SIRFLOX Data Show Mixed Results for Survival

The landmark SIRFLOX trial, a randomized controlled trial of SIR-Spheres Y90 microspheres (Sirtex) in patients with metastatic colorectal cancer (mCRC), has shown evidence suggesting that a first-line treatment strategy of standard of care chemotherapy plus SIR-Spheres microspheres is more effective in delaying cancer progression than chemotherapy alone in patients with inoperable liver metastases from primary colorectal cancer. This was a secondary endpoint for SIRFLOX. The study did not, however, meet its primary endpoint of improvement in overall progression-free survival (PFS).

At more than 100 leading hospitals globally, 530 patients participated in the study over a 6-year period. Patients were diagnosed initially with colorectal cancers that had spread only to the liver, or in whom the majority of the cancer was in the liver with a small amount of tumor in the lungs or lymph nodes. The patients received either standard chemotherapy with FOLFOX-6 only or with added liver radiation using selective internal radiation therapy (SIRT) with SIR-Spheres. The Y90 microspheres selectively target liver tumors with a dose of internal radiation up to 40 times higher than conventional radiotherapy while sparing healthy tissue.

Most common side effects included abdominal pain and/or nausea, which usually subsided in a short time, mild fever, and fatigue. Some patients received additional medication such as painkillers, anti-inflammatory, anti-nausea, and anti-ulcer drugs to minimize side effects.

Study results were presented in May at the 2015 American Society of Clinical Oncology meeting by co-principal investigator Peter Gibbs, MD, a medical oncologist from Australia’s Royal Melbourne Hospital. Patients who were treated with SIR-Spheres Y90 microspheres in combination with a FOLFOX-based regimen (with bevacizumab), experienced a statistically significant improvement in PFS in the liver. In patients who received only the FOLFOX regimen, tumors in the liver progressed with a median 12.6 months while patients treated with SIR-Spheres Y90 progressed with a median 20.5 months, and a corresponding 31% lower risk of progression in liver metastases.¹ 

“This finding matters a great deal,” Gibbs stated in a press release, “because the liver is almost invariably the organ where colorectal cancer spreads to first. While half the patients initially diagnosed with colorectal cancer survive thanks to surgical removal of the primary tumor before the disease has spread elsewhere in the body, liver metastases eventually cause the death of the majority of the remaining hundreds of thousands of patients each year whose tumors spread but are inoperable.”

Additional results were presented in July at the European Society for Medical Oncology 17th World Congress of Gastrointestinal Cancer. The new findings show that patients with unresectable mCRC that has spread only to the liver experienced the greatest improvement in progression-free survival (PFS) in the liver from the addition of SIR-Spheres Y-90 resin microspheres to first-line chemotherapy regimen. These patients reached a median of 21.1 months before their liver disease progression, compared to 12.4 months for only first-line chemotherapy. Also, the benefit of bevacizumab was the same in each arm (2 months incremental PFS benefit), demonstrating that addition of SIR-Spheres Y-90 resin microspheres did not negatively impact the activity of bevacizumab.  

SIRFLOX Study Key Findings

• Based on preliminary analysis, the primary endpoint of the SIRFLOX study was not achieved.
• Adding SIR-Spheres Y90 resin microspheres to a current first-line systemic chemotherapy regimen for the treatment of nonresectable mCRC does not result in statistically significant improvements in overall PFS. 
• However, the preliminary analysis also showed that SIR-Spheres Y-90 resin microspheres did result in a statistically significant improvement in PFS in the liver:
• statistically significant improvement of 7.9 months in median PFS in the liver, from 12.6 to 20.5 months;
• 31% reduction in risk of progression in the liver;
• 3-fold increase in complete response rate in the liver; and
• Statistically significant increase in hepatic response rate.

Andrew S. Kennedy, MD, FACRO, director of radiation oncology research at the Sarah Cannon Research Institute, Nashville, Tennessee, was lead investigator in a 2014 MORE (Metastatic colorectal cancer liver metastases Outcomes after Radio Embolization) study at the American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium. He believes this more aggressive, interventional SIR-Spheres regimen could be a key benefactor in patients presenting with colorectal cancer for the first time.

“Patterns suggest that earlier, more aggressive intervention creates better patient outcomes,” Kennedy said. “If you can deal with metastatic disease in the liver, you can cure some patients and dramatically increase the survival of others while preserving their quality of life.”

For example, he continued, some patients with tumors in both right and left lobes may safely undergo surgical removal of the primary tumor. However, surgeons must first measure how much of the normal liver they can remove to ensure patient survival. So not all patients may be surgical candidates.

“The SIR-Spheres procedure can eradicate tumor from one or both lobes or greatly reduce the amount of tumor. Then over the next 3, 6, or 9 months of chemotherapy, the chemo clears out tumor cells outside the liver so the only tumor remaining is in one portion of the liver.

“The experimental arm, with chemo and radiation used together, could offer patients a longer survival time than those who undergo straight chemo. This aggressive surgical approach could be the last chance to convert someone from not being a candidate for liver surgery to undergoing treatment that could lead to a cure,” Kennedy said.

The influence on clinical decision-making could lead to bringing interventional procedures into cancer care earlier, in Kennedy’s opinion.

“This is the first time there has been a prospective randomized study with interventional treatment in the liver,” Kennedy said. “It breaks new ground: it’s safe to do, there’s every expectation that it will benefit the patient, and there is a very large data set in a very well done study. It overcomes flaws in older studies and gives us rationale and proof that we can give patients a chance.” Kennedy also commented on the primary endpoint results.

“The primary endpoint in the SIRFLOX study would be difficult to achieve given the inclusion of patients with extrahepatic disease,” he said. “In liver-only patients there is an opportunity to improve survival with lower incidence of metastases. The reassuring results of the study are that toxicity from radiation was not significant, and there was clinically important improvement in patients’ liver disease.” 

According to Sirtex, additional data, including overall survival data, are expected to be released in 2017.

Editor's note: Suggested citation: Rhodes MK. SIRFLOX data show mixed results for survival. Intervent Oncol 360. 2015;3(8):E89-E92. 

Reference

1. Gibbs P, Heinemann V, Sharma NK, 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).