Evaluation of Contrast-enhanced Ultrasound Imaging for the Early Estimate of Bevacizumab Effect on Colorectal Cancer Liver Metastases

Medical and Economical Evaluation of Contrast-enhanced Ultrasound Imaging for the Early Estimate of Bevacizumab Effect on Colorectal Cancer Liver Metastases

Bevacizumab, an anti-angiogenic agent, plus fluorouracil based chemotherapy is considered a new standard for the treatment of metastatic colorectal cancer. Contrast-enhanced ultrasound with gas-encapsulated microbubbles can be used to assess tumour vascularity, particularly hepatic metastases, and may become a useful tool for monitoring anti-angiogenic therapies. The aim of this prospective, multicenter, non-randomized study is to evaluate the usefulness of hepatic contrast-enhanced ultrasound to predict response to bevacizumab based chemotherapy in patient with metastatic colorectal cancer. The primary objective of this study is to compare the functional vascular changes related to bevacizumab based chemotherapy and evaluated by hepatic contrast-enhanced ultrasound with classic RECIST criteria. The secondary objectives are to do a characterization of the pharmacokinetic of bevacizumab, to explore the pharmacodynamic effects of bevacizumab on functional vascular changes of hepatic metastases evaluated by hepatic contrast-enhanced ultrasound and to analyze the possible relationships between treatment efficacy or toxicity and constitutional gene polymorphisms linked to the bevacizumab.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Device: real-time contrast-enhanced ultrasound imaging (CEUS)

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Angers, France, 49033
    • CHRU d'Angers
  • Angers, France, 49033
    • CRLCC, Centre Paul Papin
  • Besançon, France, 25000
    • CHRU Besançon
  • Bordeaux, France, 33075
    • Hôpital Saint-André, CHRU Bordeaux
  • Nantes St Herblain, France, 44805
    • CRLCC, Centre René Gauducheau
  • Paris, France, 75651
    • Hôpital Pitié Salpétrière, Assistance Publique Hôpitaux de Paris
  • Pessac, France, 33604
    • Hôpital Haut-Lévêque
  • Poitiers, France, 86000
    • Hôpital La Milétrie, CHRU Poitiers
  • Reims, France, 51092
    • Hôpital Robert Debré, CHRU Reims
  • Rennes, France, 35033
    • CHU Pontchaillou
  • Rennes, France, 35042
    • CRLCC, Centre Eugène Marquis
  • Tours, France, 37044
    • CHRU Tours

Participation Criteria

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:

• Histologically confirmed colorectal tumor
• first line treatment by a bevacizumab based chemotherapy
• Target hepatic metastases of size lower than 5 cm and higher than 5 mm detected by conventional ultrasonography and CT or MRI
• Life expectancy > 2 months
• OMS status =< 2
• Major surgery, open biopsy, or significant traumatic injury within 28 days prior to Day 0
• informed consent signed

Exclusion Criteria:

• no target hepatic lesion detected by conventional ultrasonography
• Prior bevacizumab treatment
• Prior chemotherapy treatment for advanced disease
• Clinically significant cardiac disease (e.g. myocardial infarction or stroke within 12 months, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure not well controlled with medication, endocarditis and prosthetic valve) and any contraindications in sulphur hexafluoride administration
• Blood pressure >= 180/110 mmHg
• Daily and chronic treatment by aspirin or AINS
• Anticipation of need for major surgical procedure within 7 days prior day 0
• Urine protein > 1g/24 Hours
• Any contraindication in enhancing bevacizumab treatment
• Serious, uncontrolled, concurrent infection(s) or illness(es)
• pregnant and lactating woman

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1 (single arm); patient with histologically confirmed colorectal tumor treated in first line by a bevacizumab based chemotherapy	Device: real-time contrast-enhanced ultrasound imaging (CEUS); Real time contrast enhanced sonography was performed using an ultrasound dedicated system after bolus injection of 1.2 and 2x2.4 ml Sonovue ® (Bracco, Milan, Italy)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
functional vascular changes in tumour vascularity of hepatic metastases	2 months
Pharmacokinetic of bevacizumab between each cure of bevacizumab based chemotherapy	2 months
ratio cost/benefit of a strategy of therapeutic monitoring by contrast-enhanced ultrasound	2 months
evaluation of the response to bevacizumab based chemotherapy by RECIST criteria	2 months

