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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. 16.9 months in non-MH (hazard ratio, 0.857; 95% CI 0.387-1.899)], and GS [median OS, 21.5 vs. 14.9 months (hazard ratio, 0.670; 95% CI 0.310-1.447)] arms. CONCLUSIONS: The safety and efficacy of gemcitabine-based chemotherapy were comparable between patients who underwent MH and those who underwent other surgeries.

5-Fluorouracil metabolic pathway genes predict recurrence risk following adjuvant S-1 therapy: Results of an ancillary analysis from a phase III trial of resected biliary tract cancer (JCOG1202A1).

BACKGROUND: S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy for resected biliary tract cancer (BTC), based on the results of the JCOG1202, a phase III trial evaluating the survival benefit with adjuvant S-1 following curative resection for BTC compared to surgery alone. This multicenter ancillary study of the JCOG1202 aimed to evaluate the prognostic impact of the 5-fluorouracil (5-FU) metabolic pathway genes including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). METHODS: The 5-FU metabolic pathway genes were measured in tumor cells from formalin-fixed paraffin-embedded resected specimens from 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89). We randomly divided them into training (n = 96) and validation sets (n = 87) for evaluating the interaction between gene levels and RFS benefits in the treatment arm. RESULTS: RFS benefits of adjuvant S-1 were observed in the low DPD (HR = 0.440 and 0.748, respectively in the training and validation sets) and the low TP groups (HR = 0.709 and 0.602, respectively). Clinicopathological characteristics were well balanced between low and high DPD populations. More advanced stage tumors were observed in high TP populations as compared to those in low TP populations (p = .0332). CONCLUSION: The results suggest the RFS benefit of adjuvant S-1 in resected BTC patients with low DPD and low TP gene expressions.

Real-world data of anamorelin in advanced gastrointestinal cancer patients with cancer cachexia.

BACKGROUND: Cancer cachexia is characterized by the loss of body weight (BW) and anorexia. Anamorelin (ANAM) is a selective ghrelin receptor agonist with appetite-enhancing anabolic action. The ONO-7643-05 trial demonstrated that ANAM increased lean body mass and improved anorexia in a Japanese population. However, the clinical outcomes of patients on ANAM have not yet been reported. PATIENTS AND METHODS: We investigated the clinical outcomes of patients with unresectable, advanced, or recurrent gastrointestinal cancer (colorectal, gastric, or pancreatic cancer) who were treated with ANAM between April 2017 and August 2022. Cachexia was defined as the presence of anorexia and a loss of ≥ 5% of BW within 6 months. To evaluate the response to ANAM, the patients who had discontinued ANAM within 3 weeks were excluded. Response to ANAM was defined as maintenance of or increase in BW and improved appetite from baseline at every 3-week evaluation. We also collected data on the reasons for the discontinuation of ANAM and the correlation between clinical factors and ANAM response. Safety analysis of ANAM was performed for all patients who received ANAM. RESULTS: Seventy-four patients were included in this study (49 males and 25 females), with a median age of 67.1 years (range, 36-83). The primary tumors were colorectal cancer in 27 (36.5%), gastric cancer in 20 (27.0%), and pancreatic cancer in 27 (36.5%). The Eastern Cooperative Oncology Group performance status was 0 in 10 (13.5%), 1 in 44 (59.5%), and ≥ 2 in 20 (27.0%). The number of previous chemotherapy regimens was 0 in 20 (27.0%), 1 in 22 (29.7%), and ≥ 2 in 32 (43.2%). ANAM was discontinued within 3 weeks in 28 patients for the following reasons: low-grade (grade 1 or 2) adverse events in 15 patients, ileus in three, grade 3 fatigue in one, progressive disease in one, censored follow-up in six, and unknown reasons in three. The proportion of ANAM responders was 63.6% (95% confidence interval, 47.8-77.6%). Among baseline characteristics, age ≥ 75 attenuated the ANAM response (p = 0.03). ANAM responders showed better disease control with chemotherapy than non-responders (75.0% vs. 37.5%, p = 0.02). CONCLUSIONS: ANAM may improve the outcomes of patients with gastrointestinal cancer cachexia in clinical practice.

Two Japanese families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A: a case report.

BACKGROUND: Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM) (OMIM #155,601), which is associated with an increased risk of pancreatic ductal adenocarcinoma and melanoma. FAMMM has been reported globally, but it is quite rare in Japan. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling. CASE PRESENTATION: The first case is a 74-year-old woman with a diagnosis of pancreatic carcinoma with multiple liver metastases. She had family histories of pancreatic cancer, but no personal or family history of malignant melanoma. Whole exon sequencing detected a germline CDKN2A variant evaluated as likely pathogenic. The results were disclosed to her daughters after she died, and the same CDKN2A variant was detected in one of the daughter. The daughter was referred to a nearby hospital for her clinical management. The second case is a 65-year-old man with pancreatic ductal adenocarcinoma. He had family histories of pancreatic cancer, but no personal or family history of malignant melanoma. He underwent a comprehensive genomic profiling test using pancreatic cancer tissue, and detected a presumed germline pathogenic variant of CDKN2A. Germline testing confirmed the same CDKN2A variant. Genetic analysis of his relatives produced negative results. Other blood relatives are scheduled for genetic analysis in the future. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling. CONCLUSIONS: In current Japanese precision medicine, comprehensive genetic analysis can reveal rare genetic syndromes and offer us the opportunity to provide health management for patients and their relatives. However, gene-specific issues are raised in terms of the evaluation of a variant's pathogenicity and the extent of surveillance of the at-risk organs due to a lack of genetic and clinical data concerning CDKN2A variant carriers in Japan.

A Phase II Placebo-Controlled Study of the Effect and Safety of Nanvuranlat in Patients with Advanced Biliary Tract Cancers Previously Treated by Systemic Chemotherapy.

PURPOSE: To evaluate the efficacy and safety of nanvuranlat [an L-type amino acid transporter 1 inhibitor] monotherapy as a later-line treatment in advanced, metastatic, and refractory biliary tract cancers. PATIENTS AND METHODS: A multicenter, randomized, double-blind, placebo-controlled phase II study was conducted across fourteen leading Japanese cancer centers and hospitals. Nanvuranlat 25 mg/m2/day or placebo was given intravenously in cycles of 5 consecutive days, followed by 9 days off. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and disease control rate. Subgroup analysis was performed in patients with high L-type amino acid transporter 1 expression and biliary tract cancer subtypes. RESULTS: A total of 211 patients were screened, of which 105 eligible patients were randomized. Among these, 70 received nanvuranlat and 35 received placebo. Nanvuranlat demonstrated an improvement in PFS when compared with placebo (HR, 0.56; 95% confidence interval, 0.34-0.90; P = 0.02). Grade 3 or higher adverse events were reported in 30.0% and 22.9% of those in the nanvuranlat and placebo groups, respectively. The overall survival was not statistically different between nanvuranlat- and placebo-treated patients. An exploratory analysis indicated that nanvuranlat is warranted to evaluate its long-term clinical benefit in patients with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer. CONCLUSIONS: Compared with placebo, nanvuranlat improved PFS in patients with advanced and refractory biliary tract cancer with an acceptable safety profile. Further studies of this promising compound are warranted in the population of patients who are exhausted from treatment options.

The response of pancreatic acinar cell carcinoma to platinum and olaparib therapy in a germline BRCA2 variant carrier: case report and literature review.

A 73-year-old Japanese man with a history of distal biliary cancer treated by pancreatoduodenectomy developed pancreatic acinar cell carcinoma (PACC) treated by remnant pancreatectomy and adjuvant chemotherapy. Thirteen months after surgery, multiple liver metastases developed and FOLFOX chemotherapy was initiated. Based on the PACC diagnosis and a positive family history for breast and ovarian cancer genetic testing was performed which revealed a pathogenic germline BRCA2 variant (c.8629G > T, p.Glu2877Ter). Olaparib therapy was initiated and the metastases responded well (partial response). PACC is a BRCA2-associated cancer which may respond well to PARP inhibitors.

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

BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

FOLFIRINOX in Pancreatic Cancer: Risk Factors for Febrile Neutropenia and Severe Neutropenia - Nationwide Study Analysis.

BACKGROUND/AIM: FOLFIRINOX (FFX) is a standard treatment for patients with advanced pancreatic cancer. However, it often causes serious hematological adverse events. This study aimed to identify the risk factors for febrile neutropenia (FN) and grade 4 (G4) neutropenia during treatment with FFX in the real world. PATIENTS AND METHODS: We analyzed data obtained from a nationwide multicenter observational study (JASPAC 06) that included 399 patients with unresectable or recurrent pancreatic cancer who received FFX at 27 institutions in Japan. RESULTS: Nadir neutrophil counts occurred from day 8 to day 22 of cycle 1, and granulocyte colony-stimulating factor was administered to over a quarter of the patients in the first cycle. Of 399 patients, FN and G4 neutropenia occurred in 51 (13%) and 108 (27%) patients, respectively. Most FN (83%) and G4 neutropenia (75%) occurred in the first or second cycles. Multivariate logistic regression analyses showed that total bilirubin (TB) > the upper limit of normal range (ULN) and no dose modification from the original regimen were significantly associated with FN, and that TB > ULN, no dose modification from the original regimen, low platelet count (<15×104/µl), and recurrent disease after pancreatectomy were independent risk factors for G4 neutropenia. CONCLUSION: No dose modification from the original regimen and TB > ULN were risk factors for FN and G4 neutropenia.

A Multicenter Survey on Eligibility for a Randomized Phase III Trial of Adjuvant Chemotherapy for Resected Biliary Tract Cancer (JCOG1202, ASCOT).

BACKGROUND: The Adjuvant S-1 for Cholangiocarcinoma Trial (JCOG1202, [ASCOT]) was a multicenter, randomized controlled trial aimed at investigating the efficacy and safety of adjuvant chemotherapy (AC) with S-1 for resected biliary tract cancer (BTC). This trial reported that overall survival was prolonged with AC compared with observation. METHODS: With the aim of increasing enrollment, the present survey biannually recorded the number of patients eligible for enrollment into ASCOT and reasons for ineligibility among patients who had undergone surgery for BTC from April 2015 to September 2017 at 36 institutions participating in ASCOT. RESULTS: Of 2039 patients who underwent surgery for BTC, 211 (10.3%) were already enrolled, 166 (8.1%) were eligible but had not been enrolled, and 1662 (81.5%) were ineligible. Among ineligible patients, the predominant reasons for ineligibility were patient refusal (n = 332, 20.0%), pathologic stage (pT1N0; n = 248, 14.9%), age (≥ 81 years; n = 196, 11.8%), and prolonged postoperative complications (n = 176, 10.6%). CONCLUSIONS: Patients undergoing surgery for BTC are a heterogeneous cohort comprising patients with earlier pathologic stage, advanced age, and prolonged postoperative complications. These factors should be considered during the design of future clinical trials of perioperative treatments for resectable BTC.

Discordant microsatellite instability findings in two samples from a patient with biliary cancer that responded to pembrolizumab.

Microsatellite instability (MSI) is a key marker to predict response to immune checkpoint inhibitors; however, only 1-2% of biliary cancers have this genomic feature. In a patient with hilar biliary cancer, MSI was examined in two cancer specimens (forceps biopsy from the biliary stricture and endoscopic ultrasound-guided fine-needle aspiration biopsy [EUS-FNAB] from the adjacent lymph node). We observed discordant results, as high frequency of MSI was found only in the forceps biopsy. Although the FNAB sample was 10 times larger than that of the forceps biopsy, the tumor concentration was much lower, which is a possible reason for the discordance. Besides, immunohistochemistry of four mismatch-repair (MMR) proteins showed proficient MMR expressions. The tumor became refractory to gemcitabine, cisplatin, and S-1 but responded well to pembrolizumab. Caution is needed for sample selection and for interpretation of the test's results, to avoid missing rare chance for effective molecular target agents.

