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There is a critical need for novel therapies to treat patients with advanced biliary tract cancer (BTC). This systematic review summarizes the evidence-based knowledge for the potential role of PD-1 and PD-L1 monoclonal antibodies in the treatment of patients with early-stage and advanced BTC. An Embase database search was conducted, identifying 15 eligible phase II/III clinical trials for review. Results from recent phase III trials show a statistically significant overall survival (OS) benefit from the addition of PD-1/PD-L1 inhibitors to chemotherapy in the first-line management of advanced BTC. Future research should concentrate on the discovery of biomarkers to identify patients who would benefit most from these therapies.

Background: Co-existing frailty in older patients with hepatopancreaticobiliary (HPB) malignancies is common. This study assessed the relationship between the Rockwood Clinical Frailty scale (CFS) and systemic anti-cancer therapy dose intensity (SACT-DI) and overall survival (OS) in patients with advanced HPB malignancies. Research design and methods: CFS was assessed prospectively for consecutive patients with newly diagnosed advanced HPB malignancy (The Christie; Sep-2019 to June-2020). Mann-Whitney U test assessed association between CFS, ECOG Performance Status (ECOG PS), and SACT-DI and Spearman’s rank assessed the association between ECOG PS, age, and frailty. Survival analysis was performed using Kaplan-Meier and Cox regression. Results: Two hundred patients met inclusion criteria. SACT-DI was higher in Group-1 (not frail) (CFS 1–3)(median = 61%) than Group-2 (vulnerable/mildly frail) (CFS 4–5)(median = 25.1%), p

Phase 3 trials have established standard first-line (1L) and 2L systemic therapy options for patients with advanced biliary cancer (ABC). However, a standard 3L treatment remains undefined. Clinical practice and outcomes for 3L systemic therapy in patients with ABC were therefore evaluated from three academic centres. Included patients were identified using institutional registries; demographics, staging, treatment history, and clinical outcomes were collected. Kaplan–Meier methods were used to assess progression-free survival (PFS) and overall survival (OS). Ninety-seven patients, treated between 2006 and 2022, were included; 61.9% had intrahepatic cholangiocarcinoma. At the time of analysis, there had been 91 deaths. Median PFS from initiating 3L palliative systemic therapy (mPFS3) was 3.1 months (95%CI 2.0–4.1), while mOS3 was 6.4 months (95%CI 5.5–7.3); mOS1 was 26.9 months (95%CI 23.6–30.2). Among patients with a therapy-targeted molecular aberration (10.3%; n = 10; all received in 3L), mOS3 was significantly improved versus all other included patients (12.5 vs. 5.9 months; p = 0.02). No differences in OS1 were demonstrated between anatomical subtypes. Fourth-line systemic therapy was received by 19.6% of patients (n = 19). This international multicentre analysis documents systemic therapy use in this select patient group, and provides a benchmark of outcomes for future trial design.

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly common cancer with a persistently poor prognosis, and only approximately 20% of patients are clearly anatomically resectable at diagnosis. Historically, a paucity of effective therapy made it inappropriate to forego the traditional gold standard of upfront surgery in favour of neoadjuvant treatment; however, modern combination chemotherapy regimens have made neoadjuvant therapy increasingly viable. As its use has expanded, the rationale for neoadjuvant therapy has evolved from one of 'downstaging' to one of early treatment of micro-metastases and selection of patients with favourable tumour biology for resection. Defining resectability in PDAC is problematic; multiple differing definitions exist. Multidisciplinary input, both in initial assessment of resectability and in supervision of multimodality therapy, is therefore advised. European and North American guidelines recommend the use of neoadjuvant chemotherapy in borderline resectable (BR)-PDAC. Similar regimens may be applied in locally advanced (LA)-PDAC with the aim of improving potential access to curative-intent resection, but appropriate patient selection is key due to significant rates of recurrence after excision of LA disease. Upfront surgery and adjuvant chemotherapy remain standard-of-care in clearly resectable PDAC, but multiple trials evaluating the use of neoadjuvant therapy in this and other localised settings are ongoing.

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.

Poorly differentiated neuroendocrine carcinomas (PD-NEC) are rare cancers garnering interest as they become more commonly encountered in the clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of “NE lineage plasticity,” whereby nonneuroendocrine (non-NE) epithelial cancers transition to aggressive NE phenotypes after targeted treatment. Effective treatment options for patients with PD-NEC are challenging for several reasons. This includes a lack of targetable, recurrent molecular drivers, a paucity of patient-relevant preclinical models to study biology and test novel therapeutics, and the absence of validated biomarkers to guide clinical management. Although advances have been made pertaining to molecular subtyping of small cell lung cancer (SCLC), a PD-NEC of lung origin, extrapulmonary (EP)-PD-NECs remain understudied. This review will address emerging SCLC-like, same-organ non-NE cancer-like and tumor-type–agnostic biological vulnerabilities of EP-PD-NECs, with the potential for therapeutic exploitation. The hypotheses surrounding the origin of these cancers and how “NE lineage plasticity” can be leveraged for therapeutic purposes are discussed. SCLC is herein proposed as a paradigm for supporting progress toward precision medicine in EP-PD-NECs. The aim of this review is to provide a thorough portrait of the current knowledge of EP-PD-NEC biology, with a view to informing new avenues for research and future therapeutic opportunities in these cancers of unmet need.

