Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial

Heikki Joensuu, Pirkko-Liisa Kellokumpu-Lehtinen, Riikka Huovinen, Arja Jukkola, Minna Tanner, Johan Ahlgren, Päivi Auvinen, Outi Lahdenperä, Kenneth Villman, Paul Nyandoto, Greger Nilsson, Paula Poikonen-Saksela, Vesa Kataja, Petri Bono, Jouni Junnila, Henrik Lindman, Heikki Joensuu, Pirkko-Liisa Kellokumpu-Lehtinen, Riikka Huovinen, Arja Jukkola, Minna Tanner, Johan Ahlgren, Päivi Auvinen, Outi Lahdenperä, Kenneth Villman, Paul Nyandoto, Greger Nilsson, Paula Poikonen-Saksela, Vesa Kataja, Petri Bono, Jouni Junnila, Henrik Lindman

Abstract

Purpose: Few data are available regarding the influence of adjuvant capecitabine on long-term survival of patients with early breast cancer.

Methods: The Finland Capecitabine Trial (FinXX) is a randomized, open-label, multicenter trial that evaluates integration of capecitabine to an adjuvant chemotherapy regimen containing a taxane and an anthracycline for the treatment of early breast cancer. Between January 27, 2004, and May 29, 2007, 1,500 patients with axillary node-positive or high-risk node-negative early breast cancer were accrued. The patients were randomly allocated to either TX-CEX, consisting of three cycles of docetaxel (T) plus capecitabine (X) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX, 753 patients), or to T-CEF, consisting of three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF, 747 patients). We performed a protocol-scheduled analysis of overall survival on the basis of approximately 15-year follow-up of the patients.

Results: The data collection was locked on December 31, 2020. By this date, the median follow-up time of the patients alive was 15.3 years (interquartile range, 14.5-16.1 years) in the TX-CEX group and 15.4 years (interquartile range, 14.8-16.0 years) in the T-CEF group. Patients assigned to TX-CEX survived longer than those assigned to T-CEF (hazard ratio 0.81; 95% CI, 0.66 to 0.99; P = .037). The 15-year survival rate was 77.6% in the TX-CEX group and 73.3% in the T-CEF group. In exploratory subgroup analyses, patients with estrogen receptor-negative cancer and those with triple-negative cancer treated with TX-CEX tended to live longer than those treated with T-CEF.

Conclusion: Addition of capecitabine to a chemotherapy regimen that contained docetaxel, epirubicin, and cyclophosphamide prolonged the survival of patients with early breast cancer.

Trial registration: ClinicalTrials.gov NCT00114816.

Conflict of interest statement

Heikki JoensuuEmployment: Orion CorporationStock and Other Ownership Interests: Orion Corporation, Sartar TherapiesHonoraria: Neutron Therpeutics, DecipheraConsulting or Advisory Role: Neutron Therapeutics, OrionPatents, Royalties, Other Intellectual Property: Sartar Therapeutics Riikka HuovinenHonoraria: RocheConsulting or Advisory Role: Roche, Lilly, Novartis, Pfizer, Gilead Minna TannerConsulting or Advisory Role: Roche, Pfizer, Novartis, Lilly, AstraZeneca, Pierre FabreSpeakers' Bureau: Novartis, Roche, AstraZeneca, Pfizer, LillyExpert Testimony: SOBI, Pfizer, Amgen, Novartis, Pierre Fabre Greger NilssonHonoraria: AstraZeneca, Bristol Myers SquibbConsulting or Advisory Role: Merck, Pierre Fabre Vesa KatajaEmployment: Kaiku HealthLeadership: Kaiku Health Petri BonoEmployment: TerveystaloLeadership: TerveystaloStock and Other Ownership Interests: TILT Biotherapeutics, Faron Pharmaceuticals, TerveystaloConsulting or Advisory Role: MSD Oncology, Ipsen, Faron Pharmaceuticals, Oncorena, TILT Biotherapeutics, EUSA pharma, Herantis Pharma Henrik LindmanHonoraria: Lilly, Novartis, AstraZeneca, Daiichi SankyoConsulting or Advisory Role: Lilly, Oasmia Pharmaceutical AB, MSD Oncology, Daiichi Sankyo, Novartis, Pierre Fabre, Seattle Genetics, BioNTechResearch Funding: Roche (Inst)No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
CONSORT diagram. CEF, cyclophosphamide and epirubicin plus fluorouracil; CEX, cyclophosphamide and epirubicin plus capecitabine; ITT, intention-to-treat patient population; T, docetaxel; TX, docetaxel plus capecitabine.
FIG 2.
FIG 2.
OS. The 5-year, 10-year, and 15-year survival rates are shown. Patients censored are indicated with a bar. CEF, cyclophosphamide and epirubicin plus fluorouracil; CEX, cyclophosphamide and epirubicin plus capecitabine; HR, hazard ratio; OS, overall survival; T, docetaxel; TX, docetaxel plus capecitabine. Adjuvant capecitabine added to conventional chemotherapy improves survival of patients with early breast cancer.
FIG 3.
FIG 3.
Exploratory analyses of OS in subgroups. CEF, cyclophosphamide and epirubicin plus fluorouracil; CEX, cyclophosphamide and epirubicin plus capecitabine; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; OS, overall survival; PR, progesterone receptor; T, docetaxel; TX, docetaxel plus capecitabine.
FIG A1.
FIG A1.
OS in selected subgroups: (A) patients with ER-positive and/or PR-positive , HER2-negative cancer, (B) patients with ER-positive and/or PR-positive, HER2-positive cancer, (C) patients with ER-negative, PR-negative, and HER2-positive cancer, and (D) patients with ER-negative, PR-negative, and HER2-negative cancer. Patients censored are indicated with a bar. CEF, cyclophosphamide and epirubicin plus fluorouracil; CEX, cyclophosphamide and epirubicin plus capecitabine; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; PR, progesterone receptor; OS, overall survival; T, docetaxel; TX, docetaxel plus capecitabine.

