Title: CRUK/07/030: FOXFIRE: Randomised phase II-III trial of 5-Fluorouracil, Oxaliplatin, Folinic acid +/- Interventional Radio-Embolisation with yttrium-90 SIR-Spheres in metastatic colorectal cancer (supported by the Bobby Moore fund)
Funder: Cancer Research UK

Abstract: (1) Recent Phase I data confirm that radioembolisation (RE) can be administered with concomitant systemic radiosensitising oxaliplatin-based (FOLFOX4) chemotherapy with acceptable levels of toxicity. The dose limiting toxicity was grade 3 and 4 neutropenia and the maximum tolerated dose was 60 mg/m2 of oxaliplatin for 3 cycles from RE followed by full FOLFOX4 doses thereafter. In the 20 patients treated, the radiological response rate (PR+CR) was 90% and 2 patients had SD. Median progression free survival (PFS) in all patients was 9.3 months; in the subset of patients without extra-hepatic disease, it was at 14.2 months. In addition to these phase I data, two other small randomised Phase II studies of RE + 5FU-based chemotherapy regimes versus chemotherapy alone have reported response rates over 80% and TTP/PFS of 12+ to 18.6 months, both significantly in favour of the RE arm. (2) Despite recent major advances in the systemic treatment of metastatic colorectal cancer (mCRC), the 5-year overall survival remains disappointingly low at approximately 7%. It is notable that in a subset of patients with liver-only mCRC, in whom surgical resection of disease can be achieved, the 5-year survival probability is 30-40%, with 20% of patients achieving long term cure. Of all patients with mCRC, 20-30% have liver-only metastases and approximately 50% of recurrences following resection of the primary tumour are confined to the liver alone. Increasingly, the focus for improving survival for patients with mCRC aims to expand this sub-group. It is anticipated that long term survivors from all patients with mCRC could be at least doubled with multi-modality combinations of systemic therapy and liver surgery. (3) The proposed randomised controlled trial will compare 12 cycles of OxMdG chemotherapy alone with the same plus RE. The primary outcome measure will be overall survival. The trial will also study: progression-free survival (PFS), Liver-specific PFS, safety and toxicity, healthcare costs, quality of life, cost-effectiveness, response rate, resection rate,% or patients receiving second line treatment and interval from randomisation to start of second line chemotherapy. (4) Following baseline eligibility screening, patients will be randomised to: A) Chemotherapy alone. Patients in arm A will receive 12 cycles of OxMdG as standard therapy (oxaliplatin dose 85 mg/m2 unless toxicity is experienced) B) Chemotherapy + Radioembolisation with SIR-spheres. Chemotherapy: Cycle 1 of OxMdG (oxaliplatin dose 85 mg/m2) then 3 cycles of OxMdG with an oxaliplatin dose of 60 mg/m2 (i.e. reduced dose compared to Arm A) because RE will be performed on day 3 or 4 of cycle 2 of chemotherapy. Full dose of OxMdG chemotherapy will be used for cycles 5-12. Following completion of protocol therapy in arm A or B, all patients will undergo CT scanning and further therapy (including surgery) may be offered at the discretion of the treating physician. Last updated 03/04/2007 Despite major advances over the past decade in the treatment of colorectal cancer that has spread to the liver, the number of patients that survive 5-years from the diagnosis of spread remains disappointingly low. Radioembolisation (RE) is a technique that has been developed to target multiple sites of malignant disease within the liver as a form of internal radiation therapy. SIR-Spheres« (Sirtex Medical Ltd, Sydney, Australia) contain radioactivity and can be administered directly into the artery supplying the liver in a single out-patient procedure. They have been used to treat over 4000 patients in over 100 centres worldwide. Recent clinical trial data have suggested that RE can be safely combined with chemotherapy to try to improve the anti-cancer effects of both types of treatment. It is therefore proposed to study whether this combination of treatments significantly improves clinical outcomes for patients with colorectal cancer that has spread to the liver. Last updated 03/04/2007


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS