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PURPOSE The BILCAP study described a modest benefit for capecitabine as adjuvant therapy for curatively resected biliary tract cancer (BTC), and capecitabine has become the standard of care. We present the long-term data and novel exploratory subgroup analyses. METHODS This randomized, controlled, multicenter, phase III study recruited patients age 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer after resection with curative intent and an Eastern Cooperative Oncology Group performance status of < 2. Patients were randomly assigned 1:1 to receive oral capecitabine (1,250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation. The primary outcome was overall survival (OS). This study is registered with EudraCT 2005-003318-13. RESULTS Between March 15, 2006, and December 4, 2014, 447 patients were enrolled; 223 patients with BTC resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. At the data cutoff of January 21, 2021, the median follow-up for all patients was 106 months (95% CI, 98 to 108). In the intention-to-treat analysis, the median OS was 49.6 months (95% CI, 35.1 to 59.1) in the capecitabine group compared with 36.1 months (95% CI, 29.7 to 44.2) in the observation group (adjusted hazard ratio 0.84; 95% CI, 0.67 to 1.06). In a protocol-specified sensitivity analysis, adjusting for minimization factors, nodal status, grade, and sex, the OS hazard ratio was 0.74 (95% CI, 0.59 to 0.94). We further describe the prognostic impact of R status, grade, nodal status, and sex. CONCLUSION This long-term analysis supports the previous analysis, suggesting that capecitabine can improve OS in patients with resected BTC when used as adjuvant chemotherapy after surgery and should be considered as the standard of care.

Background\ud \ud Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer.\ud \ud \ud \ud Methods\ud \ud The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0–1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30.\ud \ud \ud \ud Findings\ud \ud Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2–30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4–7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1–5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50–0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2–46·0) at 6 months and 11·4% (5·6–19·5) at 12 months, compared with 50·6% (39·3–60·9) at 6 months and 25·9% (17·0–35·8) at 12 months in the ASC plus FOLFOX group. Grade 3–5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3–5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients).\ud \ud \ud \ud Interpretation\ud \ud The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials.\ud \ud \ud \ud Funding\ud \ud Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research.

Additional file 1: Supplementary Appendix 1. The Consensus on Exercise Reporting Template (CERT). Supplementary Appendix 2 Table S1. Summary of CPET variables at week 0, 3, 6 and 9. Supplementary Appendix 3. Individual Graphical Plots. Figure S1. Changes in oxygen uptake at anaerobic threshold (ml.kg-1.min-1) at week 0/post-neoadjuvant cancer treatment, week 3, 6 and 9 in the exercise group. Figure S2. Changes in oxygen uptake at anaerobic threshold (ml.kg-1.min-1) at week 0/post-neoadjuvant cancer treatment, week 3, 6 and 9 in the usual care control group. Supplementary Appendix 4 Table S2. Summary of CPET variables between pre- and post-NCRT. Supplementary Appendix 5 Table S3. Themes, subthemes, and representative quotes from patients following neoadjuvant cancer treatment and the exercise training programme. Supplementary Appendix 6 Table S4. Post-Operative Morbidity Scores. Supplementary Appendix 7 Table S5. Summary of response to treatment and histopathology

Aim: To determine whether a liver tumor burden ≤25% and well-preserved liver function (albumin-bilirubin grade 1) are appropriate criteria for identifying patients with unresectable hepatocellular carcinoma who may benefit from selective internal radiation therapy (SIRT) using 90yttrium resin microspheres versus sorafenib. Patients & methods: Post-hoc analysis of patients in the intention-to-treat population of the SARAH trial (SIRT vs sorafenib) with ≤25% tumor burden and albumin-bilirubin grade 1. Primary end point: overall survival. Results: Median overall survival was 21.9 months (95% CI: 15.2–32.5, n = 37) with SIRT and 17.0 months (11.6–20.8, n = 48) with sorafenib (hazard ratios: 0.73; 95% CI: 0.44–1.21; p = 0.22). Conclusion: A combination of good liver function and low tumor burden may be relevant for selection of hepatocellular carcinoma patients for SIRT.

Importance The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear. Objective To define patterns of recurrence after adjuvant chemotherapy and the association with survival. Design, Setting, and Participants Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019. Interventions Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine. Main Outcomes and Measures Overall survival, recurrence, and sites of recurrence. Results Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98;P = .03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45;P = .04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09;P = .27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P = .85 andP = .35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98;P = .03). Conclusions and Relevance There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection. Trial Registration ClinicalTrials.gov identifier:NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434.

Background: \ud \ud Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo.\ud \ud Methods: \ud \ud We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2–5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (

Background & aims: The ALBI grade was proposed as an objective means to evaluate liver function in patients with Hepatocellular Carcinoma (HCC). ALBI grade 1 vs 2 were proposed as stratification factors within the Child Pugh (CP) A class. However, the original publication did not provide comparison with the sub-classification by points (5 to 15) within the CP classification. \ud Methods: We retrospectively analyzed data from patients treated with sorafenib for HCC from 17 centers in United Kingdom and France. Overall survival (OS) was analyzed with the Kaplan-Meier method and a Cox regression model. Discriminatory abilities of the classifications were assessed with the log likelihood ratio, Harrell’s C statistics and Akaike information criterion. \ud Results: Data from 1,019 patients were collected, of which 905 could be assessed for both scores. 92% of ALBI grade 1 were CP A5 while ALBI 2 included a broad range of CP scores of which 44% were CP A6. Median OS was 10.2, 7.0 and 3.6 months for CP scores A5, A6 and >A6, respectively (P