Abstract
BackgroundColorectal 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/DesignFOXFIRE 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.DiscussionThis 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.Trial registrationISRCTN83867919
Highlights
Colorectal cancer (CRC) is the second most common malignancy in Europe and a leading cause of cancer-related death
This trial is establishing a network of Selective Internal Radiation Therapy (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
Summary
The need for robust quality of life information from patients having SIRT was emphasised by NICE in its guidance published in July 2011 To address this deficit in the published literature, FOXFIRE has incorporated 3 quality of life instruments at 4 timepoints, plus annually, as an important secondary endpoint of the clinical trial. In addition to these data, a bespoke health economics questionnaire is being collected at baseline and annually to provide information about potential health economic benefits for patients treated with SIRT. A substudy of Perfusion Liver CT in a subgroup of the FOXFIRE patients is open to recruitment and is gathering data to study the role of this imaging modality in predicting response to chemotherapy and to SIRT (PERFORM, University of Oxford, UK: NCT01410760). All authors read and approved the final draft of the manuscript for submission
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