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International audience; 3502 Background: The SIRFLOX study was designed to assess the efficacy and safety of combining FOLFOX chemotherapy (\+/-\ bev) with SIRT using yttrium-90 (Y-90) resin microspheres as first-line treatment of pts with liver metastases from mCRC. Methods: SIRFLOX was an international, multi-center, open-label, RCT in chemotherapy-naive pts with non-resectable, liver only or liver dominant (liver plus lung and/or lymph node metastases) mCRC. Arm A: mFOLFOX6 \+/-\ bev was compared to arm B: mFOLFOX6 + SIRT (SIR-Spheres; Sirtex) administered once with cycle 1 \+/-\ bev until disease progression. The primary endpoint was progression free survival (PFS) using RECIST v1.0. Stratification variables included presence of extra hepatic disease (EHD; liver only v liver dominant), degree of liver involvement ( [≤] 25% v \textgreater 25%), and treatment with bev (at clinician discretion). Results: From Oct 2006 to Apr 2013,530 pts were randomised (arm A, n = 263; arm B, n = 267), 212 (40%) had EHD. Median follow-up was 36.1 months. The median overall PFS was 10.2 v 10.7 months in arms A v B respectively (hazard ratio [HR]: 0.93; 95% CI 0.77-1.12; p=0.428) by Kaplan Meier analysis. The median PFS in the liver was 12.6 v 20.5 months in arm A v B (HR: 0.69; 95% CI 0.55-0.90; p = 0.002) by competing risk analysis. Overall response rate (PR + CR) was 68.0% v 76.4% in arm A v B, respectively (p = 0.113). Hepatic response rate was 68.8% v 78.7% in arm A v B (p = 0.042), including CR rate 1.9% v 6.0% (p = 0.02). The liver resection rate was 13.7% v 14.2% in arm A v B (p = 0.857). Adverse events [≥] grade 3 were noted in 73.3% v 85.4% of pts in arm A v B. Most common toxicities were hematologic; 32.9% v 51.2% and gastrointestinal; 21.2% v 32.9%, including gastric ulcer 0.0% v2.4%. Conclusion: In first-line treatment of pts with non-resectable CRC liver metastases, the addition of SIRT to standard chemotherapy failed to improve overall PFS. However, median liver PFS was significantly extended. The addition of SIRT was associated with acceptable toxicity. Overall survival analyses, combining data from SIRFLOX and two other ongoing studies in this disease setting, are awaited. Clinical trial information: NCT00724503

Background In colorectal cancer (CRC), unresectable liver metastases are linked to poor prognosis. Systemic chemotherapy with regimens such as FOLFOX (combination of infusional 5-fluorouracil, leucovorin and oxaliplatin) is the standard first-line treatment. The SIRFLOX trial was designed to assess the efficacy and safety of combining FOLFOX-based chemotherapy with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-Spheres®; Sirtex Medical Limited, North Sydney, Australia). Methods/Design SIRFLOX is a randomised, multicentre trial of mFOLFOX6 chemotherapy ± SIRT as first-line treatment of patients with liver-only or liver-predominant metastatic CRC (mCRC). The trial aims to recruit adult chemotherapy-naïve patients with proven liver metastases with or without limited extra-hepatic disease, a life expectancy of ≥3 months and a WHO performance status of 0–1. Patients will be randomised to receive either mFOLFOX6 or SIRT + mFOLFOX6 (with a reduced dose of oxaliplatin in cycles 1–3 following SIRT). Patients in both arms can receive bevacizumab at investigator discretion. Protocol chemotherapy will continue until there is unacceptable toxicity, evidence of tumour progression, complete surgical resection or ablation of cancerous lesions, or the patient requests an end to treatment. The primary endpoint of the SIRFLOX trial is progression-free survival (PFS). Secondary endpoints include: PFS in the liver; tumour response rate (liver and any site); site of tumour progression; health-related quality of life; toxicity and safety; liver resection rate; and overall survival. Assuming an increase in the median PFS from 9.4 months to 12.5 months with the addition of SIRT to mFOLFOX6, recruiting ≥450 patients will be sufficient for 80% power and 95% confidence. Discussion The SIRFLOX trial will establish the potential role of SIRT + standard systemic chemotherapy in the first-line management of mCRC with non-resectable liver metastases. Trial registration SIRFLOX ClinicalTrials.gov identifier: NCT00724503. Registered 25 July 2008. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-897) contains supplementary material, which is available to authorized users.

Purpose: Radioembolisation is part of the multimodal treatment of hepatocellular carcinoma (HCC) at specialist liver centres. This study analysed the impact of prior treatment on tolerability and survival following radioembolisation. Methods: This was a retrospective analysis of 325 consecutive patients with a confirmed diagnosis of HCC, who received radioembolisation with yttrium-90 resin microspheres at eight European centres between September 2003 and December 2009. The decision to treat was based on the clinical judgement of multidisciplinary teams. Patients were followed from the date of radioembolisation to last contact or death and the nature and severity of all adverse events (AEs) recorded from medical records. Results: Most radioembolisation candidates were Child-Pugh class A (82.5%) with multinodular HCC (75.9%) invading both lobes (53.1%); 56.3% were advanced stage. Radioembolisation was used first-line in 57.5% of patients and second-line in 34.2%. Common prior procedures were transarterial (chemo)embolisation therapies (27.1%), surgical resection/transplantation (17.2%) and ablation (8.6%). There was no difference in AE incidence and severity between prior treatment subgroups. Median (95% confidence interval [CI]) survival following radioembolisation was similar between procedure-naive and prior treatment groups for Barcelona Clinic Liver Cancer (BCLC) stage A: 22.1 months (15.1–45.9) versus 30.9 months (19.6–46.8); p = 0.243); stage B: 18.4 months (11.2–19.4) versus 22.8 months (10.9–34.2); p = 0.815; and stage C: 8.8 months (7.1–10.8) versus 10.8 months (7.7–12.6); p = 0.976. Conclusions: Radioembolisation is a valuable treatment option for patients who relapse following surgical, ablative or vascular procedures and remain suitable candidates for this treatment.

A multicenter analysis was conducted to evaluate the main prognostic factors driving survival after radioembolization using yttrium-90-labeled resin microspheres in patients with hepatocellular carcinoma at eight European centers. In total, 325 patients received a median activity of 1.6 GBq between September 2003 and December 2009, predominantly as whole-liver (45.2%) or right-lobe (38.5%) infusions. Typically, patients were Child-Pugh class A (82.5%), had underlying cirrhosis (78.5%), and had good Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0-1; 87.7%), but many had multinodular disease (75.9%) invading both lobes (53.1%) and/or portal vein occlusion (13.5% branch; 9.8% main). Over half had advanced Barcelona Clinic Liver Cancer (BCLC) staging (BCLC C, 56.3%) and one-quarter had intermediate staging (BCLC B, 26.8%). The median overall survival was 12.8 months (95% confidence interval, 10.9-15.7), which varied significantly by disease stage (BCLC A, 24.4 months [95% CI, 18.6-38.1 months]; BCLC B, 16.9 months [95% CI, 12.8-22.8 months]; BCLC C, 10.0 months [95% CI, 7.7-10.9 months]). Consistent with this finding, survival varied significantly by ECOG status, hepatic function (Child-Pugh class, ascites, and baseline total bilirubin), tumor burden (number of nodules, alpha-fetoprotein), and presence of extrahepatic disease. When considered within the framework of BCLC staging, variables reflecting tumor burden and liver function provided additional prognostic information. The most significant independent prognostic factors for survival upon multivariate analysis were ECOG status, tumor burden (nodules >5), international normalized ratio >1.2, and extrahepatic disease. Common adverse events were: fatigue, nausea/vomiting, and abdominal pain. Grade 3 or higher increases in bilirubin were reported in 5.8% of patients. All-cause mortality was 0.6% and 6.8% at 30 and 90 days, respectively. Conclusion: This analysis provides robust evidence of the survival achieved with radioembolization, including those with advanced disease and few treatment options. © 2011 American Association for the Study of Liver Diseases.