GEST Study Research Articles

SLCO1B1 Polymorphism Is a Drug Response Predictive Marker for Advanced Pancreatic Cancer Patients Treated With Gemcitabine, S-1, or Gemcitabine Plus S-1.

The aim of this study was to evaluate the effects of single-nucleotide polymorphisms (SNPs) on advanced pancreatic cancer risk and overall survival (OS) in a candidate-gene approach. Overall, 5438 SNPs in 219 candidate genes encoding several drug-metabolizing enzymes or transporters were analyzed. In the screening study, 3 SNPs were found associated with OS (P ≤ 0.0005). We validated these SNPs as part of the randomized phase 3 study (GEST study). The associations between OS and SNPs were investigated using log-rank test and Cox proportional hazards model. From the GEST study, the SNP rs4149086 in the 3' UTR of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene showed significant interaction with treatment (P = 0.02). In the gemcitabine group, the SNP was associated with short OS (hazard ratio [HR], 3.75; 95% confidence interval [CI], 1.30-10.8; P = 0.008) even after multiple-comparisons adjustment. In contrast, the SNP was not associated with OS in S-1 (HR, 0.77; 95% CI, 0.33-1.81; P = 0.55) or gemcitabine plus S-1 groups (HR, 1.18; 95% CI, 0.46-3.00; P = 0.72). Patients with advanced pancreatic cancer with the rs4149086 AG or GG genotype may obtain good clinical results when treated with S-1-containing regimens.

A randomised controlled trial of gemcitabine hydrochloride plus S-1 combination therapy versus gemcitabine hydrochloride therapy alone in pancreatic cancer patients aged ≥75 years: a study protocol for an open-label randomised feasibility study

IntroductionIn Japan, the age of patients with pancreatic cancer has increased. Combination chemotherapies such as 5-fluorouracil/leucovorin, oxaliplatin and irinotecan therapy and gemcitabine hydrochloride (GEM) +nab paclitaxel therapy have been developed...

Updated results from GEST study: a randomized, three-arm phase III study for advanced pancreatic cancer

PurposeThe GEST study showed non-inferiority of S-1 but not superiority of gemcitabine plus S-1 (GS) to gemcitabine alone for overall survival with the data by the cut-off date of 31st July in 2010 for chemo-naïve patients with advanced pancreatic cancer. We considered it important to determine whether S-1 maintains non-inferiority after a long-term follow-up in the GEST study and to obtain a firm positive conclusion. In addition, it may be an interesting challenge to explore the efficacious profile of GS in the long-term follow-up study. Using the data from the follow-up period, background and efficacy in patients from Taiwan and Japan, as well as the rates of tumor shrinkage in locally advanced and metastatic patients (Waterfall plot) were also analyzed.MethodsThe results of the primary analysis were reconfirmed, and subset analysis of overall survival and progression-free survival was performed based on the overall survival data updated by the cut-off date of 31st July in 2011.ResultsThe median follow-up period was 29.8 months, and 795 deaths occurred (95.6%). The median overall survival was 8.8 months for gemcitabine, 9.7 months for S-1 (hazard ratio [HR], 0.96; 97.5% confidence interval [CI], 0.79–1.17), and 9.9 months for GS (HR 0.91; 97.5% CI 0.75–1.11). In patients with performance status (PS) 0, the median overall survival was 9.8 months for gemcitabine, 10.9 months for S-1, and 10.5 months for GS. In patients with PS 1, the median overall survival was 6.2 months for gemcitabine, 6.3 months for S-1, and 9.6 months for GS.ConclusionOur survey reconfirmed the non-inferiority of S-1 to gemcitabine and showed S-1 can be used as one of the standard treatment options for advanced pancreatic cancer.Trial registrationClinicalTrials.gov: NCT00498225.

Multicenter randomized phase II study comparing alternate-day oral therapy using S-1 with the standard regimen as a first-line treatment for patients with locally advanced and metastatic pancreatic cancer: PAN-01 study.

4107Background: S-1 is an active agent for the treatment of pancreatic cancer. GEST study has previously shown the noninferiority of S-1 to gemcitabine in advanced pancreatic cancer. However, the s...

Clinical outcome of elderly patients with unresectable pancreatic cancer treated with gemcitabine plus S-1, S-1 alone, or gemcitabine alone: Subgroup analysis of a randomised phase III trial, GEST study.

BackgroundIn the GEST study of unresectable pancreatic cancer, S-1 demonstrated non-inferiority compared to gemcitabine, but gemcitabine plus S-1 (GS) did not show superiority over gemcitabine for overall survival (OS). We performed subgroup analysis of these data focused on the efficacy and safety of these regimens as a first-line treatment for elderly patients. MethodsElderly patients (≥70 years, n = 261) treated for unresectable pancreatic cancer (GS: n = 90, S-1: n = 85 and gemcitabine: n = 86) were analysed. ResultsNo significant differences between the GS, S-1, or gemcitabine groups in OS (median: 10.2, 8.0 and 8.5 months, respectively) or objective response rates (27.6%, 25.3% and 14.3%, respectively) were noted. Grade ≥III adverse haematological events were observed more frequently in GS-treated than in S-1- or gemcitabine-treated elderly patients (p < 0.001 and p = 0.016, respectively). Four of 8 patients aged ≥80 years experienced serious adverse events. ConclusionsS-1 and gemcitabine are both efficacious options for treatment of elderly patients with unresectable pancreatic cancer. Conversely, first-line treatment of elderly patients with GS should only be used after careful consideration.

ISS1-3-2 - Prognostic index model for overall survival in advanced unresectable pancreatic cancer from GEST study

ISS1-3-2 - Prognostic index model for overall survival in advanced unresectable pancreatic cancer from GEST study

2375 Prognostic index based on the phase III study of gemcitabine plus S-1, S-1 alone or gemcitabine alone in patients with advanced pancreatic cancer (GEST study)

2375 Prognostic index based on the phase III study of gemcitabine plus S-1, S-1 alone or gemcitabine alone in patients with advanced pancreatic cancer (GEST study)

Interim safety analysis of a randomized phase II trial comparing alternate-day oral therapy using S-1 with the standard regimen as a first-line treatment for patients with advanced pancreatic cancer

e15267 Background: Based on the results of the GEST study, S-1 was confirmed to be non-inferior to gemcitabine. However, the recommended standard regimen frequently causes adverse events(AEs). On the other hand, a multi-center prospective phase II study showed that the alternate-day administration of S-1 reduced AEs and was tolerable for unresectable advanced pancreatic ductal adenocarcinoma (PDAC) patients. Accordingly, we conducted a multi-center randomized phase II study to investigate the non-inferiority of S-1 using alternate-day administration, compared with the standard regimen for unresectable PDAC. Herein, we report the interim safety analysis results of this study. Methods: Patients who met the study criteria (histologically-confirmed PDAC, age > 20, ECOG Performance Status of 0 or 1, no prior chemotherapy or radiotherapy, and adequate organ functions) were randomly assigned at a ratio of 1:2 to standard daily S-1 administration (Arm A: 4 weeks of administration followed by 2 weeks of rest) or a...

S-1 in the treatment of pancreatic cancer.

S-1 is an oral 5-fluorouracil (5-FU) prodrug, which is designed to improve the antitumor activity of 5-FU by inhibiting dihydropyrimidine dehydrogenase, the key enzyme of 5-FU catabolism. Recently, two important studies on the clinical use of S-1 for pancreatic cancer have been reported from Japan. In the first study (GEST study), S-1 demonstrated non-inferiority to gemcitabine (GEM) in overall survival (OS) for metastatic or locally advanced pancreatic cancer, but combination chemotherapy with GEM and S-1 did not show superiority to GEM in OS. In the second study (JASPAC-01 study), S-1 showed superiority to adjuvant chemotherapy with GEM in OS in patients with resected pancreatic cancer. In addition to GEM, S-1 is now regarded as the key drug in the management of pancreatic cancer in Japan. To date, many studies have investigated the effectiveness of S-1 in various settings, such as first-line chemotherapy for metastatic or locally advanced pancreatic cancer, second-line chemotherapy after GEM failure, and chemoradiotherapy for locally advanced disease. In this review, we focus on recent clinical trials of S-1-based chemotherapy for advanced pancreatic cancer.

