Warszawa 2020
lek. Ewa Witkowska-Patena
OCENA PRZYDATNOŚCI BADANIA 18F-PSMA-1007 PET/CT
W OBRAZOWANIU RAKA GRUCZOŁU KROKOWEGO
CYKL PUBLIKACJI MONOTEMATYCZNYCH
ROZPRAWA NA STOPIEŃ DOKTORA NAUK MEDYCZNYCH
BADANIA WYKONANO W MAZOWIECKIM CENTRUM MEDYCZNYM
PET/CT AFFIDEA
PROMOTOR:
dr hab. n. med. Mirosław Dziuk, prof. nadzw. WIM
2
Składam szczególne podziękowania Panu Profesorowi Mirosławowi Dziukowi Za inspirację, cenne uwagi merytoryczne i mobilizację do pracy.
Pani Doktor Agnieszce Giżewskiej
Serdecznie dziękuję za poświęcony czas i nieocenioną pomoc w analizie badań.
Wszystkim Pracownikom Mazowieckiego Centrum Medycznego PET/CT Affidea
Dziękuję za życzliwość i wsparcie w organizacji badań.
Dziękuję również Mojemu Mężowi Za nieustające wsparcie i wszelką pomoc.
3 Praca uzyskała zgodę Komisji Bioetycznej przy Wojskowej Izbie Lekarskiej
Uchwała nr 179/17 z dnia 27.01.2017
Pracę wykonano w ramach projektu statutowego – grantu promotorskiego
dla młodego naukowca nr 400 (5/8925) w latach 2016-2019 Decyzja nr 9/PMN/2016
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Spis treści
SKRÓTY ... 5
WSTĘP ... 7
CELE ROZPRAWY ... 14
CYKL PRAC MONOTEMATYCZNYCH ... 15
18F-Prostate-Specific Membrane Antigen-1007 and 18F-FCH PET/CT in Local Recurrence of Prostate Cancer ... 16
Head-to-Head Comparison of Prostate-Specific Membrane Antigen-1007 and 18F-Fluorocholine PET/CT in Biochemically Relapsed Prostate Cancer ... 21
Diagnostic Performance of 18F-PSMA-1007 PET/CT in Biochemically Relapsed Patients With Prostate Cancer With PSA Levels ≤2.0 ng/ml ... 36
Ordered Subset Expectation Maximisation vs Bayesian Penalised Likelihood Reconstruction Algorithm in 18F-PSMA-1007 PET/CT ... 48
PODSUMOWANIE ... 63
WNIOSKI ... 65
STRESZCZENIE ... 66
SUMMARY ... 68
5
SKRÓTY
18F-FCH fluorocholina wyznakowana radioaktywnym fluorem-18
18F-PSMA-1007 kwas
(3S,10S,14S)-1-(4-(((S)-4-karboksy-2-((S)-4-karboksy-2-(6- fluoronikotynamido)butanamido)butanamido)metylo)fenylo)-3-(naftalen- 2-ylmetylo)-1,4,12-triokso-2,5,11,13-tetraazaheksaadekano-10,14,16-trikarboksylowy
ADT terapia antyandrogenowa (ang. androgen-deprivation therapy)
AS aktywny nadzór (ang. active surveillance)
BCR wznowa biochemiczna (ang. biochemical relapse)
BPL algorytm rekonstrukcji obrazów PET/CT (ang. Bayesian Penalised Likelihood)
BS scyntygrafia kości (ang. bone scan)
CT tomografia komputerowa (ang. computed tomography)
EBRT radioterapia z pól zewnętrznych (ang. external-beam radiation therapy) GS skala Gleasona (ang. Gleason scale)
ISUP Międzynarodowe Towarzystwo Uropatologów (ang. International Society of Urological Pathology)
MBq megabekerel (jednostka radioaktywności odpowiadająca 106 rozpadów radioaktywnych na sekundę)
MIP projekcja maksymalnej intensywności (ang. maximum intensity projection)
MRI rezonans magnetyczny (ang. magnetic resonance imaging)
NPV negatywna wartość predykcyjna (ang. negative predictive value) OSEM algorytm rekonstrukcji obrazów PET/CT (ang. Ordered Subset
Expectation Maximisation)
PCa rak gruczołu krokowego (ang. prostate cancer)
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PET/CT pozytonowa tomografia emisyjna / tomografia komputerowa (ang.
positron emission tomography / computed tomography)
PPV pozytywna wartość predykcyjna (ang. positive predictive value)
PSA antygen swoisty dla gruczołu krokowego (ang. prostate-specific antigen) PSMA antygen błonowy swoisty dla gruczołu krokowego (ang. prostate-specific
membrane antigen)
RP radykalna prostatektomia (ang. radical prostatectomy)
SRT ratująca radioterapia (ang. salvage radiotherapy)
SUV standaryzowany współczynnik gromadzenia (ang. standarised uptake value)
TBR stosunek aktywności zmiany do tła (ang. tumour-to-background ratio) TNM klasyfikacja zaawansowania nowotworów (ang. tumour node metastasis) WW baczna obserwacja (ang. watchful waiting)
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WSTĘP
Rak gruczołu krokowego (ang. prostate cancer, PCa) jest drugim co do częstości występowania nowotworem wśród mężczyzn w Polsce i na świecie. W 2018 roku zapadalność na raka gruczołu krokowego w Polsce wyniosła 292,5 na 100 000 ludności. Na świecie w tym samym czasie odnotowano ponad 1,2 mln nowych przypadków PCa oraz ponad 350 tys. zgonów. Zapadalność na raka stercza jest najwyższa w krajach rozwiniętych (na pierwszym miejscu znajduje się Australia i Oceania) [1,2]. Do czynników ryzyka PCa zaliczane są: wiek (najwięcej zachorowań odnotowuje się powyżej 65. roku życia), rasa afroamerykańska, czynniki genetyczne, dieta, otyłość, brak aktywności fizycznej, hiperglikemia oraz ekspozycja na niektóre substancje chemiczne i promieniowanie jonizujące [3,4]. Zachorowalność na PCa w Polsce i na świecie wzrasta. Szacuje się, że do roku 2040 zapadalność na PCa wzrośnie o 79,7% i zostanie postawionych ok. 1 mln nowych rozpoznań raka gruczołu krokowego [5]. W świetle powyższych danych można jednoznacznie stwierdzić, że PCa stanowi istotny problem kliniczny, który w nadchodzących latach stanie się jeszcze większym wyzwaniem dla systemów opieki zdrowotnej na całym świecie.
Podejrzenie PCa najczęściej stawiane jest na podstawie podwyższonego poziomu antygenu swoistego dla gruczołu krokowego (ang. prostate-specific antigen, PSA) oraz nieprawidłowości w badaniu stercza przez odbytnicę. O ostatecznym rozpoznaniu decyduje natomiast wynik badania histopatologicznego materiału pobranego zazwyczaj w czasie biopsji gruczołu krokowego [6]. Dalsze postępowanie ustalane jest w oparciu o zaawansowanie choroby wg klasyfikacji TNM (Tabela 1) oraz ryzyko jej nawrotu (Tabela 2), a także wiek i stan kliniczny pacjenta.
