Influence of cirrhosis on outcomes of patients with advanced intrahepatic cholangiocarcinoma receiving chemotherapy.

BACKGROUND: Cirrhosis is a risk factor for intrahepatic cholangiocarcinoma (iCC). However, its exact prevalence is uncertain and its impact on the management of advanced disease is not established. METHODS: Retrospective analysis of patients treated with systemic chemotherapy for advanced iCC in the 1st-line setting at 2 tertiary cancer referral centres. Cirrhosis was diagnosed based on at least one element prior to any treatment: pathological diagnosis, baseline platelets <150 × 109/L, portal hypertension and/or dysmorphic liver on imaging. RESULTS: In the cohort of patients (n = 287), 82 (28.6%) had cirrhosis (45 based on pathological diagnosis). Patients with cirrhosis experienced more grade 3/4 haematologic toxicity (44% vs 22%, respectively, P = 0.001), and more grade 3/4 non-haematologic toxicity (34% vs 14%, respectively, P = 0.001) than those without. The overall survival (OS) was significantly shorter in patients with cirrhosis: median 9.1 vs 13.1 months for those without (HR = 1.56 [95% CI: 1.19-2.05]); P = 0.002), confirmed on multivariable analysis (HR = 1.48 [95% CI: 1.04-2.60]; P = 0.028). CONCLUSION: Cirrhosis was relatively common in patients with advanced iCC and was associated with increased chemotherapy-induced toxicity and shorter OS. Formal assessment and consideration of cirrhosis in therapeutic management is recommended.

Sodium Bicarbonate for Metabolic Acidosis in the ICU: Results of a Pilot Randomized Double-Blind Clinical Trial.

OBJECTIVES: To identify the best population, design of the intervention, and to assess between-group biochemical separation, in preparation for a future phase III trial. DESIGN: Investigator-initiated, parallel-group, pilot randomized double-blind trial. SETTING: Eight ICUs in Australia, New Zealand, and Japan, with participants recruited from April 2021 to August 2022. PATIENTS: Thirty patients greater than or equal to 18 years, within 48 hours of admission to the ICU, receiving a vasopressor, and with metabolic acidosis (pH < 7.30, base excess [BE] < -4 mEq/L, and Pa co2 < 45 mm Hg). INTERVENTIONS: Sodium bicarbonate or placebo (5% dextrose). MEASUREMENTS AND MAIN RESULT: The primary feasibility aim was to assess eligibility, recruitment rate, protocol compliance, and acid-base group separation. The primary clinical outcome was the number of hours alive and free of vasopressors on day 7. The recruitment rate and the enrollment-to-screening ratio were 1.9 patients per month and 0.13 patients, respectively. Time until BE correction (median difference, -45.86 [95% CI, -63.11 to -28.61] hr; p < 0.001) and pH correction (median difference, -10.69 [95% CI, -19.16 to -2.22] hr; p = 0.020) were shorter in the sodium bicarbonate group, and mean bicarbonate levels in the first 24 hours were higher (median difference, 6.50 [95% CI, 4.18 to 8.82] mmol/L; p < 0.001). Seven days after randomization, patients in the sodium bicarbonate and placebo group had a median of 132.2 (85.6-139.1) and 97.1 (69.3-132.4) hours alive and free of vasopressor, respectively (median difference, 35.07 [95% CI, -9.14 to 79.28]; p = 0.131). Recurrence of metabolic acidosis in the first 7 days of follow-up was lower in the sodium bicarbonate group (3 [20.0%] vs. 15 [100.0%]; p < 0.001). No adverse events were reported. CONCLUSIONS: The findings confirm the feasibility of a larger phase III sodium bicarbonate trial; eligibility criteria may require modification to facilitate recruitment.

The nature and impact of patient and public involvement in cancer prevention, screening and early detection research: A systematic review.

