Elsevier

The Lancet Oncology

Volume 14, Issue 13, December 2013, Pages 1278-1286
The Lancet Oncology

Articles
Leucovorin, 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

https://doi.org/10.1016/S1470-2045(13)70490-XGet rights and content

Summary

Background

Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. 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.

Methods

We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20–80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m2 oxaliplatin, 200 mg/m2 l-leucovorin, 400 mg/m2 bolus fluorouracil, and 2400 mg/m2 infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m2 intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699.

Findings

Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7–13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7–12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86–1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab).

Interpretation

SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations.

Funding

Taiho.

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.

Section snippets

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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