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Tabela 1. Klasyfikacja TNM raka gruczołu krokowego [7]. T – wielkość guza pierwotnego
Tx Nie można ocenić guza pierwotnego T0 Nie stwierdza się guza pierwotnego
T1 Guz niewykrywalny w badaniu palpacyjnym lub obrazowym
T1a Guz wykryty przypadkowo w badaniu histopatologicznym stanowiący ≤5%
usuniętej tkanki gruczołu krokowego
T1b Guz wykryty przypadkowo w badaniu histopatologicznym stanowiący >5% tkanki usuniętej tkanki gruczołu krokowego
T1c Guz wykryty podczas biopsji
T2 Guz wyczuwalny w badaniu palpacyjnym, ograniczony do gruczołu krokowego T2a Guz zajmuje nie więcej niż połowę jednego płata
T2b Guz zajmuje ponad połowę jednego płata, ale nie zajmuje obu płatów T2c Guz zajmuje oba płaty
T3 Guz przekracza torebkę gruczołu krokowego
T3a Guz przekracza torebkę gruczołu krokowego (jedno- lub obustronnie), w tym
również nacieka szyję pęcherza moczowego
T3b Guz nacieka pęcherzyki nasienne
T4 Guz nieruchomy lub nacieka sąsiednie struktury inne niż pęcherzyki nasienne (zwieracz zewnętrzny cewki moczowej, odbytnicę, pęcherz moczowy, mięśnie dźwigacze i/lub ścianę miednicy)
N – regionalne węzły chłonne
Nx Nie można ocenić okolicznych węzłów chłonnych
N0 Nie stwierdza się przerzutów w okolicznych węzłach chłonnych N1 Przerzuty w regionalnych węzłach chłonnych
M – przerzuty odległe
M0 Nie stwierdza się przerzutów odległych M1 Przerzuty odległe
M1a Przerzuty do pozaregionalnych węzłów chłonnych M1b Przerzuty do kości
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Tabela 2. Ryzyko nawrotu raka gruczołu krokowego [6]. Rak niskiego
ryzyka
Rak pośredniego ryzyka
Rak wysokiego ryzyka
PSA <10 ng/ml oraz GS < 7 (ISUP 1) oraz cT1-2a PSA 10-20 mg/dl lub GS 7 (ISUP 2/3) lub cT2b PSA >20 ng/ml lub GS >7 (ISUP 4/5) lub cT2c jakiekolwiek PSA jakiekolwiek GS/ISUP cT3-4 lub cN+
Rak ograniczony do stercza Rak miejscowo
zaawansowany
PSA – antygen swoisty dla gruczołu krokowego; GS – punktacja wg skali Gleasona; ISUP – punktacja wg International Society for Urological Pathology
W pierwotnej ocenie zaawansowania PCa najczęściej wykorzystuje się rezonans magnetyczny (ang. magnetic resonance imaging, MRI), tomografię komputerową (ang.
computed tomography, CT) oraz scyntygrafię kości (ang. bone scan, BS). Wyniki badań
wskazują, że przydatna w tym celu (szczególnie w określaniu cechy N i M nowotworu) może też być pozytonowa tomografia emisyjna (ang. positron emission tomography, PET)/CT, jednak metoda ta nie została dotychczas uwzględniona w wytycznych [6].
Możemy wyróżnić trzy strategie postępowania z chorymi na raka gruczołu krokowego: leczenie odroczone, leczenie radykalne oraz leczenie choroby przerzutowej. Leczenie odroczone to baczna obserwacja (ang. watchful waiting, WW) lub aktywny nadzór (ang. active
surveillance, AS). Baczna obserwacja czyli leczenie nakierowane na objawy to postępowanie
skierowane głownie do starszych mężczyzn (przewidywana długość życia nie przekracza 10 lat) z licznymi chorobami towarzyszącymi oraz rakiem prostaty ograniczonym do stercza. W tej grupie leczenie włączane jest w przypadku progresji choroby, ma jednak charakter objawowy (nie jest nastawione na wyleczenie, ale utrzymanie dobrej jakości życia). W odróżnieniu od strategii WW, postępowanie AS ma na celu wyleczenie chorego jednak początek terapii odracza się do momentu wystąpienia wcześniej określonych wskaźników progresji (np. podwojenie stężenia PSA) [6].
Podstawowymi sposobami leczenia radykalnego są prostatektomia radykalna (ang.
radical prostatetectomy, RP) i radykalna radioterapia. W zależności od sytuacji klinicznej
i możliwości ośrodka pacjentom można zaproponować różne techniki operacyjne (prostatektomia klasyczna, laparoskopowa czy w asyście robota) i różne metody naświetlania (radioterapię z pól zewnętrznych (ang. external beam radiation therapy, EBRT), brachyterapię czy terapię protonową). RP i radioterapia mogą być stosowane samodzielnie bądź
10 w połączeniu, czasem też łącznie z leczeniem obniżającym stężenie androgenów (ang.
androgen-deprivation therapy, ADT). Jako leczenie radykalne coraz częściej stosowana jest
też krioablacja i HIFU (skupiona wiązka ultradźwięków o wysokim natężeniu) [6].
Leczenie pacjentów, u których PCa rozpoznano już w stadium przerzutowym opiera się głównie na ADT oraz, jeśli pacjent jest w dobrym stanie klinicznym, chemioterapii (najczęściej stosowanym chemioterapeutykiem jest docetaksel) [6].
Pomimo postępów w diagnostyce i leczeniu odsetek wznów PCa po leczeniu radykalnym pozostaje wysoki i sięga 53% [8]. Wznowa biochemiczna (ang. biochemical
relapse, BCR) raka gruczołu krokowego, czyli wzrost stężenia PSA po zakończonym leczeniu,
w zależności od rodzaju zastosowanej terapii jest definiowana jako:
• stężenie PSA >0,2 ng/ml z tendencją wzrostową w dwóch kolejnych pomiarach (po radykalnej prostatektomii) lub
• wzrost stężenia PSA o ≥2,0 ng/ml od minimalnego stężenia osiągniętego po zakończeniu radioterapii.
Pierwszym krokiem po wykryciu BCR powinna być próba odnalezienia ognisk wznowy. Szybkie wdrożenie leczenia ratującego (np. radioterapii ratującej (ang. salvage radiotherapy, SRT)) ma kluczowe znaczenie dla rokowania. Wykazano, że nawet 60% pacjentów, u których SRT rozpoczęto przy PSA <0,5 ng/ml osiągnie nieoznaczalnie niskie stężenia tego markera, a pięcioletni czas przeżycia bez progresji choroby (ang. progression-free survival, PFS) PCa wyniesie 80%. Im wyższe stężenie PSA w momencie włączenia SRT, tym gorsze rokowanie dla pacjenta – w badaniu Siegmanna i wsp. 6-letnie PFS wyniosło odpowiednio 48%, 40%, 28% i 18% dla stężeń PSA ≤0,5 ng/ml, 0,51-1 ng/ml, 1,01-1,5 ng/ml i >1,5 ng/ml. Co więcej, nie udowodniono istotnej skuteczności SRT u pacjentów ze stężeniami PSA >2,0 ng/ml [9–12].
Niestety czułość konwencjonalnych metod obrazowania tj. BS czy CT u pacjentów z wczesną wznową biochemiczną jest bardzo niska. U pacjentów po radykalnej prostatektomii z BCR i stężeniem PSA <7,0 ng/ml prawdopodobieństwo dodatniego wyniku scyntygrafii kości nie przekracza 5%. CT pozwala na identyfikację ognisk wznowy tylko u 11-14% pacjentów z BCR i rzadko kiedy są to osoby, u których stężenia PSA są wystarczająco niskie aby rozpocząć SRT [13,14].
11 Wykazano, że średnie stężenie i prędkość narastania PSA przy których CT daje wynik dodatni wynoszą odpowiednio 27,4 ng/ml i 1,8 ng/ml/miesiąc [15]. Dlatego też BS i CT zaleca się wykonywać tylko u tych pacjentów z BCR, u których:
• stężenie PSA wynosi >10 ng/ml lub
• czas podwojenia stężenia PSA wynosi <6 miesięcy lub
• tempo zwiększania się stężenia PSA wynosi >0,5 ng/ml/miesiąc lub • obecne są objawy sugerujące przerzuty do układu kostnego [13,15].
Lepsze wyniki obrazowania BCR przy małych stężeniach PSA daje PET/CT. Jako pierwsza zastosowanie znalazła cholina (marker proliferacji błon komórkowych) znakowana radioaktywnym fluorem-18 (18F) lub węglem-11 (11C). W metaanalizach wykazano, że czułość i swoistość radiocholin w wykrywaniu ognisk wznowy PCa wynosi odpowiednio 86-89% i 89-93% [16,17]. Co więcej, PET/CT z radiocholiną może uwidocznić mnogie ogniska przerzutowe w kościach u pacjentów z pojedynczym przerzutem widocznym w BS i jakiekolwiek przerzuty do układu kostnego u 15% pacjentów z ujemnym wynikiem BS [18,19]. Czułość PET/CT z radiocholiną w istotny sposób zależy jednak od stężenia PSA. U pacjentów z BCR po radykalnej prostatektomii badanie daje dodatni wynik zaledwie u 5-24% pacjentów z PSA <1,0 ng/ml, u pacjentów z PSA >5,0 ng/ml odsetek ten wzrasta do 67-100% [20–22]. Zaleca się, aby obrazowanie PET/CT z radiocholiną przeprowadzać tylko u tych chorych, u których stężenie PSA przekracza 1,0 ng/ml [9].
