FOLFOX Plus SIR-SPHERES MICROSPHERES Versus FOLFOX Alone in Patients With Liver Mets From Primary Colorectal Cancer (SIRFLOX)

Randomised Comparative Study Of Folfox6m Plus Sir-Spheres® Microspheres Versus Folfox6m Alone As First Line Treatment In Patients With Nonresectable Liver Metastases From Primary Colorectal Carcinoma

This study is a randomized multi-center trial that will assess the effect of adding Selective Internal Radiation Therapy (SIRT), using SIR-Spheres microspheres®, to a standard chemotherapy regimen of FOLFOX as first line therapy in patients with non-resectable liver metastases from primary colorectal adenocarcinoma.

Treatment with the biologic agent bevacizumab, if part of the standard of care at participating institutions, is allowed within this study at the discretion of the treating Investigator.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Liver Metastases; Colorectal Carcinoma
• Intervention / Treatment: Device: SIR-Spheres yttrium-90 microspheres; Drug: Systemic chemotherapy (FOLFOX)

• Study Type: Interventional
• Enrollment (Actual): 530
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Concord Hospital
    • Darlinghurst, New South Wales, Australia, 2010
      • St. Vincent's Hospital
    • Kingswood, New South Wales, Australia
      • Nepean Cancer Care Centre
    • Kogarah, New South Wales, Australia, 2217
      • St. George Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
    • Wahroonga, New South Wales, Australia, 2076
      • Sydney Adventist Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Auchenflower, Queensland, Australia, 4066
      • Wesley Medical Centre
    • Cairns, Queensland, Australia, 4870
      • Cairns Private Hospital
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
    • Southport, Queensland, Australia, 4215
      • Gold Coast Health Service District
    • Southport, Queensland, Australia, 4215
      • HOCA Gold Coast Centre
    • Woolloongabba, Queensland, Australia
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • Royal Adelaide Hospital
    • Ashford, South Australia, Australia
      • Ashford Cancer Centre
    • Bedford Park, South Australia, Australia
      • Flinders Medical Centre
    • Elizabeth Vale, South Australia, Australia, 5012
      • Lyell McEwin Hospital
    • Woodville South, South Australia, Australia
      • Queen Elizabeth II Hospital
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
  • Victoria
    • Bentleigh East, Victoria, Australia
      • Monash Medical Centre
    • Coburg, Victoria, Australia, 3058
      • John Fawkner Private Hospital
    • Footscray, Victoria, Australia, 3011
      • Western Hospital
    • Frankston, Victoria, Australia, 3199
      • Peninsula Oncology Centre
    • Noble Park, Victoria, Australia, 3174
      • South Eastern Private
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
    • Ringwood, Victoria, Australia, 3135
      • Ringwood/Knox Private
    • Ringwood East, Victoria, Australia, 3135
      • Maroondah Public
  • Western Australia
    • Nedlands, Western Australia, Australia
      • Sir Charles Gairdner Hospital
    • Nedlands, Western Australia, Australia, 6009
      • Hollywood Private Hospital
    • Perth, Western Australia, Australia
      • Royal Perth Hospital
    • Perth, Western Australia, Australia, 6005
      • Mount Medical Centre
• Belgium
  • Aalst, Belgium, 9300
    • OL Vrouw Ziekenhuis Aalst Gastro-Enterologie
  • Antwerp, Belgium
    • Antwerp University Hospital
  • Antwerpen, Belgium, 2020
    • ZNA Middelheim
  • Bonheiden, Belgium, 2820
    • Imelda Ziekenhuis GI Clinical Research Centre
  • Bornem, Belgium, 2880
    • Sint-Josef Ziekenhuie (Campus Bornem)
  • Brussels, Belgium
    • Institut Jules Bordet - Centre de Tumeurs d'ULB
  • Gent, Belgium
    • AZ Maria Middelares
  • Gent, Belgium, 9000
    • Universiteits Ziekenhuis Gent
  • Haine-Saint-Paul, Belgium, 7100
    • Hospital de Jolimont
  • Leuven, Belgium, 3000
    • UZ Leuven, Campus Gasthuisberg
  • Liege, Belgium
    • Centre hospitalier universitaire de Liege
  • Mechelen, Belgium, 2800
    • VZW Emmaus St. Maarten Ziekenhuis Mechelen and St. Marten Ziekenhuis Duffel
  • Reet, Belgium, 2840
    • AZ Heilige Familie
  • Wilrijk, Belgium, 2610
    • Sint-Augustinus ziekenhuis
• France
  • Bordeaux, France, 33000
    • CHU de Bordeau
  • La Tronche, France, 38700
    • Hospitalier Universitaire de Grenoble C.H.U.
  • Longjumeau, France, 91161
    • Centre Hospitalier Général de Longjumeau
  • Nice, France, 06202
    • Hopital de l'Archet II, CHU de Nice
  • Paris, France, 7590
    • Hospital european Georges pompidou
  • Rennes Cedex, France
    • Centre Eugène Marquis
• Germany
  • Altstadt, Germany, 84028
    • Internistische Gemeinschaftspraxis
  • Berlin, Germany, 1335
    • Charite Campus Virchow Klinikum
  • Bonn, Germany
    • Universitaetsklinikum Bonn
  • Bonn, Germany, 53123
    • Braxiskooperation Bonn, Fachartze fur Innere Medizin
  • Bonn, Germany
    • Johanniterkrankenhaus Bonn
  • Essen, Germany, 45136
    • Kliniken Essen Mitte
  • Essen, Germany
    • Gemeinschaftspraxis Hamatologie und internistische Onkologie
  • Frankfurt, Germany, 6059
    • Universitat Frankfurt Institute fur Diagnostic und Interventionelle Radiologie
  • Hamburg, Germany, 20367
    • Asklepios Klinik Altona, Abt. Radiologie, Neuroradiologie, Nuklearmedizin
  • Hamburg, Germany
    • Universitastsklinikum Saarland
  • Holzkirch, Germany, 83607
    • Praxisgemeinschaft Dr. med. Peter Sandor und Peter Kohl
  • Ingolstadt, Germany, 85049
    • Onklogische Praxis Dr. Gerald Gehbauer
  • Karlsruhe, Germany, 76133
    • Klinikum Karlsruhe, Stadtisches Klinikum Karlsruhe, Zentralinstitut fur Bildgebende Diagnostik
  • Magdeburg, Germany, 39104
    • Schwerpunktpraxis für Hämatologie und Onkologie
  • Magdeburg, Germany, 39130
    • Klinikum Magdeburg GmbH, Klinik für Hämatologie/Onkologie
  • Magdeburg, Germany
    • Universitaetsklinikum Magdeburg
  • Marburg, Germany, 35043
    • Universitatsklinikum GieBen und Marburg
  • Muenchen, Germany
    • Klinikum Bogenhausen
  • Muenchen, Germany
    • Klinikum der Universitaet Muenchen
  • Munchen, Germany
    • Hamato-Onkologische Schwerpunktspraxis
  • Munchen, Germany
    • Klinikum rechts der Isar der TU München
  • Munchen, Germany
    • Schwerpunktspraxis fur Hamatologie und Internistische Onkologie
  • Velbert, Germany, 42551
    • Praxis fur Hamatologie und Internnistische Onkologie
  • Weilheim, Germany
    • Schwerpunktspraxis und Tagesklinik Dr. Perker/Dr. Sandherr
• Israel
  • Haifa, Israel
    • Rambam Medical Center
  • Jerusalem, Israel, 91031
    • Shaare-Zedek Medical Centre
  • Petah Tiqva, Israel, 49100
    • Rabin Medical Center, Beilinson Hospital
  • Ramat Gan, Israel, 52621
    • Sheba Medical Center
  • Tel Aviv, Israel, 64239
    • TA Sourasky Medical Center
• Italy
  • Bologna, Italy, 40138
    • A.O.U. die Bologna
• New Zealand
  • Auckland, New Zealand
    • University of Auckland
  • Christchurch, New Zealand
    • Christchurch Hospital
  • Dunedin, New Zealand
    • Dunedin Hospital
  • Newtown, New Zealand
    • Wellington Hospital
  • Palmerston, New Zealand
    • Palmerston North Hospital
• Poland
  • Warsaw, Poland, 04-141
    • Wojskowy Instytut Medyczny (WIM)
• Spain
  • Pamplona, Spain, 31008
    • Clinica Universitaria de Navarra
  • Pamplona, Spain, 31008
    • Hospital de Navarra, Servicio de Ongoligia, Planta Baja
• Switzerland
  • Zurich, Switzerland, CH-8091
    • Universitatsspital Zurich
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Pinnacle Oncology Hematology
  • California
    • Duarte, California, United States, 91010
      • City of Hope Hospital
  • Florida
    • North Miami Beach, Florida, United States, 33169
      • Florida International University College of Medicine Practice
  • Illinois
    • Berwyn, Illinois, United States, 60402
      • Vanguard Health
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
    • Harvey, Illinois, United States, 80426
      • Ingalls Memorial Hospital
    • Hinsdale, Illinois, United States, 60525
      • Adventist Hinsdale Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute
  • New Jersey
    • Teaneck, New Jersey, United States, 07666
      • Holy Name Hospital
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Hematology-Oncology Associates
  • North Dakota
    • Grand Forks, North Dakota, United States, 58201
      • Altru Health Systems
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84124
      • St. Mark's Hospital
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin/Froedtert Memorial Lutheran Hospital
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Unequivocal and measurable CT evidence of liver metastases which are not treatable by surgical resection or local ablation.
• Limited extra-hepatic metastases in the lung and/or lymph nodes are permitted (Lung: 5 lesions total, < 1 cm, or 1 single lesion of up to 1.7 cm; Lymph nodules in one single anatomic area (pelvis, abdomen or chest): any number, < 2 cm).
• Suitable for either treatment regimen.
• Prior chemotherapy for metastatic colorectal cancer is not allowed.
• WHO performance status 0-1.
• Adequate hematological, renal and hepatic function.
• Age 18 years or older.
• Willing and able to provide written informed consent.
• Life expectancy of at least 3 months without any active treatment.

