The site and pattern of first disease progression in control and SIRT patients offer insight into the apparent discordance between PFS at any site and PFS in the liver. Whereas control of intra- and extrahepatic disease is required to achieve a benefit in PFS at any site, the analysis of first progression site suggests that progressive disease in nonliver sites (7.9% v 27.7%) may mitigate the benefit of controlling liver disease with SIRT. Furthermore, the appearance of new lesions accounted for a substantially greater proportion of first progressions in the liver in SIRT (Appendix Table A2). Collectively, these data suggest that although SIRT used in conjunction with systemic chemotherapy provides prolonged control of evident liver disease, this is insufficient to influence PFS at any site. The increased incidence of progression within the lungs for SIRT patients would seem to reflect lung progression destined to occur in patients receiving a liver-directed intervention.
Other factors that may have compromised the ability of SIRT to significantly affect PFS at any site and the gains achieved in control of liver metastases include the 21 patients (7.9%) randomly assigned to SIRT but not receiving SIRT and the 19 patients (7.7%) with bilobar disease who received SIRT in only one liver lobe. Ultimately, only 84% of patients allocated to SIRT received SIRT as per protocol. This is explained partly by the random assignment of patients before consideration of their suitability for SIRT, but, on the basis of previous experience, the proportion of patients not receiving SIRT as per protocol was unexpectedly high.14,15,24 Also unanticipated was the large proportion of patients (approximately 45%) with an intact primary tumor; this had an uncertain impact on the primary study end point of PFS at any site and was reported to be associated with inferior survival outcomes.25 There are also uncertainties regarding the 10 patients (3.8%) who withdrew consent after being randomly assigned to control (and may have received SIRT off protocol as part of first-line therapy) but were included in the ITT population PFS analyses for control.
The median 20.5-month liver PFS for patients treated with chemotherapy plus SIRT represents a substantial prolongation of local disease control compared with systemic chemotherapy alone (median, 12.6 months). Because, to the best of our knowledge, this is the first study to evaluate PFS in the liver, there are no other studies that provide context for this result. However, recently reported data from the Chemotherapy + Local Ablation Versus Chemotherapy (CLOCC) study, which combined radiofrequency ablation with FOLFOX-based systemic chemotherapy in patients with unresectable mCRC confined to the liver, demonstrated that improved control of hepatic metastases can translate to a substantial impact on OS.26 In contrast to those in SIRFLOX, all patients randomly assigned in the CLOCC study, which also demonstrated an improvement in PFS at any site (HR, 0.57; 95% CI 0.38 to 0.85; P = .005), had a low burden of liver disease and no extrahepatic disease, and all had had their primary CRC resected.