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), according to findings from the phase III SIRFLOX study published in the Journal of Clinical Oncology.
Journal of Clinical Oncology.
In the randomized study, patients treated with resin-based selective internal radiation therapy (SIRT) had a median PFS in the liver of 20.5 months compared with 12.6 months without SIRT (HR, 0.69; 95% CI, 0.55-0.90;P= .002). The addition of SIRT was not found to impact the duration of systemic therapy and was associated with acceptable toxicity. However, the primary endpoint of PFS at any site was not met. However, these findings were not unexpected, investigators noted, since SIRT is a liver-directed treatment and mCRC is a systemic disease.
“In terms of treatment algorithms, the metastatic colorectal cancer space is complex and rapidly evolving,” said Mike Mangano, president of Sirtex Medical Inc, the company developing the Y-90 resin microspheres. “The publication of the SIRFLOX study in JCO is a significant milestone for Sirtex, which we believe will reinforce SIR-Spheres Y-90 resin microspheres as an important tool for physicians and patients in the treatment of metastatic colorectal cancer.”
In the phase III study, patients with non-resectable liver-only or liver-dominant metastatic CRC were treated with mFOLFOX6 plus SIRT during the first cycle (n = 263) or without SIRT (n = 267). In the SIRT arm, patients received oxaliplatin at a lower 60-mg/m2dose compared with 85 mg/m2in the arm without SIRT. At cycle 4 the oxaliplatin dose was escalated to 85 mg/m2and bevacizumab administration was allowed. In the arm without SIRT, patients were allowed to receive bevacizumab starting at cycle 1.
For the primary endpoint of PFS at any site, the median in the SIRT arm was 10.7 months versus 10.2 months (HR, 0.93; 95% CI, 0.77-1.12;P= .43). For objective response rates (ORR), a significant difference was not seen for all sites, at 68.1% without SIRT versus 76.4% with SIRT (P= .113). The ORR in the liver was significantly different, 68.6% without SIRT and 78.7% with SIRT (P= .042).
The rate of complete response (CR) in the liver was significantly improved with the addition of SIRT. In the microsphere arm the CR rate was 6.0% versus 1.9% without SIRT (P= .02).
“Controlling colorectal liver metastases is critically important since hepatic failure due to tumor progression is frequently believed to be the cause of death and is a common reason why patients are unable to get the multiple lines of chemotherapy available,” said US lead investigator of the SIRFLOX trial Navesh K. Sharma, DO, PhD, associate professor in the Division of Radiation Oncology at Penn State Hershey Cancer Institute. “SIRFLOX has shown us, in an unbiased manner, that not only can we deliver high doses of radiation to the liver with this approach but also that we can do so safely, even while using concurrent first-line standard of care chemotherapy.”
While patients treated with SIRT plus chemotherapy did experience additional toxicity these events had no impact on duration of systemic therapy and were expected. The most common adverse events (AEs) that were significantly increased in the SIRT arm were neutropenia (40.7%) and thrombocytopenia (9.8%) compared with the control arm (28.5% and 2.6%, respectively).
Febrile neutropenia was seen in 6.1% of patients treated with SIRT versus 1.9% without the use of microspheres. SIRT-associated events were gastric or duodenal ulcer (3.7%), ascites (2.8%), hepatic failure (1.2%), and radiation hepatitis (0.8%). None of these events were seen without SIRT.
Liver-directed therapy with Y-90 resin microspheres results in the deployment of tens of millions of radioactive Y-90coated particles through a catheter, delivering a high dose of radiation directly to the liver tumors. Y-90 is a beta-emitting isotope with no primary gamma emission. The treatment is administered once, during the first cycle.
SIRFLOX is the first of three randomized controlled trials in a preplanned combined analysis of SIRT’s impact on overall survival (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.