Imperial College London

ProfessorAndreaFrilling

Faculty of MedicineDepartment of Surgery & Cancer

Chair in Endocrine Surgery
 
 
 
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Contact

 

+44 (0)20 3313 3210a.frilling

 
 
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Location

 

BN2/13 B BlockHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

434 results found

Modlin IM, Kidd M, Frilling A, Falconi M, Filosso PL, Malczewska A, Kitz Aet al., 2021, Molecular genomic assessment using a blood-based mRNA signature (NETest) is cost effective and predicts neuroendocrine tumor recurrence with 94% accuracy., Annals of Surgery, Vol: 274, Pages: 481-490, ISSN: 0003-4932

INTRODUCTION: Identification of residual disease after neuroendocrine tumor (NET) resection is critical for management. Post-surgery imaging is insensitive, expensive and current biomarkers ineffective. We evaluated whether the NETest, a multigene liquid biopsy blood biomarker, correlated with surgical resection and could predict recurrence. METHODS: Multicenter evaluation of NET resections over 24 months (n=103): 47 pancreas, 26 small bowel, 26 lung, 2 appendix, 1 duodenum, 1 stomach. Surgery: R0 (83), R1/R2 (20). 1 ml blood collected at D0 and POD30. Transcript quantification by PCR (normal: ≤20), CgA by NeoLISA (normal≤108ng/mL). Standard-of-care (SoC) follow-up costs were calculated and compared to POD30 NETest-stratification approach. Analyses: Wilcoxon-paired test, Chi2-test. RESULTS: D0 biomarkers: NETest: 103/103 (100%)-positive while 23/103 (22%) were CgA-positive (Chi2=78, p<0.0001).In the R0 group, the NETest decreased 59±28 to 26±23 (p<0.0001); 36% (30/83) remained elevated. No significant decrease was evident for CgA. In the R1/R2 group the NETest decreased but 100% remained elevated. CgA levels did not decrease.An elevated POD30 NETest were present in R0 and 25 (83%) developed radiological recurrences. Normal score R0 s (n=53) did not develop recurrence (Chi2=56, p<0.0001). Recurrence prediction was 94% accurate with the NETest.Cost evaluation: Using the NETest to stratify postoperative imaging resulted in a cost-savings of 42%. CONCLUSION: NETest diagnosis is more accurate than CgA (100% vs. 22%). Surgery significantly decreased NETest. An elevated POD30 NETest predicted recurrence with 94% accuracy and post-surgical POD30 NETest follow-up stratification decreased costs by 42%. CgA had no surgical utility. Further studies would define the accuracy and cost-effectiveness of the NETest in the detection of post-operative recurrent disease.

Journal article

Modlin IM, Kidd M, Falconi M, Filosso PL, Frilling A, Malczewska A, Toumpanakis C, Valk G, Pacak K, Bodei L, Öberg KEet al., 2021, A multigenomic liquid biopsy biomarker for neuroendocrine tumor disease outperforms CgA and has surgical and clinical utility., Annals of Oncology, ISSN: 0923-7534

BACKGROUND: Biomarkers are key tools in cancer management. In neuroendocrine tumors (NETs), Chromogranin A (CgA) was considered acceptable as a biomarker. We compared the clinical efficacy of a multigenomic blood biomarker (NETest) to CgA over a 5-year period. PATIENTS AND METHODS: An observational, prospective, cross-sectional, multicenter, multinational, comparative cohort assessment. Cohort 1: NETest evaluation in NETs (n = 1684) and cancers, benign diseases, controls (n = 731). Cohort 2: (n = 1270): matched analysis of NETest/CgA in a sub-cohort of NETs (n = 922) versus other diseases and controls (n = 348). Disease status was assessed by response evaluation criteria in solid tumors (RECIST). NETest measurement: qPCR [upper limit of normal (ULN: 20)], CgA (EuroDiagnostica, ULN: 108 ng/ml). STATISTICS: Mann-Whitney U-test, AUROC, chi-square and McNemar' test. RESULTS: Cohort 1: NETest diagnostic accuracy was 91% (P < 0.0001) and identified pheochromocytomas (98%), small intestine (94%), pancreas (91%), lung (88%), gastric (80%) and appendix (79%). NETest reflected grading: G1: 40 ± 1, G2 (50 ± 1) and G3 (52 ± 1). Locoregional disease levels were lower (38 ± 1) than metastatic (52 ± 1, P < 0.0001). NETest accurately stratified RECIST-assessed disease extent: no disease (21 ± 1), stable (43 ± 2), progressive (62 ± 2) (P < 0.0001). NETest concordance with imaging (CT/MRI/68Ga-SSA-PET) 91%. Presurgery, all NETs (n = 153) were positive (100%). After palliative R1/R2 surgery (n = 51) all (100%) remained elevated. After curative R0-surgery (n = 102), NETest levels were normal in 81 (70%) with no recurrence at 2 years. In the 31 (30%) with elevated levels, 25 (81%) recurred within 2 years. Cohort #2: NETest diagnostic accuracy was 87% and CgA 54% (P < 0.0001). NETest was more accurate than CgA for grading (chi-square = 7.7, OR = 18.5) and metastatic identification

