title: 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.
abstract: BACKGROUND
  In colorectal cancer (CRC), unresectable liver metastases are associated with a poor prognosis. The FOXFIRE (an open-label randomized phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver-only or liver-predominant metastatic colorectal cancer), SIRFLOX (randomized 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), and FOXFIRE-Global (assessment of overall survival of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma in a randomized clinical study) clinical trials were designed to evaluate the efficacy and safety of combining first-line chemotherapy with selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres, also called transarterial radioembolization.
  
  
  OBJECTIVE
  The aim of this analysis is to prospectively combine clinical data from 3 trials to allow adequate power to evaluate the impact of chemotherapy with SIRT on overall survival.
  
  
  METHODS
  Eligible patients are adults with histologically confirmed CRC and unequivocal evidence of liver metastases which are not treatable by surgical resection or local ablation with curative intent at the time of study entry. Patients may also have limited extrahepatic metastases. Final analysis will take place when all participants have been followed up for a minimum of 2 years.
  
  
  RESULTS
  Efficacy and safety estimates derived using individual participant data (IPD) from SIRFLOX, FOXFIRE, and FOXFIRE-Global will be pooled using 2-stage prospective meta-analysis. Secondary outcome measures include progression-free survival (PFS), liver-specific PFS, health-related quality of life, response rate, resection rate, and adverse event profile. The large study population will facilitate comparisons of low frequency adverse events and allow for more robust safety analyses. The potential treatment benefit in those patients who present with disease confined to the liver will be investigated using 1-stage IPD meta-analysis. Efficacy will be analyzed on an intention-to-treat basis.
  
  
  CONCLUSIONS
  This analysis will assess the impact of SIRT combined with chemotherapy on overall survival in the first-line treatment of metastatic CRC. If positive, the results will change the standard of care for this disease.
  
  
  BACKGROUND
  FOXFIRE ISRCTN Registry ISRCTN83867919; http://www.isrctn.com/ISRCTN83867919 (Archived by WebCite at http://www.webcitation.org/6oN7axrvA). SIRFLOX ClinicalTrials.gov NCT00724503; https://clinicaltrials.gov/ ct2/show/NCT00724503 (Archived by WebCite at http://www.webcitation.org/6oN7lEGbD). FOXFIRE-Global ClinicalTrials.gov NCT01721954; https://clinicaltrials.gov/ct2/show/NCT01721954 (Archived by WebCite at http://www.webcitation.org/ 6oN7vvQvG).
authors.affiliation: Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Pradeep S
authors.identifier: http://orcid.org/0000-0002-3006-8730
authors.initials: PS
authors.lastname: Virdee
authors.affiliation: Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Joanna
authors.identifier: http://orcid.org/0000-0002-7169-0892
authors.initials: J
authors.lastname: Moschandreas
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
authors.forename: Val
authors.identifier: http://orcid.org/0000-0001-8748-1844
authors.initials: V
authors.lastname: Gebski
authors.affiliation: Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Sharon B
authors.identifier: http://orcid.org/0000-0002-6695-5390
authors.initials: SB
authors.lastname: Love
authors.affiliation: Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: E Anne
authors.identifier: http://orcid.org/0000-0003-4618-774X
authors.initials: EA
authors.lastname: Francis
authors.affiliation: Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom.
authors.forename: Harpreet S
authors.identifier: http://orcid.org/0000-0002-6268-2030
authors.initials: HS
authors.lastname: Wasan
authors.affiliation: University of Western Australia, Perth, Australia.
authors.forename: Guy
authors.identifier: http://orcid.org/0000-0001-9717-7993
authors.initials: G
authors.lastname: van Hazel
authors.affiliation: Western Hospital, Footscray, Victoria, Australia.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0003-1423-4484
authors.initials: P
authors.lastname: Gibbs
authors.affiliation: National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, United Kingdom.|Cancer Research United Kingdom-Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Ricky A
authors.identifier: http://orcid.org/0000-0002-4873-9918
authors.initials: RA
authors.lastname: Sharma
keywords: colorectal neoplasms; liver; meta-analysis; neoplasm metastasis; radiation oncology; survival analysis