Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth
NCT ID: NCT00659022
Last Updated: 2011-09-12
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
PHASE2
60 participants
INTERVENTIONAL
2008-07-31
2014-04-30
Brief Summary
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• 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
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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A
immediate surgery of the primary colorectal tumor, no neoadjuvant therapy
immediate surgery (resection of primary colorectal tumor)
no neo-adjuvant treatment, immediate surgery
B
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
neo-adjuvant treatment with bevacizumab
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
C
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
neoadjuvant treatment with capecitabine and oxaliplatin
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
D
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
Interventions
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immediate surgery (resection of primary colorectal tumor)
no neo-adjuvant treatment, immediate surgery
neo-adjuvant treatment with bevacizumab
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
neoadjuvant treatment with capecitabine and oxaliplatin
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
18 Years
80 Years
ALL
No
Sponsors
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Radboud University Medical Center
OTHER
Responsible Party
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The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital Amsterdam
Principal Investigators
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Theo Ruers, PhD
Role: PRINCIPAL_INVESTIGATOR
The Netherlands Cancer Institute
Kees Punt, PhD
Role: PRINCIPAL_INVESTIGATOR
Radboud University Nijmegen Medical Center
Wim Oyen, PhD
Role: PRINCIPAL_INVESTIGATOR
Radboud University Nijmegen Medical Center
Locations
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The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital
Amsterdam, , Netherlands
Radboud University Nijmegen Medical Center
Nijmegen, , Netherlands
Countries
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Central Contacts
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Facility Contacts
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References
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Gorelik E, Segal S, Feldman M. On the mechanism of tumor "concomitant immunity". Int J Cancer. 1981 Jun 15;27(6):847-56. doi: 10.1002/ijc.2910270618. No abstract available.
O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315-28. doi: 10.1016/0092-8674(94)90200-3.
O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997 Jan 24;88(2):277-85. doi: 10.1016/s0092-8674(00)81848-6.
Peeters CF, Westphal JR, de Waal RM, Ruiter DJ, Wobbes T, Ruers TJ. Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients. Int J Cancer. 2004 Nov 20;112(4):554-9. doi: 10.1002/ijc.20374.
Yang AD, Bauer TW, Camp ER, Somcio R, Liu W, Fan F, Ellis LM. Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy. Cancer. 2005 Apr 15;103(8):1561-70. doi: 10.1002/cncr.20942.
Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure - an obstacle in cancer therapy. Nat Rev Cancer. 2004 Oct;4(10):806-13. doi: 10.1038/nrc1456.
Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004 Jun 1;64(11):3731-6. doi: 10.1158/0008-5472.CAN-04-0074.
Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005 Jan 7;307(5706):58-62. doi: 10.1126/science.1104819.
Other Identifiers
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SILENT
Identifier Type: -
Identifier Source: org_study_id
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