Evaluation of treatment-naive high-grade neuroendocrine tumors with 68Ga-DOTA-RGD2 PET/CT and a comparison with 68Ga-DOTANOC PET/CT: a pilot study

Introduction: Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that display neuroendocrine characteristics and variable somatostatin receptor (SSTR) expression. As per the pathological classification based on cell differentiation and mitotic index (Ki 67), their spectrum varies from well-differentiated neuroendocrine tumors (NETs) to poorly differentiated neuroendocrine carcinomas (NECs). High-grade NETs are more aggressive and poorly differentiated. Neoangiogenesis is a marker of aggressiveness and is essential for tumor growth, invasion, and metastatic spread. In vivo, we evaluated the angiogenesis using novel imaging marker 68Ga-DOTA- RGD2 PET/CT in patients with high-grade NETs and compared it with 68Ga-DOTANOC PET/CT for SSTR expression.

Methods: This prospective study was approved by the institutional review board, and informed consent was obtained from all patients. Twenty-two patients (12M, 10F; mean age: 47.4y, range: 32-69y) with histopathologically proven WHO grade 2 (n=17) and grade 3 (n=5) NETs underwent 68Ga-DOTA-RGD2 PET/CT and 68Ga-DOTANOC PET/CT within five days before starting any form of treatment. PET/CT scans were interpreted qualitatively (positive vs. negative) and semi-quantitatively as follows: maximum and mean standardized uptake value (SUVmax and SUVmean) and target to background ratio (TBR) for both studies. Pearson correlation test was used to analyze the correlation between two normally distributed continuous quantitative data and Spearman’s rho test for non-continuous and non-normally distributed data. The unpaired t-test was used to compare normally distributed continuous variables.

Results: Lesion detectability with 68Ga-DOTA RGD2 was 77.8% for primary lesions and 44.7% for metastatic sites including lymph nodes (64.2%), liver (15%), bone (76.1%), and brain (100%). Primary was localized to pancreas (38.9%), small intestine (22.2%), stomach (11.1%), retroperitoneum (11.1%), mesenteric NET (5.5%), breast (5.5%) and liver (5.5%). Lesion detectability with 68Ga-DOTANOC was 88.8% for primary lesions and 85.7% for metastatic sites including lymph nodes (100%), liver (72.3%), bone (99%), and brain (100%). The SUVmax and TBRmax values were significantly higher for 68Ga-DOTANOC PET/CT at all disease-involved sites than on 68Ga-DOTA RGD2 PET/CT. The SUVmax and TBRmax on 68Ga- DOTA RGD2 PET did not show a statistically significant correlation (p=0.904; p=0.946 respectively) with the grade of the tumor. We also observed intra-patient heterogeneity in RGD2 uptake in the disease-involved sites.

Conclusions: Angiogenesis imaging using 68Ga-DOTA RGD2 PET/CT can be considered in patients with high-grade neuroendocrine tumors. There is comparable lesion detectability as compared to 68Ga-DOTANOC PET/CT, except for metastatic lesions involving the liver.