Irinotecan drug-eluting beads (DEBIRI) given simultaneously with FOLFOX (leucovorin, fluorouracil, oxaliplatin) and bevacizumab (Avastin) in patients with unresectable colorectal liver metastasis improved response rates, increased resectability, and prolonged hepatic progression–free survival in a study reported at the 2014 Gastrointestinal Cancers Symposium in San Francisco, by Robert C.G. Martin, MD, PhD, Sam and Lolita Weakley Professor and
 Director of Surgical Oncology at the University of Louisville in Kentucky.¹

Less Toxic Option

“Reports have demonstrated the activity of combining both irinotecan and oxaliplatin into a FOLFOXIRI [­FOLFOX/irinotecan] therapy. An option to gain similar benefits and less toxicity would be to administer the irinotecan through a hepatic arterial approach,” Dr. Martin explained.

The study assessed the maximal response and adverse event rates of irinotecan drug-eluting beads with FOLFOX and bevacizumab as a first-line treatment for unresectable colorectal liver metastasis. The drug-eluting beads are a proprietary product that contains 100 mg of irinotecan in the form of 100- to 300-micron beads that are administered via infusion into the hepatic artery.

The study included 70 patients with metachronous and synchronous colorectal liver metastases, who were randomly assigned to modified ­FOLFOX6 plus bevacizumab (n = 30) or modified FOLFOX6, bevacizumab, and DEBIRI (FOLFOXDEBIRI, n = 40).

FOLFOX/bevacizumab and the drug-eluting beads were generally administered on alternate weeks. All 40 patients in the experimental arm received at least one infusion of DEBIRI, 37 received two, 18 received three, 13 received four, 4 received five, and 3 received six infusions.

The primary endpoints were response rates and adverse events. Secondary endpoints were conversion to resection and progression-free survival. Patients in each arm received a median number of eight chemotherapy cycles.

High Response Rates

The overall response rate was significantly higher with FOLFOXDEBIRI than with FOLFOX/bevacizumab. By modified RECIST criteria, responses were observed in 79% vs 54%, respectively, at 2 months; 91% vs 59% at 4 months; 83% vs 64% at 6 months; 54% vs 27% at 9 months; and 50% vs 24% at 12 months. These differences were statistically significant; however, differences in response by standard RECIST 1.1 criteria were not.

Dr. Martin explained that standard RECIST 1.1 assessment depends upon the diameter of the tumor, whereas modified RECIST does not.

“The challenge with this, using any hepatic arterial therapy, is that the diameter of liver tumors doesn’t change much, but you do see tumors go from hypervascular to partially vascular,” he said in an interview with The ASCO Post. “So by standard RECIST, we don’t see much tumor change, ie, response, but we do see stable disease. By modified RECIST, we showed a statistically significant improvement in both overall response and target response.”

‘Great Downsizing’

With FOLFOXDEBIRI, significantly more patients were downsized to resectability (35% vs 16%, P = .05), and in this group, median progression-free survival was improved from 7.6 months in the control arm to 15.3 months with FOLFOXDEBIRI.

“The enhanced response rate led to great downsizing to resection and subsequent improvement in hepatic progression–free survival,” Dr. Martin noted.

Overall progression-free survival, however, was not improved in the experimental arm, whose median progression-free survival was 12 months, compared with 15 months for FOLFOX alone (P = .18).

Dr. Martin said that due to the size of the study and limited follow-up, statistically significant differences in these endpoints would not be expected.

“Simultaneous [modified] ­FOLFOX6 with bevacizumab and hepatic arterial irinotecan drug-eluting beads is safe, without causing chemotherapy delivery delays and without increasing chemotherapy toxicity,” Dr. Martin said.

There were 144 grade 3/4 adverse events in 32 patients on the DEBIRI arm and 36 among 18 patients in the control arm. Serious adverse events numbered 57 and 15, respectively, which was significantly higher for the DEBIRI arm (P = .03). Chemotherapy-related adverse events numbered 38 and 21, respectively (P = .08).

Keys to Effectiveness

“Simultaneous FOLFOXDEBIRI leads to improved overall response rates, improved hepatic progression–free survival [not statistically significant], and more durable overall progression-free survival in patients downsized to resection,” Dr. Martin concluded.

He suggested that the “keys to effectiveness and expansion” will be to define patients with liver-dominant disease, to maintain proper DEBIRI techniques and dosing, to collaborate with medical oncologists, and to follow an appropriate treatment strategy that follows up in the reevaluation for surgical resection.

Dr. Martin indicated that a phase III trial would need to stratify patients according to KRAS status and include cetuximab (Erbitux) and bevacizumab. ■

Disclosure: Dr. Martin has a consulting or advisory role with Biocompatibles International.

Reference

1. Martin RCG, Scoggins CR, Rilling WS, et al: Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liver-limited metastasis. 2014 Gastrointestinal Cancers Symposium. Abstract 174. Presented January 17, 2014.