ADJUPANET is an open label, double arm, multicenter, phase 3 trial that aims to investigate the efficacy of systemic chemotherapy in locally resected aggressive pancreatic neuroendocrine tumors. The two arms of patients are the following : i. control arm : active surveillance only, standard of care. ii. experimental arm : adjuvant chemotherapy with 6 cycles of CAPECITABINE-TEMOZOLOMIDE (per os) and active surveillance. Patients enrolled in the experimental arm will receive Capecitabine CAPECITABINE per os 750 mg/m² (twice a day: D1 to D14) D1=D28 and TEMOZOLOMIDE per os 200 mg/m² (once a day: D10 to D14) D1=D28.

Inclusion Criteria:

1. Pathologically proven well differentiated neuro-endocrine tumour of the pancreas by local teams

2. Availability of the primary tumor specimen, allowing accurate WHO classification and determination of MGMT status

3. Stage I-III based ENETS-UICC 8th classification

4. Early postoperative context (≤ 4 months)

5. R0 resection

6. Absence of distant metastasis or local tumor remnant as defined by a negative post-operative thorax CT and -abdomen CT or MRI and negative (best of DOTA-peptide 68Ga or, FDG) PET imaging if performed preoperatively

7. ECOG 0-1

8. No prior systemic therapy

9. Intermediate to high risk of recurrence as defined by the following situations:

   • Ki67 ≥ 10% (i.e.: Grade 3 or high Ki67 Grade 2)
   • Ki67 5-9% AND (tumor size > 3 cm OR Node positive)
   • Ki67 3-5% AND tumor size > 3 cm AND Node positive
   • Ki67 < 3% AND tumor size > 3 cm AND Node positive AND (Vascular Emboli OR perineural invasion)

10. Age ≥ 18 years at the time of consent, no superior limit

11. Adequate bone marrow reserve (hemoglobine > 8 g/dL, absolute neutrophils count ≥ 1500/mm³ and platelets ≥ 80 000/mm³)

12. Effective contraception

13. Written, dated and signed informed consent by the patient prior to any specific protocol procedure

14. Ability to comply with the protocol procedures

15. Patient affiliated to a social security system or beneficiary of the same

Exclusion Criteria:

1. Poorly differentiated tumours (NEC)
2. Mixed NeuroEndocrine Non NeuroEndocrine tumors (MiNEN)
3. Neoadjuvant treatment or treatment with chemotherapy regimen used for another malignancy
4. Pregnant women or breastfeeding women
5. ECOG performance status > 1
6. Age < 18 years
7. PanNET arising in a genetic syndrome with other NETs already diagnosed (NF1, VHL or MEN)
8. History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, or other treated malignancies with no evidence of disease for at least five years
9. Severe renal insufficiency (measured GFR according to MDRD < 30 ml/mn or nephrotic syndrome) or hepatic insufficiency (ALT / AST > 2.5 x ULN or ALT/AST > 5 x ULN if liver function abnormalities are due to the underlying malignancy and/or total serum bilirubin > 2.5 x ULN)
10. Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range
11. Current treatment with another investigational drug
12. Unrecovered toxicity from surgery
13. Active or suspected acute or chronic uncontrolled disease that would impart, in the judgment of the Investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the Investigator, would make the patient inappropriate for entry into this study
14. Dihydropyrimidine dehydrogenase (DPD) deficiency or not done
15. Recent or concomitant treatment with brivudine
16. Hypersensitivity to Capecitabine or Temozolomide or to any of the excipients