Overall survival in the FOXFIRE-SIRFLOX-FOXFIRE global prospective randomized studies of first-line SIRT in patients with mCRC

Background: The FOXFIRE randomized studies [FOXFIRE, SIRFLOX and FOXFIRE-Global (FF-SF-FFG)] were designed to evaluate the efficacy and safety of selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres plus first-line chemotherapy for unresectable metastatic colorectal cancer (mCRC). The design and eligibility criteria of the three studies were similar, which facilitated this prospective combined analysis of overall survival (OS). Methods: Chemotherapy-naïve mCRC patients with liver metastases unsuitable for curative resection/ablation were randomized (1:1) to the Control arm with standard oxaliplatin-based chemotherapy (mFOLFOX6 or OxMdG) ± bevacizumab, or the Test arm to receive the same chemotherapy, plus a single SIRT treatment. Limited extra-hepatic metastases and primary tumor in situ were included. The primary endpoint OS was analysed on an intention-to-treat basis using individual participant data. Secondary endpoints included progression-free survival (PFS), liver PFS, response rate and adverse events (AEs). Results: A total of 1103 patients (Control arm n = 549; Test arm n = 554) with a median age of 63 years were enrolled. Median follow-up was 43.3 months. There was no difference in median OS between the two treatment arms (pooled hazard ratio [HR] 1.04; 95% confidence interval [CI], 0.90-1.19; p = 0.609) or in median PFS (pooled HR 0.90; 95% CI, 0.79-1.02; p = 0.108). The objective response rate was higher in the SIRT arm than in the Control arm (72.2% and 63.0%, respectively, p = 0.001). The risk of progression in the liver as a first event was lower in patients in the SIRT arm (pooled HR 0.51; CI 0.43-0.62; p < 0.001). There was a higher likelihood of grade 3-5 AEs in the Test arm than in the Control arm (74.0% vs 66.5%, respectively, p = 0.009). The addition of SIRT appeared to have a significant OS benefit in patients with right-sided tumors. Conclusions: This combined analysis showed no improvement when SIRT is added to first-line oxaliplatin-fluorouracil chemotherapy. However, the addition of SIRT achieved higher tumor response rates and improved liver-specific PFS. The addition of SIRT appeared to have a significant OS benefit in patients with right-sided tumors. Clinical trial indentification: FOXFIRE has ISRCTN Registry number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov with registration numbers NCT00724503 and NCT01721954, respectively. Legal entity responsible for the study: FOXFIRE, SIRFLOX and FOXFIRE-Global trial investigators. Funding: Bobby Moore Fund of Cancer Research U.K., the University of Oxford and Sirtex Medical Ltd. Disclosure:, H. Wasan: grants, personal fees, non-financial support and other uncompensated work from Sirtex Medical., G. van Hazel, V. Gebski: compensation for participation in Advisory Committees from Sirtex., V. Heinemann: honoraria from Amgen, Roche, Sanofi and Sirtex for consulting roles, participation in advisory boards, and his institution has received study grants from Amgen, Merck, Roche, Sanofi and Sirtex., N. Sharma: honoria from Sirtex Medical, J. Taieb: honoraria from Genentech, Merck Serono, Amgen, Celgene, Sanofi, Eli Lilly/ImClone Systems., J. Ricke: personal fees and grants from Sirtex Medical., M. Peeters: research funding and personal fees from Sirtex Medical., M. Findlay: grants from Sirtex Medical., P. Virdee, S.B. Love, J. Moschandreas: h grants from Cancer Research UK, grants from Sirtex Medical and non-financial support from Sirtex Medical., P. Dutton: grants from Cancer Research UK, grants from Sirtex Medical and non-financial support from Sirtex Medical, A. Gray: grants from Cancer Research UK, R. Sharma: research funding, honoraria, and consultancy fees from Sirtex Medical., P. Gibbs: honoraria from Sirtex Medical for participation in advisory boards and for giving presentations.