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

Sponsor:	National Surgical Adjuvant Breast and Bowel Project (NSABP)
Collaborators:	National Cancer Institute (NCI) Cancer and Leukemia Group B
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00058474

Purpose

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.

Condition	Intervention	Phase
Colorectal Cancer	Drug: capecitabine Drug: fluorouracil Drug: oxaliplatin Radiation: radiation therapy	Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Active Control
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

Resource links provided by NLM:

MedlinePlus related topics: Cancer Colorectal Cancer Surgery

Drug Information available for: Fluorouracil Oxaliplatin Capecitabine

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Loco-regional disease control as assessed by evidence of tumor at 3 years [ Designated as safety issue: No ]

Secondary Outcome Measures:

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 ]

Estimated Enrollment:	1606
Study Start Date:	July 2004
Estimated Primary Completion Date:	May 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Arm I: Active Comparator Patients receive fluorouracil IV continuously and undergo radiotherapy once daily 5 days a week for 5-6 weeks.	Drug: fluorouracil Given IV continuously Radiation: radiation therapy Given 5 days a week for 5-6 weeks
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.	Drug: fluorouracil Given IV continuously Drug: oxaliplatin Given IV Radiation: radiation therapy Given 5 days a week for 5-6 weeks
Arm III: Experimental Patients receive oral capecitabine twice daily and undergo radiotherapy once daily 5 days a week for 5-6 weeks.	Drug: capecitabine Given by mouth Radiation: radiation therapy Given 5 days a week for 5-6 weeks
Arm IV: Experimental Patients receive capecitabine and undergo radiotherapy as in arm III. Patients also receive oxaliplatin as in arm II.	Drug: capecitabine Given by mouth Drug: oxaliplatin Given IV Radiation: radiation therapy Given 5 days a week for 5-6 weeks

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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, 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)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00058474

Show 499 Study Locations

Sponsors and Collaborators

National Surgical Adjuvant Breast and Bowel Project (NSABP)

National Cancer Institute (NCI)

Cancer and Leukemia Group B

Investigators

Study Chair:	Robert W. Beart, MD	USC/Norris Comprehensive Cancer Center
Study Chair:	David P. Ryan, MD	Massachusetts General Hospital

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Featured trial article This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	National Surgical Adjuvant Breast and Bowel Project ( Norman Wolmark )
Study ID Numbers:	CDR0000298755, NSABP-R-04, CALGB-NSABP-R-04
Study First Received:	April 7, 2003
Last Updated:	November 21, 2009
ClinicalTrials.gov Identifier:	NCT00058474 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

stage II rectal cancer
stage III rectal cancer
adenocarcinoma of the rectum

Additional relevant MeSH terms:

Antimetabolites
Capecitabine
Antimetabolites, Antineoplastic
Digestive System Neoplasms
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Rectal Neoplasms
Gastrointestinal Diseases
Physiological Effects of Drugs
Colonic Diseases
Intestinal Diseases

Immunosuppressive Agents
Rectal Diseases
Pharmacologic Actions
Intestinal Neoplasms
Oxaliplatin
Neoplasms
Neoplasms by Site
Digestive System Diseases
Therapeutic Uses
Fluorouracil
Gastrointestinal Neoplasms
Colorectal Neoplasms

ClinicalTrials.gov processed this record on November 27, 2009