Background: Pancreatic neuroendocrine tumors (pNETS) account for about 1-2% of all the pancreas tumors for which resection is the only curative intent modality, however, despite surgery, many patients will experience recurrence. Tumor size, positive lymph nodes and higher grade are prognostic factors for recurrence. The U.S. Neuroendocrine Tumor Study Group published a predictive score (Zaidi score, see table) demonstrating that tumors with a score≥6 had a 33% likelihood of recurrence by 24 months. Furthermore, it is known that that patients with metastatic disease who undergo curative intent resection also have a great risk of recurrence. Despite these known risk factors for recurrence, to date, no prospective study exploring the role of adjuvant cytotoxic chemotherapy has ever been performed in this population. Supported by the E2211 results using capecitabine and temozolomide (CAPTEM) in the metastatic setting, S2104 investigates the role of CAPTEM in the adjuvant setting. Methods: S2104 is a randomized phase II trial designed to evaluate recurrence-free survival (RFS) in participants with resected pNETs randomized on a 2:1 fashion to CAPTEM or observation. Patient are eligible if they had resected well-differentiated grade 2 or 3 (ki-67 up to 55%) pNETS with a Zaidi score of ≥ 3. Patients may have received resection/ablation of liver oligo-metastatic disease (up to 5 liver metastases) at the time of well-differentiated pNET resection. Key eligibility criteria: age ≥18 years, Zubrod performance status of 0-2, adequate organ and marrow function. Stratification factors include 1) Disease status prior to resection (metastatic vs. non-metastatic disease) and 2) Zaidi score (≥ 6 vs. < 6). Participants will be followed with imaging for 5 years. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180821, U10CA180868. Clinical trial information: NCT05040360.