Wyższą od choliny czułością przy bardzo małych stężeniach PSA cechują się radioznaczniki nakierowane na antygen błonowy swoisty dla stercza (ang. prostate-specific
membrane antigen, PSMA). PSMA jest glikoproteiną przezbłonową o aktywności
enzymatycznej, która ulega ekspresji na powierzchni komórek prostaty, a także ślinianek, nerek, komórek nerwowych, dwunastnicy i jelita grubego. Ekspresja PSMA w komórkach PCa zwiększa się 100-1000-krotnie w porównaniu do zdrowych tkanek, co (pomimo braku specyficzności) umożliwia jego wykorzystanie w obrazowaniu PET/CT raka stercza. Wszystkie stosowane obecnie radioznaczniki nakierowane na PSMA należą do tzw. inhibitorów drobnocząsteczkowych – łączą się z miejscem aktywnym enzymu na powierzchni komórki, które w wyniku aktywacji podlega internalizacji i uwięzieniu wewnątrz komórki. Dzięki temu komórki wykazujące nadekspresję antygenu PSMA tj. komórki raka gruczołu krokowego są widoczne w badaniu PET/CT jako miejsca zwiększonego wychwytu znacznika [23–25].
12 Najlepiej dotychczas przebadanym znacznikiem z tej grupy jest PSMA-11 znakowane radioaktywnym galem-68 (68Ga-PSMA-11). U pacjentów z BCR i stężeniem PSA 0,2-1 ng/ml i 1-2 ng/ml czułość badania 68Ga-PSMA-11 PET/CT wynosi odpowiednio 58% i 76%, co wyraźnie przewyższa czułość radiocholin [26]. Wykazano, że wynik badania PET/CT ze znacznikiem 68Ga-PSMA-11 może zmienić sposób leczenia nawet u 76% pacjentów [27].
Obrazowanie z użyciem radiofarmaceutyków wyznakowanych 68Ga ma jednak dość istotne wady. 68Ga-PSMA-11 wydalany jest przez układ moczowy, w związku z tym radioaktywny mocz gromadzący się w pęcherzu moczowym utrudnia ocenę gruczołu krokowego, loży po jego usunięciu i przylegających struktur. Dodatkowo, 68Ga jest izotopem o dość ograniczonej dostępności – z generatora 68Ge/68Ga można uzyskać zaledwie 2-4 dawki izotopu na dobę, a jego krótki okres półtrwania (ok. 68 min) właściwie uniemożliwia jego transport na dalsze odległości, w związku z czym obrazowanie z 68Ga mogą wykonywać tylko jednostki posiadające generatory. Okres półtrwania 18F wynosi natomiast ok. 110 min, dlatego może być on produkowany w cyklotronach w dużych ilościach, a następnie transportowany nawet do oddalonych jednostek badawczych [23,24]. Obrazy PET z radioznacznikami wyznakowanymi 18F cechują się też dużo lepszą rozdzielczością obrazu w porównaniu do 68Ga [28].
Korzystny profil farmakokinetyczny i farmakodynamiczny radioznaczników celowanych na PSMA wyznakowanych 18F sprawia, że są one coraz częściej wykorzystywane w obrazowaniu PET/CT. Opublikowane dotychczas wyniki badań wskazują, że 18F-PSMA-1007 jest najbardziej obiecującym radioznacznikiem z tej grupy.
Radioznacznik 18F-PSMA-1007 (kwas (3S,10S,14S)-1-(4-(((S)-4-karboksy-2-((S)-4- karboksy-2-(6-fluoronikotynamido)butanamido)butanamido)metylo)fenylo)-3-(naftalen-2-ylmetylo)-1,4,12-triokso-2,5,11,13-tetraazaheksaadekano-10,14,16-trikarboksylowy) został opracowany i zsyntetyzowany po raz pierwszy w 2016 roku przez badaczy w Heidelbergu w Niemczech (Ryc. 1). Spośród pozostałych drobnocząsteczkowych inhibitorów PSMA zdecydowanie wyróżnia się korzystnym sposobem wydalania. 18F-PSMA-1007 wydala się z moczem, ale w wyniku czasowej retencji radioznacznika w miąższu nerek, jest filtrowany do moczu z opóźnieniem. Dzięki temu w pęcherzu moczowym rejestrowane są śladowe ilości promieniowania – po 0-2 godz. od podania dawki wynoszą ok. 1,2% dawki podanej, a po 4-6 godz. ok. 0,5%. Dawki pochłonięte przez pęcherz moczowy są więc minimalne. Małe gromadzenie znacznika w pęcherzu moczowym umożliwia dokładną ocenę gruczołu
13 krokowego i tkanek otaczających, co w przypadku innych znaczników z tej grupy obarczone jest dużym ryzykiem błędu [24,29].
Rycina 1. Struktura chemiczna 18F-PSMA-1007 [24].
Największa ilość publikacji oceniających przydatność 18F-PSMA-1007 w kontekście raka gruczołu krokowego dotyczy pacjentów z wznową biochemiczną PCa. Wykazano, że obrazowanie PET/CT z tym znacznikiem może uwidaczniać zmiany patologiczne u 81-95% badanych. Widoczne są nawet zmiany o bardzo małych rozmiarach, np. przerzuty do niepowiększonych węzłów chłonnych. Tak jak w przypadku radiocholin czy innych znaczników celowanych na PSMA, czułość PET/CT z 18F-PSMA-1007 istotnie zależy od stężenia PSA. Przy stężeniu PSA >2 ng/ml wynosi 94-100%. U pacjentów z bardzo małymi stężeniami PSA (<0,5 ng/ml) wykrywalność jest nadal stosunkowo wysoka i sięga 61-85% [24,30,31]. Warto jednak dodać, że dane na temat 18F-PSMA-1007, jakie obecnie posiadamy, pochodzą głównie z badań retrospektywnych, pilotażowych i opisów przypadków obejmujących niewielką grupę pacjentów.
18F-PSMA-1007 stanowi przedmiot badań prezentowanych w dalszej części opracowania jako cykl publikacji.
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CELE ROZPRAWY
Przedstawiony w kolejnej części niniejszego opracowania cykl prac monotematycznych miał na celu:
1. Prospektywne porównanie wartości diagnostycznej badań PET/CT z choliną i 18F-PSMA-1007 w obrazowaniu ognisk wznowy raka gruczołu krokowego u pacjentów po leczeniu radykalnym, z niskimi (≤2,0 ng/ml), rosnącymi stężeniami PSA.
2. Prospektywną ocenę wykrywalności zmian, czułości, swoistości, pozytywnej i negatywnej wartości predykcyjnej 18F-PSMA-1007 PET/CT u pacjentów po radykalnym leczeniu raka gruczołu krokowego z niskimi (≤2,0 ng/ml), rosnącymi stężeniami PSA.
3. Porównanie algorytmów rekonstrukcji obrazów OSEM (Ordered Subset Maximisation
Expectation) i BPL (Bayesian Penalised Likelihood) pod kątem
jakościowym i ilościowym u pacjentów poddawanych badaniu 18F-PSMA-1007 PET/CT.
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CYKL PRAC MONOTEMATYCZNYCH
Sformułowane w poprzednim rozdziale cele badawcze zrealizowano w cyklu publikacji prezentowanych na kolejnych stronach rozprawy. Zestawienie prac wraz z wartością impact
factor i punktacją Ministerstwa Nauki i Szkolnictwa Wyższego przedstawiono w Tabeli 3.
Tabela 3. Zestawienie publikacji wchodzących w skład cyklu.
Lp. PUBLIKACJA IF MNiSW
1
Witkowska-Patena E, Giżewska A, Miśko J, Dziuk M. 18F-Prostate-Specific Membrane Antigen-1007 and 18F-FCH PET/CT in Local Recurrence of Prostate Cancer. Clin Nucl Med. 2019;44(6):e401-e403.
6.703 140.00
2
Witkowska-Patena E, Giżewska A, Dziuk M, Miśko J, Budzyńska A, Walęcka-Mazur A. Head-to-Head Comparison of 18F-Prostate-Specific Membrane Antigen-1007 and 18F-Fluorocholine PET/CT in Biochemically Relapsed Prostate Cancer. Clin Nucl Med.
2019;44(12):e629-e633.
