Gemcitabine Plus S-1 Research Articles

Influence of major hepatectomy on gemcitabine-based chemotherapy for recurrent biliary tract cancer after surgery: a subgroup analysis of JCOG1113.

Major hepatectomy (MH) can increase the risk of adverse events (AEs) owing to impaired drug metabolism due to decreased liver volume and surgical injury. Thus, we performed this subgroup analysis using data from JCOG1113, a phase III trial comparing gemcitabine plus S-1 (GS) and gemcitabine plus cisplatin (GC) in patients with advanced and recurrent biliary tract cancer (BTC), to evaluate the effect of MH on the safety and efficacy of GC and GS regimens in patients with recurrent BTC. Of the 354 patients with advanced BTC enrolled in JCOG1113, 76 patients with postoperative recurrence (30 in the MH group and 46 in the non-MH group) were analyzed. Grade ≥ 3 platelet count decreased in both arms was more frequent in the MH group than in non-MH group (GC, 0.0 vs. 17.6%; GS, 3.9 vs. 15.4%). However, in the MH group, the white blood cell decreased (GC, 55.0 vs. 38.5%; GS, 23.1 vs. 7.7%) and anemia (GC, 15.0 vs. 11.8%; GS, 23.1 vs. 7.7%) were less common than in the non-MH group. The MH and non-MH groups showed no significant difference in overall survival (OS) in both GC [median OS, 23.0 in MH vs. 16.9months in non-MH (hazard ratio, 0.857; 95% CI 0.387-1.899)], and GS [median OS, 21.5 vs. 14.9months (hazard ratio, 0.670; 95% CI 0.310-1.447)] arms. The safety and efficacy of gemcitabine-based chemotherapy were comparable between patients who underwent MH and those who underwent other surgeries.

Results of a Randomized Clinical Study of Gemcitabine Plus Nab-Paclitaxel Versus Gemcitabine Plus S-1 as Neoadjuvant Chemotherapy for Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma (RCT, CSGO-HBP-015)

BackgroundThe optimal neoadjuvant chemotherapy (NAC) regimen for patients with localized pancreatic ductal adenocarcinoma (PDAC) remains uncertain. This trial aimed to evaluate the efficacy and safety of two neoadjuvant chemotherapy (NAC) regimens, gemcitabine plus nab-paclitaxel (GA) and gemcitabine plus S-1 (GS), in patients with resectable/borderline-resectable (R/BR) PDAC.Patients and MethodsTreatment-naïve patients with R/BR-PDAC were enrolled and randomly allocated. They received two cycles (2 months) of each standard protocol, followed by radical surgery for those without tumor progression in general hospitals belonging to our intergroup. The primary endpoint was to determine the superior regimen on the basis of achieving a 10% increase in the rate of patients with progression-free survival (PFS) at 2 years from allocation.ResultsA total of 100 patients were enrolled, with 94 patients randomly assigned to the GS arm (N = 46) or GA arm (N = 48). The 2-year PFS rates did not show the stipulated difference [GA, 31% (24–38%)/GS, 26% (18–33%)], but the Kaplan–Myer analysis showed significance (median PFS, GA/GS 14 months/9 months, P = 0.048; HR 0.71). Secondary endpoint comparisons yielded the following results (GA/GS arm, P-value): rates of severe adverse events during NAC, 73%/78%, P = 0.55; completion rates of the stipulated NAC, 92%/83%, P = 0.71; resection rates, 85%/72%, P = 0.10; average tumor marker (CA19-9) reduction rates, −50%/−21%, P = 0.01; average numbers of lymph node metastasis, 1.7/3.2, P = 0.04; and median overall survival times, 42/22 months, P = 0.26.ConclusionsThis study found that GA and GS are viable neoadjuvant treatment regimens in R/BR-PDAC. Although the GA group exhibited a favorable PFS outcome, the primary endpoint was not achieved.

