Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer

Key Points Question Is S-1 plus oxaliplatin (SOX) safe and effective as a perioperative chemotherapy regimen for patients with locally advanced gastric cancer? Findings A total of 583 patients were enrolled in this phase 3 randomized clinical trial. SOX was noninferior to fluorouracil, leucovorin plus oxaliplatin as perioperative chemotherapy regimen for patients with locally advanced gastric cancer. Meaning These findings suggest that SOX could be recommended as an alternative perioperative treatment for patients with locally advanced gastric cancer in Asia.


Introduction
Gastric cancer is the fifth most common malignant neoplasm and the third leading cause of cancerrelated death worldwide. 1 The prognosis remains poor for patients with advanced gastric cancer, especially when the primary tumor penetrates the serosa or invades the surrounding structures, and the 5-year survival rate for these patients is approximately 25%. 2,3 Therefore, multimodal treatment is necessary to improve the prognosis of patients with advanced gastric cancer.
Perioperative chemotherapy has been shown to improve the overall survival (OS) of patients with resectable gastric cancer compared with surgery alone in 2 phase 3 randomized clinical trials (RCTs). 4,5 One of the RCTs demonstrated that perioperative chemotherapy with a triplet regimen of epirubicin, cisplatin, and fluorouracil improved survival. 4 The other study also showed a significant increase of 5-year OS in patients who received perioperative chemotherapy with fluorouracil and cisplatin. 5 In spite of these advances, the prognosis of patients with locally advanced, resectable gastric cancer remains unsatisfactory.
S-1 (TS-1; Taiho Pharmaceutical) is an oral anticancer drug that combines tegafur (a prodrug of fluorouracil), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase), and potassium oteracil (an inhibitor of the phosphorylation of fluorouracil in the gastrointestinal tract) in a molar ratio of 1:0.4:1. 6 S-1 monotherapy has been shown to be an effective adjuvant treatment for advanced gastric cancer after radical resection. 7 It has been reported that S-1 is noninferior to infusion fluorouracil in unresectable or recurrent gastric cancer. 8 Although cisplatin plus S-1 did not demonstrate superiority to cisplatin plus infusion fluorouracil in Western countries, S-1 could be substituted for infusion fluorouracil for a more convenient administration. 8 Given that the clinical response of S-1 combined with oxaliplatin (SOX) for unresectable or recurrent gastric adenocarcinoma ranged from 55% to 59%, with a favorable hematological toxic effects profile, 9,10 it is reasonable that SOX could be an appropriate candidate regimen as perioperative chemotherapy for advanced gastric cancer. Therefore, we conducted the FOCUS (S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Calcium Plus Oxaliplatin as Perioperative Chemotherapy for Advanced Gastric Carcinoma) trial to compare the efficacy and safety of SOX with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as a perioperative chemotherapy regimen for locally advanced, resectable gastric cancer.

Randomization
Eligible patients were randomly assigned (1:1) to receive either perioperative FOLFOX or SOX, in addition to surgery. The randomization sequence was generated by a statistician using SAS statistical software version 9.1 (SAS Institute). Every patient had a unique identification number and the allocation results were sent to investigators. Patients and investigators were not masked to the treatment allocation because the study was open label.

Treatment
A total of 6 cycles of perioperative chemotherapy were scheduled for enrolled patients. SOX or FOLFOX was administered for 2 to 4 preoperative cycles followed by 2 to 4 postoperative cycles.
Postoperative chemotherapy was to be started within 4 to 6 weeks after surgery. In the SOX group, oxaliplatin was administered as a 2-hour intravenous infusion (130 mg/m 2 ) on day 1, and S-1 was given orally twice daily for 2 weeks followed by a 7-day rest period. The dose of S-1 was 80 mg/day for body surface area less than 1.25 m 2 , 100 mg/day for body surface area greater than or equal to 1.25 to less than 1.5 m 2 , and 120 mg/day for body surface area greater than or equal to 1. and before the initiation of every cycle, enrolled patients in both groups were evaluated by medical history, physical examination, ECOG performance status, and hematological tests.

Surgery
Surgery was scheduled within 2 weeks after completion of the last cycle of preoperative chemotherapy. Distal or total gastrectomy was conducted depending on the location and extent of the primary tumor. En bloc resection was performed if the tumor invaded the surrounding organs or structures. D2 lymphadenectomy (ie, resection of the regional lymph nodes, including the lymph nodes along right and left cardiac artery, lesser and greater curvature, suprapyloric along the right gastric artery, infrapyloric area, left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery) was performed by experienced surgeons according to the criteria established by Japanese Gastric Cancer Association. 14 Experienced surgeons who had performed at least 50 subtotal or total gastrectomies with D2 lymphadenectomy for patients with advanced gastric cancer annually participated in the trial. Any postoperative complications were evaluated within 30 days after surgery and graded using the Clavien-Dindo criteria. 15 Pathological TNM staging was evaluated according to the 7th edition of TNM classification for gastric cancer. 11

Follow-up
After completion of the treatment, enrolled patients were followed up every 3 to 6 months from 1 to 2 years, 6 to 12 months from 3 to 5 years, and then annually after 5 years. The follow-up included complete blood counts, chemistry profile, tumor markers, and radiological examinations.
Gastrointestinal endoscopy was conducted annually. Whether the tumor recurred or progressed was determined by radiological findings or tissue biopsy, if it was feasible. Cause of death and sites of recurrence or progression were assessed and recorded by investigators.

