Gemcitabine Plus S-1 Research Articles

Abstract B54: The clinical impact and analysis for neoadjuvant chemotherapy against borderline resectable pancreatic cancer: Gemcitabine plus S-1 vs. gemcitabine plus nab-paclitaxel

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) shows a highly invasive and metastatic potential. Curative resection with multidisciplinary therapy is crucial for PDAC patients to improve the prognosis. It is also important to determine suitable regimen of neoadjuvant therapy (NAT) for locally advanced PDAC patients. Materials and Methods: In this study, 104 consecutive patients with BR PDAC who underwent pancreatectomy at Chiba University Hospital from Jan. 2008 to Dec. 2017 were retrospectively analyzed. We assessed the clinical significance of NAT compared to Surgery First (SF) in patients with borderline resectable (BR) PDAC. Furthermore, we compared the clinical impact between gemcitabine plus S-1 (GS) and gemcitabine plus nab-paclitaxel (GnP) for neoadjuvant chemotherapy (NAC) in BR PDAC. Results: In 84 BR head-PDAC and 20 BR body/tail-PDAC patients, 47 head-PDAC (56%) and 17 body/tail-PDAC (85%) were administered NAT, respectively. Comparing between SF and NAT group in each category, no significant differences were observed in the major clinicopathologic factors such as sex, operation time, blood volume loss, UICC-T, N factors, stage, or surgical curability. Median survival time (MST) for overall survival was 22.2 months for SF group and 23.1 months for NAT group in head-PDAC (p=0.08, log-rank), and not reached for SF group and 43.3 months for NAT group in body/tail-PDAC. Next, focusing on the differences of each strategy for NAC, we compared the clinical outcomes of patients between GS group (n=26) and GnP group (n=14) in head-PDAC and GS group (n=10) and GnP group (n=5) in body/tail-PDAC, respectively. The mean of NAC duration was 3.2 months for GS group and 2.7 months for GnP group. Among the clinicopathologic parameters, no differences of backgrounds for patients were observed between these two regimens. The response rates for RECIST criteria were 33.3% for GS group and 47.4% for GnP group in head-PDAC, notably 20% for GS group and 100% for GnP group in body/tail PDAC (p=0.001). The decrease rate of CA19-9 during NAC were 52.4% for GS group and 67.7% for GnP group (p=0.07). The Kaplan-Meier analysis revealed that the median survival time (MST) for disease-free survival after surgery was 9.7 months for GS group and 8.9 months for GnP group in head-PDAC, and 18.2 months for GS group and 14.7 months for GnP group in body/tail-PDAC. The MST for overall survival was 29.2 months for GS group and 24.7 months for GnP group in all BR PDAC. Conclusion: NAT (NAC) is a promising option in the treatment for patients with BR PDAC. Randomized prospective studies will be warranted for the strategy of treatment for patients with BR PDAC. Citation Format: Shigetsugu Takano, Hideyuki Yoshitomi, Shingo Kagawa, Katsunori Furukawa, Tsukasa Takayashiki, Satoshi Kuboki, Daisuke Suzuki, Nozomu Sakai, Takashi Mishima, Eri Nakadai, Masayuki Ohtsuka. The clinical impact and analysis for neoadjuvant chemotherapy against borderline resectable pancreatic cancer: Gemcitabine plus S-1 vs. gemcitabine plus nab-paclitaxel [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B54.

828TiP - Simultaneous resection of pancreatic cancer and liver oligometastases after induction chemotherapy in stage IV patients: An open-label prospective randomized multicenter phase III trial (CSPAC-1)

