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Background: Biliary Tract Cancers (BTC) are rare malignancies with a poor prognosis. There are many challenges encountered in treating these patients in daily practice as well as in clinical, translational and basic research. Objective: This review summarises the most relevant challenges in clinical and translational research in BTCs and suggests potential solutions towards an improvement in quality of life and outcomes of patients diagnosed with such malignancies. Findings: The main challenge is the low number of patients with BTCs, complicated by the aggressive natural behaviour of cancer and the lack of funding sources for research. In addition, the clinical characteristics of these patients and the specific cancer-related complications challenge clinical research and clinical trial recruitment. It is worth highlighting that BTCs are a group of different malignancies (cholangiocarcinoma, gallbladder cancer and ampullary cancer) rather than a unique homogeneous disease. These subgroups differ not only in molecular aspects, but also in clinical and demographic characteristics. In addition, tailored imaging and quality of life assessment are required to tackle some of the issues specific to BTCs. Finally, difficulties in tissue acquisition both in terms of biopsy size and inclusion of sufficient tumour within the samples, may adversely impact translational and basic research. Conclusion: Increasing awareness among patients and clinicians regarding BTC and the need for further research and treatment development may address some of the main challenges in BTC research. International collaboration is mandatory to progress the field.

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.

Fibrolamellar carcinoma (FLC) is a rare and poorly understood malignancy, which seems to be more prevalent in young patients compared with conventional hepatocellular carcinoma (HCC). Performing prospective clinical trials recruiting patients diagnosed with FLC has proven challenging with scarce data available guiding clinical management. The use of a number of chemotherapy compounds in these patients, including cisplatin, epirubicin, 5-fluorouracil (5-FU) and recombinant interferon α-2B (IFN-α-2B), has been reported in the literature, mainly in the form of case reports. The most promising systemic therapy tested so far is the combination of 5-FU infusion and 3-weekly IFN-α-2B, based on results from a phase II clinical trial. This article provides an overview of our own experience with this treatment schedule for patients with FLC, confirming its activity and treatment-derived benefit in the real world. Current challenges being faced by healthcare professionals treating patients with advanced FLC are discussed, especially the increasingly limited access to IFN-α-2B, which could compromise the access to an active therapy in the coming future, and the difficulties in the development of new treatment options for advanced FLC.

BACKGROUND The prognostic significance of lymph nodes (LNs) metastases and the optimum number of LN yield in gastroenteropancreatic neuroendocrine tumours (GEP NETs) undergoing curative resection is still debatable. Many studies have demonstrated that cure rate for patients with GEP NETs can be improved by the resection of the primary tumour and regional lymphadenectomy AIM To evaluate the effect of lymph node (LN) status and yield on relapse-free survival (RFS) and overall survival (OS) in patients with resected GEP NETs. METHODS Data on patients who underwent curative resection for GEP NETs between January 2002 and March 2017 were analysed retrospectively. Grade 3 tumours (Ki67 > 20%) were excluded. Univariate Cox proportional hazard models were computed for RFS and OS and assessed alongside cut-point analysis to distinguish a suitable binary categorisation of total LNs retrieved associated with RFS. RESULTS A total of 217 patients were included in the study. The median age was 59 years (21-97 years) and 51% (n = 111) were male. Primary tumour sites were small bowel (42%), pancreas (25%), appendix (18%), rectum (7%), colon (3%), gastric (2%), others (2%). Median follow up times for all patients were 41 mo (95%CI: 36-51) and 71 mo (95%CI: 63–76) for RFS and OS respectively; 50 relapses and 35 deaths were reported. LNs were retrieved in 151 patients. Eight or more LNs were harvested in 106 patients and LN positivity reported in 114 patients. Three or more positive LNs were detected in 62 cases. The result of univariate analysis suggested perineural invasion (P = 0.0023), LN positivity (P = 0.033), LN retrieval of ≥ 8 (P = 0.047) and localisation (P = 0.0049) have a statistically significant association with shorter RFS, but there was no effect of LN ratio on RFS: P = 0.1 or OS: P = 0.75. Tumour necrosis (P = 0.021) and perineural invasion (P = 0.016) were the only two variables significantly associated with worse OS. In the final multivariable analysis, localisation (pancreas HR = 27.33, P = 0.006, small bowel HR = 32.44, P = 0.005), and retrieval of ≥ 8 LNs (HR = 2.7, P = 0.036) were independent prognostic factors for worse RFS. CONCLUSION An outcome-oriented approach to cut-point analysis can suggest a minimum number of adequate LNs to be harvested in patients with GEP NETs undergoing curative surgery. Removal of ≥ 8 LNs is associated with increased risk of relapse, which could be due to high rates of LN positivity at the time of surgery. Given that localisation had a significant association with RFS, a prospective multicentre study is warranted with a clear direction on recommended surgical practice and follow-up guidance for GEP NETs. Chiramel J, Almond R, Slagter A, Khan A, Wang X, Lim KHJ, Frizziero M, Chakrabarty B, Minicozzi A, Lamarca A, Mansoor W, Hubner RA, Valle JW, McNamara MG. Prognostic importance of lymph node yield after curative resection of gastroenteropancreatic neuroendocrine tumours. World J Clin Oncol 2020; 11(4): 205-216 [PMID: 32355642 DOI: 10.5306/wjco.v11.i4.205]

Receptor tyrosine kinases (RTKs) are widely expressed transmembrane proteins that act as receptors for growth factors and other extracellular signalling molecules. Upon ligand binding, RTKs activate intracellular signalling cascades, and as such are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis, and survival under physiological as well as pathological conditions. Aberrant RTK activation can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogene and proto-oncogene transcripts involved in cancer code for RTKs. Consequently, these receptors are broadly studied as targets in the treatment of different tumours, and a large variety of small-molecule tyrosine kinase inhibitors (TKIs) are approved for therapy. In most cases, patients develop resistance to the TKIs within a short time. MicroRNAs are short (18-22 nucleotides) non-protein-coding RNAs that fine-tune cell homeostasis by controlling gene expression at the post-transcriptional level. Deregulation of microRNAs is common in many cancers, and increasing evidence exists for an important role of microRNAs in the development of resistance to therapies, including TKIs. In this review we focus on the role of microRNAs in mediating resistance to small-molecule TKIs in solid tumours.

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) represent a rare diagnosis of the gastro-entero-pancreatic tract. Evidence from the current literature regarding their epidemiology, biology, and management is of variable quality and conflicting. Based on available data, the MiNEN has an aggressive biological behaviour, mostly driven by its (often high-grade) neuroendocrine component, and a dismal prognosis. In most cases, the non-neuroendocrine component is of adenocarcinoma histology. Due to limitations in diagnostic methods and poor awareness within the scientific community, the incidence of MiNENs may be underestimated. In the absence of data from clinical trials, MiNENs are commonly treated according to the standard of care for pure neuroendocrine carcinomas or adenocarcinomas from the same sites of origin, based on the assumption of a biological similarity to their pure counterparts. However, little is known about the molecular aberrations of MiNENs, and their pathogenesis remains controversial; molecular/genetic studies conducted so far point towards a common monoclonal origin of the two components. In addition, mutations in tumour-associated genes, including TP53, BRAF, and KRAS, and microsatellite instability have emerged as potential drivers of MiNENs. This systematic review (91 full manuscripts or abstracts in English language) summarises the current reported literature on clinical, pathological, survival, and molecular/genetic data on MiNENs.

The incidence of neuroendocrine neoplasms (NENs) is increasing, especially for patients with early stages and grade 1 tumours. Current evidence also shows increased prevalence, probably reflecting earlier stage diagnosis (e.g. at the time of endoscopy) and improvement of treatment options.Definition of adequate post-surgical follow-up for NENs is a current challenge. There are limited guidelines and heterogeneity in adherence to those available is notable. Unfortunately, the population of patients at greatest risk of recurrence has not been defined clearly. Some studies support that for patients with pancreatic neuroendocrine tumours (PanNETs), factors such as primary tumour (T), stage, grade (Ki-67), tumour size and lymph node metastases (N) are of relevance. For bronchial (LungNETs) and small intestinal (siNETs), similar factors have been identified. This review summarises the evidence supporting the rationale behind follow-up after curative resection in well-differentiated PanNETs, siNETs and LungNETS. Since surgery for poorly-differentiated tumours has a limited role, the focus of these recommendations will be limited to patients with well-differentiated tumours. Published evidence informing relapse rate, disease-free survival and relapse patterns are discussed, together with an overview of current guidelines informing post-surgical investigations and duration of follow-up.

Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate.A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis.Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function.CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful).

Background Platinum-etoposide (PE) chemotherapy (CH) is a globally established combination for extra-pulmonary high grade neuroendocrine carcinoma (EP-G3-NEC); the optimal schedule has not been established. Methods An international survey was designed, and completed by clinicians with an expertise in the field to assess consistency in clinical practice. Results Seventy-five replies were received (June-Nov’17). A minority of physicians (13; 17.6%) did not take Ki-67 or morphology (9; 12.0%) into consideration for selection of CH. Most (72; 96.0%) selected PE-CH as first-line treatment for EP-G3-NEC. CH schedules varied: cisplatin-based (37/71; 52.1%), carboplatin-based (34/71; 47.9%); intravenous etoposide (64/71; 90.1%), oral etoposide (7/71; 9.9%). Choice of second-line CH depended on time to progression on PE-based first-line: if > 6 months, re-challenge with PE was the preferred choice (34; 45.9%); if

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.

Background: Patients with advanced well-differentiated neuroendocrine tumours (Wd-NETs) are commonly treated with somatostatin analogues (SSAs). Some patients may develop SSA-related side effects such as pancreatic exocrine insufficiency (PEI). Methods: In this prospective, observational study, the frequency of SSA-induced PEI in 50 sequential patients with advanced Wd-NETs treated with SSAs was investigated. Toxicity was assessed monthly and faecal elastase-1 (FE1) and quality of life (QoL) were assessed 3-monthly. Results: The median age was 65.8 years, 58% were male and the majority (92%) of patients had metastatic disease; patients received 4-weekly long acting octreotide (60%) or lanreotide (40%). Twelve patients (24%) developed SSA-related PEI after a median of 2.9 months from SSA initiation; FE1 was a reliable screening tool for PEI, especially in symptomatic (abdominal bloating, flatulence and/or diarrhea) patients (risk ratio 8.25 (95% confidence interval 1.15–59.01)). Most of these patients (11/12; 92%) required PERT. Other SSA-related adverse events (any grade) included flatulence (50%), abdominal pain (32%), diarrhoea (30%) and fatigue (20%). Development of PEI did not significantly worsen overall QoL, however gastrointestinal symptoms and diarrhoea were increased. Conclusion: This study demonstrated that PEI occurs at a higher rate than previously reported; clinicians need to diagnose and treat this SSA-related adverse-event which occurs in 1 in 4 patients with Wd-NETs treated with SSAs. Screening with FE1 in symtomatic patients is recommend.

Background Immune checkpoint blockade (ICB) has improved overall survival (OS) in selected patients (pts) with cancers, but predictive biomarkers are required. TMB has been proposed as a potential biomarker, but challenges exist as to its optimal definition, quantification and utility. Methods A search of Medline and Embase identified studies reporting association of TMB (high vs low) with survival in pts with solid tumors, irrespective of exposure to ICB. The influence of TMB on OS was explored by meta-analysis, utilizing the generic inverse variance method. Association between baseline factors (age, gender, primary tumor site, stage, smoking history, proportion of pts with squamous histology, receipt of ICB) and survival were assessed with mixed effects meta-regression, weighted by study sample size. Results Of 493 studies, 35 were eligible (ICB used in 28); 13 prospective, 22 retrospective; correlation between PD-L1 expression and TMB was not possible due to limited reporting studies. Analysis comprised 10,433 pts; median age: 63 yrs (range 53-73; reported in 18 studies). Median proportion male: 62.5% (range 40-83%), primary tumor site lung: 17 studies (9 squamous histology), melanoma: 5, urothelial: 3, breast: 2, head & neck, biliary and hepatocellular carcinoma: all 1, multiple sites: 5. Eleven different assays for TMB determination were utilized (Foundation One in 15 studies). Amongst 22 studies, where reported, 5 different TMB definitions were used, with only 10 studies reporting a median TMB (Mut/Mb); 11 different TMB “high” thresholds were reported. In the absence of ICB, high TMB was associated with increased risk of death (HR 2.87, 95% CI 1.41-5.82, p=.004). In the presence of ICB, high TMB was associated with improved OS (HR 0.60, 95% CI 0.42-0.86, p=.005), albeit with significant heterogeneity (p=.002). Studies with a higher proportion of male pts had increased hazard of death (β=.75) and those with a higher proportion of pts receiving ICB had a lower hazard of death (β=-.56). Conclusions High TMB is a poor prognostic factor in solid tumors, but is predictive of improved OS with ICB. Standardization of TMB analysis/reporting is imperative for reliable clinical application. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90, p = 0.15) or overall survival (HR: 0.94, p = 0.18). EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR): 5.18, p = 0.007), and grade (G)3/4 rash (OR: 4.82, p = 0.03). There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, p = 0.06), but no effect on treatment discontinuation without progression (OR: 0.87, p = 0.25). Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS) appeared greater in studies with a greater proportion of LA rather than metastatic patients (R = −0.69, p < 0.001). Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined.

Surgery is the only potentially curative option for patients with pancreatic ductal adenocarcinoma (PDAC), but metastatic relapse remains common. We hypothesized that the expression levels of inflammatory cytokines could predict recurrence of PDAC, thus allowing to select patients who most likely could benefit from surgical resection. We prospectively collected plasma at diagnosis from 287 patients with pancreatic resectable neoplasms. The expression levels of 23 cytokines were measured in 90 patients with PDAC by using a multiplex analyte profiling assay. Levels higher than cutoff identified of the TH2 cytokines interleukin (IL)4, IL5, IL6 of macrophage inflammatory protein (MIP)1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)1, and of IL17α, IFNγ-induced protein (IP)10, and IL1b were significantly associated with a shorter median OS. In particular, levels of IL4 and IP10 higher than cutoff identified, and level of TH1 cytokines TNFα and INFγ, and of IL9 and IL1Rα lower than cutoff identified were significantly associated with a shorter DFS. In the multivariate analysis, high IP10 was confirmed as negatively associated with OS (HR = 3.097, p = 0.014) and IL4 and TNFα remain negatively (HR = 2.75, p = 0.002) and positively (HR = 0.224, p = 0.049) associated with DFS, respectively. Simultaneous expression of low IL4 and high TNFα identified patients with best prognosis (HR = 0.313, p < 0.0001). In conclusion, we demonstrated that, among a series of cytokines, IL4 is the most significant independent prognostic factor for DFS in resectable PDAC patients, and it could be useful to select patients with high risk of early recurrence who may avoid an unnecessary resection.

Background: MANEC is a rare entity and evidence on its prognosis and management is limited. Methods: Demographic/clinicopathological/survival data of consecutive patients (pts) with a diagnosis of MANEC (2010 WHO criteria) from 4 European centres were retrospectively reviewed. Results: Fifty-three pts were identified (01/06-03/17); median (med) age: 62 yrs (range 34-89), male: 70%, ECOG PS 0-1: 60%, with primary tumours from small/large bowel in 34 (64%), oesophagus/stomach: 13 (24.5%), pancreas/biliary tract: 5 (9.5%), unknown (UNK): 1 (2%). Forty percent had an adult comorbidity evaluation (ACE)-27 score of 0. The neuroendocrine (NE) component (predominant histology in 40%) was poorly-differentiated (PD) in 45 (85%) [Ki-67≥55%: 58%]. Most frequently-expressed immunohistochemical (IHC) markers were synaptophysin (100%), chromogranin A (CgA) (58.5%) and CDX2 (51%). Histology was PD NE in 64% from recurrent/metastatic sites (n = 14 pts). Of 28 (53%) pts with localised disease (LA), 26 (93%) had curative surgery (7 had neoadjuvant chemo-radiotherapy (CT-RT), 6 adjuvant CT, 1 peri-operative CT), 1 (3.5%) had definitive CT-RT and 1 (3.5%) had UNK management; 16 (57%) recurred. Forty-one pts (77%) were treated for advanced (adv) disease: 20 (49%) platinum-based CT, 3 (7%) irinotecan-based CT, 1 (2.4%) gemcitabine, 3 (7%) UNK CT regimen, 1 (2.4%) RT, 1 (2.4%) CT-RT, 11 (27%) best supportive care (BSC), and 1 (2.4%) UNK management. Med follow-up time was 10.4 months (mo) (95% Confidence Interval (CI) 5.15-13.09). Med overall survival (OS) for all pts was 18.6 mo (95% CI 11.4-40). Med recurrence-free survival and OS in pts with LA was 19.4 mo (95%CI 5.8-30.9) and 21 mo (95%CI 12.1-40). Med progression free survival (PFS) and OS in pts with adv disease was 4.6 mo (95%CI 3.3-6.7) and 13.6 mo (95%CI 8.8-33.1). On univariable analysis, ACE-27 score (0 vs ≥ 1) was prognostic for better PFS and OS (both p

Background: Advanced wd-NET patients (pts) are commonly treated with SSAs. PEI may be under-estimated in trials due to difficulties in distinguishing carcinoid syndrome-related diarrhoea and PEI.Methods: In this single-institution, prospective, observational study, sequential pts with advanced wd-NET were commenced on SSAs and followed for a minimum of 12 months (or until disease progression). Toxicity was prospectively assessed monthly. Faecal elastase testing (FE) (for diagnosis of PEI) and quality of life (QoL) questionnaires (QLQ-C30 and QLQ-GI.NET21) were performed 3-monthly.Results: Of 52 pts recruited (Jan 15-Apr 16), 50 were eligible: median age 65.8 yrs; 58% male; ECOG performance status 0 (42%), 1 (46%) or 2 (12%); primary: small bowel (60%), pancreas (22%), lung (12%) and other (6%). Baseline median Ki-67 was 3.1% (range 0.7-25), serum 5HIAA: 195 nmol/L (95%CI 145-318) and chromogranin A (CgA): 327 ng/mL (95%CI 140-582). Most pts were metastatic (92%), non-functional (66%) and started SSA first-line (88%); depot SSA was octreotide in 60%, lanreotide in 40%. Forty-one pts (82%) started full-dose SSA (4-weekly octreotide 30mg or lanreotide 120mg); 96% achieved full dose; 3 pts required dose reduction due to toxicities. Grade (G) 1-2 toxicities were flatulence (50%), abdominal pain (32%), diarrhoea (30%), fatigue (20%), PEI (22%), nausea (16%), hyperglycaemia (6%), anorexia (4%) and constipation (2%). G 3-4 toxicities were few (G3 hyperglycaemia (n = 1) and G3 PEI (n = 1); no G4). Twelve pts (24%) developed SSA-related PEI (4 clinical diagnosis, 8 FE-confirmed) at a median of 2.9 mo (95%CI 1.7-8.6) after starting SSA; 11/12 (92%) pts received enzyme replacement. Questionnaires identified fatigue, insomnia and diarrhoea as the most important baseline symptoms; SSA therapy did not negatively-affect QoL. Estimated median progression-free survival (PFS) was 29.9 mo (95%CI 21.4-not reached). High baseline CgA was an independent factor for shorter PFS (HR 1.01 (95%CI 1.001-1.1); p-value 0.001) after adjustment for other factors (baseline 5HIAA, Ki-67).Conclusions: SSA-induced PEI occurs in 1:4 pts; clinicians should actively identify and treat.

Background: TemCap is an option for treatment of NENs; benefit of treatment until progression rather than a fixed 6-month (mo) course remains unclear.Methods: Patients (pts) diagnosed with advanced NEN (pathology-confirmed), treated with TemCap with follow-up and available radiological response data were eligible for this retrospective study. Efficacy was assessed by RECIST v1.1.Results: Of 62 pts identified (Jan’12-Jan’17), 60 were eligible. Median (med) age at starting TemCap was 63.6 yrs; 50% were male; Performance Status (PS) 0-1 (83.3%), 2 (16.7%); with NEN of lung (33.3%), pancreas (21.7%), small bowel (16.7%), colorectal (3.3%) and other (25.0%) origin. The med Ki-67 was 12% (range 1-29); most (83.3%) were well-differentiated [grade (G)1/typical (18.3%); G2/atypical (65%); G3 (16.7%)], non-functional (75.0%) and metastatic (90.0%). Pts received TemCap as first- (33.3%) or second- (35.0%) line, for a med of 5.58 mo (95%CI 5.33-5.78). After 6 cycles, 38 pts (63.3%) were progression-free (i.e. eligible for maintenance TemCap [mTemCap]); 11 received mTemCap, 27 did not. Rationale for mTemCap was good response (n = 7), good tolerance (n = 3) or pts’ wishes (n = 1). Overall, 29 pts (48.3%) had stable disease and 14 pts (23.3%) achieved a partial response (PR); med reduction in responding pts was -56.7% (95%CI -76.4 to -33.3); 4 additional pts (6.67%) achieved a reduction >20% but