Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0 - 1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78-1.15; P = 0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months with GS (HR 0.86; 95% CI 0.70-1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

This study analyzed outcomes of systemic chemotherapy for advanced neuroendocrine carcinoma (NEC) of the digestive system. Clinical data from 258 patients with unresectable or recurrent NEC of the gastrointestinal tract (GI) or hepato‐biliary‐pancreatic system (HBP), who received chemotherapy, were collected from 23 Japanese institutions and analyzed retrospectively. Patients had primary sites in the esophagus (n = 85), stomach (n = 70), small bowel (n = 6), colorectum (n = 31), hepato‐biliary system (n = 31) and pancreas (n = 31). Median overall survival (OS) was 13.4 months the esophagus, 13.3 months for the stomach, 29.7 months for the small bowel, 7.6 months for the colorectum, 7.9 months for the hepato‐biliary system and 8.5 months for the pancreas. Irinotecan plus cisplatin (IP) and etoposide plus cisplatin (EP) were most commonly selected for GI‐NEC and HBP‐NEC. For patients treated with IP/EP (n = 160/46), the response rate was 50/28% and median OS was 13.0/7.3 months. Multivariate analysis among patients treated with IP or EP showed that the primary site (GI vs HBP; hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.35–0.97) and baseline serum lactate dehydrogenase levels (not elevated vs elevated; HR 0.65, 95% CI 0.46–0.94) were independent prognostic factors for OS, while the efficacy of IP was slightly better than for EP (HR 0.80, 95% CI 0.48–1.33; P = 0.389). IP and EP are the most common treatment regimens for NEC of the digestive system. HBP primary sites and elevated lactate dehydrogenase levels are unfavorable prognostic factors for survival. A randomized controlled trial is required to establish the appropriate chemotherapy regimen for advanced NEC of the digestive system. This study was registered at UMIN as trial number 000005176.

The combination chemotherapy consisting of cisplatin and etoposide, one of the standard regimens for small cell lung cancer, has been widely used to treat extrapulmonary poorly differentiated neuroendocrine carcinomas. However, there were no prior reports limited to the hepatobiliary tract and pancreas as the primary sites. We reviewed the cases in our database from October 1995 to January 2009 and retrospectively examined the clinical data of patients, with unresectable or recurrent poorly differentiated neuroendocrine carcinoma arising from the hepatobiliary tract and pancreas, who received combination chemotherapy with cisplatin and etoposide as the first-line treatment. The chemotherapy regimen consisted of cisplatin 80 mg/m² given intravenously on day 1 and etoposide 100 mg/m² intravenously on days 1–3, repeated every 3–4 weeks. Twenty-one patients were treated with the above regimen of cisplatin and etoposide combination chemotherapy. The primary tumor site was the liver in 2 patients, gallbladder in 8 patients, pancreas in 10 patients and ampulla of Vater in 1 patient. Although no complete responses were obtained, three patients had partial responses, resulting in an overall response rate of 14%. Median progression-free survival was 1.8 months, and median overall survival was 5.8 months. The major adverse events were myelosuppression and gastrointestinal toxicities, with Grade 3 or 4 neutropenia (90%), nausea (33%) and anorexia (24%). Cisplatin and etoposide combination as the first-line chemotherapy for hepatobiliary or pancreatic poorly differentiated neuroendocrine carcinoma had only marginal antitumor activity and relatively severe toxicity compared with previous studies on extrapulmonary poorly differentiated neuroendocrine carcinoma treated with the same regimen.

Importance: Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for advanced neuroendocrine carcinoma (NEC).Objective: To identify whether EP or IP is a more effective regimen in terms of overall survival (OS) in patients with advanced NEC of the digestive system.Design, Setting, and Participants: This open-label phase 3 randomized clinical trial enrolled chemotherapy-naive patients aged 20 to 75 years who had recurrent or unresectable NEC (according to the 2010 World Health Organization classification system) arising from the gastrointestinal tract, hepatobiliary system, or pancreas. Participants were enrolled across 50 institutions in Japan between August 8, 2014, and March 6, 2020.Interventions: In the EP arm, etoposide (100 mg/m²/d on days 1, 2, and 3) and cisplatin (80 mg/m²/d on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m²/d on days 1, 8, and 15) and cisplatin (60 mg/m²/d on day 1) were administered every 4 weeks.Main Outcomes and Measures: The primary end point was OS. In total, data from 170 patients were analyzed to detect a hazard ratio (HR) of 0.67 (median OS of 8 and 12 months in inferior and superior arms, respectively) with a 2-sided α of 10% and power of 80%. The pathologic findings were centrally reviewed following treatment initiation.Results: Among the 170 patients included (median [range] age, 64 [29-75] years; 117 [68.8%] male), median OS was 12.5 months in the EP arm and 10.9 months in the IP arm (HR, 1.04; 90% CI, 0.79-1.37; P = .80). The median progression-free survival was 5.6 (95% CI, 4.1-6.9) months in the EP arm and 5.1 (95% CI, 3.3-5.7) months in the IP arm (HR, 1.06; 95% CI, 0.78-1.45). A subgroup analysis of OS demonstrated that EP produced more favorable OS in patients with poorly differentiated NEC of pancreatic origin (HR, 4.10; 95% CI, 1.26-13.31). The common grade 3 and 4 adverse events in the EP vs IP arms were neutropenia (75 of 82 [91.5%] patients vs 44 of 82 [53.7%] patients), leukocytopenia (50 of 82 [61.0%] patients vs 25 of 82 [30.5%] patients), and febrile neutropenia (FN) (22 of 82 [26.8%] patients vs 10 of 82 [12.2%] patients). While incidence of FN was initially high in the EP arm, primary prophylactic use of granulocyte colony-stimulating factor effectively reduced the incidence of FN.Conclusions and Relevance: Results of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although AEs were generally manageable, grade 3 and 4 AEs were more common in the EP arm.Trial Registration: Japan Registry of Clinical Trials: jRCTs031180005; UMIN Clinical Trials Registry: UMIN000014795