Selective Internal Radiation Therapy With Yttrium-90 Resin Microspheres in Metastatic Colorectal Carcinoma: The SIRFLOX Study: Articles From the Official Show Daily for Synergy 2015

Selective internal radiation therapy (SIRT) with yttrium-90 (Y90) resin microspheres has demonstrated support of level I evidence in phase 3 clinical trials in first-line colorectal disease (in an older era of chemotherapeutic intervention, in conjunction with hepatic infusion pump), as well as in the chemo salvage/chemo refractory situation of metastatic colorectal carcinoma.^1,2 Retrospective matched pair analysis in the chemorefractory setting, and prospective phase 2 trials in second line and third line, have demonstrated a significant improvement in the control of liver tumors and a strong signal that this translates into an improvement in survival.^3-5 In a phase 2a clinical trial, Gibbs et al demonstrated a dramatic improvement in progression-free survival (PFS) within the liver for patients undergoing first-line contemporary chemotherapy and SIRT (single-arm, prospective design). This study laid the groundwork and rationale for the SIRFLOX and FOXFIRE trials.^6,7

What Is SIRFLOX?

SIRFLOX is an international phase 3 randomized control trial examining the use of Y90 loaded resin coated microspheres in the first-line setting of metastatic colorectal carcinoma. The trial was designed as an open-label study, with randomization to 2 arms. The control arm consisted of standard first-line chemotherapy (oxaliplatin, leucovorin, 5-fluorouracil, and an institutional choice as to whether bevacizumab would be used in the first-line setting) (Figure 1).

The primary objective of this study was to determine whether PFS, at any site within or outside of the liver, could be improved with the introduction of SIRT in the first-line setting using contemporary chemotherapeutic regimens.

Secondary objectives of the SIRFLOX study included PFS in the liver, overall survival (this is not yet reported; see further discussion of overall survival below), tumor response rate both in the liver and in any site, quality of life, liver resection rate (otherwise known as downstaging), toxicity, and safety.

What Did It Report? 

So far, 2 major abstracts have been presented with respect to the study. The first abstract was presented at the American Society of Clinical Oncology (ASCO) in Chicago in May of 2015 by the primary investigator of the study, Peter Gibbs, MD.⁷ The second presentation was at the World Congress of Gastrointestinal Cancer (WCGIC) in Barcelona on July 2015 by one of the site investigators, Guy Van Hazel, MD.⁸

The patient population was randomized to a 1:1 ratio, with 530 patients recruited (Figure 2). Forty percent of these patients had extrahepatic disease at presentation (which is a fundamental issue with the trial design, as discussed below).

The results in summary of the 2 clinical trials are as follows:

• SIRFLOX failed its primary endpoint of all-site PFS, reporting PFS at any site as 10.2 months in the control arm vs 10.7 months in the treatment arm (HR: 0.93 [95% CI: 0.77–1.12], P=.43).
• The secondary endpoint of PFS within the liver demonstrated a dramatic difference, reporting 12.6 months in the control arm vs 20.5 months in the treatment arm (HR: 0.69 [95% CI: 0.55–0.90], P=.002)
• A subset analysis of those patients with liver-only disease revealed a further benefit in this patient population, with PFS of 12.4 months in the control arm vs 21.1 months in the treatment arm (HR: 0.64 [95% CI: 0.48–0.86], P=.0003)
• Aside from a reported 3.7% ulceration rate in the SIRT arm, toxicities in both cohorts were considered acceptable and expected.
• A significantly higher number of patients were able to undergo downstaging to surgical resection in the intervention arm vs the control arm.
• The introduction of bevacizumab, based on intent to treat analysis, did not affect toxicity or the efficacy of response within the liver.

Opinion: What Does This Mean?

Upon first examination, the reporting of a negative primary outcome would seem disappointing, and potentially to be a setback for the technology platform. However, unique to this clinical study is the fact that the control arm and intervention arm both have the same degree/intensity of chemotherapy for the treatment of extrahepatic disease. To put it another way, both the control and interventional arm treated extrahepatic disease in the same way, with standard chemotherapy. Unless the intervention within the liver resulted in a significant immunologic response (the so-called abscopal effect), one would not expect a difference in the progression of, for example, a pulmonary metastasis based on liver-directed therapy. Therefore, the strongest and most encouraging signal is actually with respect to the liver-specific response (a very strong signal in the reported results), which has been demonstrated to be a potential surrogate of overall survival.⁹

The reality is that we understand metastases little as a chronic condition. Large population-based reviews of curative intent surgical resection demonstrate that a significant number of patients develop recurrence of disease specifically within the liver, in addition to a high percentage that present with liver and extrahepatic metastases. In essence, many of the curative intent therapies that we apply to liver metastases are not actually curative, but cytoreductive.^10-12

Selective internal radiation therapy follows along the same spectrum of therapy, and thus is part of the continuum of care within liver-directed therapy. Under no circumstances are any of these liver-directed therapies intended to address microscopic extrahepatic disease. However, all is not lost, as ultimately the most important endpoint is an improvement in overall survival. The SIRFLOX study was specifically designed to work in conjunction with 2 other major phase 3 clinical trials: FOXFIRE, an NHS sponsor trial executed within the United Kingdom, and FOXFIRE Global, essentially an extension of FOXFIRE. All three studies are similar in design, with the aggregated data of both survival and PFS of all three studies anticipated some time in the later quarters of 2017, representing 1,103 patients. This will be the largest randomized controlled trial ever conducted in interventional oncology, and the fourth largest trial ever executed in medical oncology (Table 1).  

References

1. Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001;12(12):1711-1720.

2. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010;28(23):3687-3694.

3. Sharma RA, Van Hazel GA, Morgan B, et al. Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy. J Clin Oncol. 2007;25(9):1099-1106.

4. Cosimelli M, Golfieri R, Cagol PP, et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. Br J Cancer. 2010;103(3):324-331.

5. Seidensticker R, Denecke T, Kraus P, et al. Matched-pair comparison of radioembolization plus best supportive care versus best supportive care alone for chemotherapy refractory liver-dominant colorectal metastases. Cardiovasc Intervent Radiol. 2012;35(5):1066-1073.

6. Dutton SJ, Kenealy N, Love SB, et al. FOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional Selective Internal Radiation Therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer. BMC Cancer. 2014;14:497.

7. Gibbs P, Heinemann V, Sharma N, et al. SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 + selective internal radiation therapy (SIRT) ± bev in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 2015;33(suppl):Abstr 3502.

8. van Hazel GA, Heinemann V, Sharma NK, et al. O-019SIRFLOX: Randomized trial comparing first-line mFOLFOX6 ± bevacizumab versus mFOLFOX6 + selective internal radiation therapy (SIRT) ± bevacizumab in patients with metastatic colorectal cancer (mCRC) – analysis by presence or absence of extra-hepatic metastases and bevacizumab treatment. Annals of Oncology. 2015;26(suppl 4):iv115.

9. Gill S, Berry S, Biagi J, et al. Progression-free survival as a primary endpoint in clinical trials of metastatic colorectal cancer. Curr Oncol. 2011;18 Suppl 2:S5-S10.

10. de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg. 2009;250(3):440-448.

11. Ruers T, Punt C, Van Coevorden F, et al. Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004). Ann Oncol. 2012;23(10):2619-2626.

12. Reurs T, Punt C, van Coevorden F, Peirie JP, al. e. Radiofrequency ablation (RFA) combined with chemotherapy for unresectable colorectal liver metastases (CRC LM): Long-term survival results of a randomized phase II study of the EORTC-NCRI CCSG-ALM Intergroup 40004 (CLOCC). J Clin Oncol. 2015;33(suppl):Abstr 3501.

Editor’s note: This article first appeared in the Synergy Daily conference newspaper, available to attendees of the Synergy Miami interventional oncology meeting, published November 6, 2015. This article did not undergo peer review. Dr. Liu reports consultanct to Sirtex Medical and grants from Sirtex Medical and BTG.

Suggested citation: Liu D. Selective internal radiation therapy with yttrium-90 resin microspheres in metastatic colorectal carcinoma: the SIRFLOX study: articles from the ifficial show daily for Synergy 2015. Intervent Oncol 360. 2016;4(2):E27-E31.