title: 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.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fernanda G
authors.initials: FG
authors.lastname: Herrera
authors.forename: Philip
authors.initials: P
authors.lastname: Chan
authors.forename: Corinne
authors.initials: C
authors.lastname: Doll
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.forename: Amit
authors.initials: A
authors.lastname: Oza
authors.forename: Amy
authors.initials: A
authors.lastname: Syed
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.forename: Wilfred
authors.initials: W
authors.lastname: Levin
authors.forename: Lee
authors.initials: L
authors.lastname: Manchul
authors.forename: Anthony
authors.initials: A
authors.lastname: Fyles
mesh_terms: 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*
chemical_list: D014408:Biomarkers, Tumor; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib