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Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated. In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer (SPIRITS) trial, we aimed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin than with S-1 alone. In this phase III trial, chemotherapy-naive patients with advanced gastric cancer were enrolled betweeen March 26, 2002, and Nov 30, 2004, at 38 centres in Japan, and randomly assigned to S-1 plus cisplatin or S-1 alone. In patients assigned to S-1 plus cisplatin, S-1 (40–60 mg depending on patient's body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m 2 cisplatin was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks, followed by a 2-week rest period, within a 6-week cycle. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportions of responders, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00150670. 305 patients were enrolled; seven patients were ineligible or withdrew consent, therefore, 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone. Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin (13·0 months [IQR 7·6–21·9]) than in those assigned to S-1 alone (11·0 months [5·6–19·8]; hazard ratio for death, 0·77; 95% CI 0·61–0·98; p=0·04). Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone (median progression-free survival 6·0 months [3·3–12·9] vs 4·0 months [2·1–6·8]; p<0·0001). Additionally, of 87 patients assigned S-1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, ie, a total of 54% (range 43–65). Of 106 patients assigned S-1 alone who had target tumours, one patient had a complete response and 32 had partial responses, ie, a total of 31% (23–41). We recorded more grade 3 or 4 adverse events including leucopenia, neutropenia, anaemia, nausea, and anorexia, in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone. There were no treatment-related deaths in either group. S-1 plus cisplatin holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer.

This trial tested the efficacy of S-1, an oral prodrug that converts to fluorouracil within cells, in the adjuvant treatment of gastric cancer in Japanese patients after gastrectomy and an extended (D2) lymph-node dissection. Treatment with S-1 for 1 year after surgery was associated with longer overall survival than surgery alone. An important feature of this trial is the D2 dissection, which is not commonly performed in Western countries. After gastrectomy and an extended (D2) lymph-node dissection, treatment with S-1 for 1 year was associated with longer overall survival than surgery alone. S-1 is an oral prodrug that converts to fluorouracil within cells. Meta-analyses have shown that adjuvant chemotherapy is effective in treating gastric cancer. 1 – 6 However, the effectiveness of specific regimens has not been verified in large clinical trials. In 2001, the Intergroup-0116 (INT-0116) study investigators reported that postoperative chemoradiotherapy was effective in treating adenocarcinoma of the stomach or gastroesophageal junction. 7 Subsequently, the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial 8 showed the efficacy of perioperative chemotherapy. Both studies assessed the benefits of adjuvant therapy after only limited surgery, but the type of surgical procedure for gastric cancer can influence the results of postoperative chemotherapy. 9 , 10 In Japan, gastrectomy with extended . . .

The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer. We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20–75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m 2 per day, on days 1–5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m 2, on days 1 and 15) and cisplatin (80 mg/m 2, on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m 2, twice a day, on days 1–28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350, and with UMIN-CTR, number C000000062. All randomised patients were included in the primary analysis. Median overall survival was 10·8 months (IQR 5·7–17·8) for individuals assigned fluorouracil, 12·3 months (8·1–19·5) for those allocated irinotecan plus cisplatin (hazard ratio 0·85 [95% CI 0·70–1·04]; p=0·0552), and 11·4 months (6·4–21·3) for those assigned S-1 (0·83 [0·68–1·01]; p=0·0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group. S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting. Ministry of Health, Labour, and Welfare of Japan; Taiho Pharmaceutical; Yakult Honsha.

Background Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC). Methods In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125 mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125 mg/m2 on days 1 and 8; gemcitabine 1000 mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS). Results Between July 16, 2019, and September 9, 2022, 62 patients (AS, n = 32; AG, n = 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; P = .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; P < .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; P = .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group. Conclusion The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308). Encouraging antitumor activity of nab-paclitaxel plus S-1 has been shown in several small-scale studies. This study compared the efficacy and safety of nab-paclitaxel plus S-1 versus standard-of-care nab-paclitaxel plus gemcitabine as a first-line treatment for advanced pancreatic cancer.

This study aimed to evaluate the safety and feasibility of two neoadjuvant chemotherapy (NAC) regimens, gemcitabine plus nab-paclitaxel (GA) and gemcitabine plus S-1 (GS), for elderly patients (aged 75 years and older) with resectable and borderline resectable pancreatic ductal adenocarcinoma (R/BR-PDAC). A post hoc analysis was conducted using data from a randomized controlled trial on NAC for R/BR-PDAC (CSGO-HBP-015). Patients were divided into two groups: those aged 75 years and older (7/46 in GS and 16/48 in GA) and those under 75 years. Short-term outcomes, including resection rates, adverse events (AEs), postoperative complications, and the administration of adjuvant chemotherapy, were compared between age groups for both regimens. The incidence of AEs in patients aged 75 years and older tended to be higher than those of younger patients in both chemotherapy arms, but the differences were not statistically significant. However, the resection rates, postoperative complication rates, and the administration of adjuvant chemotherapy were not affected by age. Both regimens showed comparable safety profiles in elderly and younger cohorts. The GA and GS regimens can be safely administered as NAC for R/BR-PDAC in elderly patients without adversely affecting postoperative outcomes. These findings suggest that both regimens are feasible NAC options even for patients 75 years and older, supporting the need for further randomized controlled trials to validate these outcomes in the elderly population. Trial registration . UMIN Clinical Trials Registry UMIN000021484. This trial began in April 2016, and first registration (First Posted date) is 01/04/2016.

Background Nivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited. Methods ATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician’s choice of SOX (oral S-1 [tegafur–gimeracil–oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints—centrally assessed progression-free survival (PFS) and overall survival (OS)—and landmark analyses of OS among patients alive using 3-year follow-up data. Results At the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55–0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75–1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy. Conclusion This 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer. Trial registration NCT02746796

Oral fluoropyrimidines are used for the first-line treatment of metastatic breast cancer to avoid severe adverse effects, although firm supporting evidence is lacking. We aimed to establish whether S-1 is non-inferior to taxanes in this setting. We did an open-label, non-inferiority, phase 3 trial at 154 hospitals in Japan. We enrolled individuals who had HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease, and who were resistant to endocrine treatment. Patients were randomly assigned (1:1) either to taxane (docetaxel 60–75 mg/m2 at intervals of 3–4 weeks; paclitaxel 80–100 mg/m2 weekly for 3 of 4 weeks; or paclitaxel 175 mg/m2 at intervals of 3–4 weeks) or to S-1 (40–60 mg twice daily for 28 consecutive days, followed by a 14-day break). Randomisation was done centrally with the minimisation method, with stratification by institution, liver metastasis, oestrogen and progesterone receptor status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence. The primary endpoint was overall survival, with a prespecified non-inferiority margin of 1·333 for the hazard ratio (HR). The primary efficacy analysis was done in the full analysis set, which consisted of all patients who took at least one study treatment and who had all data after randomisation. This trial is registered with the University Hospital Medical Information Network, Japan (protocol ID C000000416). Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients (309 assigned to taxane; 309 assigned to S-1). The full analysis set consisted of 286 patients in the taxane group and 306 in the S-1 group. Median follow-up was 34·6 months (IQR 17·9–44·4). Median overall survival was 35·0 months (95% CI 31·1–39·0) in the S-1 group and 37·2 months (33·0–40·1) in the taxane group (HR 1·05 [95% CI 0·86–1·27]; pnon-inferiority=0·015). The most common grade 3 or worse adverse events were neutropenia (20 [7%] of 307 patients in the S-1 group vs nine [3%] of 290 patients in the taxane group), fatigue (ten [3%] vs 12 [4%]), and oedema (one [<1%] vs 12 [4%]). Treatment-related deaths were reported in two patients in the taxane group. S-1 is non-inferior to taxane with respect to overall survival as a first-line treatment for metastatic breast cancer. S-1 should be considered a new option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. Comprehensive Support Project for Oncology Research of the Public Health Research Foundation, Japan; Taiho.

