US NET recently published a novel, validated recurrence scoring system, Zaidi score, to guide surveillance strategies after pNET resection (see Figure 1 ).4 Of 1,020 patients who underwent pNET resection over a 10-year period, 15% developed recurrence. Patients with a high Zaidi score (score 6–10) had a 33% likelihood of recurrence 24 months following resection, and patients who experienced recurrence had shorter overall survival.5 It also is well-established that patients with metastatic disease who undergo curative-intent resection have a high risk of recurrence despite complete resection of gross disease.6-7 Median recurrence-free survival is 15 months following resection for metastatic disease.
A Turning Point
In 2018, the Eastern Cooperative Oncology Group and American College of Radiology Imaging Network (ECOG-ACRIN) phase II randomized trial of temozolomide or temozolomide and capecitabine (CAPTEM) in patients with advanced low- to intermediate-grade pancreatic neuroendocrine tumors (E2211) demonstrated a progression-free survival (PFS) benefit of CAPTEM cytotoxic chemotherapy in the metastatic setting.8 PFS was significantly longer in the CAPTEM group compared with temozolomide alone (22.7 months versus 14.4 months, p = 0.02), as was median overall survival (not reached versus 38 months, p = 0.01). This finding was pivotal, especially as other systemic therapeutic options for metastatic pNETs, such as somatostatin analogs, everolimus, or sunitinib, are cytostatic rather than cytotoxic. This distinction is important to consider when evaluating the role of adjuvant therapy as cytotoxic, but not cytostatic, therapy has the potential to eliminate micrometastatic disease absent of measurable disease in the adjuvant setting. Despite known risk factors for recurrence, no prospective study has evaluated the benefit of adjuvant cytotoxic chemotherapy in patients with high-risk pNETs to date.9
New Trial Tests Postoperative Chemotherapy versus Observation
Randomized Phase II Trial of Postoperative Adjuvant Capecitabine and Temozolomide versus Observation in High-Risk Pancreatic Neuroendocrine Tumors (S2104) is a recently activated National Clinical Trials Network randomized phase II trial designed to compare CAPTEM chemotherapy versus observation following resection of pNETs (see Figure 2). Patients with well-differentiated grade 2 or 3 (Ki-67 up to 55%) pNETS with a Zaidi score of ≥3 who underwent resection (or ablation) for either localized disease with or without up to five liver metastases are eligible for enrollment. Patients must be older than 18 years of age, have a Zubrod performance status of 0–2, and have adequate bone marrow function. Prior neoadjuvant therapy for treatment of pancreatic neuroendocrine tumor is prohibited, with the exception of prior somatostatin analog use. Stratification factors for randomization are disease status before resection (metastatic versus nonmetastatic) and Zaidi score (≥6 versus <6 versus not applicable due to presence of metastatic disease).
FIGURE 2. Randomized Phase II Trial of Postoperative Adjuvant Capecitabine and Temozolomide Vs. Observation In High-Risk pNET: Swog S2104
