RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which chemotherapy regimen is more effective for stage III colon cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of fluorouracil plus leucovorin with or without irinotecan in treating patients who have undergone surgery for stage III colon cancer.

OBJECTIVES: I. Compare the overall and disease free survival of patients with stage III colon cancer treated with adjuvant fluorouracil and leucovorin calcium with or without irinotecan. II. Assess prognostic markers and correlate their expression with disease free and overall survival of these patients. III. Assess the influence of diet, body mass index, and physical activity on the risk of cancer recurrence and survival in these patients. IV. Assess the influence of diet, obesity, and physical activity on the risk of toxicity associated with adjuvant therapy in these patients. V. Determine whether pathological features (including tumor grade, tumor mitotic (proliferation) index, tumor border configuration, and host lymphoid response to tumor; and lymphatic vessel, venous vessel and perineural invasion) predict outcome in this patient population.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to lymph node involvement (1-3 vs 4 or more), histology (poorly differentiated or undifferentiated vs well or moderately differentiated), and preoperative serum CEA (less than 5.0 ng/mL vs at least 5.0 ng/mL vs unknown). Study therapy must begin within 21-56 days after surgery. Patients are randomized to one of two treatment arms: Arm I: Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV beginning 1 hour into leucovorin calcium infusion weekly for 6 weeks. Treatment is repeated every 8 weeks for 4 courses. Arm II: Patients receive irinotecan IV over 90 minutes, followed by leucovorin calcium IV, then followed by fluorouracil IV weekly for 4 weeks. Treatment is repeated every 6 weeks for 5 courses. Patients complete a food questionnaire at the beginning of the third course and then at 6 months after study therapy. Patients are followed every 3 months for 2 years, every 4 months for 2 years, then annually thereafter.

PROJECTED ACCRUAL: A total of 1260 patients will be accrued for this study within 3 years.

• Drug: FOLFIRI regimen
• Drug: fluorouracil
• Drug: irinotecan hydrochloride
• Drug: leucovorin calcium

• Bertagnolli MM, Niedzwiecki D, Compton CC, Hahn HP, Hall M, Damas B, Jewell SD, Mayer RJ, Goldberg RM, Saltz LB, Warren RS, Redston M. Microsatellite Instability Predicts Improves Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803. J Clin Oncol. 2009 Mar 9; [Epub ahead of print]
• Bertagnolli MM, Warren RS, Niedzwiecki D, Mueller E, Compton CC, Redston M, Hall M, Hahn HP, Jewell SD, Mayer RJ, Goldberg RM, Saltz LB, Loda M. p27Kip1 in Stage III Colon Cancer: Implications for Outcome following Adjuvant Chemotherapy in Cancer and Leukemia Group B Protocol 89803. Clin Cancer Res. 2009 Mar 15;15(6):2116-22. Epub 2009 Mar 10.
• Chan JA, Meyerhardt JA, Niedzwiecki D, Hollis D, Saltz LB, Mayer RJ, Thomas J, Schaefer P, Whittom R, Hantel A, Goldberg RM, Warren RS, Bertagnolli M, Fuchs CS. Association of family history with cancer recurrence and survival among patients with stage III colon cancer. JAMA. 2008 Jun 4;299(21):2515-23.
• Meyerhardt JA, Niedzwiecki D, Hollis D, Saltz LB, Mayer RJ, Nelson H, Whittom R, Hantel A, Thomas J, Fuchs CS; Cancer and Leukemia Group B 89803. Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: findings from Cancer and Leukemia Group B 89803. J Clin Oncol. 2008 Sep 1;26(25):4109-15.
• Meyerhardt JA, Niedzwiecki D, Hollis D, Saltz LB, Hu FB, Mayer RJ, Nelson H, Whittom R, Hantel A, Thomas J, Fuchs CS. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA. 2007 Aug 15;298(7):754-64.
• Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, Fields AL, Mayer RJ. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007 Aug 10;25(23):3456-61.
• Meyerhardt JA, Heseltine D, Niedzwiecki D, Hollis D, Saltz LB, Mayer RJ, Thomas J, Nelson H, Whittom R, Hantel A, Schilsky RL, Fuchs CS. Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Clin Oncol. 2006 Aug 1;24(22):3535-41. Epub 2006 Jul 5.

DISEASE CHARACTERISTICS: Histologically proven stage III (Tx, N1-2, M0) adenocarcinoma of the colon Gross inferior (caudal) margin of primary tumor must be above the peritoneal reflection Completely resected with negative radial resecting margins No distant metastatic disease

PATIENT CHARACTERISTICS: Age: 18 and over Performance status: Zubrod 0-2 Life expectancy: Not specified Hematopoietic: Granulocyte count at least 1,500/mm3 Platelet count at least 100,000/mm3 Hepatic: Bilirubin no greater than upper limit of normal (ULN) Renal: Creatinine no greater than 1.5 times ULN Other: No other prior or concurrent malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix Not pregnant or nursing Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior chemotherapy for colon cancer No other concurrent chemotherapy Endocrine therapy: No concurrent hormone therapy except: Steroids for adrenal failure Hormones for nondisease related conditions (e.g., diabetes) Intermittent dexamethasone as an antiemetic Radiotherapy: No prior radiotherapy for colon cancer Surgery: See Disease Characteristics

• National Cancer Institute (NCI)
• North Central Cancer Treatment Group
• NCIC Clinical Trials Group
• Southwest Oncology Group
• Eastern Cooperative Oncology Group