Prospective multicenter study to investigate the introduction rate of second-line S-1 in gemcitabine-refractory unresectable pancreatic cancer

Purpose

S-1 is one of the second-line candidate agents for gemcitabine-refractory unresectable pancreatic cancer. Two phase II studies have been reported for second-line chemotherapy with S-1, but these studies did not investigate introduction rate and suitable dose of second-line S-1. Therefore, we conducted a prospective multicenter study in which chemo-na?ve patients were enrolled and had two levels of S-1 dose.

Methods

Chemo-na?ve patients with unresectable pancreatic cancer were enrolled. This study started with 80?mg/m²/day dose of S-1 as second-line chemotherapy and tolerability was checked. When tolerability was not confirmed in initial patients, the dose of S-1 was shifted to 60?mg/m²/day. When tolerability was confirmed at 80 or 60?mg/m²/day, the study continued, and up to 20 patients were accumulated with the dose. In addition, the introduction rate of second-line S-1 was examined.

Results

Six of the initial 7 patients with 80?mg/m²/day dose of S-1 completed one course of second-line chemotherapy. Twenty patients were accumulated with an 80?mg/m²/day dose of S-1. With the exception of one patient continued gemcitabine chemotherapy, two of the remaining 19 patients withdrew from this study because of toxicity during the period of gemcitabine chemotherapy. Fifteen of the remaining 17 gemcitabine-refractory patients could complete one course of S-1 as second-line chemotherapy with acceptable toxicity.

Conclusions

This prospective multicenter study showed that 15 (78.9%) out of 19 chemo-na?ve unresectable pancreatic cancer patients could complete one course of 80?mg/m²/day dose of S-1 as second-line chemotherapy after first-line gemcitabine chemotherapy failure with tolerable toxicity.     

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.     

晚期胰腺癌患者应用GS方案一线化疗引起的中性粒细胞减少与预后的相关性

目的:探讨晚期胰腺癌患者应用吉西他滨联合替吉奥方案一线化疗引起的中性粒细胞减少(chemotherapy induced neutropenia,CIN)与预后的相关性。方法:回顾性分析2012年7月至2016年6月,接受吉西他滨联合替吉奥方案一线化疗的37例晚期胰腺癌患者,根据CTCAE(common terminology criteria for adverse events) 4.0的标准,将中性粒细胞减少分级为G0级,G1级,G2级,G3级,G4级。观察患者化疗2周期内出现的中性粒细胞减少程度,利用Kaplan-Meier曲线和COX风险模型分析CIN与总生存时间（OS）的相关性。结果:晚期胰腺癌患者接受吉西他滨联合替吉奥方案一线化疗后,未发生CIN（0级）的患者中位总生存期为158天（95%CI:128~187天）,发生CIN（1-4级）患者中位总生存期294天（95%CI,211~368天）。多因素分析显示,发生CIN（HR:0.379,95%CI:0.177~0.811,P=0.012）和接受二线化疗（HR:0.426,95%CI:0.186~0.976,P=0.044）是晚期胰腺癌患者接受吉西他滨联合替吉奥方案一线化疗的独立预后因素。结论:CIN是晚期胰腺癌一线GS方案化疗判断预后的独立影响因素,监测CIN将有助于早期判断预后并及时调整化疗药物剂量。     

Phase II trial of S-1 in combination with gemcitabine for chemo-naïve patients with locally advanced or metastatic pancreatic cancer

Background

We performed a phase II study of combination chemotherapy with S-1 plus gemcitabine for treating chemo-naïve patients with unresectable pancreatic cancer to evaluate the efficacy and toxicity.

Patients and methods

Patients with histologically confirmed unresectable pancreatic cancer were eligible. The treatment consisted of S-1 (40 mg/m² p.o. b.i.d. from D1 to 14) and gemcitabine (1,250 mg/m² on D1 and 8), repeated every 3 weeks.

Results

Thirty-two patients were enrolled between March 2005 and December 2007. No complete response was observed and a partial response was observed in 14 patients (44.0%), stable disease in eight patients (25.0%), and progressive disease in eight patients (25.0%). The median time to progression was 4.92 months (95% CI: 4.16–5.67 months), and the median overall survival was 7.89 months (95% CI: 5.96–9.82 months). The survival duration was significantly longer for the patients with a good performance status compared with that of the patients with a poor performance status. The major toxicities were grade 3–4 neutropenia (9, 28.1%), grade 3/4 thrombocytopenia (5, 15.6%), and grade 3 diarrhea (5, 15.6%).

Conclusion

The combination chemotherapy of S-1 and gemcitabine showed promising antitumor activity and manageable toxicities, and especially for the good performance status patients with unresectable pancreatic cancer.     

Phase II Trial of Combination Nab-paclitaxel and Gemcitabine in Non–squamous Non–small Cell Lung Cancer After Progression on Platinum and Pemetrexed

BackgroundBetter therapies are needed to improve survival in metastatic non–small cell lung cancer (NSCLC). Given the synergy of combination nab-paclitaxel and gemcitabine in metastatic pancreatic cancer and their individual activity in advanced NSCLC, we sought to determine whether the same combination would confer a therapeutic benefit in the second-line therapy of recurrent or metastatic non–squamous (NSQ) NSCLC.Materials and MethodsThis single-arm phase II trial of nab-paclitaxel and gemcitabine was performed from June 2015 to April 2020 at an academic referral cancer center. Patients with advanced NSQ-NSCLC whose disease progressed on first-line pemetrexed plus platinum +/- immunotherapy were enrolled. Patients received intravenous nab-paclitaxel 100 mg/m² and gemcitabine 1000 mg/m² on days 1 and 8 of each 21-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety and tolerability were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.ResultsThirty-seven patients (15 men [41%] and 22 women [59%]; median age, 66 years [range, 41-81 years]) were accrued. ORR was 13.5% (95% CI, 2.5-24.5%). DCR was 59.5% (95% CI, 43.5-75.5%). Median PFS was 2.6 months (95% CI, 1.4-3.8 months). Median OS was 6.2 months (95% CI, 4.2-8.2 months). 1-year OS was 24% (95% CI, 10-38%). Safety and tolerability were similar to other second-line chemotherapies, although there was an 11% incidence of grade 2-3 pneumonitis.ConclusionCombination nab-paclitaxel and gemcitabine after platinum and pemetrexed for NSQ-NSCLC was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting. The higher-than-expected risk of pneumonitis was also concerning.Trial RegistrationClinicalTrials.gov Identifier: NCT02303977Micro-AbstractIn this phase II trial, 37 patients with metastatic non–squamous non–small cell lung cancer were treated with nab-paclitaxel/gemcitabine in second-line. ORR = 13.5% (95% CI, 2.5%-24.5%). Median PFS = 2.6 months (95% CI, 1.4-3.8 months). Median OS = 6.2 months (95% CI, 4.2-8.2 months). Nab-paclitaxel and gemcitabine was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting.     

Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials

BackgroundTwo recent studies (ABC-02 [UK] and BT22 [Japan]) have demonstrated the superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone for patients with pathologically proven advanced biliary tract cancer (BTC: cholangiocarcinoma, gallbladder and ampullary cancers). This pre-planned analysis evaluates the efficacy of CisGem with increased statistical power.Patients and methodsWe carried out a meta-analysis of individual patient-level data of these studies to establish the effect of CisGem versus Gem on progression-free survival (PFS), overall survival (OS) and carried out exploratory subgroup analyses.ResultsCisGem demonstrates a significant improvement in PFS [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.53–0.76, P < 0.001] and OS (HR = 0.65, 95% CI 0.54–0.78, P < 0.001) over Gem. This effect is most marked among patients with good performance status (PS 0–1): HR for PFS is 0.61 (95% CI 0.51–0.74), P < 0.001 and OS HR = 0.64 (95% CI 0.53–0.77), P < 0.001. CisGem resulted in improved PFS and OS for intra- and extra-hepatic cholangiocarcinomas and gallbladder cancer. The treatment effect between UK and Japanese patients was consistent with respect to OS (HR = 0.65, 95% CI 0.53–0.79 and 0.65, 95% CI 0.42–1.03, respectively); with similar OS in the combination arms (median 11.7 and 11.1 months, respectively). Subgroups least likely to benefit included patients with ampullary tumours and poor performance status (PS2).ConclusionsCisGem is the standard of care for the first-line treatment of good-PS patients with advanced BTC regardless of ethnicity. Future studies should aim to enhance the effectiveness of this regimen in the first-line setting, establish the role of subsequent (second-line) therapy and assess the role of rationally developed molecular-targeted therapies.     