6.703 140.00
3
Witkowska-Patena E, Giżewska A, Dziuk M, Miśko J, Budzyńska A, Walęcka-Mazur A. Diagnostic Performance of 18F-PSMA-1007 PET/CT in Biochemically Relapsed Patients With Prostate Cancer With PSA Levels ≤2.0 ng/ml. Prostate Cancer Prostatic Dis. 2019. doi: 10.1038/s41391-019-0194-6. [Epub ahead of print]
4.600 100.00
4
Witkowska-Patena E, Budzyńska A, Giżewska A, Dziuk M, Walęcka-Mazur A. Ordered Subset Expectation Maximisation vs Bayesian Penalised Likelihood Reconstruction Algorithm in 18F-PSMA-1007 PET/CT. Ann Nucl Med. 2020;34(3):192-199.
1.648 70.000
SUMA 19.654 450.00
16
18F-Prostate-Specific Membrane Antigen-1007 and 18F-FCH PET/CT in
Local Recurrence of Prostate Cancer
Witkowska-Patena E, Giżewska A, Miśko J, Dziuk M.
Clin Nucl Med. 2019;44(6):e401-403.
Wskaźnik IF: 6.703
Punktacja MNiSW: 140.00
17
ABSTRACT
18F-PSMA-1007 is one of the most promising radiotracers for PET imaging of relapsing prostate cancer. Minimal urinary clearance seems to be its most valuable and outstanding feature. Here we present images of biochemically relapsed prostate cancer where 18F-PSMA-1007 PET/CT (performed to verify an ambiguous finding adjacent to the urinary bladder found in 18F-FCH PET/CT) proved superior to radiocholine and precisely visualised site of local recurrence.
18
Figure 1. 18F-FCH (fluorocholine) PET/CT images (a – maximum intensity projection, MIP;
b – fused sagittal PET/CT image; c – axial PET image; d – axial CT image; e – fused axial PET/CT image) of a 77-year-old man with prostate cancer after radical prostatectomy (Gleason score 6) and biochemical relapse (PSA level 1.4 ng/ml). Radiocholine scan shows an equivocal tracer uptake in the upper urethra region (a, b, c, e, white arrows) with SUVmax (maximum standardized uptake value) only slightly higher than in the bladder (3.2 vs 2.9) and no morphological representation seen in CT (d, white arrow).
19
Figure 2. 18F-PSMA (prostate-specific membrane antigen)-1007 PET/CT, a more prostate
cancer-specific imaging, was performed for verification [1–4]. 18F-PSMA-1007, a small-molecule inhibitor of PSMA, has a unique route of excretion - due to temporary retention in the kidney parenchyma its clearance via urinary pathway is minimal [3,5–8]. Hence, we had expected to obtain images allowing for a better evaluation of prostate gland and surrounding tissues. As anticipated, 18F-PSMA-1007 PET/CT (a – MIP; b – fused sagittal PET/CT image; c – axial PET image; d – axial CT image; e – fused axial PET/CT image) showed a distinct, tracer-avid focal uptake (a, b, c, e, white arrows), highly contrasting with urinary bladder (SUVmax 9.2 vs 1.9) – a site of local recurrence. PSMA-1007 proved superior to 18F-FCH in a man with biochemically relapsed prostate cancer, low PSA level and a suspicious lesion adjacent to urinary bladder.
20
REFERENCES
1. Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J
Nucl Med. 2015;56:668–674.
2. Afshar-Oromieh A, Avtzi E, Giesel FL, et al. The diagnostic value of PET/CT imaging with the 68Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2015;42:197–209.
3. Giesel FL, Cardinale J, Schäfer M, et al. 18F-Labelled PSMA-1007 shows similarity in structure, biodistribution and tumour uptake to the theragnostic compound PSMA-617.
Eur J Nucl Med Mol Imaging. 2016;43:1929–1930.
4. Giesel FL, Knorr K, Spohn F, et al. Detection efficacy of [ 18 F]PSMA-1007 PET/CT in 251 Patients with biochemical recurrence after radical prostatectomy. J Nucl Med. 2018;jnumed.118.212233.
5. Cardinale J, Schäfer M, Benešová M, et al. Preclinical Evaluation of 18 F-PSMA-1007, a New Prostate-Specific Membrane Antigen Ligand for Prostate Cancer Imaging. J Nucl
Med. 2017;58:425–431.
6. Giesel FL, Hadaschik B, Cardinale J, et al. F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients. Eur J Nucl Med Mol Imaging. 2017;44:678–688.
7. Benešová M, Bauder-Wüst U, Schäfer M, et al. Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors. J Med Chem. 2016;59:1761–1775.
8. Rahbar K, Afshar-Oromieh A, Seifert R, et al. Diagnostic performance of 18F-PSMA-1007 PET/CT in patients with biochemical recurrent prostate cancer. Eur J Nucl Med
21
Head-to-Head Comparison of 18F-Prostate-Specific Membrane
Antigen-1007 and 18F-Fluorocholine PET/CT in Biochemically Relapsed Prostate
Cancer
Witkowska-Patena E, Giżewska A, Dziuk M, Miśko J, Budzyńska A, Walęcka-Mazur A.
Clin Nucl Med. 2019; 44(12):e629-e633.
Wskaźnik IF: 6.703
22
ABSTRACT
Purpose of the Report: The aim of the study was to prospectively compare performance of
18F-FCH and 18F-PSMA-1007 PET/CT in patients with biochemical relapse (BCR) of prostate cancer and low prostate-specific antigen (PSA) levels.
Materials and Methods: We prospectively enrolled 40 BCR patients after radical treatment
and PSA levels ≤2.0 ng/ml. 18F-FCH and 18F-PSMA-1007 PET/CT imaging was performed within a mean interval of 54±21 days. Scans were done 87±10 min and 95±12 min after injecting 248±35 MBq and 295±14 MBq of 18F-FCH and 18F-PSMA-1007, respectively. Rate of negative, equivocal and positive scan results was compared per patient. Per lesion, findings were grouped as equivocal or highly suspicious for malignancy and then compared for their number, localisation (local relapse, lymph nodes, bones) and SUVmax values.
Results: Positive, equivocal and negative results were reported in 60%, 27.5% and 12.5% of
18F-PSMA-1007 and in 5%, 37.5% and 57.5% of 18F-FCH scans, respectively. In 70% of scans, 18F-PSMA-1007 PET/CT upgraded 18F-FCH PET/CT results. 18F-PSMA-1007 scans also showed significantly more lesions (184 vs 63, p=0.0006). Local relapse, lymph node and bone lesions accounted respectively for 9%, 58% and 33% of 18F-PSMA-1007 and 5%, 89% and 6% FCH of PET/CT findings. Highly suspicious lesions accounted for 74% of 18F-PSMA-1007 and 11% of 18F-FCH PET/CT findings. In 18F-18F-PSMA-1007 PET/CT SUVmax values of highly suspicious lesions were significantly higher than in equivocal lesions (median, 3.6 vs 2.5, p<0.00001).
Conclusions: In early BCR patients PSMA-1007 showed a higher detection rate than
18F-FCH PET/CT. The former also showed more lesions in total, more highly suspicious lesions and less equivocal lesions.
23
INTRODUCTION
Prostate cancer (PCa) is the second most frequent cancer in males worldwide [1]. Biochemical relapse (BCR) after primary treatment occurs in 20-30% of patients after surgical treatment and in up to 60% of patients after primary external-beam therapy [2,3]. Early diagnosis of BCR is crucial for further patient management – salvage radiation therapy is the most beneficial at prostate-specific antigen (PSA) levels ≤0.5 ng/ml and almost ineffective when PSA levels exceed 2 ng/ml [4].
Radiocholine positron emission tomography/computed tomography (PET/CT) value for the detection of recurrent PCa is limited in patients with PSA levels <2.5 ng/ml. In patients with PSA <1.0 ng/ml the probability of a positive radiocholine scan is only 19% and may be as low as 12.5% when PSA levels fall below 0.5 ng/dl [5,6]. Radiotracers targeting prostate-specific membrane antigen (PSMA) are a relatively new tool for imaging PCa. 18F-PSMA-1007 seems to be one of the most promising representatives of this group [7]. Its sensitivity also strongly depends on PSA levels, yet it is reported to reach 61-86% at PSA levels <0.5 ng/ml [8,9]. Head to head comparisons of radiocholine and 18F-PSMA-1007 PET/CT have not been published so far.
The aim of the study was to perform a head to head, prospective comparison of diagnostic efficacy of 18F-PSMA-1007 and 18F-fluorocholine (FCH) PET/CT in prostate cancer patients after radical treatment and low rising PSA levels.
MATERIALS AND METHODS Patients
We prospectively enrolled PCa patients after (1) radical prostatectomy with BCR or (2) radical radiation beam therapy with PSA levels rising in at least two consecutive measurements. In both groups PSA levels were ≤2.0 ng/ml. Radiation-beam therapy was performed in addition to surgery in 17 (42.5%) patients. Ten (25%) of the patients received androgen-deprivation therapy, yet none of them within 6 months prior to the study. Each patient had two PET/CT scans (18F-FCH followed by 18F-PSMA-1007) performed. Patient and PET/CT scan characteristics are summarised in Table 1.
Before inclusion all patients had signed written informed consent forms. The study was performed in accordance with the Helsinki Declaration and with national regulations. Study was approved by the Military Medical Chamber Ethics Committee in Warsaw, Poland (149/17).
24
Radiotracer synthesis
Production of 18F-fluorocholine (18F-FCH) was performed with GE TracerLab MX (Loncin, Belgium) synthesizer. 18F-fluoride was produced in Siemens Eclipse (Knoxville, USA) cyclotron in nuclear reaction 18O(p,n)18F by the bombardment of enriched 18O-water with protons. 18F-fluoride was then collected at anion exchange cartridge (QMA) and released by Kryptofix 2.2.2. to reaction vial where azeotropic distillation of acetonitrile was applied to remove residual traces of water. Subsequently, dibromomethane dissolved in acetonitrile was added to the reaction vial and heated to 95 °C ± 10°C for 5 minutes to produce volatile 18F-fluorobromomethane. 18F-fluorobromomethane was distilled from the reactor in a steam of inert gas and transferred through three silica cartridges (purification), then trapped on two Oasis HLB cartridges, one of them coated with pure dimethylethanolamine (DMAE) . DMAE was fluoromethylated by 18F-fluorobromomethane to 18F-FCH. Cartridge were then rinsed with water and ethanol (EtOH) to remove all lipophilic impurities. The raw product 18F-FCH was subsequently trapped on two cation exchange cartridges (CM) and eluted with 15 ml of saline in a stream of inert gas. Finally, quality control was performed (radiochemical and chemical purity, physical properties, bacterial endotoxins, sterility). The process was validated. Product owns marketing authorization.
Production of 18F-PSMA-1007 was performed with a Trasis AiO (Ans, Belgium) synthesizer. 18F-fluoride, synthesized as described above, was collected at anion exchange cartridge (QMA) and released by tetrabutylammonium hydroxide (TBA-HCO3) eluent to reaction vial where residual traces of water were evaporated in 130°C for 8 minutes. Then, PSMA-1007 precursor (ABX, Radeberg, Germany) dissolved in 2 ml of dimethyl sulfoxide (DMSO) was added to dried complex. Fluorination reaction was processed in 105°C for 5 minutes. During labelling two cleaning cartridges ( C18ec and PS-H) were conditioned by rinsing 5% EtOH in WFI, EtOH and again 5% EtOH in WFI. Crude product was trapped on cartridges and rinsed by 5% EtOH in WFI to remove side-products. Product was eluted from cartridges by 30%EtOH to the end vial by 0,22µm sterilizing filter and then diluted by phosphate buffered saline. Quality control was performed as described above. The product does not hold a marketing authorisation and was prepared for the purpose of the study.
25
Imaging protocol
PET/CT imaging was performed using a dedicated hybrid PET/CT system (Discovery 710, GE Healthcare, Chicago, Illinois, US). A scout view and a non-contrast-enhanced low-dose spiral 64-slice CT scan was performed for attenuation correction of the PET emission data as well as anatomic localization.
The CT scan was acquired with a tube voltage of 140 kV in the helical mode with a Smart/Auto mA (range: 40–120 mA). The X-ray tube rotation time was 0.6 s. The pitch and table speed were as follows: 0.984:1 and 39.37 mm/rot. The helical thickness was 3.75 mm. For standard type of reconstruction the slice thickness was 1.25 mm. The GE ASIR (Adaptive Statistical Iterative Reconstruction) with the level of 20% was used to reduce patient radiation dose from CT scans.
Immediately after CT scanning a whole-body three-dimensional PET was acquired. For the PSMA protocol the scan range was from the top of the head to mid-thighs. For the 18F-FCH PET/CT whole-body protocol covered the skull base to mid-thighs. For each bed position (15.7 cm with 23% bed overlap) a 1 min 45 sec (18F-FCH) and 3 min (18F-PSMA-1007) acquisition time was used. The emission data was corrected for geometrical response and detector efficiency (normalization) as well as for system dead time, random coincidences, scatter and attenuation. For non-attenuation corrected images the 3D iterative reconstruction technique (GE VUE Point HD) with 2 iterations/24 subsets and a filter cut-off of 6.4 mm was conducted. The matrix size was 192x192.
For attenuation corrected images reconstruction was conducted with 3D iterative algorithm with time of flight PET reconstruction algorithm (GE VUE Point FX) and a resolution recovery algorithm (GE SharpIR) with 3 iterations/18 subsets and a filter cut-off of 5.5 mm. The matrix size was 256x256.
Image analysis
PET/CT images were analysed visually and semiquantitatively with GE Healthcare Advantage Workstation (Chicago, Illinois, United States) by three physicians with at least four-year experience in nuclear medicine. All disagreements were resolved by consensus. Per-patient and per-lesion analysis was performed. Per-patient, general impression of each PET/CT scan was categorized (negative, equivocal or positive [with at least one highly suspicious for malignancy lesion]) and then compared between the two tracers. Per-lesion, reported lesions were categorized (equivocal or highly suspicious for malignancy), localized (prostate bed, lymph nodes or bones) and assessed semiquantitatively – maximum standarised uptake values
26 (SUVmax) were calculated. To do so, rectangular regions of interest (ROI) were drawn around areas with focally increased uptake in axial slices and then adapted to 3-D volume of interest. Uptake in normal brain, lungs, liver, urinary bladder as well as in the blood pool (thoracic aorta) was measured.
Detection rate was defined as the percentage of subjects in whom at least one highly suspicious for malignancy lesion (category 2) was reported.
Statistical analysis
Statistica 13 software (StatSoft Polska Sp. z o. o. Cracow, Poland) was used for statistical analysis. Descriptive analysis was performed by calculating mean, median, standard deviation and range. Paired samples were compared using the Wilcoxon signed-rank test and the sign test. The Mann-Whitney U test was used to evaluate differences in unpaired samples. To evaluate correlation the Kruskall-Wallis test, the Spearman’s rank correlation coefficient and multiple linear regression were used. A p value <0.05 was considered significant.
RESULTS
No adverse effects were observed after injection of the radiotracers. Patients did not report any alarming symptoms.
PET/CT results differed significantly (p=0.000005) in per-patient analysis. 18F-PSMA-1007 PET/CT detection rate was 60.0%, 18F-FCH PET/CT – 5.0%. Negative and equivocal results were reported in 12.5% and 27.5% of 18F-PSMA-1007 PET/CT scans, respectively. In 18F-FCH scans, it was 57.5% and 37.5%, respectively.
In patient-based analysis, 18F-PSMA-1007 and 18F-FCH PET/CT scans were concordant in 25% of cases – both were negative in 3 (7.5%), equivocal in 5 (12.5%) and positive in 2 (5.0%) patients. In equivocal scans, 18F-FCH showed more lesions (13 vs. 10). In positive scans, more lesions were reported in 18F-PSMA-1007 PET/CT (10 vs. 7). In 70% of cases 18F-PSMA-1007 PET/CT upgraded 18F-FCH results from negative to positive (35.0%), equivocal to positive (20.0%) or from negative to equivocal (15.0%). 18F-FCH PET/CT upgraded 18F-PSMA-1007 PET/CT results in 5.0% (from negative to equivocal) (Figure 1).
Per-lesion, 18F-PSMA-1007 PET/CT showed significantly more lesions than 18F-FCH PET/CT (184 vs. 63, p=0.0006)(Figure 2 and Figure 3). Lymph node lesions comprised 59% vs. 89% (107 vs. 56, p=0.03), bone lesions 33% vs. 6% (61 vs. 4, p=0.001) and prostate bed lesions 8% vs. 5% (16 vs. 3, p=0.006) of changes reported in 18F-PSMA-1007 and 18F-FCH
27 PET/CT, respectively. Majority of lesions reported in 18F-PSMA-1007 PET/CT scans were categorised as highly suspicious for malignancy. In 18F-FCH PET/CT scans, on the other hand, equivocal lesions comprised majority or all of reported changes, depending on localisation (Figure 4).
SUVmax values of suspicious lesions were higher than equivocal lesions (Table 2). For 18F-PSMA-1007 differences were statistically significant (p<0.00001), for 18F-FCH they did not reach level of significance (p=0.089). SUVmax values of lesions of corresponding categories did not differ significantly between the two tracers (p=0.38 and p=0.61).
There was a significantly higher mean uptake of 18F-PSMA-1007 in blood pool (SUVmax 1.82 ± 0.41 vs. 0.82 ± 0.22, p<0.000001) and in the liver (SUVmax 11.81 ± 2.45 vs. 10.03 ± 2.12, p=0.0009). 18F-PSMA-1007 showed significantly lower mean uptake in the brain (SUVmax 0.22 ± 0.16 vs. 0.57 ± 0.22, p=0.000003) and in the urinary bladder (SUVmax 3.76 ± 2.87 vs 4.75 ± 4.07, p=0.003).
DISCUSSION
In our study 18F-PSMA-1007 detection rate was higher than 18F-FCH PET/CT. It also showed more lesions, especially in bones, and more of them were categorised as highly suspicious for malignancy. 18F-PSMA-1007 presented higher uptake in blood pool and the liver and lower uptake in the urinary bladder.
Relapse of the disease was reported in 60.0% of PSMA-1007 and 5.0% of 18F-FCH PET/CT scans, which is slightly below the sensitivity levels noted in the literature [5,6,8,9]. In the cited studies, however, equivocal findings were not discriminated which means they may include some false positives. We speculate that detection rates in our study would have been higher had we chosen two result categories (negative/positive) instead of three.
18F-PSMA-1007 PET/CT detected almost three times as many lesions as 18F-FCH PET/CT, majority of them categorised as highly suspicious malignancy. It also showed significantly less equivocal results. 18F-PSMA-1007 is more specific than 18F-FCH per se as it targets PSMA, a glycoprotein which overexpression seems more characteristic for PCa than upregulation of choline kinase [10]. It has been shown that specificity of 18F-PSMA-1007 may be as high as 97.4% and for choline it may range from 36% to 100% [11,12]. Yet, it must be emphasized that the data is either scarce (18F-PSMA-1007) or, as in case of 18F-FCH, comes from heterogenous study groups with PSA levels ranging from <0.1 to >500 ng/ml.
28 18F-PSMA-1007 PET/CT detected significantly more lesions in all three localisations. Percentage share of bone lesions was especially notable as they comprised over one-third of all changes detected in 18F-PSMA-1007 PET/CT (vs. 6% in 18F-FCH PET/CT). It is in accordance with published studies reporting that PSMA PET shows significantly more lesions than radiocholines, especially in patients with PSA levels <2.0 ng/ml (2.0 ng/ml was the maximum PSA level in our study). Lesions reported in PSMA PET also showed a significantly higher uptake [13–15]. It was alike in our study, yet the differences did not reach significance levels. Nonetheless, it was 68Ga-PSMA that was used in the studies and the subjects had higher PSA levels.
Normal organ uptake was in accordance with published data. 18F-PSMA-1007 showed higher uptake in the liver as it is excreted via hepatobiliary system. On the other hand, it showed significantly lower uptake in the urinary bladder. 18F-PSMA-1007 shows delayed urinary excretion due to its temporary retention in the kidney parenchyma. Hence, clearance via urinary pathway is minimal (0.5% 4-6 hours after injection). This results in lower doses absorbed by the bladder wall and allows for a better evaluation of prostate gland and surrounding tissues [11,16]. Correspondingly, in our study 18F-FCH PET/CT showed three equivocal lesions in prostate/prostate bed while in 18F-PSMA-1007 16 lesions were reported, 12 of them (75%) highly suspicious for malignancy.
In our study we present a first prospective, head to head comparison of 18F-PSMA-1007 and 18F-FCH PET/CT in biochemically relapsed prostate cancer patients after radical prostatectomy and patients with rising PSA levels after radiation beam therapy in whom PSA levels are ≤2.0 ng/ml. Lack of histopathological validation seems to be a major limitation of the study. However, published data suggests that specificity of 18F-PSMA-1007 may reach 97.4% [11]. Patients enrolled in our study will be followed up and the subject will be further investigated. A relatively small number of participants might have been the cause for lack of significant differences in some statistical analyses. Heterogenous time interval between the scans might also have been a source of bias due to possible tumour progression. Yet, as PCa is considered a slow-growing malignancy and the mean time interval between examinations was 54 days, we believe that noticeable changes are unlikely.
29
CONCLUSIONS
In PCa patients after radical treatment and low (≤2.0 ng/ml) rising PSA levels 18F-PSMA-1007 shows higher detection rate than 18F-FCH PET/CT. It shows more lesions in lymph nodes, prostate bed and, especially, bones. Contrarily to 18F-FCH, it shows significantly more suspicious than equivocal lesions.
REFERENCES
1. McGuire S. World Cancer Report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press. Adv Nutr. 2016;7:418–419.
2. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65:124–137.
3. Ceci F, Uprimny C, Nilica B, et al. 68Ga-PSMA PET/CT for restaging recurrent prostate cancer: which factors are associated with PET/CT detection rate? Eur J Nucl ;Med Mol
Imaging. 2015;42:1284–1294.
4. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467–479.
5. Giovacchini G, Picchio M, Coradeschi E, et al. Predictive factors of [(11)C]choline PET/CT in patients with biochemical failure after radical prostatectomy. Eur J Nucl Med
Mol Imaging. 2010;37:301–309.
6. Rinnab L, Simon J, Hautmann RE, et al. [(11)C]choline PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy. World J Urol. 2009;27:619–625.
7. Cardinale J, Schäfer M, Benešová M, et al. Preclinical Evaluation of 18 F-PSMA-1007, a New Prostate-Specific Membrane Antigen Ligand for Prostate Cancer Imaging. J Nucl
Med. 2018;58:425–431.
8. Giesel FL, Knorr K, Spohn F, et al. Detection Efficacy of 18 F-PSMA-1007 PET/CT in 251 Patients with Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy. J Nucl Med. 2018;60:362–368.
9. Rahbar K, Afshar-Oromieh A, Seifert R, et al. Diagnostic performance of 18F-PSMA-1007 PET/CT in patients with biochemical recurrent prostate cancer. Eur J Nucl Med
Mol Imaging. 2018;45:2055–2061.
10. Ghosh A, Heston WDW. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem. 2004;91:528–539.
30 11. Giesel FL, Hadaschik B, Cardinale J, et al. F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients. Eur J Nucl Med Mol Imaging. 2017;44:678–688.
12. Kitajima K, Murphy RC, Nathan MA. Choline PET/CT for imaging prostate cancer: an update. Ann Nucl Med. 2013;27:581–591.
13. Schwenck J, Rempp H, Reischl G, et al. Comparison of (68)Ga-labelled PSMA-11 and (11)C-choline in the detection of prostate cancer metastases by PET/CT. Eur J Nucl Med
Mol Imaging. 2017;44:92-101.
14. Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J Nucl Med. 2015;56:1185–1190.
15. Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET imaging with a 68Ga-labelled PSMA ligand and 18F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014;41:11–20.
16. Witkowska-Patena E, Giżewska A, Miśko J, et al. 18F–Prostate-Specific Membrane Antigen 1007 and 18F-FCH PET/CT in Local Recurrence of Prostate Cancer. Clin Nucl
31
TABLES
Table 1. Characteristics of patients and performed PET/CT scans.
CHARACTERISTIC VALUE Number of patients 40 Age mean ± SD median (range) 69 ± 7 years 68 (58-83) years
Radical treatment Radical prostatectomy 80% Radical radiotherapy 20% PSA level mean ± SD median (range) 0.77 ± 0.61 ng/ml 0.7 (0.01-2.0) ng/ml Gleason score mean ± SD median (range) 7.1 ± 1 7 (5-9) Administered activity mean ± SD median (range) 18F-FCH 248 ± 35 MBq 243 (187-340) MBq 18F-PSMA-1007 296 ± 14 MBq 296 (267-322) MBq Time to acquisition mean ± SD median (range) 18F-FCH 87 ± 10 min 85 (74-116) min 18F-PSMA-1007 95 ± 12 min 90 (84-141) min PET/CT interval mean ± SD median (range) 54 ± 21 days 58 (12-105) days
SD – standard deviation, PSA – specific antigen, FCH – fluorocholine, PSMA – prostate-specific membrane antigen, MBq – megabecquerels,
Table 2. Descriptive statistics of SUVmax values of equivocal (1) and highly suspicious for
malignancy (2) lesions. 18F-FCH 18F-PSMA-1007 1 2 1 2 Mean 2,73 3,80 2,61 4,93 Median 2,30 3,20 2,50 3,60 Minimum 1,00 1,50 1,40 1,50 Maximum 6,90 8,10 3,80 32,00 SD 1,45 2,12 0,62 4,68 SD – standard deviation
32
FIGURES
Figure 1. Results (0 – negative, 1 – equivocal, 2 – positive) of 18F-PSMA-1007 and 18F-FCH
scans. Number of scans within each category is presented above the bars. 0 1 2 0 1 2 18F-PSMA-1007 3 6 14 2 5 8 0 0 2
33
Figure 2. 18F-FCH PET/CT images (A – maximum intensity projection [MIP], B – transaxial
CT scan, C – transaxial fused PET/CT scan) of a 64-year-old man after radical radiotherapy of prostate cancer (Gleason score 6, pT1a G2) with biochemical recurrence and prostate-specific antigen level of 0.9 ng/ml. 18F-FCH PET/CT showed increased uptake in prostate gland (white arrows) with maximum standardised uptake value (SUVmax) of 6.9 – local relapse. Other body regions showed normal 18F-FCH uptake.
34
Figure 3. 18F-PSMA-1007 PET/CT images (A – MIP, B, D, F – transaxial CT scans, C, D, G
– transaxial fused PET/CT scans) of the patient from Figure 2. Scan performed 47 days later also showed local relapse in prostate gland (SUVmax 3.6, G, white arrow). Additionally, it was positive for bone metastases: in the sacral bone (SUVmax 3.3, E, white arrow) and in the fifth right rib (SUVmax 2.9, C, white arrow). In CT, no lesions in prostate gland were visible (F, white arrow) and only slight opacities were reported in the sacral bone (D, white arrow) and the fifth right rib (B, white arrow).
35
Figure 4. Percentage share of highly suspicious for malignancy lesions in prostate/prostate bed,
lymph nodes and bones. 0% 12% 0% 75% 70% 80%
prostate/prostate bed lymph nodes bones
0% 20% 40% 60% 80% 100% 18F-FCH 18F-PSMA-1007
36
Diagnostic Performance of 18F-PSMA-1007 PET/CT in Biochemically
Relapsed Patients With Prostate Cancer With PSA Levels ≤2.0 ng/ml
Witkowska-Patena E, Giżewska A, Dziuk M, Miśko J, Budzyńska A, Walęcka-Mazur A.
Prostate Cancer Prostatic Dis. 2019; doi: 10.1038/s41391-019-01946. [Epub ahead of print]
Wskaźnik IF: 4.600
37
ABSTRACT
Background: The aim of the study was to prospectively evaluate diagnostic performance of
18F-PSMA-1007 PET/CT in prostate cancer (PCa) patients after radical treatment and low but rising prostate-specific antigen (PSA) levels.
Methods: We prospectively enrolled 40 consecutive patients after radical treatment (80% -
radical prostatectomy, 20% - radiation beam therapy) of PCa and low (0.008 to ≤2.0 ng/ml), rising PSA. Skull to mid-thigh PET/CT imaging was performed 95 (±12) minutes after injection of 295.5 (±14.1) MBq 18F-PSMA-1007. Detection rate was correlated with PSA levels, Gleason score (GS) and T stage ≥3. PET/CT results were verified during 10.3 (±4.7) months follow-up to calculate sensitivity, specificity, negative (NPV) and positive predictive values (PPV).
Results: 18F-PSMA-1007 PET/CT was positive in 24/40 patients which yielded overall
detection rate of 60%. Detection rate was 39%, 55% and 100% for PSA <0.5 ng/ml, 0,5 to <1,0 ng/ml and 1.0 to ≤2.0 ng/ml, respectively. PET/CT showed metastases in locoregional lymph nodes in 55% of patients, bones in 36% of patients and local recurrence in 9% of patients. Detection rate was correlated with PSA - a 0.1 ng/ml rise in PSA level increased odds for positive PET/CT by approximately 30%. PET/CT positivity was independent of GS and T stage. Verification of 40 lesions yielded sensitivity, specificity, PPV and NPV of 100%, 94.4%, 66.7% and 100%, respectively.
Conclusions: 18F-PSMA-1007 PET/CT shows relatively high detection rate in PCa patient
after radical treatment and low, rising PSA levels. Like other PSMA-targeting radiotracers, its detection rate is dependent on PSA levels. 18FPSMA-1007 also presents excellent sensitivity, specificity and NPV.
38
INTRODUCTION
Rising prostate-specific antigen (PSA) levels after radical treatment (radical prostatectomy or radiotherapy) concern up to 53% men with prostate cancer (PCa) (1). Early diagnosis of relapse is crucial for further management – prompt initiation of salvage treatment tailored to the patient yields very good outcomes. Over 60% of men with biochemical relapse who will be treated before PSA rises >0.5 ng/ml will achieve undetectable PSA levels, which corresponds to a 80% chance of being progression-free five years later (2–4).
18F-prostate-specific membrane antigen (PSMA)-1007 seems to be one of the most promising radiotracers for diagnosing PCa relapse at low PSA levels. Even though its sensitivity falls with decreasing PSA levels like 68Ga-PSMA-11 and radiocholines, it is reported to reach 61-86% at PSA levels <0.5 ng/ml, which is superior to other commonly used radiotracers (5– 7). Yet, the number of studies assessing 18F-PSMA-1007 diagnostic performance is still rather limited and lacks verification of PET/CT findings.
The aim of our study was to prospectively evaluate detection rate, sensitivity, specificity, positive predictive value and negative predictive value of 18F-PSMA-1007 PET/CT in prostate cancer patients after radical treatment and low rising PSA levels.
MATERIALS AND METHODS Patients
We prospectively enrolled 40 consecutive PCa patients after (1) radical prostatectomy with biochemical relapse (BCR) or (2) radiation beam therapy with PSA levels rising in at least two consecutive measurements. In both groups PSA levels were ≤2.0 ng/ml. Radiation-beam therapy was performed in addition to surgery in 16 (40%) patients. Ten (25%) of the patients received androgen-deprivation therapy, yet none of them within 6 months prior to the study. In all patients 18F-PSMA-1007 PET/CT scan was performed. Afterwards, during the follow-up period we gathered data on further therapeutic decisions, results of diagnostic procedures and clinical outcomes in order to calculate per-lesion sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 18F-PSMA-1007 PET/CT. Histopathology or biopsy of prostatic bed or metastases, correlative imaging results and clinical data (normalisation or >20% reduction of PSA after salvage therapy) were used as a reference standard. Detailed information on patients, follow-up and PET/CT scans are presented in Table 1.
39 Informed consent was obtained from all individual participants included in the study. All procedures performed in the study were in accordance with the ethical standards of the institutional research committee (Military Medical Chamber Ethics Committee in Warsaw, Poland, ref. no. 149/17), with national regulations and with the 1964 Helsinki declaration and its later amendments.
Radiotracer synthesis
18F-PSMA-1007 was made with a Trasis AiO (Ans, Belgium) synthesizer. 18F-fluoride was produced in Siemens Eclipse (Knoxville, USA) cyclotron by bombarding enriched 18O-water with protons. It was then collected at anion exchange cartridge (QMA) and released by tetrabutylammonium hydroxide (TBA-HCO3) eluent to reaction vial where residual traces of water were evaporated at 130°C for 8 minutes. Then, PSMA-1007 precursor (ABX, Radeberg, Germany) dissolved in 2 ml of dimethyl sulfoxide (DMSO) was added to the dried complex. Fluorination reaction was processed at 105°C for 5 minutes. During labelling two cleaning cartridges (C18ec and PS-H) were conditioned by rinsing 5% EtOH in water for injection (WFI), EtOH and again 5% EtOH in WFI. Crude product was trapped on cartridges and rinsed with 5% EtOH in WFI to remove side-products. Product was eluted from cartridges by 30%EtOH to the end vial by 0,22µm sterilizing filter and then diluted by phosphate buffered saline. In the end, quality control was performed. The product does not hold a marketing authorisation and was prepared for the purpose of the study.
Imaging protocol
PET/CT imaging was performed with a hybrid PET/CT system (Discovery 710, GE Healthcare, Chicago, Illinois, US). First, a scout view and a non-contrast-enhanced low-dose spiral 64-slice CT scan was performed for attenuation correction of PET emission data and anatomic localisation. CT scan was acquired with a tube voltage of 140 kV in the helical mode with a Smart/Auto mA (range: 40–120 mA). The X-ray tube rotation time was 0.6 s. The pitch and table speed were 0.984:1 and 39.37 mm/rot, respectively. The helical thickness was 3.75 mm. For standard type of reconstruction the slice thickness was 1.25 mm. The GE ASIR (Adaptive Statistical Iterative Reconstruction) with the level of 20% was used to reduce patient radiation dose from CT scans.
40 Following CT, top-of-the-head to mid-thigh three-dimensional PET was acquired. For each bed position (15.7 cm with 23% bed overlap) a three-minute long acquisition time was used. The emission data was corrected for geometrical response, detector efficiency, system dead time, random coincidences, scatter and attenuation.
For non-attenuation corrected images the 3D iterative reconstruction technique (GE VUE Point HD) with 2 iterations/24 subsets and a filter cut-off of 6.4 mm was conducted. The matrix size was 192x192. For attenuation corrected images reconstruction was conducted with a 3D iterative algorithm with time of flight PET reconstruction algorithm (GE VUE Point FX) and a resolution recovery algorithm (GE SharpIR) with 3 iterations/18 subsets and a filter cut-off of 5.5 mm. The matrix size was 256x256.
Image analysis
PET/CT images were analysed visually and semiquantitatively with GE Healthcare Advantage Workstation (Chicago, Illinois, United States) by three physicians with at least four-year experience in nuclear medicine. All disagreements were resolved by consensus. Scans were defined as positive if at least one lesion highly suspicious for malignancy was reported. Identified lesions were grouped according to their localisation (prostate bed, lymph nodes or bones) and assessed semiquantitatively – maximum standardised uptake values (SUVmax) and tumour-to-background ratios (TBR) were calculated. To measure SUVmax, rectangular regions of interest (ROI) were drawn around areas with focally increased uptake in axial slices and then adapted to 3-D volume of interest. To calculate TBR, lesion uptake was divided by uptake in thoracic aorta. We also looked for correlation between PET/CT positivity and PSA level, Gleason score (GS) and T stage ≥3.
Statistical analysis
Statistica 13 software (StatSoft Polska Sp. z o. o. Cracow, Poland) was used for statistical analysis. Descriptive analysis was performed by calculating mean, median, standard deviation and range. The Shapiro-Wilk test was used to check if samples were normally distributed. Quantitative variables were compared with the Mann-Whitney U test. Percentage variables were compared with the chi-squared test and its modifications and the Fisher test. To evaluate correlation linear and logistic regression were used. A p value of <0.05 was considered significant.
41
RESULTS
No adverse effects were observed after injection of 18F-PSMA-1007. Patients did not report any alarming symptoms.
18F-PSMA-1007 PET/CT was positive in 24 (60%) patients. In this group we identified 136 lesions highly suspicious for malignancy. The most common site of relapse were locoregional lymph nodes (n=75, 55%), followed by bones (n=49, 36%) and prostatic bed (n=12, 9%). Mean ± SD SUVmax values were 5.54 ± 5.99, 3.75 ± 1.76 and 5.87 ± 2.89 for all three locations, respectively. Mean ± SD TBR values for lymph nodes, bones and prostatic bed were 2.79 ± 2.44, 2.05 ± 0.99 and 3.50 ± 1.95, respectively.
PSA level significantly correlated with positive PET/CT result – the higher the PSA level the higher the odds for a positive scan (OR=1.31 [1.08-1.60], p=0.009). Scans were positive: in 39% (7/18) patients with PSA <0.5 ng/ml, 55% (6/11) with PSA 0,5 to <1,0 ng/ml and in 100% (11/11) with PSA 1.0 to ≤2.0 ng/ml. All patients with PSA ≥0.9 ng/ml (n=15, 37.5%) had positive PET/CT scans. We found that a 0.1 ng/ml rise in PSA level increased odds for positive PET/CT by approximately 30%.
In our study neither GS ≥7 nor T stage ≥3 significantly correlated with positive PET/CT result (p=0.29 and p=0.79, respectively) (Table 2).
During follow up period 40 lesions were verified. Thirty-eight lesions underwent histopathologic examination, one lesion (bone metastasis in scapula) was confirmed in 68Ga-PSMA PET/CT and one lesion (bone metastasis in sacral bone) was a target for radiotherapy which led to PSA level decrease >20% (Fig. 1). Out of 38 lesions that underwent histopathologic examination, 37 were surgically dissected lymph nodes. The remaining one lesion was prostate gland that was biopsied. Out of 6 lesions positive in 18F-PSMA-1007 PET/CT, 4 were truly positive and 2 were false positive. All 18F-PSMA-1007-negative lesions (n=34) were truly negative. This resulted in sensitivity and specificity of 100% and 94.4%, respectively. PPV and NPV of 18F-PSMA-1007 PET/CT was 66.7% and 100%, respectively.
DISCUSSION
In our study we found that 18F-PSMA-1007 PET/CT has a relatively high detection rate in PCa patients after radical treatment and low, rising PSA levels. We observed that the higher the PSA level the greater the odds for a positive PET/CT scan. On the other hand, Gleason score and T stage ≥3 did not significantly correlate with PET positivity. 18F-PSMA-1007 also showed excellent sensitivity, specificity and NPV.
42 In the present study 18F-PSMA-1007 detection rate was 60.0% which is lower than reported in literature (81.3-95%) (1,2). In the cited studies, however, PSA levels were higher – they ranged from 0.04 to 228 ng/ml with median values of 1.2-1.34 ng/ml. In our study, on the other hand, we selected only patients with PSA ≤2.0 ng/ml – median PSA was 0.65 (0.008-2.0) ng/ml. Also, nearly half of the patients (18/40) had very low PSA levels (<0.5 ng/ml).
We hypothesize that low PSA levels may also be the reason for relatively low SUVmax values. It has been reported that SUVmax values are positively correlated with PSA values. According to Rahbar et al. median SUVmax in patients with PSA >2.0 ng/ml tends to be significantly higher than in patients with lower PSA (7). It has been also shown that SUVmax values are higher the longer the uptake time. In the present study median time from injection to scanning was 90 minutes, while in some studies where higher SUVmax values are reported it was up to 120 minutes (8). Low SUVmax values have surely lowered TBR values. Additionally, blood pool activity was the background. As 18F-PSMA-1007 presents high plasma protein binding and delayed blood pool clearance, tumour-to-blood ratios are usually low (5,9).
In accordance with published data, we showed that 18F-PSMA-1007 PET/CT detection rate seems to be strongly dependent on PSA levels. It seems to be the case for other PSMA radioligands such as 68Ga-PSMA-11 and 18F-DCFPyL and radiocholines as well (10– 13). On the other hand, GS and T stage ≥3 did not seem to correlate with 18F-PSMA-1007 PET/CT positivity.
Data on histopathologic confirmation of 18G-PSMA-1007-positive lesions is scarce. In a study by Giesel et al. (309 pelvic lymph nodes were histologically examined) 18F-PSMA-1007 PET/CT showed 94.7% sensitivity. In our study, where combined reference standard was used, we verified 40 lesions and yielded sensitivity, specificity, PPV and NPV of 100%, 94.4%, 66.7% and 100%, respectively. These values seem comparable to 68Ga-PSMA-11 (14–16).
In the study we presented a prospective evaluation of 18F-PSMA-1007 PET/CT diagnostic accuracy in PCa patients after radical treatment and low (≤2.0 ng/ml), rising PSA levels. It must, however, be stated that despite follow-up and combined reference standard not all PSMA-positive lesions have been verified. Another limitation of the study is that the relatively small group of subjects might have been the cause for lack of significance in some statistical analyses.
43
CONCLUSIONS
18F-PSMA-1007 PET/CT presented a relatively high detection rate in PCa patients after radical treatment and low (≤2.0 ng/ml), rising PSA levels. Scan positivity was strongly dependent on PSA levels. 18F-PSMA-1007 also showed excellent sensitivity, specificity and NPV.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
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