JASPAC 01: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer.

4008 Background: Adjuvant chemotherapy with gemcitabine (G) has been standard treatment for resected pancreatic cancer (PC). In the GEST study, S-1 (S) had shown non-inferiority to G in overall survival (OS) for unresectable PC. The aim of this phase III study is to investigate non-inferiority of S to G on OS as adjuvant chemotherapy for resected PC. Methods: Patients (pts) after macroscopically curative resection of PC with an ECOG PS of 0-1 and adequate organ functions were randomly assigned to G (1000 mg/m2, iv, d1, 8 and 15, q4w, for 6 courses) or S (80/100/120 mg/day based on BSA, po, d1-28, q6w, for 4 courses) with balancing by surgical margins (R), nodal status (N) and institution. Primary endpoint was OS. With 180 pts per arm, the study had 80% power to prove non-inferiority with a margin of hazard ratio (HR) 1.25 on the basis of expected HR 0.87, with 0.05 two-sided alpha. Secondary endpoints were relapse-free survival (RFS), safety, and quality of life (EQ-5D). One interim analysis was planned after 180 deaths. Results: From 4/2007 to 6/2010, 385 pts were enrolled from 33 hospitals in Japan. 378 pts (G/S: 191/187) were included in the full analysis set. Pts characteristics (G/S) were well balanced (PS0: 67%/70%, R0: 86%/88%, N0: 38%/36%). Based on the interim analysis with 205 OS events, IDMC recommended to publish the results. OS at 2-years were 53% for G and 70% for S. HR for S to G was 0.56 (95% CI, 0.42-0.74, p&lt;0.0001 for non-inferiority, p&lt;0.0001 for superiority). On subgroup analysis, HRs for R0/R1, N0/N1 pts were 0.57 (95% CI, 0.42-0.78)/0.53 (0.27-1.05), 0.48 (0.28-0.83)/0.58 (0.41-0.80), respectively. RFS at 2-years were 29% for G and 49% for S. HR of relapse for S to G was 0.56 (95% CI, 0.43-0.71, log-rank p&lt;0.0001). Incidences of grade 3/4 toxicities in G/S were leukopenia 39%/9%, hemoglobin decrease 17%/13%, thrombocytopenia 9%/4%, elevated AST 5%/1%, fatigue 5%/5%, and anorexia 6%/8%. Relative dose intensity of G/S was 84%/97%. EQ-5D QOL score in S was significantly better than that in G (p&lt;0.0001). Conclusions: S-1 adjuvant chemotherapy is shown non-inferior, and furthermore, even superior to GEM. S-1 is considered as the new standard treatment for resected PC pts. Clinical trial information: UMIN000000655.

Randomized Phase III Study of Gemcitabine Plus S-1, S-1 Alone, or Gemcitabine Alone in Patients With Locally Advanced and Metastatic Pancreatic Cancer in Japan and Taiwan: GEST Study

The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival. The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m(2) on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle). In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P < .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group. Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer.

O3-004 - Efficacy of Gemcitabine as Second-Line Therapy after Failure of S-1 Therapy for Metastatic Pancreatic Carcinoma

ABSTRACT Background S-1 is regarded one of the standard first-line regimens for advanced pancreatic cancer (APC) in Japan, because the GEST study, a randomized phase III clinical trial, revealed the non-inferiority of S-1 alone to GEM. However, no matter whether first-line therapy is S-1 or gemcitabine, no standard second-line chemotherapy has been established yet for cases of APC. In our study, we have evaluated the efficacy and outcomes of second-line GEM therapy after S-1 therapy failure for metastatic pancreatic carcinoma. Method We retrospectively examined the data for 27 patients with metastatic pancreatic carcinoma refractory to first-line S-1 therapy. All the patients had undergone second-line GEM therapy during October 2000–February 2009 at the National Cancer Center Hospital, Tokyo, Japan. Tumor responses were analyzed using the Response Evaluation Criteria in Solid Tumors (RECIST). The Kaplan–Meier method was used to evaluate tumor progression and survival. Result The Eastern Cooperative Oncology Group Performance Status was 0 or 1. The male:female ratio was 16:11 and median age was 62 years (range, 42–72 years). Four patients (14%) exhibited a partial response to second-line GEM therapy, 11 (40%) showed stable disease, and 12 (44%) showed progressive disease. Grade 3 adverse events for second-line GEM therapy were neutropenia in four patients and upper gastrointestinal hemorrhage in two. Grade 4 adverse events were not observed. The median progression-free survival was 70 days (95% confidence interval, 44–95 days) and the median OS after second-line GEM therapy was 229 days (95% confidence interval, 117–340 days). Conclusion Although this study had a small sample population and the design was retrospective, the results indicated that second-line GEM therapy exerted favorite antitumor activity with tolerable toxicity.

