Trends in liver transplantation for primary biliary cholangitis in Europe over the past three decades

BACKGROUND: The importance of primary biliary cholangitis as an indication for liver transplantation has probably been influenced by the introduction of therapies, and changes in selection criteria and disease epidemiology. AIMS: To assess the time trends in liver transplantation for primary biliary cholangitis and to evaluate the characteristics of the patient population during the past three decades. METHODS: Patients undergoing liver transplantation from 1986 to 2015 in centres reporting to the European Liver Transplantation Registry were included. We excluded combined organ transplantations and patients <18 years. Trends were assessed using linear regression models. RESULTS: We included 112 874 patients, of whom 6029 (5.3%) had primary biliary cholangitis. After an initial increase in the first decade, the annual number of liver transplantation for primary biliary cholangitis remained stable at around 200. The proportion of liver transplantations for primary biliary cholangitis decreased from 20% in 1986 to 4% in 2015 (P < 0.001). Primary biliary cholangitis was the only indication showing a consistent proportional decrease throughout all decades. From the first to the third decade, the age at liver transplantation increased from 54 (IQR 47-59) to 56 years (IQR 48-62) and the proportion of males increased from 11% to 15% (both P < 0.001). CONCLUSIONS: We have found a proportional decrease in primary biliary cholangitis as indication for liver transplantation. However, despite treatment with ursodeoxycholic acid and improved disease awareness, the absolute annual number of liver transplantations has stabilised

Neoadjuvant chemotherapy with FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy for borderline resectable and resectable pancreatic cancer (PREOPANC-2):A multicenter randomized controlled trial

BackgroundThe PREOPANC trial demonstrated an overall survival (OS) benefit of neoadjuvant gemcitabine-based chemoradiotherapy compared with upfront surgery in patients with borderline resectable and resectable pancreatic cancer (PDAC). FOLFIRINOX may further improve OS in the neoadjuvant setting.MethodsThis multicenter, phase 3, randomized trial included patients with borderline resectable and resectable PDAC from 19 Dutch centers. Patients received FOLFIRINOX every 14 days for 8 cycles followed by surgery without adjuvant treatment (FFX arm) versus 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions during the second cycle), followed by surgery and 4 cycles of adjuvant gemcitabine (CRT arm). Randomization was stratified by center and resectability status. Primary endpoint was OS. Secondary endpoints included resection rate and serious adverse event (SAE) rate. To demonstrate a hazard ratio (HR) of 0.70 with two-sided α = 0.05 and 80% power, 368 patients (252 events) were needed. HR and 95% CI were estimated using a stratified Cox model.ResultsBetween June 2018 and January 2021, 375 patients were randomized to the FFX arm (n=188) or the CRT arm (n=187). Six patients (3 per arm) were excluded because of ineligibility (n=4) or withdrawal of informed consent immediately after randomization (n=2). After a median follow-up of 41.7 months with 254 events, median OS was 21.9 months in the FFX arm and 21.3 months in the CRT arm (HR 0.87; 95% CI 0.68-1.12, p=0.28). Resection rates were 77% in the FFX arm and 75% in the CRT arm (p=0.69). SAE rates were 49% in the FFX arm and 43% in the CRT arm (p=0.26).ConclusionsNeoadjuvant chemotherapy with FOLFIRINOX did not improve OS compared with neoadjuvant gemcitabine-based chemoradiotherapy in patients with borderline resectable and resectable PDAC

Neoadjuvant chemotherapy with FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy for borderline resectable and resectable pancreatic cancer (PREOPANC-2):A multicenter randomized controlled trial

BackgroundThe PREOPANC trial demonstrated an overall survival (OS) benefit of neoadjuvant gemcitabine-based chemoradiotherapy compared with upfront surgery in patients with borderline resectable and resectable pancreatic cancer (PDAC). FOLFIRINOX may further improve OS in the neoadjuvant setting.MethodsThis multicenter, phase 3, randomized trial included patients with borderline resectable and resectable PDAC from 19 Dutch centers. Patients received FOLFIRINOX every 14 days for 8 cycles followed by surgery without adjuvant treatment (FFX arm) versus 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions during the second cycle), followed by surgery and 4 cycles of adjuvant gemcitabine (CRT arm). Randomization was stratified by center and resectability status. Primary endpoint was OS. Secondary endpoints included resection rate and serious adverse event (SAE) rate. To demonstrate a hazard ratio (HR) of 0.70 with two-sided α = 0.05 and 80% power, 368 patients (252 events) were needed. HR and 95% CI were estimated using a stratified Cox model.ResultsBetween June 2018 and January 2021, 375 patients were randomized to the FFX arm (n=188) or the CRT arm (n=187). Six patients (3 per arm) were excluded because of ineligibility (n=4) or withdrawal of informed consent immediately after randomization (n=2). After a median follow-up of 41.7 months with 254 events, median OS was 21.9 months in the FFX arm and 21.3 months in the CRT arm (HR 0.87; 95% CI 0.68-1.12, p=0.28). Resection rates were 77% in the FFX arm and 75% in the CRT arm (p=0.69). SAE rates were 49% in the FFX arm and 43% in the CRT arm (p=0.26).ConclusionsNeoadjuvant chemotherapy with FOLFIRINOX did not improve OS compared with neoadjuvant gemcitabine-based chemoradiotherapy in patients with borderline resectable and resectable PDAC

Evaluation of Adjuvant Chemotherapy in Patients With Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX Treatment

Importance The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear. Objective To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment. Design, Setting, and Participants This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded. Exposures The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise. Results We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28;P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75];P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10;P = .73). Conclusions and Relevance These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.Question Do patients who underwent resection of pancreatic cancer after neoadjuvant combination folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy benefit from adjuvant chemotherapy? Findings This international cohort study of 520 patients with resected pancreatic cancer found that adjuvant chemotherapy was significantly associated with improved survival in 254 patients with pathology-proven node-positive disease but not in 256 patients with node-negative disease. Meaning Adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease.This cohort study uses data from an existing cohort of patients undergoing resection of pancreatic cancer to assess the overall survival of patients treated with neoadjuvant FOLFIRINOX after surgery for pancreatic ductal adenocarcinoma