麻豆传媒

Upfront FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab (Avastin) followed by re-introduction of the regimen at disease progression appears to be "an optimal therapeutic option" for certain patients with metastatic colorectal cancer, researchers reported.

In the so-called study of 679 patients -- the majority of whom were in ECOG performance status 0 -- there was about a 3-month improvement in progression-free "survival 2" among patients assigned to the FOLFOXIRI re-introduction regimen compared with those assigned to mFOLXFOX6 (fluorouracil, leucovorin, and oxaliplatin) followed by FOLFIRI at progression. ("Survival 2" was defined as the time from randomization to disease progression on any treatment given after the first disease progression, or death, analyzed by intention to treat.)

Median progression-free survival 2 was 19.2 months for FOLFOXIRI re-introduction compared with 16.4 months for mFOLFOX6/FOLFIRI (hazard ratio 0.74, 95% CI 0.63-0.88, P=0.0005), Alfredo Falcone, MD, of Azienda Ospedaliera-Universitaria Pisana in Pisa, Italy, and colleagues reported in the .

Writing in an , Rob Glynne-Jones, MD, and Mark Harrison, MD, both of Mount Vernon Hospital in Northwood, U.K., said that "combining most of the available effective cytotoxic drugs simultaneously with antiangiogenic drugs in the same regimen provides different concerns for different oncologists practicing in different parts of the world," with U.K. oncologists often taking more conservative approaches.

The survival difference seen in TRIBE2 was achieved, however, the editorialists noted, with an additional 2.8 months of chemotherapy exposure and resulted in acute adverse events.

Specifically, grade 3/4 neurotoxicity from oxaliplatin after second disease progression was 5% in the FOLFOXIRI group compared with 0% in the control arm. Additionally, more than a third (36%) of patients in the FOLFOXIRI group reported grade 1/2 neurotoxicity after progression, and there were eight treatment-related deaths in the FOLFOXIRI group compared with four in the mFOLFOX6/FOLFIRI arm.

Asked for his perspective, Leonard Saltz, MD, head of the Colorectal Oncology Section of Memorial Sloan Kettering Cancer Center in New York City, said he agreed with Glynne-Jones and Harrison, and noted that although the comfort of U.S. oncologists with using oxaliplatin and irinotecan together in first-line therapy has increased in the last 5 years, the drugs have been combined only in carefully selected patients who are most likely to benefit and least likely to be harmed.

"We are tending to use it more in people with bulky disease who need a response early and will feel better if we shrink their tumor volume," Saltz told 麻豆传媒. "We aren't necessarily using it in people who wouldn't know they had metastatic cancer but for a CT scan."

Saltz pointed out another subtlety of the study involving the dosing of the various drugs used in these regimens: "The FOLFOXIRI regimen used in this article is one I would be very reluctant to recommend to patients in the United States. The reason for that is the infusion [fluorouracil] dose is 50% higher in the FOLFOXIRI arm than in the standard FOLFOX arm."

Study participants were randomly assigned to one of the following:

• First-line mFOLFOX6 (85 mg/m² intravenous oxaliplatin with 200 mg/m² leucovorin over 120 minutes; 400 mg/m² intravenous bolus fluorouracil; 2,400 mg/m² continuous infusion fluorouracil for 48 hours) plus bevacizumab followed by FOLFIRI (180 mg/m² intravenous irinotecan over 120 minutes with 200 mg/m² leucovorin; 400 mg/m² intravenous bolus fluorouracil; 2,400 mg/m² continuous infusion fluorouracil for 48 hours) plus bevacizumab

• FOLFOXIRI (165 mg/m² leucovorin over 120 minutes; 3,200 mg/m² continuous infusion of fluorouracil for 48 hours) plus bevacizumab followed by re-introduction of FOLFOXIRI

"Some difference in outcomes between the arms may be that the [fluorouracil] schedule is more intense in the FOLFOXIRI arm," Saltz suggested, adding that there are published data showing that American patients tolerate fluorouracil less well than patients in other parts of the world.

"There is no perfect explanation but it is probably because, as a society, we have higher serum folic acid because there is folic acid added to our grain products," he speculated.

Bottom line, Saltz said, is that the study is another piece of evidence that shows that the combination of oxaliplatin, irinotecan, and fluorouracil together is a reasonable option for some patients, but is not the right thing for everyone.

"There is no one right standard for colon cancer," Saltz said. "If a doctor is using only one approach for all patients with colon cancer, he or she is not thinking broadly and deeply enough about the individual in front of them."

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