NEONEC is a single-phase, phase II study evaluating the efficacy of the 12-month neoadjuvant chemotherapy in patients with locally differentiated digestive NEC. The recommended chemotherapy is based on the current reference combination of platinum (cisplatin or carboplatin) and etoposide (VP16). For anorectal locations, radiochemotherapy is proposed to avoid the morbidity of conventional surgery.

The objective of the study is to improve relapse-free survival (RFS) in NEC patients treated with neoadjuvant chemotherapy followed by surgery or chemoradiotherapy.

In parallel, we will perform a prospective cohort study with patients whose diagnosis is made during surgery, who have not received neoadjuvant treatment, and who are offered an adjuvant treatment of the same type (combination of platinum and platinum salts and etoposide).

A total of 48 patients is to be included in phase II and 30 patients in prospective cohort during the inclusion period of phase II.

Phase II study treatment:

Neoadjuvant chemotherapy: Administration of 4 cycles of chemotherapy (3 months) with platinum based chemotherapy (carboplatin or cisplatin, at the choice of the investigator) + etoposide.

Surgery or chemoradiotherapy depending on the tumor localization (the irradiation modalities and associated chemotherapy treatment will be left to the discretion of the referring radiotherapists according to current recommendations for each localization).

Prospective cohort:

• Surgery (prior to study entry)
• Adjuvant chemotherapy : Administration of 4 cycles of chemotherapy (3 months) with platinum based chemotherapy (carboplatin or cisplatin, at the choice of the investigator) + etoposide.

Inclusion Criteria:

Phase II

1. Histologically proven digestive CNE, (the WHO 2017 classification: poorly differentiated and Ki 67 > 20%),
2. Patients with localized CNE, without metastasis (computed tomography [CT], thoraco-abdominopelvic CT scan [TAP] according to RECIST 1.1; examinations performed no later than 21 days before starting the study treatment, possible locoregional lymph node involvement defined according to the TNM classification),
3. Positron emission tomography (PET) and CT for lymph node status and elimination of secondary visceral and/or bone disorders, 4. Resectable tumor, according to the consensus decision made during local multidisciplinary surgical consultation meeting,

5. Age ≥ 18 years, 6. Written informed consent obtained from the patient, willing and able to comply with the protocol, 7. Registration in a National Health Care System (Protection Universelle Maladie [PUMa] included), 8. For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study treatment.

Men and women are required to use a reliable and adequate birth control during the study (if applicable) during the period of treatment and during 6 months from the last treatment administration.

Prospective cohort

1. Patients with localized digestive CNE histologically proven on the operative specimen (the WHO 2017 classification: poorly differentiated and Ki 67> 20%),
2. Localized, without metastasis on computed tomography [CT], thoracoabdominopelvic CT scan [TAP] RECIST 1.1, and/or locoregional lymph node involvement,
3. Age ≥ 18 years,
4. Written informed consent obtained from the patient, willing and able to comply with the protocol,
5. Registration in a National Health Care System (PUMa - Protection Universelle Maladie included),
6. For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study treatment.

Men and women are required to use a reliable and adequate birth control methods during the study (if applicable) during the period of treatment and during 6 months from the last treatment administration.

Exclusion Criteria:

Phase II

1. Well-differentiated NEC, whatever the grade,
2. Metastatic disease,
3. Cancer of unknown primary
4. Organ failure that does not allow chemotherapy treatment,
5. Previous malignancy within 5 years prior to the study except for cutaneous basal cell carcinoma and uterine cancer in situ
6. Tumor with a mixed component (component accounts for ≥ 30%),
7. Patient impossible to follow-up,
8. Other than platinum-etoposide chemotherapy administrated,
9. Tutelage or guardianship or patient protected by law

Prospective cohort

1. Well-differentiated NEC, whatever the grade,
2. Metastatic disease,
3. Cancer of unknown primary
4. Organ failure that does not allow chemotherapy treatment,
5. Previous malignancy within 5 years prior to the study except for cutaneous basal cell carcinoma and uterine cancer in situ
6. Tumor with a mixed component (component accounts for ≥ 30%),
7. Patient impossible to follow-up,
8. Other than platinum-etoposide chemotherapy administrated,
9. Tutelage or guardianship or patient protected by law.