RATIONALE: Drugs used in chemotherapy, such as irinotecan, leucovorin, fluorouracil, and oxaliplatin, use 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. Combining radiation therapy with chemotherapy may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of induction chemotherapy followed by chemoradiotherapy in treating patients who have locally advanced adenocarcinoma of the rectum.

Condition	Treatment or Intervention	Phase
stage II rectal cancer stage III rectal cancer adenocarcinoma of the rectum	Drug: capecitabine  Drug: fluorouracil  Drug: irinotecan  Drug: leucovorin calcium  Drug: oxaliplatin  Procedure: chemotherapy  Procedure: radiation therapy	Phase II

Further Study Details: 

OBJECTIVES:

• Determine the feasibility of obtaining a pre-treatment determination of intratumoral molecular markers (TS, DPD, and ERCC-1) for use in selection of the appropriate regimen for induction cytotoxic combination chemotherapy in patients with cT4 rectal adenocarcinoma.
• Determine the response probability (unconfirmed, complete and partial) in patients treated with targeted induction cytotoxic chemotherapy.
• Determine the toxicity of targeted induction cytotoxic chemotherapy and chemoradiotherapy in these patients.
• Determine the response probability in these patients treated with chemoradiotherapy.

OUTLINE: This is a multicenter study.

• Patients are assigned to 1 of 3 treatment groups based on molecular analysis of the pretreatment tumor specimen.
• Group I (lower likelihood of resistance to a fluorouracil-based regimen): Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1.
• Group II (higher likelihood of resistance to a fluorouracil-based regimen): Patients receive oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on day 1.
• Group III (high likelihood of sensitivity to oxaliplatin and fluorouracil therapy): Patients receive oxaliplatin IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1. Treatment in all groups repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients are evaluated for response approximately 2 weeks after the completion of induction chemotherapy. Patients with stable disease or better receive chemoradiotherapy.

• Chemoradiotherapy: Beginning approximately 3 weeks after the completion of induction chemotherapy, patients receive oral capecitabine twice daily continuously for 5 weeks and concurrent radiotherapy once daily 5 days a week for 5 weeks. After chemoradiotherapy, patients may undergo attempted surgical resection at the discretion of the treating physician.

Patients are followed every 3 months for 1 year and then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 10-65 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed primary adenocarcinoma of the rectum
• Locally advanced disease (clinical T4, N0-2, M0) based on at least 1 of the following criteria:
• Clinically fixed tumors on rectal examination with tumor adherent to the pelvic sidewall and/or sacrum
• Sciatica attributed to sacral root invasion with CT scan/MRI evidence of the lack of clear tissue plane is considered evidence of fixation
• Hydronephrosis on CT scan or intravenous pyelogram of ureteric or bladder invasion by cystoscopy and cytology or biopsy
• Invasion into the prostate, vagina, or uterus
• Transmural penetration of tumor through the muscularis propria as evidenced by CT scan or MRI and endorectal ultrasound
• Distal border of the tumor must be at or below the peritoneal reflection (within 12 cm of the anal verge) by proctoscopic examination
• Measurable disease by x-ray, scans, or physical examination
• Available tumor tissue to determine molecular profile of the tumor before study treatment
• No clinical evidence of high-grade (lumen diameter < 1 cm) large bowel obstruction unless a diverting colostomy has been performed

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

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

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• SGOT or SGPT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN

Renal

• See Disease Characteristics
• Creatinine ≤ 1.5 times ULN OR
• Estimated creatinine clearance > 50 mL/min

Cardiovascular

• No significant cardiac disease
• No recent myocardial infarction

Gastrointestinal

• See Disease Characteristics
• Able to swallow oral medication
• No active inflammatory bowel disease

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No prior unanticipated severe reaction to study drugs
• No known dihydropyrimidine dehydrogenase deficiency
• No serious uncontrolled infection
• No other serious medical illness that would preclude study treatment

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy for colon or rectal cancer

Endocrine therapy

• Not specified

Radiotherapy

• No prior pelvic radiotherapy
• No prior intra-operative radiotherapy or brachytherapy
• No concurrent intra-operative radiotherapy or brachytherapy
• No concurrent intensity-modulated radiotherapy

Surgery

• See Disease Characteristics
• See Radiotherapy

Arizona
      Arizona Cancer Center at University of Arizona Health Sciences Center, Tucson,  Arizona,  85724,  United States; Recruiting
California
      University of California Davis Cancer Center, Sacramento,  California,  95817,  United States; Recruiting
      USC/Norris Comprehensive Cancer Center and Hospital, Los Angeles,  California,  90033,  United States; Recruiting
Massachusetts
      Cancer Research Center at Boston Medical Center, Boston,  Massachusetts,  02118,  United States; Recruiting
Texas
      MD Anderson Cancer Center at University of Texas, Houston,  Texas,  77030-4095,  United States; Recruiting
      University of Texas Health Science Center at San Antonio, San Antonio,  Texas,  78229-3900,  United States; Recruiting

Study chairs or principal investigators

Charles R. Thomas, MD,  University of Texas   
Heinz-Josef Lenz, MD,  University of Southern California   
Robert P. Whitehead, MD,  University of Texas   
James L. Abbruzzese, MD,  M.D. Anderson Cancer Center   
Stephen R. Smalley, MD,  Radiation Oncology Center of Olathe   
Morton S. Kahlenberg, MD,  University of Texas   

Study ID Numbers:  CDR0000334469; SWOG-S0304; NCT00070434
Record last reviewed:  September 2004
Last Updated:  February 4, 2005
Record first received:  October 3, 2003
ClinicalTrials.gov Identifier:  NCT00070434
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08