A prospective phase I-II trial of the cyclooxygenase-2 inhibitor celecoxib in patients with carcinoma of the cervix with biomarker assessment of the tumor microenvironment.
OBJECTIVE
To evaluate the toxicity and effectiveness of celecoxib in combination with definitive chemoradiotherapy (CRT) in women with locally advanced cervical cancer.


METHODS
Thirty-one patients were accrued to a phase I-II trial of celecoxib 400 mg by mouth twice per day for 2 weeks before and during CRT. Tumor oxygenation (HP(5)) and interstitial fluid pressure (IFP) were measured before and 2 weeks after celecoxib administration alone. The median follow-up time was 2.7 years (range, 1.1-4.4 years).


RESULTS
The most common acute G3/4 toxicities were hematologic (4/31, 12.9%) and gastrointestinal (5/31, 16.1%) largely attributed to chemotherapy. Late G3/4 toxicity was seen in 4 of 31 patients (13.7% actuarial risk at 2 yr), including fistulas in 3 patients (9.7%). Within the first year of follow-up, 25 of 31 patients (81%) achieved complete response (CR), of whom 20 remained in CR at last follow-up. After 2 weeks of celecoxib administration before CRT, the median IFP decreased slightly (median absolute, -4.6 mm Hg; p = 0.09; relative, -21%; p = 0.07), whereas HP(5) did not change significantly (absolute increase, 3.6%; p = 0.51; median relative increase, 11%; p = 0.27). No significant associations were seen between changes in HP(5) or IFP and response to treatment (p = 0.2, relative HP(5) change and p = 0.14, relative IFP change).


CONCLUSIONS
Celecoxib in combination with definitive CRT is associated with acceptable acute toxicity, but higher than expected late complications. Celecoxib is associated with a modest reduction in the angiogenic biomarker IFP, but this does not correspond with tumor response.
Herrera
Fernanda G
FG
Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.
Chan
Philip
P
Doll
Corinne
C
Milosevic
Michael
M
Oza
Amit
A
Syed
Amy
A
Pintilie
Melania
M
Levin
Wilfred
W
Manchul
Lee
L
Fyles
Anthony
A
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D000068579:Celecoxib; D015687:Cell Hypoxia / Q000187:drug effects; D003131:Combined Modality Therapy / Q000379:methods; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D004311:Double-Blind Method; D045604:Extracellular Fluid / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008875:Middle Aged; D010101:Oxygen Consumption; D011446:Prospective Studies; D011720:Pyrazoles / Q000009:adverse effects* / Q000627:therapeutic use; D012006:Rectovaginal Fistula / Q000139:chemically induced; D012074:Remission Induction; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy*
D014408:Biomarkers, Tumor; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib