Impact of celecoxib on capecitabine tolerability and activity in pretreated metastatic breast cancer: results of a phase II study with biomarker evaluation
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Preclinical evidence suggests that the cyclo-oxygenase-2 (COX-2) enzyme plays an important role in breast cancer progression. The aim of the present phase II study was to determine the activity and safety of the combination of the COX-2 inhibitor celecoxib with capecitabine in metastatic breast cancer (MBC) patients pretreated with anthracyclines and/or taxanes.
Eligible patients received capecitabine 1,000 mg/m² twice daily on days 1–14 every 21 days and celecoxib 200 mg twice daily, continuously, until disease progression or unacceptable toxicity.
About 42 pretreated MBC patients were enrolled into the study. Median number of previous chemotherapy lines for metastatic disease was 2 (0–3). Seven patients (19%) responded to treatment while disease stabilization occurred in 17 patients (40.5%). Overall, 20 patients (47.5%) achieved clinical benefit [objective responses (CR) plus stable disease (SD) ≥6 months]. Median time to progression (TTP) and median overall survival (OS) were 5.2 and 17.8 months, respectively. Treatment was very well tolerated: grade 3 toxicities were observed in only five patients, respectively, and no grade 4 adverse events were reported. Celecoxib was never discontinued for toxicity. Analysis of COX-2 expression in the 22 patients with available tissue revealed a significantly longer TTP and OS for patients whose tumors over-expressed COX-2.
The combination of capecitabine and celecoxib is active and safe in far advanced MBC patients. Interestingly, this association resulted in a lower-than-expected toxicity, as compared to single-agent capecitabine. The clinical relevance of COX-2 as determinant of sensitivity to treatment with celecoxib should be further evaluated in larger series of patients.
KeywordsCapecitabine Celecoxib COX-2 Metastatic breast cancer
- 6.Arun B, Zhang H, Mirza NQ (2001) Growth inhibition of breast cancer cells by celecoxib. Breast Cancer Res Treat 69:234aGoogle Scholar
- 8.Hida T, Kozaki K, Ito H Miyaishi O, Tatematsu Y, Suzuki T, Matsuo K, Sugiura T, Ogawa M, Takahashi T, Takahashi T (2002) Significant growth inhibition of human lung cancer cells both in vitro and in vivo by the combined use of a selective cyclooxygenase 2 inhibitor, JTE-522, and conventional anticancer agents. Clin Cancer Res 8:2443–2447PubMedGoogle Scholar
- 12.Lin E, Morris JS, Ayers GD (2002) Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity. Oncology (Williston Park) 16(suppl 14):31–37Google Scholar
- 13.Lin EH, Curley SA, Crane CC, Feig B, Skibber J, Delcos M, Vadhan SR, Morris J, Ayers GD, Ross A, Brown T, Rodriguez-Bigas MA, Janjan N (2006) Retrospective study of capecitabine and celecoxib in metastatic colorectal cancer: potential benefits and COX-2 as the common mediator in pain, toxicities and survival? Am J Clin Oncol 29:232–239PubMedCrossRefGoogle Scholar
- 14.Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274–1281PubMedCrossRefGoogle Scholar
- 17.Reichardt P, Von Minckwitz G, Thuss-Patience PC, Jonat W, Kolbl H, Janicke F, Kieback DG, Kuhn W, Schindler AE, Mohrmann S, Kaufmann M, Luck HJ (2003) Multicenter phase II study of oral capecitabine (Xeloda(“)) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol 14:1227–1233PubMedCrossRefGoogle Scholar
- 18.Fumoleau P, Largillier R, Clippe C, Dièras V, Orfeuvre H, Lesimple T, Culine S, Audhuy B, Serin D, Curé H, Vuillemin E, Morère JF, Montestruc F, Mouri Z, Namer M (2004) Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 40:536–542PubMedCrossRefGoogle Scholar
- 19.Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, Catena L, Ricotta R, Longarini R, Zilembo N, Buzzoni R (2005) Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 23:2155–2161PubMedCrossRefGoogle Scholar
- 20.Hennessy BT, Gauthier AM, Michaud LB, Hortobagyi G, Valero V (2005) Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: retrospective analysis of patients treated at M. D. Anderson Cancer Center and a review of capecitabine toxicity in the literature. Ann Oncol 16:1289–1296PubMedCrossRefGoogle Scholar
- 21.National Cancer Institute (2007) Common toxicity criteria version 3.0. Available from URL: http://ctep.cancer.gov/forms/CTCAEv3.pdf [accessed June 9, 2007]
- 25.Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, Tang J, Rosenstein RB, Wittes J, Corle D, Hess TM, Woloj GM, Boisserie F, Anderson WF, Viner JL, Bagheri D, Burn J, Chung DC, Dewar T, Foley TR, Hoffman N, Macrae F, Pruitt RE, Saltzman JR, Salzberg B, Sylwestrowicz T, Gordon GB, Hawk ET, APC Study Investigators (2006) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355:873–884PubMedCrossRefGoogle Scholar
- 27.O’Shaughnessy JA, Blum J, Moiseyenko V, Jones SE, Miles D, Bell D, Rosso R, Mauriac L, Osterwalder B, Burger HU, Laws S (2001) Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 12:1247–1254CrossRefGoogle Scholar
- 28.Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792–799PubMedCrossRefGoogle Scholar
- 29.Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743PubMedCrossRefGoogle Scholar
- 32.National Cancer Institute (2007) ClinicalTrials.gov. Available from URL: http://clinicaltrials.gov/ct/show/NCT00305643?order=1 [Accessed June 9, 2007]