S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial

Fluoropyrimidines (5FU) have remained the most commonly prescribed agents for gastrointestinal cancer, including colorectal cancer (CRC). 5FU is administered as a continuous infusion by a portable pump or by an inserted chemo-port, methods that provide continuous exposure and modest improvement in efficacy. However, continuous infusion is inconvenient and unsafe [1, 2]. Thus, the development of oral FU (capecitabine and S-1) has opened new possibilities for the treatment of gastrointestinal tumors, especially gastric cancers [3‐5]. For the first-line treatment of patients with metastatic CRC, oxaliplatin plus either fluorouracil or capecitabine has been one of the reference doublet cytotoxic chemotherapy strategies [6, 7]. S-1 is a novel oral FU consisting of a 5FU prodrug, tegafur, the dihydropyrimidine dehydrogenase inhibitor, 5-chloro-2, 4-dihydroxypyrimidine, and the orotate phosphoribosyl transferase inhibitor, potassium oxonate, which suppresses the gastrointestinal toxicity of tegafur [8]. Although several trials have shown the feasibility and efficacy of S-1 plus oxaliplatin (SOX) as an upfront chemotherapy for metastatic CRC [9, 10], S-1 and capecitabine have not been directly compared when either is combined with oxaliplatin. To address this dearth of information, we conducted our initial randomized, non-inferiority phase III trial of SOX versus capecitabine plus oxaliplatin (CapeOX) for the first-line treatment of patients with metastatic colorectal cancer [11]. We found the S-1 group to have nearly 2 months longer PFS than the capecitabine group, suggesting that the SOX regimen could be an alternative first-line doublet chemotherapy strategy for patients with metastatic CRC. However, which particular S-1s can be used as substitutes for capecitabine may be controversial in CRC. Thus, we intend to update the overall survival (OS) and progression free survival (PFS) results, and we intend to conduct exploratory analyses to determine whether the effect of S-1 on these end points appears to vary in selected patient groups.

The primary analysis of this study showed that SOX is non-inferior to CapeOX in terms of PFS, OS, and response rate as a first-line chemotherapy in patients with metastatic colorectal cancer (CRC) [11]. To the best of our knowledge, this study is the first large, phase III clinical trial that directly compares SOX with CapeOX in metastatic CRC. This updated analysis also demonstrates that SOX and CapeOX have statistically similar PFS and OS, confirming the conclusion reached in our previous publication.

In this updated analysis, patients in the CapeOX group had a PFS of 6.3 months and an OS of 18.5 months, which are similar values to those reported in previous trials [6, 12‐14]. Likewise, the SOX group in our analysis showed favorable results, which are similar to values recorded for CapeOX or FU plus oxaliplatin plus Leucovorin (FOLFOX) treatment in previous studies [12‐14]. Based on our updated analysis with a long-term follow-up, no significant differences were observed in PFS and OS between the SOX and CapeOX groups, which is consistent with previous gastrointestinal cancer studies [15‐18]. In addition, a meta-analysis by Zhang et al. reported that both the S-1 and capecitabine-based regimens were equally active and well tolerated in patients with gastric cancer and CRC [19].

In this updated analysis, we also investigated the post-progression survival (PPS) for both treatment groups. In cancer treatment, the goal is to prolong survival and/or to improve the patient’s quality of life. In the era of multiple lines of chemotherapy, therapeutic options have been expanded, especially in CRC. In breast cancer, lung cancer, and CRC, OS becomes more associated with PPS than PFS [20‐23]. In CRC, the association of PPS with OS may be due to the increasing number of active compounds available, or to the available second or third-line therapies. In this analysis, there was no significant difference in PPS between the SOX and CapeOX groups (Table 2). These findings suggest that effective treatments, equal in quality, were provided to both groups after the failure of the first-line therapy. The dose of S-1 in this study was 80 mg/m2 per day, which is higher than doses used in the reference trial that combined S-1 with oxaliplatin. As mentioned in a previously published report, this dose finding explains the high frequency of adverse events in SOX-treated patients. However, the high frequency of adverse events in the SOX group might not affect subsequent treatment strategies.

In patients with metastatic CRC, the addition of bevacizumab to the first-line chemotherapy has improved survival. Previous studies have shown that bevacizumab plus FOLFOX, FOLFIRI (leucovorin, fluorouracil, and irinotecan), or CapeOX improves PFS [12, 14, 24‐26]. However, the role of bevacizumab with SOX has not been established. Recently, Yamada et al. showed that bevacizumab plus SOX was non-inferior to bevacizumab plus FOLFOX as a first-line treatment for metastatic CRC with respect to PFS [27]. Thus, bevacizumab plus SOX might be a possible option as a standard first-line treatment, although S-1 and capecitabine have not been directly compared when either is combined with bevacizumab and oxaliplatin.

Our updated analysis confirms that a combination of S-1 and oxaliplatin can be considered as an alternative doublet chemotherapy strategy to CapeOX. Further investigation is needed to explore its potential when used together with other targeted agents or as adjuvant chemotherapy.

Updated survival analysis shows that SOX is similar to CapeOX, confirming the initial PFS analysis. Therefore, the SOX regimen could be an alternative first-line doublet chemotherapy strategy for patients with metastatic colorectal cancer.