility and efficacy. J Clin Oncol 17: 93–100, 1999.PubMedGoogle Scholar
  12. 12.
    Skipper HE: Laboratory models: The historical perspective. Cancer Treat Rep 70: 3–7, 1986.PubMedGoogle Scholar
  13. 13.
    Skipper HE, Schabel FM, Jary R, Wilcox WS. Experimental evaluation of antitumor agents. Cancer Chemother Rep 35: 1–34, 1964.PubMedGoogle Scholar
  14. 14.
    Frei, III E, Antman K, Teicher B, Eder P, Schnipper L: Bone marrow autotransplantation for solid tumors — prospects. J Clin Oncol 7: 515–526, 1989.PubMedGoogle Scholar
  15. 15.
    Henderson IC, Hayes DF, Gelman R: Dose-response in the treatment of breast cancer: A critical review. J Clin Oncol 6: 1501–1515, 1988.PubMedGoogle Scholar
  16. 16.
    Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with standard chemotherapy in relapses of chemotherapy sensitive non-Hodgkin’s lymphoma. N Engl J Med 332: 1045–1051, 1995.CrossRefGoogle Scholar
  17. 17.
    Haioun C, Lepage E, Gisselbrecht C, et al: Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade non-Hodgkin’s lymphoma in first complete remission: A study of 464 patients. J Clin Oncol 12: 2543–2551, 1994.PubMedGoogle Scholar
  18. 18.
    Verdonck LF, Van Putten WLJ, Hagenbeek A, et al: Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin’s lymphoma. N Engl J Med 333: 1540–1051, 1995.CrossRefGoogle Scholar
  19. 19.
    Burnett AK, Goldstone AH, Stevens RMF, et al: Randomized comparison of addition of autologous bone marrow transplantation to intensive chemotherapy for acute myeloid leukemia in first remission: Results of MRC AML 10 trial. Lancet 351: 700–709, 1998.PubMedCrossRefGoogle Scholar
  20. 20.
    Cassileth RA, Harrington DP, Appelbaum FP, et al: Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. New Engl J Med 339: 1649–1656, 1998.PubMedCrossRefGoogle Scholar
  21. 21.
    Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A, Chopra R, Milligan D, Hudson GV: Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomized trial. Lancet 341: 1051–1054, 1993.PubMedCrossRefGoogle Scholar
  22. 22.
    Schmitz N, Sextro M, Pfistner D, Hasenclever H, et al: High-dose therapy (HDT) followed by hematopoietic stem cell transplantation (HSCT) for relapsed chemosensitive Hodgkin’s disease (HD): Final results of a randomized GHSG and EBMT Trial (HD-R1).. Proc Am Assoc Clin Oncol 18:2a, 1999 (Abst #5).Google Scholar
  23. 23.
    Beyer J, Kingreen D, Krause M, Schleicher, et al: Long term survival of patients with recurrent or refractory germ cell tumors after high dose chemotherapy. Cancer 79: 161–168, 1997.PubMedCrossRefGoogle Scholar
  24. 24.
    Motzer RJ, Mazumdar M, Bosl GJ, Bajorin D, et al: High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: treatment results and prognostic factors for survival and toxicity. J Clin Oncol 14: 1098–1105, 1996.PubMedGoogle Scholar
  25. 25.
    Schmidt N, Lynch DC, Dreger P et al. Randomized trial of filgrastimmobilized peripheral blood progenitor cell transplantation versus autologous bone marrow transplantation in lymphoma patients. Lancet 347: 353–357, 1996.CrossRefGoogle Scholar
  26. 26.
    Dercksen MW, Rodenhuis S, Dirkson MKA, et al. Subsets of CD34+ cells and rapid hematologic recovery after peripheral blood stem cell transplantation. J Clin Oncol 13: 1922–1932, 1995.PubMedGoogle Scholar
  27. 27.
    Shpall EJ, Wheeler CA, Turner SA, et al. A randomized phase 3 study of peripheral blood progenitor cell mobilization with stem cell factor and filgrastim in high-risk breast cancer patients. Blood 93: 2491–2501, 1999.PubMedGoogle Scholar
  28. 28.
    Antman KH, Rowlings A, Vaughan WP, Pelz CJ, Fay JW, et al: High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America. J Clin Oncol 15: 1870–1879, 1997.PubMedGoogle Scholar
  29. 29.
    Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4: 1162–1170, 1986.PubMedGoogle Scholar
  30. 30.
    Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node positive breast carcinoma. N Engl J Med 330: 1253–1259, 1994.PubMedCrossRefGoogle Scholar
  31. 31.
    Tannock IF, Boyd NF, De Boer G, et al: A randomised trial of two dose levels of cyclophosphamide, methotrexate and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol 6: 1377–1387, 1988.PubMedGoogle Scholar
  32. 32.
    Focan C, Andrien JM, Closon MTK, et al: Dose response relationship of epirubicin based first line chemotherapy for advanced breast cancer: a prospective randomised trial. J Clin Oncol 11: 1253–1263, 1993.PubMedGoogle Scholar
  33. 33.
    Blomqvist K, Elomma I, Rissanen P, et al: Influence of treatment schedule on toxicity and efficacy of cyclophosphamide, epirubicin, and flurouracil in metastatic breast cancer: a randomised trial comparing weekly and every 4 week administration. J Clin Oncol 11: 467–473, 1993.PubMedGoogle Scholar
  34. 34.
    Bastholt L, Dalmark M, Gjedde SB, et al: Dose-response relationship of epirubicin in the treatment of postmenopausal women with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol 14: 1146–1155, 1996.PubMedGoogle Scholar
  35. 35.
    Stadtmauer EA, O’Neill A, Goldstein LJ, Crilley P, et al: Phase III randomized trial of high-dose chemotherapy and stem cell support shows no difference in overall survival or severe toxicity compared to maintenance chemotherapy with cyclophosphamide, methotrexate and 5fluorouracil for women with metastatic breast cancer who are responding to conventional induction chemotherapy: The “Philadelphia” Intergroup study. Proc Am Assoc Clin Oncol 18:1a, 1999 (Abst #1).Google Scholar
  36. 36.
    Antman K, Ayash L, Elias A, et al: A phase II study of high-dose cyclophosphamide, thiotepa and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy. J Clin Oncol 10: 102–110, 1992.PubMedGoogle Scholar
  37. 37.
    Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol 13: 2483–2489, 1995.PubMedGoogle Scholar
  38. 38.
    Stewart DJ, Evans WK, Shepherd FA, Wilson KS, Pritchard KI, Trudeau ME, Wilson JJ, Martz K: Cyclophosphamide and fluorouracil combined with mitoxantrone versus doxorubicin for breast cancer: Superiority of doxorubicin. J Clin Oncol 15: 1897–1905, 1997.PubMedGoogle Scholar
  39. 39.
    Lotz J-P, Cure H, Janvier M, Morvan F, et al: High-dose chemotherapy (HD-CT) with hematopoietic stem cells transplantation (HSCT) for metastatic breast cancer (MBC): Results of the French protocol PEGASE 04). Proc Am Soc Clin Oncol 18: 43a, 1999. (abst # 161).Google Scholar
  40. 40.
    Peters WP, Jones RB, Vredenburgh JJ, et al: A large, prospective randomized trial of high-dose combination alkylating agents (CPB) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (AFM). Breast Cancer Res Treat 37: 11, 1996 (abstract 11).CrossRefGoogle Scholar
  41. 41.
    Rowlings PA, Williams SF, Antman KH, et al.: Factors correlated with progression-free survival after high-dose chemotherapy and hematopoietic stem cell transplantation for metastatic breast cancer. JAMA 282: 1335–1343, 1999.PubMedCrossRefGoogle Scholar
  42. 41a.