Background Advanced hepatocellular carcinoma (HCC) is commonly diagnosed using non-invasive radiological criteria (NIRC) defined by the European Association for the Study of the Liver or the American Association for the Study of Liver Diseases. In 2017, The National Institute for Clinical Excellence mandated histological confirmation of disease to authorise the use of sorafenib in the UK. Methods This was a prospective multicentre audit in which patients suitable for sorafenib were identified at multidisciplinary meetings. The primary analysis cohort (PAC) was defined by the presence of Child-Pugh class A liver disease and performance status 0–2. Clinical, radiological and histological data were reported locally and collected on a standardised case report form. Results Eleven centres reported 418 cases, of which 361 comprised the PAC. Overall, 76% had chronic liver disease and 66% were cirrhotic. The diagnostic imaging was computed tomography in 71%, magnetic resonance imaging in 27% and 2% had both. Pre-existing histology was available in 45 patients and 270 underwent a new biopsy, which confirmed HCC in 93.4%. Alternative histological diagnoses included cholangiocarcinoma (CC) and combined HCC-CC. In cirrhotic patients, NIRC criteria had a sensitivity of 65.4% and a positive predictive value of 91.4% to detect HCC. Two patients (0.7%) experienced mild post-biopsy bleeding. Conclusion The diagnostic biopsy is safe and feasible for most patients eligible for systemic therapy

Introduction: Pancreatic exocrine insufficiency (PEI) in patients with advanced pancreatic cancer (aPC) is well documented, but there is no consensus regarding optimal screening. Methods and analysis: Patients diagnosed with aPC referred for palliative therapy were prospectively recruited. A full dietetic assessment (including Mid-Upper Arm Circumference (MUAC), handgrip and stair-climb test), nutritional blood panel, faecal elastase (FE-1) and 13C-mixed triglyceride breath tests were performed. Primary objective: prevalence of dietitian-assessed PEI (demographic cohort (De-ch)); design (diagnostic cohort (Di-ch)) and validation (follow-up cohort (Fol-ch)) of a PEI screening tool. Logistic and Cox regressions were used for statistical analysis. Results: Between 1 July 2018 and 30 October 2020, 112 patients were recruited (50 (De-ch), 25 (Di-ch) and 37 (Fol-ch)). Prevalence of PEI (De-ch) was 64.0% (flatus (84.0%), weight loss (84.0%), abdominal discomfort (50.0%) and steatorrhea (48.0%)). The derived PEI screening panel (Di-ch) included FE-1 (normal/missing (0 points); low (1 point)) and MUAC (normal/missing (>percentile 25) (0 points); low (2 points)) and identified patients at high-risk (2–3 total points) of PEI [vs. low-medium risk (0–1 total points)]. When patients from the De-ch and Di-ch were analysed together, those classified by the screening panel as “high-risk” had shorter overall survival (multivariable Hazard Ratio (mHR) 1.86 (95% CI 1.03–3.36); p-value 0.040). The screening panel was tested in the Fol-ch; 78.4% patients classified as “high-risk”, of whom 89.6% had dietitian-confirmed PEI. The panel was feasible for use in clinical practice (64.8% patients completed all assessments), with high acceptability (87.5% would repeat it). Most patients (91.3%) recommended dietetic input for all patients with aPC. Conclusions: PEI is present in most patients with aPC; early dietetic input provides a holistic nutritional overview, including, but not limited to, PEI. This proposed screening panel may help to prioritise those at higher risk of PEI, requiring urgent dietitian input. Its prognostic role needs further validation.

Introduction The aim of the study is to estimate the cost-effectiveness of TheraSphere against other embolic treatments in a population with early to intermediate stage hepatocellular carcinoma (HCC) who are unresectable at presentation and are eligible for transarterial embolization (TAE), conventional transarterial chemoembolization (cTACE) or drug-eluting bead TACE (DEB-TACE). Materials and methods A Markov model was constructed using a UK National Health Service (NHS) perspective, a 20-year time horizon, and four-week cycles. The eight health states included ‘watch and wait’, ‘transplantation’ (pre-, post and post (No HCC)), ‘resection’, ‘no HCC other’, ‘pharmacological management’ and ‘death’. Clinical data were sourced from literature and expert opinion. Resource use and costs were reflective of the NHS, and benefits were quantified using Quality-Adjusted Life Years (QALYs), with utility weights sourced from literature. Comparators were TAE, cTACE and DEB-TACE. The primary output was the Incremental Cost-Effectiveness Ratio (ICER) expressed as cost per QALY gained. An ICER of under £20,000/QALY gained for an intervention is cost-effective and represents efficient use of healthcare resources. Extensive deterministic and probabilistic sensitivity analyses were undertaken. Results TheraSphere patients were predicted to gain 0.7 additional QALYs compared to all other treatments. The base case ICERs for TheraSphere were £17,300, £17,279 and £23,020 per QALY gained compared to TAE, cTACE and DEB-TACE, respectively. In the TheraSphere cohort, 87% more patients were predicted to achieve downstaging compared to all other treatment options. Conclusions This study indicates that treatment with TheraSphere is a potentially cost-effective option for patients with early to intermediate stage HCC.

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. 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. 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. 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.

Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient’s cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.

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.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.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).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.

Hepatocellular carcinoma (HCC) is a frequent and increasing cause of cancerrelated deaths worldwide. Reversing this trend is complicated by the varied aetiological factors leading to liver cirrhosis resulting in molecular genetic and clinical heterogeneity, combined with frequent presentation at advanced stage. Large-scale genomic studies have identified alterations in key signalling pathways for HCC development and progression, but these findings have not yet directly influenced patient management in the clinical setting. Despite these translational challenges, a small number of anti-angiogenic systemic therapy agents have succeeded in recent randomized trials enriching the repertoire of available treatments for advanced HCC. In addition, the early promise of immune checkpoint inhibition is now on the cusp of delivering changes to standard systemic therapy algorithms. This review focuses on recent translational and clinical developments that have advanced current practice and explores the challenges encountered in attempting to improve the outcomes and experience of patients diagnosed with advanced HCC.

