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Clinical Studies

Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: final long-term results of the Hellenic Cooperative Oncology Group Phase III HE10/05 Trial

British Journal of Cancer volume 127, pages 695–703 (2022)Cite this article

Subjects

Abstract

Background

Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation.

Methods

Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease.

Results

At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms.

Conclusions

Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period.

Trial registration

Australian New Zealand Clinical Trials Registry ACTRN12610000151033.

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Fig. 1: Kaplan-Meier curves with respect to DFS and OS.
Fig. 2: Distribution of relapses over time.
Fig. 3

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Data availability

All data are available upon request.

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Acknowledgements

The authors are grateful to all patients and their families for their trust and participation in the trial. The authors wish to thank Dimitra Katsala for monitoring the study, Maria Moschoni for coordinating the data management and Stella Dallidou for secretarial assistance. This work has been presented in part at the 2021 San Antonio Breast Cancer Symposium, Texas, US.

Funding

The study was supported by a Hellenic Cooperative Oncology Group internal research grant (HE TRANS_BR).

Author information

Authors and Affiliations

  1. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

    Flora Zagouri, Christos Papadimitriou & Αngeliki Andrikopoulou

  2. Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece

    Georgia-Angeliki Koliou

  3. Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece

    Foteinos Dimitrakopoulos & Angelos Koutras

  4. Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece

    Ioannis Binas

  5. Department of Medical Oncology, Hippokration Hospital, Athens, Greece

    Pavlos Papakostas

  6. Second Department of Prop. Surgery, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

    Christos Markopoulos

  7. Breast Unit, Metropolitan Hospital, Piraeus, Greece

    Vasileios Venizelos

  8. Breast Unit, IASO, General Maternity and Gynecology Clinic, Athens, Greece

    Grigorios Xepapadakis

  9. Department of Medical Oncology, 424 Army General Hospital, Thessaloniki, Greece

    Charisios Karanikiotis

  10. Section of Medical Oncology, Department of Internal Medicine, Attikon University Hospital, Faculty of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

    Amanda Psyrri

  11. First Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece

    Dimitrios Bafaloukos

  12. Second Department of Medical Oncology, Hygeia Hospital, Athens, Greece

    Paris Kosmidis

  13. Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece

    Gerasimos Aravantinos

  14. Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece

    Eleni Res

  15. Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece

    Davide Mauri

  16. Hematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Anna Koumarianou

  17. Pathology Department, Metropolitan Hospital, Piraeus, Greece

    Kalliopi Petraki

  18. Pathology Department, Agii Anargiri Cancer Hospital, Athens, Greece

    Anna Tsipoura

  19. Oncology Section, Second Department of Internal Medicine, Hippokratio” Hospital, Athens, Greece

    Dimitrios Pectasides

  20. First Department of Medicine, Laiko General Hospital, University of Athens, Medical School, Athens, Greece

    Helen Gogas

  21. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece

    George Fountzilas

  22. Aristotle University of Thessaloniki, Thessaloniki, Greece

    George Fountzilas

  23. Department of Medical Oncology, German Oncology Center, Limassol, Cyprus

    George Fountzilas

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  1. Flora Zagouri
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Contributions

Flora Zagouri: conceptualisation, resources and writing—original draft. Georgia-Angeliki Koliou: formal analysis and writing—original draft. Foteinos Dimitrakopoulos: resources and writing—original draft. Christos Papadimitriou: resources and writing—review and editing. Ioannis Binas: resources and writing—review and editing. Angelos Koutras: resources and writing—review and editing. Pavlos Papakostas: resources and writing—review and editing. Christos Markopoulos: resources and writing—review and editing. Vasileios Venizelos: resources and writing—review and editing. Grigorios Xepapadakis: resources and writing—review and editing. Angeliki Andrikopoulou: resources and writing—review and editing. Charisios Karanikiotis: resources and writing—review and editing. Amanda Psyrri: resources and writing—review and editing. Dimitrios Bafaloukos: resources and writing—review and editing. Paris Kosmidis: resources and writing—review and editing. Gerasimos Aravantinos: resources and writing—review and editing. Eleni Res: resources and writing—review and editing. Davide Mauri: resources and writing—review and editing. Anna Koumarianou: resources and writing—review and editing. Kalliopi Petraki: resources and writing—review and editing. Anna Tsipoura: resources and writing—review and editing. Dimitrios Pectasides: resources and writing—review and editing. Helen Gogas: resources and writing—review and editing. George Fountzilas: conceptualisation, supervision and writing—original draft.

Corresponding author

Correspondence to Flora Zagouri.

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Competing interests

FZ: Honoraria and advisory role: AstraZeneca, Daiichi, Eli-Lilly, Merck, Novartis, Pfizer and Roche. CP: Honoraria and advisory role: Novartis, AstraZeneca, Genesis, MSD, Amgen, Pfizer, Merck and Roche. Research grants: BMS and Roche. AK: consulting or advisory role: Novartis, Roche, Genesis, AstraZeneca. Speaker’s bureau: GSK. Travel: Sanofi-Aventis, Astellas, Genesis, Amgen, BMS, Merck Serono. PP: advisory role: Roche, Merck, Genesis Pharmaceuticals, Honoraria: Roche, Merck. AP: consulting or advisory role: Amgen, Merck Serono, Roche, BMS, AstraZeneca, MSD, Honoraria: Amgen, Merck Serono, Roche, BMS, AstraZeneca, MSD. Research funds: BMS Kura. PK: Honoraria: Novartis, MSD, Pfizer. Travel: Pfizer, MSD, Genesis. GA: advisory boards: Novartis, BMS, Roche Hellas, Astra Zeneca, Sanofi, Amgen, Genesis Pharma, Merck, Pfizer. ER: consulting or advisory role: Novartis; Honoraria: Novartis; Travel: Genesis Pharmaceuticals, Pfizer, Roche, Bristol-Myers Squibb, Genekor. AK: Advisory Role: Genesis Pharma. Honoraria: Pfizer. Speaker’s bureau: Roche. Research funding: Merck. Travel: MSD. Educational grants: Novartis, Pfizer, Merck, Roche, BMS, MSD, Genesis, and Ipsen. DP: advisory role: Roche, MSD, Astellas. Honoraria: Roche, MSD, Astellas. HG: Advisory Role: Bristol-Myers Squibb, MSD Oncology, Amgen, Novartis, Roche, Pierre-Fabre, Honoraria: Bristol-Myers Squibb, MSD Oncology, Roche, Amgen, Novartis, research funding (institution): Bristol-Myers Squibb, Roche, MSD Oncology, Travel: Roche, Bristol-Myers Squibb. George Fountzilas: Advisory Board of Pfizer, Sanofi and Roche. Honoraria from AstraZeneca. Stock ownership: Genprex, Daiichi Sankyo, RFL Holdings, Formycon. The remaining authors declare no competing interests.

Ethics approval and consent to participate

All patients provided written informed consent before participating in the study. The clinical protocol was approved by the Institutional Review Boards in participating centres, by the National Organization for Medicines and by the National Ethics Committee and was registered in the Australian New Zealand Clinical Trials Registry (ACTRN12610000151033). The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki.

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Distribution of the number of relapses over years by molecular subtype.

41416_2022_1846_MOESM4_ESM.jpg

Swimmer plot showing the time to death caused by cardiac events. Each bar represents one patient in study who experienced a cardiac event that led to death. Bar lengths represent study follow-up time

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Zagouri, F., Koliou, GA., Dimitrakopoulos, F. et al. Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: final long-term results of the Hellenic Cooperative Oncology Group Phase III HE10/05 Trial. Br J Cancer 127, 695–703 (2022). https://doi.org/10.1038/s41416-022-01846-y

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