Hanna K. Sanoff, MD, MPH

Study discussant Hanna K. Sanoff, MD, MPH, of the University of North Carolina Lineberger Comprehensive Center, summarized the key results of VISNU-1: first, survival is shorter for patients with high circulating tumor cell (CTC) count; second, the incremental benefit from FOLFOXIRI (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) is consistent with prior studies; and third, CTC counts are prognostic—but not predictive—of greater benefit from FOLFOXIRI.

The results of the subgroup analysis are “reassuring that there is not a particular subgroup for which FOLFOXIRI won’t work,” said Dr. Sanoff. “However, there are limits to the extent that we can generalize these findings to the patient sitting in front of us.” In particular, the study excluded patients older than age 70 and those with an Eastern Cooperative Oncology Group performance status of 2. In addition, and most notably, patients treated with prior adjuvant oxaliplatin were largely excluded, she explained.

“We should not assume that FOLFOXIRI offers a progression-free or overall survival benefit in patients who received adjuvant oxaliplatin,” Dr. Sanoff offered.“And I don’t feel comfortable generalizing the results to patients older than age 70 or those with a poor performance status,” because neither group was represented in the study.

Physical and Financial Toxicities

Because of the considerable increase in grade ≥ 3 toxicity with -FOLFOXIRI, Dr. Sanoff also questioned the effect of the more intensive regimen on the patient experience and whether the additional toxicity was worth the survival benefit. “The bottom line is that we have no systematically collected patient-related outcomes data to know how the [toxicities] relate to the patient experience versus chemotherapy,” she said.

Finally, there is the issue of financial toxicity associated with FOLFOXIRI. According to Dr. Sanoff, the Medicare drug cost of a single cycle is $3,775 for FOLFOX (5-FU, leucovorin, oxaliplatin)/bevacizumab but $8,454 for FOLFOXIRI/bevacizumab—if granulocyte colony-stimulating factor is used, as it was in this study. Without growth factors, the cost is virtually the same as FOLFOX/bevacizumab, she pointed out.

Concluding Points

Dr. Sanoff concluded her discussion with the following points about FOLFOXIRI/bevacizumab, based on the VISNU-1 trial:

• It has “reproducibly” been shown to improve efficacy over FOLFOX/bevacizumab.
• It is not appropriate for all patients; it should be used with caution in older, less robust patients.
• It should not be used routinely in patients treated with adjuvant oxaliplatin.
• CTC counts are an adverse prognostic marker but are not predictive for FOLFOXIRI; they do not have a role yet in patient selection.
• In the second line, there is little benefit to FOLFOXIRI reintroduction. Instead, a doublet regimen should be considered without prespecified maintenance and with an EGFR inhibitor for patients with RAS wild-type disease.
• Due to the small incremental benefit achieved with FOLFOXIRI/bevacizumab, patient engagement is key. ■

DISCLOSURE: Dr. Sanoff has received institutional research funding from Bayer and Merck.