Exclusion Criteria

• Evidence of ascites, cirrhosis, portal hypertension, main portal or venous tumor involvement or thrombosis as determined by clinical or radiologic assessment.
• Previous radiotherapy delivered to the upper abdomen.
• Non-malignant disease that would render the patient unsuitable for treatment according to the protocol.
• Peripheral neuropathy > grade 1 (NCI-CTC).
• Dose limiting toxicity with previous adjuvant 5-FU or oxaliplatin chemotherapy.
• Prior non-adjuvant chemotherapy for any malignancy. Adjuvant chemotherapy for colorectal cancer is not an exclusion criteria provided that it was completed more than 6 months before entry into the study.
• Pregnant or breast-feeding.
• Other active malignancy.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: mFOLFOX6 + SIRT; A single injection of SIR-Spheres microspheres into the liver plus systemic chemotherapy consisting of Oxaliplatin + Leucovorin + 5-Fluorouracil (FOLFOX)	Device: SIR-Spheres yttrium-90 microspheres; SIR-Spheres microspheres (yttrium-90 [Y-90] labelled resin microspheres), hepatic artery injection administered on Day 3 or 4 of cycle 1. mFOLFOX6 administered on Day 1 and at the start of each cycle every 14 days: 85 or 60 mg/m2 oxaliplatin by 2-hour intravenous (IV) infusion + 200 mg/m2 leucovorin by 2-hour IV infusion + 400 mg/m2 5-fluorouracil (5-FU) by IV bolus + 2.4 g/m2 5-FU by 46-hour continuous IV infusion. Treatment with the biologic agent bevacizumab, if part of standard practice at the participating institution, was permitted at the discretion of the treating Investigator. In the event that leucovorin was not available, use of levofolinic acid (the active S enantiomer) was acceptable at half the dose of the racemic leucovorin i.e. 100 mg/m2.; Other Names: mFOLFOX6m + SIRT; SIR-Spheres Y-90 microspheres
Active Comparator: mFOLFOX6; Systemic chemotherapy consisting of Oxaliplatin + Leucovorin + 5- Fluorouracil (FOLFOX).	Drug: Systemic chemotherapy (FOLFOX); mFOLFOX6 administered on Day 1 and at the start of each cycle every 14 days: 85 or 60 mg/m2 oxaliplatin by 2-hour intravenous (IV) infusion + 200 mg/m2 leucovorin by 2-hour IV infusion + 400 mg/m2 5-fluorouracil (5-FU) by IV bolus + 2.4 g/m2 5-FU by 46-hour continuous IV infusion. Treatment with the biologic agent bevacizumab, if part of standard practice at the participating institution, was permitted at the discretion of the treating Investigator. In the event that leucovorin was not available, use of levofolinic acid (the active S enantiomer) was acceptable at half the dose of the racemic leucovorin i.e. 100 mg/m2.; Other Names: mFOLFOX6

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) at Any Site	PFS defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as an increase in the sum of the longest diameters of ≥ 20% and an absolute increase in the sum of the longest diameters of ≥ 5 mm, or the appearance of a new lesion.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Overall Response	Tumour Response Rate per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT: Complete Response (CR) - Disappearance of all target lesions which is confirmed if determined by two observations not less than 4 weeks apart; Partial Response (PR) - >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	Through study completion, up to 60 months

Collaborators and Investigators

• Sponsor: Sirtex Medical
• Investigators: Principal Investigator: Peter Gibbs, MD, Melbourne Health; Principal Investigator: Guy van Hazel, MD, Mount Medical Centre

Publications and helpful links

General Publications

• van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodriguez J, Kroning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. doi: 10.1200/JCO.2015.66.1181. Epub 2016 Feb 22. Erratum In: J Clin Oncol. 2016 Nov 20;34(33):4059.
• Wolstenholme J, Fusco F, Gray AM, Moschandreas J, Virdee PS, Love S, Van Hazel G, Gibbs P, Wasan HS, Sharma RA. Quality of life in the FOXFIRE, SIRFLOX and FOXFIRE-global randomised trials of selective internal radiotherapy for metastatic colorectal cancer. Int J Cancer. 2020 Aug 15;147(4):1078-1085. doi: 10.1002/ijc.32828. Epub 2020 Jan 9.
• Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A; FOXFIRE trial investigators; SIRFLOX trial investigators; FOXFIRE-Global trial investigators, van Hazel G, Sharma RA. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. doi: 10.1016/S1470-2045(17)30457-6. Epub 2017 Aug 3.
• Virdee PS, Moschandreas J, Gebski V, Love SB, Francis EA, Wasan HS, van Hazel G, Gibbs P, Sharma RA. Protocol for Combined Analysis of FOXFIRE, SIRFLOX, and FOXFIRE-Global Randomized Phase III Trials of Chemotherapy +/- Selective Internal Radiation Therapy as First-Line Treatment for Patients With Metastatic Colorectal Cancer. JMIR Res Protoc. 2017 Mar 28;6(3):e43. doi: 10.2196/resprot.7201.
• Gibbs P, Gebski V, Van Buskirk M, Thurston K, Cade DN, Van Hazel GA; SIRFLOX Study Group. Selective Internal Radiation Therapy (SIRT) with yttrium-90 resin microspheres plus standard systemic chemotherapy regimen of FOLFOX versus FOLFOX alone as first-line treatment of non-resectable liver metastases from colorectal cancer: the SIRFLOX study. BMC Cancer. 2014 Dec 1;14:897. doi: 10.1186/1471-2407-14-897.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2006
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: July 25, 2008
• First Submitted That Met QC Criteria: July 28, 2008
• First Posted (Estimate): July 29, 2008

Study Record Updates

• Last Update Posted (Actual): March 26, 2019
• Last Update Submitted That Met QC Criteria: March 1, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: bevacizumab; colon cancer; metastatic colorectal cancer; liver metastases; FOLFOX; Colorectal carcinoma; SIR-Spheres microspheres; yttrium-90
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Liver Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Carcinoma; Colorectal Neoplasms; Neoplasm Metastasis; Liver Neoplasms
• Other Study ID Numbers: STX0206