HOLLYWOOD, FloridaPreliminary data from the TREE-2
randomized study of first-line regimens for metastatic colorectal cancer show
that bevacizumab (Avastin) can be safely added to oxaliplatin (Eloxatin)/fluoro-pyrimidine
regimens and that the addition of bevacizumab significantly improves response
rates.
The data also show that bolus fluorouracil (5-FU) is less
active than infusional 5-FU in this setting. Howard S. Hochster, MD, of New
York University School of Medicine, reported the early results at the 2005
Gastrointestinal Cancers Symposium (abstract 241).
The TREE-2 study is a continuation of TREE-1, which is a
randomized phase II study of three oxaliplatin/fluoropyrimidine regimens in
metastatic colorectal cancer (see Table 1):
■ modified FOLFOX6:
bolus plus infusional 5-FU/leucovorin (LV)
■ bFOL: bolus
5-FU/low-dose LV
■CapeOx: oral
capecitabine (Xeloda)/oxaliplatin
After publication of studies showing that adding bevacizumab
improves survival of patients treated with irinotecan (Camptosar)/5-FU/LV (IFL)
by about 35% (N Engl J Med 350:2335-2342, 2004), the TREE-1 protocol was
amended in November 2003 to add bevacizumab to all three study regimens.
"This randomized, multicenter study is the first to
determine the safety and tolerability of oxaliplatin/fluoropyrimidine regimens
(bolus, infusional, and oral) in combination with bevacizumab for first-line
treatment of metastatic colorectal cancer," Dr. Hochster said. "The hypothesis
was that bevacizumab plus oxaliplatin/fluoropyrimidine regimens will provide
similar incremental efficacy and comparable safety as with the IFL regimen."
The study enrolled patients with measurable, untreated
metastatic colorectal cancer and ECOG performance status of 1 or lower. The
primary endpoint was incidence of grade 3-4 toxicities on each arm during the
first 12 weeks of therapy. Secondary endpoints included standard efficacy
measures.
Toxicity
Dr. Hochster reported that 223 patients were accrued between
November 2003 and March 2004 in TREE-2, of whom 213 were treated. He reported
toxicity data for 71 patients treated with FOLFOX-bevacizumab (FOLFOX-B), 70
treated with bFOL-B, and 72 treated with CapeOx-B. "Addition of bevacizumab to
all regimens was well tolerated, and no significant additive toxicities were
noted," he said.
The absolute number of patients with specific bevacizumab-related
toxicities included two (2.8%) on each arm with gastrointestinal perforations,
and impaired would healing in five (7%) FOLFOX-B patients, two (2.5%) bFOL-B
patients, and five (4.9%) CapeOx-B patients.
There were no treatment-related deaths with FOLFOX-B, three
(4.5%) with bFOL-B, and two (2.8%) with CapeOx-B.
Dr. Hochster noted that compared with TREE-1, CapeOx
tolerability improved on TREE-2 when a lower cape-citabine dose of 850 mg/m2
twice daily was used (compared with 1,000 mg/m2 twice daily on TREE-1), with no
decrease in efficacy.
Based on preliminary analysis of response data in the TREE-2
cohort, Dr. Hochster and his colleagues found that FOLFOX-B appears to be more
active than bFOL-B, and that FOLFOX-B and CapeOx-B are approximately equivalent
in efficacy (see Table 2).