BackgroundApproximately 40% pancreatic ductal adenocarcinoma (PDAC) patients (pts) are diagnosed with distant metastasis, especially liver metastasis. The current standard treatment for these Stage IV pts is palliative chemotherapy. However, the improved safety of pancreatic surgery has led to the consideration of more aggressive approaches. There is increasing agreement that the synchronous resection of PDAC and liver metastases may benefit highly selected pts. Thus, CSPAC-1 trial to evaluate a treatment strategy for selecting pts who can benefit from the synchronous resection after induction chemotherapy is launched by Chinese Study Group for Pancreatic Cancer (CSPAC). Trial designLiver oligometastases is defined as no more than 3 metastatic lesions irrespective of distribution within liver lobes. The study contains two steps. In the first step, 1000∼1200 cases of stage IV PDAC pts 18∼75 yo who had pathologically confirmed via needle biopsy from hepatic oligometastases or pancreatic lesions, ECOG 0∼1 are eligible for inclusion. Candidates will receive standard first-line chemotherapy including standard or modified FOLFIRINOX (5-FU, leucovorin, irinotecan, oxaliplatin), NG (nab-paclitaxel plus gemcitabine) or GS (gemcitabine plus S-1). RECIST v1.1 criteria combining with tumor markers would be applied to evaluate tumor response to chemotherapy every two cycles. Approximately 30% surgical conversion rate after induction chemotherapy can be achieved according to our prior small sample study. 300 pts who meet the criteria for intervention will get access to the second step and be randomly assigned in a 1:1 ratio to simultaneous resection of primary PDAC and liver oligometastases or standard chemotherapy. The primary outcome of this clinical trial is real overall survival (from enrollment to death). Main secondary outcome measures including overall survival (from randomization to death), life quality score, postoperative morbidity, and mortality. This study was activated in July 2018 and is expected to complete accrual within 5 years. Clinical trial identificationNCT03398291. Legal entity responsible for the studyThe Chinese Study Group for Pancreatic Cancer (CSPAC), Shanghai Shenkang Hospital Development Center, BeiGene Pharmaceutical Co., Ltd. FundingThe Chinese Study Group for Pancreatic Cancer (CSPAC), Shanghai Shenkang Hospital Development Center, BeiGene Pharmaceutical Co., Ltd. DisclosureAll authors have declared no conflicts of interest.

Impact of Extravasated Platelet Activation and Podoplanin-positive Cancer-associated Fibroblasts in Pancreatic Cancer Stroma.

The aim of the study was to evaluate the status of extravasated platelet activation (EPA) surrounding podoplanin (PDPN)-positive cancer-associated fibroblasts (CAFs) in pancreatic cancer stroma by neoadjuvant chemotherapy. A total of 74 patients were enrolled in this study. We investigated CD42b and PDPN expression in the groups of untreated, gemcitabine (GEM) alone, GEM plus S-1 (GS) and GEM plus nab-paclitaxel (GnP). CD42b expression in surrounding CAFs was observed in 58% patients. CD42b expression was significantly correlated with PDPN expression. CD42b-positive cases were significantly lower in the group treated with GnP than in the untreated group and groups treated with GEM alone or GS. PDPN expression was reduced in the GnP group, as revealed by markedly disorganized collagen and a low density of PDPN-positive fibroblasts. There was a significantly lower CD42b expression and fewer PDPN-positive fibroblasts in the GnP group than in untreated, GEM alone, and GS groups, but there was no significant difference between the latter three groups. There is a significant association between EPA and PDPN-positive CAFs in pancreatic cancer stroma. Our data suggest that the GnP regimen decreases EPA through PDPN-positive CAF depletion.

AB031. S7-2. Consolidating the treatment guidelines of chemotherapy for cholangiocarcinoma between the East and West

: Chemotherapy plays an important role in the treatment of cholangiocarcinoma, including for advanced-stage disease and as adjuvant therapy after surgery. Recently, the BILCAP study comparing capecitabine with observation after surgery demonstrated a survival benefit of capecitabine. However, according to the NCCN guidelines 2019, the overall survival did not reach statistical significance in the intent-to-treat analysis. In Japan, a phase III study comparing S-1 with observation after surgery (JCOG1202) is under ongoing, and 440 patients have been enrolled. Pooled analysis of the BILCAP and JCOG1202 is proposed in the future. Systemic chemotherapy is the standard of care for patients with advanced-stage cholangiocarcinoma. Gemcitabine plus cisplatin (GC) is recognized as the global standard chemotherapy (the ESMO guidelines and NCCN guidelines), based on the results of the ABC-02 study comparing GC with gemcitabine alone. The BT22 study conducted in Japan also demonstrated the survival benefit of GC. GC is also recommended as the standard of care in Japanese guidelines. In 2018, two positive phase III studies have been reported from Japan. The JCOG1113 study comparing gemcitabine plus S-1 (GS) with GC, demonstrated non-inferiority of GS to GC in the overall survival. The KHBO1401 study comparing GC plus S-1 (GCS) with GC demonstrated superiority of GCS over GC in the overall survival. As a result, GS and GCS are recognized as alternative treatments for advanced cholangiocarcinoma in Japan. Recently, microsatellite instability-high (MSI-H) tumors have been shown to benefit from PD-1 blockade, such as pembrolizumab. Pembrolizumab was approved for the treatment of MSI-H tumors, including cholangiocarcinoma, in December 2018, in Japan. FGFR inhibitors and HER-2 inhibitors are currently under investigation for cholangiocarcinomas with FGFR2 gene fusions and HER2 gene amplification, respectively. Treatment strategies using precision medicines such as MSI-H, FGFR2, and HER2 are expected to be established in the near future.