    Rizzieri DA, Vredenburgh JJ, Jones R, et al.: Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem cell support. J Clin Oncol 17: 3064–3074, 1999.PubMedGoogle Scholar
  43. 42.
    Peters WP, Ross M, Vredenburgh JJ, Meisenberg B, et al.: High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 11: 1132–1143.Google Scholar
  44. Peters WP, Berry D, Vredenburgh JJ, et al.: Five year follow-up of high-dose combination alkylating agents with ABMT as consolidation after standard-dose CAF for primary breast cancer involving 10 axillary lymph nodes (Duke/CALGB 8782). Proc Am Soc Clin Oncol 14:316, 1995 (Abstr 933).Google Scholar
  45. 43.
    Gianni AM, Siena M, Bregni M, et al: Efficacy, toxicity and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary nodes: Five year results. J Clin Oncol 15: 1812–2321, 1997.Google Scholar
  46. 44.
    Gianni AM, Bregni M, Siena, et al: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B cell lymphoma. N Engl J Med 336: 1290–1297, 1997.PubMedCrossRefGoogle Scholar
  47. 45.
    Crump M, Goss PE, Prince M, Girouard C: Outcome of extensive evaluation before adjuvant therapy in women with breast cancer and 10 or more positive axillary lymph nodes. J Clin Oncol 14: 66–69, 1996.PubMedGoogle Scholar
  48. 46.
    Garcia-Carbonera R, Hidalgo M, Paz-Ares L, Calzas J, Gomez H, Guerra JA, Hitt R, Hornedo J, Colomer R, Corets-Funes H: Patient selection in high-dose chemotherapy trials: Relevance in high-risk breast cancer. J Clin Oncol 15: 3178–3184, 1997.Google Scholar
  49. 47.
    Rahman ZU, Frye DK, Buzdar AU, Smith TL, Asmar L, Champlin RE, Hortobagyi GN: Impact of selection process on response rate and longterm survival of potential high-dose chemotherapy candidates treated with standard-dose doxorubicin-containing chemotherapy in patients with metastatic breast cancer. J Clin Oncol 15: 3171–3177, 1997.PubMedGoogle Scholar
  50. 48.
    Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, et al: Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet 352: 515–521, 1998.PubMedCrossRefGoogle Scholar
  51. 49.
    Bezwoda WR: Randomised controlled trial of high dose chemotherapy versus standard dose chemotherapy for high risk, surgically treated, primary breast cancer. Proc Am Assoc Clin Oncol 18:2a, 1999 (Abst #4).Google Scholar
  52. 50.
    The Scandinavian Breast Cancer Study Group 9401: Results from a randomized adjuvant breast cancer study with high dose chemotherapy with CTC, supported by autologous bone marrow stem cells versus dose escalated and tailored FEC therapy. Proc Am Assoc Clin Oncol 18:2a, 1999 (Abst #3).Google Scholar
  53. 51.
    Peters W, Rosner G, Vredenburgh J: A prospective, randomized comparison of two doses of combination alkylating agents as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes: Preliminary results of CALGB 9082/SWOG 9114/NCIC MA.13. Proc Am Assoc Clin Oncol 18:1a, 1999 (Abst #2).Google Scholar
  54. 52.
    Hortobagyi G, Buzdar A, Champlin R, et al.: Lack of efficacy of adjuvant high-dose (HD) tandem combination chemotherapy (CT) for high-risk primary breast cancer (HRPBC) — A randomized trial. Proc am Soc Clin Oncol 18:471, 1998 (abstr 471).Google Scholar
  55. 53.
    Basser RL, To LB, Collins JP, et al.: Multicycle high-dose chemotherapy and filgrastim-mobilized peripheral-blood progenitor cells in women with high-risk stage II or III breast cancer: five-year follow-up. J Clin Oncol 17: 82–92, 1999.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Michael Crump
    • 1
  • Kathleen Pritchard
    • 1
  1. 1.Toronto-Sunnybrook Regional Cancer CenterCanada

Personalised recommendations