esmo NENs
INTRODUCTION
1.Most frequently, these neoplasms occur in the digestive system, followed by the lung
2.NECs represent only 10%e20% of all
NENs, The main focus of these guidelines is on sporadic small intestinal (SI)-NENs and pancreatic NENs (Pan-NENs)
3. other gastrointestinal NENs follows the same principles as in SI- or Pan-NENs taking into consideration key features of NENs
4. (Pan-NETs) are also associated with von
Hippel-Lindau (VHL) disease, tuberous sclerosis (TSC) and
neurofibromatosis.
5. most arise in the setting of the
multiple endocrine neoplasia type 1 (MEN1) syndrome.
6. The frequency of a hereditary background (MEN1, VHL syndromes) was reported as 5%
7. IHC for Ki-67 (MIB1) is mandatory to grade the NENs according to the WHO 2017 and 2019 classifications. Both the number of mitotic figures per 2 mm2 as well as the Ki-67 index based on assessment of 2000 cells should be reported
8. appropriate pathological diagnosis,
morphology, grading and immunohistochemical staining for CgA and synaptophysin should be reported
STAGING AND RISK ASSESSMENT
- For all NECs, the staging system of adenocarcinomas must be applied
- Small metastatic lymph nodes (<1 cm)
may escape detection by CT. For bone metastases, CTsensitivity is poor at 61% (range 46%e80%). - The sensitivity of CT to detect
NETs is 61%e93% and the specificity is 71%e100%. - detection rate for liver metastases (LMs) is 79%, extra-abdominal soft tissue metastases, the sensitivity is 70% and specificity 96%
- MRI sensitivity to detect Pan NETs is 79%, with fairly similar detection rates of 76%, and for LMs, the sensitivity is 75%, with near maximum specificity of 98%.
- The strength of a PET-CT is a
higher detection rate of lymph node, bone and peritoneal lesions as well as unknown primary tumours
MANAGEMENT OF LOCAL/LOCOREGIONAL DISEASE
- In functional NETs, clinical symptoms should be managed before any intervention
- Several studies demonstrated the safety of a watch-andwait strategy instead of surgery for asymptomatic NF-Pan-NETs menor de 2 cm. (ederly pts is sugest)
- Surgery is recommended for young patients and in cases when signs of local invasiveness (e.g. dilation of the main pancreatic duct and/ or presence of jaundice and/or suspicion of nodal involvement) are present
- surgery is mandatory in the presence
of functioning Pan-NETs irrespective of tumour size, radical surgery + linfadenectomy in lesion mayor of 2 cm, vs enucleation in lesion < 2 cm - The role of enucleation
for NF-Pan-NETs is currently limited to selected patients with small lesions in whom a watch-and-wait management is contraindicated. - Pancreatectomy with vascular resection is associated with improved outcomes and it should be carefully considered in the presence of portal and/or superior mesenteric vein invasion.
- 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
- Macroscopic radical resection with systematic mesenteric lymphadenectomy or localised SI-NETs reduces the risk of intestinal complications (bowel obstruction and ischaemia), is associated with improved outcomes
MANAGEMENT OF ADVANCED/METASTATIC DISEASE surgical treat
- A surgical approach is indicated in selected patients affected by stage IV GEP-NETs who have exclusive or predominant
liver involvement - Upfront surgery should be excluded in the presence of extra-abdominal metastases and high-grade GEP-NENs
- the presence of an advanced NEC G3 as an absolute contraindication for surgery, whereas NET G3 should not be excluded
- A curative resection (R0, R1) of
GEP-NETs with LMs is associated with a 5-year overall survival (OS) rate of around 85%. - A recent large single-centre experience
demonstrated no survival benefit in patients with stage IV disease after prophylactic palliative SI-NET resection,
compared with no or delayed resection when needed - patients with symptoms related to tumour burden, debulking surgery may also be of benefit
- funtional panets debulking surgery is recomended, non funtional is debated
- Liver transplantation if met creterias: 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, a 5-year OS of 69—97.2% - LMs who are ineligible for complete surgical resection, vascular and ablative locoregional modalities can be considered
- aggressive NENs (NEC G3), adjuvant therapy with platinum-based chemotherapy (ChT) can be considered
MANAGEMENT OF ADVANCED/METASTATIC DISEASE Medical therapy
- The goal of systemic therapy is to control the tumourassociated clinical symptoms and the tumour growth
- The use of SSAs (octreotide,
lanreotide) is standard first-line therapy in functioning NETs - interferon alpha (IFN-a) is approved for symptom control (3,5 million IU s.c. three times weekly) with similar efficacy compared with SSA, but it is usually used in second-line as an add-on treatment to SSA in patients with refractory syndrome
- Telotristat ethyl is an oral inhibitor of tryptophan hydroxylase, a rate-limiting enzyme in the synthesis of serotonin, that has demonstrated a significant improvement in the number of bowel movements
- mTOR inhibitor everolimus and the TKI sunitinib, have been introduced more recently in the management of NETs
- The PROMID study showed prolongation of time to tumour progression (TTP) in therapy-naive advanced metastatic midgut NETs (mostly G1 and with low tumour burden) by 8.3 months; TTP with octreotide LAR 30 mg was 14.3 months and 6 months with placebo.
