Published Data in Metastatic Colorectal Cancer

The SIRFLOX study results on the combination of SIR-Spheres® Y-90 resin microspheres with first-line chemotherapy were published in JCO in early 2016.1 The results from this first large-scale, randomized controlled trial (RCT) of 530 chemotherapy-naive patients with liver-only or liver-dominant metastatic colorectal cancer (mCRC) showed that the addition of SIR-Spheres Y‑90 resin microspheres significantly improved median liver Progression Free Survival (PFS) by 7.9 months, corresponding to a 31% risk reduction of progression in the liver.1 There was no statistically significant improvement in PFS at any site with the addition of SIR-Spheres Y-90 resin microspheres, a finding that was not unexpected with a liver-directed treatment.

A subsequent sub-analysis of Depth of Response (DpR) in SIRFLOX, a relatively new methodology that has been shown to correlate with Overall Survival (OS) and Post-Progression Survival in earlier mCRC studies,2 showed a significantly greater DpR (75.0% vs. 67.8% mean reduction in liver tumour burden; p=0.039) in patients who received SIR-Spheres Y-90 resin microspheres combined with chemotherapy. Patients also had a statistically significant, two-month longer time to DpR or maximal tumour shrinkage (median 266 vs. 206 days; p<0.001), compared to those who received chemotherapy alone.3

The analysis also revealed that the treatment effect following SIR-Spheres Y-90 resin microspheres was most evident in the patients who entered the study with a greater baseline liver tumour burden (>12% of the liver having been replaced by tumour, a statistical cut-point that was pre-determined in order to identify potential predictors of DpR). This group of more compromised patients, representing over half the patients in the SIRFLOX study, experienced a statistically significant, 20% greater DpR (77.5% vs. 57.2%; p=0.003) and over three-month longer time to DpR (median 298 vs. 196 days; p<0.001) compared to those treated with chemotherapy alone.3 SIR-Spheres Y-90 resin microspheres was also associated with a doubling of median PFS in the liver by competing risk analysis (27.2 vs. 13.1 months; p=0.003) in these patients.3 Conversely, patients who had a smaller liver tumour burden (≤12%) on study entry were more than six times more likely to experience a complete response or disappearance of all liver tumours following SIR-Spheres Y-90 resin microspheres compared to those who received only chemotherapy (11.3% vs. 1.7%; p=0.003).3

In the SIRFLOX study, the addition of SIR-Spheres Y-90 resin microspheres did not adversely affect the delivery of chemotherapy. Furthermore, the safety profile from the addition of SIR-Spheres Y-90 resin microspheres to the mFOLFOX6 chemotherapy regimen in SIRFLOX was as anticipated and manageable, with no unexpected toxicities observed.

Other smaller-scale RCTs have confirmed the efficacy of SIR-Spheres Y-90 resin microspheres when added to first-line chemotherapy for patients with mCRC (with improved Objective Response Rate [ORR] and Time to Progression [TTP]).4,5 One of these studies also showed a significantly increased OS with the addition of SIR-Spheres Y-90 resin microspheres to chemotherapy.4

Beyond the first-line use of SIR-Spheres Y-90 resin microspheres there are also multiple prospective studies and retrospective analyses which show positive effects of SIR-Spheres Y-90 resin microspheres on TTP/PFS (overall and liver) and OS when added as consolidation of first-line chemotherapy (i.e., in patients deemed unresectable 12–26 weeks after first-line chemotherapy),6 when combined with chemotherapy in patients who have already failed at least first-line chemotherapy,7,8 and in heavily pretreated patients who are chemorefractory and have failed standard of care.9-11 Several other single-arm studies investigated SIR-Spheres Y-90 resin microspheres as a salvage therapy and demonstrated median survival of approximately 10–12 months, which is an improvement on historical control data.11 As such, ESMO guidelines recommend Selective Internal Radiation Therapy (SIRT) in this setting.12

Summary of SIR-Spheres Y-90 resin microspheres in mCRC

1 van Hazel GA et al. J Clin Oncol 2016; 34: 1723-1731.
2 Heinemann V et al. Eur J Cancer 2015; 51: 1927–1936.
3 Heinemann V et al. ESMO WCGIC, Annals of Oncology 2016; 27 (Suppl 2): Abs. O-014.
4 van Hazel GA et al. J Surg Oncol 2004; 88: 78-85.
5 Gray B et al. Ann Oncol 2001; 12: 1711-1720.
6 Sangro B et al. ASCO Gastrointestinal Cancers Symposium 2010; Abs. 250.
7 Lim L et al. BMC Cancer 2005; 5: 132.
8 van Hazel GA. et al. J Clin Oncol 2009; 27: 4089-4095.
9 Hendlisz A et al. J Clin Oncol 2010; 28: 3687-3694.
10 Seidensticker R et al. Cardiovasc Intervent Radiol 2012; 35: 1066-1073.
11 Bester L et al. J Vasc Interv Radiol 2012; 23: 96-105.
12 Van Cutsem E et al. Ann Oncol 2016 Jul 5; ePub: doi:10.1093/annonc/mdw235.



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