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Prospective Phase II Randomized Trial of Postoperative Adjuvant Chemotherapy in Patients With High Risk Colon Cancer

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ClinicalTrials.gov Identifier: NCT00201331
Recruitment Status : Unknown
Verified December 2005 by National Health Research Institutes, Taiwan.
Recruitment status was:  Recruiting
First Posted : September 20, 2005
Last Update Posted : December 16, 2005
Information provided by:

Study Description
Brief Summary:
Based on the astonishing high response rate in metastatic colorectal cancer in weekly high dose 5-FU and leucovorin, we will conduct a clinical trial to clarify the activity of this regimen in the adjuvant setting. The regimen of 5-FU and high dose leucovorin administered as the schedule of INT-0089 will be chosen as the controlled arm which was proven as effective as standard 5-FU plus levamisole regimen with short duration of treatment.21 In this study, continuous infusion of 5-FU (HDFL, Arm B) and bolus injection of 5-FU (Arm A) will be administered to the high risk colon cancer(N2 disease) patients. The role of TS level and inhibition of TS as a predictor of adjuvant chemotherapy with 5-FU based treatment will be clearly defined prospectively.

Condition or disease Intervention/treatment Phase
Colonic Diseases Adenocarcinoma Drug: leucovorin+5-FU Phase 2

Detailed Description:

Approximately 75% of all patients with colon carcinoma present at a stage when all gross tumor can be surgically resected. Despite that high resectability rate, about 50% of all colon adenocarcinoma patients die of subsequent metastatic disease not apparent at surgery. These individuals could benefit from adjuvant local or systemic chemotherapy.

Based on the encouraging antitumor activity of 5-FU plus leucovorin(LV) in patients with metastatic colon carcinoma6,7, several investigators reported their results using this combination in the adjuvant setting. Results of an NSABP C-038 suggested that postoperative 5-FU plus leucovorin reduces the risk of colon cancer recurrence by 30% and the associated mortality by 32% compared with MOF(semustine, vincristine, and 5-FU). Recently, investigators from the IMPACT group9 analyzed the role of adjuvant 5-FU plus high dose leucovorin given 5 days every 28 days for a total of six courses versus no treatment in patients with stage II or III colon cancer. The treatment arm showed a significant reduction (by 22%) in mortality (P=0.029) and a 35% reduction in relapse rate (P=0.0001). Preliminary results from other studies have also suggested benefits of 5-FU plus leucovorin as adjuvant treatment of colon cancer10,11,12. Those studies had employed chemotherapy with 5-FU plus leucovorin, although there were differences in duration of treatment and drug dose among those trials, it is striking that all revealed a similar magnitude of benefit for adjuvant chemotherapy with 5-FU and leucovorin in node positive patients. At the present time, both 5-FU plus levamisole and 5-FU plus leucovorin can be considered acceptable adjuvant chemotherapy regimens for patients with node positive disease.

Thymidylate synthase(TS) is a critical therapeutic target for the fluoropyrimidine cytotoxic drugs that are the mainstay of the treatment for patients with advanced colorectal cancer. TS provide the sole de nono source of thymidylate for DNA synthesis. The clinical importance of TS in determining fluoropyrimidine cytotoxicity has been established in both clinical and preclinical study. Increased expression of TS protein due to underlying gene amplification has been described in cell lines selected for drug resistance by exposure to 5-FU.22,23 Several investigators have also demonstrated that intratumoral TS activity are predictive for response to 5-FU.24-26 High TS activity was associated with no response, whereas a low TS activity was associated with good response to 5-FU.

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 162 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective Phase II Randomized Trial of Postoperative Adjuvant Chemotherapy in Patients With High Risk Colon Cancer
Study Start Date : April 2002
Estimated Study Completion Date : October 2012
Arms and Interventions

Outcome Measures

Primary Outcome Measures :
  1. To compare the DFS and OS of HDFL vs. weekly bolus 5-FU plus high dose LV as adjuvant chemotherapy for N2 colon cancer

Secondary Outcome Measures :
  1. 1. To evaluate safety and toxicity of both arm
  2. 2. To assess the impact of TS overexpression on patients with resectable N2 colon carcinoma.
  3. 3. To assess the disease-free survival of patients with high or low TS level of N2 colon cancer, when adjuvant chemotherapy of 5-FU was administered by bolus or continuous infusion .

Eligibility Criteria

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Signed written informed consent. Curative resection of colon cancer and upper rectal cancer, which is not planned for radiotherapy. Histologically proved adenocarcinoma of the colon. Stages: T1-4N2M0 (LN ≧4) Age less or equal to 70 years old. Performance status: 0 to 1 (ECOG) Adequate liver function (Bil. < 2 mg/dl, GOT, GPT< 3x normal limit) Adequate renal function (Cr < 2.0 mg/dl) Adequate bone marrow function(WBC ≧3500/mm3, Platelet ≧100000/mm3) Individual regular follow-up possible. 3.320 Patient who can receive adjuvant chemotherapy within 6 weeks after operation.

Patient who can receive a "indwelling catheter" surgery.

Exclusion Criteria:

Uncontrolled intercurrent illness, e.g. active infection or concurrent major systemic disease (e.g. psychosis, ESRD, heart failure [NYHA class III], liver cirrhosis [Child B&C], or AIDS). Intestinal obstruction or occlusion postoperation. Pregnant or lactating woman. Allergy to 5-Fluorouracil or leucovorin. Other primary cancer except skin squamous or basal cell carcinoma or cured in-situ cancer of the cervix.

Previous treatment of chemotherapy or radiotherapy.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00201331

Contact: Chiou Mei Liu 886-2-26534401 ext 25158 michelle@nhri.org.tw

Chang Gung Memorial Hospital Recruiting
Tao-Yuan, Taiwan, 333
Contact: Tsai-Sheng Yang, MD    886-3-3281200 ext 2114    a481124@adm.cgmh.org.tw   
Sponsors and Collaborators
National Health Research Institutes, Taiwan
Chang Gung Memorial Hospital
Changhua Christian Hospital
China Medical University Hospital
Mackay Memorial Hospital
Chi Mei Medical Hospital
Kaohsiung Veterans General Hospital.
National Cheng-Kung University Hospital
Taichung Veterans General Hospital
Study Chair: Cheng-Yi Wang, PHD Chang Gung Memorial Hospital
More Information

Additional Information:
ClinicalTrials.gov Identifier: NCT00201331     History of Changes
Other Study ID Numbers: T1202
First Posted: September 20, 2005    Key Record Dates
Last Update Posted: December 16, 2005
Last Verified: December 2005

Additional relevant MeSH terms:
Colonic Neoplasms
Colonic Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases