Radiation Therapy Plus Celecoxib, Fluorouracil, and Cisplatin in Patients With Locally Advanced Cervical Cancer

RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving radiation therapy in different ways and combining it with chemotherapy may kill more tumor cells. Celecoxib may slow the growth of cervical cancer by stopping blood flow to the tumor.

PURPOSE: Phase I/II trial to study the effectiveness of radiation therapy plus celecoxib, fluorouracil, and cisplatin in treating patients who have locally advanced cervical cancer.

OBJECTIVES:

• Determine treatment-related toxicity rates in patients with locally advanced cervical cancer treated with external beam radiotherapy and brachytherapy concurrently with celecoxib, fluorouracil, and cisplatin.
• Determine whether this regimen increases locoregional control rates, distant control, disease-free survival, and overall survival in these patients.
• Determine whether first-failure patterns in patients treated with this regimen are changed compared to historical controls.

OUTLINE: This is a multicenter study.

Patients undergo external beam pelvic radiotherapy once daily five days a weeks for 5 weeks beginning on day 1. Within 8 weeks, patients undergo low-dose or high-dose brachytherapy. Patients also receive concurrent chemotherapy comprising fluorouracil IV continuously over days 2-5, 23-26, and 44-47 and cisplatin IV over 4 hours on days 1, 22, and 43. Oral celecoxib is administered twice daily beginning on day 1 and continuing for 12 months.

Patients are followed every 3 months for 2 years, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 83 patients will be accrued for this study within 1.5 years.

• Drug: celecoxib
• Drug: cisplatin
• Drug: fluorouracil
• Radiation: brachytherapy
• Radiation: radiation therapy

• Weidhaas JB, Li SX, Winter K, Ryu J, Jhingran A, Miller B, Dicker AP, Gaffney D. Changes in Gene Expression Predicting Local Control in Cervical Cancer: Results from Radiation Therapy Oncology Group 0128. Clin Cancer Res. 2009 Jun 9; [Epub ahead of print]
• Zempolich K, Fuhrman C, Milash B, Flinner R, Greven K, Ryu J, Forbes A, Kerlin K, Nichols RC, Gaffney DK. Changes in gene expression induced by chemoradiation in advanced cervical carcinoma: A microarray study of RTOG C-0128. Gynecol Oncol. 2008 Feb 23; [Epub ahead of print]
• Gaffney DK, Winter K, Dicker AP, Miller B, Eifel PJ, Ryu J, Avizonis V, Fromm M, Greven K. A Phase II study of acute toxicity for Celebrex (celecoxib) and chemoradiation in patients with locally advanced cervical cancer: primary endpoint analysis of RTOG 0128. Int J Radiat Oncol Biol Phys. 2007 Jan 1;67(1):104-9. Epub 2006 Nov 2.
• Gaffney DK, Winter K, Dicker AP, Miller B, Eifel PJ, Ryu J, Avizonis V, Fromm M, Small W, Greven K. Efficacy and Patterns of Failure for Locally Advanced Cancer of the Cervix Treated with Celebrex (Celecoxib) and Chemoradiotherapy in RTOG 0128. Int J Radiat Oncol Biol Phys. 2007 May 3; [Epub ahead of print]
• Gaffney DK, Winter K, Dicker AP, et al.: Celebrex™ (celecoxib) and chemoradiation in patients with locally advanced cervical cancer. an efficacy report of RTOG 0128. [Abstract] Int J Radiat Oncol Biol Phys 66 (3 Suppl 1): A-70, S41, 2006.
• Gaffney DK, Winter K, Dicker A, et al.: 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. [Abstract] Int J Radiat Oncol Biol Phys 63 (2 Suppl 1): A-155, S93, 2005.
• Gaffney DK, Winter K, Fuhrman C, Flinner R, Greven K, Ryu J, Forbes A, Kerlin K, Nichols RC, Zempolich K. Feasibility of RNA collection for micro-array gene expression analysis in the treatment of cervical carcinoma: a scientific correlate of RTOG C-0128. Gynecol Oncol. 2005 May;97(2):607-11.
• Zempolich K, Milash B, Fuhrman C, et al.: Changes in gene expression induced by chemoradiation in advanced cervical carcinoma: a microarray study of RTOG C-0128. [Abstract] Int J Radiat Oncol Biol Phys 63 (2 Suppl 1): A-159, S96, 2005.
• Gaffney DK, Winter K, Fuhrman C, et al.: Feasibility of RNA collection for micro-array gene expression analysis in the treatment of cervical carcinoma: a scientific correlate of RTOG C-0128. [Abstract] Int J Radiat Oncol Biol Phys 60 (Suppl 1): A-2239, S479, 2004.
• Viswanathan AN, Moughan J, Small W Jr, Levenback C, Iyer R, Hymes S, Dicker AP, Miller B, Erickson B, Gaffney DK. The Quality of Cervical Cancer Brachytherapy Implantation and the Impact on Local Recurrence and Disease-Free Survival in Radiation Therapy Oncology Group Prospective Trials 0116 and 0128. Int J Gynecol Cancer. 2012 Jan;22(1):123-131.

DISEASE CHARACTERISTICS:

• Histologically confirmed squamous, adenocarcinoma, or adenosquamous carcinoma of the cervix

  • Stage IIB-IVA OR
  • Stage IB-IIA with pelvic node metastases and/or tumor size at least 5 cm
• No small cell, carcinoid, glassy cell, clear cell, or adenoid cystic disease
• No metastatic disease outside of pelvis
• No para-aortic disease

PATIENT CHARACTERISTICS:

Age:

• 18 to 85

Performance status:

• Zubrod 0-2

Life expectancy:

• At least 6 months

Hematopoietic:

• WBC at least 3,000/mm^3
• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• AST or ALT no greater than 2.5 times upper limit of normal (ULN)

Renal:

• Creatinine no greater than 1.5 mg/dL
• Creatinine clearance at least 50 mL/min
• Calcium no greater than 1.3 times ULN

Cardiovascular:

• No severe heart disease

Other:

• Not pregnant or nursing
• Negative pregnancy test
• HIV negative
• No prior allergy to sulfonamides or non-steroidal anti-inflammatory drugs (NSAIDs)
• No prior hypersensitivity to celecoxib or any component of its formulation
• No medical or psychiatric illness that would preclude study
• No active gastrointestinal (GI) ulcer, GI bleeding, or inflammatory bowel disease
• No other prior malignancy within the past 5 years except cutaneous basal cell skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No recent prior celecoxib or other cyclo-oxygenase-2 inhibitor

Chemotherapy:

• No prior systemic chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy to pelvis except transvaginal radiotherapy to control bleeding

Surgery:

• No prior surgery for cervical cancer except biopsy

Other:

• No concurrent phenytoin or lithium
• No other concurrent NSAIDs