References

    1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Peto R Davies C et al. : Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379:432-444, 2012
    1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG) : Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: A patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet 393:1440-1452, 2019
    1. von Minckwitz G, Kummel S, Vogel P, et al. : Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: Phase III randomized GeparTrio trial. J Natl Cancer Inst 100:542-551, 2008
    1. von Minckwitz G, Rezai M, Loibl S, et al. : Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: Phase III GeparQuattro study. J Clin Oncol 28:2015-2023, 2010
    1. Bear HD, Tang G, Rastogi P, et al. : Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366:310-320, 2012
    1. Ohno S, Chow LW, Sato N, et al. : Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil–epirubicin–cyclophosphamide (FEC) in early-stage breast cancer: Exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy. Breast Cancer Res Treat 142:69-80, 2013
    1. Steger GG, Greil R, Lang A, et al. : Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: Final results of a randomized phase III study (ABCSG-24). Ann Oncol 25:366-371, 2014
    1. Möbus V, von Minckwitz G, Jackisch C, et al. : German adjuvant intergroup node-positive study (GAIN): A phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients. Ann Oncol 28:1803-1810, 2017
    1. Martin M, Ruiz Simon A, Ruiz Borrego M, et al. : Epirubicin plus cyclophosphamide followed by docetaxel versus epirubicin plus docetaxel followed by capecitabine as adjuvant therapy for node-positive early breast cancer: Results from the GEICAM/2003-10 study. J Clin Oncol 33:3788-3795, 2015
    1. O'Shaughnessy J, Koeppen H, Xiao Y, et al. : Patients with slowly proliferative early breast cancer have low five-year recurrence rates in a phase III adjuvant trial of capecitabine. Clin Cancer Res 21:4305-4311, 2015
    1. von Minckwitz G, Conrad B, Reimer T, et al. : A randomized phase 2 study comparing EC or CMF versus nab-paclitaxel plus capecitabine as adjuvant chemotherapy for nonfrail elderly patients with moderate to high-risk early breast cancer (ICE II-GBG 52). Cancer 121:3639-3648, 2015
    1. Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, et al. : Adjuvant capecitabine in combination with docetaxel, epirubicin, and cyclophosphamide for early breast cancer: The randomized clinical FinXX trial. JAMA Oncol 3:793-800, 2017
    1. Masuda N, Lee SJ, Ohtani S, et al. : Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017
    1. Cameron D, Morden JP, Canney P, et al. : Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): A multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol 18:929-945, 2017
    1. Muss HB, Polley MC, Berry DA, et al. : Randomized trial of standard adjuvant chemotherapy regimens versus capecitabine in older women with early breast cancer: 10-year update of the CALGB 49907 trial. J Clin Oncol 37:2338-2348, 2019
    1. Lluch A, Barrios CH, Torrecillas L, et al. : Phase III trial of adjuvant capecitabine after standard neo-/adjuvant chemotherapy in patients with early triple-negative breast cancer (GEICAM/200311_CIBOMA/2004-01). J Clin Oncol 38:203-213, 2020
    1. Li J, Yu K, Pang D, et al. : Adjuvant capecitabine with docetaxel and cyclophosphamide plus epirubicin for triple-negative breast cancer (CBCSG010): An open-label, randomized, multicenter, phase III trial. J Clin Oncol 38:1774-1784, 2020
    1. van Mackelenberg M, Seither F, Möbus V, et al. : Effects of capecitabine as part of neo-/adjuvant chemotherapy. A meta-analysis of individual patient data from 12 randomized trials including 15,457 patients. Cancer Res 80, 2020. (suppl 4; abstr GS1-07)
    1. Fujimoto-Ouchi K, Tanaka Y, Tominaga T: Schedule dependency of antitumor activity in combination therapy with capecitabine/5'-deoxy-5-fluorouridine and docetaxel in breast cancer models. Clin Cancer Res 7:1079-1086, 2001
    1. Endo M, Shinbori N, Fukase Y, et al. : Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5'-deoxy-5-fluorouridine by cyclophosphamide in mammary tumor models. Int J Cancer 83:127-134, 1999
    1. Myers RE, Johnston M, Pritchard K, et al. : Baseline staging tests in primary breast cancer: A practice guideline. CMAJ 164:1439-1444, 2001
    1. Ravaioli A, Pasini G, Polselli A, et al. : Staging of breast cancer: New recommended standard procedure. Breast Cancer Res Treat 72:53-60, 2002
    1. Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, et al. : Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: An open-label, randomised controlled trial. Lancet Oncol 10:1145-1151, 2009
    1. National Cancer Institute Cancer Therapy Evaluation Program: Common Terminology for Adverse Events v3.0.
    1. Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, et al. : Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: Final analysis of the randomized FinXX trial. J Clin Oncol 30:11-18, 2012
    1. Statistics Finland.
    1. Swedish Population Register.
    1. Petrelli F, Cabiddu M, Coinu A, et al. : Adjuvant dose-dense chemotherapy in breast cancer: A systematic review and meta-analysis of randomized trials. Breast Cancer Res Treat 151:251-259, 2015
    1. Bonilla L, Ben-Aharon I, Vidal L, et al. : Dose-dense chemotherapy in nonmetastatic breast cancer: A systematic review and meta-analysis of randomized controlled trials. J Natl Cancer Inst 102:1845-1854, 2010
    1. Cancer Genome Atlas Network : Comprehensive molecular portraits of human breast tumours. Nature 490:61-70, 2012
    1. Mayer IA, Zhao F, Arteaga CL, et al. : Randomized phase III postoperative trial of platinum-based chemotherapy versus capecitabine in patients with residual triple-negative breast cancer following neoadjuvant chemotherapy: ECOG-ACRIN EA1131 J Clin Oncol 39:2539-2551, 2021
    1. Tutt ANJ, Garber JE, Kaufman B, et al. : Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384:2394-2405, 2021
    1. He Q, Peng Y, Sun J, et al. : Platinum-based chemotherapy and immunotherapy in early triple-negative breast cancer: A meta-analysis and indirect treatment comparison. Front Oncol 11:693542, 2021
    1. Sawada N, Ishikawa T, Fukase Y, et al. : Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 4:1013-1019, 1998
    1. Denduluri N, Chavez-MacGregor M, Telli ML, et al. : Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol 36:2433-2443, 2018
    1. Cardoso F, Kyriakides S, Ohno S, et al. : Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 30:1674, 2019
    1. Prabhu JS, Korlimarla A, Desai K, et al. : A majority of low (1-10%) ER positive breast cancers behave like hormone receptor negative tumors. J Cancer 5:156-165, 2014

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi