title: FOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional Selective Internal Radiation Therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer.
abstract: BACKGROUND
  Colorectal cancer (CRC) is the second most common malignancy in Europe and a leading cause of cancer-related death. Almost 50% of patients with CRC develop liver metastases, which heralds a poor prognosis unless metastases can be downsized to surgical resection or ablation. The FOXFIRE trial examines the hypothesis that combining radiosensitising chemotherapy (OxMdG: oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-Spheres®; Sirtex Medical Limited, North Sydney, Australia) as a first-line treatment for liver-dominant metastatic CRC will improve clinical outcomes when compared to OxMdG chemotherapy alone.
  
  
  METHODS
  FOXFIRE is an open-label, multicentre, randomised controlled trial of OxMdG with or without the addition of SIRT (1:1 randomisation). Eligible adult patients have histologically confirmed colorectal adenocarcinoma, liver metastases measurable on computed tomography scan and untreatable by either surgical resection or local ablation, and they may have limited extra-hepatic disease, defined as ≤5 nodules in the lung and/or one other metastatic site which is amenable to future definitive treatment. Eligible patients may have received adjuvant chemotherapy following resection of the primary tumour, but are not permitted to have previously received chemotherapy for metastatic disease, and must have a life expectancy of ≥3 months and a WHO performance status of 0-1. The primary outcome is overall survival. Secondary outcomes include progression free survival (PFS), liver-specific PFS, patient-reported outcomes, safety, response rate, resection rate and cost-effectiveness. FOXFIRE shares a combined statistical analysis plan with an international sister trial called SIRFLOX.
  
  
  CONCLUSIONS
  This trial is establishing a network of SIRT centres and 'feeder' chemotherapy-only centres to standardise the delivery of SIRT across the whole of the UK and to provide greater equity of access to this highly specialised liver-directed therapy. The FOXFIRE trial will establish the potential role of adding SIRT to first-line chemotherapy for unresectable liver metastatic colorectal cancer, and the impact on current treatment paradigms for metastatic CRC.
  
  
  BACKGROUND
  ISRCTN83867919.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Dutton
authors.forename: Nicola
authors.initials: N
authors.lastname: Kenealy
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Love
authors.forename: Harpreet S
authors.initials: HS
authors.lastname: Wasan
authors.affiliation: CRUK-MRC Oxford Institute for Radiation Oncology, NIHR Biomedical Research Centre Oxford, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, UK. ricky.sharma@oncology.ox.ac.uk.
authors.forename: Ricky A
authors.initials: RA
authors.lastname: Sharma
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy / Q000556:secondary*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D000077150:Oxaliplatin; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D011878:Radiotherapy / Q000379:methods; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011838:Radiation-Sensitizing Agents; D015021:Yttrium Radioisotopes; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil