July 2015, Special ASCO Edition

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Adding Radiation to First-Line FOLFOX Reduces Progression of Liver Metastases in Patients with Metastatic Colorectal Cancer

Gastrointestinal Cancer

In patients with metastatic colorectal cancer (mCRC) with liver-dominant metastases who received first-line FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without bevacizu­mab plus selective internal radiation therapy (SIRT) compared with FOLFOX with or without bevacizumab, progression-free survival (PFS) in the liver was extended by 7.9 months, according to the results from the SIRFLOX trial.

Commenting on the SIRFLOX trial, Ricky Sharma, PhD, MA, MB BChir, FRCP, FRCR, Associate Professor, University of Oxford, England, called the benefit “an impressive change in local control,” but cautioned that it came at the cost of increased adverse events.

In SIRFLOX, SIRT was delivered to liver tumors via a hepatic artery injection of yttrium-90 resin microspheres (Sirtex), said lead investigator Peter Gibbs, MBBS, MD, FRACP, Associate Professor, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Sirtex was approved by the FDA in 2002 for the treatment of liver metastases from CRC. Gibbs noted that despite several decades of work with other liver-directed therapies, uncertainty remains about their clinical utility, because large phase 3 randomized controlled trials are lacking. The liver is the dominant disease site in mCRC, and liver metastases are the predominant cause of death, he added.

The international, multicenter, open-label, randomized controlled SIRFLOX trial enrolled chemotherapy-naive patients with nonresectable, liver-only or liver-dominant (liver plus lung and/or lymph node metastases) mCRC. The patients received either modified (m)FOLFOX6 with or without bevacizumab (n = 263) or mFOLFOX6 plus Sirtex administered once with cycle 1 with or without bevacizumab (n = 267) until disease progression. PFS was the primary end point.

The primary tumor was removed in approximately 45% of patients. Extrahepatic disease was present in 40% of the patients.

The PFS at any site was similar between the groups: 10.2 months for FOLFOX with or without bevacizumab, and 10.7 months for FOLFOX with or without bevacizumab plus SIRT, Gibbs reported. The PFS in the liver, however, was 12.6 months for FOLFOX, with or without bevacizumab, and 20.5 months for FOLFOX, with or without bevacizumab, plus SIRT (hazard ratio, 0.69; 95% CI, 0.55-0.90; P = .002), a 7.9-month improvement.

In addition, the objective response rate, although modestly higher overall for the SIRT arm (76.4% vs 68.1%; P = .113), was significantly higher in the liver (72.7% vs 66.9%; P = .042). Furthermore, the complete response rate overall displayed a trend for improvement in the SIRT-containing arm (4.5% vs 1.5%; P = .054), but in the liver it was significantly higher (6.0% vs 1.9%; P = .02).

“Adverse events had no negative impact on duration of systemic therapy and were acceptable and as predicted,” Gibbs stated. Grade ?3 events were significantly increased in the SIRT arm, including neutropenia (40.7% vs 28.5%) and thrombocytopenia (9.8% vs 2.6%). Gastric or duodenal ulcers and ascites were higher for the SIRT group as well.

Sharma speculated that the failure to achieve an overall PFS advantage with Sirtex in SIRFLOX could likely be attributed to the inclusion of the 40% of patients with extrahepatic disease. Also, he stressed that there is a need for additional therapies for this population. Despite the FDA approval of 71 drugs for solid cancers between 2002 and 2014, improvements in median PFS and median overall survival have been only 2.5 months and 2.1 months, respectively, Sharma said.

“We eagerly anticipate the subgroup analyses and the combined analysis, which will tell us which patients benefit the most from SIRT,” he said. Sharma’s current recommendation is, “For local control of liver metastases not amenable to surgery plus thermal ablation, consider SIRT in combination with chemotherapy.”

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