ArticlesLeucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial
Introduction
FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus bevacizumab have been widely used for first-line treatment of metastatic colorectal cancer.1, 2 The NO16966 trial showed that capecitabine and oxaliplatin plus bevacizumab was non-inferior to FOLFOX plus bevacizumab for progression-free survival (PFS), thereby establishing the therapeutic usefulness of oral anticancer agents.3, 4
S-1 is an oral anticancer preparation that combines tegafur (a prodrug of fluorouracil) with two modulators: gimeracil, which reversibly inhibits dihydropyrimidine dehydrogenase (the primary metabolising enzyme of fluorouracil) and therefore maintains fluorouracil concentrations in the blood for a long time; and oteracil potassium, which suppresses, and thereby decreases, the activity and toxicity of fluorouracil in gastrointestinal tissue.5 A phase 3 trial6 showed that S-1 plus irinotecan is non-inferior to FOLFIRI as second-line chemotherapy for metastatic colorectal cancer. Clinical trials of first-line chemotherapy with S-1 plus oxaliplatin (SOX) have been done in Japan7 and South Korea.8 These studies showed promising outcomes, with median PFS of 6·4 months7 and 8·5 months.8 Additionally, a phase 3 study in South Korea9 showed that SOX is non-inferior to capecitabine and oxaliplatin as first-line treatment for advanced, recurrent colorectal cancer, establishing that S-1 is another option for first-line chemotherapy in colorectal cancer.
To confirm and extend the results of previous clinical trials, we aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer.
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Study design and participants
We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 centres in Japan (appendix). We enrolled individuals who met eligibility criteria: age 20–80 years; histologically proven colorectal adenocarcinoma; curatively unresectable, advanced, or recurrent colorectal cancer; Eastern Cooperative Oncology Group performance status of 0 or 1; presence of assessable lesions as confirmed by CT or MRI; no previous chemotherapy or radiotherapy; could take drugs orally; leucocyte count
Results
Between Feb 1, 2009, and March 31, 2011, we enrolled 512 patients (figure 1). The cutoff date for primary analysis of the primary endpoint was June 30, 2012. One patient assigned to receive mFOLFOX6 plus bevacizumab was identified as not having a colorectal adenocarcinoma after randomisation and so was excluded from primary analyses (figure 1). The demographic characteristics of patients included in the primary analyses were similar in the two groups (table 1). Six patients had sequentially
Discussion
We have shown that SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab in terms of PFS in patients with metastatic colorectal cancer. PFS of longer than 11 months was recorded with both regimens. Adverse events in both groups differed but were generally tolerable. Unlike patients assigned to mFOLFOX6 plus bevacizumab, patients assigned to SOX plus bevacizumab did not need an intravenous port or an ambulatory infusion pump. Additionally, patients who received SOX plus bevacizumab
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