AB026. S5A-2. The role of TS-1 in cholangiocarcinoma

: Gemcitabine plus platinum, notably cisplatin, is conceived as the standard regimen for advanced biliary tract cancer (ABTC). S-1 consists of tegafur and two biomodulators that maintain high serum 5-flurouracil concentrations while reducing gastrointestinal toxicity. A phase II study, JCOG0805 showed that gemcitabine plus S-1 was more promising than S-1 alone in ABTC, and a recently phase III JCOG1113 (FUGA-BT) showed gemcitabine plus S-1 (GS) is non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) benefit. Our TCOG T1308 trial also demonstrated that modified GS is an active regimen with excellent safety profiles as the first-line treatment in patients with ABTCs. For the triplet regimen, KHBO1002 trial, a single-arm phase II study of GC plus S-1 combination therapy (GCS), demonstrated a favorable survival benefit in ABTC patients. Recently, KHBO1401 trial was aimed to confirm the superiority of GCS to GC in terms of survival in patients with ABTC. This phase III study demonstrated the significant survival benefits of GCS treatment over GC treatment (13.5 versus 12.6 months, P=0.046), indicating that GCS could be a new standard treatment for patients with advanced BTC in Japan. In this talk, I will briefly introduce above clinical trials and share our experience of S-1 application in the treatment of ABTCs.

Successful treatment of a locally advanced unresectable pancreatic cancer patient with interstitial pneumonitis by conversion surgery following gemcitabine plus nab-paclitaxel chemotherapy: A case report.

Conversion surgery is an attractive strategy to improve the outcomes for locally advanced unresectable (UR-LA) pancreatic ductal adenocarcinoma (PDAC). The present case report, presents a case of successful conversion surgery following the treatment of a patient with UR-LA PDAC, suffering from interstitial pneumonitis (IP), using a combination of gemcitabine and nab-paclitaxel (GnP). A 67-year-old woman presented at the hospital with a high level of carbohydrate antigen 19-9 (CA19-9; 1,713 U/ml). Radiological examination revealed a pancreatic tumor in contact with the superior mesenteric artery, with invasion extending to the most proximal draining jejunal branch into the superior mesenteric vein. The patient was diagnosed with UR-LA PDAC. Following 6 courses of GnP therapy, the tumor size markedly decreased from 50 to 18 mm, and the level of CA19-9 also decreased from 1,713 to 60.1 U/ml. Due to the progression of IP, the patient was administered steroid medication along with a restart of tacrolimus for the treatment of dermatomyositis and IP. After recovery from her lung condition, an additional 3 courses of GnP therapy were administered, and then pancreatoduodenectomy was performed. The patient was still alive 14 months post-surgery with no recurrence. Between July 2009 and September 2017, conversion surgery was performed for 18 cases of UR-LA PDAC treated with gemcitabine plus S-1 (GS) therapy, and 11 cases with GnP therapy. The percentage of median CA19-9 and median tumor volume reductions were 73.7 and 51.6%, respectively, following GS therapy, and 86.7 and 68.8%, respectively, following GnP therapy. Tumor reduction following GnP therapy was significantly higher than that after GS therapy (P=0.02). GnP therapy is a suitable regimen to shrink the tumor mass in patients with UR-LA PDAC. Careful management of systemic conditions is required to treat patients with PDAC and IP when using GnP therapy. Conversion surgery should be considered for recognizing radiological responses (tumor shrinkage adjacent to major arteries) and reductions in CA19-9 levels.

The clinical outcomes of combination chemotherapy in elderly patients with advanced biliary tract cancer: An exploratory subgroup analysis of JCOG1113.