Patient and public involvement can produce high-quality, relevant research that better addresses the needs of patients and their families. This systematic review investigated the nature and impact of patient and public involvement in cancer prevention, screening and early detection research. Two patient representatives were involved as members of the review team. Databases (Medline, EMBASE, Emcare, Involve Evidence Library) were searched for English-language studies published 1995-March 2022. Titles/abstracts were screened by two reviewers independently. For eligible studies, data were extracted on study characteristics, patient and public involvement (who, when, how, and impact on research outcomes), and reporting quality using the Guidance for Reporting Involvement of Patients and the Public 2-Short Form. Of 4095 articles screened, 58 were eligible. Most research was from the United States (81%) and examined cancer screening or prevention (82%). Community members/organisations/public were the most involved (71%); fewer studies involved patients and/or carers (14%). Over half reported a high-level of involvement (i.e. partner and/or expert involvement), although this declined in later stages of the research cycle, e.g. data analysis. Common positive impacts included improved study design, research methods and recruitment, although most papers (62%) did not describe methods to determine impact. Reporting quality was sub-optimal, largely due to failure to consider challenges. This review found that high-level involvement of patients and the public in cancer prevention, screening and early detection research is feasible and has several advantages. However, improvements are needed to encourage involvement across the research cycle, and in evaluating and reporting its impact.

Plain language summary of the TOPAZ-1 study: durvalumab and chemotherapy for advanced biliary tract cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary describing the results of a Phase III study called TOPAZ-1. The study looked at treatment with durvalumab (a type of immunotherapy) and chemotherapy to treat participants with advanced biliary tract cancer (BTC). Advanced BTC is usually diagnosed at late stages of disease, when it cannot be cured by surgery. This study included participants with advanced BTC who had not received previous treatment, or had their cancer come back at least 6 months after receiving treatment or surgery that aimed to cure their disease. Participants received treatment with durvalumab and chemotherapy or placebo and chemotherapy. The aim of this study was to find out if treatment with durvalumab and chemotherapy could increase the length of time that participants with advanced BTC lived, compared with placebo and chemotherapy. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took durvalumab and chemotherapy had a 20% lower chance of experiencing death at any point in the study compared with participants who received placebo and chemotherapy. The side effects experienced by participants were similar across treatment groups, and less than 12% of participants in either treatment group had to stop treatment due to treatment-related side effects. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, these results support durvalumab and chemotherapy as a new treatment option for people with advanced BTCs. Based on the results of this study, durvalumab is now approved for the treatment of adults with advanced BTCs in combination with chemotherapy by government organizations in Europe, the United States and several other countries.

Potential influence of the microbiome environment in patients with biliary tract cancer and implications for therapy.

Biliary tract cancers, including intra- and extra-hepatic cholangiocarcinoma as well as gallbladder cancer, are associated with poor prognosis and the majority of patients present with advanced-stage, non-resectable disease at diagnosis. Biliary tract cancer may develop through an accumulation of genetic and epigenetic alterations and can be influenced by microbial exposure. Furthermore, the liver and biliary tract are exposed to the gastrointestinal microbiome through the gut-liver axis. The availability of next-generation sequencing technology has led to an increase in studies investigating the relationship between microbiota and human disease. In particular, the interplay between the microbiome, the tumour micro-environment and response to systemic therapy is a prospering area of interest. Given the poor outcomes for patients with biliary tract cancer, this emerging field of research, through which new biomarkers may be identified, offers potential as a tool for early diagnosis, prognostication or even as a future therapeutic target. This review summarises the available evidence on the microbiome environment in patients with biliary tract cancer, including a discussion around confounding factors, implications for therapy and proposed future directions.

Intrahepatic cholangiocarcinoma hidden within cancer of unknown primary.

BACKGROUND: Many patients referred with a provisional diagnosis of cancer of unknown primary (pCUP) present with presumed metastatic disease to the liver. Due to the lack of definitive histological markers, intrahepatic cholangiocarcinoma (iCCA) may be overlooked. This study assessed the frequency of iCCA within a pCUP cohort. METHODS: A single UK cancer-center study of sequential patients referred with pCUP from January 2017 to April 2020. Baseline diagnostic imaging was reviewed independently by a radiologist and oncologist; those with radiological features of iCCA (dominant liver lesion, capsular retraction) were identified. RESULTS: Of 228 patients referred with pCUP, 72 (32%) had malignancy involving the liver. 24/72 patients had radiological features consistent with iCCA; they were predominantly female (75%) with an average age of 63 years and 63% had an ECOG PS ≤ 2. The median overall survival (OS) of the iCCA group and the remaining liver-involved CUP group were similar (OS 4.1 vs 4.4 months, p-value = 0.805). Patients, where a primary diagnosis was subsequently determined, had better OS (10.2 months, p-values: iCCA = 0.0279: cCUP = 0.0230). CONCLUSIONS: In this study, 34% of patients with liver-involved pCUP, fulfilled the radiological criteria for an iCCA diagnosis. Consideration of an iCCA diagnosis in patients with CUP could improve timely diagnosis, molecular characterisation and treatment.