The high recurrence rate after surgery for colorectal cancer liver metastasis (CLM) remains a crucial problem. The aim of this trial was to evaluate the efficacy of adjuvant therapy with uracil-tegafur and leucovorin (UFT/LV). In the multicenter, open-label, phase III trial, patients undergoing curative resection of CLM were randomly assigned in a 1:1 ratio to either the UFT/LV group or surgery alone group. The UFT/LV group orally received 5 cycles of adjuvant UFT/LV (UFT 300mg/m2 and LV 75mg/day for 28 days followed by a 7-day rest per cycle). The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included overall survival (OS). Between February 2004 and December 2010, 180 patients (90 in each group) were enrolled into the study. Of these, 3 patients (2 in the UFT/LV group and 1 in the surgery alone group) were excluded from the efficacy analysis. Median follow-up was 4.76 (range, 0.15-9.84) years. The RFS rate at 3 years was higher in the UFT/LV group (38.6%, n = 88) than in the surgery alone group (32.3%, n = 89). The median RFS in the UFT/LV and surgery alone groups were 1.45 years and 0.70 years, respectively. UFT/LV significantly prolonged the RFS compared with surgery alone with the hazard ratio of 0.56 (95% confidence interval, 0.38-0.83; P = 0.003). The hazard ratio for death of the UFT/LV group against the surgery alone group was not significant (0.80; 95% confidence interval, 0.48-1.35; P = 0.409). Adjuvant therapy with UFT/LV effectively prolongs RFS after hepatic resection for CLM and can be recommended as an alternative choice. UMIN Clinical Trials Registry C000000013.

The phase III randomized trial, JCOG1113 has demonstrated the non-inferiority of gemcitabine and S-1 (GS) therapy to gemcitabine and cisplatin (GC) therapy for advanced biliary tract cancer (BTC). However, biomarkers for favorable therapy or to predict patient prognosis remain lacking. In this study, we evaluated five candidate biomarkers potentially involved in the efficacy of cisplatin or S-1 by immunostaining tumor specimens obtained from JCOG1113 participants. The participants were randomly divided into training or test sets and classified into high- or low-expression groups based on the cutoff value calculated from the immunostaining results for each biomarker in the training set. Associations between the expression of each biomarker and the outcomes in JCOG1113 were analyzed. Among the 148 eligible participants, no interaction was observed between the treatment arms of GC or GS for any factor or biomarker. However, high excision repair cross-complementing gene 1 (ERCC1) was associated with poor overall survival (HR, 2.226; 95% CI, 1.160–4.272) and progression-free survival (HR, 1.793; 95% CI, 0.945–3.402) compared with low ERCC1 in the training set. Similar trends were observed for the test set. Our results indicate that in advanced BTC, high ERCC1 expression is a poor prognostic factor.

Background The ideal neoadjuvant treatment protocol for patients with pancreatic cancer (PDAC) remains unclear. We evaluated the efficacy and safety of neoadjuvant hypofractionated chemoradiotherapy with S-1 for patients with resectable (R) and borderline resectable (BR) PDAC. Methods Eligibility criteria included patients with R and BR PDAC, performance status 0–1, and age 20–85 years. Hypofractionated external-beam radiotherapy (30 Gy in 10 fractions) with concurrent S-1 (60 mg/m 2 ) was delivered 5 days/week for 2 weeks prior to pancreatectomy. Results Fifty-seven patients were enrolled in this study, including 33 R and 24 BR [19 BR tumors with portal vein contact (BR-PV) and 5 BR tumors with arterial contact (BR-A)]. The total rates of protocol treatment completion and resection were 91% (50/57) and 96% (55/57), respectively. Seven patients failed to complete S-1 due to cholangitis ( n  = 5) or neutropenia ( n  = 2). The most common grade 3 toxicities [Common Terminology Criteria for Adverse Events (CTCAE) version 4.0] were anorexia (7%), nausea (5%), neutropenia (4%), and leukopenia (4%). No patient experienced grade 4 toxicity. Pathologically negative margins (R0) were achieved in 54 of 55 patients (98%) who underwent pancreatectomy. Pathological response was classified as Evans grade I in 8 patients (15%), IIa in 31 patients (56%), IIb in 14 patients (25%), III in 1 patient (2%), and IV in 1 patient (2%), and operative morbidity (Clavien-Dindo grade IIIb or less) was observed in 4 patients (8%). The 1- and 2-year overall survival (OS) rates were 91 and 83% in R patients, respectively, and 77 and 58% in BR patients, respectively ( p  = 0.03). Conclusion Neoadjuvant S-1 with concurrent hypofractionated radiotherapy is tolerable and appears promising for patients with R and BR PDAC.