Introduction
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of tumors with rising incidence. Despite several available treatments, including somatostatin analogues (SSAs), targeted therapies (everolimus, sunitinib), and chemotherapy (capecitabine-temozolomide, CAPTEM), predicting therapeutic response and disease progression remains difficult. Tumor-related features (e.g., grading, metastatic burden) influence outcomes but whether some patient-related variables (e.g., lifestyle, comorbidities) play a role is poorly explored.
Aims & Methods
This study aimed to identify tumor and patient-related factors associated with progression and survival outcomes in GEP-NENs treated with SSAs, CAPTEM, or targeted therapies. This is a multicenter, retrospective observational cohort study including patients with well-differentiated GEP-NENs treated with SSAs, CAPTEM, or EVE/SUN. Inclusion criteria were age ≥18 years, histologically confirmed GEP-NEN, and at least 6 months of treatment. Exclusion criteria included poorly differentiated tumors, prior radioligand therapy, and MiNENs. Clinical, pathological, therapeutic, and exposome-related variables were collected. The primary endpoint was progression-free survival (PFS); overall survival (OS) was also evaluated. A target sample size of 400 was estimated for adequate power in subgroup analyses. Univariate analyses were conducted using t-tests or chi-square tests as appropriate. Associations with PFS and OS were further assessed through Cox proportional hazards models.
Results
A total of 301 patients (52.2% pancreatic) from four Italian referral centers for neuroendocrine tumors (Itanet centers) were included: 258 (85.7%) received SSAs, 32 (10.6%) CAPTEM, and 17 (5.6%) EVE/SUN. Median age at diagnosis was 59 years; 51.9% were female. Most patients (73.7%) presented with metastatic disease at diagnosis, and the majority were G2 (58%) or G3 (2.3%).
In univariate analysis, patient-related variables were not significantly associated with PFS, except for lower age at diagnosis and shorter duration of metformin use (both p = 0.05). Conversely, tumor-related variables (grading, Ki67 and presence of bone or liver metastases) were significantly associated with PFS. In multivariable Cox analysis, only liver metastases (HR 2.0), bone metastases (HR 2.15), and G3 tumors (HR 3.35) were associated with shorter PFS. For OS, univariate analysis showed worse survival in male patients (p = 0.017), those with a history of alcohol use (p = 0.027), liver disease (p = 0.013), higher tumor grading/Ki67 (p < 0.001), absence of primary tumor resection (p < 0.001), and presence of bone (p = 0.004) or liver metastases (p < 0.001). Cox multivariable analysis confirmed association of OS with male sex (HR 2.73), alcohol use (HR 6.46), G3 tumors (HR 8.26), liver metastases (HR 6.45), and absence of primary tumor resection (HR 6.45). A subgroup analysis restricted to SSA-treated patients and pancreatic NENs patients revealed similar trends.
Conclusion
In this multicenter real-world study, progression and survival outcomes in GEP-NENs were primarily driven by tumor-related variables such as grading and metastatic spread, while patient-related factors played a limited role. However, results are currently underpowered, having reached approximately 75% of the planned sample size. Future efforts will aim to expand the EVE/SUN and CAPTEM groups to enhance subgroup analyses and improve robustness of findings.