A prognostic model in patients treated for metastatic gastric cancer with second-line chemotherapy

BackgroundThis retrospective study was carried out to evaluate the prognostic significance of clinical factors in patients treated for metastatic gastric cancer with second-line chemotherapy.Patients and methodsWe evaluated the prognostic significance of various clinical factors in 126 patients, who were treated with second-line chemotherapy.ResultsMedian progression-free and overall survival (OS) for second-line chemotherapy were 3.3 and 5.3 months, respectively, with an overall response rate of 11.1%. Multivariate analysis identified three independent prognostic factors: performance status: Eastern Cooperative Oncology Group zero to one [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.7–5.4], hemoglobin (Hb) level: ≥10 g/dl (HR 2.2, 95% CI 2.1–2.4) and time-to-progression (TTP) under first-line therapy: ≥5 months (HR 0.5, 95% CI 0.3–0.8). From the obtained data, a prognostic index was constructed, dividing the patients into three risk groups: good (n = 40), intermediate (n = 36) and poor risk group (n = 56). The median survival for good, intermediate and poor risk groups were 13.5, 6.0 and 2.9 months, respectively, whereas the 1-year OS rates were 50.2%, 14.2% and 2.6%, respectively (P = 0.00001).ConclusionsWith inadequate data from randomized controlled trials at the moment, our report indicates that second-line chemotherapy is effective and beneficial in patients with good performance status, higher Hb level along with higher TTP under first-line therapy.     

Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer

BackgroundThe randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61–0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL).Patients and methodsPatients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety.ResultsOf the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59–1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68–1.05) or OS (HR = 0.96, 95% CI 0.76–1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected.ConclusionsIn this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life.ClinicalTrials.govNCT01250379.     

S-1 and Gemcitabine as an Outpatient-based Regimen in Patients with Advanced or Metastatic Pancreatic Cancer

Objective: The standard beneficial chemotherapy proved for patients withpancreatic cancer is a regimen containing gemcitabine. Noveloral fluoropyrimidine, S-1, can be added to gemcitabine to improvethe efficacy of chemotherapy and to provide better conveniencefor patients. We aimed to evaluate the efficacy and safety ofS-1 plus gemcitabine combination chemotherapy as a first-linetreatment in patients with locally advanced or metastatic pancreaticcancer. Methods: Patients with histologically confirmed, bidimensionally measurableadvanced/metastatic pancreatic cancer were eligible for thestudy. Chemotherapy consisted of S-1 (30 mg/m² p.o. bid fromDay 1 to 14) and gemcitabine (1000 mg/m² on Days 8 and 15) every3 weeks based on the results of a previously reported PhaseI trial. Treatment was repeated until disease progression orunacceptable toxicity occurred. Results: From January 2005 to August 2007, 22 patients were enrolled.Median age was 62 years (range, 50–73). Nineteen patients(86.3%) had metastases and of these, 11 patients (57.9%) hadmultiple liver metastases. The overall response rate was 27.3%(95% CI, 8.7–45.9), with a partial response in six patients,stable disease in nine (40.9%) and progressive disease in seven(31.8%). With a median follow-up of 25.4 months, the mediantime to progression and overall survival were 4.6 (95% CI, 2–7.2months) and 8.5 months (95% CI, 6.8–10.1 months), respectively,and 1-year survival rate was 27.3%. S-1 plus gemcitabine waswell tolerated. Grade 3/4 hematological adverse events wereneutropenia (9.1/9.1%) and anemia (4.5/0%). Non-hematologicaladverse events were mainly gastrointestinal events. Twenty patients(91%) received chemotherapy on an outpatient basis. Conclusions: Combination chemotherapy of S-1 plus gemcitabine appears tobe active and well tolerated as first-line treatment in patientswith advanced/metastatic pancreatic cancer.     

Treatments of pancreatic cancer from the standpoint of medical oncology

The early diagnosis of pancreatic cancer is difficult because of the lack of specific early symptoms,and surgery with curative intent can be performed in only 20% of patients. Chemotherapy for unresectable pancreatic cancer has been advancing ever since gemcitabine (GEM) was confirmed to provide a survival advantage in patients with advanced pancreatic cancer. For more than 20 years, the standard treatment for locally advanced diseases has been chemoradiotherapy using 5-FU, but more effective chemotherapy regimens are required. New standard treatments for locally advanced pancreatic cancer, including GEM chemotherapy and chemoradiotherapy using new agents, should be investigated. Several randomized clinical trials comparing GEM-based chemotherapy and GEM alone for the treatment of unresectable pancreatic cancer have been conducted, but a new standard chemotherapy regimen superior to GEM alone has not established. In Japan, phase II studies of S-1 or a combination of GEM and S-1 have produced promising survival rates, and a large phase III study using GEM and S-1 is necessary to establish the standard chemotherapy. Furthermore, second-line chemotherapy regimens for use after GEM chemotherapy should be investigated to improve the survival of patients with advanced pancreatic cancer.     

A phase 3 randomized,double-blind,placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial

This double-blind, phase 3 study assessed the efficacy and safety of ganitumab plus gemcitabine as first-line treatment of metastatic pancreatic cancer. The study was stopped after a preplanned futility analysis indicated a positive outcome was unlikely at primary analysis. Ganitumab plus gemcitabine had manageable toxicity but did not improve OS versus gemcitabine alone in unselected patients.BackgroundThis double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer.Patients and methodsPatients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m² (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers.ResultsOverall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77–1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab.ConclusionGanitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer.Clinical trial registrationClinicalTrials.gov NCT01231347.     

Results from the prospective German TPK clinical cohort study: Treatment algorithms and survival of 1,174 patients with locally advanced,inoperable, or metastatic pancreatic ductal adenocarcinoma

Pancreatic cancer is a highly lethal malignancy. Developments in recent years have broadened our therapeutic armamentarium. Novel drugs such as nab-paclitaxel, liposomal irinotecan and chemotherapy regimens such as FOLFIRINOX have been successfully tested in clinical trials. Data on patients outside of clinical trials are scarce but necessary to assess and improve the standard of care. We present data on treatment and survival of 1,174 patients with locally advanced, inoperable, or metastatic pancreatic ductal adenocarcinoma. Between February 2014 and June 2017, patients were recruited by 104 sites at start of first-line therapy into the ongoing, prospective clinical cohort study TPK (Tumour Registry Pancreatic Cancer). As first-line therapy, 89% of patients received one of the three treatment regimens: gemcitabine monotherapy (23%), nab-paclitaxel plus gemcitabine (42%), or FOLFIRINOX (24%). The corresponding subgroups differed: Patients receiving gemcitabine monotherapy were older and more comorbid (median age 78 years, 73% ECOG ≥ 1) than patients receiving nab-paclitaxel plus gemcitabine (median age 71, 64% ECOG ≥ 1) or patients receiving FOLFIRINOX (median age 60, 52% ECOG ≥ 1). At least 40% of patients died before receiving second-line treatment. First-line progression-free survival was 4.6 months (95% CI: 3.7–5.2) for gemcitabine, 5.6 months (95% CI: 5.0–6.2) for nab-paclitaxel plus gemcitabine, and 6.3 months (95% CI: 5.5–6.9) for FOLFIRINOX. Our data represent the treatment reality in a German community setting. Although there are no stringent inclusion criteria for our cohort study, overall survival is comparable to that reported by randomised clinical trials.     

A multicenter phase II study of gemcitabine and S-1 combination chemotherapy in patients with unresectable pancreatic cancer

Purpose

To confirm the efficacy and toxicity of gemcitabine and S-1 combination chemotherapy when used as a first-line therapy in patients with unresectable pancreatic cancer.

Methods

Patients with locally advanced or metastatic or recurrent pancreatic adenocarcinoma, which was histologically or cytologically proven, with at least one measurable lesion were eligible for the study. Gemcitabine at a dose of 1,000 mg/m² was intravenously given over 30 min on days 1 and 8, while S-1 at a dose of 40 mg/m² was orally given twice daily from day 1 to 14, and the cycle was repeated every 3 weeks. The objective response rate, which was assessed according to RECIST criteria, was the primary end point.

Results

A total of 38 patients were enrolled between June 2006 and June 2007. The median number of treatment courses was 5.5 (range 1–22). Thirty-four patients were evaluable for response. Although no complete response was seen, partial responses were achieved in 11 patients, resulting in an overall response rate of 32% [95% confidence interval (CI) 17–48%]. The median response duration was 6.0 months (95% CI 4.6–8.3 months), the median time-to-progression was 5.4 months (95% CI 2.9–8.0 months), and the median overall survival was 8.4 months (95% CI 5.7–11.1 months). The major grade 3/4 hematologic toxicities were neutropenia (39.5%), leukopenia (15.8%), thrombocytopenia (2.6%), and anemia (7.9%). The major grade 3/4 non-hematologic toxicities included anorexia (10.5%), stomatitis (2.6%), rash (7.9%), fatigue (7.9%) and hyperbilirubinemia (5.3%).

Conclusions

Gemcitabine and S-1 combination chemotherapy was effective and tolerable in patients with unresectable pancreatic cancer.     

Phase II trial of gemcitabine and S-1 for patients with advanced pancreatic cancer

Purpose

To evaluate the efficacy and safety of combined gemcitabine and S-1 as first-line chemotherapy for patients with locally advanced or metastatic pancreatic cancer.

Methods

This study included patients who had been diagnosed with unresectable, locally advanced or metastatic adenocarcinoma arising from the pancreas, which was histologically or cytologically confirmed and involved at least 1 unidimensionally measurable lesion. The regimen consisted of intravenous 1,000 mg/m² gemcitabine on day 1 and 8 combined with oral S-1 on days 1–14 every 21 days. The dosage of S-1 was based on the body surface area (BSA) as follows: 40 mg bid (total 80 mg/day) for a BSA of <1.25, 50 mg bid (total 100 mg/day) for a BSA of ≥1.25 but <1.5, and 60 mg bid (total 120 mg/day) for a BSA of ≥1.5. Treatment consisted of at least 2 courses unless rapid disease progression was noted. The primary end points were the response and disease control rates, and the secondary end points were toxicity and survival.

Results

Thirty-seven patients were enrolled between August 2005 and December 2010. The median number of chemotherapy cycles was 4 (range 1–28 cycles). Response to treatment could be evaluated in 31 patients. None of the patients showed complete response, but 5 achieved partial response. The response rate was thus 13.5 % [95 % confidence interval (CI) 2.7–24.3 %] in the intent-to-treat population. Sixteen patients (43.2 %; 95 % CI 27–59.5 %) showed stable disease, and the overall disease control rate was 56.8 % (95 % CI 40.6–72.9 %). For all 37 patients, the median progression-free survival was 4.6 months (95 % CI 1.8–7.6 month), and the median overall survival was 9.4 month (95 % CI 5.8–12.6 month). Chemotherapy-related grade 3/4 hematological toxicities were neutropenia (36.1 %), leucopenia (22.2 %), and anemia (13.9 %). The non-hematological toxicities were generally mild.

Conclusions

Combination chemotherapy with gemcitabine and S-1 was effective, convenient, and safe in patients with advanced pancreatic cancer.     

Role of gemcitabine as second-line therapy after progression on FOLFIRINOX in advanced pancreatic cancer: a retrospective analysis

Background

Cancer of the exocrine pancreas is a highly lethal malignancy. Surgical resection is the only potentially curative treatment. Unfortunately, because of the late presentation, the majority have either locally advanced cancer at initial diagnosis. Systemic chemotherapy provides benefit to patients with advanced pancreatic cancer, improving disease-related symptoms and survival when compared to best supportive care alone. Based on fase III study, FOLFIRINOX regimen became the standard first-line treatment. But, the optimal management strategy for patients who fail initial FOLFIRINOX is undefined. Despite the lack of clinical trials that report the real benefit of gemcitabine in patients with advanced exocrine pancreatic cancer as second line treatment. We aim at reporting our experience with this regimen.

Methods

Patients with advanced exocrine pancreatic cancer who received gemcitabine (1.000 mg/m² on days 1, 8 and 15 every 4 weeks) until disease progression, as second-line therapy at our institution were retrospectively evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method.

Results

A total of 20 patients were reviewed. Median age was 57 years (range, 43-74 years), and 55% were older than 60 years. Most patients were male (80%), had metastatic disease (60%), and ECOG performance status of 0 or 1 (65%). PFS and OS were 2.0 (95% CI, 1.2-2.8) and 5.7 months (95% CI, 3.9-7.4), respectively. There were no deaths due to the treatment.

Conclusions

In this study, gemcitabine was a reasonable second-line treatment option for patients with advanced pancreatic adenocarcinoma and good ECOG performance status. Phase III trials are urgently needed comparing gemcitabine versus best supportive of care (BSC) can evaluate the real benefit of this chemotherapy after progression on FOLFIRINOX.     

Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan Clinical Oncology Group Trial JCOG9912

BackgroundSince the best chemotherapy regimen for each patient with advanced gastric cancer is uncertain, we aimed to identify molecular prognostic or predictive biomarkers from biopsy specimens in JCOG9912, a randomized phase III trial for advanced gastric cancer.Patients and methodsEndoscopic biopsy specimens from primary lesions were collected in 445 of 704 randomized patients in JCOG9912. We measured the mRNA expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase, dihydropyrimidine dehydrogenase, and five other genes, then, categorized them into low and high groups relative to the median, and examined whether gene expression was associated with efficacy end point.ResultsMultivariate analyses showed that high ERCC1 expression [HR 1.37; 95% confidence interval (CI) 1.08–1.75; P = 0.010], performance status ≥1 (HR 1.45; 95% CI 1.13–1.86; P = 0.004), and number of metastatic sites ≥2 (HR 1.66; 95% CI 1.28–1.86; P < 0.001) were associated with a poor prognosis, and recurrent disease (versus unresectable; HR 0.75; 95% CI 0.56–1.00; P = 0.049) was associated with a favorable prognosis. None of these molecular factors were a predictive marker for choosing irinotecan plus cisplatin or 5-fluorouracil rather than S-1.ConclusionThese correlative analyses suggest that ERCC1 is an independent prognostic factor for overall survival in the first-line treatment of gastric cancer.Clinical Trial NumberC000000062, www.umin.ac.jp.     

Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05)

BackgroundIn Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC.Patients and methodsPatients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40–60 mg/m²) on days 1–14 and intravenous irinotecan (150 mg/m²) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS).ResultsFrom February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78–1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group.ConclusionThe consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy.Clinical Trials.govNCT00639327.     

A feasibility study of gemcitabine,S-1 and leucovorin combination therapy (GSL) for advanced biliary tract cancer

Objective: Gemcitabine and cisplatin (GC) combination chemotherapy is the current standard of care for patients with advanced biliary tract cancer (BTC). Recently, a randomized controlled trial showed the non-inferiority in overall survival of gemcitabine and S-1 (GS) compared to GC. Because leucovorin is known to enhance the activity of S-1, we conducted this study to evaluate the feasibility of combination therapy of gemcitabine, S-1 and leucovorin (GSL). Methods: Advanced BTC patients without prior treatment other than surgery or adjuvant chemotherapy were eligible to this study. Gemcitabine was administered at a dose of 1000?mg/m² on day 1, and oral S-1 at a dose of 40?mg/m² and oral leucovorin at a dose of 25?mg twice daily on days 1–7, every 2?weeks. The primary endpoint was PFS and the secondary endpoints included OS, objective tumour response and the safety. Results: Between June 2013 and December 2015, 20 patients with advanced BTC (12 gallbladder, 4 extrahepatic, 2 intrahepatic, 2 ampulla) including 16 unresectable disease and 4 recurrent disease were enroled. The median PFS and OS were 5.5 (95% confidence interval [CI], 1.8 – not reached) and 16.0 (95% CI, 6.4–20.8) months, respectively. A partial response was achieved in 3 (15%) and stable disease in 8 (40%), giving a disease control rate of 55%. Major grade 3/4 toxicities included neutropenia (30%), anaemia (5%), stomatitis (15%), diarrhoea (15%) and anorexia (10%). There were no treatment-related deaths. Conclusions: This study showed the feasibility and potential efficacy of GSL as a first-line treatment in patients with advanced BTC.     

Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis

BackgroundMany patients with refractory or relapsed gastric cancer after first-line chemotherapy have received salvage chemotherapy in routine clinical practice. However, there was no evidence to support this treatment until recent phase III trials demonstrated substantial prolongation of overall survival. Therefore, we conducted a meta-analysis of these trials and investigated whether second-line chemotherapy was more effective than best supportive care.Patients and methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2013), MEDLINE (1950 to March week 4, 2013) and EMBASE (1980–2013, week 13). In addition, we searched all abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences held between 2004 and 2013.ResultsThe search process yielded 578 studies, two of which were randomized phase III trials that compared chemotherapy with supportive care. From the abstracts and virtual meeting presentations of ASCO held between 2004 and 2013, 127 abstracts were identified that evaluated second-line chemotherapy; only one relevant abstract was included in the meta-analysis.A total of 410 patients were eligible for analysis, of whom 150 received docetaxel chemotherapy, and 81 received irinotecan chemotherapy. A significant reduction in the risk of death [HR = 0.64, 95% confidence interval (CI) 0.52–0.79, P < 0.0001] was observed with salvage chemotherapy.When the analysis was restricted to irinotecan or docetaxel, there was still significant reduction in the risk of death with each chemotherapeutic agent. The HR was 0.55 (95% CI 0.40–0.77, P = 0.0004) for irinotecan and 0.71 (95% CI 0.56–0.90, P = 0.004) for docetaxel.ConclusionThis meta-analysis demonstrated evidence to support second-line chemotherapy in advanced gastric cancer.     

Survival prolongation after treatment failure of first-line chemotherapy in patients with advanced gastric cancer: combined analysis of the Japan Clinical Oncology Group Trials JCOG9205 and JCOG9912

Background

Two randomized phase III trials of first-line chemotherapy for advanced gastric cancer (JCOG9205 and JCOG9912) conducted by the Japan Clinical Oncology Group used 5-fluorouracil continuous infusion (5-FUci) as the control arm. New active agents (e.g., S-1, irinotecan, and taxanes) were introduced as second-line chemotherapy in the late 1990s after JCOG9205. This combined analysis evaluated whether patients in the 5-FUci arm of JCOG9912 exhibited better survival after adjusting for baseline factors and also investigated the cause of survival prolongation.

Patients and methods

The subjects were patients assigned to the 5-FUci arms who met the eligibility criteria of both JCOG9205 and JCOG9912. Overall survival (OS), time to treatment failure (TTF), and survival after treatment failure in the first-line chemotherapy (OS-TTF) were compared after adjusting baseline characteristics using the Cox proportional hazard model. Second-line chemotherapy details were also reviewed.

Results

The combined analysis included 89 and 230 patients in JCOG9205 and JCOG9912, respectively. After adjusting baseline characteristics, TTF was similar between groups (HR 0.95; 95 % CI, 0.73–1.26). However, both OS (HR, 0.74; 95 % CI, 0.56–0.99) and OS-TTF (HR, 0.76; 95 % CI, 0.57–1.01) were longer in JCOG9912. More patients in JCOG9912 received second-line chemotherapy (83 vs. 52 %) with new drugs (77 vs. 10 %) than in JCOG9205. OS-TTF was substantially prolonged in patients who received second-line chemotherapy (HR, 0.66; 95 % CI, 0.46–0.95).

Conclusion

OS and OS-TTF were longer in JCOG9912 than JCOG9205. Second-line chemotherapy with new drugs is a potential reason for the observed prolongation of survival.