Addition of zoledronic acid to consolidation chemotherapy in Ewing sarcoma-EURO EWING 2012 (EE2012): an international, open-label, randomised controlled phase III trial

Brennan Bernadette; Laura Kirton; Perrine Marec-Bérard; Nathalie Gaspar; Valerie Laurence; Javier Martín-Broto; Hans Gelderblom; Cormac Owens; Jennifer Anderton; Sandra J Strauss; Jane Wingrove; Veronica Moroz; Jeremy Whelan; Lisa L. Hjalgrim; Keith Wheatley; Piers Gaunt

doi:10.1038/s41416-026-03367-4

Addition of zoledronic acid to consolidation chemotherapy in Ewing sarcoma-EURO EWING 2012 (EE2012): an international, open-label, randomised controlled phase III trial

Brennan Bernadette^*
, Laura Kirton
, Perrine Marec-Bérard
, Nathalie Gaspar
, Valerie Laurence
, Javier Martín-Broto
, Hans Gelderblom
, Cormac Owens
, Jennifer Anderton
, Sandra J Strauss
, Jane Wingrove
, Veronica Moroz
, Jeremy Whelan
, Lisa L. Hjalgrim
, Keith Wheatley
, Piers Gaunt

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Background

Pre-clinical data demonstrated anti-tumour effect in Ewing sarcoma (ES) for zoledronic acid. This provided the rationale for the second randomisation (R2) in the EURO EWING 2012 (EE2012) trial, whether the addition of zoledronic acid to consolidation chemotherapy improved clinical outcomes.

Methods

EE2012 was a European academic, open-label, randomised controlled phase III clinical trial. Patients with ES or Ewing-like sarcomas were included (R1). Patients meeting the R2 eligibility criteria (age 5–49 years) were randomised (1:1) to receive either nine cycles of zoledronic acid or no zoledronic acid with the R1 allocated consolidation chemotherapy. Primary and secondary outcome measures were event-free and overall survival, respectively.

Findings

Between 12-Aug-2014 and 20-Sep-2019, of the 640 R1 patients, 272 patients (136 in each group) were enrolled to R2. Median follow-up was 5.5 years. Three-year EFS was 59% in the zoledronic acid group and 57% in the no zoledronic acid group (adjusted hazard ratio = 0·92 (95% CI: 0·64, 1.31), p = 0.632). Three-year OS was 75% for both groups (adjusted hazard ratio = 0.84 (95% CI: 0.56, 1.25), p = 0.386).

Conclusion

Adding zoledronic acid did not improve clinical outcomes in ES.

Trial registration

The trial was prospectively registered with EudraCT 2012-002107-17 and ISRCTN 54540667.

Original language	English
Number of pages	10
Journal	British Journal of Cancer
DOIs	https://doi.org/10.1038/s41416-026-03367-4
Publication status	Published - 15 Mar 2026

Bibliographical note

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Development and internal validation of prognostic models for event-free survival in newly diagnosed Ewing sarcoma patients based on routinely collected clinical characteristics from the European randomised controlled trial, EE2012
Kirton, L., Riley, R., Gaunt, P., Brennan, B. & Snell, K., 20 Dec 2024, In: BMJ Open. 14, 12, 6 p., e082941.
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Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial
Brennan, B., Kirton, L., Marec-Bérard, P., Gaspar, N., Laurence, V., Martín-Broto, J., Sastre, A., Gelderblom, H., Owens, C., Fenwick, N., Strauss, S., Moroz, V., Whelan, J. & Wheatley, K., 29 Oct 2022, In: The Lancet. 400, 10362, p. 1513-1521 9 p.
Research output: Contribution to journal › Article › peer-review
International randomised controlled trial for the treatment of newly diagnosed EWING sarcoma family of tumours - EURO EWING 2012 Protocol
Anderton, J., Moroz, V., Marec-Bérard, P., Gaspar, N., Laurence, V., Martín-Broto, J., Sastre, A., Gelderblom, H., Owens, C., Kaiser, S., Fernández-Pinto, M., Fenwick, N., Evans, A., Strauss, S., Whelan, J., Wheatley, K. & Brennan, B., 17 Jan 2020, In: Trials. 21, 1, 96.
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(102MTHS)International Randomised Controlled Trial for the Treatment of Newly Diagnosed Ewing's Sarcoma Family of Tumours (Euro Ewing's 2012 - EE2012)
Kearns, P. (Co-Investigator), Wheatley, K. (Co-Investigator), Gaunt, P. (Principal Investigator) & Kirton, L. (Researcher)
Cancer Research UK
1/05/12 → 30/08/24
Project: Research

