Journal of the National Cancer Institute Advance Access published online on January 8, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm287
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ARTICLES |
Adjuvant Chemotherapy With Sequential or Concurrent Anthracycline and Docetaxel: Breast International Group 02–98 Randomized Trial
On behalf of the BIG 02-98 Collaborative Group
Affiliations of authors: Peter MacCallum Cancer Centre, Melbourne, Australia (PF); Australian New Zealand Breast Cancer Trials Group, Newcastle, Australia (PF); International Breast Cancer Study Group, Bern, Switzerland (PF); Irish Clinical Oncology Research Group, Dublin, Ireland (JC); Hospital of Prato, Prato, Italy (ADL); International Drug Development Institute, Louvain-la-Neuve, Belgium (MB); Grupo Español de Investigacion en Cancer de Mama, Madrid, Spain (AB); Hospital Arnau de Vilanova, Lleida, Spain (AB); Danish Breast Cancer Cooperative Group, Copenhagen, Denmark (MA); Swedish Breast Cancer Group, Universitetssjukhuset, Linkoping, Sweden (BN); National Institute of Oncology, Budapest, Hungary (IL); Austrian Breast and Colorectal Cancer Study Group, Vienna Medical School, Vienna, Austria (RJ); Sandton Oncology Centre, Johannesburg, South Africa (DV); Grupo Oncologico Cooperativo Chileno De Investigacion, Clinica Las Condes, Santiago, Chile (JG); Mount Hospital, Perth, Australia (GvH); Breast European Adjuvant Studies Team, Jules Bordet Institute, Brussels, Belgium (SD, SJ, MPG); sanofi-aventis, Paris, France (BB); International Breast Cancer Study Group (IBCSG), Statistical Centre and Dana Farber Cancer Institute, Boston, MA (RDG); IBCSG Scientific Committee, European Institute of Oncology, Milan, Italy (AG); IBCSG Coordinating Centre and Inselspital, Bern, Switzerland (MCG)
Correspondence to: Prudence Francis, MB, BS, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Locked Bag #1, A’Beckett Street, Melbourne 8006, Australia (e-mail: prue.francis{at}petermac.org).
Background: Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel.
Methods: Patients with lymph node–positive breast cancer (n = 2887) were randomly assigned to one of four treatments: 1) sequential control (four cycles of doxorubicin at 75 mg/m2, followed by three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]); 2) concurrent control (four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2, followed by three cycles of CMF); 3) sequential docetaxel (three cycles of doxorubicin at 75 mg/m2, followed by three cycles of docetaxel at 100 mg/m2, followed by three cycles of CMF); 4) concurrent docetaxel (four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2, followed by three cycles of CMF). The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival (DFS) events (ie, relapse, second primary cancer, or death from any cause). Docetaxel and control treatment groups were compared by log-rank tests, and hazard ratios (HR) of DFS events were calculated by Cox modeling. All statistical tests were two-sided.
Results: Due to a lower-than-anticipated rate of relapse, this analysis was performed after 5 years with 732 events. Patients in control arms had a 5-year DFS of 73% (95% confidence interval [CI] = 70% to 75%). Docetaxel treatment resulted in an improvement in DFS of borderline statistical significance compared with control treatment (HR = 0.86, 95% CI = 0.74 to 1.00; P = .05). However, DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm (HR = 0.83, 95% CI = 0.69 to 1.00) and in the sequential control arm (HR = 0.79, 95% CI = 0.64 to 0.98).
Conclusions: Incorporating docetaxel into anthracycline-based therapy resulted in an improvement in DFS that was of borderline statistical significance. However, important differences may be related to doxorubicin and docetaxel scheduling, with sequential but not concurrent administration, appearing to produce better DFS than anthracycline-based chemotherapy.