349 Background: JCOG1113 is a randomized phase III trial to confirm the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for advanced biliary tract cancer (BTC) in overall survival (OS). In the final analysis, GS demonstrated non-inferiority to GC in OS and was considered as a new option of standard of care for advanced BTC. However, there are few reports on the efficacy and safety of combination chemotherapy in elderly patients with advanced BTC. Therefore, this study aimed to explore the clinical outcomes of combination chemotherapy in elderly patients with advanced BTC. Methods: Among all enrolled patients in JCOG1113, ≥ 75 years old patients were included in this exploratory subgroup analysis. Cox regression analysis was performed to investigate the influence of age at baseline on OS and PFS. Clinically relevant adverse events (AEs) were defined as any of grade 2 or more fatigue, appetite loss, nausea, vomiting, oral mucositis, and diarrhea, and were compared using Fisher’s exact test. Results: Among all enrolled patients, 155 patients in GC and 139 patients in GS were included in < 75 years old cohort and 20 patients in GC and 40 patients in GS were included in ≥ 75 years old cohort.The HR of ≥ 75 years old cohort to < 75 years old cohort for OS was 0.96 (95% CI 0.71–1.30) in all enrolled patients. The HR of ≥ 75 years old cohort to < 75 years old cohort for OS was 1.26 (95% CI 0.77–2.04) in GC, and 0.84 (95% CI 0.56–1.24) in GS. The HR of ≥ 75 years old cohort to < 75 years old cohort for PFS was 1.01 (95% CI 0.63–1.61) in GC, and 0.78 (95% CI 0.54–1.12) in GS. Clinically relevant AEs were 36.1% in < 75 years old cohort and 25.0% in ≥ 75 years old cohort in GC, and 29.5% in < 75 years old cohort and 32.5% in ≥ 75 years old cohort in GS. Conclusions: The clinical outcomes of combination chemotherapy in elderly patients were comparable to non-elderly patients. Clinical trial information: 000010667.

Prognostic Factors for Advanced Pancreatic Cancer Treated with Gemcitabine Plus S-1: Retrospective Analysis and Development of a Prognostic Model.

Gemcitabine plus S-1 (GS) is commonly used to treat advanced pancreatic cancer (APC) in Asia. Few clinical experiments have demonstrated the clinical efficacy of GS in routine clinical practice. We aimed to identify the prognostic factors and develop a prognostic model for survival prediction in patients with APC, treated with GS. Records of 111 patients with newly diagnosed APC who received first-line palliative GS chemotherapy during 2010–2016 in Taiwan were analyzed retrospectively. Univariate and multivariate analyses were performed for the identification of prognostic factors. A prognostic model using prognosticators from the multivariate analysis was developed for survival prediction. The median overall survival (OS) for the cohort was 9.3 months (95% confidence interval [CI], 8.0–10.6). The prognostic model was constructed based on four independent prognosticators: performance status, tumor stage, pre-treatment albumin level, and neutrophil-to-lymphocyte ratio. Patients were categorized by tertiles into good, intermediate, and poor prognostic groups. The median OS values for each of these groups were 21.1 (95% CI, 8.2–33.9), 9.2 (95% CI, 8.3–10.1), and 5.8 months (95% CI, 4.4–7.1; log-rank p < 0.001), respectively. The bootstrapped corrected C-index of this model was 0.80 (95% CI, 0.71–0.89). The developed model was robust and could accurately predict survival in this population, and can assist clinicians and patients in survival discrimination and the determination of appropriate medical care goals. Additional research is needed to externally validate the model’s performance.

Clinical Significance of Neoadjuvant Chemotherapy With Gemcitabine Plus S-1 for Resectable Pancreatic Ductal Adenocarcinoma.

Little is known about the efficacy of neoadjuvant chemotherapy (NAC) with gemcitabine plus S-1 (GS) for patients with resectable pancreatic ductal adenocarcinoma (R-PDAC). The aim of this study was to investigate differences in the long-term outcome of patients with R-PDAC undergoing pancreatectomy with and without NAC-GS to clarify the clinical significance of NAC-GS. A total of 77 patients with R-PDAC who were scheduled for pancreatectomy between January 2012 and December 2017 were enrolled. Of these patients, 39 received NAC-GS (GS group) and 38 had upfront surgery (UFS group). Among the 77 patients, one patient in each group did not undergo pancreatectomy due to intraoperative non-curative factors. Median tumor size and the number of lymph nodes with metastasis were significantly lower in the GS group than in the UFS group (p=0.002 and p=0.017). However, the 5-year overall survival rate was similar in the two groups (26.1% versus 21.5%, p=0.930). NAC-GS may not be recommended for patients with R-PDAC since it does not seem to offer any survival benefits.

Gemcitabine plus S-1 for metastatic pancreatic cancer.

To investigate the treatment effects of gemcitabine plus S-1 (GS) for metastatic pancreatic cancer in our institution.Data from 41 patients with metastatic pancreatic cancer treated with GS regimen in West China Hospital, Sichuan University were reviewed. The therapeutic efficacy and toxicity were evaluated. The influencing factors of progression-free survival (PFS) and overall survival (OS) were also explored.At the last follow-up, all patients had died. The objective response rate was 22.0% (9/41) and the disease control rate was 65.9% (27/41). The median PFS and OS times were 5.1 (range, 1.5–21) and 10.6 months (range, 1.5–40), respectively. The 0.5-, 1-, and 2-year OS rates were 65.9%, 41.5%, and 9.8%, respectively. In multivariate analysis, body mass index and carbohydrate antigen 19-9 change were the significant influencing factors of PFS, compared to tumor site and chemotherapy cycles for OS. The adverse effects were moderate and tolerable.The effects of GS for metastatic pancreatic cancer in our institution were good. The adverse effects were moderate and tolerable. However, further investigation in future prospective clinical studies is warranted.

Randomized phase III study of gemcitabine plus S-1 combination therapy versus gemcitabine plus cisplatin combination therapy in advanced biliary tract cancer: A Japan Clinical Oncology Group study (JCOG1113, FUGA-BT).

205 Background: Gemcitabine (GEM) plus cisplatin (GC) is the standard of care for advanced biliary tract cancer (BTC). However, GC is considered to be toxic because of nausea, vomiting, and appetite loss, and inconvenient due to requiring hydration before and after administration. GEM plus S-1 (GS) was reported to be promising with preferable efficacy and acceptable toxicity profile (UMIN000001685). This phase III study aimed to confirm the non-inferiority of GS to GC in terms of overall survival (OS). Methods: Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable biliary tract adenocarcinoma (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), an ECOG-PS of 0–1, and adequate organ function. In the GC arm, 1 g/m2 of GEM and 25 mg/m2 of cisplatin was infused on days 1 and 8 of a 21-day cycle. In the GS arm, 1 g/m2 of GEM was infused on days 1 and 8, and S-1 60, 80, or 100 mg/day according to body-surface area was administered from days 1 to 14 of a 21-day cycle. The primary endpoint was OS and the secondary endpoints included progression-free survival (PFS), response rate (RR), adverse events (AEs), clinically relevant AEs defined as any of grade 2 or more fatigue, appetite loss, nausea, vomiting, oral mucositis, and diarrhea. The sample size was calculated to be 350 with a one-sided alpha of 5%, a power of 80%, non-inferiority margin of 1.155 in terms of hazard ratio (HR). Results: From May 2013 to March 2016, 354 patients were enrolled. The non-inferiority of GS to GC was demonstrated (median OS: 13.4 months (m) in GC and 15.1 m in GS, HR 0.95; 90% confidence interval (CI), 0.78 to 1.15; P = 0.046 for non-inferiority). Median PFS was 5.8 m in GC and 6.8 m in GS (HR 0.86, 95% CI, 0.70-1.07). RR was 32.4% in GC and 29.8% in GS. Preliminary AEs data demonstrated that both treatments were generally well tolerated, although clinically relevant AEs were observed 34.7% in GC and 31.2 % in GS. Conclusions: GS demonstrated non-inferiority to GC in OS with good tolerability and was considered as new convenient option of standard of care without hydration for advanced BTC. Clinical trial information: UMIN000010667.

Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-paclitaxel Reduces the Number of Cancer-associated Fibroblasts Through Depletion of Pancreatic Stroma.

In this study, the effects of neoadjuvant chemotherapy (NAC) on cancer-associated fibroblasts (CAFs) in pancreatic cancer stroma were investigated. Density of α-smooth muscle actin (αSMA)-positive fibroblasts in resected surgical specimens from untreated patients, patients receiving conventional gemcitabine plus S-1 (GS), and patients receiving gemcitabine plus nab-paclitaxel (GnP) was determined by hybrid cell counting. 18F-Fluorodeoxyglucose positron-emission tomography (FDG-PET) scans and carbohydrate antigen 19-9 (CA19-9) concentrations were used to assess tumor activity before and after chemotherapy in the GnP group. In this retrospective study of 65 patients, αSMA expression was reduced in the GnP group, as revealed by markedly disorganized collagen and a low density of αSMA-positive fibroblasts. There were significantly fewer αSMA-positive fibroblasts in the GnP than in the untreated and GS groups, but there was no significant difference between the latter two groups. αSMA density reflected a decrease in standardized uptake value on FDG-PET, but not CA19-9 concentration, after GnP chemotherapy. These data suggest that the GnP regimen induces stromal depletion, resulting in fewer CAFs.

Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data

Background:Three randomised trials (GEST, JACCRO PC-01, and GEMSAP) were conducted to evaluate the efficacy of gemcitabine plus S-1 (GS) vs gemcitabine alone in patients with advanced pancreatic cancer (PC). In this pooled analysis, the efficacy and safety of GS vs gemcitabine were evaluated.Methods:Additional follow-up was conducted and survival data were updated in each study. A total of 770 patients (gemcitabine 389; GS 381) were included in the pooled analysis. The efficacy and safety data were analysed according to disease extent: locally advanced PC (LAPC) or metastatic PC (MPC).Results:There were 738 (95.8%) overall survival events. In patients with LAPC (n=193), the median survival was 11.83 months for gemcitabine and 16.41 months for GS (hazard ratio (HR)=0.708; 95% confidence intervals (CI), 0.527–0.951; P=0.0220). In patients with MPC (n=577), the median survival was 8.02 months for gemcitabine and 9.43 months for GS (HR=0.872; 95% CI, 0.738–1.032; P=0.1102). The rate of grade 3/4 toxicity (rash and thrombocytopenia in LAPC; rash, diarrhoea, vomiting, and neutropaenia in MPC) was significantly higher for GS than for gemcitabine.Conclusions:Gemcitabine plus S-1 is a viable treatment alternative to gemcitabine, which is one of the standard treatments in patients with LAPC.

Health-related quality of life in a randomised phase III study of gemcitabine plus S-1, S-1 alone and gemcitabine alone for locally advanced or metastatic pancreatic cancer: GEST study

Objective:This study was performed to compare health-related quality of life (HRQOL) of gemcitabine plus S-1 (GS), S-1 alone and gemcitabine alone as first-line chemotherapy for locally advanced or metastatic pancreatic cancer in the GEST (Gemcitabine and TS-1 Trial) study and to assess the impacts of adverse events and tumour response on HRQOL.Methods:Patients were randomly assigned to receive gemcitabine alone (1000 mg/m2 weekly for 3 of 4 weeks), S-1 alone (80, 100 or 120 mg/day twice daily for 4 of 6 weeks) or GS (gemcitabine at 1000 mg/m2 weekly plus S-1 at 60, 80 or 100 mg/day twice daily for 2 of 3 weeks). HRQOL was assessed using the EuroQoL-5D (EQ-5D) questionnaire at baseline and weeks 6, 12, 24, 48 and 72. EQ-5D scores, quality-adjusted life months (QALMs), quality-adjusted progression-free months (QAPFMs) and time until definitive HRQOL deterioration (TUDD) were compared among the three groups. The impacts of adverse events and tumour response on EQ-5D scores were analysed.Results:Including EQ-5D scores after death as 0, the mean profile was significantly better in the GS than gemcitabine group (difference, 0.069; p=0.003), but not the S-1 group (difference, −0.011; p=0.613). The mean profiles until death were similar in the three groups. QALMs, QAPFMs and TUDD were significantly longer in the GS than gemcitabine group (p<0.001, p<0.001 and p=0.004, respectively), but not the S-1 group (p=0.563, p=0.741 and p=0.701, respectively). Fatigue, anorexia and tumour response were significantly associated with changes in EQ-5D scores.Conclusions:GS achieved better HRQOL than gemcitabine alone, resulting a good balance between overall survival and HRQOL benefits. S-1 alone provides HRQOL similar to that provided by gemcitabine alone. Preventing fatigue and anorexia and maintaining better response would improve HRQOL.

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.

Randomized phase II study of S-1 monotherapy versus gemcitabine plus S-1 in gemcitabine-refractory advanced pancreatic cancer.