Randomised, Phase II study of selumetinib, an oral inhibitor of MEK, in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer.

INTRODUCTION: Cisplatin and gemcitabine (CisGem) are standard chemotherapy for advanced biliary tract cancer (BTC). The MEK inhibitor selumetinib showed synergy with gemcitabine when administered sequentially in BTC. This randomised Phase 2 trial aimed to assess the efficacy of sequential or continuous selumetinib with CisGem. METHODS: Patients with advanced BTC received CisGem; arm A included selumetinib every day, arm B: selumetinib, days 1-5, 8-19 each cycle. Arm C received CisGem alone. Selumetinib was dosed at 75 mg BID but amended to 50 mg BID due to toxicity. RESULTS: In all, 51 participants were evaluable for response. No significant difference was seen in mean change in tumour size at 10 weeks between arms A and C (-7.8% vs -12.8%, P = 0.54) or arms B and C (-15% vs -12.8%, P = 0.78). There was no difference in median progression-free survival (6.0, 7.0, 6.3 months, P > 0.95) or overall survival (11.7, 11.7, 12.8 months, P = 0.70) for arms A, B and C, respectively. More participants experienced grade 3-4 toxicities in selumetinib-containing arms. More participants in arm A required chemotherapy dose reductions (P = 0.01) with lower chemotherapy dose intensity during the first 10 weeks. CONCLUSION: Adding sequential or continuous selumetinib to CisGem failed to improve efficacy and increased toxicity in patients with advanced BTC.

Everolimus-Induced Pneumonitis in Patients with Neuroendocrine Neoplasms: Real-World Study on Risk Factors and Outcomes.

BACKGROUND: Everolimus-induced pneumonitis (EiP) has been poorly studied in patients with neuroendocrine neoplasms (NEN) outside clinical trials. The aim of this study was to evaluate the incidence, risk factors, and outcomes of EiP in patients with NENs using real-world data. METHODS: Retrospective study of everolimus-treated patients with advanced NENs. Imaging reports were systematically reviewed for the presence of pneumonitis. Clinical features and treatment profiles for EiP were summarized. Overall survival (OS) was calculated from the initiation of everolimus to the date of death or last follow-up using the Kaplan-Meier method. RESULTS: A total of 122 patients were included. Median age at start of everolimus was 62 (19-86) years, 62% (76/122) were male, and half were from pancreatic origin (62, 51%). Twenty-eight patients (23%) developed EiP: 82% grade (G)1 or G2, 14% G3 and 4% G4. The median time to EiP was 3.6 (0.8-51) months. Primary tumor site, concurrent lung disease, smoking history, and prior therapies were not associated with the onset of EiP. Patients who developed EiP had longer time on everolimus treatment (median 18 months vs 6 months; P = .0018) and OS (77 months vs 52 months; P = .093). Everolimus-induced pneumonitis was a predictor of improved OS by multivariable analysis (HR 0.39, 95% CI 0.19-0.82; P = .013). CONCLUSION: Everolimus-induced pneumonitis in the real-world clinical setting is present in one quarter of patients with NENs receiving everolimus and often occurs early. While risk factors for EiP were not identified, patients with EiP had improved survival.

Markers of tumor inflammation as prognostic factors for overall survival in patients with advanced pancreatic cancer receiving first-line FOLFIRINOX chemotherapy.

