Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth

Colorectal Neoplasms Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00659022
• Other study ID #: SILENT
• Status: Recruiting
• Phase: Phase 2
• First received: April 3, 2008
• Last updated: September 9, 2011
• Start date: July 2008
• Est. completion date: April 2014

Study information

• Verified date: February 2009
• Source: Radboud University
• Contact: Patricia Bottenberg, Ma ANP
• Phone: +31-20-5122639
• Email: p.bottenberg[@]nki.nl
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: April 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Liver Neoplasms
• Neoplasms

Intervention

Procedure:
• immediate surgery (resection of primary colorectal tumor)
no neo-adjuvant treatment, immediate surgery

Drug:
• 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

Locations

Country	Name	City	State
Netherlands	The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital	Amsterdam
Netherlands	Radboud University Nijmegen Medical Center	Nijmegen

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

References & Publications (8)

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

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Difference in response of liver metastases between control group and experimental groups determined by histopathological scoring of vascular density,apoptotic and mitotic index		12 weeks	No
Primary	Difference in response of liver metastases between control group and experimental groups determined by FDG-PET		12 weeks	No
Secondary	Toxicity of neo-adjuvant treatment		12 weeks	Yes
Secondary	Complications of surgery		4 weeks	Yes