Dual FDG/PSMA PET imaging to predict lesion-based progression of mCRPC during PSMA-RLT

Abstract

Candidates for prostate-specifc membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have “mismatch” lesions with pronounced 18-fuorodeoxyglucose ([18F]FDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To defne such criteria, we retrospectively analyzed 267 randomlyselected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined [ 18F]FDG and [ 68Ga]Ga-PSMA-11 maximum standardized uptake value (SUVmax), and calculated the [ 18F]FDG SUVmax/[68Ga]Ga-PSMA-11 SUVmax quotient (FPQ). From follow-up [ 18F]FDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in [ 18F] FDG SUVmax. Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables difering signifcantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-ofs with optimal sensitivity and specifcity were determined using the maximum value of Youden’s index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median [ 68Ga]Ga-PSMA-11 SUVmax was signifcantly lower (p < 0.001), median FPQ signifcantly higher (p< 0.001), and median [ 18F]FDG SUVmax similar in progressing versus non-progressing lesions. [ 68Ga]Ga-PSMA-11 SUVmax and FPQ showed predictive power regarding progression (AUCs: 0.89, 0.90). An introduced clinical score combining both further improved predictive performance (AUC: 0.94). Optimal cut-ofs to foretell progression were: [ 68Ga]Ga-PSMA-11 SUVmax < 11.09 (88.2% sensitivity, 81.9% specifcity), FPQ≥ 0.92 (90.2% sensitivity, 78.7% specifcity), clinical score≥ 6/9 points (88.2% sensitivity, 87.5% specifcity). At baseline, a low [ 68Ga]Ga-PSMA-11 SUVmax and a high FPQ predict early lesional progression under RLT; [ 18F]FDG SUVmax does not. A score combining [ 68Ga]Ga-PSMA-11 SUVmax and FPQ predicts early lesional progression even more efectively and might therefore be useful to quantitatively identify mismatch lesions.