Background In the Phase 3 REFLECT trial in patients with unresectable hepatocellular carcinoma (uHCC), the multitargeted tyrosine kinase inhibitor, lenvatinib, was noninferior to sorafenib in the primary outcome of overall survival. Post-hoc review revealed imbalances in prognostic variables between treatment arms. Here, we re-analyse overall survival data from REFLECT to adjust for the imbalance in covariates. Methods Univariable and multivariable adjustments were undertaken for a candidate set of covariate values that a physician panel indicated could be prognostically associated with overall survival in uHCC. The values included baseline variables observed pre- and post-randomisation. Univariable analyses were based on a stratified Cox model. The multivariable analysis used a “forwards stepwise” Cox model. Results Univariable analysis identified alpha-fetoprotein (AFP) as the most influential variable. The chosen multivariable Cox model analysis resulted in an estimated adjusted hazard ratio for lenvatinib of 0.814 (95% CI: 0.699–0.948) when only baseline variables were included. Adjusting for post-randomisation treatment variables further increased the estimated superiority of lenvatinib. Conclusions Covariate adjustment of REFLECT suggests that the original noninferiority trial likely underestimated the true effect of lenvatinib on overall survival due to an imbalance in baseline prognostic covariates and the greater use of post-treatment therapies in the sorafenib arm. Trial registration Trial number: NCT01761266 (Submitted January 2, 2013).

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.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis and significant symptom burden. This prospective observational study aimed to evaluate expectations and priorities of patients with advanced PDAC and their clinicians through a study survey and two quality of life (QoL) questionnaires (QLQ-C30 and PAN26) at three time-points: baseline (T1), before (T2) and after (T3) their 1st on-treatment CT scan. Over a 1-year period, 106 patients were approached, 71 patients and 12 clinicians were recruited. Choosing between treatment options, patients prioritised: 54% overall survival (OS), 26% balance between side-effects and OS, 15% could not choose and 5% favoured symptom control. These were significantly different from the clinician’s answers (p < 0.001). Patients who prioritised OS had higher symptom burden (p = 0.03) and shorter OS compared to those who prioritised balance (p = 0.01). Most (86%) patients had personal goals they wanted to reach; clinicians knew of these in 12% of instances. Patient and clinicians’ views regarding survival improvement from chemotherapy were significantly different: 81% of clinicians and 12% of patients thought 1–2 or 3–6 months extension, 58% of patients and 0% physicians thought 1–5 or >5 years (p < 0.001). At T1, patients had low QoL and worst symptoms were: ‘Future worries’, ‘planning of activities’, fatigue and pain. Patients were willing to accept significantly higher amounts of side-effects as a trade-off for extra time, than clinicians thought (p < 0.001). Overall, there are significant discrepancies between patient and clinicians’ views about the aims, priorities and expected extension of life.Keywords: pancreatic cancer; quality of life; patient views on treatment

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.

ObjectivesAn algorithm was designed aiming to provide consistency of pancreatic enzyme replacement therapy (PERT) dosing/titration across healthcare professionals in pancreaticobiliary cancers (PBC). This prospective observational study aimed to validate this algorithm.MethodsConsecutive patients with inoperable or post-operative PBC with pancreatic exocrine insufficiency (PEI) symptoms, not taking PERT, or taking below the algorithm ‘starting dose’, were eligible. A dietitian or clinical nurse specialist reviewed patients for up to 3 weeks, titrating PERT as per the algorithm. Feasibility of algorithm deliverability was assessed by the percentage of patients with successful completion (primary objective). ResultsEligible patients (n = 25): at baseline 22 taking PERT [100% on suboptimal doses, 54.5% taking incorrectly], 3 initiated PERT due to PEI symptoms. Algorithm completion 20/25 (80%) patients, confirming deliverability by dietitians (11/12; 92%) and Clinical nurse specialist (9/13; 69%). Symptom resolution in 8/19 (42%), 3/7 (43%) and 1/3 (33%) patients at 1st, 2nd and 3rd reviews, respectively; advice compliance between 63-86%. ConclusionThis algorithm provides a structured method to titrate PERT. At diagnosis, all patients with PBC should be assessed for PEI and adequate PERT initiated. Regular reviews are required for timely symptom resolution and adequate escalation, facilitating differential diagnosis if refractory symptoms exist.Key wordsPancreatic Exocrine Insufficiency; Pancreatic Cancer; Pancreatic Enzyme Replacement Therapy

293 Background: NET-02 was a multi-centre, randomised (1:1), non-comparative phase II trial of nal-IRI/5-FU/folinic acid (ARM A) or docetaxel (ARM B) in pts with progressive PD-EP-NEC, aimed at selecting a treatment for evaluation in a phase III trial. Primary analysis (N = 58) showed ARM A, but not ARM B, achieved the target 6-month progression-free survival rate primary endpoint (McNamara et al. ASCO 2022). HRQoL was a secondary endpoint in NET-02. Methods: HRQoL was assessed using the EORTC QLQ-C30 and GINET21 (at baseline (BL), 6-weekly intervals and at disease progression). The mean change from BL was estimated for each scale by timepoint and treatment arm. Results are presented where there were ≥4 responses per time point. Scores were considered stable if they did not change by > 10 points from BL. The mean BL C30 scores for all pts were compared to United Kingdom (UK) population normative C30 data using a 2-sample t-test. Results: Fifty-four of 58 pts (93%) completed a BL questionnaire; of these, 39 (72%) completed ≥1 post-BL questionnaire, with 21 (51%) completing questionnaires at progression. Global health status (GHS) and all functional scales in ARM A remained stable from BL to intervals pre-progression, with a sustained improvement in role functioning observed post-BL. In ARM B, GHS and all C30 functional scales decreased by > 10 points between BL and week 18 (worsening of QoL). Both arms had a > 10-point increase from BL in constipation and diarrhoea in ≥1 post-BL time point. In ARM A, pain, insomnia and financial problems decreased from BL. No C30 symptom scales in ARM B were consistently lower post-BL. Patterns of change in GINET21 mean score were similar in both arms: body image, disease-related worries, information/communication, sexual function and social function all had a > 10-point reduction in score from BL (indicating improvement in symptoms/problems); endocrine and gastrointestinal symptoms remained stable; muscle/bone pain varied across time points, initially showing a reduction in pain followed by an increase, compared to BL. In comparison to the UK C30 norms (BL all pts), 11 of 15 C30 scales did not significantly differ (P > 0.05). Mean scores for fatigue and appetite loss were significantly higher than UK C30 norms (worse symptoms in pts from NET-02) (P = 0.03, P = 0.0003 respectively). However, emotional functioning and GHS were significantly better in pts from NET-02 (P = 0.001, P = 0.03 respectively). Role and social functioning were lower in pts from NET-02 (both P = 0.06) (poorer level of functioning). Conclusions: HRQoL was maintained and potentially improved with nal-IRI/5-FU/folinic acid, but not docetaxel. Compared to the UK general population, BL QoL did not substantially differ in pts from NET-02. Clinical trial information: NCT03837977.

BackgroundLocoregional treatments (LRT) including radioembolisation (SIRT), transarterial chemo-embolisation (TACE), hepatic arterial infusion (HAI) of chemotherapy, external beam radiotherapy (EBRT) and ablation have been studied for the management of intrahepatic cholangiocarcinoma (iCC). The aim of this systematic review was to provide outcome benchmarks for clinical trial design.MethodsIdentification of studies reporting outcomes of patients treated with LRT for iCC was performed using PubMed and Embase. Pooled weighted means were calculated for progression-free survival (PFS) and overall survival (OS); meta-analysis of proportions was used for estimation of pooled response rate.Results6325 entries were reviewed; 93 studies were eligible, representing 101 cohorts and 3990 patients: 15 cohorts (645 patients) for ablation, 18 cohorts (541 patients) for EBRT, 27 cohorts (1232 patients) for SIRT, 22 cohorts (1145 patients) for TACE, 16 cohorts (331 patients) for HAI and 3 cohorts (96 patients) not pooled. 74% of the studies were retrospective, 99% non-randomised.The pooled mean weighted OS was 30.2 months (95% confidence interval (CI): 21.8–38.6) for ablation, 18.9 (14.2–23.5) for EBRT, 14.1 (12.1–16.0) for SIRT, 15.9 (12.9–19.0) for TACE and 21.3 (15.4–27.1) for HAI. The pooled complete response rate was 93.9% for ablation. When analysed together, SIRT, TACE and HAI had a pooled mean weighted OS of 15.7 months, and 25.2 months for patients treated in first-line with concomitant systemic chemotherapy.ConclusionsAvailable literature on LRT for iCC was heterogeneous and of insufficient quality to make strong recommendations. Ablation achieved satisfactory outcomes, and may be recommended when surgery is not feasible.

Gastroenteropancreatic neoplasms (GEP-NENs)can potentially be cured through surgical resection, but only 42-57% achieve 5-year disease-free survival.There is a lack of consensus regarding the factorsassociated withrelapse followingresection ofGEP-NENs.Asystematic review identified studies reporting factors associated with relapse in patients with GEP-NENs following resection of a primary tumour. Meta-analysis was performed to identify the factors prognostic for relapse-free survival (RFS)oroverall survival (OS).63 studies comprising 13,715 patients were included; 56 studies reported on pancreatic NENs (12,418 patients), 24 reported on patients with grade 1-2 tumours (4,735 patients). Median follow-up was 44.2 months, median RFS was 32 months. Pooling of multivariable analyses of GEP-NENs (all sites and grades) found the following factors predicted worse RFS (all p values 0.05): vascular resection performed, metastatic disease resected, grade 2 disease, grade 3 disease, tumour size 20 mm, R1 resection, microvascular invasion, perineural invasion, Ki-67 5% and any lymph node positivity. In a subgroup of studies comprising exclusively of grade 1-2 GEP-NENs, R1 resection, perineural invasion, grade 2 disease, any lymph node positivity and tumour size 20 mm predicted worse RFS (all p values 0.05). Few OSdata were available for pooling; in univariableanalysis(entire cohort), grade 2 predicted worse OS (p = 0.007), whileR1 resectiondid not (p = 0.14).The factors prognostic for worse RFS following resection of a GEP-NEN identified in this meta-analysis could be included in post-curative treatment surveillance clinical guidelines and inform the stratification and inclusion criteria of future adjuvant trials.

Purpose: This study aimed to evaluate the feasibility and repeatability of [18F]-fluorothymidine positron emission tomography (FLT-PET) and its utility as a proliferative imaging marker to evaluate response in patients with advanced pancreatic adenocarcinoma (PDAC) receiving gemcitabine-based chemotherapy. Methods: PDAC patients due to commence gemcitabine-based chemotherapy underwent FLT-PET over 60 minutes, before (baseline) and after 28 days of chemotherapy. Repeatability was assessed by a second FLT-PET scan within 7 days of baseline scan and before starting chemotherapy. Scans were assessed by two independent physician’s to determine inter-reporter concordance. FLT-PET uptake over 45-60 minutes was estimated as maximum and mean standardised uptake values (SUVmax and SUVmean). Exploratory analysis of tissue biomarkers was performed from archival tissue samples. Results: All 18 of the 21 patients consented who were imaged had primary tumour in-situ and 83% had metastases with 60% in liver. 17 patients received gemcitabine-based treatment. Thirty-five FLT-PET scans were acquired (89% evaluable) and 26 lesions delineated (17 primary tumours, 9 liver metastases). At baseline, liver metastases showed higher uptake compared with primary tumour with mean (SD) SUVmax [7.2 (1.1) vs 4.5 (1.3); p < 0.001] and SUVmean [4.7 (0.6) vs 2.1 (0.6); p < 0.001)]. There was good intra-patient repeatability and inter-reporter concordance with mean (SD) test-retest difference and inter-reporter Lin’s concordance coefficient being 4.9% (17.6) and 0.703 for SUVmax and -5.4% (SD 9.8) and 0.710 for SUVmean, respectively. FLT uptake between baseline and post-treatment scans were variable and did not predict for benefit from gemcitabine. However, gemcitabine-capecitabine combination therapy resulted in a higher FLT uptake compared to gemcitabine alone, although this did not translate to clinical benefit. No relationship was observed between tissue markers and FLT in half subjects imaged whose tissue was available. Conclusions FLT-PET is a feasible and reproducible imaging technique in patients with PDAC to evaluate proliferation-targeting therapy, using a simplified imaging protocol in well-designed clinical trials.

BACKGROUND Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare diagnosis, mainly encountered in the gastro-entero-pancreatic tract. There is limited knowledge of its epidemiology, prognosis and biology, and the best management for affected patients is still to be defined. AIM To investigate clinical-pathological characteristics, treatment modalities and survival outcomes of a retrospective cohort of patients with a diagnosis of MiNEN. METHODS Consecutive patients with a histologically proven diagnosis of MiNEN were identified at 5 European centres. Patient data were retrospectively collected from medical records. Pathological samples were reviewed to ascertain compliance with the 2017 World Health Organisation definition of MiNEN. Tumour responses to systemic treatment were assessed according to the Response Evaluation Criteria in Solid Tumours 1.1. Kaplan-Meier analysis was applied to estimate survival outcomes. Associations between clinical-pathological characteristics and survival outcomes were explored using Log-rank test for equality of survivors functions (univariate) and Cox-regression analysis (multivariable). RESULTS Sixty-nine consecutive patients identified; Median age at diagnosis: 64 years. Males: 63.8%. Localised disease (curable): 53.6%. Commonest sites of origin: colon-rectum (43.5%) and oesophagus/oesophagogastric junction (15.9%). The neuroendocrine component was; predominant in 58.6%, poorly differentiated in 86.3%, and large cell in 81.25%, of cases analysed. Most distant metastases analysed (73.4%) were occupied only by a poorly differentiated neuroendocrine component. Ninety-four percent of patients with localised disease underwent curative surgery; 53% also received perioperative treatment, most often in line with protocols for adenocarcinomas from the same sites of origin. Chemotherapy was offered to most patients (68.1%) with advanced disease, and followed protocols for pure neuroendocrine carcinomas or adenocarcinomas in equal proportion. In localised cases, median recurrence free survival (RFS); 14.0 mo (95%CI: 9.2-24.4), and median overall survival (OS): 28.6 mo (95%CI: 18.3-41.1). On univariate analysis, receipt of perioperative treatment (vs surgery alone) did not improve RFS (P = 0.375), or OS (P = 0.240). In advanced cases, median progression free survival (PFS); 5.6 mo (95%CI: 4.4-7.4), and median OS; 9.0 mo (95%CI: 5.2-13.4). On univariate analysis, receipt of palliative active treatment (vs best supportive care) prolonged PFS and OS (both, P < 0.001). CONCLUSION MiNEN is most commonly driven by a poorly differentiated neuroendocrine component, and has poor prognosis. Advances in its biological understanding are needed to identify effective treatments and improve patient outcomes.

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 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.

BACKGROUNDIdentification of germ-line mutations in pancreatic ductal adenocarcinoma (PDAC) could impact on patient/family.AIMTo assess the referral pathways for genetic consultations in PDAC.METHODSElectronic records of PDAC patients were reviewed retrospectively. Patients eligible for genetic consultation referral were identified following the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) criteria. RESULTSFour-hundred patients were eligible. Of 113 patients (28.3%) meeting EUROPAC criteria, 8.8% were referred for genetic opinion. Germ-line mutations were identified in 0.75% of the whole population.CONCLUSION Earlier referrals and increased awareness may be able to overcome the low rate of successful genetic appointments.

Background Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of ≥1 year) in the NAPOLI-1 trial. Patients and methods Patients with mPDAC were randomised to receive nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 151), or 5-FU/LV (n = 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived ≥1 year. Through 16th November 2015, 382 overall survival events had occurred. Results The overall survival advantage for nal-IRI+5-FU/LV vs 5-FU/LV was maintained from the original nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) analysis (6.2 vs 4.2 months, respectively; HR, 0.75; 95% confidence interval: 0.57–0.99). Median progression-free survival, objective response rate and disease control rate also favoured nal-IRI+5-FU/LV therapy. Estimated one-year overall survival rates were 26% with nal-IRI+5-FU/LV and 16% with 5-FU/LV. Baseline characteristics associated with long-term survival in the nal-IRI+5-FU/LV arm were Karnofsky performance status ≥90, age ≤65 years, lower CA19-9 levels, neutrophil-to-lymphocyte ratio ≤5 and no liver metastases. No new safety concerns were detected. Conclusions The survival benefits of nal-IRI+5-FU/LV versus 5-FU/LV were maintained over an extended follow-up, and prognostic markers of survival ≥1 year were identified. Clinical trial registration number NCT01494506 .

IntroductionPancreatic exocrine insufficiency (PEI) in patients with pancreatic malignancy is well documented in the literature and is known to negatively impact on overall survival and quality of life. A lack of consensus opinion remains on the optimal diagnostic test that can be adapted for use in a clinical setting for this cohort of patients. This study aims to better understand the prevalence of PEI and the most suitable diagnostic techniques in patients with advanced pancreatic malignancy.Methods and analysisThis prospective observational study will be carried out in patients with pancreatic malignancy (including adenocarcinoma and neuroendocrine neoplasms). Consecutive patients with inoperable pancreatic malignancy referred for consideration of first-line chemotherapy will be considered for eligibility. The study comprises three cohorts: demographic cohort (primary objective to prospectively investigate the prevalence of PEI in patients with inoperable pancreatic malignancy); sample size 50, diagnostic cohort (primary objective to design and evaluate an optimal diagnostic panel to detect PEI in patients with inoperable pancreatic malignancy); sample size 25 and follow-up cohort (primary objective to prospectively evaluate the proposed PEI diagnostic panel in a cohort of patients with inoperable pancreatic malignancy); sample size 50. The following is a summary of the protocol and methodology.Ethics and disseminationFull ethical approval has been granted by the North West Greater Manchester East Research and Ethics Committee, reference: 17/NW/0597. This manuscript reflects the latest protocol V.8 approved 21 April 2020. Findings will be disseminated by presentation at national/international conferences, publication in peer-review journals and distribution via patient advocate groups.Trial registration number194255, NCT0361643.

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.

Background and purpose Combined mTORC1 inhibition with everolimus (EVE) and phosphatidylinositol 3-kinase catalytic subunit p110α blockade with alpelisib (ALP) has demonstrated synergistic efficacy in preclinical models and supports testing the combination of ALP and EVE in the clinical setting. The primary objective was to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of ALP in combination with EVE and in combination with EVE and exemestane (EXE) and subsequently assess safety, preliminary efficacy and effect of ALP on the pharmacokinetics of EVE and determine the magnitude of the drug-drug interaction. Patients and methods Dose escalation phases were conducted in patients with advanced solid tumours and in postmenopausal women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC). The dose expansion phase was conducted in patients with pancreatic neuroendocrine tumour and renal cell carcinoma (RCC) (both mechanistic target of rapamycin inhibitor [mTORi]–naive), in patients with mTORi-pretreated solid tumours and in postmenopausal women with HR+, HER2– ABC. Results During the doublet escalation phase, dose-limiting toxicities (DLTs) were reported in 5 of 10 (50%) patients: one patient had grade (Gr) 2 hyperglycemia and one patient had Gr 3 diarrhoea in the 300 mg dose group, one patient had Gr 2 hyperglycemia and one patient had Gr 4 hypocalcaemia in the 250 mg dose group, and one patient in the 200 mg dose group had Gr 3 diarrhoea and Gr 3 stomatitis. The combination of ALP 250 mg + EVE 2.5 mg was declared as the MTD/RDE in subjects with advanced solid tumours. In the triplet escalation phase, one patient who received ALP 200 mg + EVE 2.5 mg + EXE 25 mg had a DLT of Gr 3 acute kidney injury. This dose combination was declared as the MTD and RDE in subjects with advanced HR-positive HER2-negative BC. The common adverse events (≥30% patients), occurring across all phases, were hyperglycaemia, stomatitis, diarrhoea, nausea, asthenia, decreased appetite and fatigue. The sixteen-week progression-free survival rate was 52.4% (90% confidence interval [CI]: 32.8, 71.4) in the RCC cohort, 35.3% (90% CI: 16.6, 58.0) in the prior pNET cohort and 30.0% (90% CI: 8.7, 60.7) in the prior mTORi cohort. The pharmacokinetics of 2.5 mg of EVE was largely unchanged in the presence of ALP, independent of the dose (250 mg or 300 mg). There were no clinically relevant drug-drug interactions observed between ALP and EVE. Conclusion The overall safety profile of ALP with EVE and EXE is manageable and reversible; no unexpected safety signals were noted compared with the individual safety profiles. Pharmacokinetics of ALP, EVE and EXE was largely unchanged in combination with each other.

Pancreatic ductal adenocarcinoma has historically been considered refractory to systemic chemotherapy. The past two decades have seen the stepwise development of active regimens in the setting of advanced disease. From the emergence of gemcitabine monotherapy in 1997, through the development of active gemcitabine-based doublet combinations, we have arrived at FOLFIRINOX, currently the most active regimen in this disease. The choice of regimen is largely based on an individual patient’s performance status after weighing up the potential benefits, toxicities and impact on quality of life. Second-line chemotherapy options have also emerged for patients remaining fit enough to consider additional chemotherapy. In this era of precision medicine, the first indication of benefit has been seen in the improvement in progression-free survival in patients with germline mutation in BRCA-1/-2 after induction platinum-based chemotherapy, highlighting the importance of germline testing in this disease. Many challenges remain in this highly aggressive malignancy including development of highly efficacious therapies targeting intracellular pathways as well as the tumour stroma, and learning to harness the immune response.

Introduction: Cholangiocarcinomas (CCA) are rare tumors that are associated with a variety of molecular alterations. Many of these alterations are now actionable using drugs currently in development, and CCA may be a perfect example of application of a precision oncology approach. However, development of drugs in CCA faces the challenge of targeting rare alterations in a rare disease.Areas covered: In this review, we present the current data on targeted therapies in development for CCA, focusing on IDH1, FGFR2, BRAF, and HER2 alterations. We also discuss rationale for targeting other alterations, currently without specific development in CCA. We searched PubMed and google scholar in February 2021 for relevant articles and presentation in recent congress regarding the literature on molecular alterations, drugs in cholangiocarcinomas and biliary tract cancers.Expert opinion: Despite a strong rationale and promising early results, applying a precision oncology approach in CCA for everyday patients is still exposed to significant challenges: obtaining the molecular portrait of these tumors due to difficulties with biopsy access, complexities of drug development in subgroups of these relatively rare tumors, and sub-optimal access to drugs outside clinical trials.

Objective This systematic review and meta-analysis aimed to develop an evidence-based summary of current knowledge of bone metastases (BMs) in neuroendocrine neoplasms (NENs), inform diagnosis and treatment and standardise management between institutions. Methods PubMed, Medline, EMBASE and meeting proceedings were searched for eligible studies reporting data on patients with BMs and NENs of any grade of differentiation and site; poorly-differentiated large/small cell lung cancer were excluded. Data were extracted and analysed using STATA v.12. Meta-analysis of proportions for calculation of estimated pooled prevalence of BM and calculation of weighted pooled frequency and weighted pooled mean for other variables of interest was performed . Results A total of 149 studies met the eligibility criteria. Pooled prevalence of BMs was 18.4% (95% CI 15.4–21.5). BMs were mainly metachronous with initial diagnosis of NEN (61.2%) and predominantly osteoblastic; around 61% were multifocal, with a predisposition in axial skeleton. PET/CT seemed to provide (together with MRI) the highest sensitivity and specificity for BM detection. Almost half of patients (46.4%) reported BM-related symptoms: pain (66%) and skeletal-related events (SREs, fracture/spinal cord compression) (26.2%; weightedweighted mean time-to-SRE 9.9 months). Management of BMs was multimodal [bisphosphonates and bone-modifying agents (45.2%), external beam radiotherapy (34.9%), surgery (14.8%)] and supported by little evidence. Overall survival (OS) from the time of diagnosis of BMs was long [weighted mean 50.9 months (95% CI 40.0–61.9)]. Patients with BMs had shorter OS [48.8 months (95% CI 37.9–59.6)] compared to patients without BMs [87.4 months (95% CI 74.9–100.0); p = 0.001]. Poor performance status and BM-related symptoms were also associated with worse OS. Conclusions BMs in patients with NENs remain underdiagnosed and undertreated. Recommendations for management of BMs derived from current knowledge are provided. Prospective studies to inform management are required.

Background: Neuroendocrine tumours (NETs) are a rare and heterogeneous group of neoplasms that mainly originate from the gastroenteropancreatic tract (GEP-NETs). The vast majority of NETs tend to overexpress somatostatin receptors (SSTRs), which can be targeted by somatostatin analogues (SSAs). 68Gallium DOTA SSTR peptide positron emission tracer computed tomography (68Ga PET-CT) has emerged as superior to other imaging modalities in identifying SSTRs. This study aimed to assess whether patients with GEP- NETs treated with SSAs have similar outcomes irrespective of tracer uptake intensity on 68Ga PET-CT.Methods: Patient cases undergoing 68Ga PET-CT imaging between November 2015 and September 2020 at The Christie NHS Foundation Trust, with diagnosis of histologically-confirmed advanced GEP-NETs receiving SSAs, were reviewed retrospectively. Kaplan-Meier and Cox regression were utilised to analyse progression free (PFS) and overall survival (OS).Results: Of 644 patients imaged with 68Ga PET-CT, 132 met inclusion criteria. The median age of patients was 62 years; ECOG performance status 0: 62 (47%), 1: 56 (42%), 2: 13 (10%); primary sites: ileum: 54 (41%), pancreas: 26 (20%), cancer of unknown primary: 20 (15%), Grade (G)1: 63 (47%), G2: 56 (42%), G3: 3 (2%), unknown: 11 (8%); 68Ga PET-CT tracer uptake increased: 124 (94%), no increased tracer uptake: 8 (6%). 66 patients (50%) progressed, and 99 (74%) were alive at analysis. Median PFS on SSAs was 20.82 months (95% confidence interval (CI) 12.2–30.03) for patients with increased tracer uptake (n=63) and 8.26 months (95% CI 4.55-not available (NA)) for patients with no increased tracer uptake (n=3) (Hazard Ratio (HR): 4.19 (95% CI 1.238–14.28), P=0.022). Median OS from commencement of SSA was: 99.51 months (95% CI 95.96 – NA) for patients with increased tracer uptake and 47.67 months for patients with no increased tracer uptake (95% CI 13.41 – NA) (HR 2.93 (95% CI 1.011–8.49), P=0.048).Conclusions: 68Ga PET-CT scans are an accurate tool for diagnosis and localisation of NETs. Median PFS and OS appears to be greater in patients receiving SSAs with increased uptake on the 68Ga PET-CT. However, further evaluation in larger cohorts is needed to definitively assess clinical benefit of SSAs in the 68Ga PET-CT negative cohort.

BACKGROUND Brain metastases (BMs) incidence in patients with extra-pulmonary neuroendocrine neoplasms (EP-NENs) is unclear, with no available management recommendations. This study aimed to review the clinical presentation, management and survival outcomes of patients with EP-NENs and BMs at a European Centre of Excellence. METHODS A retrospective single-centre analysis of consecutive patients with EP-NENs (Aug 2004-Feb 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis were estimated (Kaplan Meier). RESULTS Of 786 patients, 15 (1.9%) had BMs, median age 61y (range 15–77); 8 (53%) male, primary NEN site: unknown 40%; oesophageal 13%; small bowel 13%; pancreas 13%; gastric 7%; cervix 7% and bladder 7%. Most patients with BMs had grade 3 (G3) NENs (11, 73%), 3 (20%) were G2 and 1 (7%)G1. Eight (53%) had poorly-differentiated NENs, 6 well-differentiated and 1 not recorded. Two (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. Median time to development of BMs after initial NEN diagnosis: 15.9 months (range 2.5–139.5). Five patients had a solitary BM, 4 had 2–9 lesions and 6 had >10 BMs. The most commonly affected sites were the cerebrum (13, 87%), cerebellum (6, 40%), leptomeninges (2, 13%) and orbit (1, 7%). The most common presenting symptoms were limb weakness, headache, confusion, visual disturbance (each n=3, 20%), seizures (2, 13%), word-finding difficulty (2, 13%) and facial weakness/ptosis (1, 7%). Median OS from initial NEN diagnosis was 23.6-months [95%-CI 15.2–31.3]; median time to death from BMs diagnosis was 3.0-months [95%-CI 0.0–8.3]. Treatment of BMs was surgery (n=3); radiotherapy (n=6); 5 had WBRT, one localised radiotherapy (orbit). Six (40%) had best supportive care. CONCLUSION BMs in patients with EP-NENs are rare and predominantly in G3 NENs, with diverse intracranial distribution. Although uncommon, BMs from NENs behave aggressively and greater understanding is needed to improve therapeutic outcomes.

Background: Molecular profiling is becoming increasingly relevant in the management of patients with advanced cancer, to identify targetable aberrations and prognostic markers to enable a precision medicine strategy. Methods: Eligible patients were those diagnosed with advanced biliary tract cancer (BTC) including intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC), and ampullary carcinoma (Amp) who underwent molecular profiling between April 2017 and June 2020 based on analysis of either tumour samples (FoundationOne CDx&reg, /Oncomine&reg, platforms) or ctDNA (FoundationOne Liquid&reg, platform (Foundation Medicine, Cambridge, MA, USA)). Baseline patient characteristics and molecular profiling outcomes were extracted. The primary aim was to describe sample failure rate. Secondary aims included description of reason for sample failure, summary of findings derived from molecular profiling, and assessment of concordance between paired tissue and ctDNA samples. Results: A total of 149 samples from 104 individual patients diagnosed with advanced BTC were identified and eligible for this analysis: 68.2% iCCA, 100% advanced stage, 94.2% received palliative therapy. The rate of sample failure was 26.8% for tissue and 15.4% for ctDNA, p-value 0.220, predominantly due to insufficient (defined as &lt, 20%) tumour content in the sample (the reason for 91.2% of tissue sample failure). Of the 112 samples successfully analysed, pathological molecular findings were identified in the majority of samples (88.4%) and identification of pathological findings using ctDNA, was possible regardless of whether the patient was on active treatment at time of blood acquisition or not (p-value 1.0). The rate of targetable alterations identified was 40.2% across all successfully-analysed samples (39 iCCA, 6 non-iCCA): IDH1 mutations (19.1% of individual patients), FGFR2 alterations (10.1% and 5.6% of individual patients had FGFR2 fusions and mutations, respectively), 10.6% of all patients (12.4% of patients with successfully analysed samples) entered trials with matched targeted therapies as a consequence. Concordance of findings for paired tissue and paired tissue-ctDNA was high (3/3, 100% and 6/6, 100%, respectively). Twelve ctDNA samples were taken prior to palliative treatment initiation, median maximum mutant allele frequency (MAF) was 0.47 (range 0.21&ndash, 19.8), no significant association between reported maximum MAF and progression-free survival (PFS) or overall survival (OS) (all Cox regression p-values &gt, 0.273). A total of 15 patients (16.6%) harboured alterations in DNA damage repair (DDR) genes, when treated with platinum-based chemotherapy, there was a trend towards increased partial response rate (21.4% vs. 15.9%, p-value 0.653), radiological benefit rate (64.3% vs. 36.2%, p-value 0.071), and longer OS (median OS 20.4 months (95% CI 7.9&ndash, 26.7) vs. 13.3 (95 CI 11.0&ndash, 16.4), Cox Regression HR 0.79 (95% CI 0.39&ndash, 1.61), p-value 0.527). Conclusions: Molecular profiling is of use for identification of novel therapeutic strategies for patients with advanced BTC (mainly iCCA). One in four archived tissue samples may have insufficient tumour content for molecular profiling, ctDNA-based approaches may overcome these obstacles.