Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Related Information
Registry Information

Alternate Title

Radiation Therapy and Either Capecitabine or Fluorouracil With or Without Oxaliplatin Before Surgery in Treating Patients With Resectable Rectal Cancer

Basic Trial Information

Special Category: CTSU trial, NCI - CMS pilot project trial, NCI Web site featured trial

Objectives

Primary

1. 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

1. Compare the rate of clinical complete response in patients treated with these regimens.
2. Compare the rate of pathologic complete response in patients treated with these regimens.
3. Determine the increase in the number of patients who are able to undergo sphincter-saving surgery after treatment with these regimens.
4. Correlate genetic patterns and the presence or absence of specific tissue biomarkers with response and prognosis in patients treated with these regimens.
5. Compare preoperative quality of life (QOL) of patients treated with oral capecitabine versus continuous infusion with fluorouracil.
6. Determine the impact of oxaliplatin on neurotoxicity in patients treated with these regimens.
7. Compare the toxic effects of these regimens in these patients.
8. Compare the convenience of care in patients treated with these regimens.
9. Determine the impact of the type of surgical management on QOL at 1 and 5 years postoperatively in these patients.
10. Describe the long-term impact of cancer treatment on symptoms (e.g., vitality and neurotoxicity) and QOL at 5 years after randomization (5-year follow-up visit).

Entry Criteria

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, N₀ [N₀is 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 T₄ 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

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)

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/mm³
• Platelet count ≥ 100,000/mm³

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

Expected Enrollment

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

Outcomes

Loco-regional disease control as assessed by evidence of tumor at 3 years

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

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 and 5 years after surgery.

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

Roh MS, Yothers GA, O'Connell MJ, et al.: The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. [Abstract] J Clin Oncol 29 (Suppl 15): A-3503, 2011.

Trial Contact Information

Trial Lead Organizations

National Surgical Adjuvant Breast and Bowel Project

Robert Beart, MD, Protocol chair		Ph: 323-865-3690; 800-865-0102 Email: rbeart@usc.edu

Cancer and Leukemia Group B

David Ryan, MD, Protocol chair		Ph: 617-724-0234; 877-726-5130

Related Information

Featured trial article

Registry Information
Official Title		A Clinical Trial Comparing Preoperative Radiation Therapy And Capecitabine With or Without Oxaliplatin With Preoperative Radiation Therapy And Continuous Intravenous Infusion Of 5-Fluorouracil With or Without Oxaliplatin In The Treatment Of Patients With Operable Carcinoma Of The Rectum
Trial Start Date		2004-07-23
Trial Completion Date		2013-09-30 (estimated)
Registered in ClinicalTrials.gov		NCT00058474
Date Submitted to PDQ		2003-03-05
Information Last Verified		2010-08-17
NCI Grant/Contract Number		CA12027

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