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Bernadette, B., Kirton, L., Marec-Bérard, P., Gaspar, N., Laurence, V., Martín-Broto, J., Gelderblom, H., Owens, C., Anderton, J., Strauss, S. J., Wingrove, J., Moroz, V., Whelan, J., Hjalgrim, L. L., Wheatley, K., & Gaunt, P. (2026). Addition of zoledronic acid to consolidation chemotherapy in Ewing sarcoma-EURO EWING 2012 (EE2012): an international, open-label, randomised controlled phase III trial. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03367-4

@article{f4a245b589e44119abadb94ebaa315de,

title = "Addition of zoledronic acid to consolidation chemotherapy in Ewing sarcoma-EURO EWING 2012 (EE2012): an international, open-label, randomised controlled phase III trial",

abstract = "BackgroundPre-clinical data demonstrated anti-tumour effect in Ewing sarcoma (ES) for zoledronic acid. This provided the rationale for the second randomisation (R2) in the EURO EWING 2012 (EE2012) trial, whether the addition of zoledronic acid to consolidation chemotherapy improved clinical outcomes. MethodsEE2012 was a European academic, open-label, randomised controlled phase III clinical trial. Patients with ES or Ewing-like sarcomas were included (R1). Patients meeting the R2 eligibility criteria (age 5–49 years) were randomised (1:1) to receive either nine cycles of zoledronic acid or no zoledronic acid with the R1 allocated consolidation chemotherapy. Primary and secondary outcome measures were event-free and overall survival, respectively. FindingsBetween 12-Aug-2014 and 20-Sep-2019, of the 640 R1 patients, 272 patients (136 in each group) were enrolled to R2. Median follow-up was 5.5 years. Three-year EFS was 59\% in the zoledronic acid group and 57\% in the no zoledronic acid group (adjusted hazard ratio = 0·92 (95\% CI: 0·64, 1.31), p = 0.632). Three-year OS was 75\% for both groups (adjusted hazard ratio = 0.84 (95\% CI: 0.56, 1.25), p = 0.386). ConclusionAdding zoledronic acid did not improve clinical outcomes in ES. Trial registrationThe trial was prospectively registered with EudraCT 2012-002107-17 and ISRCTN 54540667.",

author = "Brennan Bernadette and Laura Kirton and Perrine Marec-B{\'e}rard and Nathalie Gaspar and Valerie Laurence and Javier Mart{\'i}n-Broto and Hans Gelderblom and Cormac Owens and Jennifer Anderton and Strauss, \{Sandra J\} and Jane Wingrove and Veronica Moroz and Jeremy Whelan and Hjalgrim, \{Lisa L.\} and Keith Wheatley and Piers Gaunt",

note = "{\textcopyright} 2026. The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2026",

month = mar,

day = "15",

doi = "10.1038/s41416-026-03367-4",

language = "English",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Cancer Research UK",

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Bernadette, B, Kirton, L, Marec-Bérard, P, Gaspar, N, Laurence, V, Martín-Broto, J, Gelderblom, H, Owens, C, Anderton, J, Strauss, SJ, Wingrove, J, Moroz, V, Whelan, J, Hjalgrim, LL, Wheatley, K & Gaunt, P 2026, 'Addition of zoledronic acid to consolidation chemotherapy in Ewing sarcoma-EURO EWING 2012 (EE2012): an international, open-label, randomised controlled phase III trial', British Journal of Cancer. https://doi.org/10.1038/s41416-026-03367-4

TY - JOUR

T1 - Addition of zoledronic acid to consolidation chemotherapy in Ewing sarcoma-EURO EWING 2012 (EE2012)

T2 - an international, open-label, randomised controlled phase III trial

AU - Bernadette, Brennan

AU - Kirton, Laura

AU - Marec-Bérard, Perrine

AU - Gaspar, Nathalie

AU - Laurence, Valerie

AU - Martín-Broto, Javier

AU - Gelderblom, Hans

AU - Owens, Cormac

AU - Anderton, Jennifer

AU - Strauss, Sandra J

AU - Wingrove, Jane

AU - Moroz, Veronica

AU - Whelan, Jeremy

AU - Hjalgrim, Lisa L.

AU - Wheatley, Keith

AU - Gaunt, Piers

PY - 2026/3/15

Y1 - 2026/3/15

N2 - BackgroundPre-clinical data demonstrated anti-tumour effect in Ewing sarcoma (ES) for zoledronic acid. This provided the rationale for the second randomisation (R2) in the EURO EWING 2012 (EE2012) trial, whether the addition of zoledronic acid to consolidation chemotherapy improved clinical outcomes. MethodsEE2012 was a European academic, open-label, randomised controlled phase III clinical trial. Patients with ES or Ewing-like sarcomas were included (R1). Patients meeting the R2 eligibility criteria (age 5–49 years) were randomised (1:1) to receive either nine cycles of zoledronic acid or no zoledronic acid with the R1 allocated consolidation chemotherapy. Primary and secondary outcome measures were event-free and overall survival, respectively. FindingsBetween 12-Aug-2014 and 20-Sep-2019, of the 640 R1 patients, 272 patients (136 in each group) were enrolled to R2. Median follow-up was 5.5 years. Three-year EFS was 59% in the zoledronic acid group and 57% in the no zoledronic acid group (adjusted hazard ratio = 0·92 (95% CI: 0·64, 1.31), p = 0.632). Three-year OS was 75% for both groups (adjusted hazard ratio = 0.84 (95% CI: 0.56, 1.25), p = 0.386). ConclusionAdding zoledronic acid did not improve clinical outcomes in ES. Trial registrationThe trial was prospectively registered with EudraCT 2012-002107-17 and ISRCTN 54540667.

AB - BackgroundPre-clinical data demonstrated anti-tumour effect in Ewing sarcoma (ES) for zoledronic acid. This provided the rationale for the second randomisation (R2) in the EURO EWING 2012 (EE2012) trial, whether the addition of zoledronic acid to consolidation chemotherapy improved clinical outcomes. MethodsEE2012 was a European academic, open-label, randomised controlled phase III clinical trial. Patients with ES or Ewing-like sarcomas were included (R1). Patients meeting the R2 eligibility criteria (age 5–49 years) were randomised (1:1) to receive either nine cycles of zoledronic acid or no zoledronic acid with the R1 allocated consolidation chemotherapy. Primary and secondary outcome measures were event-free and overall survival, respectively. FindingsBetween 12-Aug-2014 and 20-Sep-2019, of the 640 R1 patients, 272 patients (136 in each group) were enrolled to R2. Median follow-up was 5.5 years. Three-year EFS was 59% in the zoledronic acid group and 57% in the no zoledronic acid group (adjusted hazard ratio = 0·92 (95% CI: 0·64, 1.31), p = 0.632). Three-year OS was 75% for both groups (adjusted hazard ratio = 0.84 (95% CI: 0.56, 1.25), p = 0.386). ConclusionAdding zoledronic acid did not improve clinical outcomes in ES. Trial registrationThe trial was prospectively registered with EudraCT 2012-002107-17 and ISRCTN 54540667.

U2 - 10.1038/s41416-026-03367-4

DO - 10.1038/s41416-026-03367-4

M3 - Article

C2 - 41832299

SN - 0007-0920

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

Addition of zoledronic acid to consolidation chemotherapy in Ewing sarcoma-EURO EWING 2012 (EE2012): an international, open-label, randomised controlled phase III trial

Abstract

Bibliographical note

Access to Document

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Research output

Development and internal validation of prognostic models for event-free survival in newly diagnosed Ewing sarcoma patients based on routinely collected clinical characteristics from the European randomised controlled trial, EE2012

Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial

International randomised controlled trial for the treatment of newly diagnosed EWING sarcoma family of tumours - EURO EWING 2012 Protocol

Projects

(102MTHS)International Randomised Controlled Trial for the Treatment of Newly Diagnosed Ewing's Sarcoma Family of Tumours (Euro Ewing's 2012 - EE2012)

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