429 Background: Gemcitabine is one of the standard chemotherapeutic agents for pancreatic cancer in a first-line setting. In a second-line setting, there are various unmet needs. After gemcitabine chemotherapy, S-1 is mainly used and sometimes gemcitabine plus S-1 (GS) is used. Cytotoxic effect of gemcitabine had been reported to have the potential to be enhanced when used with fluorouracil. This randomized study aimed to evaluate the efficacy and safety of gemcitabine plus S-1 in gemcitabine-refractory advanced pancreatic cancer. Methods: This phase II study consisted of patients (pts) who were randomly allocated into the GS group (gemcitabine 1,000 mg/m2 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) or the S-1 group (S-1 80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle) at a 1:1 ratio. The primary endpoint was the evaluation of progression-free survival (PFS). The sample size of 90 pts was chosen based on the randomized phase II selection design reported by Simon et al.(1985). The design suggests a correct selection probability of 75% with two-sided significance level of 0.10 if median PFS is 3.3 mo and 2.0 mo in GS and S-1 groups. Results: From Jan 2012 to March 2015, randomized 51 pts were examined (GS: 26, S-1: 25). This study was discontinued due to slow accrual. The median PFS of GS group was 2.0 mo while the S-1 group was 2.1 mo. The hazard ratio was 1.06 [95%CI 0.60-1.86]; (p=0.844). The median survival times were 3.8 mo in GS group and 5.5 mo in S-1 group, respectively. The hazard ratio was 1.02 [95%CI 0.57-1.81]; (p=0.96). The response rates were 4.2% and 4.3%. The disease control rates were 33.4% and 30.4%. Although bone marrow suppression is higher in GS group, the toxicities were manageable in both groups. Grade 3/4 toxicities (GS/S-1 %) included: neutropenia, 53.8/8; hemoglobin, 30.8/28.0; thrombocytopenia, 7.7/4.0; nausea, 0/8.0; anorexia 11.5/16.0, fatigue 7.7/0 and diarrhea, 3.8/4.0. Conclusions: Gemcitabine plus S-1 is not more effective than S-1 in gemcitabine-refractory advanced pancreatic cancer. Clinical trial information: 000007173.

Survival impact of neoadjuvant gemcitabine plus S-1 chemotherapy for patients with borderline resectable pancreatic carcinoma with arterial contact.

The aim of this study was to evaluate the efficacy of neoadjuvant gemcitabine plus S-1 (GS) chemotherapy as measured by overall survival for patients with pancreatic carcinoma with arterial contact. Medical records of 77 patients with pancreatic carcinoma with arterial contact who intended to undergo tumor resection were analyzed retrospectively. These patients were divided into two groups: patients who underwent upfront surgery and patients who underwent tumor resection after neoadjuvant GS chemotherapy. Clinicopathological factors were compared between the two groups. Of the 77 patients, 25 patients underwent upfront surgery while the remaining 52 patients received neoadjuvant GS chemotherapy. Seven patients did not undergo tumor resection due to distant metastasis. No serious adverse effects associated with neoadjuvant GS chemotherapy were observed. The R0 resection rate of patients who received neoadjuvant GS chemotherapy was significantly higher than that of patients who did not (P<0.001). Overall survival of patients who received neoadjuvant GS chemotherapy was significantly longer than that of patients who did not among all 77 patients (P=0.003, median survival time, 27.1 vs. 11.6months) as well as among the 70 patients who underwent tumor resection (P=0.001, median survival time, 27.2 vs. 11.6months). Multivariate analysis demonstrated that neoadjuvant GS chemotherapy was an independent prognostic factor of overall survival for patients who underwent tumor resection (P=0.019). Neoadjuvant GS chemotherapy may provide a survival benefit to patients with pancreatic carcinoma with arterial contact.

Combined gemcitabine and S-1 chemotherapy for treating unresectable hilar cholangiocarcinoma: a randomized open-label clinical trial.

