ESMO guidelines GEP NET

 Reference: ESMO guidelines

Localized or locoregional

1. G1/G2 NET if local or locoregional-- surgery

2. Functional NET- need symptom control before resection.

3. Pancreatic NET:

    a. If functional, needs resection even if small

    b. If non functional and less than 2 cm, if no symptoms, ok to observe.

    c. If resectable, even if liver Mets, or if primary is resectable , the aim should be to resect. If on the other hand, Ki 67 is > 10% and tumor growth is quick, do medical treatment first, then reassess if resectable.

    d. If pancreatic NET < 2 cm, enucleation may suffice but if > 2 cm pancreato-duodenectomy +LN dissection or splenectomy depending on location is appropriate.

    e. The presence of other high-risk features (e.g. large tumour size and/or high-grade Pan-NEC G3) should discourage an upfront surgical approach. Despite the lack of evidence, in selected patients with high-risk features, a neoadjuvant treatment may be considered. The role of surgery for localised Pan-NEC G3 is still controversial, as upfront surgery may not have a clear benefit in terms of survival.

4. SI NET- resect when possible, palpate for multiple primaries, remove at least 8 LN. Surgery should be considered in all situations except in widely metastatic ( outside liver) and fast growing ie Ki 67 > 10%.

5. Adjuvant therapy only if respected G3 NEC with platinum doublet.

Management of advanced disease

1. Surgery is indicated in stage IV GEP-NETs who have exclusive or predominant liver involvement, after having carefully evaluated the tumour grading, distribution of LMs and primary site 

2. No upfront surgery if extra abdominal Mets, and G3 NEC.

3.  curative resection (R0, R1) of GEP-NETs with liver mets is associated with a 5-year overall survival (OS) rate of around 85%.

4. If pt has advanced SI-NET, the role of prophylactic resection of the primary small intestinal tumor is controversial. No role in survival but may prevent bowel obstruction and or ischemia.

Medical therapy

1.  Octreotide, Lanreotide standard dose q 4 weeks, change to q 2-3 weeks if symptoms not controlled. Can use short acting octreotide for breakthrough symptoms.

2.  Pasireotide LAR off label ( approved for acromegaly) and IFN alpha can be used.

3. Telotristat ethyl (250 mg t.i.d.) is approved for treatment of diarrhoea associated with CS in patients insufficiently controlled with SSA and can be recommended for this indication as an add-on treatment to SSA 

5. Role of Debulking surgery is also not clear- can be undertaken in carcinoid with symptoms (after SSA to control symptoms) and also in NF SI NET if symptoms due to the disease bulk.

6. Liver transplantation may be a valid option in very selected patients with unresectable LMs when the following criteria are met: absence of extrahepatic disease, histological confirmation of a well-differentiated (G1/G2, Ki-67 <10%) NET, previous removal of primary tumour, metastatic diffusion <50% of the total liver volume, stable disease in response to therapy for at least 6 months before transplant consideration and age <60 years [IV, B].20 In these selected patients with good baseline prognostic factors, a 5-year OS of 69%–97.2% has been reported.46 Liver transplantation is preferably considered in patients with functioning tumours (CS refractory to systemic therapies due to high liver tumour burden and in those affected by SI-NETs who usually exhibit a more favourable prognosis). Liver transplantation should be thoroughly discussed within a NET-dedicated multidisciplinary team, carefully considering all the alternative therapeutic options.

Neuroendocrine Tumor

 Neuroendocrine tumor

• Site of origin
• Ki 67
• Mitoses
• Stage
• Differentiation

Pearls:

1. NETs are well differentiated, NEC are poorly differentiated.
2. All poorly differentiated NECs are grade 3, but not all Grade 3 are poorly differentiated. Therefore 2017 update included a more indolent Grade 3 tumor that is classified under NET rather than NEC.
3. Prognostic factors in survival-- LN and distant Mets, but not the T size.
4. The classification for lung and thymus NET differ from GI-Panc. The former includes necrosis but not Ki 67
5. Pancreatic NET metastatic 5 yr OS < 20%
6. No single biomarker as yet diagnostic, predictive or prognostic
7. Bronchial and thymic NET may cause Cushing's
8. NET in small intestine and appendix when metastatic to the liver or retroperitoneum can cause carcinoid syndrome
9. Genetic testing if lung, thymic NET, adrenal, paraganglioma, pheochromocytomas, parathyroid adenoma before age 30
10. 24 hr urine HIAA for carcinoid screening in symptomatic individuals.

Management of Loco regional disease: 

Resection is the mainstay. Although hormone hypersecretion is more common with mets, it can be seen in localized disease and can use octreotide and lanreotide

Grade 1 NET Less than 1 cm

• Gastric: observation, endoscopic FU
• Pancreatic NF- observation, 
• Rectal: endoscopic resection

Grade 1 NET 1-2 cm

• Gastric: Endoscopic resection
• Colon: Curative resection, polypectomy
• Rectal-curative local resection

Grade 2/3, > 2 cm

• Gastric: Total gastrectomy, LN dissection
• Colon: resection and hemicolectomy+ LN dissection
• Pancreatic NF:  pancreatic-duodenectomy+ splenectomy
• Pancreatic functional- Debulking surgery
• Rectal: TME+ LN dissection
• Small bowel - resection +LN dissection, if terminal ileum hemicolectomy

Gastric NET if > 2cm, angioinvasion,higher grade 2/3--> gastrectomy+LN

Type 2 Gastric NET associated with ZE syndrome, high gastrin levels. Antrectomy not useful. Need PPI.  Remove the gastrinoma, likely in the duodenum.

Thymic NET- stage I, II, III A/B --resection if neg margins, no adjuvant therapy.

• Somatostatin analogs are the typical first systemic therapy for GEP-NETs and primarily lead to disease stabilization. ¹⁷⁷Lu-dotatate combined with a somatostatin analog is an option for patients with somatostatin receptor (SSTR)–positive higher-grade GEP-NETs (Ki-67 >10%).
• ¹⁷⁷Lu-dotatate is a second-line option for patients with SSTR-positive GEP-NETs and is the preferred second-line systemic option for most patients with a history of carcinoid syndrome/small bowel primary tumors. Contraindicated if significant peritoneal disease.
• Everolimus can be used as a second-line therapy, particularly in patients who do not qualify for ¹⁷⁷Lu-dotatate. This is approved in pancreatic NET, non functional mid gut and lung NET.
• Capecitabine/temozolomide (CAPTEM) is an active regimen for progressive pancreatic NETs and can be used in grade 3 NETs of different primary sites. This is not useful in small bowel NET except as a last resort.