Intraoperative ketorolac in high-risk breast cancer patients: A prospective, randomized, placebo-controlled clinical trial

Patrice Forget; Gauthier Bouche; Francois P. Duhoux; Pierre G. Coulie; Jan Decloedt; Alain Dekleermaker; Jean-Edouard Guillaume; Marc Ledent; Jean-Pascal Machiels; Véronique Mustin; Walter Swinnen; Aline van Maanen; Lionel Vander Essen; Jean-Christophe Verougstraete; Marc De Kock; Martine Berliere

doi:10.1371/journal.pone.0225748

Intraoperative ketorolac in high-risk breast cancer patients: A prospective, randomized, placebo-controlled clinical trial

Patrice Forget^* (Corresponding Author), Gauthier Bouche, Francois P. Duhoux, Pierre G. Coulie, Jan Decloedt, Alain Dekleermaker, Jean-Edouard Guillaume, Marc Ledent, Jean-Pascal Machiels, Véronique Mustin, Walter Swinnen, Aline van Maanen, Lionel Vander Essen, Jean-Christophe Verougstraete, Marc De Kock, Martine Berliere

^*Corresponding author for this work

Applied Health Sciences

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Abstract

Background
Ketorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival.

Methods
The KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival.

Findings
Between February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years.

At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65–2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34–3.51).

Conclusions
A single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed.

Original language	English
Article number	0225748
Number of pages	13
Journal	PloS ONE
Volume	14
Issue number	12
Early online date	4 Dec 2019
DOIs	https://doi.org/10.1371/journal.pone.0225748
Publication status	Published - 4 Dec 2019

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Copyright: © 2019 Forget et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
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Forget, P., Bouche, G., Duhoux, F. P., Coulie, P. G., Decloedt, J., Dekleermaker, A., Guillaume, J-E., Ledent, M., Machiels, J-P., Mustin, V., Swinnen, W., van Maanen, A., Vander Essen, L., Verougstraete, J-C., De Kock, M., & Berliere, M. (2019). Intraoperative ketorolac in high-risk breast cancer patients: A prospective, randomized, placebo-controlled clinical trial. PloS ONE, 14(12), [0225748]. https://doi.org/10.1371/journal.pone.0225748

Forget, P, Bouche, G, Duhoux, FP, Coulie, PG, Decloedt, J, Dekleermaker, A, Guillaume, J-E, Ledent, M, Machiels, J-P, Mustin, V, Swinnen, W, van Maanen, A, Vander Essen, L, Verougstraete, J-C, De Kock, M & Berliere, M 2019, 'Intraoperative ketorolac in high-risk breast cancer patients: A prospective, randomized, placebo-controlled clinical trial', PloS ONE, vol. 14, no. 12, 0225748. https://doi.org/10.1371/journal.pone.0225748

@article{20b50af2d95941e0bd94875fefe30efd,

title = "Intraoperative ketorolac in high-risk breast cancer patients: A prospective, randomized, placebo-controlled clinical trial",

abstract = "BackgroundKetorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival.MethodsThe KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival.FindingsBetween February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years.At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65–2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34–3.51).ConclusionsA single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed.",

author = "Patrice Forget and Gauthier Bouche and Duhoux, {Francois P.} and Coulie, {Pierre G.} and Jan Decloedt and Alain Dekleermaker and Jean-Edouard Guillaume and Marc Ledent and Jean-Pascal Machiels and V{\'e}ronique Mustin and Walter Swinnen and {van Maanen}, Aline and {Vander Essen}, Lionel and Jean-Christophe Verougstraete and {De Kock}, Marc and Martine Berliere",

note = "Funding: This work is financed by grants received by PF, in the name of his institution: the Anticancer Fund (no grant number) (www.anticancerfund.org); the Belgian Society of Anaesthesia and Resuscitation (no grant number) (www.sarb.be); the Fondation Saint-Luc (no grant number) (www.uclouvain.be); the Commission du Patrimoine of the Universit{\'e} catholique de Louvain, St-Luc Hospital (exceptional grant, no number) (www.uclouvain.be). None of the funders had any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript except the scientific advise of GB, scientific director of the Anticancer Fund.",

year = "2019",

month = dec,

day = "4",

doi = "10.1371/journal.pone.0225748",

language = "English",

volume = "14",

journal = "PloS ONE",

issn = "1932-6203",

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number = "12",

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TY - JOUR

T1 - Intraoperative ketorolac in high-risk breast cancer patients

T2 - A prospective, randomized, placebo-controlled clinical trial

AU - Forget, Patrice

AU - Bouche, Gauthier

AU - Duhoux, Francois P.

AU - Coulie, Pierre G.

AU - Decloedt, Jan

AU - Dekleermaker, Alain

AU - Guillaume, Jean-Edouard

AU - Ledent, Marc

AU - Machiels, Jean-Pascal

AU - Mustin, Véronique

AU - Swinnen, Walter

AU - van Maanen, Aline

AU - Vander Essen, Lionel

AU - Verougstraete, Jean-Christophe

AU - De Kock, Marc

AU - Berliere, Martine

N1 - Funding: This work is financed by grants received by PF, in the name of his institution: the Anticancer Fund (no grant number) (www.anticancerfund.org); the Belgian Society of Anaesthesia and Resuscitation (no grant number) (www.sarb.be); the Fondation Saint-Luc (no grant number) (www.uclouvain.be); the Commission du Patrimoine of the Université catholique de Louvain, St-Luc Hospital (exceptional grant, no number) (www.uclouvain.be). None of the funders had any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript except the scientific advise of GB, scientific director of the Anticancer Fund.

PY - 2019/12/4

Y1 - 2019/12/4

N2 - BackgroundKetorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival.MethodsThe KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival.FindingsBetween February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years.At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65–2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34–3.51).ConclusionsA single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed.

AB - BackgroundKetorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival.MethodsThe KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival.FindingsBetween February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years.At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65–2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34–3.51).ConclusionsA single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed.

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U2 - 10.1371/journal.pone.0225748

DO - 10.1371/journal.pone.0225748

M3 - Article

C2 - 31800611

VL - 14

JO - PloS ONE

JF - PloS ONE

SN - 1932-6203

IS - 12

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Intraoperative ketorolac in high-risk breast cancer patients: A prospective, randomized, placebo-controlled clinical trial

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