Prädiktoren für das Auftreten des ungünstigen molekular-bildgebenden Mismatch-Metastasenphänotypes mit diskrepanter PSMA-Expression und Glukosemetabolismus bei Patienten mit metastasierendem Prostatakarzinom

Hintergrund Durch die PSMA-gerichtete Radioligandentherapie (PSMA-RLT) wurden bei Patienten mit metastasierten kastrationsresistenten Prostatakarzinom (mCRPC) beeindruckende Ergebnisse erzielt. Für eine erfolgreiche PSMA-RLT ist jedoch eine hohe Expression von PSMA ist unerlässlich. Im Verlauf der Behandlung entwickeln sich bei einigen Patienten 18F- FDG-avide Läsionen mit geringer oder keiner PSMA-Expression, sogenannte 18F-FDG /68Ga- PSMA-11-Mismatch-Befunde, in der PET/CT. Die PSMA-RLT kann diese Läsionen nicht beeinflussen. Dies macht eine Änderung des Therapiemanagements erforderlich. Zur frühzeitigen Erkennung dieser Mismatch-Befunde, wurden mögliche Blutparameter als hinweisgebend für das Auftreten dieser Läsionen untersucht. In einem weiteren Schritt wurde der Wert der kombinierten 18F-FDG- und 68Ga-PSMA-11-PET-Bildgebung und der Einfluss auf den Krankheitsverlauf untersucht Methoden Bei dieser Arbeit handelt es sich um eine retrospektive Studie an n = 66 Patienten mit fortgeschrittenen mCRPC, die für eine 177Lu-PSMA-617-Radioligandentherapie überwiesen wurden oder diese erhielten. Alle erhielten eine duale Bildgebung mit 68Ga-PSMA-11- und 18F- FDG -PET/CT-Bildgebung innerhalb von 4 Wochen. Als Indikatoren für das Auftreten von 18F- FDG/68Ga-PSMA-11-Mismatch-Befunden wurden Prostata-spezifisches Antigen (PSA), Neuronenspezifische Enolase (NSE), Gamma-Glutamyltransferase (γ-GT) und alkalische Phosphatase (ALP) getestet. Zusätzlich zu den absoluten Werten dieser Parameter wurden, um die Dynamik zu beurteilen, auch die relativen Veränderungen (ΔPSA, ΔNSE, Δ γ-GT, ΔALP) über einen Zeitraum von 4 ± 1 Wochen vor der 18F-FDG -PET/CT analysiert. Bei n = 29 mCRPC-Patienten mit einer Verschlechterung der Erkrankung nach durchschnittlich vier Zyklen 177Lu-PSMA-617-RLT, wurde eine kombinierte 18F-FDG - und 68Ga-PSMA-11-PET- Bildgebung durchgeführt, um 18F-FDG -avide Läsionen mit geringer oder keiner PSMA- Expression zu erkennen. Um die prognostische Bedeutung von Mismatch-Befunden besser bewerten zu können, wurden Überlebenszeitanalysen hinsichtlich des Vorhandenseins, der Lage und der von 18F-FDG-PET abgeleiteten Parameter SUVmax, metabolisches Tumorvolumen (MTVm) und Gesamtläsionsglykolyse (TLGm) von Mismatch-Läsionen durchgeführt. Ergebnisse Insgesamt wiesen 41/66 (62 %) Patienten mindestens einen 18F-FDG /68Ga-PSMA-11- Mismatch-Befund im PET/CT auf. Diese Mismatch-Befunde wurden bei 13/41 (32 %) Patienten beim Screening und bei 28/41 (68 %) Patienten während der PSMA-RLT festgestellt. Die NSE-Serumspiegel (55,4 ± 44,6 µg/l vs. 18,5 ± 8 µg/l, p < 0,001) und ΔNSE (93,8 ± 124,5% vs. 2,9 ± 39,5%, p < 0,001) waren in der Mismatch-Gruppe signifikant höher als in der Non- Mismatch-Gruppe. Keine signifikanten Unterschiede konnten für Serum-PSA (p = 0,424), ΔPSA (p = 0,417), Serum-ALP (p = 0,937), ΔALP (p = 0,611), Serum- γ-GT (p = 0,773) und Δγ-GT (p = 0,971) festgestellt werden. In der ROC-Analyse für NSE und ΔNSE lag der maximale Wert des Youden-Index bei einem Cut-off-Wert von 26,8 µg/l (Sensitivität 78 %, Spezifität 96 %) bzw. bei + 13,9 % (Sensitivität 84 %, Spezifität 75 %). Ein eingeführtes Scoring-System aus der Kombination beider Parameter erreichte eine Sensitivität von 90 % und eine Spezifität von 88 % für das Auftreten von 18F-FDG/68Ga-PSMA-11-Mismatch- Befunden. In den Überlebenszeitanalysen wiesen 17/29 Patienten (59 %) mindestens eine Mismatch-Metastase auf. Ab dem Zeitpunkt der kombinierten PET-Bildgebung war das mediane Überleben (OS) der Patienten mit Mismatch-Befunden signifikant (p = 0,008) kürzer als das der Patienten ohne Mismatch-Befunde (3,3 vs. 6,1 Monate). Patienten mit einem hohen MTVm wiesen ein signifikant (p = 0,034) kürzeres OS von 2,6 Monaten auf als Patienten mit einem niedrigen MTVm (5,3 Monate). Zusätzlich konnte gezeigt werden, dass Patienten mit hepatischen Mismatch-Befunden ein signifikant (p = 0,049) kürzeres OS aufwiesen als Patienten ohne diese Fehlanpassung (2,9 vs. 5,3 Monate). Hinsichtlich SUVmax und TLGm ließen sich keine signifikanten Unterschiede in den Überlebenszeitanalysen zeigen. Schlussfolgerung Es wurde in dieser Arbeit eine signifikant höhere absolute Serumkonzentration und ein höherer relativer Anstieg von NSE bei mCRPC-Patienten mit 18F-FDG/68Ga-PSMA-11-Mismatch- Befunden in der PET/CT beobachtet. NSE könnte als potenzieller Laborindikator für 18F- FDG/68Ga-PSMA-11-Mismatch-Befunde verwendet werden, wenn diese Beobachtung in künftigen, idealerweise prospektiven, Studien an größeren Patientenkohorten bestätigt werden kann. Bei mCRPC-Patienten, deren Krankheit sich während der PSMA-RLT verschlimmerte, ist eine kombinierte 18F-FDG- und 68Ga-PSMA-11-PET-Bildgebung unerlässlich, um Mismatch-Befunde zu identifizieren, da diese mit signifikant schlechteren Ergebnissen verbunden sind, die eine Änderung des Therapiekonzepts erfordern.Background PSMA-targeted radioligand therapy (PSMA-RLT) has shown promising results in patients diagnosed with metastatic castration-resistant prostate cancer (mCRPC). However, for successful therapy, high expression of PSMA is crucial. During the course of treatment, some patients develop 18F-FDG-avid lesions despite no or low PSMA expression, referred to as 18FFDG/ 68Ga-PSMA-11 mismatch findings, on PET/CT. These lesions remain unaffected by PSMA-RLT. A change in therapy management is necessary. In order to detect these mismatch findings at an early stage, blood parameters were investigated as possible indicators for the occurrence of these lesions. Additionally, the value of combined 18F-FDG and 68Ga-PSMA-11 imaging and its influence on disease progression and overall survival was evaluated. Methods This work is a retrospective analysis of n = 66 patients with advanced mCRPC who were either referred for or received 177Lu-PSMA-617 radioligand therapy. Within a four weeks time frame all received dual imaging with 18F-FDG-PET/CT and 68Ga-PSMA-11 imaging. Prostate-specific antigen (PSA), neuron-specific enolase (NSE), gamma-glutamyltransferase (γ-GT), and alkaline phosphatase (ALP) were evaluated as potential indicators of the presence of 18FFDG/ 68Ga-PSMA-11 mismatch findings. In addition to absolute values of these parameters, relative changes (ΔPSA, ΔNSE, Δ γ-GT, ΔALP) were also analyzed over a period of 4 ± 1 weeks prior to the 18F-FDG -PET/CT to asses dynamics. In n = 29 mCRPC patients who experienced disease worsening after an average of four cycles of 177Lu-PSMA-617-RLT, combined 18F-FDG- and 68Ga-PSMA-11-PET imaging was conducted to detect 18F-FDG-avid lesions with no or low PSMA expression. To asses the prognostic significance of mismatch findings, overall survival analyses were conducted based on regarding the occurrence, location, and 18F-FDG-PET-derived parameters metabolic tumor volume (MTVm), SUVmax, and total