Although the combination of cisplatin and gemcitabine (GEM) is considered the standard first-line chemotherapy against unresectable hilar cholangiocarcinoma (HC), its efficacy is discouraging. The present randomized open-label clinical trial aimed to evaluate the efficacy and safety of the GEM plus S-1 (GEM-S-1) combination against unresectable HC. Twenty-five patients per group were randomly assigned to receive GEM, S-1 or GEM-S-1. Neutropenia (56%) and leukopenia (40%) were the most common chemotherapy-related toxicities in the GEM-S-1 group. Median overall survival (OS) in the GEM-S-1, GEM and S-1 groups was 11, 10 and 6 months, respectively. GEM plus S-1 significantly improved OS compared to S-1 monotherapy (OR=0.68; 95%CI, 0.50–0.90; P=0.008). Median progression-free survival (PFS) times in the GEM-S-1, GEM and S-1 groups were 4.90, 3.70 and 1.60 months, respectively. GEM plus S-1 significantly improved PFS compared to S-1 monotherapy (OR=0.50; 95%CI, 0.27–0.91; P=0.024). Response rates were 36%, 24% and 8% in the GEM-S-1, GEM and S-1 groups, respectively. A statistically significant difference was found in response rates between the gemcitabine-S-1 and S-1 groups (36% vs 8%, P=0.017). Patients with CA19-9<466 U/ml were more responsive to chemotherapeutic agents than those with CA19-9≥571 U/ml (88.9% vs 0%, P<0.001). We conclude that the combination of GEM plus S-1 provides a better OS, PFS and response rate than S-1 monotherapy, but it did not significantly differ from GEM monotherapy. (ChiCTR-TRC-14004733).

Phase II study of gemcitabine plus S-1 chemotherapy in recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-based chemotherapy

No standard salvage regimen has been established for patients with recurrent and metastatic nasopharyngeal carcinoma (NPC) and disease progression after prior platinum-based chemotherapy. This phase II study was designed to evaluate the efficacy and safety of gemcitabine plus S-1 (GS) chemotherapy as a remedial regimen in this setting. In this multicenter phase II study, 49 patients with recurrent and metastatic NPC who failed previous platinum-based chemotherapy received gemcitabine (1.0 g/m(2) on days 1 and 8) plus oral S-1 chemotherapy (twice daily from day 1 to 14). Each cycle was repeated every 3 weeks for two cycles at least. The dose of S-1 was determined according to the body surface area (BSA): 40 mg twice a day for BSA <1.25 m(2); 50 mg twice a day for 1.25 m(2) ⩽ BSA <1.5 m(2); and 60 mg twice a day for BSA ⩾1.5 m(2). Treatment was generally well-tolerated. A total of seven patients (14.3%) had grade 3 toxicities and the main toxicity was myelosuppression, whereas the nonhematology adverse events were minimal. There were 3 complete responses (6.4%), 17 partial responses (36.2%), and the overall response rate was 42.6% (95% confidence interval: 27.3-61.2). Median time to progression was 5.8 months and median survival was 14.8 months. The 1- and 2-year survival rates were 64% and 30%, respectively. Gemcitabine plus S-1 offers a satisfactory clinical activity and an acceptable safety profile for recurrent and metastatic NPC patients after failure of platinum-based chemotherapy.

A phase II study of biweekly gemcitabine at fixed dose rate infusion plus S1 as first-line chemotherapy in patients with locally advanced or metastatic pancreatic cancer.

357 Background: The combination regimen of gemcitabine plus S1 (GS) as first-line chemotherapy has shown good efficacy in advanced pancreatic cancer. However, it is inconvenient to deliver gemcitabine on days 1 and 8 within one treatment cycle. In addition, previous studies have demonstrated that the gemcitabine administration by fixed dose rate infusion of 10 mg/m2/min should maximize the rate of intracellular accumulation of gemcitabine triphosphate and might improve clinical efficacy. The aim of this study was to evaluate the efficacy and safety of biweekly gemcitabine at fixed dose rate infusion combined with S1 (FGS) in chemonaive patients with locally advanced or metastatic pancreatic cancer. Methods: Forty-three eligible patients with locally advanced or metastatic pancreatic cancer received gemcitabine at a fixed dose of 10 mg/m2/min intravenously over a 2-h period on day 1, together with oral S1 40mg/m2twice daily on days 1 to 10, every 2 weeks. Tumor assessment was performed for every 3 cycles of chemotherapy. Results: All patients were evaluable for toxicity and 42 patients for efficacy. The overall response rate was 35.7% with 1 complete response, 14 partial responses, 17 stable diseases, and 10 progressions. Median time to progression was 5.9 months and median overall survival was 9.6 months. The main grade 3/4 toxicities included neutropenia (30.2%), thrombocytopenia (6.9%), anemia (2.3%), nausea (4.6%), diarrhea (2.3%). Conclusions: The biweekly FGS regimen is active, well tolerated and conveniently delivered as first-line chemotherapy for patients with locally advanced or metastatic pancreatic cancer.