European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma

This ENETS guidance paper, developed by a multidisciplinary working group, provides up‐to‐date and practical advice on the diagnosis and management of digestive neuroendocrine carcinoma, based on recent developments and study results. These recommendations aim to pave the road for more standardized care for our patients resulting in improved outcomes. Prognosis is generally poor for digestive NEC, most are advanced at diagnosis and median survival in metastatic disease is 11–12 months. Surgery can be of benefit for localized disease after extensive preoperative imaging. Carboplatin in combination with etoposide is recommended as first‐line treatment for metastatic disease. Irinotecan with fluoropyrimidines has the best evidence as second‐line treatment. Immunotherapy plays a minor role in biomarker‐unselected patients. Molecular profiling if available is encouraged to identify new targets. More prospective clinical trials are highly needed to fulfil the unmet needs in this field, especially on new predictive and prognostic biomarkers and to improve survival of patients with advanced disease.


| INTRODUCTION
This ENETS guidance paper aims to answer 10 major questions on clinical, pathological as well as molecular diagnostics, prognostic factors and management of digestive neuroendocrine carcinoma (NEC) ( Table 1). Data were identified by MEDLINE database searches and expert opinion/recommendations given according to the best available evidence and author's experiences. Each recommendation for treatment and diagnosis will have a level of evidence and grade of recommendation as per the GRADE system 1 (Table S1). In the paper, the term localized disease is used for the combined group of stage I-III cases. High-grade neuroendocrine tumors (NET G3) have a different prognosis, treatment, genetics and outcome compared to NEC, and will not be covered in this guidance paper. Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), which is an entity of controversy, will be covered in Q10.

| Digestive NEC vs. small-cell lung cancer
Traditionally, extra-pulmonary NEC have been considered to be similar to small-cell lung cancer (SCLC). However, there are major differences such as their pathological definitions that include expression of neuroendocrine markers and a much higher incidence compared to digestive NEC. Furthermore, unlike digestive NEC, SCLC is strongly associated with smoking, frequent brain metastases and higher response rates to platinum-based chemotherapy. 5,6 Digestive NEC differ genetically from SCLC 7,8 and from head/neck and cervical NEC. 9,10 Due to their differences, one should therefore be careful in extrapolating data from SCLC and extra-pulmonary NEC to digestive NEC. In this paper, data are focused specifically on digestive NEC.

| Prognosis and survival
Patients with localized digestive NEC may be cured with surgery; however, relapse is frequent and associated with a poor prognosis.
The digestive NEC entity is completely different from welldifferentiated digestive NET. Patients with localized NET G1-2 have a 5-year survival of 70%-80% while 5-year survival for localized NEC is 25%-40%. 11 Furthermore, patients with metastatic small intestinal NET (G1-G2) have a median survival of 8-10 years and metastatic pancreatic NET (G1-G2) 3-5 years while median survival for metastatic digestive NEC treated with chemotherapy is 11-12 months.
In contrast to other cancers where immediate disease progression on first-line treatment in metastatic disease is rare (<10%-15%), this is seen after first-line treatment in up to 30% for digestive NEC and progression free survival (PFS) is only 4-5 months. [12][13][14][15] This clearly illustrates the aggressiveness of the disease and the need for improvement of treatment.

Recommendation
Treatment of patients with digestive NEC beyond general established principles should be considered in a multidisciplinary tumor board setting at a specialized center (grade 5A).
T A B L E 1 Ten major questions on clinical, pathological as well as molecular diagnostics, prognostic factors and management of digestive neuroendocrine carcinoma (NEC). Q1 What clinical examinations for diagnosis and staging should be performed in a newly diagnosed digestive NEC? Primary tumor site is a factor when considering surgery in local- ized digestive NEC, as survival varies according to the primary site. 2,11 For localized esophageal NEC, initial surgery seems inferior to initial chemoradiation, especially for stage III. 46,47 In a cohort of 630 pancreatic NEC cases, surgery was, after propensity score matching, significantly and independently associated with improved survival (36 vs. 8 months). 48 In a large colorectal NEC cohort, surgery was a beneficial prognostic factor for OS in a multivariable analysis. 49 In another study of 502 NEC stage I-III 3-year survival after surgery was 40% versus 18% in cases without surgery. 33 Patients with localized non-small cell colorectal NEC had better survival benefit after surgery (21 vs. 6 m), compared to small-cell (18 vs. 14 m), questioning the benefit of surgery for localized small-cell anorectal NEC.

| Chemoradiation
There is remarkably little data on the use of chemoradiation for local- In the US National Cancer Database, radiotherapy for digestive NEC was frequently used in esophageal (74%), rectal (61%) and anal (83%) NEC, 11  Patients with Ki-67 in the lower range (<55%), might be candidates for less toxic treatments, as they have a lower RR to platinum/etoposide. 12 Everolimus/temozolomide combination treatment in a first-line phase II trial had little benefit in digestive NEC. 67 The current data are insufficient to support the first-line use of targeted agents in NEC.
There are no data to support the use of somatostatin analogs in NEC, and they should not be used in NEC. For possible use of immunotherapy in first-line treatment-see Q8.
T A B L E 2 Prospective and retrospective studies on first-line chemotherapy in advanced digestive neuroendocrine carcinoma.

| Treatment of MiNEN
The MiNEN entity is complex and treatment controversial. Surgery is the only potential curative option for initial localized digestive MiNEN.
5-year survival after surgery has been reported to be 20%-50%. 58,89 In seven retrospective studies on digestive NEC/MiNEN, a positive prognostic effect of surgery was indicated with PFS 8-32 months and OS 21-92 months. 93  investigation; writingoriginal draft; writingreview and editing.