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SIRFLOX Study Design Confounds Primary Efficacy Findings

John Otrompke
Published: Wednesday, Apr 27, 2016

Navesh K. Sharma, DO, PhD

Navesh K. Sharma, DO, PhD

The addition of Yttrium-90 (Y-90) resin microspheres (SIR-Spheres) to standard frontline FOLFOX-based chemotherapy with or without bevacizumab significantly improved liver-specific progression-free survival (PFS) for patients with liver metastatic colorectal cancer (CRC); however, PFS at any site, the primary endpoint of the study, was not changed with the addition of liver-directed therapy, according to data from the phase III SIRFLOX study published in the Journal of Clinical Oncology (JCO).1

PFS at any site was conceived as a proxy for a cure; however, the minor advantage seen in those who received selective internal radiation therapy (SIRT) along with chemotherapy was too small to be statistically significant. In the SIRT arm, patients experienced a median PFS of 10.7 months compared with 10.2 months in those who received chemotherapy alone (HR, 0.93; 95% CI, 0.77-1.12; P = .43).

However, shortcomings in the study may have confounded the main findings, as the trial seemed plagued by a large number of confounding factors and a shifting trial design. Ultimately, only 84% of patients allocated to receive SIRT actually got therapy that aligned with the protocol, including 7.7% of patients (n = 19) with bilobar disease who only received SIRT in one lobe of the liver and 7.9% of patients (n = 21) who were randomized to combination therapy but did not receive SIRT at all. Additionally, the percentage of patients with an intact primary tumor was unexpectedly high, at around 45%, which may have been impacted by the international design of the study.

Despite these shortcomings, there was, however, a substantial benefit seen for PFS in the liver, and this increase was highly statistically significant. Those in the arm that received SIRT plus chemotherapy enjoyed a median liverspecific PFS of 20.5 months compared with 12.6 months for those who received chemotherapy alone (HR, 0.69; 95% CI, 0.55-0.90; P = .002)

The SIRFLOX study sought to validate earlier findings from 2001 that showed an improvement in overall survival (OS) with SIRT plus floxuridine. In SIRFLOX, 530 patients were enrolled across the globe between October 2006 and April 2013. All patients were previously untreated for metastatic CRC, and were considered to have unresectable liver metastases when the study was initiated.

In addition to missing the primary endpoint, the study also did not show a significant increase in the number of liver resections. Of the patients in the arm that received SIRT, 38 (14.2%) went on to have a liver resection compared with 36 patients (13.7%) of those in the control arm.

SIRFLOX is the first of three randomized controlled trials in a preplanned combined analysis of SIRT’s impact on OS. SIRFLOX, FOXFIRE, and FOXFIRE Global have accrued a total of 1103 patients. Combined analysis of OS data from these three trials will be examined in 2017.

To gain further insight into the findings, OncLive spoke with Navesh K. Sharma, DO, PhD, US lead investigator of the SIRFLOX trial and one of the coauthors on the JCO paper. Sharma is the section chief of radiation oncology and associate professor at Penn State Health St Joseph Medical Center in Reading, Pennsylvania.

OncLive: What are the main findings from the study?

Sharma: The biggest message from the study is that SIRT can be given safely, because patients in both arms of the study were able to get the same chemotherapy. A lot of chemotherapy drugs are processed through the liver, and traditionally people were concerned that SIRT would damage the liver enough that chemotherapy would not be possible.

What are your thoughts on PFS at all sites as a primary endpoint?

I was not involved in the design of this study, but that endpoint in some ways was doomed to fail from the start. Development of new lung or bone metastasis was a failure of the endpoint, but it’s not surprising that people failed elsewhere than the liver. Technically, it was a failure of the systemic chemotherapy.

Could the chemotherapy used in this trial have been a confounding factor?

In a study described in 2001 in the Annals of Oncology,2 they were not using the chemotherapy regimen that is currently used now. No oxaliplatin was involved. In general, the OS for stage 4 disease has increased from 6 months to 2 years, which is what we normally quote patients today. It’s a huge jump.

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