• Clinical complete response as assessed by digital rectal exam and sigmoidoscopy or proctoscopy at time of definitive analysis [ Designated as safety issue: No ]
• Pathologic complete response as assessed by gross and microscopic exam of surgical specimens at time of definitive analysis [ Designated as safety issue: No ]
• Sphincter-saving surgery at time of definitive analysis [ Designated as safety issue: No ]
• Survival as measured by deaths from any cause at time of definitive analysis [ Designated as safety issue: No ]
• Disease-free survival as assessed by recurrence, second primary cancer, or death from any cause at time of definitive analysis [ Designated as safety issue: No ]
• Tissue biomarkers as assessed by analysis of tumor tissue using current biotechnology after definitive analysis [ Designated as safety issue: No ]
• Quality of life as assessed by FACT-C trial outcome index and EORTC CR38 after definitive analysis [ Designated as safety issue: No ]
• Neurotoxicity as assessed by FACT-NTX scale after definitive analysis [ Designated as safety issue: Yes ]
• Symptoms as assessed by fluoropyrimidine symptom scale adapted from SWOG after definitive analysis [ Designated as safety issue: No ]
• Vitality as assessed by SF-36 vitality scale after definitive analysis [ Designated as safety issue: No ]
• Convenience of care as assessed by NSABP C-06 convenience of care scale adapted from ECOG after definitive analysis [ Designated as safety issue: No ]

• Clinical complete response as assessed by digital rectal exam and sigmoidoscopy or proctoscopy at time of definitive analysis
• Pathologic complete response as assessed by gross and microscopic exam of surgical specimens at time of definitive analysis
• Sphincter-saving surgery at time of definitive analysis
• Survival as measured by deaths from any cause at time of definitive analysis
• Disease-free survival as assessed by recurrence, second primary cancer, or death from any cause at time of definitive analysis
• Tissue biomarkers as assessed by analysis of tumor tissue using current biotechnology after definitive analysis
• Quality of life as assessed by FACT-C trial outcome index and EORTC CR38 after definitive analysis
• Neurotoxicity as assessed by FACT-NTX scale after definitive analysis
• Symptoms as assessed by fluoropyrimidine symptom scale adapted from SWOG after definitive analysis
• Vitality as assessed by SF-36 vitality scale after definitive analysis
• Convenience of care as assessed by NSABP C-06 convenience of care scale adapted from ECOG after definitive analysis

RATIONALE: Drugs used in chemotherapy, such as capecitabine, fluorouracil, and oxaliplatin work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells.

PURPOSE: This randomized phase III trial is studying radiation therapy and either capecitabine or fluorouracil with or without oxaliplatin and comparing them to see how well they work when given before surgery in treating patients with resectable rectal cancer. It is not yet known whether radiation therapy and either capecitabine or fluorouracil is more effective with or without oxaliplatin in treating rectal cancer.

OBJECTIVES:

Primary

• Compare the rate of local-regional relapse in patients with resectable rectal cancer treated with chemoradiotherapy comprising radiation therapy and either capecitabine or fluorouracil with or without oxaliplatin.

Secondary

• Compare the rate of clinical complete response in patients treated with these regimens.
• Compare the rate of pathologic complete response in patients treated with these regimens.
• Determine the increase in the number of patients who are able to undergo sphincter-saving surgery after treatment with these regimens.
• Correlate genetic patterns and the presence or absence of specific tissue biomarkers with response and prognosis in patients treated with these regimens.
• Compare preoperative quality of life (QOL) of patients treated with oral capecitabine versus continuous infusion with fluorouracil.
• Determine the impact of oxaliplatin on neurotoxicity in patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.
• Compare the convenience of care in patients treated with these regimens.
• Determine the impact of the type of surgical management on QOL at 1 year postoperatively in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, gender, clinical tumor stage (stage II vs stage III), and surgical intent (sphincter saving vs non-sphincter saving). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive fluorouracil IV continuously and undergo radiotherapy once daily 5 days a week for 5-6 weeks.
• Arm II: Patients receive fluorouracil and undergo radiotherapy as in arm I. Patients also receive oxaliplatin IV over 1 hour once weekly for 5 weeks.
• Arm III: Patients receive oral capecitabine twice daily and undergo radiotherapy once daily 5 days a week for 5-6 weeks.
• Arm IV: Patients receive capecitabine and undergo radiotherapy as in arm III. Patients also receive oxaliplatin as in arm II.

Within 6-8 weeks after the completion of chemoradiotherapy, patients with responding or stable disease undergo surgery. Patients with progressive disease are treated at the discretion of the investigator and continue to be followed.

