Oxaliplatin, Capecitabine, and Radiation Therapy in Treating Patients With Locally Advanced Cancer of the Rectum

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of neoadjuvant oxaliplatin and capecitabine when combined with radiotherapy in patients with locally advanced adenocarcinoma of the rectum. (Phase I closed to accrual as of 06/2005.)
• Determine the rate of complete pathological response in patients treated with this regimen.

Secondary

• Determine the overall survival of patients treated with this regimen.
• Determine the rate of local and overall failure in patients treated with this regimen.
• Determine the utility of TS, TP, DPD, ERCC-1, and apoptosis to predict response in patients treated with this regimen.
• Determine the rate of pathologic down-staging in patients treated with this regimen.
• Determine the safety and toxicity of this regimen in these patients.
• Determine the rate of sphincter-saving rectal surgery in patients treated with this regimen who had been deemed candidates for abdominoperineal resection at diagnosis.

OUTLINE: This is a multicenter, phase I (phase I closed to accrual as of 06/2005), dose-escalation study of oxaliplatin and capecitabine followed by a phase II study.

• Phase I (closed to accrual as of 06/2005): Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks and receive oral capecitabine twice daily on days radiotherapy is administered. Beginning on day 1 of radiotherapy, patients also receive oxaliplatin IV over 2 hours on days 1, 8, 15, 22, and 29.

Cohorts of 3-6 patients receive escalating doses of oxaliplatin and capecitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients undergo radiotherapy and receive capecitabine and oxaliplatin as in phase I at the MTD.

All patients undergo curative-intent surgery 6-8 weeks after the completion of chemoradiotherapy.

Patients are followed every 3 months for 3 years and then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 31-40 patients (6-15 for phase I [phase I closed to accrual as of 06/2005] and 25 for phase II) will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the rectum

• Tumor involving the distal 12 cm of the rectum (above the anal verge)
• Clinically staged by endoscopic ultrasound with one of the following criteria:

• T3-T4 disease
• Evidence of lymph node involvement, defined by the presence of ≥ 1 enlarged peri-rectal lymph node (≥ 1 cm in size)
• No known distant metastases

PATIENT CHARACTERISTICS:

Age

• 18 to 75

Performance status

• ECOG 0-1 OR
• Karnofsky 70-100%

Life expectancy

• More than 1 year

Hematopoietic

• WBC ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin normal
• AST and ALT ≤ 2.5 times upper limit of normal

Renal

• Creatinine normal OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• Able to receive oral medication
• No other malignancy within the past 5 years except nonmelanoma skin cancer
• No prior or concurrent significant neuropathy
• No prior allergic reaction attributed to compounds of similar chemical or biological composition to study drugs
• No ongoing or active infection
• No other concurrent uncontrolled illness
• No psychiatric illness or social situation that would preclude study compliance
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective double-method contraception during and for 3 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent granulocyte-stimulating factors

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior pelvic radiotherapy

Surgery

• Not specified

Other

• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies