The addition of selective internal radiation (SIRT) to first-line fluorouracil/leucovorin/oxaliplatin (FOLFOX) chemotherapy in patients with unresectable liver-dominant metastatic colorectal cancer did not improve progression-free survival at any site, investigators reported.

SIRT did, however, significantly delay disease progression in the liver by 7.9 months for a risk reduction of 31%, according to results from the international randomized phase 3 SIRFLOX trial published online in the Journal of Clinical Oncology.

"The median 20.5-month liver [progression-free survival] for patients treated with chemotherapy plus SIRT represents a substantial prolongation of local disease control compared with systemic chemotherapy alone (median, 12.6 months)," Guy A. van Hazel, MBBS, a medical oncologist at the University of Western Australia, Perth, and colleagues wrote.

Furthermore, SIRT did not adversely affect the delivery of chemotherapy, and the adverse event profile was anticipated and manageable, with more but not unexpected toxicities observed.

The study provides data for a technique that has often been considered and offered to patients without support from a randomized clinical trial, commented Jeffrey A. Meyerhardt, MD, of Dana-Farber Cancer Institute in Boston.



"It is significant to know that, while liver disease may be controlled, overall progression is not improved with SIRT, and that is important data to know when considering this technology," Meyerhardt said in an email to MedPage Today.

"Ultimately, for this patient population, overall survival is the most important endpoint. The investigators have already planned to team up with two other trials to pool data to look at overall survival. This will be really important information since, at the end of the day, if overall survival is not different, then it really questions the utility of SIRT for most metastatic colorectal cancer patients."

The trial results also emphasized "that it is really important that the oncology community continues to push to do such trials on technologies that seem promising but do not have data to know true efficacy," Meyerhardt added.

SIRFLOX was launched after previous phase 2 research showing that SIRT plus first-line fluoropyrimidine-based chemotherapy increased objective response rates and extended time to progression and overall survival in metastatic colorectal cancer patients.

From October 2006 to April 2013, investigators in the 87-center SIRFLOX study randomly assigned 530 chemotherapy-naïve patients with liver metastases, plus or minus limited extrahepatic metastases, to receive one of two regimens: modified FOLFOX (mFOLFOX6, 263 controls) or mFOLFOX6 plus SIRT, with or without bevacizumab (Avastin) at the discretion of individual investigators. SIRT was delivered as yttrium-90-labeled resin microspheres.

The median age of patients in both arms was 63, and more than two-thirds were male. The primary endpoint was progression-free survival at any site as assessed by blinded independent and centralized radiological review.

Median progression-free survival at any site was 10.2 months in controls versus 10.7 months in SIRT patients, for a hazard ratio (HR) of 0.93 (95% CI 0.77-1.12, P=0.43). Median progression-free survival in the liver by competing risk analysis was 12.6 months in controls versus 20.5 months in SIRT recipients, for an HR of 0.69 (95% CI 0.55-0.90, P=0.002). "This finding was consistent irrespective of tumor burden, bevacizumab therapy, or performance status," the authors noted.

Objective response rates at any site were similar in the control and intervention arms (68.1% versus 76.4%, P=0.113), but were superior in the liver with added SIRT (68.8% versus 78.7%, P=0.042). The complete response rate in the liver was significantly improved: 1.9% versus 6.0% (P=0.020).

Not unexpectedly, grade ≥ 3 adverse events, including established SIRT-related effects, were reported in 73.4% of controls and 85.4% of SIRT patients, and this group suffered more hematologic toxicities. Disappointingly, SIRT's improvement of objective response rates in the liver was not reflected in improved resectability, and no difference in metastases resection rates emerged: 36 controls (13.7%) underwent resection compared with 38 SIRT patients (14.2%). This finding contrasted with previous research reports that higher response rates have typically translated into higher resection rates.

Interestingly, there was some discordance between progression-free survival at any site and in the liver. "Whereas control of intra- and extrahepatic disease is required to achieve a benefit in [progression-free survival] at any site, the analysis of first progression site suggests that progressive disease in nonliver sites (7.9% v 27.7%) may mitigate the benefit of controlling liver disease with SIRT," Van Hazel and associates wrote.

The long-term overall survival impact of integrating SIRT into first-line treatment should be clearer when a combined analysis of the 1110+ patient SIRFLOX, FOXFIRE, and FOXFIRE Global studies is disseminated in 2017, the authors noted. In comments made to Medpage Today, Bruce D. Minsky, MD, of the University of Texas MD Anderson Cancer Center, Houston (who was not involved in the study), said, "The results are in line with what you would predict of a local therapy. The data show that tumors in the liver tend to respond well to the radiation, but tumors in other parts of the body do not."

The more interesting question, he added, is whether controlling disease in the liver as an independent site has an impact on overall prognosis in metastatic colorectal cancer. "We still don't know the answer to that question, and these data don't bring us any closer to answering it," Minsky said.

The results do confirm that radiation is an effective treatment for liver metastases and that these microspheres, which are delivered by interventional radiology and accumulate in the liver, are one of a few therapeutic options for liver metastases, alongside radiofrequency ablation, stereotactic radiation, and surgery.