Advanced neuroendocrine tumors (NETs) are rare cancers, characterized by prolonged survival (median>5 years). If five medical options are now approved and 4 others are only recommended, the best sequence is still unknown. No single study on long-term cumulative toxicity of consecutive treatment interventions has been published so far. Taking into account real-world context is required for sound decision- making that cannot be answered by randomized trials.

Project objectives and brief description of the methods, which will be used to achieve them: Study team will construct a longitudinal prospective cohort of consecutive non resectable or metastatic NET patients using the GTE-RENATEN network to evaluate the real world cumulative and limiting toxicities. They will expect, as primary endpoint, a difference in survival without limiting (>grade 1 adverse event according to nci.ctc V5) persistent (>6 months) toxicity between therapeutics classes or therapeutics sequences in the real life conditions all along the treatments lines, since metastasis diagnosis. All NET primary patients will be enrolled.

Patients will be followed until the primary endpoint is reached, death or until 5 years.

Based on our pilot study, we plan to enroll 1100 patients to detect 150 events and adjust for 15 cofounders and 10% of lost to follow-up. Cox model adapted to time-related dependency will be used to analyze the data and machine learning will be utilized to take into account the number of confounding factors, interactions and nonlinear relationship. The best model of prediction will be validated in a subgroup of the cohort population.

Expected results: Study team will create a tool to help therapeutic decision in order to identify in a given patient the best therapeutic class or sequence with the lowest risk of persistent limiting toxicity.

Tolerate is a real life longitudinal prospective cohort of NET unresectable or metastatic patients. Patients included in this study are patients followed in ENDOCAN - RENATEN expert centres which decide for each patient therapeutic sequential strategy over time according to published ESMO and national guidelines multidisciplinary local and national boards of ENDOCAN-RENATEN network.

In addition to the follow-up performed by the ENDOCAN-RENATEN centres, the TOLERATE study will propose a remote monitoring of the adverse effects caused by cancer and treatments in patients' real life by a monthly survey (TOLERATE PRO-CTC-AE) coordinated by RESILIENCE or CUREETY which are companies approved and specialized in remote monitoring in oncology.

TOLERATE study does not affect patient's care. However, patients enrolled in this study, should not be opposed (using a non-opposition letter) to answer , in addition to the monthly survey, at baseline, every 6 months and 1 month after the administration of each new treatment, up to 5 years, quality of life questionnaires (EORTC QLQ C30, GINET-21, EQ-5D-5L, preference questionnaire and pedometer)

Inclusion Criteria:

• Unresectable local or metastatic NET naive of treatment tumor except somatostatin analogues or primary surgery.
• Unresectable local or metastatic NET newly diagnosed<6 months whatever the primary NET site
• Well differentiated neuroendocrine tumor (WHO classifications) pathologically reviewed locally
• No initial medical absolute contraindication to any of the authorized or recommended treatments (no AE>grade 1 according to NCI CTC v.5 criteria),
• Patient who have full medical follow-up in an expert center of the French ENDOCAN network for the management of their advanced neuroendocrine tumor
• Patient not opposed to data collection in the on GTE databasis
• Patient not opposed to participate in the clinical study

Exclusion Criteria:

• Patients with severe illness that contraindicates participation to any study
• Age <18 years old

unresectable or metastatic NET patients