Impact of previous S-1 treatment on efficacy of liposomal irinotecan plus 5-fluorouracil and leucovorin in patients with metastatic pancreatic cancer

Background/objectivesLiposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) provides survival benefits for metastatic pancreatic adenocarcinoma (mPDAC) refractory to gemcitabine-based treatment, mainly gemcitabine plus nab-paclitaxel (GA), in current practice. Gemcitabine plus S-1 (GS) is another commonly administered first-line regimen before nab-paclitaxel reimbursement; however, the efficacy and safety of nal-IRI + 5-FU/LV for mPDAC after failed GS treatment has not been reported and was therefore explored in this study. MethodsIn total, 177 patients with mPDAC received first-line GS or GA treatment, followed by second-line nal-IRI + 5-FU/LV treatment (identified from a multicenter retrospective cohort in Taiwan from 2018 to 2020); 85 and 92 patients were allocated to the GS and GA groups, respectively. Overall survival (OS), time-to-treatment failure (TTF), and adverse events were compared between the two groups. ResultsThe baseline characteristics of the two groups were generally similar; however, a higher median age (67 versus 62 years, p < 0.001) and fewer liver metastases (52% versus 78%, p < 0.001) were observed in the GS versus GA group. The median OS was 15.0 and 15.9 months in the GS and GA groups, respectively (p = 0.58). The TTF (3.1 versus 2.8 months, p = 0.36) and OS (7.6 versus 6.7 months, p = 0.83) after nal-IRI treatment were similar between the two groups. More patients in the GS group developed mucositis during nal-IRI treatment (15% versus 4%, p = 0.02). ConclusionsThe efficacy of second-line nal-IRI +5-FU/LV treatment was unaffected by prior S-1 exposure. GS followed by nal-IRI treatment is an alternative treatment sequence for patients with mPDAC.

Efficacy of nab‑paclitaxel vs. Gemcitabine in combination with S‑1 for advanced pancreatic cancer: A multicenter phase II randomized trial.

Patients with advanced pancreatic cancer (PC) need a cost-effective treatment regimen. The present study was designed to compare the efficacy and safety of nab-paclitaxel plus S-1 (AS) and gemcitabine plus S-1 (GS) regimens in patients with chemotherapy-naïve advanced PC. In this open-label, multicenter, randomized study named AvGmPC, eligible patients with chemotherapy-naïve advanced PC were randomly assigned (1:1) to receive AS (125 mg/m2 nab-paclitaxel, days 1 and 8; 80-120 mg S-1, days 1-14) or GS (1,000 mg/m2 gemcitabine, days 1 and 8; 80-120 mg S-1, days 1-14). The treatment was administered every 3 weeks until intolerable toxicity or disease progression occurred. The primary endpoint was progression-free survival (PFS). Between December 2018 and March 2022, 101 of 106 randomized patients were treated and evaluated for analysis (AS, n=49; GS, n=52). As of the data cutoff, the median follow-up time was 11.37 months [95% confidence interval (CI), 9.31-13.24]. The median PFS was 7.16 months (95% CI, 5.19-12.32) for patients treated with AS and 6.41 months (95% CI, 3.72-8.84) for patients treated with GS (HR=0.78; 95% CI, 0.51-1.21; P=0.264). The AS regimen showed a slightly improved overall survival (OS; 13.27 vs. 10.64 months) and a significantly improved ORR (44.90 vs. 15.38%; P=0.001) compared with the GS regimen. In the subgroup analyses, PFS and OS benefits were observed in patients treated with the AS regimen who had KRAS gene mutations and high C-reactive protein (CRP) levels (≥5 mg/l). The most common grade ≥3 adverse events were neutropenia, anemia and alopecia in the two groups. Thrombocytopenia occurred more frequently in the GS group than in the AS group. While the study did not meet the primary endpoint, the response benefit observed for AS may be suggestive of meaningful clinical activity in this population. In particular, promising survival benefits were observed in the subsets of patients with KRAS gene mutations and high CRP levels, which is encouraging and warrants further investigation. This trial was retrospectively registered as ChiCTR1900024588 on July 18, 2019.

