RATIONALE: Drugs used in chemotherapy 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 chemotherapy, radiation therapy, and surgery may be effective treatment for rectal cancer.

PURPOSE: Phase I trial to study the effectiveness of radiation therapy plus chemotherapy followed by surgery and additional chemotherapy in treating patients who have advanced nonmetastatic primary cancer of the rectum.

Condition	Treatment or Intervention	Phase
stage II rectal cancer stage III rectal cancer adenocarcinoma of the rectum	Drug: fluorouracil  Drug: leucovorin calcium  Drug: oxaliplatin  Procedure: adjuvant therapy  Procedure: chemotherapy  Procedure: conventional surgery  Procedure: neoadjuvant therapy  Procedure: radiation therapy  Procedure: surgery	Phase I

Further Study Details: 

OBJECTIVES:

• Determine the maximum tolerated dose and dose-limiting toxicity of oxaliplatin when combined preoperatively with concurrent radiotherapy and fluorouracil in patients with locally advanced rectal adenocarcinoma.
• Evaluate the resection rate for T4 rectal cancers, the pathological complete response rate for T3 and T4 rectal cancers, and the expected vs actual type of resection (abdominoperineal resection vs low anterior resection [LAR] vs LAR/coloanal anastomosis) in patients treated with this regimen.
• Determine survival and patterns of recurrence in this patient population after this treatment regimen.
• Evaluate anastomotic and sphincter function in these patients after preoperative combined modality therapy.

OUTLINE: This is a dose-escalation study of preoperative oxaliplatin.

Patients receive fluorouracil IV continuously with concurrent radiotherapy for 5.5 weeks. Patients also receive oxaliplatin IV over 2 hours on day 1 of weeks 1, 3, and 5.

Cohorts of 5 patients each receive escalating doses of oxaliplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 5 patients experience dose-limiting toxicity. Additional patients are treated at the MTD.

Patients undergo surgery 6-8 weeks after completing preoperative chemotherapy and radiotherapy. The surgical procedure is determined by the extent of the tumor before preoperative therapy. The type of operative procedure may be abdominoperineal resection, low anterior resection (LAR), or LAR/coloanal anastomosis.

Postoperative chemotherapy begins within 6 weeks after surgery, comprising leucovorin calcium and fluorouracil IV on days 1-5. Treatment repeats every 21 days for 4 courses.

Patients are followed every 3 months for 2.5 years, every 6 months for 3 years, then annually for 5 years.

PROJECTED ACCRUAL: A total of 20 patients will be accrued for this study within 1 year.

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

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed locally advanced, nonmetastatic primary adenocarcinoma of the rectum
• Stage II or III (T3 or T4)
• Clinically resectable OR
• Clinically fixed or initially not completely resectable (T4, N0-2, M0) based on the presence of at least one of the following criteria:
• Clinically fixed tumor on rectal exam with tumor adherent to the pelvic sidewall or sacrum
• Sciatica attributed to sacral root invasion with CT scan/MRI evidence of lack of clear tissue plane as evidence of fixation
• Hydronephrosis on CT scan or IVP, or ureteric or bladder invasion by cystoscopy and cytology or biopsy, or invasion into prostate
• Vaginal or uterine involvement
• No tumor outside of the pelvis, including:
• Liver metastases
• Peritoneal seeding
• Metastatic inguinal lymphadenopathy
• Distal border of tumor must be at or below the peritoneal reflection, defined as within 12 cm of anal verge by proctoscopic exam
• Transmural penetration through the muscularis propria demonstrated by CT scan plus endorectal ultrasound or MRI
• No high-grade (lumen diameter less than 1 cm) large bowel obstruction, unless diverting colostomy has been performed

PATIENT CHARACTERISTICS: Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 3500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin less than 2.0 mg/dL
• Alkaline phosphatase no greater than 2 times upper limit of normal (ULN)
• SGOT no greater than 2 times ULN

Renal:

• Creatinine no greater than 2.0 mg/dL

Other:

• Caloric intake at least 1500 kilocalories per day
• No other prior malignancy within the past 5 years except nonmelanoma skin cancer or carcinoma in situ of the cervix
• No active inflammatory bowel disease
• No other serious medical illness
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior pelvic radiotherapy
• No concurrent intraoperative radiotherapy or brachytherapy

Surgery:

• Not specified

Georgia
      Emory University Hospital - Atlanta, Atlanta,  Georgia,  30322,  United States
      Veterans Affairs Medical Center - Atlanta (Decatur), Decatur,  Georgia,  30033,  United States
Pennsylvania
      Abramson Cancer Center of the University of Pennsylvania, Philadelphia,  Pennsylvania,  19104,  United States

Study chairs or principal investigators

David I. Rosenthal, MD,  Study Chair,  M.D. Anderson Cancer Center   

Study ID Numbers:  CDR0000066943; E-1297; ECOG-1297
Record last reviewed:  January 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00003799
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08