Implications of fluorodeoxyglucose uptake in low-intermediate grade metastatic neuroendocrine tumors from peptide receptor radionuclide therapy outcome viewpoint: A semi-quantitative standardized uptake value-based analysis

Abstract

Dual tracer positron emission tomography (PET) imaging approach (with 68Ga-DOTATATE PET-computed tomography (CT) for somatostatin receptor and 18-fluorodeoxyglucose (18FDG) PET-CT for glucose transporter receptor) plays a vital role in baseline differentiation, treatment decision-making, and prognostic assessment of neuroendocrine tumors (NETs). The aims of this study were to observe and compare the clinical behavior of low-/intermediate-grade NETs depending on their baseline FDG metabolism (calculated through pre-peptide receptor radionuclide therapy [PRRT] FDG standardized uptake value [SUV]) and to determine its prognostic importance in predicting extent of therapeutic response (post-PRRT) in terms of symptomatic, biochemical, and scan parameters along with the long-term impact on progression-free survival (PFS) and overall survival (OS). Fifty-nine patients with low (≤2%) and intermediate (3–20% Mib-1/Ki-67 index) grade metastatic NET were selected for this retrospective analysis and divided into three groups: Group 1 consisted of patients having low-grade FDG uptake at baseline, predefined as SUVmax< 5 (n = 13); Group 2 consisted of those having intermediate-grade FDG uptake at baseline, SUVmax5–10 (n = 34), and Group 3 consisted of patients having high-grade FDG uptake at baseline, defined as SUVmax>10 (n = 12). The trend of FDG avidity was studied from the baseline till the time of analysis and the overall outcomes were compared in terms of symptomatic response (Karnofsky and ECOG performance score), biochemical response, scan response (anatomical and metabolic, RECIST 1.1 and PERCIST 1.0), PFS and OS. Patients in Groups 1 and 2 showed highest proportion of symptomatic complete response, biochemical partial response, and stable disease on scan. These patients also demonstrated better PFS and OS and lowest hazard ratio compared to patients in the Group 3. An important finding was a substantial fraction of the complete metabolic responders (CMRs) across the groups, achieved CMR within first 2 cycles of PRRT (85% of Group 1, 51% of Group 2, and 47% of Group 3). In conclusion, most of the patients of low-/intermediate-grade NET having low-to-moderate baseline tumor FDG metabolism (SUVmax≤10) showed favorable symptomatic response with good biochemical and anatomical disease control and were associated with prolonged PFS and OS, compared to that of those having high-grade baseline tumor FDG metabolism (SUVmax> 10).

Clinical Utility of 18F-FDG PET in Neuroendocrine Tumors Prior to Peptide Receptor Radionuclide Therapy: A Systematic Review and Meta-Analysis

“…Five studies in our meta-analysis included patients of G1 and G2 only [ 32 , 33 , 34 , 35 ]; (and seven studies included NET patients of all grades [ 12 , 36 , 37 , 38 , 39 , 40 , 41 ]. Overall, 491 patients with G1 (32.9%), 720 patients with G2 (48.2%), 63 patients with no clear distinction between G1 and G2 (4.2%), 85 patients with G3 (5.7%), and 133 patients with an unspecified grade (8.9%; among these were also patients with mediastinal NETs) were included in the present systematic review and meta-analysis ( Table 1 ).…”

“…Eight studies reported DCR following PRRT and were stratified by 18 F-FDG status using OR analysis [ 32 , 33 , 34 , 35 , 36 , 37 , 39 , 42 ]. The DCR rate for patients with a negative 18 F-FDG status prior to PRRT initiation was 91.9%, compared to 74.2% in patients with positive 18 F-FDG imaging ( Figure 2 ; random effects OR:4.85; 95%CI: 2.27–10.36; Figure 2 ).…”

“…However, as none of the studies reported patient data at the individual level, we were not able to perform a diagnostic test accuracy meta-analysis, i.e., apply a receiver-operating-characteristic (ROC) analysis to determine the positive threshold for SUV with respect to a prognostic and predictive evaluation. In two studies, SUVmax stratified analysis was presented applying the following strata: SUVmax < 5, SUVmax: 5–10, SUVmax > 10 with evidence of a negative correlation between higher lesional FDG uptake and PRRT responses/survival outcomes [ 12 , 32 ]. In addition, Binderup et al demonstrated a higher risk of progression and death for patients receiving PRRT with a baseline SUVmax > 3 and > 9, respectively [ 53 ].…”

“…In addition, the included studies were mostly retrospective, and selection bias is very likely due to the assignment of patients for 18 FDG-PET prior to PRRT based on age, performance status, primary tumor site, grade, extent of metastatic disease, and prior treatments. Furthermore, the variation in the number of administered PRRT cycles in the included studies may have affected our findings, as there is evidence of a proportional correlation between the dose received by the tumor and the PRRT response outcome [ 32 , 33 , 38 , 66 ]. Other limitations were the ambiguity over FDG SUVmax cut-offs and considerable tumor heterogeneity observed across the included studies.…”

The Challenge of Evaluating Response to Peptide Receptor Radionuclide Therapy in Gastroenteropancreatic Neuroendocrine Tumors: The Present and the Future

“…Furthermore, their study highlights the heterogeneity of NETs by the number of patients with G1 NETs but with a NETPET score greater than 1. Several studies have confirmed these data [ 116 , 117 ]. In particular, Thapa et al [ 116 ] confirmed that high baseline 2-[ 18 F]FDG SUVmax was associated with poor PRRT outcome in GEP-NETs, and also that 78% of responders showed high uptake on baseline [ 68 Ga]Ga-DOTA-SSTa PET and low uptake or negative findings on baseline 2-[ 18 F]FDG PET.…”