Efficacy and safety of gemcitabine plus S-1 vs. gemcitabine plus nab-paclitaxel in treatment-naïve advanced pancreatic ductal adenocarcinoma.

Gemcitabine plus nab-paclitaxel (GnP) is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC). S-1, an oral fluoropyrimidine derivative, as compared with gemcitabine, is non-inferior in terms of overall survival (OS) and is associated with lower hematologic toxicity. Accordingly, S-1 is a convenient oral alternative treatment for advanced PDAC. This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1 (GS) vs. GnP as first-line chemotherapy for advanced PDAC. Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated. A total of 300 patients were assessed, of whom 84 received GS and 216 received GnP. The chemotherapy completion rate was higher with GS than GnP (50.0% vs. 30.3%, P = 0.0028). The objective response rate (ORR) was slightly higher (14.3% vs. 9.7%, P = 0.35), and the median OS was significantly longer (17.9 months vs. 13.3 months, P = 0.0078), in the GS group than the GnP group. However, the median progression-free survival (PFS) did not significantly differ between groups. Leukopenia risk was significantly lower in the GS group than the GnP group (14.9% vs. 28.1%, P = 0.049). As first-line chemotherapy for advanced PDAC, the GS regimen led to a significantly longer OS than the GnP regimen. The PFS, ORR, and incidence of severe adverse events were comparable between the GS and GnP groups.

Early Tumor Shrinkage and Depth of Response as Predictors of Survival for Advanced Biliary Tract Cancer: An Exploratory Analysis of JCOG1113.

Recent studies suggest that early tumor shrinkage (ETS) and depth of response (DpR) reflect outcomes of chemotherapy in various cancers. This study evaluated the association of ETS and DpR with clinical outcomes using data from JCOG1113, which demonstrated the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for chemotherapy-naïve advanced biliary tract cancer. In total, 354 (289 with measurable target lesions) patients enrolled in JCOG1113 were divided into ETS-unachieved and ETS-achieved groups (≥20% tumor reduction at week 6) and DpR-low and DpR-high groups (≥40% maximum shrinkage) until 12 weeks after enrollment. The impact of ETS and DpR on survival outcome was evaluated using the multivariable Cox proportional hazard model. The proportions of patients in the ETS-achieved and DpR-high groups were similar between the 2 treatment arms. The hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for the ETS-achieved group were 0.70 (95% confidence interval (CI), 0.52-0.93) and 0.60 (95%CI, 0.44-0.81), respectively. The HRs of PFS and OS for the DpR-high group were 0.67 (95%CI, 0.48-0.94) and 0.64 (95%CI, 0.46-0.90), respectively. In the subpopulation treatment effect pattern plot analysis, most patients in the ETS-achieved group in the GC arm did not experience disease progression after 12 weeks from the landmark. As on-treatment markers, ETS and DpR were effective tools. ETS was clinically useful, because it can be used to evaluate the outcomes of treatment early at a specific time.

Favorable Management of Repeated Serous Retinal Detachment with Continued Tumor Response in a Patient with Intrahepatic Cholangiocarcinoma During Treatment with Pemigatinib: A Case Report.

Pemigatinib is a fibroblast growth factor receptor inhibitor (FGFRi) approved for the treatment of patients with previously treated biliary tract cancer with FGFR2 fusion. Although infrequent, ocular toxicity manifested as serous retinal detachment (SRD) has been observed and is regarded as a serious side effect. We herein report the case of a 54-year-old woman with unresectable cholangiocarcinoma-initiated pemigatinib after failure of gemcitabine plus S-1 (GS). Although the patient experienced repeated SRD after pemigatinib, dose interruption and dose reduction of pemigatinib from 13.5 mg to 9 mg, and from 9 mg to 4.5 mg led to complete recovery of SRD, and continued tumor shrinkage.

Clinical outcomes of second‑line chemotherapy after gemcitabine and cisplatin plus S‑1 treatment for patients with advanced biliary tract cancer in the KHBO1401‑3A study.

Since the completion of the KHBO1401 study, which evaluated the efficacy of the combination of gemcitabine (GEM) and cisplatin (GC) compared with GC plus S‑1 (GCS), GCS has become a standard chemotherapy for patients with advanced biliary tract cancer (BTC). However, there are currently no data revealing second‑line therapy options after GCS. The present study aimed to evaluate the survival outcomes of patients receiving second‑line chemotherapy for advanced BTC, refractory or intolerant to GCS, using data from the KHBO1401 study. Patients who received a second‑line treatment after GCS chemotherapy between July 2014 and February 2016 were retrospectively studied. Overall survival (OS) was calculated from the day of GCS treatment failure or the first day of second‑line chemotherapy to the final follow‑up date or until death from any cause. Among 83patients refractory or intolerant to GCS chemotherapy, 51 (61%) received second‑line chemotherapy, including GCS (n=8), GC (n=15), GEM (n=6), GEM plus S‑1 (GS) (n=4) and S‑1 (n=18). The 6‑ and 12‑month OS rates were 66.7 and 44.4%, respectively, following second‑line chemotherapy, and 6.3 and 3.1%, respectively, in the best supportive care group (P<0.0001). In addition, the 12‑ and 24‑month OS rates were 59.3 and 36.2%, respectively, in the multidrug chemotherapy group, and 26.9 and 9.0%, respectively, in the single‑agent chemotherapy group (P=0.0191). These results suggested that second‑line combination chemotherapy is a viable treatment option for patients with advanced BTC that is refractory or intolerant to first‑line GCS therapy.

Comparison of adjuvant gemcitabine plus S-1 with S-1 monotherapy for pancreatic ductal adenocarcinoma: Retrospective real-world data

BackgroundS-1 has been recognized as one of the standard adjuvant chemotherapies for pancreatic ductal adenocarcinoma (PDAC) in East Asia, but the optimal adjuvant chemotherapy regimen has not been determined. We aimed to compare the efficacy and safety of adjuvant gemcitabine plus S-1 (GS) with S-1 monotherapy for PDAC. MethodsPatients with resected PDAC who received adjuvant GS or S-1 chemotherapy in Peking Union Medical College Hospital between May 2014 and May 2022 were reviewed. Data retrieved from medical records were used to evaluate efficacy and toxicity. ResultsA total of 241 patients were included, with 167 receiving GS and 74 receiving S-1. The patients who received GS were generally younger (median [range] age: 62 [36-78] versus 64 [44-87] years, p = 0.004), but chemotherapy began later (median [range] interval between chemotherapy and surgery: 49 [17-125] versus 40 [16-100] days, p < 0.001). The median disease-free survival (DFS, 15.1 versus 15.9 months, p = 0.52) and overall survival (OS, 34.8 versus 27.1 months, p = 0.34) did not differ significantly between the GS and S-1 groups, even after adjustment for the biases. However, the chemotherapy completion rate was higher in the patients treated with S-1 (52.4% versus 75.7%, p = 0.006), while grade 3-4 neutropenia occurred more frequently in the GS group (49.5% versus 18.2%, p = 0.015). ConclusionsAdjuvant S-1 monotherapy demonstrated noninferiority to the GS regimen in DFS and OS with better tolerability for PDAC following surgery.

Prognosis following an extended duration of adjuvant gemcitabine plus S-1 chemotherapy in patients with pancreatic ductal adenocarcinoma: Analysis using inverse probability of treatment weighting.

