The role of high-dose chemotherapy in breast cancer is still controversial despite 20 years of clinical studies. Several nonrandomized studies had demonstrated improvement for patients with primary breast cancer. This led to the premature acceptance of high-dose therapy as a new standard of care for patients with high-risk breast cancer. There followed a phase of disillusionment after some of the randomized studies did not show any significant benefit and after a case of scientific misconduct. High-dose chemotherapy studies in breast cancer have been unpopular for the last 5 years. There is new evidence that warrants a new critical look. Fourteen randomized studies with a total of 5,592 patients have been carried out in patients with high-risk breast cancer on adjuvant therapy. Some of them showed significant improvement; others are coming to maturation now. In all randomized studies high-dose therapy in metastatic breast cancer leads to an equivalent or better disease-free survival, but because of their low power, none of these studies achieved an improvement in overall survival. It is thus necessary to perform a meta-analysis of all these studies to acquire insight into the choice of high-dose regimens. It is further necessary to look at the biology of breast cancer in the context of high-dose chemotherapy studies.

Keywords:
Breast cancer, High-dose therapy, Prognostic factors
1.
Bonadonna G, Valagussa P, Miloterni A, Zambetti M, Brambilla C: Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995;332:901–906.
2.
Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer. An overview of the randomised trials. Lancet 1998;352:930–942.
3.
Albain KS, Green SJ, Ravdin PM, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Schneider DJ, Abeloff MD, Norton L, Henderson IC, Lew DD, Livingston RB, Martino S, Osborne CK: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814) (abstract). Proc ASCO 2002;21:37a.
4.
Swenerton KD, Legha SS, Smith T, Hortobagyi GN, Gehan EA, Yap HY, Gutterman JU, Blumenschein GR: Prognostic factors in metastatic breast cancer treated with combination chemotherapy. Cancer Res 1979;39:1552–1562.
5.
Smalley RV, Carpenter J, Bartolucci A, Vogel C, Krauss S: A comparison of cyclophosphamide, Adriamycin, 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer: a Southeastern Cancer Study Group project. Cancer 1977;40:625–632.
6.
Fisher B, Anderson S, Wickerham DL, DeCillis, A, Dimitrov N, Mamounas E, Wolmark N, Pugh R, Atkins JN, Meyers FJ, Abramson N, Wolter J, Bornstein RS, Levy L, Romond EH, Caggiano V, Grimaldi M, Jochimsen P, Deckers P: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 1997;15:1858–1869.
7.
Nabholtz J, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Vogel C, Weaver C, Walley B, Martin M, Chap L, Tomiak E, Juhos E, Guevin R, Howell A, Hainswirth J, Fornander T, Blitz S, Gazel S, Loret C, Riva A: Phase 3 trial comparing TAC with FAC in the adjuvant treatment of node positive breast cancer (abstract). Proc ASCO 2002;21:141a.
8.
Nieto Y, Cagnoni PJ, Nawaz S, Shpall EJ, Yerushalmi R, Cook B, Russell P, McDermit J, Murphy J, Bearman SI, Jones RB: Evaluation of the predictive value of Her-2/neu overexpression and p53 mutations in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem cell transplantation. J Clin Oncol 2000;18:2070–2080.
9.
Allred DC, Harvey JM, Berardo M, Clark GM: Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 1998;11:155–168.
10.
Chang J, Powles TJ, Allred DC, Ashley SE, Clark GM, Makris A, Assersohn L, Gregory RK, Osborn CK, Dowsett M: Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. J Clin Oncol 1999;17:3058–3063.
11.
Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, Ruby SG, O’Malley F, Simpson JF, Connolly JL, Hayes DF, Edge SB, Lichter A, Schnitt SJ: Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124:966–978.
12.
Hamilton A, Piccart M: The contribution of molecular markers to the prediction of response in the treatment of breast cancer: a review of the literature on Her-2-neu, p53 and BCL-2. Ann Oncol 2000;11:647–663.
13.
Peters WP, Ross M, Vredenburgh JJ, Meisenberg B, Marks LB, Winder E, Kurtzberg J, Bast RC Jr, Jones R, Shpall E: High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 1993;11:1132–1143.
14.
Peters WP, Berry D, Vredenburgh JJ, Hussein A, Rubin P, Elkordy M, Ross M, Henderson IC, Budman D, Norton L, Weiss R, Hurd D: Five-year follow-up of high-dose combination alkalyting agents with ABMT as consolidation after standard-dose CAF for primary breast cancer involving 10 axillary lymph nodes (Duke/CALGB 8782) (abstract No 933). Proc ASCO 1995;14:317.
15.
