Combination Chemotherapy in Treating Patients With Liver Metastases From Colorectal Cancer

PHASE III STUDY OF HEPATIC ARTERY FLOXURIDINE (FUDR), LEUCOVORIN (LV), AND DEXAMETHASONE (DEX) VERSUS SYSTEMIC 5-FLUOROURACIL (5-FU) AND LEUCOVORIN (LV) AS TREATMENT FOR HEPATIC METASTASES FROM COLORECTAL CANCER

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 cancer cells. It is not yet known which chemotherapy regimen is more effective for metastatic colorectal cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of intrahepatic floxuridine, leucovorin, and dexamethasone with that of systemic fluorouracil and leucovorin in treating patients who have unresectable liver metastases from colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Metastatic Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium; Drug: dexamethasone; Procedure: conventional surgery; Drug: floxuridine; Procedure: laparotomy

Detailed Description

OBJECTIVES:

• Compare the efficacy, toxicity, and cost of hepatic artery infusion of floxuridine, leucovorin calcium (CF), and dexamethasone vs IV fluorouracil and IV CF after resection of primary disease in patients with hepatic metastases secondary to colorectal cancer.
• Compare the quality of life of patients treated with these regimens.
• Measure the level of thymidylate synthase present in liver metastases, and correlate these levels with objective response and survival in patients treated with these regimens.
• Assess the p53 mutations, and correlate findings with objective response and survival in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to center, percentage of liver involvement on CT scan or MRI (less than 30% vs 30% to under 70%), prior chemotherapy (none vs adjuvant chemotherapy comprising fluorouracil (5-FU) and leucovorin calcium (CF) or 5-FU, CF, and levamisole (LEV) completed at least 1 year before study vs adjuvant chemotherapy comprising 5-FU with or without LEV completed at least 6 months before study), and synchronous disease (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Study Type: Interventional
• Enrollment (Actual): 135
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
• Peru
  • Lima, Peru, 34
    • Instituto De Enfermedades Neoplasicas
• Puerto Rico
  • San Juan, Puerto Rico, 00936-7344
    • San Juan City Hospital
• United States
  • Iowa
    • Cedar Rapids, Iowa, United States, 52403-1206
      • CCOP - Cedar Rapids Oncology Project
    • Des Moines, Iowa, United States, 50309
      • John Stoddard Cancer Center at Iowa Methodist Medical Center
    • Des Moines, Iowa, United States, 50309-1016
      • CCOP - Iowa Oncology Research Association
    • Des Moines, Iowa, United States, 50316-2301
      • Iowa Lutheran Hospital
    • Des Moines, Iowa, United States, 50314
      • Mercy Cancer Center at Mercy Medical Center-Des Moines
  • Nebraska
    • Papillion, Nebraska, United States, 68128-4157
      • Midlands Cancer Center at Midlands Community Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • MBCCOP - University of New Mexico HSC
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3453
      • CCOP - St. Vincent Hospital Cancer Center, Green Bay

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Unresectable liver metastases secondary to colorectal cancer

  • Less than 70% liver involvement on CT scan or MRI

  • Liver biopsy required before study unless 1 of the following conditions are met:

    • Carcinoembryonic antigen greater than 30
    • 5 or more liver metastases visible on CT scan or MRI
    • Greater than 50% to under 70% liver involvement on CT scan or MRI

• Histologically proven primary colorectal cancer that is resected or appears resectable on CT scan and physical exam

  • Documentation of previously resected primaries must be based on pathologic results of the resected tumor

  • Histological documentation of synchronous disease must be based on 1 of the following:

    • Biopsy of primary colorectal tumor before study
    • Suspicious lesion on barium enema, colonoscopy, or sigmoidoscopy, and a liver biopsy positive for adenocarcinoma consistent with the primary colorectal tumor

• Measurable disease

  • Clearly defined liver mass measuring at least 2 cm or at least 3 liver masses on CT scan or MRI
• No evidence of extrahepatic disease on CT scan and physical exam
• No portal vein occlusion or ascites

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Hepatic:

• Bilirubin no greater than 2 times normal

Other:

• No other malignancy within the past 5 years except inactive nonmelanomatous skin cancer, carcinoma in situ of the cervix, or grade 1 bladder cancer
• Not pregnant or nursing
• Fertile patients must use effective contraception

Chemotherapy:

• At least 1 year since prior adjuvant chemotherapy comprising fluorouracil (5-FU) and leucovorin calcium (CF) or 5-FU, CF, and levamisole (LEV)
• At least 6 months since prior adjuvant chemotherapy comprising 5-FU with or without LEV
• No other prior chemotherapy
• No other concurrent chemotherapy

Endocrine therapy:

• No concurrent hormonal therapy except for nondisease-related conditions, e.g.:

  • Steroids for adrenal failure
  • Insulin for diabetes
  • Intermittent dexamethasone as an antiemetic

Radiotherapy:

• No prior radiotherapy to the liver

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 - laparotomy + conventional surgery + chemotherapy; Patients undergo laparotomy for placement of a hepatic artery catheter and then subcutaneous placement of a hepatic artery infusion pump. Patients with unresected primary disease also undergo resection at the time of catheter and pump placement. Beginning within 1-2 weeks after surgery, patients receive floxuridine, dexamethasone, and leucovorin calcium (CF) via continuous hepatic artery infusion on days 1-14. Treatment for patients continues every 4 weeks in the absence of disease progression or unacceptable toxicity. Quality of life and medical resource utilization are assessed at baseline, every 3 months for 1 year, and then at 18 months. Patients are followed every 3 months.	Drug: leucovorin calcium; Drug: dexamethasone; Procedure: conventional surgery; Drug: floxuridine; Procedure: laparotomy
Experimental: Arm II - conventional surgery + chemotherapy; Patients receive CF IV and fluorouracil IV on days 1-5. Patients with unresected primary disease undergo resection within 3-4 weeks before initiation of chemotherapy. Treatment for patients continues every 4 weeks in the absence of disease progression or unacceptable toxicity. Quality of life and medical resource utilization are assessed at baseline, every 3 months for 1 year, and then at 18 months. Patients are followed every 3 months.	Drug: fluorouracil; Drug: leucovorin calcium; Procedure: conventional surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival	Up to 5 years
Time to progression	Up to 5 years

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Nancy E. Kemeny, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

General Publications

• Kemeny NE, Niedzwiecki D, Hollis DR, Lenz HJ, Warren RS, Naughton MJ, Weeks JC, Sigurdson ER, Herndon JE 2nd, Zhang C, Mayer RJ. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol. 2006 Mar 20;24(9):1395-403. doi: 10.1200/JCO.2005.03.8166. Epub 2006 Feb 27.
• Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ, Ladner RD. A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res. 2003 Jun 1;63(11):2898-904.
• Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, Warren R, Tsao-Wei D, Groshen S, Lenz HJ. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1(1):65-70. doi: 10.1038/sj.tpj.6500012.

Study record dates

Study Major Dates

• Study Start: January 1, 1996
• Primary Completion (Actual): March 1, 2006
• Study Completion (Actual): August 1, 2006

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): July 13, 2016
• Last Update Submitted That Met QC Criteria: July 12, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; stage IV colon cancer; adenocarcinoma of the colon; recurrent colon cancer; recurrent rectal cancer; liver metastases
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Dexamethasone; Fluorouracil; Leucovorin; Calcium; Levoleucovorin; Floxuridine
• Other Study ID Numbers: CALGB-9481; U10CA031946 (U.S. NIH Grant/Contract); CDR0000064553 (Registry Identifier: NCI Physician Data Query)