title: A stratified randomized double-blind phase II trial of celecoxib for treating patients with cervical intraepithelial neoplasia: The potential predictive value of VEGF serum levels: An NRG Oncology/Gynecologic Oncology Group study.
abstract: To examine the effect of celecoxib on cervical intraepithelial neoplasia 3 (CIN 3). This is a NRG Oncology/Gynecologic Oncology Group study with translational biomarkers.
  
  
  
  Patients with CIN 3 were randomized to celecoxib 400mg once daily (67 patients) or placebo (63 patients) for 14-18weeks. The primary outcome measure was histologic regression. A test of equal probabilities of success between two therapies was conducted, using Fisher's Exact Test at alpha=10% and 90% power when the treatment arm boosted the probability of success by 30%. Translational analysis included cervical tissue HPV genotyping, COX-2 expression in biopsies, and serum celecoxib and VEGF levels.
  
  
  
  In primary analysis, histologic regression was not significantly higher in the celecoxib group (40%) than in the placebo group (34.1%). However, exploratory analyses suggest patients with high serum VEGF levels exhibited greater regression in the celecoxib arm (47.3%) than in the placebo arm (14.3%). Regression rates were similar by treatment group in patients with low VEGF. VEGF levels increased over time in the placebo group, but remained the same in the treatment group. COX-2 expression in cervical biopsies declined from pre-treatment to the end of treatment with celecoxib; it did not change with placebo.
  
  
  
  Celecoxib at 400mg once daily for 14-18weeks did not significantly decrease the severity of CIN 3 compared with placebo except, possibly, in subjects with high baseline VEGF. Therefore, serum VEGF levels might identify patients who may benefit from celecoxib or other therapies, personalizing future chemoprevention trials for CIN 3.
authors.affiliation: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, United States. Electronic address: jrader@mcw.edu.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Rader
authors.affiliation: NRG Oncology/Gynecologic Oncology Group Statistics & Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, United States. Electronic address: msill@gogstats.org.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sill
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Department of Pharmaceutical Sciences, School of Pharmacy, Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States; Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States. Electronic address: beumerjh@upmc.edu.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: NRG Oncology/Gynecologic Oncology Group Statistics & Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, United States. Electronic address: hlankes@gogstats.org.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Lankes
authors.affiliation: Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73165. Electronic address: Doris-Benbrook@ouhsc.edu.
authors.forename: Doris Mangiaracina
authors.initials: DM
authors.lastname: Benbrook
authors.affiliation: Department of Obstetrics & Gynecology, University of Arizona, Mel & Enid Zuckerman College of Public Health, Tucson, AZ 85724, United States. Electronic address: Francisco.Garcia@pima.gov.
authors.forename: Francisco
authors.initials: F
authors.lastname: Garcia
authors.affiliation: Division of Gynecologic Specialties, Johns Hopkins Medical Institutions, Baltimore, MD 21287, United States. Electronic address: ctrimbl@jhmi.edu.
authors.forename: Connie
authors.initials: C
authors.lastname: Trimble
authors.affiliation: Department of Gynecologic Oncology, University of Mississippi Medical Center, Jackson, MS 39216, United States.
authors.forename: J
authors.initials: J
authors.lastname: Tate Thigpen
authors.affiliation: Division of OB/GYN and Pathology, University of Michigan Health System, Ann Arbor, MI 48109, United States. Electronic address: jakrwl@med.umich.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Lieberman
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States. Electronic address: Rosemary-Zuna@ouhsc.edu.
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Zuna
authors.affiliation: Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, United States. Electronic address: cleath@uabmc.edu.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Leath
authors.affiliation: Division of Gynecologic Oncology, Women's Cancer Center of Nevada, Las Vegas, NV 89169, United States. Electronic address: nspirtos@wccenter.com.
authors.forename: Nick M
authors.initials: NM
authors.lastname: Spirtos
authors.affiliation: Department of OB/GYN, First Health of the Carolinas - Moore Regional Hospital, Southern Pines, NC 28388, United States. Electronic address: JByron@spwhc.com.
authors.forename: John
authors.initials: J
authors.lastname: Byron
authors.affiliation: Division of Gynecologic Oncology, Washington University School of Medicine, Saint Louis, MO 63110, United States. Electronic address: thakerp@wudosis.wustl.edu.
authors.forename: Premal H
authors.initials: PH
authors.lastname: Thaker
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, United States. Electronic address: shashi.lele@roswellpark.org.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Lele
authors.affiliation: Department of Medical Oncology, The University of Arizona Cancer Center-North Campus, Tucson, AZ 85724, United States. Electronic address: DAlberts@uacc.arizona.edu.
authors.forename: David
authors.initials: D
authors.lastname: Alberts
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D000068579:Celecoxib / Q000097:blood / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000097:blood / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D027383:Papillomaviridae / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000097:blood / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000821:virology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000097:blood* / Q000188:drug therapy* / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; D052246:Cyclooxygenase 2 Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib
keywords: CIN 3; COX-2; Celecoxib; Cervix; Chemoprevention; VEGF