lesion glycolysis (TLGm) of mismatch lesions. Results Out of a total of n=66 patients, 41/66 (62%) patients had at least one 18F-FDG/68Ga-PSMA-11 mismatch finding on PET/CT. These mismatch findings were detected in 13/41 (32%) patients during the screening process and in 28/41 (68%) patients while undergoing PSMA RLT. Serum NSE levels (55.4 ± 44.6 μg/l vs. 18.5 ± 8 μg/l, p < 0.001) and ΔNSE (93.8 ± 124.5% vs. 2.9 ± 39.5%, p < 0.001) were significantly higher in the mismatch group compared to the nonmismatch group. However there were no significant differences between the two groups for serum ALP (p = 0.937), ΔALP (p = 0.611), serum PSA (p = 0.424), ΔPSA (p = 0.417), serum γ-GT (p = 0.773) and Δγ-GT (p = 0.971). In the ROC analysis, the maximum Youden-Index value was achieved at a cut-off value of 26.8 μg/l for NSE (sensitivity 78%, specificity 96%) and + 13.9% for ΔNSE (sensitivity 84%, specificity 75%), respectively. A scoring system that combined both parameters achieved a sensitivity of 90% and a specificity of 88% for detecting the occurrence of 18F-FDG/68Ga-PSMA-11 mismatch findings. In survival analyses, 17/29 patients (59%) had at least one mismatch metastasis. From the time of combined PET imaging, the median survival (OS) was significantly (p = 0.008) shorter for patients with mismatch findings compared to that of patients without mismatch findings (3.3 vs. 6.1 months). Patients with a high MTVm had a significantly (p = 0.034) shorter OS of 2.6 months than patients with a low MTVm (5.3 months). In addition, it was shown that patients with hepatic mismatch findings had a significant (p = 0.049) shorter OS than patients without this mismatch (2.9 vs. 5.3 months). However, no significant differences were found regarding SUVmax and TLGm in the overall survival analyses. Conclusion Significantly higher absolute serum concentration and relative increase of NSE were observed in mCRPC patients with 18F-FDG/68Ga-PSMA-11 mismatch findings on PET/CT in this work. The results suggest that NSE could serve as a potential laboratory indicator of 18F-FDG/68Ga- PSMA-11 mismatch findings if this observation can be confirmed in future, ideally prospective, studies with larger patient cohorts. In mCRPC patients whose disease worsened during PSMARLT it is essential to identify mismatch findings with combined 68Ga-PSMA-11 and 18F-FDG PET imaging, as these lesions are associated with significantly worse outcomes requiring a change in therapeutic approach

Value of Combined PET Imaging with [18F]FDG and [68Ga]Ga-PSMA-11 in mCRPC Patients with Worsening Disease during [177Lu]Lu-PSMA-617 RLT

Despite the promising results of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) in metastatic castration-resistant prostate cancer (mCRPC), some patients show worsening disease during PSMA-RLT. We investigated the value of combined [18F]FDG and [ 68Ga]Ga-PSMA-11 PET imaging in this setting. In n = 29 mCRPC patients with worsening disease after a median of four cycles of [177Lu]Lu-PSMA-617 RLT, combined [18F]FDG and [68Ga]Ga-PSMA11 PET imaging was performed to detect [18F]FDG-avid lesions with low or no PSMA expression (mismatch lesions). To evaluate prognostic implication of mismatch, survival analyses regarding presence, location, and [18F]FDG PET-derived parameters such as SUVmax, metabolic tumor volume (MTVm), and total lesion glycolysis (TLGm) of mismatch findings were performed. Seventeen patients (59%) showed at least one mismatch metastasis. From the time point of