A Phase I-II Study of COX-2 Inhibitor, Celebrex (Celecoxib) and Chemoradiation in Patients With Locally Advanced Cervical Cancer: Primary Endpoint Analysis of RTOG 0128

Reviewer: Voika BarAd, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 19, 2005

Presenter: Presenter: D.K.Gaffney
Presenter's Affiliation: Radiation Oncology, University of Utah, Salt Lake City, UT, Statistics, RTOG, Philadelphia, PA, Radiation Oncology, Thomas Jefferson Univ., Philadelphia, PA, Obstetrics/Gynecology, Wake Forest Univ.,
Type of Session: Scientific


  • Cyclooxygenase 2 (COX-2) is an enzyme induced by inflammatory and mitogenic stimuli and results in enhanced synthesis of prostaglandins in inflamed and neoplastic tissues. It is associated with cell proliferation and growth in various cancerous conditions.
  • COX-2 overexpression may promote tumorigenesis through vascular endothelial growth factor (VEGF)-mediated neoangiogenesis, and bcl-2-mediated inhibition of apoptosis (programmed cell death). 
  • COX-2 inhibitors have been shown experimentally to induce tumor regression through proapoptotic and antiangiogenic effects and to inhibit tumor invasion to surrounding tissues.
  • The study assessed related toxicity rates in patients with locally advanced cervical cancer treated by oral celecoxib (selective COX-2 inhibitors), intravenous cisplatin and 5-FU, and concurrent pelvic radiation therapy (the chemoradiation protocol from RTOG 9001).

Materials and Methods

  • 84 patients were accrued to the study between August 2001 and March 2004, and 77 were evaluable for toxicity.
  • All patients had cervical cancer, FIGO stage IIB-IVA, or had FIGO stage IB through IIA with biopsy-proven pelvic lymph node metastases or tumor size greater than 5 cm.
  • The stage distributions were: IB 23%, IIA 4%, IIB 52%, IIIB 17%, and IVA 4%.
  • The median age was 45 years.
  • All patients received pelvic radiotherapy to a dose of 45 Gy in 25 fractions, and either low dose rate brachytherapy times 2 or high dose rate brachytherapy times 5.
  • Celecoxib was prescribed at 400 mg twice daily, beginning on day 1 for 1 year.
  • Cisplatin (75 mg/m2, day 1) and 5-FU (1g/m2, days 1-4) were administered every 3 weeks, times 3.
  • The primary endpoint of the study was treatment-related toxicity, as defined by grade 3-4 nausea, vomiting, or diarrhea despite medical intervention, grade 4 neutropenia and leucopenia persisting more than 7 days, grade 3-4 thrombocytopenia and anemia, and grade 3-4 other toxicity, including gastrointestinal, renal, cardiac, pulmonary, hepatic, and neurological toxicities.
  • The primary endpoint hypothesis assumed a treatment-related toxicity rate of 22%, with an alternative rate of greater than 35%, at which point the treatment regimen would be considered excessively toxic.


  • The treatment-related toxicities observed were blood/bone marrow (16 patients), gastrointestinal (12 patients), pain (7 patients),renal/genitourinary (6 patients), cardiovascular (3 patients), hemorrhage ( 1 patient), and neurological (1 patient).
  • For the first 75 evaluable patients, toxicity was identified in 35 patients for a rate of 47%.
  • Additionally, for all grade 3 and 4 toxicity, non-hematological toxicity was observed in 53% and 13% of patients, respectively.
  • The accrual of patients was closed earlier than planned due to excessive toxicity.
  • The compliance with the oral medication was low, especially after the end of chemoradiotherapy.

Author's Conclusions

  • Celecoxib at 400 mg twice per day, together with concurrent cisplatin and 5FU and pelvic irradiation, is an excessively toxic regimen.
  • The most frequent toxicities were hematological, gastrointestinal, and metabolic/laboratory.
  • The efficacy of the treatment is scheduled to be evaluated in 2006.
  • Investigation of other biologically targeted therapies is warranted for the treatment of advanced cervix cancer.

Clinical/Scientific Implications

  • Recent studies showed that the selective COX-2 inhibitors block growth and promote apoptosis in different cancer cells. It was also concluded that COX-2 selective inhibitors may be promising agents for prevention and treatment of cancer.
  • The presented study shows that the addition of selective COX-2 inhibitors to chemoradiotherapy for cervical cancer may be extremely toxic. Furthermore, the efficacy of the regimen is unknown. Longer follow-up is required in order to determine the late effects of the treatment.

Frequently Asked Questions