Impact of celecoxib on capecitabine tolerability and activity in pretreated metastatic breast cancer: results of a phase II study with biomarker evaluation.
BACKGROUND
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.


METHODS
Eligible patients received capecitabine 1,000 mg/m(2) twice daily on days 1-14 every 21 days and celecoxib 200 mg twice daily, continuously, until disease progression or unacceptable toxicity.


RESULTS
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.


CONCLUSIONS
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.
Fabi
Alessandra
A
Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
Metro
Giulio
G
Papaldo
Paola
P
Mottolese
Marcella
M
Melucci
Elisa
E
Carlini
Paolo
P
Sperduti
Isabella
I
Russillo
Michelangelo
M
Gelibter
Alain
A
Ferretti
Gianluigi
G
Tomao
Silverio
S
Milella
Michele
M
Cognetti
Francesco
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D001932:Brain Neoplasms / Q000188:drug therapy / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000069287:Capecitabine; D000068579:Celecoxib; D003131:Combined Modality Therapy; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008875:Middle Aged; D011355:Prodrugs / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000556:secondary; D013449:Sulfonamides / Q000627:therapeutic use*; D015996:Survival Rate
D000964:Antimetabolites, Antineoplastic; D016861:Cyclooxygenase Inhibitors; D011355:Prodrugs; D011720:Pyrazoles; D013449:Sulfonamides; D003841:Deoxycytidine; D000069287:Capecitabine; D000068579:Celecoxib; D005472:Fluorouracil