Comprehensive review of undifferentiated carcinoma of the pancreas: from epidemiology to treatment.

Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer displaying no definitive direction of differentiation. UC has been reported as a highly aggressive malignant neoplasm, with a median overall survival of <1 year, except for several surgical series. On the other hand, UC tissue sometimes contains non-neoplastic osteoclast-like giant cells (OGCs), and such cases have been reported to have relatively longer survival. Thus, the World Health Organization (WHO) classification histologically distinguishes UC with OGCs (UCOGCs) from UC, and UCs were subclassified into three subtypes: anaplastic UC, sarcomatoid UC and carcinosarcoma. However, still less is known about UC due to its rarity, and such situations lead to further difficulties in treatment for UC. To date, only surgical resection can offer curative treatment for patients with UC, and no clear evidence for chemotherapy exists for them. However, a retrospective cohort study and case reports showed that relatively promising results paclitaxel-containing regimens for treatment of patients with unresectable UC. Furthermore, high programmed cell death protein 1 expression has been reported in sarcomatoid UCs and UCOGCs, and promising responses to anti-programmed death-ligand 1 therapy have been described in case reports of UCOGCs. Recent advances in chemotherapeutic agents and molecular technologies are opening up the possibilities for expanded treatments.

Bevacizumab, Irinotecan, and Biweekly Trifluridine/Tipiracil for Metastatic Colorectal Cancer: MODURATE, a Phase Ib Study.

BACKGROUND: In this phase Ib study MODURATE, we optimized the dosing schedule and tested the efficacy and safety of trifluridine/tipiracil, irinotecan, and bevacizumab in patients with metastatic colorectal cancer with fluoropyrimidine and oxaliplatin treatment failure. METHODS: We included a dose escalation (3 + 3 design) and an expansion cohort. Patients were administered trifluridine/tipiracil (25-35 mg/m2 twice daily, days 1-5), irinotecan (150-180 mg/m2, day 1), and bevacizumab (5 mg/kg, day 1) every 2 weeks. The recommended phase II dose (RP2D) in the dose escalation cohort was administered to at least 15 patients in both cohorts combined. RESULTS: Twenty-eight patients were enrolled. Five dose-limiting toxicities were observed. RP2D was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of 16 patients who received RP2D, 86% (14/16) experienced grade ≥3 neutropenia without febrile neutropenia. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. Three patients (19%) showed partial response and 5 had stable disease for >4 months, with a median progression-free and overall survival of 7.1 and 21.7 months, respectively. CONCLUSION: Biweekly trifluridine/tipiracil, irinotecan, and bevacizumab administration may have moderate antitumor activity with high risk of severe myelotoxicity in previously treated patients with metastatic colorectal cancer [UMIN Clinical Trials Registry (UMIN000019828) and Japan Registry of Clinical Trials (jRCTs041180028)].

Effect of systemic inflammatory response on induction chemotherapy followed by chemoradiotherapy for locally advanced pancreatic cancer: an exploratory subgroup analysis on systemic inflammatory response in JCOG1106.

OBJECTIVE: JCOG1106, a randomized phase II trial conducted to compare chemoradiotherapy (S-1 concurrent radiotherapy) with (Arm B) or without (Arm A) induction chemotherapy using gemcitabine in patients with locally advanced pancreatic cancer, showed a more favorable long-term survival in Arm A. This study was aimed at exploring whether some subgroups classified by the systemic inflammatory response might derive greater benefit from either treatment. METHODS: All subjects eligible for JCOG1106 were included in this analysis (n = 51/49 in Arm A/B). This exploratory subgroup analysis was performed by Cox regression analysis to investigate the impact of the systemic inflammatory response, as assessed based on the serum C-reactive protein, serum albumin (albumin), Glasgow Prognostic Score and derived neutrophil-lymphocyte ratio, at the baseline on overall survival. P values <0.1 for the interaction were regarded as denoting significant association. RESULTS: Glasgow prognostic score showed significant treatment interactions for overall survival. Hazard ratios of Arm B to Arm A were 1.35 (95% confidence interval, 0.82-2.23) in the Glasgow Prognostic Score 0 (C-reactive protein ≤10 mg/L and albumin ≥35 g/L) (n = 44/34 in Arm A/B) and 0.59 (95% confidence interval, 0.24-1.50) in the Glasgow Prognostic Score 1/2 (C-reactive protein >10 mg/L and/or albumin <35 g/L) (n = 7/15) (P-interaction = 0.06). C-reactive protein alone and albumin alone also showed significant treatment interactions for overall survival. CONCLUSIONS: Survival benefits of induction chemotherapy in chemoradiotherapy for locally advanced pancreatic cancer were observed in patients with elevated Glasgow Prognostic Score, high C-reactive protein and low albumin. These results suggest that systemic inflammatory response might be considered to apply induction chemotherapy preceding chemoradiotherapy.

Phase I study of the VEGF/Ang-2 inhibitor BI 836880 alone or combined with the anti-programmed cell death protein-1 antibody ezabenlimab in Japanese patients with advanced solid tumors.

PURPOSE: This two-part, open-label, non-randomized dose-escalation study aimed to define the maximum tolerated dose (MTD) of BI 836880 (humanized bispecific nanobody® targeting vascular endothelial growth factor and angiopoietin-2) as monotherapy and in combination with ezabenlimab (programmed death protein-1 inhibitor) in Japanese patients with advanced and/or metastatic solid tumors. METHODS: In part 1, patients received an intravenous infusion of BI 836880 at 360 or 720 mg every 3 weeks (Q3W). In part 2, patients received BI 836880 at doses of 120, 360, or 720 mg in combination with ezabenlimab 240 mg Q3W. The primary endpoints were the MTD and the recommended phase II dose (RP2D) of BI 836880 as monotherapy and in combination with ezabenlimab, based on dose-limiting toxicities (DLTs) during the first cycle. RESULTS: Twenty-one patients were treated; nine in part 1 and 12 in part 2. No DLTs were reported in either part and the MTD was not reached. The RP2Ds were BI 836880 720 mg Q3W as monotherapy and BI 836880 720 mg plus ezabenlimab 240 mg Q3W. The most common adverse events were hypertension and proteinuria (33.3%) with BI 836880 monotherapy and diarrhea (41.7%) with the combination. Four patients (44.4%) in part 1 had stable disease as best overall tumor response. In part 2, two patients (16.7%) had confirmed partial responses and five had stable disease (41.7%). CONCLUSION: MTD was not reached. BI 836880 alone and in combination with ezabenlimab had a manageable safety profile with preliminary clinical activity in Japanese patients with advanced solid tumors. TRIAL REGISTRATION AND DATE: NCT03972150, registered on June 3, 2019.

Long-term adjuvant chemotherapy after resection for pancreatic cancer patients with positive peritoneal lavage cytology.

PURPOSE: The significance of resection for pancreatic cancer with positive peritoneal lavage cytology (CY +) remains controversial, and the lack of evidence concerning adjuvant chemotherapy (AC) in these patients remains an issue. The aim of the present study was to investigate the prognostic impacts of AC and its duration on the survival outcome in patients with CY + pancreatic cancer. METHODS: A total of 482 patients with pancreatic cancer who underwent pancreatectomy between 2006 and 2017 were retrospectively analyzed. The overall survival (OS) was compared among the patients with CY + tumors according to the duration of AC. RESULTS: Among the resected patients, 37 (7.7%) had CY + tumors: 13 received AC for > 6 months, 15 received AC for ≤ 6 months and 9 did not receive AC. The OS of 13 patients with resected CY + tumors who received AC for > 6 months was comparable to that of 445 patients with resected CY- tumors (median survival time 43.0 vs. 33.6 months, P = 0.791), and was significantly better than that of 15 patients with resected CY + tumors who received AC for ≤ 6 months (vs. 16.6 months, P = 0.017). The duration of AC (> 6 months) was an independent prognostic factor in patients with resected CY + tumors (hazard ratio 3.29, P = 0.005). CONCLUSION: Long-term AC (> 6 months) may improve postoperative survival in pancreatic cancer patients with CY + tumors.