- The CLARINET study demonstrated efficacy not only in midgut but also in Pan-NETs and NETs with high liver tumour burden (>25%), and NET G2 with a Ki-67 of <10%. Most patients (96%) had stable disease at study onset.
- The registration trial (RADIANT-3 study) with 410 patients (including 40% therapy-naive patients) showed prolongation
of PFS by 6.4 months in advanced progressive Pan-NETs; median PFS was 11 months with everolimus and 4.6
months with placebo. - The efficacy of everolimus in advanced NF-GI NETs with poor prognosis has been demonstrated by the RADIANT-4 trial, Median PFS was 11 months with everolimus and 3.9 months with placebo
- There are no data to support the use of everolimus in NECs
- Sunitinib is the only multiple TKI that is approved in Pan-NETs, longer PFS (11.4 versus 5.5 months) was noticed in favour of sunitinib vs placebo
- Sunitinib is recommended in the management of advanced progressive Pan-NETs
- The use of systemic ChT is recommended in advanced Pan-NETs and in NEN G3 of any site, not recommended in well-differentiated G1/G2 GI NETs, higher Ki-67 in the range of 15% a 20%; significant progression might be associated
with benefit - Systemic ChT is indicated in patients with non-resectable LMs and/or other distant metastases from G1/G2 Pan-NETs
using a combination of STZ and 5-fluorouracil - temozolomide (TEM) combined with capecitabine (CAP) preliminary results from the prospective trial of CAPTEM versus TEM in patients with progressive Pan-NETs confirm the efficacy of TEM based
ChT and suggest superiority of the combination therapy (CAPTEM) compared with TEM alone with respect to PFS prolongation (22.7 months versus 14.4 months, respectively; HR 0.58, P ¼ 0.023)
16.liver and/or other distant metastases from high-grade small or large-cell NEC G3, using cisplatin/etoposide or carboplatin/etoposide is recommended
17.PRRT is a therapeutic option in progressive SSTRpositive NETs with homogenous SSTR expression, most commonly used for PRRT are DOTATOC and DOTATATE
18.Median PFS (mPFS) with 177Lu-DOTATATE was 28.4 months while it was 8.5 months with high-dose octreotide (HR for disease progression 0.214)
19.Treatment was also associated with
an improvement in symptoms and time to QoL deterioration for global health status, physical functioning, fatigue, pain and diarrhoea - PRRT can be recommended in patients
with midgut NETs with disease progression on SSAs who fulfil the general requirements for PRRT that are reported elsewhere, also in patients
with Pan-NETs
follow up
Follow-up investigations should include clinical symptom monitoring, biochemical parameters and conventional and SSTR imaging.
In patients with R0/R1-resected NET G1eG2, it is recommended that imaging is carried out every 3-6 months (CT or MRI), and in NEC G3 every 2e3 months. Similar staging intervals apply to advanced disease.
Follow-up should be lifelong, although the staging intervals may be extended to 1e2 years with increasin length of follow-up.
Small localised NET G1 (<1 cm in size) with origin in the appendix or rectum do not need any follow-up if R0-resected and in the absence of adverse histological
features
