Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial.

Autor:	Velikova G; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds Cancer Centre, St James's University Hospital, Leeds, UK. Electronic address: g.velikova@leeds.ac.uk., Morden JP; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds Cancer Centre, St James's University Hospital, Leeds, UK., Haviland JS; Institute of Cancer Research Clinical Trials and Statistics Unit, Institute of Cancer Research, London, UK., Emery C; Institute of Cancer Research Clinical Trials and Statistics Unit, Institute of Cancer Research, London, UK., Barrett-Lee P; Department of Oncology, Velindre University NHS Trust, Cardiff, UK., Earl H; Department of Oncology, University of Cambridge, Cambridge, UK; NIHR Cambridge Biomedical Research Centre, Cambridge, UK., Bloomfield D; Department of Oncology, University Hospitals Sussex, Brighton, UK., Brunt AM; School of Medicine, University of Keele, Keele, UK; Department of Oncology, University Hospitals of North Midlands, Stoke-on-Trent, UK., Canney P; Beatson Oncology Center, Glasgow, UK., Coleman R; Department of Oncology, Weston Park Hospital, Sheffield, UK., Verrill M; Department of Oncology, Northern Centre for Cancer Care, Freeman Hospital, Newcastle, UK., Wardley A; Outreach Research and Innovation Group, Manchester, UK., Bertelli G; Department of Oncology, University Hospitals Sussex, Brighton, UK., Ellis P; King's College London and Leaders in Oncology Care, London, UK., Stein R; University College London Hospitals, London, UK., Bliss JM; Institute of Cancer Research Clinical Trials and Statistics Unit, Institute of Cancer Research, London, UK., Cameron D; University of Edinburgh Cancer Centre, Institute of Genetics and Cancer, Western General Hospital, Edinburgh, UK.
Jazyk:	angličtina
Zdroj:	The Lancet. Oncology [Lancet Oncol] 2023 Dec; Vol. 24 (12), pp. 1359-1374. Date of Electronic Publication: 2023 Nov 02.
DOI:	10.1016/S1470-2045(23)00460-6
Abstrakt:	Background: Adjuvant chemotherapy for patients with early breast cancer improves outcomes but its toxicity affects patients' quality of life (QOL). The UK TACT2 trial investigated whether accelerated epirubicin improves time to recurrence and if oral capecitabine is non-inferior to cyclophosphamide, methotrexate, and fluorouracil (CMF) for efficacy with less toxicity. Results showed no benefit for accelerated epirubicin and capecitabine was non-inferior. As part of the QOL substudy, we aimed to assess the effect of chemotherapies on psychological distress, physical symptoms, and functional domains. Methods: TACT2 was a multicentre, phase 3, open-label, parallel-group, randomised, controlled trial done in 129 UK centres. Participants were aged 18 years or older with histologically confirmed node-positive or high-risk node-negative invasive primary breast cancer, who had undergone complete excision, and due to receive adjuvant chemotherapy. Patients were randomly assigned (1:1:1:1) to four cycles of 100 mg/m 2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either CMF (600 mg/m 2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m 2 orally on days 1-14; 40 mg/m 2 methotrexate intravenously on days 1 and 8; and 600 mg/m 2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m 2 capecitabine (1250 mg/m 2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs 1-3 vs ≥4), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). QOL was one of the secondary outcomes and is reported here. All patients from a subset of 44 centres were invited to complete QOL questionnaires (Hospital Anxiety and Depression Scale [HADS] and European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire 30-item core module [QLQ-C30] and Quality of Life Questionnaire breast module [QLQ-BR23]) at baseline, end of standard or accelerated epirubicin, end of CMF or capecitabine, and at 12 and 24 months after randomisation. The QOL substudy prespecified two coprimary QOL outcomes assessed in the intention-to-treat population: overall QOL (reported elsewhere) and HADS total score. Prespecified secondary QOL outcomes were EORTC QLQ-C30 subscales of physical function, role function, and fatigue and EORTC QLQ-BR23 subscales of sexual function and systemic therapy side-effects. This