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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Cancer and Leukemia Group B
Information provided by (Responsible Party):
National Surgical Adjuvant Breast and Bowel Project (NSABP)
ClinicalTrials.gov Identifier:
NCT00058474
First received: April 7, 2003
Last updated: January 24, 2014
Last verified: January 2014
  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 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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:


Further study details as provided by National Surgical Adjuvant Breast and Bowel Project (NSABP):

Primary Outcome Measures:
  • Loco-regional disease control as assessed by evidence of tumor at 3 years [ Time Frame: Time from randomization to first local recurrence up to 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 [ Time Frame: Prior to surgery approximately 6 weeks ] [ Designated as safety issue: No ]
  • Pathologic complete response as assessed by gross and microscopic exam of surgical specimens at time of definitive analysis [ Time Frame: At the time of surgery approximately 6 weeks ] [ Designated as safety issue: No ]
  • Sphincter-saving surgery at time of definitive analysis [ Time Frame: At the time of surgery approximately 6 weeks ] [ Designated as safety issue: No ]
  • Survival as measured by deaths from any cause at time of definitive analysis [ Time Frame: From time of randomization through 5 years ] [ 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 [ Time Frame: From time of randomization through 5 years ] [ Designated as safety issue: No ]
  • Tissue biomarkers as assessed by analysis of tumor tissue using current biotechnology after definitive analysis [ Time Frame: At the time of surgery approximately 6 weeks ] [ Designated as safety issue: No ]
  • Quality of life as assessed by FACT-C trial outcome index and EORTC CR38 after definitive analysis [ Time Frame: Assessed prior to therapy and at approximately 5 weeks, 15 months, 5 years ] [ Designated as safety issue: No ]
  • Neurotoxicity as assessed by FACT-NTX scale after definitive analysis [ Time Frame: Assessed prior to therapy and at approximately 5 weeks, 15 months, 5 years ] [ Designated as safety issue: Yes ]
  • Symptoms as assessed by fluoropyrimidine symptom scale adapted from SWOG after definitive analysis [ Time Frame: Assessed prior to therapy and at approximately 5 weeks, 15 months ] [ Designated as safety issue: No ]
  • Vitality as assessed by SF-36 vitality scale after definitive analysis [ Time Frame: Assessed prior to therapy and at approximately 5 weeks, 15 months, 5 years ] [ Designated as safety issue: No ]
  • Convenience of care as assessed by NSABP C-06 convenience of care scale adapted from ECOG after definitive analysis [ Time Frame: Assessed prior to therapy and at approximately 5 weeks, 15 months ] [ Designated as safety issue: No ]

Enrollment: 1608
Study Start Date: July 2004
Estimated Study Completion Date: August 2015
Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm 1: 5-FU + RT
Patients receive fluorouracil IV continuously and undergo radiation therapy (RT) once daily 5 days a week for 5-6 weeks.
Drug: fluorouracil
225 mg/m2 IV daily continuous infusion
Other Name: 5-FU
Radiation: radiation therapy
Given 5 days a week for 5-6 weeks
Other Name: RT
Experimental: Arm 2: 5-FU + RT + Oxaliplatin
Patients receive fluorouracil and undergo RT as in arm 1. Patients also receive oxaliplatin IV over 1 hour once weekly for 5 weeks.
Drug: fluorouracil
225 mg/m2 IV daily continuous infusion
Other Name: 5-FU
Drug: oxaliplatin
50 mg/m2 IV 5 days a week on days of planned RT
Radiation: radiation therapy
Given 5 days a week for 5-6 weeks
Other Name: RT
Experimental: Arm 3: Capecitabine + RT
Patients receive oral capecitabine twice daily and undergo RT once daily 5 days a week for 5-6 weeks.
Drug: capecitabine
825 mg/m2 oral daily 5 days a week on days of planned RT
Radiation: radiation therapy
Given 5 days a week for 5-6 weeks
Other Name: RT
Experimental: Arm 4: Capecitabine + RT + Oxaliplatin
Patients receive capecitabine and undergo RT as in arm 3. Patients also receive oxaliplatin as in arm 2.
Drug: capecitabine
825 mg/m2 oral daily 5 days a week on days of planned RT
Drug: oxaliplatin
50 mg/m2 IV 5 days a week on days of planned RT
Radiation: radiation therapy
Given 5 days a week for 5-6 weeks
Other Name: RT

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 and 5 years postoperatively in these patients.
  • 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).

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 1: Patients receive fluorouracil IV continuously and undergo radiotherapy once daily 5 days a week for 5-6 weeks.
  • Arm 2: Patients receive fluorouracil and undergo radiotherapy as in arm 1. Patients also receive oxaliplatin IV over 1 hour once weekly for 5 weeks.
  • Arm 3: Patients receive oral capecitabine twice daily and undergo radiotherapy once daily 5 days a week for 5-6 weeks.
  • Arm 4: Patients receive capecitabine and undergo radiotherapy as in arm 3. Patients also receive oxaliplatin as in arm 2.

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.

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

Inclusion Criteria:

  • Patients must consent to participate in the study and must have signed and dated an IRB-approved consent form conforming to federal and institutional guidelines.
  • Patients must be > 18 years of age.
  • Patients must have a life expectancy of 5 years, excluding their diagnosis of cancer (as determined by the investigator), and must have an Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status of 0 or 1.
  • Patients must have a diagnosis of adenocarcinoma of the rectum obtained by a biopsy technique which leaves the major portion of the tumor intact.
  • The interval between the initial diagnosis of rectal adenocarcinoma and randomization must be no more than 42 days.
  • Prior to randomization, the investigator must specify the intent for sphincter saving or non-sphincter saving surgery.
  • The tumor must be either palpable by digital rectal exam or be accessible via a proctoscope or sigmoidoscope.
  • Distal border of the tumor must be located < 12 cm from the anal verge.
  • The tumor must be considered by the surgeon to be amenable to curative resection. (Note that curative resection can include pelvic exenteration.)
  • The tumor must be clinically Stage II (T3-4 N0 with N0 being defined as all imaged lymph nodes are < 1.0 cm) or Stage III (T1-4 N1-2 with the definition of a clinically positive node being any node > 1.0 cm). Stage of the primary tumor may be determined by ultrasound or Magnetic Resonance Imaging (MRI). Computed Tomography (CT) scan is acceptable provided there is evidence of T4 and/or N1-2 disease.
  • At the time of randomization, all patients must have had the following within the previous 42 days: history and physical examination; if technically feasible, a complete colonoscopic examination; if not feasible, a proctoscopic or sigmoidoscopic exam; clinical staging of the tumor; CT or MRI of the abdomen and pelvis (combined PET/CT may be substituted), and a chest x-ray (PA and lateral) or CT scan of the chest to exclude patients with metastatic disease.
  • At the time of randomization: Absolute neutrophil count (ANC) must be > 1,200/mm3; Platelet count must be > 100,000/mm3; There must be evidence of adequate hepatic function as follows: total bilirubin must be < 1.5 x the upper limit of normal (ULN) for the lab; and alkaline phosphatase must be < 2.5 x Upper Limit of Normal (ULN) for the lab; and the Aspartate Amino Transferase (AST) must be < 2.5 x ULN for the lab; and If AST is > ULN, serologic testing for Hepatitis B and C must be performed and results must be negative; Calculated creatinine clearance must be > 50 mL/min.
  • Patients with prior malignancies, including invasive colon cancer, are eligible if they have been disease-free for > 5 years and are deemed by their physician to be at low risk for recurrence. Patients with squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum that have been effectively treated are eligible, even if these conditions were diagnosed within 5 years prior to randomization.

Exclusion Criteria:

  • Findings of metastatic disease.
  • On imaging, clear indication of involvement of the pelvic side wall(s).
  • Rectal cancers other than adenocarcinoma, i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, cloacogenic carcinoma, etc.
  • History of invasive rectal malignancy, regardless of disease-free interval.
  • Pregnancy or lactation at the time of proposed randomization. Eligible patients of reproductive potential (both sexes) must agree to use adequate contraceptive methods.
  • Any therapy for this cancer prior to randomization.
  • Synchronous colon cancer.
  • History of viral hepatitis or other chronic liver disease.
  • Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude the patient from receiving any chemotherapy treatment option or would prevent required follow-up. Specifically excluded are patients with active ischemic heart disease (class III* or class IV** myocardial disease as described by the New York Heart Association), a recent history (within 6 months) of myocardial infarction, or symptomatic arrhythmia at the time of randomization. *Class III: Patients with cardiac disease resulting in marked limitation of physical activity. Such patients are comfortable at rest. Less than ordinary physical activity that causes fatigue, palpitation, dyspnea, or anginal pain. **Class IV: Patients with cardiac disease resulting in inability to perform any physical activity without discomfort. Symptoms of cardiac insufficiency or anginal syndrome may be present even at rest.
  • Patients who, in the opinion of the investigator, have uncontrolled hypertension.
  • Active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic).
  • Prior pelvic radiation therapy for any reason.
  • Known hypersensitivity to 5-fluorouracil, capecitabine, or oxaliplatin.
  • Clinically significant peripheral neuropathy at the time of randomization (defined in the NCI Common Terminology Criteria for Adverse Events Version 3.0 [CTCAE v3.0] as grade 2 or greater neurosensory or neuromotor toxicity).
  • Existing uncontrolled coagulopathy.
  • Inability to take oral medications.
  • Participation in any investigational drug study within 4 weeks prior to randomization.
  • Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Sponsors and Collaborators
National Surgical Adjuvant Breast and Bowel Project (NSABP)
Cancer and Leukemia Group B
Investigators
Principal Investigator: Norman Wolmark, MD NSABP Foundation, Inc.
  More Information

Additional Information:
No publications provided by National Surgical Adjuvant Breast and Bowel Project (NSABP)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Surgical Adjuvant Breast and Bowel Project (NSABP)
ClinicalTrials.gov Identifier: NCT00058474     History of Changes
Other Study ID Numbers: NSABP R-04, NSABP-R-04, CALGB-NSABP-R-04
Study First Received: April 7, 2003
Last Updated: January 24, 2014
Health Authority: United States: Data and Safety Monitoring Board
United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board
Canada: Ethics Review Committee
Canada: Health Canada

Keywords provided by National Surgical Adjuvant Breast and Bowel Project (NSABP):
stage II rectal cancer
stage III rectal cancer
adenocarcinoma of the rectum

Additional relevant MeSH terms:
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Colonic Diseases
Fluorouracil
Capecitabine
Oxaliplatin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 26, 2014