775 - Relations of QOL to Tumor Response and Adverse Events in Unresectable advanced Pancreatic Cancer Patients in the Gest Study

ABSTRACT Background The GEST study demonstrated the non-inferiority of S-1, but not the superiority of gemcitabine plus S-1 (GS) to gemcitabine alone (G) with respect to overall survival in unresectable advanced pancreatic cancer patients (Ioka et al. ASCO 2011, Abstract 4007). The results of QOL evaluation based on EQ-5D demonstrated that S-1 and G were equivalent and GS was superior to G (Ohashi et al. ASCO 2011, Abstract 9070). We report the relations of QOL to adverse events and tumor response. Methods Chemotherapy was administered until PD, consent withdrawal, or unacceptable adverse events. EQ-5D questionnaires were filled in at baseline and 6, 12, 24, 48, and 72 weeks and converted to 0-1 utility scores by the Japanese value set. We estimated the effects of adverse events (nausea, vomiting, diarrhea, fatigue, and anorexia leveled from 0 to 4 by CTC-AE) and of tumor response on EQ-5D utility scores, using a mixed-effects model for repeated measurements. Response was classified into 4 levels (CR/PR/SD or NE/PD). Results A total of 736 patients were analyzed. Fatigue and anorexia were significantly associated with EQ-5D utility score; they decreased the estimated score by 0.034/level (p Conclusions QOL in the studied patient population was negatively affected by fatigue and anorexia, and was improved by good response probably through decreased pain. Disclosure Y. Ohashi: I have an advisory relationship and research funding to disclose. Name of Entity: Taiho Pharmaceutical Co. Ltd. T. Ioka: I have an advisory relationship and research funding to disclose. Name of Entity: Taiho Pharmaceutical Co. Ltd. T. Okusaka: I have an advisory relationship and research funding to disclose. Name of Entity: Taiho Pharmaceutical Co. Ltd

Updated results of the GEST study: Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer in Japan and Taiwan.

4035 Background: The GEST study (Ioka et al. ASCO 2011, Abstract 4007) demonstrated the non-inferiority of S-1 to GEM with respect to the primary endpoint of overall survival (OS) in patients with pancreatic cancer (PC). We now report the updated results of this study. Methods: The GEST study was a randomized, 3-arm, phase III study. Chemotherapy-naive patients with unresectable advanced PC, an ECOG Performance status (PS) of 0-1, and adequate organ functions were randomly assigned to receive GEM (1000 mg/m2, iv, d1, 8 and 15, q4w), S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w), or GS (GEM 1000 mg/m2, iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The primary endpoint was OS, used to assess the non-inferiority of S-1 and the superiority of GS to GEM. Patient information was updated in July 2011. Results: At the time of this follow-up analysis, median follow-up was 29.8 months with 795 OS events, compared with 18.4 months with 710 OS events out of 832 patients at the previous analysis. Median OS was 8.8 months (95% CI: 8.0–9.7) in the GEM group and 9.7 months (95% CI: 7.6-10.8) in the S-1 group (HR=0.96, 97.5% CI: 0.79-1.17, p&lt;0.001 for non-inferiority), which is consistent with prior results (HR=0.96, 97.5% CI: 0.78-1.18, p&lt;0.001). In the GS group, median OS was 9.9 months (95% CI: 9.0-11.2). The HR was 0.91 (97.5%CI: 0.75-1.11, p=0.28 for superiority versus the GEM group). On subgroup analysis, GS was associated with a non-statistically significant trend toward better OS compared with GEM among patients with locally advanced disease and those with a PS of 1. Median OS was 12.7 months (95% CI: 9.7–14.9) in the GEM group and 15.9 months (95% CI: 13.0-19.7) in the GS group (HR=0.72, 95% CI: 0.51-1.03) among patients with locally advanced disease, and 6.2 months (95% CI: 4.9–8.3) in the GEM group and 9.6 months (95% CI: 8.0-10.9) in the GS group (HR=0.62, 95% CI: 0.46-0.83) among patients with a PS of 1. Conclusions: The non-inferiority of S-1 to Gem in terms of the primary endpoint of OS was reconfirmed. Monotherapy with S-1 can be used as one of the standard treatments for advanced PC. As for GS therapy, there is room for further investigation.

Efficacy of gemcitabine as second-line therapy after S-1 therapy failure in advanced pancreatic carcinoma.

248 Background: Gemcitabine (GEM) and GEM-containing combination chemotherapy have been established as standard first-line therapies for advanced pancreatic carcinoma (APC). In the GEST study, a phase III clinical trial that compared the results for GEM, S-1, and GEM+S-1 therapies, there was no significant difference between overall survival (OS) for GEM and GEM+S-1; S-1 and GEM had similar efficacies as first-line treatment for APC. Therefore, S-1 is expected to be used as first-line therapy. In our study, we have evaluated the efficacy and outcomes of second-line GEM therapy after S-1 therapy failure in APC. Methods: We retrospectively examined the data for 27 patients (pts) with APC refractory to first-line S-1 therapy. All the pts had undergone second-line GEM therapy during October 2000–February 2009 at National Cancer Center Hospital after first-line S-1 therapy. Tumor responses were analyzed using Response Evaluation Criteria in Solid Tumors. The Kaplan-Meier method was used to evaluate tumor progression and survival. Results: The Eastern Cooperative Oncology Group Performance Status was 0 or 1. The male:female ratio was 16:11 and median age was 62 years (range, 42–75 years). Four pts (14%) exhibited a partial response to second-line GEM therapy, 11 (40%) showed stable disease, and 12 (44%) showed progressive disease. Grade 3 adverse events for second-line GEM therapy were neutropenia in 2 pts and upper gastrointestinal hemorrhage in 1 pt. Grade 4 adverse events were not observed. The median progression-free survival was 77 days (95% confidence interval, 33–121 days) and the median OS after second-line GEM therapy was 240 days (95% confidence interval, 156–324 days). Conclusions: Although this study had a small sample population and retrospective design, the results indicate that GEM has good antitumor activity with tolerable toxicity. Second-line GEM therapy was found to be effective after first-line S-1 therapy failure in APC.

Analysing impacts of the economic crisis on the pre–start ups process of business students in Germany.

The article is part of the empirical research project “Starting up Businesses and Entrepreneurship by Students” (GESt–study) and analyzes potential impacts of the economic crisis on the pre–start–up process of business students surveyed before and during the downturn at four German universities (of applied sciences), what supports the advancement of entrepreneurship education and support within two different macroeconomic contexts. Though in Germany recessions typically animate more persons to self–employment, these business start–ups are mostly based on necessity–driven entrepreneurship. But particularly opportunity entrepreneurship has positive effects on economic growth and employment. Whereas no significant differences can be detected regarding their start–up propensities, the economic crisis indeed has heightened the intended start–up time as well as the necessity–driven start–up motivation of the surveyed business students, but not their start–up motivation from economic self–realization. Therefore, self–employment as vocational alternative has to be highlighted stronger and entrepreneurial basic knowledge has to be taught adequately to the students so that they are able to mature as potential entrepreneurs at their universities – the location where specialized knowledge about their subsequent professionalism is imparted – what facilitates them to generate future innovations accompanied by enduring and high–skilled employment.

Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer (PC) in Japan and Taiwan: GEST study.

