Adding liver-direceted Yttrium-90 resin microspheres to frontline FOLFOX-based chemotherapy improved liver-specific progression-free survival by 7.9 months for patients with colorectal cancer with liver-dominant metastases.
Peter Gibbs, MBBS
Adding selective internal radiation therapy (SIRT) with Yttrium-90 (Y-90) resin microspheres to frontline FOLFOX-based chemotherapy improved liver-specific progression-free survival (PFS) by 7.9 months for patients with colorectal cancer (CRC) with liver-dominant metastases. However, the primary endpoint of improvement in PFS at all sites was not achieved, according to findings from the phase III SIRFLOX study presented at the 2015 ASCO Annual Meeting.
"Liver metastases are the dominant site of disease in mCRC and the dominant cause of death in this disease," lead investigator Peter Gibbs, MBBS, associate professor, medical oncology at The Royal Melbourne and Western Hospitals in Melbourne, Australia, said during his presentation. "The addition of SIRT to frontline chemotherapy in patients with liver-dominant metastases did not improve overall PFS, the primary endpoint. However, it did achieve a major improvement in median PFS in the liver, representing a 31% reduction in risk of disease progression in the liver."
In the randomized phase III SIRFLOX study, patients were allowed to also receive frontline bevacizumab, if appropriate. In the SIRT arm, the median PFS in the liver was 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, according to Gibbs.
“SIRFLOX has shown us, in an unbiased manner, that we can not only deliver high doses of radiation to the liver safely with this approach, but we can do so using concurrent chemotherapy,” said principal US investigator of the trial, Navesh K. Sharma, DO, PhD, assistant professor at the University of Maryland Medical Center. “Concurrent chemo-radiation has been one of the most effective ways to treat cancer in general, especially those of gastrointestinal origin.”
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/m2 dose compared with 85 mg/m2 in the arm without SIRT. At cycle 4 the oxaliplatin dose was escalated to 85 mg/m2 and bevacizumab administration was allowed. In the arm without SIRT, patients were allowed to receive bevacizumab starting at cycle 1.
The majority of patients were enrolled in Australia (53%), with 36% from Europe and the Middle East and 11% in the United States. Bevacizumab was utilized at the investigators discretion. In each arm of the study, approximately half of the patients were treated with concurrent bevacizumab. The median age of patients was 63, and the majority were male (68%).
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 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).
"We did see some major changes in progression-free survival in the liver, and we did observe an improvement in the complete response rate,” Gibbs explained. "There was no difference in the number of patients undergoing hepatic resection between the two arms."
While patients treated with SIRT plus chemotherapy did experience additional toxicity these events had no impact on duration of systemic therapy. 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.
“It’s a prolonged benefit, it’s safe to administer, and it’s a one-off treatment,” said Gibbs. “All of these things are benefits of SIRT, particularly if you’re trying to choose from a range of treatments.”
Liver-directed therapy with Yttrium-90 (Y-90) resin microspheres results in the deployment of tens of millions of radioactive Y-90—coated particles through a catheter, delivering a high dose of radiation directly to the liver tumors. Yttrium-90 is a beta-emitting isotope with no primary gamma emission. The treatment is administered once, during the first cycle.
“It’s the single dose which is important,” emphasized Gibbs. “Most of the other treatments that we use in medical oncology are repeat dosing every 2 to 3 weeks–often for many months at a time. SIRT is important, because it’s a one-off treatment that has an ongoing impact over long period of time.”
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.
Gibbs P, Heinemann V, Navesh K. Sharma NK, et al. SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 Â± bevacizumab (bev) versus mFOLFOX6 + selective internal radiation therapy (SIRT) Â± bev in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 2015;33 (suppl; abstr 3502)