Dose-dense Chemotherapy Versus Conventional Chemotherapy For Early Breast Cancer: A Systematic Review With Meta-analysis

Background: Despite the widespread acceptance of dose-dense (DD) regimens as adjuvant chemotherapy for early breast cancer (EBC), studies of efficacy offer contradictory findings. This systematic review evaluates the real impact of DD chemotherapy. Methods: Randomized controlled trials comparing conventional adjuvant chemotherapy versus a DD regimen for EBC patients were searched in electronic databases. Dose-dense regimens included the same drugs and total amount as conventional chemotherapy, but applied in shorter intervals. Meta-analyses were performed using a fixed-effects model. Hazard ratios (HRs) or odds ratios (ORs) were expressed with 95% confidence intervals (95% CI). The outcomes were overall survival (OS), disease-free survival (DFS), and toxicities. Analyses were conducted according to tumor hormone receptor expression, plus tests for interaction. Results: Four studies (3418 patients) were included. The meta-analysis demonstrated that DD therapy can improve DFS (3356 patients; HR = 0.83; 95% CI 0.73-0.95; p = 0.005), independent of hormone receptor expression status. There was no OS benefit with DD therapy (3356 patients; HR = 0.86; 95% CI 0.73-1.01; p = 0.06) irrespective of tumor hormone receptor status (OS in hormone-positive stratum HR = 0.94; 95% CI 0.74-1.21; OS in hormone-negative stratum HR = 0.78; 95% CI 0.62-0.99; interaction test p = 0.28). DD regimens caused a small increase in anemia and mucositis, but had no impact on cardiac events, leukemia or myelodysplasia. Conclusions: DD adjuvant chemotherapy can improve DFS of EBC patients with little impact on safety. However there is no clear benefit in OS. Further research may indicate if there is any impact on OS not presently seen due to small sample size, and which patients may derive greater benefit. © 2012 Elsevier Ltd.213343349Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials (2005) Lancet, 365, pp. 1687-1717. , EBCTCGSparano, J.A., Wang, M., Martino, S., Jones, V., Perez, E.A., Saphner, T., Weekly paclitaxel in the adjuvant treatment of breast cancer (2008) N Engl J Med, 358, pp. 1663-1671Burnell, M., Levine, M.N., Chapman, J.A., Bramwell, V., Gelmon, K., Walley, B., Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer (2010) J Clin Oncol, 28, pp. 77-82Albain, K.S., Barlow, W.E., Shak, S., Hortobagyi, G.N., Livingston, R.B., Yeh, I.T., Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial (2010) Lancet Oncol, 11, pp. 55-65Perou, C.M., Sorlie, T., Eisen, M.B., van de Rijn, M., Jeffrey, S.S., Rees, C.A., Molecular portraits of human breast tumours (2000) Nature, 406, pp. 747-752Blows, F.M., Driver, K.E., Schmidt, M.K., Broeks, A., van Leeuwen, F.E., Wesseling, J., Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies (2010) PLoS Med, 7, pp. e1000279Jonsson, G., Staaf, J., Vallon-Christersson, J., Ringner, M., Holm, K., Hegardt, C., Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics (2010) Breast Cancer Res, 12, pp. R42von Minckwitz, G., Untch, M., Nuesch, E., Loibl, S., Kaufmann, M., Kummel, S., Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials (2011) Breast Cancer Res Treat, 125, pp. 145-156Norton, L., Simon, R., Brereton, H.D., Bogden, A.E., Predicting the course of Gompertzian growth (1976) Nature, 264, pp. 542-545Citron, M.L., Berry, D.A., Cirrincione, C., Hudis, C., Winer, E.P., Gradishar, W.J., Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741 (2003) J Clin Oncol, 21, pp. 1431-1439Venturini, M., Del Mastro, L., Aitini, E., Baldini, E., Caroti, C., Contu, A., Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial (2005) J Natl Cancer Inst, 97, pp. 1724-1733Parmar, M.K., Torri, V., Stewart, L., Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints (1998) Stat Med, 17, pp. 2815-2834Tierney, J.F., Stewart, L.A., Ghersi, D., Burdett, S., Sydes, M.R., Practical methods for incorporating summary time-to-event data into meta-analysis (2007) Trials, 8, p. 16Sterne, J.A.C., Egger, M., Smith, G.D., Investigating and dealing with publication and other biases (2001) Systematic reviews in health care: metaanalysis in context, , BMJ Publication Group, London, M. Egger, G.D. Smith, D.G. Altman (Eds.)DerSimonian, R., Laird, N., Meta-analysis in clinical trials (1986) Control Clin Trials, 7, pp. 177-188Higgins, J.P., Thompson, S.G., Deeks, J.J., Altman, D.G., Measuring inconsistency in meta-analyses (2003) BMJ, 327, pp. 557-560Altman, D.G., Bland, J.M., Interaction revisited: the difference between two estimates (2003) BMJ, 326, p. 219Liberati, A., Altman, D.G., Tetzlaff, J., Mulrow, C., Gotzsche, P.C., Ioannidis, J.P., The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration (2009) PLoS Med, 6, pp. e1000100Wildiers, H., Dirix, L., Neven, P., Prove, A., Clement, P., Squifflet, P., Delivery of adjuvant sequential dose-dense FEC-Doc to patients with breast cancer is feasible, but dose reductions and toxicity are dependent on treatment sequence (2009) Breast Cancer Res Treat, 114, pp. 103-112Budd, G.T., Barlow, W.E., Moore, H.C.F., Hobday, T.J., Stewart, J.A., Isaacs, C., First analysis of SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early breast cancer (2011) 2011 ASCO Annual Meeting., p. 29Fountzilas, G., Dafni, U., Gogas, H., Linardou, H., Kalofonos, H.P., Briasoulis, E., Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00 (2008) Ann Oncol, 19, pp. 853-860Brain, E., Levy, C., Serin, D., Roché, H., Spielmann, M., Delva, R., High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer (2011) Br J Cancer, 105, pp. 1480-1486Baldini, E., Gardin, G., Giannessi, P.G., Evangelista, G., Roncella, M., Prochilo, T., Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer (2003) Ann Oncol, 14, pp. 227-232Jones, R.L., Walsh, G., Ashley, S., Chua, S., Agarwal, R., O'Brien, M., A randomised pilot phase II study of doxorubicin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) given 2 weekly with pegfilgrastim (accelerated) vs 3 weekly (standard) for women with early breast cancer (2009) Br J Cancer, 100, pp. 305-310Hudis, C., Citron, M.L., Berry, D., Cirrincione, C., Gradishar, W., Davidson, N.E., Five year follow-up of INT C9741: dose-dense (DD) chemotherapy (CRx) is safe and effective (2005) Breast Cancer Res Treat, 94 (SUPPL. 1)Hammond, M.E., Hayes, D.F., Dowsett, M., Allred, D.C., Hagerty, K.L., Badve, S., American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (2010) J Clin Oncol, 28, pp. 2784-2795Hugh, J., Hanson, J., Cheang, M.C., Nielsen, T.O., Perou, C.M., Dumontet, C., Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial (2009) J Clin Oncol, 27, pp. 1168-1176Penault-Llorca, F., Andre, F., Sagan, C., Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer (2009) J Clin Oncol, 27, pp. 2809-2815Bonilla, L., Ben-Aharon, I., Vidal, L., Gafter-Gvili, A., Leibovici, L., Stemmer, S.M., Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials (2010) J Natl Cancer Inst, 102, pp. 1845-1854Perez, D.J., Harvey, V.J., Robinson, B.A., Atkinson, C.H., Dady, P.J., Kirk, A.R., A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer (1991) J Clin Oncol, 9, pp. 2148-215