| CONTEXT AND CAVEATS Prior knowledge Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. Study design Phase III randomized adjuvant therapy trial of sequential control (doxorubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]), concurrent control (doxorubicin plus cyclophosphamide followed by CMF), sequential docetaxel (doxorubicin followed by docetaxel followed by CMF), and concurrent docetaxel (doxorubicin plus docetaxel followed by CMF). The primary end point was the comparison of disease-free survival (DFS) events (ie, relapse, second primary cancer, or death from any cause). Contribution Incorporating docetaxel into anthracycline-based chemotherapy resulted in an improvement of DFS that was of borderline statistical significance. Important differences may be related to docetaxel and doxorubicin scheduling, with sequential administration appearing to produce better DFS than concurrent administration. Implications Scheduling of doxorubicin and docetaxel for the treatment of breast cancer appears to warrant further study. Limitations After a median follow-up of at least 5 years, less than two-thirds of the number of DFS events originally planned had occurred at the time of this analysis. Consequently, the study had reduced power. The better sequential docetaxel result could have arisen by chance. Differences in DFS may not translate into differences in overall survival.
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A. Balil died on 8th March 2007.
P. Francis and M. Piccart-Gebhart have received honoraria of less than $10000 from sanofi-aventis. J. Crown has received research support and honoraria from the sanofi-aventis speaker's bureau. A. Di Leo has been a speaker in symposia sponsored by sanofi-aventis, participated in advisory board meetings of sanofi-aventis, and received a research grant from sanofi-aventis. M. Buyse owns stock in the IDDI, a privately held company offering data management and statistical consulting. J. Gutiérrez is a member of the speaker's bureau for Roche.
We thank the patients, physicians, nurses, and data managers who participated in BIG 02-98 and the staff at the central offices of the cooperative groups. The following cooperative groups participated: Breast European Adjuvant Studies Team, International Breast Cancer Study Group (including Australian New Zealand Breast Cancer Trials Group), Irish Clinical Oncology Research Group, Grupo Español de Investigacion en Cancer de Mama, Danish Breast Cancer Cooperative Group, Swedish Breast Cancer Group, Austrian Breast and Colorectal Cancer Study Group, and Grupo Oncologico Cooperative Chileno De Investigacion.
The study design, data collection, data analysis and interpretation, and manuscript writing and submission were performed by the authors.
The following participated in the BIG 02-98 Collaborative Group
Study chairs: J. Crown, P. Francis, M. Piccart-Gebhart.
Steering committee: M. Andersson, A. Balil, B. Boussard, M. Buyse, B. Bendahmane, J. Crown, A. Di Leo, S. Dolci, P. Francis, R. Gelber, J. Gutiérrez, R. Jakesz, S. Jamin, B. Nordenskjöld, M. Piccart-Gebhart, C. Straehle.
Independent data monitoring committee: K. Pritchard, P. Ravdin, L. J. Wei.
IDDI statistical centre: M. Buyse, E. Quinaux.
BIG Coordination: C. Straehle.
Austrian Breast and Colorectal Cancer Study Group: Austria—R. Jakesz, G. Altorjai, T. Bachleitner, R. Bartsch, P. Dubsky, F. Fitzal, M. Fridrik, M. Gnant, R. Greil, D. Kandioler, H. Matzinger, C. Menzel, B. Mlineritsch, U. Pluschnig, A. Reichenauer, S. Roka, H. Samonigg, S. Schoppmann, E. Sporn, H. Spoula, G. Steger, M. Stierer, S. Taucher, K. Tögel, C Wenzel, V. Wette.
Breast European Adjuvant Studies Team: Breast Office Jules Bordet Brussels—M. Piccart-Gebhart, S. Dolci, S. Jamin, M. Vincente, A. Di Leo, F. Ferreira, R. Giuliani, C. Bernard, E. Azambuja, V. D’Hondt, J-Y Leroy, L. Punzalan, J. Helwin, D. Antoine; Austria—C. Dittrich, G. Gastl, E. Kubista, P, Sevelda; Belgium—M. Piccart, F. Bastin, A. Bols, M. Borms, V. Cocquyt, J. Demol, L. Dirix, P. Gobert, D. Becquart, J.-P. Kains, J. Michel, R. Paridaens, C. Van Steenlandt, V. Richard, A. Tagnon, S. Brahms, T. Velu, L. Marcelis, H. Bondue, D. Verhoeven, J. Vermorken; Brazil—O. Feher, S. Cabral Filho, G. Amorim, G. Schwartsmann, J. Vinholes; Czech Republic—K. Petrakova, L. Petruzelka; Germany—C. Oberhoff, H.-G. Meerpohl, G. Gitsch; Israel—R. Epelbaum, R. Isacson, A. Shani, B. Uziely; Italy—M. Nardi, E. Galligioni, A. Santoro; Portugal—C. De Oliveira, I. Furtado, F. Pimentel; South Africa—L. Goedhals, B Leon Rapoport, C. Slabber; United Kingdom—C. Mulatero, C. Topham, J. Clarke, C. Wilson; Slovak Republic—D. Sorkovska, B. Lubomir.
