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Overall survival analysis of the FOXFIRE prospective randomized studies of first-line selective internal radiotherapy (SIRT) in patients with liver metastases from colorectal cancer

Ricky A. Sharma, Harpreet Singh Wasan, Guy A. Van Hazel, Volker Heinemann, Navesh K. Sharma, Julien Taieb, et al.


Background: The FOXFIRE, SIRFLOX and FOXFIRE-Global (FF-SF-FFG) randomized studies evaluated the efficacy of combining first-line chemotherapy for metastatic colorectal cancer (mCRC) with selective internal radiotherapy (SIRT) using yttrium-90 resin microspheres in patients with liver metastases. The studies were designed for prospective, combined analysis of overall survival (OS).

Methods: FF-SF-FFG randomized (1:1) chemotherapy-naïve mCRC patients (performance status 0/1) with liver metastases not suitable for curative resection/ablation. Arm A was oxaliplatin-based chemotherapy (mFOLFOX6/ OxMdG) ± investigator-chosen biologically targeted agent. Arm B was the same systemic therapy (oxaliplatin dose modification) + single treatment SIRT with cycle 1/2 of chemotherapy. Primary tumor in situ and/or limited extra-hepatic metastases were permitted. Minimum sample size was 1075 patients (HR 0.8, 80% power, two-sided 5% significance). Secondary outcomes included PFS, liver-specific PFS and response rate. Apart from safety, outcomes were analysed on intention-to-treat population using meta-analytic methods of pooled individual patient data.

Results: Between 2006 and 2014, 1103 patients were randomized in 14 countries. Median age was 63 years (range 23-89); median follow-up 43.3 months. There were 844 deaths. There was no difference in OS (HR 1.04; 95% CI 0.90-1.19, p= 0.609) or PFS (HR 0.90, CI 0.79-1.02, p= 0.108) between Arms. Objective response rate (p= 0.001) and liver-specific progression (HR 0.51, CI 0.43-0.62, p< 0.001) were significantly more favorable in Arm B. Patients in Arm B had higher risk of non-liver progression as first event (HR 1.98, CI 1.53-2.58, p< 0.001). Grade 3-5 adverse events were more common in Arm B (74.0%) than A (66.5%), p= 0.009. In health status questionnaires, EQ-5D utility scores were not significantly different between Arms at 6, 12 or 24 months.

Conclusion: Despite higher response rates and improved liver-specific PFS, the addition of SIRT to first-line oxaliplatin-fluorouracil chemotherapy for patients with liver-only and liver-dominant mCRC did not improve OS or PFS.

Clinical trial information: 83867919

All content © 2017 American Society of Clinical Oncology. All rights reserved.

Editorial comment from Prof Ducreux:
This large trial has included more than 1100 patients to evaluate the impact on survival of a combination of systemic treatment using oxaliplatin based regimen with a local treatment of the liver metastases using yttrium-resin microspheres. This is the largest trial evaluating this kind of strategy. As previously reported, even if a local active treatment is able to control the liver disease (better response rate, better liver progression-free survival), this advantage did not convert in a prolonged overall survival. This result remains difficult to understand because it has always been considered that in patients with limited liver disease, a prolonged local control could prevent the death of the patients. It has to be imagined that extra-hepatic disease is responsible of death in these patients. It may also be considered that the administration of yttrium-resin microspheres could decrease the tolerance of further systemic patients. This is disappointing regarding the cost of this kind of procedure and all the attempts that have been made to control liver diseases in the subgroup of patients with liver limited disease (Intra-arterial hepatic chemotherapy, irinotecan loaded DC-Beads, and now yttrium-resin microspheres. Furthermore, similar negative results have been observed in trials comparing these yttrium-resin microspheres versus sorafenib in hepatocellular carcinoma. It seems to suggest that the control of the liver disease is clearly not the main problem of these patients.

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