Biomarker analysis for patients with pancreatic cancer treated with nanoliposomal irinotecan plus 5-fluorouracil/leucovorin.

BACKGROUND: Nanoliposomal irinotecan plus fluorouracil/leucovorin (5-FU/LV) is a standard second-line therapy for patients with pancreatic cancer. Identification of biomarkers is important to determine appropriate treatment strategies. We investigated the clinical practice outcomes and biomarkers associated with the nanoliposomal irinotecan plus 5-FU/LV regimen. METHODS: We retrospectively reviewed the data of patients treated with nanoliposomal irinotecan plus 5-FU/LV as a second or subsequent treatment after gemcitabine-based therapy between June 2020 and March 2021 at Shizuoka Cancer Center. RESULTS: We analyzed 55 consecutive patients who met the selection criteria. At a median of 9.4 months, median progression-free survival (PFS) and median overall survival (OS) were 2.3 and 6.6 months, respectively. Multivariate analysis showed that Glasgow prognostic score (GPS) was significantly associated with PFS (hazard ratio [HR] 2.16; 95% confidence interval [CI] 1.09-4.30; P = 0.028) and OS (0 vs. 1 or 2: HR 2.46; 95% CI 1.15-5.25; P = 0.029). The OS was significantly longer in patients with CA19-9 response than in those without CA19-9 response (12.6 vs. 5.6 months; HR 0.24; 95% CI 0.08-0.75; P = 0.014). CONCLUSIONS: Nanoliposomal irinotecan was efficacious and tolerable in clinical practice. GPS and CA19-9 response were good candidates as predictive biomarkers, whereas GPS was a good candidate prognostic biomarker for the nanoliposomal irinotecan plus 5-FU/LV regimen.

Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. METHODS: This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). FINDINGS: Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). INTERPRETATION: Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. FUNDING: The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

A randomised phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407).

AIM: We compared the efficacy of modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) with that of gemcitabine plus nab-paclitaxel (GnP) for locally advanced pancreatic cancer (LAPC). METHODS: Patients with untreated LAPC were randomly assigned (1:1) to receive mFOLFIRINOX or GnP. One-year overall survival (OS) was the primary endpoint. The major secondary end-points included progression-free survival (PFS), response rate (RR), carbohydrate antigen 19-9 (CA19-9) response, and adverse events. The sample size was 124 patients to select a more effective regimen with a minimum probability of 0.85 and to examine the null hypothesis of the 1-year OS <53%. RESULTS: Of the 126 patients enrolled from 29 institutions, 125 were deemed eligible. The 1-year OS was 77.4% (95% CI, 64.9-86.0) and 82.5% (95% CI, 70.7-89.9) in the mFOLFIRINOX and GnP arms, respectively. The median PFS was 11.2 (95% CI, 9.9-15.9) and 9.4 months (95% CI, 7.4-12.8) in the mFOLFIRINOX and GnP arms, respectively. The RR and CA19-9 response rate were 30.9% (95% CI, 19.1-44.8) and 57.1% (95% CI, 41.0-72.3) and 42.1% (95% CI 29.1-55.9) and 85.0% (95% CI, 70.2-94.3) in the mFOLFIRINOX and GnP arms, respectively. Grade 3-4 diarrhoea and anorexia were predominant in the mFOLFIRINOX arm. CONCLUSION: GnP was considered the candidate for a subsequent phase III trial because of its better RR, CA19-9 response, and mild gastrointestinal toxicities. Both regimens displayed higher efficacy in the 1-year survival than in the historical data of gemcitabine monotherapy.