Evidence for Selective Internal Radiation Therapy Continues to Emerge for Liver Tumors

Guy A. Van Hazel, MD

The treatment of colorectal cancer (CRC) has remained a significant clinical challenge, since over 50% of patients present with or develop liver metastases, which is a leading cause of death; however, a recent phase III study showed promise for selective internal radiation therapy (SIRT) in combination with standard chemotherapy as a first-line treatment.¹

SIRT is a radiotherapy technique that delivers a single, targeted dose of radiation to hepatic tumors through injection into the hepatic artery, while sparing radiation exposure to normal liver tissue. Resin microspheres are loaded with Yttrium-90 (90Y), a high-energy beta-emitter with a limited tissue-penetration range (average, 2.5 mm) and short half-life (64 hours).²

Resin microspheres are significantly smaller than those used with bead embolization technologies. They range from 20 to 60 microns in size, which allows the microspheres to flow through the blood but not through the capillary bed of the tumor. The presence of oxygen generates free radicals through the ionization of water from the emitted beta radiation. The free radicals in turn produce irreversible DNA damage and subsequent apoptosis in surrounding tissues.

In the phase III SIRFLOX study,¹investigators performed a randomized controlled trial of fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy (+/- bevacizumab) with or without SIR-Spheres as a first-line treatment in 530 patients with liver-only or liver-dominant mCRC. The primary outcome was progression-free survival (PFS) at any site, and secondary outcomes included PFS in the liver, overall survival (OS), tumor response rates in the liver and at any site, and toxicity and safety.

Although the primary endpoint, PFS at any site, was not met (10.2 months control vs 10.7 months SIRT [HR, 0.93; 95% CI, 0.77-1.12; P = .43]), PFS in the liver was significantly extended with SIRT treatment (12.6 months control vs 20.5 months SIRT [HR: 0.69; 95% CI 0.55-0.90; P = .002]). These results indicated a 31% risk reduction in tumor progression in the liver for patients treated with additional SIRT compared with chemotherapy alone.

The objective response rate in the liver was also significantly improved with SIRT treatment (68.8% control vs 78.7% SIRT;P= .042), as was the complete response rate (1.9% vs 6.0%;P= .020) and first progression only in the liver (77% vs 52.4%;P<.001). Grade 3 or above AEs were 73.4% and 85.4% in the control and SIRT treatment arms, respectively (P= .516).

&ldquo;SIRFLOX gives us the data to validate the first-line use of&hellip; SIR-Spheres Y-90 resin microspheres in mCRC,&rdquo; said Guy A van Hazel, MD, University of Western Australia. &ldquo;Until now, we have not had a randomized clinical study large enough to provide Level One evidence supporting first-line use of this treatment.&rdquo;

He added, &ldquo;This step forward matters to medical oncologists and their patients, because until the development of Y-90 resin microspheres, there was essentially no place for radiation therapy in the treatment of liver tumors. There was never a question that radiation would work in the liver, but the problem of administering the radiation in a way that spared healthy liver tissue from its effects prevented it from being an &lsquo;equal partner&rsquo; with surgery and chemotherapy in treating mCRC, as it is in almost all other forms of cancer.&rdquo;

OS data from the SIRFLOX study are not available yet, and will be combined with data obtained from 2 additional trials, FOXFIRE and FOXFIRE Global, which together enrolled over 1100 patients. Results are expected in 2017.

SIRT Versus Sorafenib in Advanced HCC

At this time, the clinical utility of SIR-Spheres in advanced hepatocellular carcinoma (HCC) has not been clearly defined because of a lack of randomized clinical trials; however, the efficacy in liver-metastatic CRC has raised interest for this approach in other liver malignancies.

Sorafenib, an oral multikinase inhibitor, is the only FDAapproved systemic agent currently available to treat metastatic HCC. Phase III trials of sorafenib, including the pivotal SHARP randomized controlled trial, established sorafenib as the standard treatment for patients with advanced HCC worldwide. Sorafenib improved clinical outcomes, with an extension in OS of nearly 3 months over placebo.³

Two ongoing, phase III studies will directly compare the efficacy of SIR-Spheres to sorafenib in patients with advanced HCC: SARAH and SIRveNIB (NCT01482442 and NCT01135056). The primary outcome measure for both studies is OS. The SARAH trial (France) has enrolled nearly 500 participants, and the SIRveNIB trial (Singapore/Asia-Pacific) is slated to enroll 360 participants.

&ldquo;SARAH is the largest randomized study ever to compare selective internal radiation therapy—or any liver-directed therapy&mdash; against the standard-of-care systemic therapy in the treatment of primary liver cancer,&rdquo; said principal investigator of the SARAH study Val&eacute;rie Vilgrain, MD, PhD, Paris Diderot University, France. &ldquo;The SARAH study team is delighted that enrolment is now complete, with results expected in late 2016.&rdquo;

A recent retrospective analysis evaluated the safety and efficacy of sorafenib plus SIR-Spheres in patients with advanced HCC.⁴In the analysis of 19 patients, the combination of sorafenib and SIR-Spheres improved both OS and PFS compared with the previous SHARP trial of sorafenib alone (OS: 19.5 vs 10.7 months; PFS: 6.6 vs 5.5 months).

The combination treatment was well tolerated, with 21% of patients experiencing grade 3 AEs. The safety results were similar to those of the phase II SORAMIC study, which randomized patients to receive either sorafenib alone or SIRSpheres followed by sorafenib, and concluded that treatments had similar tolerability and safety profiles.⁵

Although locoregional therapies, such as transarterial chemoembolization and conventional embolization, have improved survival in certain patients, they are associated with some risks and may not be suitable for patients with multiple, large tumors. Treatment with SIRT may provide a viable therapeutic option for those with advanced disease.

References:

1. van Hazel GA, Heinemann V, Sharma NK, et al. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer [published online February 22, 2016].J Clin Oncol.doi: 10.1200/JCO.2015.66.1181.
2. Mosconi C, Cappelli A, Pettinato C, Golfieri R. Radioembolization with Yttrium-90 microspheres in hepatocellular carcinoma: role and perspectives.World J Hepatol.2015;7(5):738-752.
3. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma.N Engl J Med.2008;359(4):378-390.
4. Mahvash A, Murthy R, Odisio B, et al. Yttrium-90 resin microspheres as an adjunct to sorafenib in patients with unresectable hepatocellular carcinoma.J Hepatocellular Carcinoma.2016;3:1-7.
5. Ricke J, Bulla K, Kolligs F, et al. Safety and toxicity of radioembolization plus sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC.Liver Int.2015;35(2):620-626.