4007 Background: S-1, an oral fluoropyrimidine, is one of the key drugs for PC in Japan. Phase II studies of S-1 alone as well as those of GS have shown high efficacy against the tumor as the first-line treatment of metastatic PC. Methods: The GEST study was a randomized, prospective, open-label, 3-arm, phase III study. Chemotherapy-naive patients with unresectable advanced PC, an ECOG PS of 0-1, with adequate organ functions were randomly assigned to receive GEM (1000 mg/m2, iv, d1, 8 and 15, q4w), S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w) or GS (GEM 1000 mg/m2, iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The primary endpoint was overall survival (OS) to assess the non-inferiority of S-1 alone and the superiority of GS to GEM, with a 90% power and a 1-sided alpha value of 0.0125 for each multiplicity-adjusted comparison. Secondary endpoints were progression-free survival (PFS), response rate (RR), safety, and quality of life (EQ-5D). Results: A total of 834 patients were enrolled from July 2007 to October 2009. We conducted this analysis after confirming over 680 events as expected. Demographic factors were well balanced. S-1 was confirmed to be non-inferior to GEM with respect to OS. There was no significant difference in OS between GEM and GS, while PFS differed significantly between these arms. (4.1M/5.7M, p value<0.0001) RR was 13.3%, 21.0%, and 29.3% in GEM, S-1, and GS respectively. Grade 3/4 toxicities (%) in GEM/S-1/GS were neutropenia 41.0/8.8/62.2, thrombocytopenia 11.0/1.5/17.2, anorexia 7.3/11.4/9.4, diarrhea 1.1/5.5/4.5. EQ-5D QOL score in S-1 was similar to GEM (p value=0.67), and that in GS was significantly better than that in GEM (p value=0.003). Conclusions: Without compromising QOL, oral S-1 provided similar efficacy and tolerable toxicity to GEM as the first-line treatment for PC. Our results suggested that GS contribute better QOL than GEM. Further clinical investigation might be needed to ensure the efficacy of GS. n MST HR (97.5%CI) P value GEM 277 8.8 M - - S-1 280 9.7 M 0.957 (0.780-1.175) 0.0003 (noninferiority) GS 275 10.1 M 0.875 (0.711-1.077) 0.1496 (superiority)

Quality of life (QOL) evaluation within a randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable, advanced pancreatic cancer (PC) in Japan and Taiwan: GEST study.

9070 Background: The GEST study, a randomized 3-arm phase III study, was designed to assess the non-inferiority of S-1 alone and the superiority of GS to GEM. Primary endpoint was overall survival (OS). The non-inferiority of S-1 was confirmed, GS was superior to GEM but the difference was not statistically significant. QOL was a secondary endpoint. Here we report QOL results from this study. Methods: Chemotherapy-naïve patients with unresectable advanced PC, ECOG PS of 0-1, with adequate organ functions were enrolled. Patients were equally randomized to one of three arms: GEM (1000 mg/m2, iv, d1, 8 and 15, q4w) , S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w) , or GS (GEM 1000 mg/m2, iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The patients were assessed with EQ-5D questionnaire at baseline, and at 6,12,24,48 and 72 weeks from first administration. Changes over time of EQ-5D utility score and Quality-adjusted life years (QALY) were calculated. In addition, we explored the relationship between QOL and clinical characteristics. Results: Among 832 patients, full analysis set of this study, 736(88%) had completed both baseline questionnaire and at least one questionnaire after randomization. In the EQ-5D utility score analysis by including deaths as score 0, there was a statistically significant difference in score over time between GS and GEM (p=0.0031, repeated measures ANOVA), and no statistically significant difference between S-1 and GEM. In the analysis of QALY, there was a statistically significant difference between GS and GEM (p=0.0008, generalized Wilcoxon test), but no statistically significant difference between S-1 and GEM. In the population of PS 1, GS is remarkably better than GEM in favor of EQ-5D utility score and QALY. Conclusions: Patients treated with S-1 resulted in clinically equivalent efficacy outcomes without any impact on patient QOL compared with GEM. Patients treated with GS had a statistically significant difference in QOL compared with GEM, in both overall and PS1 populations. Further research is needed to confirm the efficacy of GS in unresectable advanced PC.