BACKGROUND: Identifying pretreatment blood markers that distinguish prognostic groups of patients with advanced pancreatic ductal adenocarcinoma (PDAC) under first-line FOLFIRINOX chemotherapy has the potential to improve management of this condition. Aim of this study was to determine the prognostic utility of a range of pretreatment, inflammation-related, blood cell markers in this group of patients. MATERIAL AND METHODS: Data from a training cohort were analyzed to identify potential pretreatment blood markers correlating to survival outcomes. The most informative markers were further analyzed in a validation cohort comprised patients from a geographically separate cancer center undergoing the same treatment. RESULTS: A total of 138 consecutive patients receiving FOLFIRINOX chemotherapy between 2010 and 2019, constituted the training cohort. Neutrophil/lymphocyte (NLR), monocyte/lymphocyte (MLR), and platelet/lymphocyte ratio (PLR) as well as the systemic inflammatory response index (SIRI) and CA19.9 showed prognostic significance in addition to tumor stage. A pretreatment SIRI score cutoff of 2.35 differentiated between a poor prognostic group with median overall survival (mOS) 5.1 months and a better prognostic group, mOS 12.5 months. SIRI ≤/> 2.35 was predictive of mOS in patients with locally advanced and metastatic PDAC. SIRI was confirmed as a prognostic marker in a validation cohort of 67 patients with mOS of 13.4 months and 6.3 months for those with SIRI ≤ 2.35 and >2.35, respectively. Additional analysis revealed baseline SIRI as being prognostic within additional subgroups of patients in both cohorts. CONCLUSIONS: This large, retrospective, analysis of real-world patients receiving first-line FOLFIRINOX chemotherapy for advanced PDAC has identified the pretreatment blood SIRI as a strong prognostic marker for survival. This will allow better counseling of patients with regards to the benefits of treatment, improved stratification within clinical trials, and potentially identify groups of patients for novel therapy trials as first-line treatment.

A Phase Ib Study of NUC-1031 in Combination with Cisplatin for the First-Line Treatment of Patients with Advanced Biliary Tract Cancer (ABC-08).

BACKGROUND: Cisplatin/gemcitabine is standard first-line treatment for patients with advanced biliary tract cancer (ABC). NUC-1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites. METHODS: Patients with untreated ABC, Eastern Cooperative Oncology Group performance status 0-1 received NUC-1031 (625 or 725 mg/m2 ) and cisplatin (25 mg/m2 ) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC-1031 625 mg/m2 (n = 8 and expansion n = 7; median six cycles) or 725 mg/m2 (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment-emergent grade 3-4 adverse events occurring in more than one patient with 625 mg/m2 NUC-1031 were increased gamma-glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m2 , increased GGT, 67%, and fatigue, 33%. NUC-1031 725 mg/m2 was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3-10.1), and median OS was 9.6 months (95% CI, 6.7-13.1). The median estimates of area under the plasma concentration-time curve from time 0 to last measurable time and maximum concentration were highest for NUC-1031 (218-324 µg•h/mL and 309-889 µg/mL, respectively) and lowest for di-fluoro-deoxycytidine (0.47-1.56 µg•h/mL and 0.284-0.522 µg/mL, respectively). CONCLUSION: This is the first study reporting on the combination of NUC-1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m2 NUC-1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: NCT02351765; EudraCT ID: 2015-000100-26). IMPLICATIONS FOR PRACTICE: The prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first-line treatment for patients with ABC. NUC-1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC-08) demonstrated a favorable safety profile of NUC-1031 in combination with cisplatin for the first-line treatment of patients with ABC, and 725 mg/m2 NUC-1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling.

Liver Embolisation for Patients with Neuroendocrine Neoplasms: Systematic Review.

BACKGROUND: Liver embolisation is one of the treatment options available for patients diagnosed with neuro-endocrine neoplasms (NEN). It is still uncertain whether the benefits of the various types of embolisation treatments truly outweigh the complications in NENs. This systematic review assesses the available data relating to liver embolisation in patients with NENs. METHODS: Eligible studies (identified using MEDLINE-PubMed) were those reporting data on NEN patients who had undergone any type of liver embolisation. The primary end points were best radiological response and symptomatic response; secondary end-points included progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Of 598 studies screened, 101 were eligible: 16 were prospective (15.8%). The eligible studies included a total of 5,545 NEN patients, with a median of 39 patients per study (range 5-214). Pooled rate of partial response was 36.6% (38.9% achieved stable disease) and 55.2% of patients had a symptomatic response to therapy when pooled data were analysed. The median PFS and OS were 18.4 months (95% CI 15.5-21.2) and 40.7 months (95% CI 35.2-46.2) respectively. The most common toxicities were found to be abdominal pain (48.8%) and nausea (48.1%). Outcome did not significantly vary depending on the type of embolisation performed. CONCLUSION: Liver embolisation provides adequate symptom relief for patients with carcinoid syndrome and is also able to reach partial response in a significant proportion of patients and a reasonable PFS. Quality of studies was limited, highlighting the need of further prospective studies to confirm the most suitable form of liver embolisation in NENs.

Molecular targeted therapies: Ready for "prime time" in biliary tract cancer.

The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and -2 mutations which are each present in around 10-20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.

Landmark survival analysis and impact of anatomic site of origin in prospective clinical trials of biliary tract cancer.

BACKGROUND & AIMS: Whether all patients with advanced biliary tract cancer (aBTC) should be included in prospective trials, irrespective of the anatomic site of origin, is debated. Herein, we aimed to assess the survival impact of anatomic site of origin in prospective clinical trials of aBTC using landmark survival analysis. METHODS: Patients enrolled into prospective first-line aBTC clinical trials (Jan 97-Dec 15) were included. Overall survival (OS) was analysed using Cox proportional hazard regression; landmark survival (LS) and 95% CIs were calculated. RESULTS: Overall, 1,333 patients were included: median age 63 years (range 23-85); 46% male; 84% ECOG-PS0/1; 25% with locally advanced disease, 72% with metastatic, 3% not reported (NR). Patients were treated with mono-chemotherapy (23%), cisplatin/gemcitabine (36%), other combinations (39%), or NR (2%). Median OS was 10.2 months (95% CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs. gallbladder cancer (GBC) (p <0.001). This reduced risk vs. GBC was maintained in those receiving cisplatin/gemcitabine for extrahepatic cholangiocarcinoma (p<0.001) and intrahepatic cholangiocarcinoma (IHC, p<0.001), but not in cholangiocarcinoma-not specified (CCA-NS, p = 0.82) or ampullary carcinoma (p = 0.96). One-year OS rates amongst patients who survived beyond 1, 2, 3 and 4 years post-trial registration were 37%, 45%, 61%, and 63%, respectively. For patients who survived 1 year, those receiving combination therapy vs. mono (p = 0.008) (acknowledging potential selection bias) and those with IHC and CCA-NS vs. GBC had better LS (both p <0.05). Metastatic disease was associated with shorter LS than locally advanced disease (p = 0.002). ECOG-PS and gender were not associated with LS (p >0.05, p = 0.08 respectively). CONCLUSIONS: GBC is associated with worse OS than other BTC sites and should be considered as a stratification factor in clinical trials. LS rates enable adjusted prognostication for aBTC survivors. LAY SUMMARY: Patients with gallbladder cancer have worse overall survival compared to those with biliary tract cancers of different primary origin. Thus, gallbladder cancer should be considered as a stratification factor in future clinical trials. Landmark survival rates enable adjusted prognosis prediction for patients with advanced biliary tract cancer who survive for some time.

Adjuvant chemotherapy in biliary tract cancer: state of the art and future perspectives.

PURPOSE OF REVIEW: Biliary tract cancers (BTCs) have a poor prognosis; most patients present with advanced disease and, even after surgical resection for early-stage disease local and distant relapses are frequent. Involved resection margins and lymph node involvement are the most relevant known adverse prognostic factors. Historically clinicians have made clinical decisions based on data from institutional series and uncontrolled studies, with their inherent limitations. In this review, data from recently-reported prospective randomized trials are reviewed and clinical implications discussed. RECENT FINDINGS: Results from prospective randomized phase III trials (namely BILCAP, PRODIGE-12, and BCAT) are reviewed: none of the studies met their primary endpoint by intention-to-treat analysis. However, following a per-protocol sensitivity analysis of the BILCAP study, adjuvant capecitabine (for 6 months) showed a clinically-relevant improvement in overall survival and provides reference data for future clinical trials. SUMMARY: Adjuvant chemotherapy with capecitabine should be considered following curative resection of BTC. Identification of benefit in anatomical subgroups is ongoing and future trials should also consider the implication of molecular subtypes of BTC (for prognostic impact and on-target therapeutic options).

Impact on prognosis of early weight loss during palliative chemotherapy in patients diagnosed with advanced pancreatic cancer.

AIM: Weight loss at diagnosis is common in pancreatic cancer (PC) and can adversely affect overall survival (OS). Little is known about the impact of weight loss occurring during palliative treatment. This study aimed to investigate if early weight loss during chemotherapy for inoperable PC affects OS. METHOD: This retrospective study included patients newly-diagnosed with inoperable PC. Consecutive patients initiating first-line palliative chemotherapy between Jan'15 - Jan'19 with data on percentage weight loss at week 4 of treatment (%WLWeek4) were eligible. %WLWeek4 was dichotomised using 5% cut-off. OS was measured from chemotherapy initiation. Survival analysis was performed using Cox regression. RESULTS: Eligible patients (n = 255); 59.2% with head/neck PC; 52.6% metastatic; received triplet (32.2%), doublet (42.7%) or single-agent (25.1%) palliative chemotherapy. Median %WLWeek4 was -2.05% (95% confidence interval (CI) -2.58 to -1.56); %WLWeek4 was ≥5% in 23.1% patients. Patients on triplet chemotherapy were more likely to develop %WLWeek4 of ≥5% [35.4% (triplet) vs. 19.3% (doublet) vs 14.1% (monotherapy); multivariable Odds Ratio (triplet vs monotherapy) =3.25; 95% CI 1.40-7.56; p-value 0.006]. Median OS was 9.7 months (95% CI 8.54-10.41). Multivariable Cox regression demonstrated shorter OS if %WLWeek4 ≥5% (median OS 7.4 months (95% CI 6.27-10.01) vs. 9.9 months (95% CI 9.20-12.05); HR 2.37 (95% CI 1.64-3.42), P < 0.001); this was independent from other factors (stage, age, number of chemotherapy drugs, ECOG-PS), including response to therapy (supporting that %WLWeek4 impacted on OS regardless of response to therapy). CONCLUSION: In advanced PC treated with palliative chemotherapy, a %WLWeek4 ≥5% was more prevalent in patients undergoing triplet chemotherapy, and was associated with shorter OS, regardless of response/progression to therapy. Early identification and intervention of weight loss seems to be key to improve patient outcomes.

The assessment of pancreatic exocrine function in patients with inoperable pancreatic cancer: In need of a new gold-standard.

BACKGROUND: Pancreatic exocrine insufficiency is commonplace in patients with pancreatic cancer, adversely impacting on quality of life and survival. Whilst the management of exocrine insufficiency is well established, diagnosis remains challenging in clinical practice. A plethora of diagnostic tests exist. Nevertheless, a lack of consensus remains about the optimal diagnostic method, specifically in patients with pancreatic cancer. Research, to date, has primarily been undertaken in patients with chronic pancreatitis and cystic fibrosis. This manuscript will review the current literature and will examine the evidence around the diagnostic tests available for pancreatic exocrine insufficiency and whether any exists specifically for pancreatic cancer cohorts. FINDINGS: Evidence to recommend an individual test for the diagnosis of pancreatic exocrine insufficiency in clinical practice is lacking. Direct testing (by direct sampling of pancreatic secretions) has the highest specificity and sensitivity but is no longer routinely deployed or feasible in practice. Indirect testing, such as faecal elastase, is less accurate with high false-positive rates, but is routinely available in clinical practice. The 13C-mixed triglyceride breath test and the gold-standard 72-h faecal fat test have high specificity for indirect tests, but are not routinely available and cumbersome to undertake. A combination approach including nutritional markers and faecal elastase has more recently been proposed. CONCLUSION: Further research is required to identify the most optimal and accurate diagnostic tool to diagnose pancreatic exocrine insufficiency in patients with pancreatic cancer in clinical practice.

Identification of Areas for Improvement in the Management of Bone Metastases in Patients with Neuroendocrine Neoplasms.

BACKGROUND: There is no global consensus on the optimal management of bone metastases (BMs) in neuroendocrine neoplasms (NENs). OBJECTIVES: To review current management and outcomes of patients with BMs in NENs, in order to identify areas for improvement. METHODS: A retrospective study of all patients with NENs, except Grade 3 lung NENs (April 2002 to March 2018) was conducted. Baseline characteristics, nature of BMs, treatment received and overall survival (OS) were evaluated. Statistical analyses were performed using SPSS version 23.0/STATA v12. RESULTS: Of 1,212 patients, 85 (7%) had BMs; median age 58 years. The majority had a gastro-entero-pancreatic primary (49%, n = 42) followed by lung (25%, n = 21), unknown primary (20%, n = 17), and "others" (6%, n = 5). Two-thirds (n = 57) had G1-2 neuroendocrine tumours, and 41% (n = 35) had functional tumours. Overall, 28% (n = 24) presented with synchronous BMs at first NEN diagnosis, and 55% (n = 47) developed BMs at the same time as other distant metastases. For the subpopulation of patients in whom BMs developed metachronously to other distant metastases (45%, n = 38), median time to development of BMs was 14.0 months. BMs were "widespread" in 61% (n = 52). Although only 22% (n = 19) reported symptoms at initial diagnosis of BMs, most (78%) developed symptoms at some time during the follow-up period (pain/hypercalcaemia 64%, skeletal-related events 20%). BMs were mainly managed with analgesia (44%, n = 37). Radiotherapy and bisphosphonates were used in 34% (n = 29) and 22% (n = 19) respectively. Surgery was rarely performed (2%, n = 2). Median OS from identification of BMs was 31.0, and 18.9 months from development of BMs-related symptoms. CONCLUSIONS: In this cohort study, most patients with BMs developed symptoms. The utility of radiotherapy and/or bisphosphonates should be prospectively and systematically explored further for its potential impact on patients' quality of life and survival outcomes.

NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121).

Gemcitabine/cisplatin is standard of care for first-line treatment of patients with advanced biliary tract cancer (aBTC); new treatments are needed. NUC-1031 is designed to overcome key cancer resistance mechanisms associated with gemcitabine. The tolerability/efficacy signal of NUC-1031/cisplatin in the Phase Ib ABC-08 study suggested that this combination may represent a more efficacious therapy than gemcitabine/cisplatin for patients with aBTC, leading to initiation of the global NuTide:121 study which will include 828 patients ≥18 years with untreated histologically/cytologically-confirmed aBTC (including cholangiocarcinoma, gallbladder or ampullary cancer); randomized (1:1) to NUC-1031 (725 mg/m2)/cisplatin (25 mg/m2) or gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2), on days 1/8, Q21-days. Primary objectives are overall survival and objective response rate. Secondary objectives: progression-free survival, safety, pharmacokinetics, patient-reported quality of life and correlative studies. (Investigational new drug (IND) number: 139058, European Clinical Trials database: EudraCT Number 2019-001025-28, ClinicalTrials.gov identifier: NCT04163900).

18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) for patients with biliary tract cancer: Systematic review and meta-analysis.

BACKGROUND & AIMS: The role of 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) in the diagnosis and staging of patients with biliary tract cancers (BTCs) remains controversial, so we aimed to provide robust information on the utility of 18FDG-PET in the diagnosis and management of BTC. METHODS: This systematic review and meta-analysis explored the diagnostic test accuracy of 18FDG-PET as a diagnostic tool for diagnosis of primary tumour, lymph node invasion, distant metastases and relapsed disease. Subgroup analysis by study quality and BTC subtype were performed. Changes in management based on 18FDG-PET and impact of maximum standardised uptake values (SUVmax) on prognosis were also assessed. A random effects model was used for meta-analyses. RESULTS: A total of 2,125 patients were included from 47 eligible studies. The sensitivity (Se) and specificity (Sp) of 18FDG-PET for the diagnosis of primary tumour were 91.7% (95% CI 89.8-93.2) and 51.3% (95% CI 46.4-56.2), respectively, with an area under the curve (AUC) of 0.8668. For lymph node invasion, Se was 88.4% (95% CI82.6-92.8) and Sp was 69.1% (95% CI 63.8-74.1); AUC 0.8519. For distant metastases, Se was 85.4% (95% CI 79.5-90.2) and Sp was 89.7% (95% CI86.0-92.7); AUC 0.9253. For relapse, Se was 90.1% (95% CI 84.4-94.3) and Sp was 83.5% (95% CI 74.4-90.4); AUC 0.9592. No diagnostic threshold effect was identified. Meta-regression did not identify significant sources of heterogeneity. Sensitivity analysis revealed no change in results when analyses were limited to studies with low risk of bias/concern. The pooled proportion of change in management was 15% (95% CI 11-20); the majority (78%) due to disease upstaging. Baseline high SUVmax was associated with worse survival (pooled hazard ratio of 1.79; 95% CI 1.37-2.33; p <0.001). CONCLUSIONS: There is evidence to support the incorporation of 18FDG-PET into the current standard of care for the staging (lymph node and distant metastases) and identification of relapse in patients with BTC to guide treatment selection; especially if the identification of occult sites of disease would change management, or if diagnosis of relapse remains unclear following standard of care imaging. The role for diagnosis of the primary tumour remains controversial due to low sensitivity and 18FDG-PET should not be considered as a replacement for pathological confirmation in this setting. LAY SUMMARY: A positron emission tomography (PET scan), using 18F-fluorodeoxyglucose (18FDG), can help doctors identify areas of cancer in the body by highlighting "hot spots". These hotspots may be cancerous (true positive) but may also be non-cancerous, like inflammation (false positive). We show that PET scans are useful to assess how far advanced the cancer is (by assessing spread to lymph glands and to other organs) and also to identify if the cancer has recurred (for example after surgery), thus helping doctors to make treatment decisions. However, a biopsy is still needed for the initial diagnosis of a biliary tract cancer, because of the high chance of a "false positive" with PET scans.

Carboplatin in Combination with Oral or Intravenous Etoposide for Extra-Pulmonary, Poorly-Differentiated Neuroendocrine Carcinomas.

BACKGROUND: Carboplatin-etoposide (CarboEtop) is a 1st-line option for patients with advanced extra-pulmonary (EP), poorly-differentiated (PD) neuroendocrine carcinoma (NEC). Different schedules are used in clinical practice and randomised evidence is lacking. OBJECTIVES: To provide real-life outcomes of carboplatin combined with oral or intravenous (IV) etoposide (Etop) in advanced EP-PD-NEC, from 2 specialist centres. METHODS: Activity/efficacy/toxicity data of CarboEtop were collected retrospectively and analysed. RESULTS: We identified 113 patients; median age: 65.8 years; male: 64%; gastro-entero-pancreatic origin: 54%; stage IV: 90%; median Ki-67: 70%; median follow-up: 11.5 months. A total of 123 courses of CarboEtop (oral: 45%; IV: 55%) were administered; 106 (86%) 1st-line, 16 (13%) 2nd-line, and 1 (1%) 3rd-line. Disease control rate: 74.5% in 1st-line and 69.2% in 2nd/3rd-line, with no significant difference between oral and IV Etop in 1st-line (69.8 vs. 80.8%, p = 0.237). Median progression-free survival (PFS): 6.0 and 4.5 months in 1st-line and 2nd/3rd-line, respectively. Overall survival (OS): 11.5 and 12.5 months in 1st-line and 2nd/3rd-line, respectively. The schedule (oral versus IV Etop) did not impact on 1st-line PFS (5.6 vs. 6.2 months, p = 0.179), although there was a trend towards shorter OS (8.9 vs. 12.1 months, p = 0.069). Liver metastases correlated with worse 1st-line PFS (p = 0.015) and 1st-line OS (p < 0.001) on multivariable analysis. The commonest grade 3-4 adverse event was myelosuppression (49%), with comparable toxicity between oral and IV Etop, except for venous thromboembolism (12.5 vs. 1.7%, p = 0.04). CONCLUSIONS: CarboEtop for advanced EP-PD-NEC is active, effective, and well-tolerated. Oral and IV Etop schedules are associated with comparable toxicity; activity should be compared in larger cohorts.