Combination Chemotherapy in Treating Patients With Stage III Colon Cancer

Phase III Intergroup Trial of Irinotecan (CPT-11) (NSC# 616348) Plus Fluorouracil/Leucovorin (5-FU/LV) Versus Fluorouracil/Leucovorin Alone After Curative Resection for Patients With Stage III Colon Cancer

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. 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.

Study Overview

• Status: Completed
• Conditions: Stage III Colon Cancer; Adenocarcinoma of the Colon
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: leucovorin calcium; Drug: fluorouracil; Drug: irinotecan hydrochloride

Detailed Description

PRIMARY 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.

• Study Type: Interventional
• Enrollment (Anticipated): 1260
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60606
      • Cancer and Leukemia Group B

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have histologically documented adenocarcinoma of the colon; the gross inferior (caudad) margin of the primary tumor must lie above the peritoneal reflection; tumor must have been completely resected, including negative radial resecting margins
• There must be no history of distant metastatic disease at the time of registration
• Pathological evaluation must show Modified Astler-Coller stage C (TxN1-2M0) disease
• No previous or concurrent malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for five years
• Zubrod performance status of 0-2
• Non-pregnant and not nursing, as chemotherapy is thought to present substantial risk to the fetus/infant; men and women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method while in this study
• Granulocytes >= 1,500/ul
• Platelet count >= 100,000/ul
• Creatinine =< 1.5 x upper limits of normal
• Bilirubin =< upper limit of normal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (leucovorin calcium and fluorouracil); 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.	Other: laboratory biomarker analysis; Correlative studies; Drug: leucovorin calcium; Given IV; Drug: fluorouracil; Given IV
Experimental: Arm II (leucovorin calcium, fluorouracil, irinotrcan); 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	Other: laboratory biomarker analysis; Correlative studies; Drug: leucovorin calcium; Given IV; Drug: fluorouracil; Given IV; Drug: irinotecan hydrochloride; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to recurrence	The Cox proportional hazards model will be used to determine the association between each marker and time to recurrence and survival controlling for other baseline factors such as age, gender, treatment, primary tumor site, degree of differentiation.	From time of resection until documented disease progression, assessed up to 6 years
Survival	The Cox proportional hazards model will be used to determine the association between each marker and time to recurrence and survival controlling for other baseline factors such as age, gender, treatment, primary tumor site, degree of differentiation.	Up to 6 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: Eastern Cooperative Oncology Group; NCIC Clinical Trials Group; Southwest Oncology Group; North Central Cancer Treatment Group
• Investigators: Principal Investigator: Leonard Saltz, Cancer and Leukemia Group B

