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

Autoři: Patrice Forget aff001;  Gauthier Bouche aff002;  Francois P. Duhoux aff003;  Pierre G. Coulie aff004;  Jan Decloedt aff005;  Alain Dekleermaker aff006;  Jean-Edouard Guillaume aff007;  Marc Ledent aff008;  Jean-Pascal Machiels aff003;  Véronique Mustin aff008;  Walter Swinnen aff009;  Aline van Maanen aff010;  Lionel Vander Essen aff008;  Jean-Christophe Verougstraete aff011;  Marc De Kock aff012;  Martine Berliere aff013
Působiště autorů: Institute of Applied Health Sciences, Epidemiology group, School of Medicine, Medical Science and Nutrition, University of Aberdeen, Department of Anaesthesia, NHS Grampian, Aberdeen, United Kingdom aff001;  The Anticancer Fund, Brussels, Belgium aff002;  Institut Roi Albert II, Service d’Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (POLE MIRO), UCLouvain, Brussels, Belgium aff003;  de Duve Institute, UCLouvain, Brussels, Belgium aff004;  Department of Oncology, St-Blasius Hospital, Dendermonde, Belgium aff005;  Clinical Pharmacology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium aff006;  Department of Anesthesiology, Ste-Elisabeth hospital, Namur, Belgium aff007;  Department of Anesthesiology, St-Pierre Clinic, Ottignies, Belgium aff008;  Department of Anesthesiology, St-Blasius Hospital, Dendermonde, Belgium aff009;  Biostatistics Unit, King Albert II Institute, Cliniques Universitaires Saint-Luc, Brussels, Belgium aff010;  Department of Gynecology, St-Pierre Clinic, Ottignies, Belgium aff011;  Department of Anesthesiology, Centre Hospitalier Wallonie Picarde (CHWAPI), Tournai, Belgium aff012;  Department of Gynecology, Breast Clinic, King Albert II Institute, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium aff013
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225748



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.


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.


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).


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.

Trial registration NCT01806259.

Klíčová slova:

Adverse events – Breast cancer – Cancer treatment – NSAIDs – Retrospective studies – Surgical and invasive medical procedures – Surgical oncology


1. American Society of Anesthesiologists Task Force on Acute Pain Management: Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2012;116:248–73. doi: 10.1097/ALN.0b013e31823c1030 22227789

2. Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379(9826):1591–601. doi: 10.1016/S0140-6736(12)60209-8 22440947

3. Forget P, Machiels J-P, Coulie PG, Berliere M, Poncelet AJ, Tombal B et al. Neutrophil:lymphocyte ratio and intraoperative use of ketorolac or diclofenac are prognostic factors in different cohorts of patients undergoing breast, lung and kidney cancer surgery. Ann Surg Oncol 2013; Suppl 3:S650–60.

4. Demaria S, Pikarsky E, Karin M, Coussens LM, Chen YC, El-Omar EM et al. Cancer and inflammation: promise for biologic therapy. J Immunother. 2010;33(4):335–51. doi: 10.1097/CJI.0b013e3181d32e74 20386472

5. Hiller JG, Perry NJ, Poulogiannis G, Riedel B, Sloan EK. Perioperative events influence cancer recurrence risk after surgery. Nat Rev Clin Oncol. 2018;15(4):205–218 doi: 10.1038/nrclinonc.2017.194 29283170

6. Krall JA, Reinhardt F, Mercury OA, Pattabiraman DR, Brooks MW, Dougan M et al.The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci Transl Med. 2018;10(436).

7. Neeman E, Zmora O, Ben-Eliyahu S. A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins. Clin Cancer Res. 2012;18(18):4895–902. doi: 10.1158/1078-0432.CCR-12-1087 22753587

8. Forget P, Vandenhende J, Berliere M, Machiels JP, Nussbaum B, Legrand C et al. Do intraoperative Analgesics Influence Breast Cancer Recurrence After Mastectomy? A Retrospective Analysis. Anesth Analg 2010;110(6):1630–5. doi: 10.1213/ANE.0b013e3181d2ad07 20435950

9. Forget P, Machiels JP, Coulie PG, Berliere M, Poncelet AJ, Tombal B et al. Neutrophil:lymphocyte ratio and intraoperative use of ketorolac or diclofenac are prognostic factors in different cohorts of patients undergoing breast, lung, and kidney cancer surgery. Ann Surg Oncol. 2013;20 Suppl 3:S650–60.

10. Forget P, Bentin C, Machiels JP, Berliere M, Coulie PG, De Kock M. Intraoperative use of ketorolac or diclofenac is associated with improved disease-free survival and overall survival in conservative breast cancer surgery. Br J Anaesth. 2014;113 Suppl 1:i82–7.

11. Guo Y, Kenney SR, Cook L, Adams SF, Rutledge T, Romero E et al. A Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients. Clin Cancer Res. 2015;21(22):5064–72. doi: 10.1158/1078-0432.CCR-15-0461 26071482

12. Retsky M, Rogers R, Demicheli R, Hrushesky WJM, Gukas I, Vaidya JS et al. NSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: particular relevance to triple negative subgroup. Breast Cancer Res Treat 2012; 134(2):881–8. doi: 10.1007/s10549-012-2094-5 22622810

13. Proctor MJ, Morrison DS, Talwar D, Balmer SM, Fletcher CD, O'Reilly DS et al. A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study. Eur J Cancer 2011;47(17):2633–41. doi: 10.1016/j.ejca.2011.03.028 21724383

14. Ethier JL, Desautels D, Templeton A, Shah PS, Amir E. Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: a systematic review and meta-analysis. Breast Cancer Res. 2017;19(1):2. doi: 10.1186/s13058-016-0794-1 28057046

15. Forget P, Berlière M, van Maanen A, Duhoux FP, Machiels JP, Coulie PG et al. Ketorolac in Breast Cancer trial (KBCtrial) group. Perioperative ketorolac in high risk breast cancer patients. Rationale, feasibility and methodology of a prospective randomized placebo-controlled trial. Med Hypotheses 2013; 81:707–12. doi: 10.1016/j.mehy.2013.07.033 23937996

16. Reinhart DJ. Minimising the Adverse Effects of Ketorolac. Drug Saf 2000;22:487–497. doi: 10.2165/00002018-200022060-00007 10877042

17. Hudis CA, Barlow WE, Costantino JP, Gray RJ, Pritchard KI, Chapman JA et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. 2007;25(15):2127–32. doi: 10.1200/JCO.2006.10.3523 17513820

18. Sessler D, Ben-Eliyahu S, Mascha EJ, Parat MO, Buggy DJ. Can regional analgesia reduce the risk of recurrence after breast cancer? Methodology of a multicenter randomized trial. Contemporary Clinical Trials 2008;29:517–26. doi: 10.1016/j.cct.2008.01.002 18291727

19. Horowitz M, Neeman E, Sharon E, Ben-Eliyahu S. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat Rev Clin Oncol. 2015;12(4):213–26. doi: 10.1038/nrclinonc.2014.224 25601442

20. Hussain M, Javeed A, Ashraf M, Al-Zaubai N, Stewart A, Mukhtar MM. Non-steroidal anti-inflammatory drugs, tumour immunity and immunotherapy. Pharmacol Res. 2012;66(1):7–18. doi: 10.1016/j.phrs.2012.02.003 22449788

21. Forget P, Collet V, Lavand'homme P, De Kock M. Does analgesia and condition influence immunity after surgery? Effects of fentanyl, ketamine and clonidine on natural killer activity at different ages. Eur J Anaesthesiol. 2010;27(3):233–40. doi: 10.1097/EJA.0b013e32832d540e 19487949

22. Forget P, De Kock M. [Could anaesthesia, analgesia and sympathetic modulation affect neoplasic recurrence after surgery? A systematic review centred over the modulation of natural killer cells activity]. Ann Fr Anesth Reanim. 2009;28(9):751–68. doi: 10.1016/j.annfar.2009.07.078 19717275

23. Shakhar G, Ben-Eliyahu S. Potential prophylactic measures against postoperative immunosuppression: Could they reduce recurrence rates in oncological patients? Ann Surg Oncol 2003;10(8):972–92. doi: 10.1245/aso.2003.02.007 14527919

24. Pantziarka P, Bouche G, Sullivan R, Ilbawi AM, Dare AJ, Meheus L. Perioperative therapies—Enhancing the impact of cancer surgery with repurposed drugs. Eur J Surg Oncol. 2017;43(11):1985–8. doi: 10.1016/j.ejso.2017.08.010 28928011

25. Glasner A, Avraham R, Rosenne E, Benish M, Zmora O, Shemer S et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol. 2010;1;184(5):2449–57. doi: 10.4049/jimmunol.0903301 20124103

26. Shaashua L, Shabat-Simon M, Haldar R, Matzner P, Zmora O, Shabtai M et al. Perioperative COX-2 and β-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial. Clin Cancer Res. 2017;23(16):4651–4661. doi: 10.1158/1078-0432.CCR-17-0152 28490464

27. Retsky MW, Demicheli R, Hrushesky WJ, Baum M, Gukas ID. Dormancy and surgery-driven escape from dormancy help explain some clinical features of breast cancer. APMIS. 2008;116(7–8):730–41. doi: 10.1111/j.1600-0463.2008.00990.x 18834415

28. Jatoi I, Tsimelzon A, Weiss H, Clark GM, Hilsenbeck SG. Hazard rates of recurrence following diagnosis of primary breast cancer. Breast Cancer Res Treat. 2005;89(2):173–8. doi: 10.1007/s10549-004-1722-0 15692760

29. Hilsenbeck SG, Ravdin PM, de Moor CA, Chamness GC, Osborne CK, Clark GM. Time-dependence of hazard ratios for prognostic factors in primary breast cancer. Breast Cancer Res Treat. 1998;52(1–3):227–37. doi: 10.1023/a:1006133418245 10066085

30. Baum M, Demicheli R, Hrushesky W, Retsky M. Does surgery unfavourably perturb the "natural history" of early breast cancer by accelerating the appearance of distant metastases? Eur J Cancer. 2005;41(4):508–15. doi: 10.1016/j.ejca.2004.09.031 15737554

31. Mansell J, Monypenny IJ, Skene AI, Abram P, Carpenter R, Gattuso JM et al. Patterns and predictors of early recurrence in postmenopausal women with estrogen receptor-positive early breast cancer. Breast Cancer Res Treat. 2009;117(1):91–8. doi: 10.1007/s10549-008-0291-z 19112615

32. Desmedt C, Demicheli R, Fornili M, Bachir I, Duca M, Viglietti G et al. Potential Benefit of Intra-operative Administration of Ketorolac on Breast Cancer Recurrence According to the Patient's Body Mass Index. J Natl Cancer Inst. 2018 Apr 30. doi: 10.1093/jnci/djy042 29718396

33. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999;96(13):7563–8. doi: 10.1073/pnas.96.13.7563 10377455

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