trial is registered with ISRCTN, ISRCTN68068041, and ClinicalTrials.gov, NCT00301925. Findings: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (20 [0·5%] of whom were male) were enrolled in TACT2; 1281 (85·8%) of 1493 eligible patients were included in the QOL substudy. Eight (0·6%) participants in the QOL substudy were male and 1273 (99·4%) were female. Median follow-up was 85·6 months (IQR 80·6-95·9). Analysis was performed on the complete QOL dataset (as of Sept 15, 2011) when all participants had passed the 24-month timepoint. Prerandomisation questionnaires were completed by 1172 (91·5%) patients and 1179 (92·0%) completed at least one postrandomisation questionnaire. End-of-treatment HADS depression score (p=0·0048) and HADS total change score (p=0·0093) were worse for CMF versus capecitabine. Accelerated epirubicin led to worse physical function (p=0·0065), role function (p<0·0001), fatigue (p=0·0002), and systemic side-effects (p=0·0001), but not sexual function (p=0·36), compared with standard epirubicin during treatment, but the effect did not persist. Worse physical function (p=0·0048), sexual function (p=0·0053), fatigue (p<0·0001), and systemic side-effects (p<0·0001), but not role functioning (p=0·013), were seen for CMF versus capecitabine at end of treatment; these differences persisted at 12 months and 24 months. Interpretation: Accelerated epirubicin was associated with worse QOL than was standard epirubicin but only during treatment. These findings will help patients and clinicians make an informed choice about accelerated chemotherapy. CMF had worse QOL effects than did capecitabine, which were persistent for 24 months. The favourable capecitabine QOL compared with CMF supports its use as an adjuvant option after neoadjuvant chemotherapy in patients with triple-negative breast cancer. Funding: Cancer Research UK, Amgen, Pfizer, and Roche. Competing Interests: Declaration of interests GV has received support for the present manuscript from the University of Leeds (payment for time working on manuscript); personal fees from Pfizer, Roche, Eisai, Novartis, Sanofi, and Seagen (none related to the manuscript); and was a member of the European Organisation for Research and Treatment of Cancer board of directors (not related to this manuscript). RC has received personal fees from Sanofi, ACE Oncology, Amgen, and Beigene; has patents planned, issued, or pending with Inbiomotion; personal fees from AstraZeneca; and stock options in Inbiomotion (biomarker in development). MV has received institutional grants from AstraZeneca, Genomic Health, Novartis, Pfizer, and Roche; personal fees from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead, Lilly, Novartis, Pfizer, Roche, and Seagen; and received personal fees for advisory board work for AstraZeneca, Daiichi-Sankyo, Exact Sciences, Gilead, Lilly, Merck, Novartis, Pfizer, Roche, and Seagen. AW has received National Institute for Health Research (NIHR) Health Technology Assessment and NIHR institutional grants. RS has received a grant from NIHR (salary support). JMB has received support for the present manuscript from Cancer Research UK (research costs to the clinical trials offices); educational grants funding from Roche, Amgen, and Pfizer; and institutional grants from AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Novartis (previously GSK), Eli Lilly, Janssen-Cilag, and Clovis Oncology. DC has received personal fees from Aptitude Health, Pfizer, Celldex Therapeutics, Carnall Farrar, AstraZeneca, Celgene, Eli Lilly, Roche, Novartis, Merck Sharp & Dohme, PUMA Biotechnology, F Hoffmann-La Roche, Clovis Oncology, Daiichi Sankyo, Eisai, Exact Therapeutics, Genentech, GSK, ICON Clinical Research, Prima BioMED, RTI Health Solutions, Synthon Biopharmaceuticals BV (name changed to Byondis in April, 2020), Succinct Medical Communications, Seagen, Sanofi, Sapience Therapeutics, Bexon/Zymeworks Biopharmaceuticals, NexGen, and IQVIA; institutional grants from Cancer Research UK, Health Technology Assessment, Breast International Group, Breast Cancer Institute, and European Cancer Organisation. All other authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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