Gianni AM, Siena S, Bregni M, Di Nicola M, Orefice S, Cusumano F, Salvadori B, Luini A. Greco M, Zucali R, Rilke F, Zambetti M, Valagussa P, Bonadonna G: Efficacy, toxicity and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary lymph nodes: five-year results. J Clin Oncol 1997;15:2312–2321.
16.
Damon LE, Wolf JL, Rudo HS, Gold E, Zander AR, Cassidy M, Cecchi G, Cohen N, Irwin D, Tracy M, Ries CA, Linker CA: High-dose chemotherapy (CTM) for breast cancer. Bone Marrow Transplant 2000;26:257–268.
17.
Peters WP, Rosner G, Vredenburgh J, Shpall E, Crump M, Richardson P, Marks L, Cirrincione C, Wood W, Henderson I, Hurd D, Norton L: A prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13 (abstract No 3). Proc ASCO 1999;18:1a.
18.
Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, Baars JW, Peterse JL, Rutgers E, Borger JH, Nooijen WJ, Bakx R, Dalesio O: A randomized trial of high-dose chemotherapy and hematopoietic progenitor cell support in operable breast cancer with extensive axillary lymph node involvement. Lancet 1998;352:515–521.
19.
Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmstrom P,Kellokumpu-Lehtinen P, Bengtsson NO, Soderlund G, Anker G, Wist E, Ottosson S, Salminen E, Ljungman P, Holte H, Nilsson J, Blomqvist C, Wilking N: Tailored fluorouracil, epirubicin and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomized trial. Scandinavian Breast Group 9401 study. Lancet 2000;356:1384–1391.
20.
Bezwoda WR: Randomized, controlled trial of high-dose chemotherapy (HD-CNVp) vs. standard dose (CAF) chemotherapy for high risk, surgically treated, primary breast cancer (abstract 4). Proc ASCO 1999;18:2a.
21.
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 1995;13:2483–2489.
22.
Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ, Holmes FA, Giralt S, Khouri I, Andersson B, Gajewski JL, Rondon G, Smith TL, Singetary SE, Aames FC, Sneige N, Strom EA, McNeese MD, Deisseroth AB, Champlin RE: Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 2000;92:225–233.
23.
Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA, Voest EE, Hupperets P, van Tinteren H, Peterse HL, TenVergert EM, de Vries EG; Netherlands Working Party on Autologous Transplantation in Solid Tumors: High-dose chemotherapy with hematopoietic stem-cell rescue for high risk breast cancer. N Engl J Med 2003;349:7–16.
24.
Tokuda Y, Tajima T, Narabayashi M: Randomized phase 3 study of high-dose chemotherapy (HDC) with autologous stem cell support as consolidation in high-risk postoperative breast cancer: Japan Clinical Oncology (JCOG9208) (abstract). Proc ASCO 2001;20:38a.
25.
Roché H, Pouillard P, Meyer N: Adjuvant high-dose improves early outcome for high-risk (N>7) breast cancer patients: The PEGASE-01 trial (abstract No 102). Proc ASCO 2000;20:25a.
26.
Zander AR, Kröger N, Schmoor C, Krüger W, Möbus V, Frickhofen N, Metzner B, Schulze W, Berdel WE, Koenigsmann M, Thiel E, Wandt H, Possinger K, Trumper L, Kreienberg R, Carstensen M, Schmidt EH, Janicke F, Schumacher M, Jonat W: High-dose chemotherapy with autologous stem cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol 2004;22: 2273–2283.
27.
Crown JP, Lind M, Gould A, Verril M, Twelves C, Coleman R, Perren T, Van Belle S, Wilson C, Lederman J, Barrett-Lee PJ, Heart D, Kennedy I, Simmons P, Mansi JL, Jones A, Cameron D, Poole C, Foster L, Leonard R: High-dose chemotherapy with autograft support is not superior to cyclophosphamide methotrexate and 5-FU (UCMF) following doxorubicin induction in patients with breast cancer and four or more involved axillary lymph nodes: the Anglo-Celtic I study (abstract). Proc ASCO 2002;21:42a.
28.
Tallman MS, Gray R, Robert NJ, LeMaistre CF, Osborne CK, Vaughan WP, Gradishar WJ, Pisansky TM, Fetting J, Paietta E, Lazarus HM: Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem cell transplantation in high risk breast cancer. N Engl J Med 2003;349:17–26.
29.
Basser R, O’Neill A, Martineli G, Nasi M L, Peccatoris F, Cinieri S, Snyder R, Yeo W, Aebi S, Green M: Randomized trial comparing up-front, multi-cycle dose-intensive chemotherapy (CT) versus standard dose CT in women with high-risk stage 2 or 3 breast cancer (BC): first results from IBCSG Trial 15–95 (abstract No 20). Proc ASCO 2003:22:6.
30.
Bliss JM, Vigushin D, Kanfer E, Howell A, Gallagher C, Rubens R, Slevin M, Peckitt C, Emson M, Coombes RC: Randomized trial of high dose therapy using cyclophosphamide, thiotepa and carboplatin in primary breast cancer patients with 4 or more histologically involved positive nodes (ISRCTN: 52623943) (abstract No 58). Proc ASCO 2003;22:15.
31.
Nitz U A, Frick M, Mohrmann S, Lindemann H, Jackisch C, Werner C, Souchon R, Metzner B, Rufert U, Bender HG: Tandem high dose chemotherapy for patients with high risk breast cancer: interim results from a multicenter phase III trial (abstract No 3344). Proc ASCO 2003;22:832DELETE.
32.
Roché H: Personal communication, Ravenna Conference, 2004.
33.
Gianni A, Bonadonna G: Five-year results of the randomized clinical trial comparing standard versus high-dose myeloablative chemotherapy in the adjuvant treatment of breast cancer with >3 positive nodes (LN+) (abstract). Proc ASCO 2001;20:21a.
34.
Crump M, Gluck S, Stewart D: A randomized trial of high-dose chemotherapy (HDC) with autologous peripheral blood stem cell support (ASCT) compared to standard therapy in women with metastatic breast cancer: a National Cancer Institute of Canada (NCIC) clinical trials group study (abstract). Proc ASCO 2001;20:21a.
35.
Stadtmauer EA, O’Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 2000;342:1069–1076.
36.
Biron P, Durand M, Roche H, Delozier T, Battista C, Fargeot P, Spaeth D, Bachelot M, Poiget E, Monnot F, Tanguy M, Cure H: High dose thiotepa, cyclophosphamide and stem cell transplantation after 4 FEC 100 compared with 4 FEC alone allowed a better disease free survival but the same overall survival in first line chemotherapy for metastatic breast cancer. Results of the PEGASE 03 French Protocol. Proc ASCO 2002;221:42a.
37.
Peters W, Jones R, Vredenburgh J, Shpall EJ, Hussein A, Elkordy M, Rubin P, Ross M, Berry D: A large prospective randomized trial of high-dose combination alkylating agents (CPB) with autologous cellular support as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (AFM) (abstract). Proc ASCO 1996;15:121a.
38.
Madan B, Broadwater G, Rubin P, Edwards J, Long G, Chao NC, Rizzieri D, Marks L, Affronti ML, Petros W, Peters WP: Improved survival with consolidation high-dose cyclophosphamide, cisplatin and carmustine compared with observations in women with metastatic breast cancer and only bone metastases treated with induction Adriamycin, 5-fluorouracil and methotrexate: a phase 3 prospective randomized comparative trial (abstract). Proc ASCO 2000;19:48a.
39.
Crown J, Perey L, Lind M, Guillem V, Efremdis A, Garcia-Conde Bru J, Welch R, Montes A, Leonard R, Baselga J: Superiority of tandem high-dose chemotherapy (HDC) versus optimized conventionally-dosed chemotherapy (CDC) in patients (pts) with metastatic breast cancer (MBC): The International Randomized Breast Cancer Dose Intensity Study (IBDIS) (abstract 88). Proc ASCO 2003;22:23DELETE.
40.
Schmid P, Schippinger W, Nitsch T, Huebner G, Heilmann V, Schultze W, Hausmaninger H, Wischnewsky M, Possinger K: Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. J Clin Oncol 2005;23:432–440.
41.
Lotz JP, Cure H, Janvier M, Asselain B, Morvan F, Legros M, Audhuy B, Biron P, Guillemot M, Goubet J, Laadem A, Cailliot C, Maignan CL, Delozier T, Glaisner S, Maraninchi D, Roche H, Gisselbrecht C: High-dose chemotherapy with haematopoietic stem cell transplantation for metastatic breast cancer patients: final results of the French multicentric randomised CMA/PEGASE 04 protocol. Eur J Cancer 2005;41:71–80.
42.
Schrama JG, Faneyte IF, Schronagel JH, Baars JW, Pertese JL, van de Vijver MJ, Dalesio O, van Tinteren H, Rutgers EJ, Richelt DJ, Rodenhuis S: Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive lymph node involvement: final analysis with 7 years of follow-up. Ann Oncol 2002;13:689–698.
43.
Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 1986;4: 1162–1170.
© 2005 S. Karger AG, Basel
2005
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.