SURGERY OF NETS. Iakovos N Nomikos MD FACS. Director and Chairman, Department of Surgery METAXA Memorial Cancer Hospital Piraeus Greece

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1 SURGERY OF NETS Iakovos N Nomikos MD FACS Director and Chairman, Department of Surgery METAXA Memorial Cancer Hospital Piraeus Greece

2 Epidemiology 5-fold increase in occurrence of NETS over past 30 years United States SEER data Incidence per 100,000 Lung Rectum Small Bowel Stomach Pancreas Cecum Colon Appendix Year Most NETs are slow growing and malignant, with metastatic potential Yao, JC, Hassan M, Phan A, et al. J Clin Oncol. 2008:26(18):

3 Neuroendocrine versus non-neuroendocrine histologies Localized Regional Distant Survival Probability Survival Probability Survival Probability Years Years NET Years Non-NET

4 Metastatic Disease Is Common at Presentation Distant metastases Regional spread Data from an analysis of 28,515 cases of NET identified in the SEER registries Yao JC, et al. J Clin Oncol. 2008;26:

5 Correlation Between Tumour Grade and Survival 1.0 Cumulative Survival G1 G1 vs G2 G1 vs G3 G2 vs G3 G2 P = P < P < Grade Grading proposal for NET* Mitotic count (10 HPF) Ki67 index (%) G1 < 2 2 G G3 > 20 > G3 * ENET and AJCC grading system Survival Time (months)

6 Presentation Malignant Carcinoid Syndrome Vasomotor Cardiac Gastrointestinal Cutaneous flushing (80%) Cardiac lesions Right heart valve (41-70%) Diarrhea (76%) Hepatomegaly (71%) Insulinoma: Hypoglycemic Episodes Glycagonoma :necrolytic migratory ereythema

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8 Diagnostic Relevance of CgA Sensitivity (%) Gastric NET type I Pheochromocytoma MCC Lung NET MEN-1 (non-gep NET) Gastric NET Maximum plasma CgA concentration x ULN 1. Modlin IM et al. J Clin Gastroenterol 2006; 40: Modlin IM et al. Lancet Oncol 2008; 9: MEN-1 (gastrinoma) MEN-1 (GEP NET) type II Gastric NET type III Ileal NET Non-functioning pnet MTC Functioning pnet Paraganglioma Most frequently elevated in patients with: Gastrinomas (100%) Gastric NET (type I, II, and III; > 95%) Ileal NET (~ 80%) Nonfunctioning pnet (~ 70%) 8

9 Comparison of the Diagnostic Performance of Imaging Modalities in GI NET Diagnostic Modality PET ( 11 C/ 18 F/ 68 Ga/ 64 Cu) SRS SRS/CT CT MRI PET (FDG) S S S S S S S = calculated sensitivity PET = positron emission tomography SRS = somatostatin receptor scintigraphy CT = computed tomography MRI = magnetic resonance imaging FDG = fluorodeoxyglucose Adapted from Modlin IM, et al. Lancet Oncol. 2008;9: Detection rate, % 9

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12 Role of surgery: evidences Localized tumor surgery is curative Slow growing mets influence on prognosis Better staging influence on treatment strategy Assessment of risks and benefits of surgery

13 Gastric Neuroendocrine Tumors evidences Type I: (associated with atrophic gastritis) no surgery Type II : (associated with ZES/MEN-1) surgery only in selected cases Type III: (sporadic) aggressive surgical approach

14 Small Bowel Neuroendocrine Tumors Tumor size is an unreliable predictor of metastatic potential Metastasis can occur with primary tumors that are smaller than 1 cm in diameter Multicentric

15 Small Bowel Neuroendocrine Tumors High risk of complications Mesenteric ischemia Retractile mesenteritis Small bowel obstruction

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17 Small Bowel Neuroendocrine Tumors Surgical Treatment Aggressive approaches with curative surgical resection Entire small bowel explored to not miss a second localization Requires a lymphadenectomy as wide as possible toward the mesenteric artery origin Prophylactic cholecystectomy possible future treatment with somatostatin analogs arterial embolization of liver mets Presence of carcinoid syndrome must be treated as a priority

18 5-year survival overall 83%; 10-30% with distant metastasis Appendix: Appendiceal Endocrine Tumors (AET) Most common location of NET Most AET are diagnosed incidentally during appendectom Majority in 40s to 50s Majority asymptomatic Malignant behavior and prognosis are related to serosal and mesoappendiceal infiltration

19 Appendiceal Endocrine Tumors (AET) Evidences Tumors < 1cm, R0 resection, M0 No follow up No adjuvant treatment Tumors 1-2 cm, low risk of M+ Follow up high risk of M+ (mesoappendiceal infiltration and / or Right Colectomy + unclear or positive margins) Lymphadenectomy Tumors >2 cm Right Colectomy + Lymphadenectomy

20 Colo-rectal Neuroendocrine Tumors Evidences COLON Colectomy + lymphadenectomy compulsory if > 1cm Resection of the primary improves prognosis even in M+ lymph nodes <1cm endoscopic removal and follow up RECTUM <1 cm - Local excision (clear margins) 1 2 cm - More controversial, some recommend more extensive resection in those with muscular invasion or symptoms >2 cm - LAR or APR (similar to treatment for adenocarcinoma)

21 Neuroendocrine Liver Metastasis (NLM) Liver is the most common site of metastatic disease The majority of patients have multiple lesions NLM cause additional morbidity and mortality due to excess hormone production

22 Patterns of NELM Distribution Type I : Isolated single lesion of any type Type II : A large focus of metastatic bulk with smaller surrounding lesions (both lobes) Type III : Widely disseminated metastatic spread (essentially no normal liver) Only type I and selected type II pts are eligible for hepatic resection

23 Tumor debulking surgery is indicated : In patients with hormonal symptoms refractory to other treatments In patients with symptoms related to tumor location Biliary obstruction Gastrointestinal obstruction

24 Liver Directed Therapy Surgery Primary resection, metastasectomy, debulking, OLT, ablation Intra-arterial therapy TACE (Trans-Arterial-Chemo-Embolization) TAE (Trans-Arterial-Embolization) Yttrium -90 radioembolization PRRT (PeptideReceptorRadioTherapy) 90 Y, 177 Lu Chemotherapy for NELM Cytotoxic systemic therapy Targeted therapies

25 Figure 2 Source: Journal of the American College of Surgeons 2013; 216: (DOI: /j.jamcollsurg )

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28 Advanced NET: therapeutic options How to Sequence These Therapies? SS analogs Surgery (Primary resection, metastasectomy, debulking, OLT)

29 NET medical treatment: evolution in IEO Molecular targeted agents Chemotherapy: conventional metronomic Medical Oncology Interv. Radiology SS analogs/ifn : OCT / LAR SOM230 TACE HIFU TAE SIRT - TARF 177 Lu-Dotatate 90 Y-Dotatoc 111 In-Dotatoc Nuclear Medicine

30 Multidisciplinarity Interventional radiologist Oncologist Nuclear physician P Endocrinolo gist Referral Physician Gastroent erologist Surgeon

31 Care at Multidisciplinary Centers Can Improve Patient Outcomes Retrospective study of Australian patients with metastatic NET (n = 49) Median survival for patients managed at the medical oncology unit was longer (112 months) than elsewhere (53 months) Treatment differed between the medical oncology unit as compared to other sites Median Survival (months) Specialty Multidisciplinary Center Community Care Townsend A, et al. J Clin Gastroenterol 2009.

32 ΑΣΘΕΝΕΙΣ ΜΕ ΝΕΥΡΟΕΝΔΟΚΡΙΝΙΚΑ ΝΕΟΠΛΑΣΜΑΤΑ (ΝΕΝ) ΑΑ Φ/Ηλικ Εντόπιση Εγχείρηση Ιστολογική Παρακολούθηση 1. Θ/72 Οπισθ/περιτ. Εκτομή ογκου Παραγ/λίωμα Θ / 6 έτη (χωρίς νόσο) 2 Α/42 ΔΕ Επινεφ ΔΕ Επιν/κτομή ΝΕΝ ΟΚ / 9 έτη 3. Θ/58 Σκωληκοειδής Εκτεταμ. Καρκινοειδές ΟΚ / 14 έτη (τυχαίο εύρημα) ΔΕ κολ/μή 4. Α/77 Τυφλό/Ανιόν ΔΕ κολ/μή Καρκινοειδές ΟΚ / 2.5 έτη 5. Α/72 Ορθόν ΚΠΕ Καρκινοειδές Θ / 7 έτη Ηπατ. Μετ. 6. Α/52 Στομάχι Γαστρεκτομή Καρκινοειδές ΟΚ / 17 μ Θ/49 Αριστερό Εκτομή Merkel* Υποτροπή / 1 έτος Γόνατο Ευρεία Εκτομή 8. Α/65 Αρ. Βουβ. Χώρα Λεμφ. Καθαρ. Merkel ΟΚ / 5μήνες 9. Θ/50 Θυρεοειδής ΟΘ+ΛΚΤ Μυελοειδές* ΟΚ / 6 έτη 10. Θ/50 Θυρεοειδής ΟΘ+ΛΚΤ Μυελοειδές ΟΚ / 15 μήνες

33 Conclusions NETs: A heterogeneous group of tumors for which Multiple therapeutic options are available Treatment should be individualized by multidisciplinary teams Exciting new trial data with octreotide LAR, everolimus and sunitinib Ongoing clinical trial programs will provide additional clarity to treatment decisions

34 Future Directions Biomarkers and molecular imaging for evaluation of therapeutic response Personalized treatment based on molecular genetics and tumor biology WHO and TNM classification Molecularly targeted treatment will be the future: Targeted agents PRRT Combinations of traditional cytotoxics with targeted agents Combinations of targeted agents

35 Ευχαριστώ πολύ! Carcinoid - like syndrome? YES! Increased Chromogranin? NO!!