Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association ...between outcome and
copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785).
CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients.
amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant
CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from
-amplified aGEA.
CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.
Pancreatic neuroendocrine tumours (PanNETs) are rare diseases and a good example of how research is not only feasible, but also of crucial importance in the scenario of rare tumours. Many clinical ...trials have been performed over the past two decades expanding therapeutic options for patients with advanced PanNETs. Adequate management relies on optimal selection of treatment, which may be challenging for clinicians due to the fact that multiple options of therapy are currently available. A number of therapies already exist, which are supported by data from phase III studies, including somatostatin analogues and targeted therapies (sunitinib and everolimus). In addition, chemotherapy remains an option, with temozolomide and capecitabine being one of the most popular doublets to use. Peptide receptor radionuclide therapy was successfully implemented in patients with well-differentiated gastro-entero-pancreatic neuroendocrine tumours, but with certain questions waiting to be solved for the management of PanNETs. Finally, the role of immunotherapy is still poorly understood. In this review, the data supporting current systemic treatment options for locally advanced or metastatic PanNETs are summarized. Strategies for treatment selection in patients with PanNETs based on patient, disease, or drug characteristics is provided, as well as a summary of current evidence on prognostic and predictive biomarkers. Future perspectives are discussed, focusing on current and forthcoming challenges and unmet needs of patients with these rare tumours.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: Brain metastases (BMs) in patients with extra-pulmonary neuroendocrine neoplasms (EP–NENs) are rare, and limited clinical information is available. The aim of this study was to detail the ...clinicopathological features, management and outcomes in patients with EP–NENs who developed BMs. Methods: A retrospective single-centre analysis of consecutive patients with EP–NENs (August 2004–February 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis was estimated (Kaplan–Meier). Results: Of 730 patients, 17 (1.9%) had BMs, median age 61 years (range 15–77); 8 (53%) male, unknown primary NEN site: 40%. Patients with BMs had grade 3 (G3) EP–NENs 11 (73%), G2: 3 (20%), G1: 1 (7%). Eight (53%) had poorly differentiated NENs, 6 were well-differentiated and 1 was not recorded. Additionally, 2 (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. The relative risk of developing BMs was 7.48 in patients with G3 disease vs. G1 + G2 disease (p = 0.0001). Median time to the development of BMs after NEN diagnosis: 15.9 months (range 2.5–139.5). Five patients had a solitary BM, 12 had multiple BMs. Treatment of BMs were surgery (n = 3); radiotherapy (n = 5); 4: whole brain radiotherapy, 1: conformal radiotherapy (orbit). Nine (53%) had best supportive care. Median OS from 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. Conclusion: BMs in patients with EP–NENs are rare and of increased risk in G3 vs. G1 + G2 EP–NENs. Survival outcomes are poor, and a greater understanding is needed to improve therapeutic outcomes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
Studies JVDB and JVCZ examined alternative ramucirumab dosing regimens as monotherapy or combined with paclitaxel, respectively, in patients with advanced/metastatic gastric/gastroesophageal junction ...(GEJ) adenocarcinoma. For JVDB, randomized patients (
= 164) received ramucirumab monotherapy at four doses: 8 mg/kg every 2 weeks (Q2W) (registered dose), 12 mg/kg Q2W, 6 mg/kg weekly (QW), or 8 mg/kg on days 1 and 8 (D1D8) every 3 weeks (Q3W). The primary objectives were the safety and pharmacokinetics of ramucirumab monotherapy. For JVCZ, randomized patients (
= 245) received paclitaxel (80 mg/m
-D1D8D15) plus ramucirumab (8 mg/kg- or 12 mg/kg-Q2W). The primary objective was progression-free survival (PFS) of 12 mg/kg-Q2W arm versus placebo from RAINBOW using meta-analysis. Relative to the registered dose, exploratory dosing regimens (EDRs) led to higher ramucirumab serum concentrations in both studies. EDR safety profiles were consistent with previous studies. In JVDB, serious adverse events occurred more frequently in the 8 mg/kg-D1D8-Q3W arm versus the registered dose; 6 mg/kg-QW EDR had a higher incidence of bleeding/hemorrhage. In JVCZ, PFS was improved with the 12 mg/kg plus paclitaxel combination versus placebo in RAINBOW; however, no significant PFS improvement was observed between the 12 mg/kg and 8 mg/kg arms. The lack of a dose/exposure-response relationship in these studies supports the standard dose of ramucirumab 8 mg/kg-Q2W as monotherapy or in combination with paclitaxel as second-line treatment for advanced/metastatic gastric/GEJ adenocarcinoma.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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 and improvement of treatment options. Definition of adequate postsurgical 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 neuroendocrine tumours (LungNETs) and small intestinal neuroendocrine tumours (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. Published evidence informing relapse rate, disease-free survival, and relapse patterns are discussed, together with an overview of current guidelines informing postsurgical investigations and duration of follow-up.
Caveolin-1 (CAV1) is expressed in several solid tumors both in cancerous cells as well as in tumor stroma and is reported to be related to cancer progression, metastasis, therapy resistance and ...clinical outcomes. Many studies report contrasting functions of this protein depending on the tumor cell model, the tumor type, or the stage of cancer studied. This protein is reported to function both as tumor suppressor and as tumor promoter. In this review, we aim to summarize translational and clinical studies that provide evidence of the role of CAV1 in tumor progression and survival outcome focusing on tumors of the gastrointestinal (GI) tract.
Towards this aim, a detailed search has been performed for studies on the expression and the role of CAV1 in oesophageal, gastric, colorectal, pancreatic cancer and cholangiocarcinoma prognosis. We also review and discuss the implication of CAV1 in the outcome of pharmacological interventions.
We conclude that CAV1 has the potential to become an important prognostic, and possibly predictive, biomarker in GI malignancies. It may also become a novel target towards the development of improved cancer therapies. However, it is obvious that there remains a lack of consensus on important issues such as the methodologies and cut-off levels in caveolin assessment. This ultimately result in many studies being contradictory not only in terms of the role of CAV1 as a tumor-promoting or suppressing gene but also in terms of the tumor compartment in which the levels of this protein may be of clinical significance. Addressing these important technical issues, in conjunction with a further elucidation of the role of CAV1 in tumor formation and progression, will delineate the importance of CAV1 in prognostic and therapeutic perspectives.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
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: 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.
•BMs in patients with NENs remain underdiagnosed and undertreated.•PET/CT seemed to provide the highest sensitivity and specificity for BM detection.•OS from time of BM diagnosis is long and hence, ...it is important to secure good QoL.•Recommendations for management of BMs derived from current knowledge are provided.•Prospective studies to identify biomarkers and improve management are required.
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.
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 .
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.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To compare health-related quality of life (HRQoL), anxiety, depression, and impulsivity scores in patients with and without carcinoid syndrome (CS), and correlated them with serum ...5-hydroxyindoleacetic acid (5-HIAA) levels.
Patients with advanced gastroenteropancreatic neuroendocrine tumours (GEPNET), with and without CS completed HRQoL QLQ-C30 and QLQ-GI.NET21, Hospital Anxiety and Depression Scale (HADS) and Barratt Impulsivity Scale (BIS) questionnaires. Two-sample Wilcoxon test was applied to assess differences in serum 5-HIAA levels, two-sample Mann-Whitney
test for HRQoL and BIS, and proportion test for HADS, between those with and without CS.
Fifty patients were included; 25 each with and without CS. Median 5-HIAA in patients with and without CS was 367nmol/L and 86nmol/L, respectively (
= 0.003). Scores related to endocrine symptoms were significantly higher amongst patients with CS (
= 0.04) and scores for disease-related worries approached significance in the group without CS, but no other statistically-significant differences were reported between patients with and without CS in responses on QLQ-C30 or QLQ-GI.NET21. Fifteen patients (26%) scored ≥ 8/21 on anxiety scale, and 6 (12%) scored ≥ 8/21 on depression scale. There was no difference in median 5-HIAA between those scoring < or ≥ 8/21 on anxiety scale (
= 0.53). There were no statistically significant differences between groups in first or second-order factors (BIS) or total sum (
= 0.23).
Excepting endocrine symptoms, there were no significant differences in HRQoL, anxiety, depression or impulsivity between patients with advanced GEPNET, with or without CS. Over one quarter of patients had high anxiety scores, unrelated to peripheral serotonin metabolism.
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