Secondary Outcome Measures

Outcome Measure	Time Frame
response duration	2 years
bevacizumab-related toxicity	2 months
time to disease progression	2 years
survival time	2 years

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Investigators: Principal Investigator: François TRANQUART, Professor, Centre Hospitalier de Tours, France; Principal Investigator: Thierry LECOMTE, Doctor, Centre Hospitalier de Tours, France; Study Chair: Bruno GIRAUDEAU, Doctor, INSERM CIC 2002, Centre Hospitalier de Tours, France; Study Chair: Emmanuel RUSCH, Professor, Centre Hospitalier de Tours, France

Publications and helpful links

General Publications

• Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. doi: 10.1056/NEJMoa032691.
• Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 2005 Feb 1;65(3):671-80.
• Bleuzen A, Huang C, Olar M, Tchuenbou J, Tranquart F. Diagnostic accuracy of contrast-enhanced ultrasound in focal lesions of the liver using cadence contrast pulse sequencing. Ultraschall Med. 2006 Feb;27(1):40-8. doi: 10.1055/s-2005-858944.
• Forsberg F, Ro RJ, Potoczek M, Liu JB, Merritt CR, James KM, Dicker AP, Nazarian LN. Assessment of angiogenesis: implications for ultrasound imaging. Ultrasonics. 2004 Apr;42(1-9):325-30. doi: 10.1016/j.ultras.2003.12.026.
• Broillet A, Hantson J, Ruegg C, Messager T, Schneider M. Assessment of microvascular perfusion changes in a rat breast tumor model using SonoVue to monitor the effects of different anti-angiogenic therapies. Acad Radiol. 2005 May;12 Suppl 1:S28-33. doi: 10.1016/j.acra.2005.02.021. No abstract available.
• Niermann KJ, Fleischer AC, Donnelly EF, Schueneman AJ, Geng L, Hallahan DE. Sonographic depiction of changes of tumor vascularity in response to various therapies. Ultrasound Q. 2005 Jun;21(2):61-7; quiz 149, 153-4.
• Preda A, Novikov V, Moglich M, Turetschek K, Shames DM, Brasch RC, Cavagna FM, Roberts TP. MRI monitoring of Avastin antiangiogenesis therapy using B22956/1, a new blood pool contrast agent, in an experimental model of human cancer. J Magn Reson Imaging. 2004 Nov;20(5):865-73. doi: 10.1002/jmri.20184.
• Zondor SD, Medina PJ. Bevacizumab: an angiogenesis inhibitor with efficacy in colorectal and other malignancies. Ann Pharmacother. 2004 Jul-Aug;38(7-8):1258-64. doi: 10.1345/aph.1D470. Epub 2004 Jun 8.
• Jary M, Lecomte T, Bouche O, Kim S, Dobi E, Queiroz L, Ghiringhelli F, Etienne H, Leger J, Godet Y, Balland J, Lakkis Z, Adotevi O, Bonnetain F, Borg C, Vernerey D. Prognostic value of baseline seric Syndecan-1 in initially unresectable metastatic colorectal cancer patients: a simple biological score. Int J Cancer. 2016 Nov 15;139(10):2325-35. doi: 10.1002/ijc.30367. Epub 2016 Aug 13.

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: June 20, 2007
• First Submitted That Met QC Criteria: June 20, 2007
• First Posted (Estimate): June 21, 2007

Study Record Updates

• Last Update Posted (Estimate): January 4, 2017
• Last Update Submitted That Met QC Criteria: January 2, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: colorectal cancer; bevacizumab; Contrast-enhanced ultrasound; tumor vascularity; hepatic metastases; anti-angiogenic agent; chemotherapy regimens
• 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; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis
• Other Study ID Numbers: INCA06-FT/STIC-AVASTIN