Tumori Neuroendocrini Percorsi Diagnostico-Terapeutici. Dr. Renato Cannizzaro SOC Gastroenterologia Oncologica CRO IRCCS- Aviano

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2 Tumori Neuroendocrini Percorsi Diagnostico-Terapeutici Dr. Renato Cannizzaro SOC Gastroenterologia Oncologica CRO IRCCS- Aviano

3 NEUROENDOCRINE TUMORS Neuroendocrine Tumors are ill-understood, enigmatic malignancies An increased clinical and pathological focus as well as the advent of biochemical and immunohistochemical diagnostic technology has led to a greater awareness of the disease

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5 MEN I NETs may occur as part of multiple endocrine neoplasia type 1 (MEN1), An autosomal dominant disorder associated with the gene locus MEN1 located on 11q13. Its protein product (menin) is involved in transcriptional regulation and genome stability.

6 CLINICAL PICTURES Primary GEP-NETs can be: Asymptomatic May present with obstructive symptoms (pain, nausea, and vomiting) The syndromes are typically seen in patients with secretory tumours.

7 BIOCHEMICAL TESTS IN NEUROENDOCRINE TUMORS Specific 24h urinary 5-HIAA S-Gastrin S-Insulin S- C-peptide S- Pro-insulin S-VIP S-Glucagons S-Somatostatin Generalised Cromogranin A,B,C Pancreatic polypeptide β-hcg

8 DIAGNOSTICA DELLE NEOPLASIE NEUROENDOCRINE GEP Diagnostica strumentale TAC spirale Scintigrafia con analoghi marcati della somatostatina (Octreoscan) Endoscopia e Ecoendoscopia (EUS) Risonanza Magnetica PET/CT DOTATOC Enteroscopia con videocapsula Enteroscopia S/DB Endomicroscopia

9 Tumori Neuroendocrini Casistica raccolta nel periodo presso la S.O.C. di Gastroenterologia Oncologica del CRO Sede NET N Tumori % Stomaco Ileo Pancreas Fegato Retto Colon Duodeno Digiuno Polmone Intestino Appendice Colecisti Sigma Tenue N.S TOTALE 196* 100 * Alcuni pazienti riportano NET in più sedi. Totale pazienti: 178 (92F, 86 M) Età media: 59 anni (22-88)

10 Tumore neuroendocrino del cardias M, 69 anni Disfagia Metastasi epatiche

11 Tumore neuroendocrino del bulbo

12 Carcinoma neuroendocrino scarsamente differenziato

13 ENDOSCOPIA CAPSULARE DEL TENUE Tumore neuroendocrino dell ileo

14 Tumore neuroendocrino dell ultima F, 38 anni Dolenzia in fossa iliaca dx Emicolectomia dx con resezione ultima ansa ileale Carcinoide con 2 lindonodi metastatici ansa ileale

15 NET M, 41 anni Alvo diarroico Chirurgia: resezione ileale laparoscopica Tumore Neuroendocrino G1 cm 0.7 Il tumore infiltra lo strato superficiale della tonaca muscolare 1 linfonodo metastatico su 13 T2N1 Videocapsula Minisonda Enteroscopia Minisonda

16 Mosaic reconstructions (A, B, and C) and images (a, a, b, b, and c) obtained with pcle in a HGNEC (A, a and a ) and in two poorly differentiated adenocarcinoma patients (B, b, b and C, c).

17 NEUROENDOCRINE TUMORS TREATMENT The aim of treatment should be curative where possible but is palliative in the majority of cases. These patients often maintain a good quality of life for a long period despite having metastases. Although the rate of growth and malignancy are variable, the aim should always be to maintain a good quality of life for as long as possible.

18 NEUROENDOCRINE TUMORS TREATMENT Endoscopy- Surgery Hormonal Therapy Interferon Chemiotherapy Embolisation of hepatic artery Liver resection Liver Transplantation NEW DRUGS

19 NEUROENDOCRINE TUMORS SURGERY This is the only curative treatment for NETs. Conduct of surgery with intent to cure is dependent on the method of presentation and stage of disease.

20 TERAPIA ENDOSCOPICA Tumori neuroendocrini ben differenziati Basso indice proliferativo Dimensioni < 1 cm Localizzati nella mucosa e/o nella sottomucosa GI a livello di tutte le sedi raggiungibili da un endoscopio e quindi esofago, stomaco, duodeno, colonretto Intestino tenue

21 GASTRIC NET World J Gastrointest Endosc 2011

22 DUODENAL NET World J Gastrointest Endosc 2011

23 RECTAL NET World J Gastrointest Endosc 2011

24 CARCINOIDI RETTALI Diametro massimo della lesione di 10 mm Assenza di aree depresse od ulcerate sulla lesione (valutazione endoscopica) Non invasione della muscolare propria Assenza di adenopatie loco-regionali (staging EUS)

25 Resezione endoscopica a tutto spessore di NET rettale

26 Netazepide (YF476) is a potent, highly selective and orally-active gastrin/cck-2 receptor antagonist. October 2013 Volume 8 Issue 10 e76462

27 Endoscopic photographs from the same area of the stomach in patients 1 (a, b) and 2 (c, d) at baseline (a, c)and after 12 weeks of netazepide (b, d).

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29 Lo Studio PROMID 1 Proporzione senza progressione Octreotide LAR: 42 pazienti / 26 eventi Mediana 14.3 mesi [95% CI: ] Placebo: 43 pazienti / 40 eventi Mediana 6.0 mesi [95% CI: ] Tempo (mesi) Rinke A, et al. J Clin Oncol 2009; 27: Octreotide LAR vs placebo P= HR= 0.34 [95% CI: ] 29

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31 The CLARINET core study: key data from the primary publication Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):

32 CLARINET Study aim and design CLARINET (Controlled study of Lanreotide Antiproliferative Response In NET)* Aim To compare effect of lanreotide Autogel 120 mg vs. placebo on PFS in non-functioning enteropancreatic NETs Design International randomized double-blind placebo-controlled phase 3 study Screening weeks Lanreotide Autogel 120 mg every 28 days (s.c.) CT/MRI scan 1 CT/MRI scan 2 1:1 randomization Placebo every 28 days (s.c.) 1 (Baseline) Study visits (weeks) 32 *ClinicalTrials.gov NCT ; EudraCT PFS, progression-free survival; s.c., subcutaneous. Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33

33 CLARINET Patient disposition 204 patients randomly allocated 101 received lanreotide Autogel 120 mg Events*: 30 PD (centrally assessed) and 2 deaths 18 withdrawals 6 due to investigator decision (PD) 3 due to AEs 3 withdrew consent 2 protocol violations 4 other reasons 53 completed the study without events 103 received placebo Events*: 58 PD (centrally assessed) and 2 deaths 21 withdrawals 9 due to investigator decision (PD) 3 due to AEs 5 withdrew consent 2 protocol violations 2 other reasons 26 completed the study without events 33 *Two deaths occurred in lanreotide group after withdrawal for another reason and two deaths occurred and two PDs detected in placebo group after withdrawal for another reason; despite a central assessment of PD. AEs, adverse events. Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33

34 CLARINET PFS (primary endpoint): significantly prolonged with lanreotide Autogel 120 mg vs. placebo with 53% risk reduction of disease progression or death with Somatuline 120mg versus placebo Patients alive and with no progression (%) Lanreotide Autogel 120 mg 32 events/101 patients median, not reached during the 24 months Placebo 60 events/103 patients median, 18.0 months [95% CI: 12.1, 24.0] Lanreotide Autogel 120 mg vs. placebo p<0.001 HR=0.47 [95% CI: 0.30, 0.73] 65% at 24 months 33% at 24 months Time (months) 34 Numbers of patients at risk of death or PD Data are from the ITT population. P-value derived from stratified log-rank test; HR derived from Cox proportional hazards model. HR, hazard ratio; ITT, intention-to-treat. Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):

35 C.R.O. AVIANO Istituto Nazionale Tumori