Background: Gemcitabine/cisplatin (GC) combination therapy has been the standard palliative chemotherapy for patients with advanced biliary tract cancer (BTC). No randomized clinical trials have been able to demonstrate the survival benefit over GC during the past decade. In our previous phase II trial, adding S‐1 to GC (GCS) showed promising efficacy and we aimed to determine whether GCS could improve overall survival compared with GC for patients with advanced BTC.Methods: We performed a mulitcenter, randomized phase III trial across 39 centers. Enrolled patients were randomly allocated (1:1) to either the GCS or GC arm. The GCS regimen comprised gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) infusion on day 1 and 80 mg/m² of S‐1 on days 1–7 every 2 weeks. The primary endpoint was overall survival (OS) and the secondary endpoints were progression‐free survival (PFS), response rate (RR), and adverse events (AEs). This study is registered with Clinical trial identification: NCT02182778.Results: Between July 2014 and February 2016, 246 patients were enrolled. The median OS and 1‐year OS rate were 13.5 months and 59.4% in the GCS arm and 12.6 months and 53.7% in the GC arm, respectively (hazard ratio [HR] 0.79, 90% confidence interval [CI]: 0.628–0.996; P = .046 [stratified log‐rank test]). Median PFS was 7.4 months in the GCS arm and 5.5 months in the GC arm (HR 0.75, 95% CI: 0.577–0.970; P = .015). RR was 41.5% in the GCS arm and 15.0% in the GC arm. Grade 3 or worse AEs did not show significant differences between the two arms.Conclusions: GCS is the first regimen which demonstrated survival benefits as well as higher RR over GC in a randomized phase III trial and could be the new first‐line standard chemotherapy for advanced BTC. To exploit the advantage of its high RR, GCS is now tested in the neoadjuvant setting in a randomized phase III trial for potentially resectable BTC.

Cancer originating in the biliary tract can be classified as bile duct cancer (cholangiocarcinoma), gallbladder cancer, or ampullary cancer. Bile duct cancer is further divided to intrahepatic, perihilar and distal bile duct subtypes according to the anatomical location of the tumor. The biological characteristics of each tumor are heterogeneous. However, because of the rarity of each disease, the efficacy of new drugs has been tested in groups of patients with different biliary tract cancers. In patients with metastatic or recurrent biliary tract cancer, recent randomized clinical trials revealed the non-inferiority of gemcitabine + S-1 and the superiority of gemcitabine + cisplatin + S-1 compared with gemcitabine + cisplatin in terms of overall survival, thereby establishing a new standard treatment. In the field of adjuvant therapy for biliary tract cancer, the British BILCAP (capecitabine compared with observation in resected biliary tract cancer) study revealed longer median overall survival in the capecitabine group than in the observation group in the per-protocol analysis (but not in the intention-to-treat analysis), bringing a shift toward postoperative management. Several other studies of adjuvant therapy are ongoing, and they may lead to reforms in treatment strategy for resectable biliary tract cancer in the future. The use of neoadjuvant therapy for biliary tract cancer is in its infancy, but it is expected to overcome the limitations of adjuvant therapy for this malignancy. In this review, we summarized the evidence available from clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and described ongoing clinical trials.

Background: Chemoradiotherapy is a treatment option for locally advanced pancreatic cancer. However, the efficacy of induction chemotherapy prior to chemoradiotherapy is uncertain. The aim of this randomized, multicentre phase II study is to evaluate the efficacy and safety of chemoradiotherapy with and without induction chemotherapy to determine the significance of induction chemotherapy. Methods: Patients with locally advanced pancreatic cancer were randomly assigned to the chemoradiotherapy arm (Arm A) or induction chemotherapy followed by the chemoradiotherapy arm (Arm B). Patients in Arm A underwent radiotherapy with concurrent S-1. Patients in Arm B received induction gemcitabine for 12 weeks, and thereafter, only patients with controlled disease underwent the same chemoradiotherapy as Arm A. After chemoradiotherapy, gemcitabine was continued until disease progression or unacceptable toxicity in both arms. The primary endpoint was overall survival. Results: Amongst 102 patients enrolled, 100 were eligible for efficacy assessment. The probability of survival was greater in Arm B in the first 12 months, but the trend was reversed in the following periods (1-year survival 66.7 vs. 69.3%, 2-year survival 36.9 vs. 18.9%). The hazard ratio was 1.255 (95% confidence interval 0.816–1.930) in favour of Arm A. Gastrointestinal toxicity was slightly more frequent and three treatment-related deaths occurred in Arm A. Conclusions: This study suggested that the chemoradiotherapy using S-1 alone had more promising efficacy with longer-term survival, compared with induction gemcitabine followed by chemoradiotherapy for locally advanced pancreatic cancer. Clinical trial registration: The study was registered at the UMIN Clinical Trials Registry as UMIN000006811.

Because pancreatic cancer has a dismal prognosis, a strategy for early diagnosis is required. This study aimed to identify predictive factors of neoplastic progression in patients at high risk for pancreatic cancer and examined the efficiency of surveillance using transabdominal special ultrasonography focusing on the pancreas (special pancreatic US). Patients with slight main pancreatic duct (MPD) dilatation (≥2.5 mm) and/or pancreatic cysts (≥5 mm) were enrolled in a prospective surveillance study with special pancreatic US in a Japanese cancer referral center. A total of 498 patients undergoing surveillance for ≥3 years were included. During the median follow-up of 5.9 years, neoplastic progression developed in 11 patients (2.2%), including 9 patients who underwent pancreatectomy. Eight patients (72.7%) were diagnosed with stage 0/I disease, with an overall survival duration of 8.8 years. Findings of both MPD dilatation and pancreatic cysts at initial surveillance, MPD growth (≥0.2 mm/year) and cyst growth (≥2 mm/year) during surveillance were identified as independent risk factors for neoplastic progression. In summary, surveillance with special pancreatic US for high-risk individuals contributed to earlier detection of neoplastic progression, leading to a favorable prognosis. During surveillance, attention should be paid to MPD growth as well as to cyst growth.

Nanoliposomal irinotecan (nal-IRI) was recently authorized in Japan for unresectable pancreatic cancer after disease progression following chemotherapy. Physicians now consider certain aspects of nal-IRI safety profile as slightly different from conventional irinotecan. This report aims to explore additional aspects of the nal-IRI safety in Japanese phase 2 study. We analyzed the incidence, time to first onset, and time to resolution for adverse events that require special attention and other selected toxicities in the nal-IRI combination group (n = 46). Leukopenia/neutropenia (76.1%/71.7%), diarrhea (58.7%) and hepatic dysfunction (41.3%) were the most commonly reported treatment-emergent adverse events, with a median time to onset of 21.0 days (range: 8, 97), 9.0 days (1, 61) and 22.0 days (2, 325), respectively, and a median time to resolution of 8.0 days (95% confidence intervals: 8, 9), 4.0 days (4, 8) and 40.0 days (9, –), respectively. Eight patients experienced Grade ≥ 3 diarrhea and their symptoms were well controlled by dose modification except one patient who had drug withdrawal. The median time to resolution for Grade ≥ 3 and Grade ≤ 2 diarrhea was 17.5 days (95% confidence intervals: 1, 31) and 4 days (3, 7), respectively. Anorexia occurred in 28/46 patients (60.9%) with a median time to onset of 4.0 days (range: 2, 132) and a median time to resolution of 12.0 days (95% confidence intervals: 6, 26). We explored safety profile of nal-IRI combination regimen recognized as effective and tolerable treatment for Japanese unresectable pancreatic cancer patients. Although the treatment-emergent adverse events occurred were controllable, patients with prolonged toxicities should be closely managed.