Study of Micrometastases in Patients With Stage I or Stage II Localized Colon Cancer That Can Be Removed by Surgery

The Influence of Micrometastases on Prognosis and Survival in Stage I-II Colon Cancer Patients: The EnRoute+ Study

RATIONALE: Diagnostic procedures such as sentinel lymph node mapping may help doctors find patients who are at risk of developing micrometastases and plan better treatment.

PURPOSE: This randomized phase II/III trial is studying micrometastases in patients with stage I or stage II localized colon cancer that can be removed by surgery.

Study Overview

• Status: Unknown
• Conditions: Colorectal Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Procedure: adjuvant therapy; Drug: oxaliplatin; Drug: capecitabine; Procedure: sentinel lymph node biopsy; Other: active surveillance; Procedure: lymph node mapping

Detailed Description

OBJECTIVES:

• To determine the subset of patients with stage I or II localized, resectable colon cancer (pN0) at risk for developing systemic metastases.
• To determine the clinical and prognostic relevance of occult nodal isolated tumor cells and micrometastases in these patients.
• To determine the benefits of adjuvant chemotherapy in patients with pN0micro+ colon cancer.

OUTLINE: This is a phase II feasibility study (stage 1) followed by a phase III multicenter, open-label, randomized, and controlled study (stage 2).

• Stage 1 (phase II feasibility study) After undergoing planned curative resection followed by ex vivo sentinel lymph node mapping (SLNM). Resected samples are examined. The sentinel lymph nodes of those deemed pN0 disease (no macroscopic metastases or angioinvasion) are further evaluated for micrometastases by serial sectioning and immunohistochemistry using pan-cytokeratin. pN0micro+ disease are defined as isolated tumor cells (ITC) < 0.2 mm or micrometastasis 0.2 - 2 mm. Patients with pN0 disease are followed-up once every 6 months for 3 years and then annually for 2 years.

• stage 2 (phase III randomized study): Patients undergo planned surgery and ex vivo SLNM as in stage 1. Patients with pN0micro- disease are assigned to arm C; patients with pN0micro+ disease are randomized to 1 of 2 intervention arms (arms A and B). .

  • Arm A (pN0micro+): Patients receive oral capecitabine twice daily on days 1-14 and oxaliplatin IV over 2 hours on day 1 OR oral capecitabine twice daily on days 1-14 alone according to standard protocol. Treatment repeats every 4 weeks for up to 8 courses. Patients are followed-up once every 6 months for 3 years and then annually for 2 years.
  • Arm B (pN0micro+): Patients are followed-up once every 6 months for 3 years and then annually for 2 years.
  • Arm C (pN0micro-): Patients are followed-up once every 6 months for 3 years and then annually for 2 years.
• .

• Study Type: Interventional
• Enrollment (Anticipated): 1500
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands, 5211 NL
    • Recruiting
    • Jeroen Bosch Ziekenhuis
    • Contact: Contact Person; Phone Number: 31-73-699-2701; Email: k.bosscha@jbz.nl
  • Amsterdam, Netherlands, 1007 MB
    • Recruiting
    • Vrije Universiteit Medisch Centrum
    • Contact: Contact Person; Phone Number: 31-20-444-4300
  • Amsterdam, Netherlands, 1066 BE
    • Recruiting
    • Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
    • Contact: Contact Person; Phone Number: 31-20-512-9111
  • Amsterdam, Netherlands, 1105 AZ
    • Recruiting
    • Academisch Medisch Centrum at University of Amsterdam
    • Contact: Contact Person; Phone Number: 31-20-566-9111
  • Eindhoven, Netherlands, 5602 ZA
    • Recruiting
    • Catharina Ziekenhuis
    • Contact: Contact Person; Phone Number: 31-40-239-9111
  • Groningen, Netherlands, 9700 RB
    • Recruiting
    • University Medical Center Groningen
    • Contact: Contact Person; Phone Number: 31-50-361-2317
  • Leiden, Netherlands, 2300 RC
    • Recruiting
    • Leiden University Medical Center
    • Contact: Contact Person; Phone Number: 31-71-526-2309; Email: c.j.h.van_de_velde@lumc.nl
  • Maastricht, Netherlands, 6202 AZ
    • Recruiting
    • Academisch Ziekenhuis Maastricht
    • Contact: Contact Person; Phone Number: 31-43-387-7025
  • Nijmegen, Netherlands, NL-6500 HB
    • Recruiting
    • Universitair Medisch Centrum St. Radboud - Nijmegen
    • Contact: Contact Person; Phone Number: 31-24-361-0353; Email: c.punt@onco.umcn.nl
  • Rotterdam, Netherlands, 3000 CA
    • Recruiting
    • University Medical Center Rotterdam at Erasmus Medical Center
    • Contact: Contact Person; Phone Number: 31-10-463-5995; Email: w.r.schouten@erasmusmc.nl
  • Utrecht, Netherlands, 3584 CX
    • Recruiting
    • University Medical Center Utrecht
    • Contact: Contact Person; Phone Number: 31-30-250-9111

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

DISEASE CHARACTERISTICS:

• Histologically or radiologically confirmed primary colon cancer

  • Stage I or II disease
• Clinically localized disease judged potentially resectable for cure, without intraoperatively gross nodal involvement
• Planning to undergo elective resection of the tumor
• No histologically or radiologically confirmed locoregional lymph node or distant metastasis
• No disseminated disease
• No clinical tumor perforation or obstruction

• Patients enrolled in stage 2 and undergoing randomization must also meet the following criteria:

  • pN0micro+ disease as evidenced by detection of sentinel lymph node isolated tumor cells (<0.2 mm) or micrometastasis (0.2 - 2 mm)

  • No high-risk pN0 disease meeting any of the following criteria:

    • Less then 10 lymph nodes detected in resected specimen
    • Invasion in other organs (T4, Nx, Mx)
    • Colon perforation at presentation
    • Obstruction at presentation
    • Angioinvasion at pathological examination
  • No rectal cancer
  • No clinically positive nodal tumors or advanced disease (stage III or Dukes stage C disease)

PATIENT CHARACTERISTICS:

• Patients enrolled in stage 2 and undergoing randomization must also meet the following criteria:

  • WHO performance status 0-1 or American Society of Anesthesiologists Physical Status classification 1-2
  • Not pregnant or nursing
  • Able to comply with requirements of the study
  • Must be fit to undergo chemotherapy treatment

  • No other current serious illness or medical conditions, including any of the following:

    • Severe cardiac illness (NYHA class III-IV disease)
    • Significant neurologic or psychiatric disorders
    • Uncontrolled infections
    • Active disseminated intravascular coagulation
    • Other serious underlying medical conditions that could impair the ability of the patient to participate in the study
  • No known hypersensitivity to study drugs
  • No definite contraindications for the use of corticosteroids

PRIOR CONCURRENT THERAPY:

• No prior colorectal surgery

• Patients enrolled in stage 2 and undergoing randomization must also meet the following criteria:

  • No prior chemotherapy (for patients enrolled in stage 2 and undergoing randomization only)
  • At least 4 weeks since prior and no other concurrent experimental drugs
  • No concurrent immunosuppressive or antiviral drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Accrual rate (total number of pN0 patients included in the registration study monthly/center) (stage 1)
Rate of upstaging in pN0 colon cancer patients (stage 1)
Disease-free survival (DFS) at 3 years (stage 2)
Percentage of successful sentinel lymph node mapping procedures using multivariate analysis (stage 2)

Secondary Outcome Measures

Outcome Measure
Overall survival (OS) at 3 years (stage 2)
Stratified analysis of DFS and OS according to total harvested lymph nodes per resected specimen and chemotherapy regimen (capecitabine and oxaliplatin versus capecitabine alone) (stage 2)

Collaborators and Investigators

• Sponsor: Jeroen Bosch Ziekenhuis
• Investigators: Principal Investigator: Koop Bosscha, MD, Jeroen Bosch Ziekenhuis

Publications and helpful links

General Publications

• Lips DJ, Koebrugge B, Liefers GJ, van de Linden JC, Smit VT, Pruijt HF, Putter H, van de Velde CJ, Bosscha K. The influence of micrometastases on prognosis and survival in stage I-II colon cancer patients: the Enroute plus sign in circle Study. BMC Surg. 2011 May 11;11:11. doi: 10.1186/1471-2482-11-11.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Anticipated): January 1, 2015

Study Registration Dates

• First Submitted: March 31, 2010
• First Submitted That Met QC Criteria: March 31, 2010
• First Posted (Estimate): April 1, 2010

Study Record Updates

• Last Update Posted (Estimate): August 12, 2013
• Last Update Submitted That Met QC Criteria: August 9, 2013
• Last Verified: September 1, 2011

More Information

Terms related to this study

• Keywords: stage II colon cancer; stage I colon cancer
• 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; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Colonic Neoplasms; Neoplasm Micrometastasis; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine; Oxaliplatin
• Other Study ID Numbers: JBZ-EnRoute+; CDR0000668525 (Registry Identifier: PDQ (Physician Data Query)); EUDRACT-2010-018612-32; EU-21016