Danish Breast Cancer Cooperative Group: Denmark—Department of Oncology, Rigshospitalet University Hospital: M. Andersson; Aalborg Hospital, Aarhus University: M. Ewertz; Roskilde Hospital: P Grundtvig Sorensen; Vejle Hospital: E. Jakobseen; Herlev University Hospital: C. Kamby; Naestved Hospital: P. Phillip; Odense University Hospital: S. Cold; Soenderborg Hospital: E. Lindegaard Madsen; Esbjerg Hospital: B. Bjerregaard.
Grupo Español de Investigacion en Cancer de Mama: Spain—E. Adrover, J. Alés, A. Arcusa, A. Balil, A. Barnadas, A. Fernández, C. Jara, J. Lizón, A. Lluch, A. Lozano, E. Mahillo, M. Margeli, M. Muñoz, A. Oltra, C. Picó, A. Rizo, P. Sánchez-Rovira.
Grupo Oncologico Cooperative Chileno De Investigacion: Chile—Clinica Las Condes, Santiago: J. Gutiérrez; Hospital San Juan de Dios, Santiago: K. Pena; Instituto nacional del Cancer, Santiago: R. Torres; Hospital San Borja, Santiago: C. Del Castillo; Hospital JJ Aguirre, Santiago: M. Fodor; Fundacion Arturo Lopez, Santiago: A. Majlis; Clinica Santa Maria, Santiago: L. Orlandi.
International Breast Cancer Study Group: Coordinating centre (Bern)—M. Castiglione-Gertsch, A. Hiltbrunner, G. Egli, M. Rabaglio, B. Ruepp, R. Studer, R. Maibach, M. Bachmann; Statistical centre (Boston)—R. Gelber, K. Price; Australian New Zealand Breast Cancer Trials Group Operations Office, Newcastle—J. Forbes, A. Coates, D. Lindsay, H. Badger, L. Boyes, S. McIlvenie, K. Hancock; National Health and Medical Research Council Clinical Trials Centre, Sydney—J. Simes; Australia—Peter MacCallum Cancer Centre, Melbourne: P. Francis; Bendigo Hospital: E. Abdi, R. Blum; Royal Melbourne Hospital and Western Hospital, Footscray: M. Green; Royal Perth Hospital: E. Bayliss; Royal Prince Alfred Hospital, Sydney: J. Beith; Newcastle Mater Hospital and Lingard Private Hospital: A. Bonaventura; Sir Charles Gairdiner Hospital, Perth: M. Byrne; Austin Health, Melbourne: M. Chipman, P. Mitchell, S. White; Canberra Hospital: P. Craft; Box Hill Hospital and Maroondah Hospital: J. Chirgwin; St George Hospital, Kogarah: P. De Souza; Royal Hobart Hospital, Tasmania: R. Lowenthal; Prince of Wales Hospital, Sydney: M. Friedlander; Ashford Cancer Centre: D. Kotasek; Andrew Love Cancer Centre, Geelong: R. McLennan; Liverpool Hospital, Sydney: E. Moylan; Royal Adelaide Hospital: I. Olver. S. Selva-Nayagam; Queen Elizabeth Hospital, Woodville: K. Pittman; Monash Medical Centre: G. Richardson, M. White; Alfred Hospital: M. Schwartz; St Vincent's Hospital Melbourne: R. Snyder; Princess Alexandra Hospital, Brisbane: E. Walpole; Mount Hospital Perth: G. Van Hazel; Royal Brisbane and Women's Hospital: R. Abraham, D. Wyld; Border Medical Oncology, Albury: C. Underhill; Frankston Hospital: V. Ganju; Flinders Medical Centre, South Australia: B. Koczwara; St Andrew's Hospital, Adelaide: T. Malden; Port Macquarie Base Hospital: S. Begbie; St John Of God Hospital, Subiaco: D. Ransom; Concord Repatriation General Hospital: A. Sullivan; Royal North Shore Hospital, St Leonards: D. Bell; Westmead Hospital: N. Wilcken, New Zealand—Auckland Hospital: V. Harvey; Dunedin Hospital: D. Perez; Christchurch Hospital: M. Jeffery; Palmerston North Hospital: S. Allan. Hungary—National Institute of Oncology, Budapest: I. Lang. Italy—Istituto Europeo di Oncologia, Milan: A. Goldhirsch; Ospedale Infermi, Rimini: A. Ravaioli; Centro di Riferimento Oncologico, Aviano: A. Veronesi. Slovenia—Institute of Oncology, Ljubljana: T. Cufer, South Africa—Sandton Oncology Centre, Johannesburg: D. Vorobiof; Groote Schuur Hospital and University of Cape Town, Cape Town: E. Murray. Spain—Hospital Universitario "12 de Octubre", Madrid: H. Cortes-Funes. Sweden—Mölndal Hospital, Mölndal: S. Holmberg; Sahlgrenska University Hospital, Göteborg: E. Ekman; Boras Hospital, Boras: J.-H. Svensson; Kungälvs Hospital, Kungälv: B. Lindberg; Varberg Hospital, Varberg: L.-G. Niklasson; Skaraborgs Hospital, Skövde: A. Nissborg, Switzerland—Swiss Group for Clinical Cancer Research: Kantonsspital St. Gallen, St Gallen: B. Thürlimann; Universitätsspital Zürich, Zürich: B. Pestalozzi; Kantonsspital Aarau, Aarau: A. Schönenberger; Inselspital, Bern: M. Fey; Centre Pluridisciplinaire d’Oncologie, Lausanne: L. Perey; University Hospital Basel, Basel: R. Herrmann; Spital Thun-Simmental AG, Thun: J. M. Lüthi; Institute of Oncology of Southern Switzerland, Bellinzona: O. Pagani; Rätisches Kantons-und Regionalspital, Chur: F. Egli; Hôpital Cantonal Universitaire, Geneva: H. Bonnefoi; Brust-Zentrum, Zürich: C. Rageth; Onkologische Praxis, Rheinfelden: K. Beretta.
Irish Clinical Oncology Research Group: Ireland—J. Crown, E. Egan, J. McCaffrey, L. Grogan, J. Kennedy, P. Calvert, G. Mullins, M. Jones, B. Moulton.
Swedish Breast Cancer Group: Sweden—Coordinating center, Universitettsjukhuset, Linkoping: G. Olsson; Universitetssjukhuset, Linkoping: B. Nordenskjöld; Norrlands universitetssjukhus Umeas: N. Bengtsson; Akademiska sjukhuset, Uppsala: P. Nygren; Centrallasarattet, Vasteras: J. Hansen; Lanssjukhuset, Gavle: P. Edlund; Centralsjukhuset, Karlstad: L. Malmberg; Malarsjukhuset, Eskilstuna: J.-E. Westlin; Universitetssjukhuset, Malmo: L. Tennvall-Nittby; Sjukhuset, Sundsvall: L. Carsson; Radiumhemmet, Stockholm: J. Bergh.
Trial pathologists: D. Larsimont, G. Viale, B. Gusterson.
sanofi-aventis staff: B. Boussard, B. Bendahmane, J.-F. Aussel, S. Olsen, Y. Chen.
Manuscript received May 16, 2007; revised September 21, 2007; accepted November 27, 2007.
Correspondence about this Article
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J Natl Cancer Inst 2008 100: 683.
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J Natl Cancer Inst 2008 100: 79.
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