Statistical Analysis
This was a multicenter, open-label, RCT that was planned to show the noninferiority of perioperative chemotherapy of SOX compared with FOLFOX. The primary end point was OS, which was defined as the time from the randomization to death of any cause. The secondary end point was progressionfree survival (PFS), which was defined as the time from randomization until 1 of the following events  Figure 1 shows the trial profile and the reasons for patients who discontinued the protocol.

Chemotherapy-Associated Toxic Effects
The chemotherapy-associated toxic effects during perioperative chemotherapy are shown in the

Surgical and Pathological Findings
The surgical findings are shown in

Discussion
In this RCT of patients with locally advanced gastric cancer, we found that the absolute difference of 3-year OS rate between the 2 groups was 7.4% (75.2% in the SOX group vs 67.8% in FOLFOX group).
The lower limit of the 95% CI was -0.1%, which was greater than the prespecified noninferiority margin (-8%) and shows the noninferiority of perioperative chemotherapy with SOX compared with therapy with FOLFOX.
According to the results of several phase 3 studies, 4,5,16 perioperative chemotherapy was recommended as an alternative treatment for patients with gastric cancer of stage T2 or higher. The landmark MAGIC trial demonstrated the survival benefit of perioperative chemotherapy with epirubicin, cisplatin, and fluorouracil compared with surgery alone in locally advanced gastric cancer patients. 4 The subsequent FLOT4 trial showed that a FLOT regimen (fluorouracil plus leucovorin, oxaliplatin, and docetaxel) was superior to epirubicin and cisplatin plus either fluorouracil or capecitabine as perioperative chemotherapy. 16 However, in Asia, both SOX and FOLFOX were found to be effective and well tolerated in patients with unresectable gastric cancer, 17 In terms of adverse events, the toxic effect profiles were similar between the 2 groups, and both regimens showed acceptable tolerability. The most common toxic effects of both regimens in our study were leukocytopenia, neutrocytopenia, thrombocytopenia, and anemia. Thrombocytopenia was an important hematological toxic effect that might lead to the treatment delay and discontinuation. In previous studies, 21-23 the reported incidence of grade 3 or 4 thrombocytopenia ranged from 2% to 5% with FOLFOX regimen in patients with unresectable or recurrent gastric cancer. In the present trial, the incidence of grade 3 or 4 thrombocytopenia in the FOLFOX group was 2.8%. However, the incidence of grade 3 or 4 thrombocytopenia was much higher in the SOX group than in the FOLFOX group (11.1% vs 2.8%; P < .001). The incidence of thrombocytopenia in the SOX group in the present study was in line with the results of previous studies. 17,24 It was reported that the chemotherapy-induced sinusoidal obstruction syndrome was associated with thrombocytopenia. 25 The sinusoidal obstruction syndrome was clinically characterized by portal hypertension, splenomegaly, subsequent thrombocytopenia, and liver dysfunction, and occurred frequently during oxaliplatin-based chemotherapy. [26][27][28] Recently, one study 29 found that SOX is more likely to worsen oxaliplatin-induced hepatic sinusoidal injuries than capecitabine and oxaliplatin in patients with gastric cancer, and those authors proposed that S-1 could potentiate the toxic effects of fluorouracil-induced hepatocellular inflammation by inhibiting fluorouracil degradation through its component gimeracil. However, the exact mechanism needs to be further investigated. With regard to nonhematological toxic effects, patients in the SOX group experienced fewer gastrointestinal toxic effects (eg, anorexia or nausea) than those in the FOLFOX group in the present study. This may be associated with the potassium oteracil in S-1, which could inhibit the phosphorylation of fluorouracil in the gastrointestinal tract, subsequently decreasing gastrointestinal toxic effects.
There was no significant difference in 30-day postoperative morbidity between the 2 groups

Limitations
The current study has some limitations. First, the duration of the study was more than 8 years, and the treatment strategy for recurrent or metastatic gastric cancer has significantly improved during this period. Furthermore, the psychological and treatment intentions of patients have also been enhanced since these data were collected. These factors may be partly associated with the high rate of 3-year OS in the present study. In addition, the open-label treatment may have caused information bias.