The aim of this study was to assess whether the duration of adjuvant gemcitabine plus S-1 (GS) chemotherapy has any effect on survival in patients with pancreatic ductal adenocarcinoma (PDAC). Of the 290 patients who received adjuvant GS chemotherapy, 100 (34%) received the standard duration (20-29 weeks) and 190 (66%) received an extended duration (≥30 weeks). To reduce selection bias, the prognostic impact (recurrence-free survival [RFS] and overall survival [OS]) based on the duration of adjuvant GS chemotherapy was analyzed using inverse probability of treatment weighting (IPTW). Moreover, to reduce immortal time bias, time-dependent multivariate analyses in which implementation of adjuvant GS chemotherapy was treated as time-varying covariate was also performed. Extended duration of adjuvant GS chemotherapy was significantly correlated with prolonged RFS (P < .001) and OS (P < .001) after IPTW adjustment. Time-dependent multivariate analyses revealed that extended duration of adjuvant GS chemotherapy was an independent prognostic factor for prolonged RFS (hazard ratio [HR], 0.58, P=.002) and OS (HR, 0.56, P=.005). Extended duration (≥30 weeks) of adjuvant GS chemotherapy in patients with PDAC was associated with an improved prognosis. These findings warrant a further prospective trial on PDAC to investigate the survival benefit of extended adjuvant chemotherapy.

The influence of major hepatectomy on gemcitabine-based chemotherapy for advanced biliary tract cancer: An exploratory subset analysis of JCOG1113.

419 Background: JCOG1113 (UMIN000001685) is a randomized phase III trial in patients (pts) with advanced biliary tract cancers (BTCs) that shows the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) regarding overall survival (OS). Previous reports suggest that a history of major hepatectomy (MH) may affect dose intensity and adverse event (AE) frequency and reduce treatment efficacy in chemotherapy due to impairment of liver function and drug metabolism. We thus investigated whether a history of MH affects the frequency of AEs and treatment efficacy in recurrent BTC pts in JCOG1113. Methods: Among the 354 pts enrolled in JCOG1113, 76 recurrent pts with recurrence after surgery were included in this analysis. We compared the frequency of AEs, progression-free survival (PFS), and OS of GC vs. GS in pts treated with MH vs. non-major hepatectomy (NMH). Results: Of the 76 pts, 17 on GC and 13 on GS were included in the MH group, while 20 on GC and 26 on GS were included in the NMH group. The primary sites were only intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma in the MH group, and there were no differences between the groups regarding sex, performance status, biliary drainage, or site of recurrence. The hazard ratio (HR) of GS to GC for PFS was 0.74 (95% CI 0.35–1.56) in the MH group and 0.97 (95% CI 0.52–1.82) in the NMH group. The hazard ratio (HR) of GS to GC for OS was 0.99 (95% CI 0.418–2.36) in the MH group and 1.17 (95% CI 0.59–2.33) in the NMH group. The median PFS and OS for GS in the MH group were 12.2 months and 21.5 months. These were longer than the 6.8 months and 15.1 months in the original results for GS in JCOG1113. Regarding AEs, Grade 3-4 AEs, specifically neutrophil count decreased (73.1%/92.3%), platelet count decreased (3.9%/15.4%), and rash (7.7%/15.4%), were more common in MH pts than NMH pts on GS. On GC, AEs in the MH and NMH pts did not show any consistent trends. The relative dose intensities (RDIs) of gemcitabine (70.7%/62.5%) and S-1 (70.4%/54.5%) were lower in MH pts than NMH pts on GS. The RDIs of gemcitabine (67.4%/63.0%) and cisplatin (73.6%/65.0%) were slightly lower in MH pts than NMH pts on GC. Conclusions: For pts with a history of MH, some AEs increased, and the RDIs were lower, especially that of S-1 for GS. On the other hand, the HR for PFS suggests that GS may be more effective than GC in MH pts.

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

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly (n = 60) and the non-elderly groups (n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC (n = 20) and GS (n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC.

Comparison of the Effect of Chemotherapeutic Treatments Followed by Conversion Surgery for Initially Unresectable Locally Advanced Pancreatic Ductal Adenocarcinoma

Introduction: Surgical resection with multidisciplinary therapy, so called conversion surgery is needed to improve the prognosis of patients with initially unresectable locally advanced (UR-LA) pancreatic ductal adenocarcinoma (PDAC). Method: Seventy-seven consecutive patients with UR-LA PDAC who were performed chemotherapy and/or followed by conversion surgery (CS) at Chiba University hospital from Jan 2010 to Dec 2019 were retrospectively analyzed. We assessed the clinical significance of CS, and compared the impact of efficacy between gemcitabine plus S-1 (GS) and gemcitabine plus nab-paclitaxel (GnP) before CS in UR-LA PDAC. Results: The patients were classified into CS (n=32) and non-CS group (n=45). Comparing between CS and non-CS group, the SMA involvement was significantly lower in CS (40.6%) than that in non-CS (64.4%) group (p=0.038). The median survival time (MST) for overall survival were 13.1 months for non-CS and 30.1 months for CS group (p<0.0001). Comparing chemotherapies between GS (n=35) and GnP group (n=41), the conversion rates were 54.3% (19/35) in GS and 29.3% (12/41) in GnP (p=0.027). The median percentage of tumor shrinkage were 23% for GS and 32% for GnP (p=0.047), the decrease rate of CA19-9 level were 74% for GS and 83% for GnP (p=0.37) in CS group. The Kaplan-Meier analysis revealed that the MST for overall survival were 14.3 months for GS and 12.0 months for GnP in non-CS, and 26.8 months for GS and 45.9 months for GnP in CS group. Conclusions: Randomized prospective studies will be warranted for the strategy of treatment for patients with UR-LA PDAC.

Randomized phase II study of gemcitabine and S-1 combination therapy versus gemcitabine and nanoparticle albumin-bound paclitaxel combination therapy as neoadjuvant chemotherapy for resectable/borderline resectable pancreatic ductal adenocarcinoma (PDAC-GS/GA-rP2, CSGO-HBP-015)

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a lethal disease, and multimodal strategies, such as surgery plus neoadjuvant chemotherapy (NAC)/adjuvant chemotherapy, have been attempted to improve survival in patients with localized PDAC. To date, there is one prospective study providing evidence for the superiority of a neoadjuvant strategy over upfront surgery for localized PDAC. However, which NAC regimen is optimal remains unclear.MethodsA randomized, exploratory trial is performed to examine the clinical benefits of two chemotherapy regimens, gemcitabine plus S-1 (GS) and gemcitabine plus nab-paclitaxel (GA), as NAC for patients with planned PDAC resection. Patients are enrolled after the diagnosis of resectable or borderline resectable PDAC. They are randomly assigned to either NAC regimen. Adjuvant chemotherapy after curative resection is highly recommended for 6 months in both arms. The primary endpoint is tumor progression-free survival time, and secondary endpoints include the rate of curative resection, the completion rate of protocol therapy, the recurrence type, the overall survival time, and safety. The target sample size is set as at least 100.DiscussionThis study is the first randomized phase II study comparing GS combination therapy with GA combination therapy as NAC for localized pancreatic cancer.Trial registrationUMIN Clinical Trials Registry UMIN000021484. This trial began in April 2016.

Survival Outcomes of Gemcitabine Plus S-1 Adjuvant Chemotherapy after Surgical Resection for Advanced Biliary Tract Cancer

Introduction: The usefulness of adjuvant chemotherapy in biliary tract cancer (BTC) is poorly reported. This study aimed to evaluate the effectiveness and safety of adjuvant gemcitabine plus S-1 (GS) chemotherapy after curative surgical resection for BTC. Methods: 225 BTC patients who underwent surgical resection between January 2006 and May 2019 were enrolled in this study. Twenty-seven patients received adjuvant chemotherapy with GS (GS group), whereas 67 patients underwent surgery alone (S group). Twenty-three matching pairs were derived through propensity score (PS) matching analysis. Patients received 12 cycles of adjuvant chemotherapy (70 mg/m² oral S-1 for 7 consecutive days plus intravenous gemcitabine 1,000 mg/m² on day 7). The primary end point was recurrence-free survival (RFS). The secondary end points were the 1-, 2-, and 3-year RFS and overall survival (OS) rates, tolerability, and frequency of grade 3/4 toxicity. Results: The completion rate was 81.5%; no treatment-related deaths were observed. Grade 3/4 adverse events were seen in 40.7% of the patients. RFS (3-year RFS rate: 59.3% vs. 39.1%, p = 0.049) and OS (3-year OS rate: 71.7% vs. 53.4%, p = 0.008) were significantly better in the GS group than in the S group among PS-matched pairs. Discussion/Conclusion: GS chemotherapy after curative surgery was well tolerated, showed better clinical benefit in the adjuvant setting, and can effectively reduce BTC recurrence.

Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504–0.937) in the low CCr group. Although the total number of incidences of all Grade 3–4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.

Predictors of Poor Pathological Response to Neoadjuvant Gemcitabine Plus S-1 Chemotherapy in Patients With Pancreatic Ductal Adenocarcinoma.

Although neoadjuvant chemotherapy (NAC)-gemcitabine plus S-1 (GS) has been reported to have a survival benefit in patients with resectable pancreatic ductal adenocarcinoma (PDAC), optimal candidates for NAC-GS have not been clearly identified. A total of 81 patients with PDAC who underwent pancreatectomy after NAC-GS between 2013 and 2019 were divided into 2 groups based on Evans classification: grade I (<10% tumor cell destruction, n = 19) and grades II and III (>10% tumor cell destruction, n = 62). Univariate and multivariate analyses using clinical characteristics available before initiation of NAC were performed to predict Evans classification grade I (Evans I). The overall survival in patients with Evans I was significantly lower than that in patients with Evans II and III (P < 0.001). Multivariate analysis revealed a carcinoembryonic antigen level of >3.6 ng/mL (P = 0.001) and C-reactive protein to albumin ratio of >0.062 (P = 0.017) as independent predictors for Evans I disease. Seven of 11 patients who met both criteria had Evans I disease. Serum carcinoembryonic antigen and C-reactive protein to albumin ratio are associated with Evans I disease in patients with PDAC who receive NAC-GS. Patients who meet both predictors may not be optimal candidates for NAC-GS.

Effect and limitation of neoadjuvant chemotherapy for pancreatic ductal adenocarcinoma: consideration from a new perspective

BackgroundEffect of neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC) has remained under investigation. We investigated its effect from a unique perspective and discussed its application.Patients and methodsWe retrospecively analyzed consecutive 131 PDAC patients who underwent pancreatoduodenectomy and distal pancreatectomy. Clinicopathologic data at surgery and postoperative prognosis were compared between patients who underwent upfront surgery (UFS) (n = 64) and those who received NAC (n = 67), of which 62 (92.5%) received gemcitabine plus S-1 (GS). The GS regimen resulted in about 15% of partial response and 85% of stable disease in a previous study which analyzed a subset of this study subjects.ResultsTumor size was marginally smaller, degree of nodal metastasis and rate of distant metastasis were significantly lower, and pathologic stage was significantly lower in the NAC group than in the UFS group. In contrast, significant differences were not observed in histopathologic features such as vessel and perineural invasions and differentiation grade. Notably, disease-free and overall survivals were similar between the two groups adjusted for the pathologic stage, suggesting that effects of NAC, including macroscopically undetectable ones such as control of micro-metastasis and devitalizing tumor cells, may not be remarkable in the majority of PDAC, at least with respect to the GS regimen.ConclusionsNAC may be useful in downstaging and improving prognosis in a small subset of tumors. However, postoperative prognosis may be determined at the pathologic stage of resected specimen with or without NAC. Therefore, NAC may be applicable to borderline resectable and locally advanced PDAC for enabling surgical resection, but UFS would be desirable for primary resectable PDAC.

