Potential of a COX-2 inhibitor in lowering chemotherapy-induced neutropenia

doi:10.3877/cma.j.issn.1674-0807.2010.05.002

Objective

This study was initially designed to evaluate the effect of celecoxib on the regimen of 5-fluorouracil,epirubicin,and cyclophosphamide(FEC)combination,followed by docetaxel (T)in neoadjuvant setting.An unplanned preliminary review on safety was conducted after a halt of the study due to the concerned potential cardiovascular risk of using COX-2 inhibitors.

Methods

We studied 23 consecutive cases of operable breast cancer having received four cycles of FEC(500 mg/m²,100 mg/m²,500 mg/m²)followed by four cycles of T(100 mg/m²)with concurrent celecoxib(400 mg twice daily)(group A)or same chemotherapy regimen but without concurrent celecoxib(group B).These combined chemotherapies were administered every 3 weeks.The Chi-square test or Fisher's exact test were used to assess the difference in incidence of limiting hematological toxicites between groups.

Results

23 patients(group A:n=12;group B,n=11)received a total of 183 out of 184 planned treatment cycles;one(4%,1/23)of them omitted the fourth cycle of FEC owing to repeated incidences of febrile neutropenia.Received dose intensity(RDI)for FEC in group A (90%±11%)was higher than that in group B(80%±8%)while RDI for T was similar between group A(93%±8%)and group B(96% ±9%).Of the first 91 treatment cycles of FEC,limiting hematological toxicity,severe neutropenia including febrile neutropenia,was significantly different between group A and B[(10.4%,5/48)vs.(32.6%,14/43),P=0.009].Other toxicities commonly observed in chemotherapy receiving patients were manageable.

Conclusions

Neoadjuvant use of FEC followed by T with concurrent celecoxib appeared to be safe for treatment of operable invasive breast cancer.The observed lower incidence of chemotherapy-induced neutropenia is possibly contributed by the administration of COX-inhibitor.We believe that further investigation might provide more evidence on the use of COX-2 inhibitors in breast cancer.

关键词: Breast neoplasms, Chemotherapy, Cyclooxygenase-2, Neutropenia

Table 1 Patients'characteristics

Group	Age(years)	Menopausal status(n)		Clinical stage(n)			Hormonal Receptor(n)		Cerb-B-2 3(+)(n)	Pathology(n)			Modified Bloom and Richardson's grading(n)
Group	Age(years)	Premenopause	Postmenopause	II_A	II_B	III_A	ER positive	PR positive	Cerb-B-2 3(+)(n)	Invasive ductal	Invasive metaplastic	Mixed type^a	I	II	III	Not graded
A(n=12)	46.5±6.7	9	3	4	8	0	6	4	4	12	0	0	2	3	4	3
B(n=11)	45.9±7.4	9	2	9	2	0	4	3	5	9	1	1	2	4	4	1
P value	0.842	1.000		0.036			0.870	0.961	0.915	0.206			0.956

Table 1 Patients'characteristics

Group	Age(years)	Menopausal status(n)		Clinical stage(n)			Hormonal Receptor(n)		Cerb-B-2 3(+)(n)	Pathology(n)			Modified Bloom and Richardson's grading(n)
Group	Age(years)	Premenopause	Postmenopause	II_A	II_B	III_A	ER positive	PR positive	Cerb-B-2 3(+)(n)	Invasive ductal	Invasive metaplastic	Mixed type^a	I	II	III	Not graded
A(n=12)	46.5±6.7	9	3	4	8	0	6	4	4	12	0	0	2	3	4	3
B(n=11)	45.9±7.4	9	2	9	2	0	4	3	5	9	1	1	2	4	4	1
P value	0.842	1.000		0.036			0.870	0.961	0.915	0.206			0.956

Figure 1 Incidence of severe neutropenia and/or febrile neutropenia in each FEC cycle

Figure 2 Incidence of severe neutropenia and febrile neutropenia in 91 treatment cycles of FEC

