Neo-Adjuvant Therapy and the Effect on Synchronous Metastatic Growth - Full Text View

Sponsor:	Radboud University
Information provided by:	Radboud University
ClinicalTrials.gov Identifier:	NCT00659022

Purpose

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

Condition	Intervention	Phase
Colorectal Neoplasms Liver Neoplasms	Procedure: immediate surgery (resection of primary colorectal tumor) Drug: neo-adjuvant treatment with bevacizumab Drug: neoadjuvant treatment with capecitabine and oxaliplatin Drug: neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study
Official Title:	Accelerated Growth of Synchronous Colorectal Liver Metastases: Effects of Neo-Adjuvant Therapy

Resource links provided by NLM:

MedlinePlus related topics: Cancer Colorectal Cancer Liver Cancer Surgery

Drug Information available for: Phenylephrine Phenylephrine hydrochloride Oxaliplatin Capecitabine Bevacizumab Oxymetazoline Oxymetazoline hydrochloride

U.S. FDA Resources

Further study details as provided by Radboud University:

Primary Outcome Measures:

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 ] [ Designated as safety issue: No ]
Difference in response of liver metastases between control group and experimental groups determined by FDG-PET [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Toxicity of neo-adjuvant treatment [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
Complications of surgery [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	60
Study Start Date:	July 2008
Estimated Study Completion Date:	April 2010
Estimated Primary Completion Date:	March 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
A: Active Comparator immediate surgery of the primary colorectal tumor, no neoadjuvant therapy	Procedure: immediate surgery (resection of primary colorectal tumor) no neo-adjuvant treatment, immediate surgery
B: Experimental 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
C: Experimental 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
D: Experimental 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

Eligibility

Ages Eligible for Study:	18 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00659022

Contacts

Contact: Marian Scheer, MD	+31-24-3613956	m.scheer@chir.umcn.nl
Contact: Theo Ruers, PhD	+31-20-5122538	t.ruers@nki.nl

Locations

Netherlands
The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital	Recruiting
Amsterdam, Netherlands, 1066 CX
Contact: Theo Ruers, PhD +31-20-5122538 t.ruers@nki.nl
Radboud University Nijmegen Medical Center	Recruiting
Nijmegen, Netherlands, 6500 HB
Contact: Kees Punt, PhD +31-24-3610353 C.Punt@onco.umcn.nl

Sponsors and Collaborators

Radboud University

Investigators

Principal Investigator:	Theo Ruers, PhD	The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital Amsterdam
Principal Investigator:	Kees Punt, PhD	Radboud University Nijmegen Medical Center
Principal Investigator:	Wim Oyen, PhD	Radboud University Nijmegen Medical Center

More Information

Publications:

Gorelik E, Segal S, Feldman M. On the mechanism of tumor "concomitant immunity". Int J Cancer. 1981 Jun 15;27(6):847-56. 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.

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.

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.

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. Review.

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. Review.

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.

Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005 Jan 7;307(5706):58-62. Review.

Responsible Party:	The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital Amsterdam ( T.J.M Ruers, PhD )
Study ID Numbers:	SILENT
Study First Received:	April 3, 2008
Last Updated:	August 6, 2008
ClinicalTrials.gov Identifier:	NCT00659022 History of Changes
Health Authority:	Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Radboud University:

colorectal cancer
liver metastases
angiogenesis
metabolism

Additional relevant MeSH terms:

Antimetabolites
Liver Diseases
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Diseases
Antineoplastic Agents
Colonic Diseases
Physiological Effects of Drugs
Bevacizumab
Rectal Diseases
Liver Neoplasms
Oxaliplatin
Neoplasms by Site
Therapeutic Uses

Growth Inhibitors
Angiogenesis Modulating Agents
Capecitabine
Digestive System Neoplasms
Growth Substances
Adjuvants, Immunologic
Intestinal Diseases
Angiogenesis Inhibitors
Intestinal Neoplasms
Pharmacologic Actions
Neoplasms
Digestive System Diseases
Gastrointestinal Neoplasms
Colorectal Neoplasms

ClinicalTrials.gov processed this record on November 05, 2009