Journal article

Malczewska A, Frampton AE, Mato Prado M, Ameri S, Dabrowska AF, Zagorac S, Clift AK, Kos-Kudła B, Faiz O, Stebbing J, Castellano L, Frilling Aet al., 2021, Circulating microRNAs in small-bowel neuroendocrine tumors: a potential tool for diagnosis and assessment of effectiveness of surgical resection, Annals of Surgery, Vol: 274, Pages: e1-e9, ISSN: 0003-4932

OBJECTIVE: To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND: MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS: This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS: Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS: Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.

Journal article

Steinkraus K, Andresen JR, Clift AK, Liedke MO, Frilling Aet al., 2021, Multifocal neuroendocrine tumour of the small bowel presenting as an incarcerated incisional hernia: a surgical challenge in a high-risk patient, Journal of Surgical Case Reports, Vol: 2021, ISSN: 2042-8812

Neuroendocrine tumours (NET) of the small bowel present significant clinical challenges, such as their rate of metastasis at initial presentation, common multifocality and understaging even with gold standard imaging. Here, we present a case of a high-risk surgical patient with a complex medical history initially presenting as an acute abdomen due to an incarcerated incisional hernia. He was found at emergency laparotomy to have three small NET deposits in a 30-cm segment of incarcerated ileum which was resected. Postoperative morphological and functional imaging and biochemical markers were unremarkable, but due to clinical suspicion for undetected residual tumour bulk given the non-systematic palpation of the entire small bowel at initial operation, underwent re-operation where a further 70 cm of ileum was found to harbour multiple tumour deposits (n = 25) and was resected. There was no surgical morbidity and the patient remains tumour-free at 9-month follow-up.

Journal article

Modlin IM, Kidd M, Oberg K, Falconi M, Filosso PL, Frilling A, Malczewska A, Salem R, Toumpanakis C, Laskaratos F-M, Partelli S, Roffinella M, von Arx C, Kudla BK, Bodei L, Drozdov IA, Kitz Aet al., 2021, Early identification of residual disease after neuroendocrine tumor resection using a liquid biopsy multigenomic mRNA signature (NETest), Annals of Surgical Oncology, Pages: 1-12, ISSN: 1068-9265

IntroductionSurgery is the only cure for neuroendocrine tumors (NETs), with R0 resection being critical for successful tumor removal. Early detection of residual disease is key for optimal management, but both imaging and current biomarkers are ineffective post-surgery. NETest, a multigene blood biomarker, identifies NETs with >90% accuracy. We hypothesized that surgery would decrease NETest levels and that elevated scores post-surgery would predict recurrence.MethodsThis was a multicenter evaluation of surgically treated primary NETs (n = 153). Blood sampling was performed at day 0 and postoperative day (POD) 30. Follow-up included computed tomography/magnetic resonance imaging (CT/MRI), and messenger RNA (mRNA) quantification was performed by polymerase chain reaction (PCR; NETest score: 0–100; normal ≤20). Statistical analyses were performed using the Mann–Whitney U-test, Chi-square test, Kaplan–Meier survival, and area under the receiver operating characteristic curve (AUROC), as appropriate. Data are presented as mean ± standard deviation.ResultsThe NET cohort (n = 153) included 57 patients with pancreatic cancer, 62 patients with small bowel cancer, 27 patients with lung cancer, 4 patients with duodenal cancer, and 3 patients with gastric cancer, while the surgical cohort comprised patients with R0 (n = 102) and R1 and R2 (n = 51) resection. The mean follow-up time was 14 months (range 3–68). The NETest was positive in 153/153 (100%) samples preoperatively (mean levels of 68 ± 28). In the R0 cohort, POD30 levels decreased from 62 ± 28 to 22 ± 20 (p < 0.0001), but remained elevated in 30% (31/102) of patients: 28% lung, 29% pancreas, 27% small bowel, and 33% gastric. By 18 months, 25/31 (81%) patients with a POD30 NETest >20 had image-identifiable recurrence. An NETest score of >20 predicted recurrence with 100% sensitivity and correlated with residual disease (Chi-square 17.1, p < 0.0001). A

Journal article

Baudin E, Caplin M, Garcia-Carbonero R, Fazio N, Ferolla P, Filosso PL, Frilling A, de Herder WW, Hoersch D, Knigge U, Korse CM, Lim E, Lombard-Bohas C, Pavel M, Scoazec JY, Sundin A, Berruti Aet al., 2021, Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, ANNALS OF ONCOLOGY, Vol: 32, Pages: 439-451, ISSN: 0923-7534

Journal article

Clift AK, Frilling A, 2021, Liver-Directed Therapies for Neuroendocrine Neoplasms, CURRENT ONCOLOGY REPORTS, Vol: 23, ISSN: 1523-3790

Journal article

Frilling A, Clift AK, Frampton AE, Bomanji J, Kaemmerer D, Al-Nahhas A, Alsafi A, Kidd M, Modlin IM, Hoersch D, Baum RPet al., 2021, A combination of surgery, theranostics, and liquid biopsy - a personalised oncologic approach to treatment of patients with advanced metastatic neuroendocrine neoplasms, International Journal of Medical Sciences, Vol: 18, Pages: 2166-2175, ISSN: 1449-1907

Rationale: Neuroendocrine neoplasia (NEN) of small bowel (SBNEN) frequently present with metastatic disease. Theranostics (molecular imaging followed by targeting therapy) allow for personalised medicine. Liquid biopsies enable precise identification of residual disease and real-time monitoring of therapeutic response. Our aim was to determine the clinical utility of a combination of surgery, theranostics, and a multigene blood measurement in metastasised SBNEN. Methods: Inclusion criteria were SBNEN, G1/G2 NEN, initial tumour diagnosis, stage IV NEN, positivity on 68Ga somatostatin analogue PET/CT, eligible for surgery, and 177Lu peptide receptor radionuclide therapy (PRRT). Blood samples for NETest were collected longitudinally. Progression-free survival (PFS) and overall survival (OS) were calculated. NETest results were assessed prior to surgery and during clinical follow-up. Results: A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of 177Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively. Conclusions: Surgery combined with 177Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.

Journal article

Modlin I, Falconi M, Filosso PL, Frilling A, Malczewska A, Kidd M, Oberg Ket al., 2021, A Blood-Based Neuroendocrine Tumor mRNA Signature Identifies Residual Tumor and Accurately Predicts Recurrence After Surgery, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 444-444, ISSN: 0885-3177

Conference paper

Modlin I, Falconi M, Filosso PL, Frilling A, Malczewska A, Kidd M, Oberg Ket al., 2021, A Blood-Based Neuroendocrine Tumor mRNA Signature Identifies Residual Tumor and Accurately Predicts Recurrence After Surgery, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 444-444, ISSN: 0885-3177

Conference paper

Jimenez B, Abellona MRU, Drymousis P, Kyriakides M, Clift AK, Liu DSK, Rees E, Holmes E, Nicholson JK, Kinross JM, Frilling Aet al., 2021, Neuroendocrine neoplasms: identification of novel metabolic circuits of potential diagnostic utility, Cancers, Vol: 13, ISSN: 2072-6694

The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (1H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36–85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker 1H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine-N-oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort.

Journal article

Partelli S, Ramage JK, Massironi S, Zerbi A, Kim HB, Niccoli P, Panzuto F, Landoni L, Tomazic A, Ibrahim T, Kaltsas G, Bertani E, Sauvanet A, Segelov E, Caplin M, Coppa J, Armstrong T, Weickert MO, Butturini G, Staettner S, Boesch F, Cives M, Moulton CA, He J, Selberherr A, Twito O, Castaldi A, De Angelis CG, Gaujoux S, Almeamar H, Frilling A, Vigia E, Wilson C, Muffatti F, Srirajaskanthan R, Invernizzi P, Lania A, Kwon W, Ewald J, Rinzivillo M, Nessi C, Smid LM, Gardini A, Tsoli M, Picardi EE, Hentic O, Croagh D, Toumpanakis C, Citterio D, Ramsey E, Mosterman B, Regi P, Gasteiger S, Rossi RE, Smiroldo V, Jang J-Y, Falconi Met al., 2020, Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) <= 2 cm: Study Protocol for a Prospective Observational Study, FRONTIERS IN MEDICINE, Vol: 7

Journal article

Modlin IM, Kidd M, Falconi M, Frilling A, Malczewska A, Drozdov IA, Kitz Aet al., 2020, Blood-Based Neuroendocrine Tumor mRNA Signature Identifies Residual Disease and at Day 30 after Operation Predicts Tumor Recurrence with 98% Specificity, Annual Clinical Congress of the American-College-of-Surgeons, Publisher: ELSEVIER SCIENCE INC, Pages: E53-E53, ISSN: 1072-7515

Conference paper

Clift AK, Frilling A, 2020, Using genetics to inform pharmacological targeting of neuroendocrine neoplasms., Endocrine-Related Cancer, Vol: 27, Pages: R293-R305, ISSN: 1351-0088

Neuroendocrine neoplasms (NEN) are a class of tumours heterogeneous in terms of their anatomical sites of origin and clinical behaviour. Outdated perspectives of indolence have been superseded by appreciation for their myriad clinical challenges, such as the high rates of regional and distant metastases at initial diagnosis, lack of clarity on optimal treatment strategies/sequencing, and incompletely elucidated genetic/other pathophysiological drivers. The first randomised controlled trials in this arena were published approximately a decade ago - since then, increased understanding of the genetic drivers and signalling pathway perturbations in these tumours have suggested promise for precision therapy influenced by an individual tumour's molecular sub-type, but this is yet to be realised for manifold reasons. In this article, the authors review the genetic landscapes as currently understood for selected forms of NEN and discuss the current and developing evidence to support the use of genetic information to influence therapy. They provide a critical assessment of the potential limitations of using such approaches, and also posit avenues for future developments in this arena.

Journal article

Frilling A, Clift AK, 2020, Combining radiolabelled therapies for neuroendocrine neoplasms, NATURE REVIEWS ENDOCRINOLOGY, Vol: 16, Pages: 347-348, ISSN: 1759-5029

Journal article

Linecker M, Kambakamba P, Raptis DA, Malago M, Ratti F, Aldrighetti L, Robles-Campos R, Lehwald-Tywuschik N, Knoefel WT, Balci D, Ardiles V, De Santibanes E, Truants S, Pruvot F-R, Stavrou GA, Oldhafer KJ, Voskanyan S, Mahadevappa B, Kozyrin I, Low JK, Ferrri V, Vicente E, Prachalias A, Pizanias M, Clift AK, Petrowsky H, Clavien P-A, Frilling Aet al., 2020, ALPPS in neuroendocrine liver metastases not amenable for conventional resection - lessons learned from an interim analysis of the International ALPPS Registry, HPB, Vol: 22, Pages: 537-544, ISSN: 1365-182X

Journal article

Clift A, Frilling A, Braat A, Alsafi A, Wasan H, Al-Nahhas A, Thomas R, Drymousis P, Habib N, Tait Pet al., 2020, Radioembolization for Neuroendocrine Liver Metastases: An Institutional Case Series, Systematic Review and Meta-Analysis, 17th Annual European-Neuroendocrine-Tumor-Society (ENETS) Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: KARGER, Pages: 223-223, ISSN: 0028-3835

Conference paper

Malczewska A, Frampton A, Prado MM, Ameri S, Dabrowska AF, Zagorac S, Clift A, Kos-Kudla B, Faiz O, Stebbing J, Castellano L, Frilling Aet al., 2020, Diagnosis and Assessment of Effectiveness of Surgical Resection of Small Bowel Neuroendocrine Tumours: The Roles of Circulating MicroRNAs, 17th Annual European-Neuroendocrine-Tumor-Society (ENETS) Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: KARGER, Pages: 145-145, ISSN: 0028-3835

Conference paper

Oberg K, Califano A, Strosberg J, Ma S, Pape UF, Bodei L, Kaltsas G, Toumpanakis C, Goldenring J, Frilling A, Paulson Set al., 2020, A Meta-Analysis of the Accuracy of a Neuroendocrine Tumor mRNA Genomic Biomarker (NETest) in Blood, 17th Annual European-Neuroendocrine-Tumor-Society (ENETS) Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: KARGER, Pages: 149-149, ISSN: 0028-3835

Conference paper

Oberg K, Califano A, Strosberg JR, Ma S, Pape U, Bodei L, Kaltsas G, Toumpanakis C, Goldenring JR, Frilling A, Paulson Set al., 2020, A meta-analysis of the accuracy of a neuroendocrine tumor mRNA genomic biomarker (NETest) in blood, Annals of Oncology, Vol: 31, Pages: 202-212, ISSN: 0923-7534

BackgroundThe lack of an accurate blood biomarker in neuroendocrine tumor (NET) disease has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy—liquid biopsy—to facilitate real-time management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD).Patients and methodsA systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified ten original scientific papers that met the inclusion criteria. These were assessed by qualitative analysis and thereafter meta-analysis. Data were pooled and a median [95% confidence interval (CI)] diagnostic odds ratio (DOR), positive likelihood ratio (+LR), and negative likelihood ratio (−LR) were calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and area under the curve (AUC) data.ResultsThe ten studies exhibited moderate to high methodological quality. They evaluated NETest usage both as a diagnostic and as a monitoring tool. The meta-analysis identified the diagnostic accuracy of the NETest to be 95%–96% with a mean DOR of 5 853, +LR of 195, and −LR of 0.06. The NETest was 84.5%–85.5% accurate in differentiating stable disease from progressive disease. As a marker of natural history, the accuracy was 91.5%–97.8%. As an interventional/response biomarker, the accuracy was 93.7%–97.4%. The pooled AUC for the NETest was 0.954 ± 0.005, with a z-statistic of 175.06 (P < 0.001).ConclusionsThe NETest is an accurate biomarker suitable for clinical use in NET disease management. The meta-analysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of this as a biomarker provides information relevan

Journal article

Oberg KE, Califano A, Strosberg JR, Ma SM, Pape U-F, Bodei L, Kaltsas G, Toumpanakis C, Goldenring J, Frilling A, Paulson AS, Modlin IMet al., 2020, A meta-analysis of the accuracy of a neuroendocrine tumor mRNA biomarker (NETest) in the blood, Gastrointestinal Cancers Symposium of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Sharma R, Wang WM, Yusuf S, Evans J, Ramaswami R, Wernig F, Frilling A, Mauri F, Al-Nahhas A, Aboagye EO, Barwick TDet al., 2019, 68Ga-DOTATATE PET/CT parameters predict response to peptide receptor radionuclide therapy in neuroendocrine tumours, Radiotherapy and Oncology, Vol: 141, Pages: 108-115, ISSN: 0167-8140

PURPOSE: [177Lu]DOTATATE prolongs progression free survival (PFS) in metastatic neuroendocrine tumours (NETs). However, objective response rate is low. This, coupled with long duration of therapy and expense suggest need for better selection. We aim to assess whether baseline [68Ga]DOTATATE-PET/CT parameters, and whether response assessment by PET accurately predicts clinical outcome to [177Lu]DOTATATE. EXPERIMENTAL DESIGN: Retrospective study of patients receiving [177Lu]DOTATATE was conducted. Patients were followed 3-monthly until disease progression. Four [68Ga]DOTATATE-PET parameters (single lesion SUVmax, tumour to spleen and liver SUV ratios, and SUVmax-av using up to five target lesions in multiple organ sites) were determined at baseline and follow-up. The association between these PET parameters either at baseline, or any changes following treatment, and PET response criteria (PERCIST and modified PERCIST) to predict PFS were determined. Patients were followed 3-monthly until disease progression. Response was determined using RECIST 1.1. Baseline SSTR2 expression was assessed and compared with PET parameters. RESULTS: 55 patients with metastatic NETs were identified predominantly small bowel (N = 18) and pancreatic (N = 8) in origin. 16 were low grade, 15 intermediate and 3 high grade. Response to PRRT (N = 47): partial response (PR) 28%, stable disease (SD) 60% progressive disease (PD) 13%. Response to PRRT predicted PFS: PR 71.8 months (95%CI: not achieved), SD 29.1 months (95%CI: 15.2-43.1), and PD 9.7 months (95%CI: 0-21.02). Baseline, single lesion SUVmax predicted both response and PFS with SUV cut-off of 13.0 giving high sensitivity and specificity. Tumoural SUVmax correlated with SSTR2 expression, Spearman's rho - 0.69, p < 0.01. CONCLUSIONS: Baseline single lesion SUVmax and SUVmax-av predicts response to [177Lu]DOTATATE. Objective response following PRRT defines a subset of patients with markedly improved PFSBaseline SUVmax 13.0 defines a thre

Journal article

Braat AJAT, Ahmadzadehfar H, Kappadath SC, Stothers CL, Frilling A, Deroose CM, Flamen P, Brown DB, Sze DY, Mahvash A, Lam MGEHet al., 2019, Radioembolization with Y-90 resin microspheres of neuroendocrine liver metastases after initial peptide receptor radionuclide therapy, Cardiovascular and Interventional Radiology, Vol: 43, Pages: 246-253, ISSN: 0174-1551

PurposePeptide receptor radionuclide therapy (PRRT) and radioembolization are increasingly used in neuroendocrine neoplasms patients. However, concerns have been raised on cumulative hepatotoxicity. The aim of this sub-analysis was to investigate hepatotoxicity of yttrium-90 resin microspheres radioembolization in patients who were previously treated with PRRT.MethodsPatients treated with radioembolization after systemic radionuclide treatment were retrospectively analysed. Imaging response according to response evaluation criteria in solid tumours (RECIST) v1.1 and clinical response after 3 months were collected. Clinical, biochemical and haematological toxicities according to common terminology criteria for adverse events (CTCAE) v4.03 were also collected. Specifics on prior PRRT, subsequent radioembolization treatments, treatments after radioembolization and overall survival (OS) were collected.ResultsForty-four patients were included, who underwent a total of 58 radioembolization procedures, of which 55% whole liver treatments, at a median of 353 days after prior PRRT. According to RECIST 1.1, an objective response rate of 16% and disease control rate of 91% were found after 3 months. Clinical response was seen in 65% (15/23) of symptomatic patients after 3 months. Within 3 months, clinical toxicities occurred in 26%. Biochemical and haematological toxicities CTCAE grade 3–4 occurred in ≤ 10%, apart from lymphocytopenia (42%). Radioembolization-related complications occurred in 5% and fatal radioembolization-induced liver disease in 2% (one patient). A median OS of 3.5 years [95% confidence interval 1.8–5.1 years] after radioembolization for the entire study population was found.ConclusionRadioembolization after systemic radionuclide treatments is safe, and the occurrence of radioembolization-induced liver disease is rare.

Journal article

Sharma R, Wang W, Yusuf S, Evans J, Ramaswami R, Wernig F, Frilling A, Mauri F, Al-Nahaas A, Aboagye EO, Barwick TDet al., 2019, [Ga-68]-DOTATATE PET/CT parameters predict response to peptide receptor radionuclide therapy in neuroendocrine tumours, 32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S640-S640, ISSN: 1619-7070

Conference paper

Clift AK, Kidd M, Bodei L, Toumpanakis C, Baum RP, Oberg K, Modlin I, Frilling Aet al., 2019, Neuroendocrine neoplasms of the small bowel and pancreas, Neuroendocrinology: international journal for basic and clinical studies on neuroendocrine relationships, Vol: 110, Pages: 444-476, ISSN: 0028-3835

The traditionally promulgated perspectives of neuroendocrine neoplasms as rare, indolent tumours are blunt and have been outdated for the last two decades. Clear increments in their incidence over the past decades render them increasingly clinically relevant, and at initial diagnosis many present with nodal and/or distant metastases (notably hepatic). The molecular pathogenesis of these tumours is increasingly yet incompletely understood. Those arising from the small bowel or pancreas typically occur sporadically; the latter may occur within the context of hereditary tumour predisposition syndromes. Neuroendocrine neoplasms can also be associated with endocrinopathy of hormonal hypersecretion. Tangible advances in the development of novel biomarkers, functional imaging modalities and therapy are especially applicable to this sub-set of tumours. The management of small bowel and pancreatic neuroendocrine tumours may be challenging, and often comprises a multidisciplinary approach wherein surgical, medical, interventional radiological and radiotherapeutic modalities are implemented. This review provides a comprehensive overview of the epidemiology, pathophysiology, diagnosis and treatment of small bowel and pancreatic neuroendocrine tumours. Moreover, we provide an outlook of the future in these tumor types which will include the development of precision oncology frameworks for individualised therapy, multi-analyte predictive biomarkers, artificial intelligence-derived clinical decision support tools and elucidation of the role of the microbiome in neuroendocrine neoplasm development and clinical behaviour.

Journal article

Frilling A, Clift AK, Braat AJAT, Alsafi A, Wasan HS, Al-Nahhas A, Thomas R, Drymousis P, Habib N, Tait PNet al., 2019, Radioembolisation with 90Y microspheres for neuroendocrine liver metastases: an institutional case series, systematic review and meta-analysis, HPB, Vol: 21, Pages: 773-783, ISSN: 1365-182X

BACKGROUND: Neuroendocrine liver metastases are clinically challenging due to their frequent disseminated distribution. This study aims to present a British experience with an emerging modality, radioembolisation with yttrium-90 labelled microspheres, and embed this within a meta-analysis of response and survival outcomes. METHODS: A retrospective case series of patients treated with SIR-Spheres (radiolabelled resin microspheres) was performed. Results were included in a systematic review and meta-analysis of published results with glass or resin microspheres. Objective response rate (ORR) was defined as complete or partial response. Disease control rate (DCR) was defined as complete/partial response or stable disease. RESULTS: Twenty-four patients were identified. ORR and DCR in the institutional series was 14/24 and 21/24 at 3 months. Overall survival and progression-free survival at 3-years was 77.6% and 50.4%, respectively. There were no grade 3/4 toxicities post-procedure. A fixed-effects pooled estimate of ORR of 51% (95% CI: 47%-54%) was identified from meta-analysis of 27 studies. The fixed-effects weighted average DCR was 88% (95% CI: 85%-90%, 27 studies). CONCLUSION: Current data demonstrate evidence of the clinical effectiveness and safety of radioembolisation for neuroendocrine liver metastases. Prospective randomised studies to compare radioembolisation with other liver directed treatment modalities are needed.

Journal article

Frilling A, Clift A, Al-Nahhas A, Baum RP, Kaemmerer Det al., 2019, Surgery and peptide receptor radionuclide therapy: An effective multimodal approach for metastatic neuroendocrine tumors., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Drymousis P, Clift AK, Leaman S, von Arx C, von Roon A, Frilling Aet al., 2019, SURGERY COMBINED WITH MULTIMODAL THERAPY - A NOVEL CONCEPT IN THE TREATMENT OF ADVANCED SMALL BOWEL NEUROENDOCRINE NEOPLASMS, Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S1409-S1409, ISSN: 0016-5085

Conference paper

Braat AJAT, Kappadath SC, Ahmadzadehfar H, Stothers CL, Frilling A, Deroose CM, Flamen P, Brown DB, Sze DY, Mahvash A, Lam MGEHet al., 2019, Radioembolization with Y-90 Resin Microspheres of Neuroendocrine Liver Metastases: International Multicenter Study on Efficacy and Toxicity, CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY, Vol: 42, Pages: 413-425, ISSN: 0174-1551

Journal article

Carlsen EA, Fazio N, Granberg D, Grozinsky-Glasberg S, Ahmadzadehfar H, Grana CM, Zandee WT, Cwikla J, Walter MA, Oturai PS, Rinke A, Weaver A, Frilling A, Gritti S, Arveschoug AK, Meirovitz A, Knigge U, Sorbye Het al., 2019, Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study, Endocrine-Related Cancer, Vol: 26, Pages: 227-239, ISSN: 1351-0088

Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

Journal article

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