Analyses for clinical outcomes of GS and GnP neoadjuvant therapies followed by surgery for borderline resectable pancreatic cancer

To improve the prognosis of pancreatic ductal adenocarcinoma (PDAC) patients, curative resection with multidisciplinary therapy is needed. Consecutive 116 patients with borderline resectable (BR) PDAC who undergone pancreatectomy from Jan 2008 to Dec 2018 were analyzed. We assessed the clinical significance of neoadjuvant therapy (NAT), and compared the clinical impact between gemcitabine plus S-1 (GS) and gemcitabine plus nab-paclitaxel (GnP) for neoadjuvant chemotherapy (NAC) in BR PDAC (n=62). Comparing between surgery first (SF: n=45) and NAT (n=71) group, the Kaplan-Meier analysis showed that median survival time (MST) for overall survival were 22.2 months for SF and 29.2 months for NAT (p=0.057). Focusing on the differences of strategy for NAT, we compared the clinical outcomes of patients between GS (n=36) and GnP (n=26). The mean of NAC duration was 3.2 months for GS and 2.8 months for GnP. Among the clinico-pathological parameters, no differences of backgrounds for patients were observed between these two regimens. The response rates for RECIST criteria were 33.3% for GS and 38.5% for GnP. The decrease rate of CA19-9 during NAC were 51.6% for GS and 67.7% for GnP (p=0.07), whereas the rate of N2 positive in GS was significantly lower than that in GnP (p=0.009). The MST for overall survival were 29.2 months for GS and 24.2 months for GnP in BR, notably, 40.0 months for GS and 27.1 months for GnP in BR-A. Randomized prospective studies for the optimal NAC will be warranted for the strategy of treatment for patients with BR PDAC.

Efficacy Analysis of Adjuvant Chemotherapy with Gemcitabine Plus Platinum or S-1 in Biliary Tract Carcinoma: A Multi-Center Retrospective Study.

PurposeBiliary tract cancers (BTCs) have a poor overall prognosis, as patients who underwent curative surgery frequently experience disease recurrence. At present, there is a paucity of well-documented adjuvant chemotherapy regimen. This study aimed to assess whether gemcitabine plus platinum or S-1 adjuvant chemotherapy have different impact on relapse-free survival (RFS).Patients and MethodsWe selected patients undergoing radical biliary tract cancer surgery, pathologically confirmed adenocarcinoma and received gemcitabine plus platinum (cisplatin or oxaliplatin) or S-1 adjuvant chemotherapy from September 2013 to May 2020. The primary study endpoint was RFS. The secondary endpoint was safety.ResultsOverall 136 patients were enrolled. The median follow-up was 32.3 months and the median RFS was 17.0 months (95% CI 8.9–25.1). The median RFS was 14.1 months (95% CI 6.7–21.5) in gemcitabine plus platinum group and 33.0 months (95% CI 9.3–56.7) in gemcitabine plus S-1 (GS) group, a non-significant difference both in univariate (P=0.092) and in multivariate analysis (P=0.058). Lymph node status (N- vs N+: HR=0.477, 95% CI 0.285–0.799; P=0.005) and chemotherapy cycles (<6 vs 6–8: HR=1.828, 95% CI 1.117–2.993; P=0.016) were independent impact factors for RFS. GS group had lower incidence of adverse reactions.ConclusionCompared with gemcitabine plus platinum, GS regimen has a tendency to obtain longer RFS (although there is no statistically significant difference) and less toxic. GS regimen has the potential to be investigated as a standard regimen for adjuvant chemotherapy.