combined PET imaging, the median overall survival (OS) of patients with mismatch findings was significantly (p = 0.008) shorter than those without (3.3 vs. 6.1 mo). Patients with a high MTVm revealed a significantly (p = 0.034) shorter OS of 2.6 mo than patients with low MTVm (5.3 mo). Furthermore, patients with hepatic mismatch showed a significantly (p = 0.049) shorter OS than those without (2.9 vs. 5.3 mo). Difference in OS regarding SUVmax and TLGm was not significant. In mCRPC patients with worsening disease during PSMA-RLT, combined [18F]FDG and [68Ga]Ga-PSMA-11 PET imaging is essential to identify mismatch findings, as these are associated with poor outcomes requiring a change in therapy management

Neuron-specific enolase has potential value as a biomarker for [18F]FDG/[68Ga]Ga-PSMA-11 PET mismatch findings in advanced mCRPC patients

Background PSMA-targeted radioligand therapy (PSMA-RLT) yielded impressive results in the metastasized castration-resistant prostate carcinoma (mCRPC) setting. High expression of PSMA is essential for successful PSMA-RLT. However, some patients develop [18F]FDG-avid lesions with low or no PSMA expression ([18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT) in the course of treatment. Those lesions are not affected by PSMA-RLT and a change in therapy management is needed. To enable early mismatch detection, possible blood parameters as indicators for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT were evaluated. Methods Retrospective study of N = 66 advanced mCRPC patients with dual [68Ga]Ga-PSMA-11 and [18F]FDG PET/CT imaging within 4 weeks, who were referred for or received [177Lu]Lu-PSMA-617 radioligand therapy. Prostate-specific antigen (PSA), neuron-specific enolase (NSE), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP) were tested as indicators for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings. Additional to absolute values, relative changes (ΔPSA, ΔNSE, ΔGGT, ΔALP) over a period of 4 ± 1 weeks prior to [18F]FDG PET/CT were analyzed. Results In total, 41/66 (62%) patients revealed at least one [18F]FDG/[68Ga]Ga-PSMA-11 mismatch finding on PET/CT. These mismatch findings were detected in 13/41 (32%) patients by screening for and in 28/41 (68%) patients during PSMA-RLT. NSE serum level (55.4 ± 44.6 μg/l vs. 18.5 ± 8 μg/l, p < 0.001) and ΔNSE (93.8 ± 124.5% vs. 2.9 ± 39.5%, p < 0.001) were significantly higher in the mismatch group than in the non-mismatch group. No significant differences were found for serum PSA (p = 0.424), ΔPSA (p = 0.417), serum ALP (p = 0.937), ΔALP (p = 0.611), serum GGT (p = 0.773), and ΔGGT (p = 0.971). For NSE and ΔNSE, the maximum value of the Youden index in ROC analysis was at a cut-off level of 26.8 μg/l (sensitivity 78%, specificity 96%) and at + 13.9% (sensitivity 84%, specificity 75%), respectively. An introduced scoring system of both parameters achieved a sensitivity of 90% and a specificity of 88% for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch. Conclusion We observed a significantly higher absolute serum concentration and a higher relative increase of NSE in advanced mCRPC patients with [18F]FDG-avid and insufficient PSMA expressing metastases ([18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT) in our cohort. NSE might be used as a potential laboratory indicator for [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings, if this observation is confirmed in future, ideally prospective, studies in larger patient cohorts