Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth

September 9, 2011 updated by: Radboud University Medical Center

Accelerated Growth of Synchronous Colorectal Liver Metastases: Effects of Neo-adjuvant Therapy

Study Hypothesis

• As well as in animal models as in patients with colorectal cancer resection of the primary tumor resulted in increase in vascular density, metabolism and secondary tumor growth of the distant metastases. These data strongly suggest an inhibitory effect of the primary tumor on the outgrowth of its metastases.

In this study we investigate whether pre-operative treatment with the anti-angiogenic agent bevacizumab and/or chemotherapy before resection of the primary colorectal tumor shifts the balance between angiogenic and anti-angiogenic factors in favor of the anti-angiogenic factors and results in reduced growth of the liver metastases.

Eligibility

  • Histological proven colorectal cancer without signs of bowel obstruction or bleeding
  • Synchronous liver metastases
  • WHO performance status 0-1

Treatment

  • Arm A: immediate surgery of the primary colorectal tumor, no neoadjuvant therapy
  • Arm B: neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
  • Arm C: neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
  • Arm D: neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary

Primary endpoint Difference in response of liver metastases to resection of the primary tumor between the experimental groups and the control group, as determined by histopathological scoring of vascular density, apoptotic and mitotic index and by measurement of the metabolic activity of liver metastases by FDG-PET and SUV measurements.

Secondary endpoints Toxicity of neo-adjuvant treatment Complications of surgery

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

60

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Amsterdam, Netherlands, 1066 CX
        • Recruiting
        • The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital
        • Contact:
      • Nijmegen, Netherlands, 6500 HB
        • Recruiting
        • Radboud University Nijmegen Medical Center
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with histological proven primary colorectal cancer and synchronous unresectable liver metastases with or without additional extrahepatic disease (primary tumor in situ). Unresectable liver metastases defined as too extensive hepatic involvement or extrahepatic disease.
  • Measurable liver metastases on CT scan (RECIST), positive signal of liver metastases on FDG-PET scan
  • Age: 18-80 years
  • WHO performance scale 0-1
  • ASA category I or II
  • Negative pregnancy test in women with childbearing potential
  • Life expectancy > 12 weeks
  • Laboratory values obtained ≤ 3 weeks prior to study entry, disease evaluation performed ≤ 3 weeks prior to study entry. Adequate bone marrow function (Hb > 6.5 mmol/L, absolute neutrophil count > 1.5 x 109/L, platelets > 100 x 109/L), renal function (serum creatinine < 1.5 x ULN or creatinine clearance ≥ 50 mL/min (calculated according to Cockroft and Gault), liver function (ASAT and ALAT ≤ 3 x upper normal limit, serum bilirubin ≤ 2 x upper normal limit)
  • Written informed consent

Exclusion Criteria:

  • Signs of bowel obstruction or bleeding from primary tumor
  • Prior chemotherapy treatment for advanced disease, prior treatment with anti-angiogenic drugs
  • Resectable liver metastases
  • Diabetes mellitus
  • Continuous use of immunosuppressive agents
  • Pregnancy or lactation
  • Contra-indications for systemic therapy with bevacizumab (Avastin)/ chemotherapy (Xelox)
  • Concurrent severe or uncontrolled disease (i.e. uncontrolled hypertension, congestive heart failure, myocardial infarction < 12 months, chronic active infection)
  • Sensory neuropathy > grade 1
  • Serious non-healing wound or ulcer
  • Patients (M/F) with reproductive potential not implementing adequate contraceptive measures
  • Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to start of bevacizumab
  • Bleeding disorders or coagulopathy or need for full-dose anticoagulation
  • Signs or symptoms of brain metastases
  • Cerebrovascular accident or transient ischemic attack within the past 12 months
  • Impairment of gastrointestinal function or -disease that may significantly impair the absorption of oral drugs (i.e. uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to swallow tablets)
  • Presence of proteinuria at baseline as defined by: patients with > 1 g of protein/24 hr by a 24-hour urine collection.
  • Any concomitant disorder preventing the safe administration of study drugs or surgical procedure.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: A
immediate surgery of the primary colorectal tumor, no neoadjuvant therapy
Procedure: immediate surgery (resection of primary colorectal tumor)
no neo-adjuvant treatment, immediate surgery
Experimental: B
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
Drug: neo-adjuvant treatment with bevacizumab
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
Other Names:
  • Avastin
Experimental: C
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
Drug: neoadjuvant treatment with capecitabine and oxaliplatin
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
Other Names:
  • Xeloda
  • Eloxatin
Experimental: D
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
Drug: neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
Other Names:
  • Avastin
  • Xeloda
  • Eloxatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Difference in response of liver metastases between control group and experimental groups determined by histopathological scoring of vascular density,apoptotic and mitotic index
Time Frame: 12 weeks
12 weeks
Difference in response of liver metastases between control group and experimental groups determined by FDG-PET
Time Frame: 12 weeks
12 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
Toxicity of neo-adjuvant treatment
Time Frame: 12 weeks
12 weeks
Complications of surgery
Time Frame: 4 weeks
4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Radboud University Medical Center

Investigators

  • Principal Investigator: Theo Ruers, PhD, The Netherlands Cancer Institute
  • Principal Investigator: Kees Punt, PhD, Radboud University Nijmegen Medical Center
  • Principal Investigator: Wim Oyen, PhD, Radboud University Nijmegen Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2008

Primary Completion (Anticipated)

March 1, 2014

Study Completion (Anticipated)

April 1, 2014

Study Registration Dates

First Submitted

April 3, 2008

First Submitted That Met QC Criteria

April 10, 2008

First Posted (Estimate)

April 16, 2008

Study Record Updates

Last Update Posted (Estimate)

September 12, 2011

Last Update Submitted That Met QC Criteria

September 9, 2011

Last Verified

February 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SILENT

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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