Publications and helpful links

General Publications

• Yothers G, Sargent DJ, Wolmark N, Goldberg RM, O'Connell MJ, Benedetti JK, Saltz LB, Dignam JJ, Blackstock AW; ACCENT Collaborative Group. Outcomes among black patients with stage II and III colon cancer receiving chemotherapy: an analysis of ACCENT adjuvant trials. J Natl Cancer Inst. 2011 Oct 19;103(20):1498-506. doi: 10.1093/jnci/djr310. Epub 2011 Oct 12.
• Lee S, Ma C, Zhang S, Ou FS, Bainter TM, Niedzwiecki D, Saltz LB, Mayer RJ, Whittom R, Hantel A, Benson A, Atienza D, Kindler H, Gross CP, Irwin ML, Meyerhardt JA, Fuchs CS. Marital Status, Living Arrangement, and Cancer Recurrence and Survival in Patients with Stage III Colon Cancer: Findings from CALGB 89803 (Alliance). Oncologist. 2022 Jun 8;27(6):e494-e505. doi: 10.1093/oncolo/oyab070.
• Kosumi K, Hamada T, Zhang S, Liu L, da Silva A, Koh H, Twombly TS, Mima K, Morikawa T, Song M, Nowak JA, Nishihara R, Saltz LB, Niedzwiecki D, Ou FS, Zemla T, Mayer RJ, Baba H, Ng K, Giannakis M, Zhang X, Wu K, Giovannucci EL, Chan AT, Fuchs CS, Meyerhardt JA, Ogino S. Prognostic association of PTGS2 (COX-2) over-expression according to BRAF mutation status in colorectal cancer: Results from two prospective cohorts and CALGB 89803 (Alliance) trial. Eur J Cancer. 2019 Apr;111:82-93. doi: 10.1016/j.ejca.2019.01.022. Epub 2019 Mar 1.
• Van Blarigan EL, Ou FS, Niedzwiecki D, Zhang S, Fuchs CS, Saltz L, Mayer RJ, Venook A, Ogino S, Song M, Benson A, Hantel A, Atkins JN, Giovannucci EL, Meyerhardt JA. Dietary Fat Intake after Colon Cancer Diagnosis in Relation to Cancer Recurrence and Survival: CALGB 89803 (Alliance). Cancer Epidemiol Biomarkers Prev. 2018 Oct;27(10):1227-1230. doi: 10.1158/1055-9965.EPI-18-0487. Epub 2018 Jul 23.
• Van Blarigan EL, Fuchs CS, Niedzwiecki D, Zhang S, Saltz LB, Mayer RJ, Mowat RB, Whittom R, Hantel A, Benson A, Atienza D, Messino M, Kindler H, Venook A, Ogino S, Giovannucci EL, Ng K, Meyerhardt JA. Association of Survival With Adherence to the American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors After Colon Cancer Diagnosis: The CALGB 89803/Alliance Trial. JAMA Oncol. 2018 Jun 1;4(6):783-790. doi: 10.1001/jamaoncol.2018.0126. Erratum In: JAMA Oncol. 2019 Apr 1;5(4):579.
• Fadelu T, Zhang S, Niedzwiecki D, Ye X, Saltz LB, Mayer RJ, Mowat RB, Whittom R, Hantel A, Benson AB, Atienza DM, Messino M, Kindler HL, Venook A, Ogino S, Ng K, Wu K, Willett W, Giovannucci E, Meyerhardt J, Bao Y, Fuchs CS. Nut Consumption and Survival in Patients With Stage III Colon Cancer: Results From CALGB 89803 (Alliance). J Clin Oncol. 2018 Apr 10;36(11):1112-1120. doi: 10.1200/JCO.2017.75.5413. Epub 2018 Feb 28.
• Fuchs MA, Yuan C, Sato K, Niedzwiecki D, Ye X, Saltz LB, Mayer RJ, Mowat RB, Whittom R, Hantel A, Benson A, Atienza D, Messino M, Kindler H, Venook A, Innocenti F, Warren RS, Bertagnolli MM, Ogino S, Giovannucci EL, Horvath E, Meyerhardt JA, Ng K. Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 (Alliance). Ann Oncol. 2017 Jun 1;28(6):1359-1367. doi: 10.1093/annonc/mdx109.
• Pavelitz T, Renfro L, Foster NR, Caracol A, Welsch P, Lao VV, Grady WB, Niedzwiecki D, Saltz LB, Bertagnolli MM, Goldberg RM, Rabinovitch PS, Emond M, Monnat RJ Jr, Maizels N. MRE11-deficiency associated with improved long-term disease free survival and overall survival in a subset of stage III colon cancer patients in randomized CALGB 89803 trial. PLoS One. 2014 Oct 13;9(10):e108483. doi: 10.1371/journal.pone.0108483. eCollection 2014.
• Ogino S, Liao X, Imamura Y, Yamauchi M, McCleary NJ, Ng K, Niedzwiecki D, Saltz LB, Mayer RJ, Whittom R, Hantel A, Benson AB 3rd, Mowat RB, Spiegelman D, Goldberg RM, Bertagnolli MM, Meyerhardt JA, Fuchs CS; Alliance for Clinical Trials in Oncology. Predictive and prognostic analysis of PIK3CA mutation in stage III colon cancer intergroup trial. J Natl Cancer Inst. 2013 Dec 4;105(23):1789-98. doi: 10.1093/jnci/djt298. Epub 2013 Nov 14.
• McCleary NJ, Niedzwiecki D, Hollis D, Saltz LB, Schaefer P, Whittom R, Hantel A, Benson A, Goldberg R, Meyerhardt JA. Impact of smoking on patients with stage III colon cancer: results from Cancer and Leukemia Group B 89803. Cancer. 2010 Feb 15;116(4):957-66. doi: 10.1002/cncr.24866.

Study record dates

Study Major Dates

• Study Start: May 1, 1999
• Primary Completion (Actual): August 1, 2007

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: April 26, 2004
• First Posted (Estimate): April 27, 2004

Study Record Updates

• Last Update Posted (Estimate): October 8, 2013
• Last Update Submitted That Met QC Criteria: October 7, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Leucovorin; Irinotecan; Calcium; Levoleucovorin
• Other Study ID Numbers: NCI-2012-01844 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA031946 (U.S. NIH Grant/Contract); SWOG-C89803; NCCTG-C89803; CDR0000066992; CAN-NCIC-CO15; E-89803; CALGB 89803 (Other Identifier: Cancer and Leukemia Group B); C89803 (Other Identifier: CTEP)