[20]	Olsen SR.Taxanes and COX-2 inhibitors:from molecular pathways to clinical practice.Biomed Pharmacother,200,59:S306-S310.
[21]	Tjuljandin SA,Doig RG,Sobol MM,et al.Pharmacokinetics and toxicity of two schedules of high dose epirubicin.Cancer Res,1990,50:5095-5101.
[22]	Figgitt DP,Wiseman LR.Docetaxel:an updated of its use in advanced breast cancer.Drugs,2000,59:621-651.
[23]	Ferraresi V,Milella M,Vaccaro A,et al.Toxicity and activity of docetaxel in anthracycline-pretreated breast cancer patients:a phaseⅡstudy.Am J Clin Oncol,2000,23:132-139.
[24]	Miller AB,Hoogstraten B,Staquet M,et al.Reporting results of cancer treatment.Cancer,1981,47:207-214.
[25]	National Cancer Institute.Common terminology criteria for adverse events v3.0 (CTCAE).[2006-07-20].http://ctep.cancer.gov/forms/CTCAEv3.pdf.
[26]	Koki AT,Masferrer JL.Celecoxib:a specific COX-2 inhibitor with anticancer properties.Cancer Control,2002,9:28-35.
[27]	Harris RE.Cyclooxygenase-2(cox-2)blockade in the chemoprevention of cancers of the colon,breast,prostate,and lung.Inflammopharmacology,2009,17:55-67.
[28]	US Food and Drug Administration.FDA statement on the halting of a clinical trial of the cox-2 inhibitor Celebrex.[2006-07-20].http://www.fda.gov/bbs/topics/news/2004/NEW01144.html.
[29]	US Department of Health and Human Services.Use of non-steroidal anti-inflammatory drugs suspended in large Alzheimer's disease prevention trial.NIH news.[2006-07-20].http://www.nih.gov/news/pr/dec2004/od-20.htm.
[30]	Solomon SD,Mc Murray JJ,Pfeffer MA,et al.Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.N Engl J Med,2005,352:1071-1080.
[31]	Caldwell B,Aldington S,Weatherall M,et al.Risk of cardiovascular events and celecoxib:a systemic review and meta-analysis.J R Soc Med,2006,99:132-140.
[32]	Crofford LJ,Lipsky PE,Brooks P,et al.Basic biology and clinical application of specific cyclooxygenase-2 inhibitors.Arthritis Rheum,2000,43:4-13.
[33]	Pierga JY,Delaloge S,Espié M,et al.A multicenter randomized phase Ⅱstudy of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER-2 status,as primary chemotherapy for localized invasive breast cancer patients.Breast Cancer Res Treat,2010,122:429-437
[34]	Ohno S,Toi M,Kuroi K,et al.Update results of FEC followed by docetaxel neoadjuvant trials for primary breast cancer.Biomed Pharmacother,2005,59:S323-S324.
[35]	Iwata H,Nakamura S,Toi M,et al.Interim analysis of a phaseⅡtrial of cyclophosphamide,epirubicin and 5-fluorouracil(cef)followed by docetaxel as preoperative chemotherapy for early stage breast carcinoma.Breast Cancer,2005,12:99-103.
[36]	Crawford J,Ozer H,Stoller R,et al.Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer.N Engl J Med,1991,325:164-170.
[37]	Papaldo P,Lopez M,Marolla P,et al.Impact of five prophylactic filgrastim schedules on hematologicc toxicity in early breast cancer patients treated with epirubicine and cyclophosphamide.J Clin Oncol,2005,23:6908-6918.
[1]	Parkin DM,Bray F,Ferlay J,et al.Global cancer statistics,2002.CA Cancer J Clin,2005,55:74-108.
[2]	Hong Kong Cancer Registry.Hong Kong Cancer Stat 2006.Hong Kong:Hong Kong Cancer Registry,Hospital Authority,2008:1-35[2009-12-31].http://www.ha.org.hk/cancereg.
[3]	Eltahir A,Heys SD,Hutcheon AW,et al.Treatment of large and locally advanced breast cancers using neoadjuvant chemotherapy.Am J Surg,1998,175:127-132.
[4]	Ferriere JP,Assier I,Cure H,et al.Primary chemotherapy in breast cancer:correlation between tumor response and patient outcome.Am J Clin Oncol,1998,21:117-120.
[5]	Fisher B,Brown A,Mamounas E,et al.Effect of preoperative chemotherapy on local-regional disease in woman with operable breast cancer:findings from National Surgical Adjuvant Breast and Bowel Project B-18.J Clin Oncol,1997,15:2483-2493.
[6]	Gianni L,Baselga L,Eiermann W,et al.Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide,methotrexate and fluorouracil and its effects on tumor response as preoperative therapy.Clin Cancer Res,2005,11:8715-8721.
[7]	Gianni L,Baselga L,Eiermann W,et al.European Cooperative Trial in Operable Breast Cancer(ECTO):improved freedom from progression (FFP)from adding paclitaxel (T)to doxorubicin (A)followed by cyclophosphamide methotrexate and fluorouracil(CMF).Proc Am Soc Clin Oncol,2005:37a.
[8]	Bear HD,Anderson S,Smith RE,et al.Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer.National Surgical Adjuvant Breast and Bowel Project protocol B-27.J Clin Onco,2006,24:2019-2027.
[9]	Heys SD,Hutcheon AW,Sarkar TK,et al.Neoadjuvant docetaxel in breast cancer:3-year survival results from the Aberdeen trial.Clin Breast Cancer,2002,3:S69-S74.
[10]	Hutcheon AW,Heys SD,Sarkar TK,et al.Neoadjuvant docetaxel in locally advanced breast cancer.Breast Cancer Res Treat,2003,79:S19-S24.
[11]	Bonadonna G,Valagussa P,Brambilla C,et al.Primary chemotherapy in operable breast cancer:eight-year experience at the Milan Cancer Institute.J Clin Oncol,1998,16:93-100.
[12]	Fisher B,Bryant J,Wolmark N,et al.Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.J Clin Oncol,1998,16:2672-2685.
[13]	Kuerer H M,Newman LA,Smith TL,et al.Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy.J Clin Oncol,1999,17:460-469.
[14]	Masferrer JL,Leahy KM,Koki AT,et al.Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors.Cancer Res,2000,60:1306-1311.
[15]	Lu S,Zhang X,Badawi AF,et al.Cyclooxygenase-2 inhibitor celecoxib inhibits promotion of mammary tumorigenesis in rats fed a high fat diet rich in n-6 polyunsaturated fatty acids.Cancer Lett,2002,184:7-12.
[16]	Harris RE,Chlebowski RT,Jackson RD,et al.Breast cancer and nonsteroidal anti-inflammatory drugs:prospective results from the Women's Health Initiative.Cancer Res,2003,63:6096-6101.
[17]	Khuder SA,Mutgi AB.Breast cancer and NSAID use:a meta-analysis.Br J Cancer,2001,84:1188-1192.
[18]	Chow LWC,Toi M.Prospective pilot study of the preoperative use of celecoxib(Celebrex?)and FEC for the treatment of locally advanced breast cancer.Presented at the San Antonio Breast Cancer Symposium,December 11-14,2002.
[19]	Subbaramaiah K,Marmo TP,Dixon DA,et al.Regulation of cyclooxgenase-2 m RNA stability by taxanes:evidence for involvement of p38,MAPKAPK-2,and HuR.J Biol Chem,2003,278:37 637-37 647.

[1]	Louis Wing Cheong Chow, Wings Tjing Yung Loo, Qing Liu. Individualized therapy for breast cancer: a decade of improvement[J/OL]. 中华乳腺病杂志(电子版), 2015, 09(04): 223-230.
[2]	William Wai Nam Tsang, Wings Tjing Yung Loo, Louis Wing Cheong Chow, Elizabeth Lam Yan Ng, Adrian Yun San Yip, Jianping Chen. Effect of Tai Chi Chuan on serotonin and cortisol for monitoring stress and quality of life in post-treatment breast cancer patients[J/OL]. 中华乳腺病杂志(电子版), 2014, 08(04): 266-272.
[3]	TANG Qi, ZHOU Shao-qiang. Giant phyllodes tumor in both breasts: one case report and literature review[J/OL]. 中华乳腺病杂志(电子版), 2013, 07(02): 142-145.
[4]	Chong Le, Tian Jin-hui, Gu Jing, Yang Ke-hu. Is it necessary to do axillary dissection in old women with breast cancer? A meta-analysis of randomized clinical trials[J/OL]. 中华乳腺病杂志(电子版), 2012, 06(06): 622-630.
[5]	Per E Lønning. Mechanisms of endocrine resistance in breast cancer[J/OL]. 中华乳腺病杂志(电子版), 2012, 06(06): 597-608.
[6]	Satoko Suzuki, Miki Mori, Rena Shigenaga, Kenya Suzuki, Katsutoshi Enokido, Terumasa Sawada, Masanori Hirose, Seigo Nakamura. Efficacy of volume navigation in assessment of extent of breast cancer[J/OL]. 中华乳腺病杂志(电子版), 2012, 06(05): 533-538.
[7]	Wings T.Y. Loo, Louis W.C. Chow, Adrian Y.S Yip, Mary N.B. Cheung. Application of single and combination therapy of clarithromycin and tamoxifen to suppress breast cancer cell proliferation and metabolism[J/OL]. 中华乳腺病杂志(电子版), 2012, 06(01): 45-53.
[8]	Kentaro Tamaki, Hironobu Sasano. New development of breast cancer histological evaluation related to determination of therapeutic option for the patients[J/OL]. 中华乳腺病杂志(电子版), 2011, 05(06): 721-728.
[9]	Adrian YS Yip, WP Chu, Louis WC Chow, Wings TY Loo, Eleanor YY Ong, Wincy Chan. Methods of early detection: would clinical breast examination and breast ultrasonography be a good alternative to mammography?[J/OL]. 中华乳腺病杂志(电子版), 2011, 05(06): 646-659.
[10]	Jun-Xiang Zhang, Da-Qiang Li, Rakesh Kumar. P21-activated kinase 1 and breast cancer[J/OL]. 中华乳腺病杂志(电子版), 2010, 04(05): 544-553.
[11]	Kentaro Tamaki, Hironobu Sasano. An analysis of vascularity and neovascularization in surgical pathology materials of breast carcinoma and its clinical significance[J/OL]. 中华乳腺病杂志(电子版), 2010, 04(05): 521-529.
[12]	Per Eystein Lønning. Role of molecular markers in breast cancer therapy[J/OL]. 中华乳腺病杂志(电子版), 2010, 04(05): 479-495.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容