Quality of life is assessed at baseline, at completion of chemoradiotherapy, and at 1 year after surgery.

After completion of study treatment, patients are followed every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 1,606 patients will be accrued for this study within 4 years.

• Drug: capecitabine
  Given by mouth
• Drug: fluorouracil
  Given IV continuously
• Drug: oxaliplatin
  Given IV
• Radiation: radiation therapy
  Given 5 days a week for 5-6 weeks

• Arm I: Active Comparator
  Patients receive fluorouracil IV continuously and undergo radiotherapy once daily 5 days a week for 5-6 weeks.
  Interventions:

  • Drug: fluorouracil
  • Radiation: radiation therapy
• Arm II: Experimental
  Patients receive fluorouracil and undergo radiotherapy as in arm I. Patients also receive oxaliplatin IV over 1 hour once weekly for 5 weeks.
  Interventions:

  • Drug: fluorouracil
  • Drug: oxaliplatin
  • Radiation: radiation therapy
• Arm III: Experimental
  Patients receive oral capecitabine twice daily and undergo radiotherapy once daily 5 days a week for 5-6 weeks.
  Interventions:

  • Drug: capecitabine
  • Radiation: radiation therapy
• Arm IV: Experimental
  Patients receive capecitabine and undergo radiotherapy as in arm III. Patients also receive oxaliplatin as in arm II.
  Interventions:

  • Drug: capecitabine
  • Drug: oxaliplatin
  • Radiation: radiation therapy

DISEASE CHARACTERISTICS:

• Diagnosis of adenocarcinoma of the rectum

  • Diagnosis obtained within 42 days of randomization by a biopsy technique which leaves the major portion of the tumor intact

  • Stage II (T_3-4, N_0 [N_0is defined as all imaged lymph nodes < 1.0 cm]) OR stage III (T_1-4, N_1-2 [with the definition of a clinically positive lymph node being any node ≥ 1.0 cm]

    • Stage of the primary tumor may be determined by ultrasound or MRI (CT scan is acceptable provided there is evidence of T_4 and/or N_1-2 disease
• Tumor palpable by digital rectal exam OR accessible by proctoscope or sigmoidoscope
• Distal border of the tumor must be located < 12 cm from the anal verge
• Tumor amenable to curative resection* NOTE: *Curative resection can include pelvic exenteration
• No history of invasive rectal malignancy, regardless of disease-free interval
• No other rectal cancers (i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, or cloacogenic carcinoma)
• No synchronous colon cancer
• No clear indication of involvement of the pelvic side walls by imaging
• No evidence of metastatic disease

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1 OR
• Zubrod 0-1

Life expectancy

• At least 5 years (excluding diagnosis of cancer)

Hematopoietic

• Absolute neutrophil count ≥ 1,200/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2 times ULN
• AST ≤ 2 times ULN*
• No hepatic disease that would preclude study treatment or follow-up
• No uncontrolled coagulopathy
• No history of viral hepatitis or other chronic liver disease NOTE: *If AST is > ULN, serologic testing for Hepatitis B and C must be performed and results must be negative

Renal

• Creatinine clearance > 50 mL/min
• No renal disease that would preclude study treatment or follow-up

Cardiovascular

• No cardiovascular disease that would preclude study treatment or follow-up
• No New York Heart Association class III or IV heart disease
• No active ischemic heart disease
• No myocardial infarction within the past 6 months
• No symptomatic arrhythmia
• No uncontrolled hypertension

Gastrointestinal

• Able to take oral medications
• No lack of upper gastrointestinal tract integrity or malabsorption syndrome
• No active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic)

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• Patients with prior malignancies, including invasive colon cancer, are eligible provided they have been disease-free for ≥ 5 years and are deemed by their physician to be at low risk for recurrence
• No other malignancy within the past 5 years except effectively treated squamous cell or basal cell skin cancer, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum
• No other nonmalignant systemic disease that would preclude study therapy or follow-up
• No known hypersensitivity to fluorouracil, capecitabine, or oxaliplatin
• No clinically significant peripheral neuropathy (i.e., neurosensory or neuromotor toxicity ≥ grade 2)
• No psychiatric or addictive disorders, or other conditions that, in the opinion of the investigator, would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)

Radiotherapy

• No prior pelvic radiotherapy

Surgery

• See Disease Characteristics

Other

• No prior therapy for this cancer
• More than 4 weeks since prior participation in any investigational drug study
• No concurrent halogenated antiviral agents (e.g., sorivudine or brivudine)

• National Cancer Institute (NCI)
• Cancer and Leukemia Group B