Glucose Metabolism Modification Induced by Radioligand Therapy with [177Lu]Lu/[90Y]Y-DOTATOC in Advanced Neuroendocrine Neoplasms: A Prospective Pilot Study within FENET-2016 Trial

Abstract

[18F]F-FDG (FDG) PET is emerging as a relevant diagnostic and prognostic tool in neuroendocrine neoplasms (NENs), as a simultaneous decrease in [68Ga]Ga-DOTA peptides and increase in FDG uptake (the “flip-flop” phenomenon) occurs during the natural history of these tumors. The aim of this study was to evaluate the variations on FDG PET in NEN patients treated with two different schemes of radioligand therapy (RLT) and to correlate them with clinical–pathologic variables. A prospective evaluation of 108 lesions in 56 patients (33 males and 23 females; median age, 64.5 years) affected by NENs of various primary origins (28 pancreatic, 13 gastrointestinal, 9 bronchial, 6 unknown primary (CUP-NENs) and 1 pheochromocytoma) and grades (median Ki-67 = 9%) was performed. The patients were treated with RLT within the phase II clinical trial FENET-2016 (CTID: NCT04790708). RLT was offered for 32 patients with the MONO scheme (five cycles of [177Lu]Lu-DOTATOC) and for 24 with the DUO scheme (three cycles of [177Lu]Lu-DOTATOC alternated with two cycles of [90Y]Y-DOTATOC). Variations in terms of the ΔSUVmax of a maximum of three target lesions per patient (58 for MONO and 50 for DUO RLT) were assessed between baseline and 3 months post-RLT FDG PET. In patients with negative baseline FDG PET, the three most relevant lesions on [68Ga]Ga-DOTA-peptide PET were assessed and matched on post-RLT FDG PET, to check for any possible changes in FDG avidity. Thirty-five patients (62.5%) had at least one pathological FDG uptake at the baseline scans, but the number was reduced to 29 (52%) after RLT. In the patients treated with DUO-scheme RLT, 20 out of 50 lesions were FDG positive before therapy, whereas only 14 were confirmed after RLT (p = 0.03). Moreover, none of the 30 FDG-negative lesions showed an increased FDG uptake after RLT. The lesions of patients with pancreatic and CUP-NENs treated with the DUO scheme demonstrated a significant reduction in ΔSUVmax in comparison to those treated with MONO RLT (p = 0.03 and p = 0.04, respectively). Moreover, we found a mild positive correlation between the grading and ΔSUVmax in patients treated with the MONO scheme (r = 0.39, p < 0.02), while no evidence was detected for patients treated with the DUO scheme. Our results suggest that RLT, mostly with the DUO scheme, could be effective in changing NEN lesions’ glycometabolism, in particular, in patients affected by pancreatic and CUP-NENs, regardless of their Ki-67 index. Probably, associating [90Y]Y-labelled peptides, which have high energy emission and a crossfire effect, and [177Lu]Lu ones, characterized by a longer half-life and a safer profile for organs at risk, might represent a valid option in FDG-positive NENs addressed to RLT. Further studies are needed to validate our preliminary findings. In our opinion, FDG PET/CT should represent a potent tool for fully assessing a patient’s disease characteristics, both before and after RLT.

The Value of Semiquantitative Parameters Derived from 18F-FDG PET/CT for Predicting Response to Neoadjuvant Chemotherapy in a Cohort of Patients with Different Molecular Subtypes of Breast Cancer

“…However, breast MRI can provide only an evaluation of T and N staging after NAC, and several factors can reduce its accuracy, including molecular subtypes (Luminal BC), chemotherapy regimen (taxane and antiangiogenetic drugs), and therapy-induced inflammation and fibrosis [ 9 , 10 ]. Therefore, in recent years [ 18 F]Fluorodeoxyglucose ([ 18 F]FDG), positron emission tomography/computed tomography (PET/CT) has been evaluated with growing interest in BC patients addressed to NAC, as it can provide an in vivo functional evaluation of the metabolism of a cancer lesion before and after therapy [ 11 , 12 , 13 ]. The possibility of predicting pCR after NAC through baseline imaging data would be of great clinical meaning in BC patients, determining a more tailored treatment approach.…”

PET Criteria by Cancer Type from Imaging Interpretation to Treatment Response Assessment: Beyond FDG PET Score

“…A standardized and reliable response assessment system after RLT is an unmet clinical need, as both morphological and functional imaging have shown limitations [ 57 , 58 ]. Recently, Zwirtz et al compared the response evaluation with respect to OS in patients treated with at least two cycles of RLT introducing a new metabolic criterion, based on modified EORTC, so-called MORE criteria ( Table 14 ).…”

Relevance of Volumetric Parameters Applied to [68Ga]Ga-DOTATOC PET/CT in NET Patients Treated with PRRT

“…An interval of 8-10 weeks was observed between every cycle. Main criteria guiding the choice of the therapy scheme were already described in a previously published paper from our group [14].…”

“…Moreover, following recent reports in the literature, [ 18 F]F-fluorodeoxyglucose (FDG) PET/CT has progressively gained importance as a prognostic tool in NET diagnostic algorithm [2,11,12]. However, despite the above mentioned evidence, [ 18 F]F-FDG PET/CT is currently recommended by official guidelines only for G3 neoplasms, and its best indications and timing are still unsolved and under investigation [13][14][15]. Finally, [ 68 Ga]Ga-exendin-4, agonist of the glucagon-like protein-1 receptor, has showed high sensibility and specificity for insulinomas [16,17].…”

“…When considering patients treated with PRRT, ENETS guidelines [21] suggest treatment evaluation according to response-evaluation criteria in solid tumors (RECIST) 1.1 [22], applied to contrast-enhanced CT, as the main tool for response assessment. However, RECIST 1.1 are questioned in the evaluation of PRRT outcomes due to the possibility of PRRT-induced pseudo-progression or delayed morphological response [14,23,24]. Therefore, further research for new reliable response-evaluation tools is needed.…”