Nuclear Medicine
CLINICAL DECISION SUPPORT
Prostate-specific membrane antigen (PSMA) is, nowadays, one of the most successful targets for imaging and therapy in nuclear medicine. PSMA, is a glycoprotein (membrane-bound metallo-peptidase), encoded by FOLH1 gene on chromosome 11 that act as glutamate carboxypeptidase II (GCPII). This enzyme is expressed in several tissues, including the prostate, brain, small intestine, and kidney [194]. Although the function of GCPII in prostate remains unclear, it is well-known that this protein is over expressed in prostate cancer cells. It has been shown that this overexpression is present in 90–100% of PCa cells, making PSMA a reliable tissue biomarker for PCa functional imaging [194]. The localization of the catalytic site of PSMA in the extracellular domain has allowed the development of very small urea-based PSMA inhibitors that, once radioactively labelled, can be used as radio-pharmaceuticals for PET imaging [194].
In primary staging, in patients with high-risk disease (ISUP 4, PSA >20 ng/mL, clinical stage T3), the likelihood of lymph node and bone metastases is increased [195]. Several studies demonstrate the superiority of [68Ga]Ga PSMA PET/CT as compared to CT, MRI, or bone scan for detection of metastases for initial staging. Recently a prospective, randomized, multicentric study, brightly assessed the superiority of [68Ga]Ga PSMA PET/CT in comparison with other imaging methods [196], [68Ga]Ga PSMA PET/CT had a 27% greater accuracy than that of conventional imaging (92%] vs 65% p<0·0001) in 302 patients studied before primary surgery. The detection of radiologically occult lymph node metastases can significantly influence patient management, although the impact on overall survival of such improved sensitivity of [68Ga]Ga PSMA PET/CT remains unanswered.
In patients with BCR, the main goal [68Ga]Ga PSMA PET/CT is to guide metastasis-directed therapies including salvage pelvic lymph-node dissection and salvage radiotherapy. If correctly used [68Ga]Ga PSMA PET/CT has shown a significant influence on treatment strategy: in a recent study, major changes on treatment strategy occurred in 55% of BCR patients showing low PSA values (between 0.5-<2.0 ng/mL) [198] Very good results have been also obtained in the setting of patients showing low PSA values (<1ng/ml/L) and candidates to Salvage Therapies, In this population [68Ga]Ga PSMA PET/CT caused a treatment change in almost half of the 270 enrolled patients [199]
It is interesting to point out that in patients candidate to Salvage Radiation Therpay [68Ga]Ga PSMA PET/CT has shown an excellent negative predictive value. In 260 men eligible for Salvage RT Emmett et al showed that men with negative [68Ga]Ga PSMA PET/CT or with disease confined to the prostate bed had a longer disease free survival despite receiving less extensive therapies than those with extra fossa disease [200].
In order to reduce the number of false negative [68Ga]Ga PSMA PET/CT results, especially in patients showing low PSA values, the factors able to predict a positive [68Ga]Ga PSMA PET/CT have been studied in large cohort of BCR patients. Ceci et al studied 703 BCR patients [201]. In this large population a higher detection rate has been associated with PSA values at the time of the scan and with the kinetics of PSA. In another large study performed in 272 patients suffering from BCR and showing PSA values < 1 ng/ml, the most relevant prediction factor was the concurrent administration of ADT at the time of [68Ga]Ga PSMA PET scan [202]. Summarizing higher sensitivities are noted in patients with higher PSA values and shorter PSA kinetics and under ADT at the time of investigation [201,202]. By allowing to identify patients with high probability of being positive at a [68Ga]Ga PSMA PET/CT scanning, this nomogram might help physicians to identify suspicious PCa recurrence(s) and also to adjust subsequent treatment strategies.
In Castrate Resistant Prostate Cancer ( CRPC) patients, CT and bone scan are usually performed to differentiate between non-metastatic (nmCRPC) vs metastatic CRPC (mCRPC) patients since treatment strategy differs in these two conditions. Recently, Fendler et al. showed that PSMA-PET/CT allows detecting single or multiple metastatic lesions in the majority of the patients classified as nmCRPC by CT and Bone scan alone [203].
Finally is worth to remember that PSMA is an excellent theragnostic agent offering the possibility to highlight PCa lesions and subsequently to irradiate metastatic sites with personalized doses by use of high-energy beta or alpha particle emitters radioligand therapy (RLT) [197].
The suggested activities to administer [68Ga]Ga PSMA is 1.8 – 2.2 MBq/kg ; 100 – 200 MBq [194].
Variation of injected activity may be caused by the short half-life of Gallium-68 and variable elution efficiencies obtained during the lifetime of the Germanium-68/Gallium-68 radionuclide generator. Flushing of the administration syringe with at least 10 mL of normal saline (NaCl 0.9 %) and subsequent emptying into the i.v. access is recommended to maximize use of dispensed activity [194].
The effective dose for [68Ga]Ga PSMA is 20 µSv/MBq . The organ with the highest absorbed dose is for most PSMA targeting compounds the kidneys: 200 mGy/MBq
The range in effective dose for [68Ga]Ga PSMA is: 2 – 4 mSv per procedure [194].
The radiation exposure related to a CT scan carried out as part of a [68Ga]Ga PSMA PET/CT study depends on the intended use of the CT study and may differ from patient to patient.
Caveat
:“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
In the general review, attention should be given to prostate gland/bed, seminal vesicles, regional and distant lymph nodes, bones, lungs, and liver. Regions that may relate to any symptoms given on referral forms should also be given specific attention. In addition to semi-quantitative values [68Ga]Ga PSMA ligand accumulation should be reported as low, moderate, or intense by comparison to the background uptake. Many interpretation criteria have been published in the last few years: for the purpose of a standardized reading of [68Ga]Ga PSMA PET/CT scans performed in order to detect the site or sites or relapse and also to standardise the reading of [68Ga]Ga PSMA PET/CT in patients were the scan is performed to assess response to therapies [204–208].
Tumour lesions usually appear as focal tracer uptake higher than adjacent background. The presence of a correlate lesion on CT for each region of tracer accumulation should be reported.
Normal and variable PSMA-ligand uptake can be found in the following tissues:
Immunohistochemical and [68Ga]Ga PSMA PET/CT data have shown that increased PSMA expression can also be found in the neovasculature of non-prostate cancers such as colon cancer, oesophageal cancer, thyroid cancer, lung cancer, renal cell carcinoma, brain tumours, as well as benign tissue. So far, a variety of mainly case reports exist showing increased [68Ga]Ga PSMA uptake in non-prostate cancer related lesions [209].
An important pitfall is relevant [68Ga]Ga PSMA -ligand uptake in coeliac and cervical ganglia of the autonomic nervous system which are prone to be misinterpreted as retroperitoneal or cervical lymph node metastases. Also bone benign lesions may show some PSMA uptake like Paget disease or vertebral haemangioma [209].
Patients do not need to fast and are allowed to take all their medications.
Patients should be well hydrated before the study and during the uptake time (e.g. oral intake of 500 mL of water during a 2 h period prior to acquisition). Voiding immediately before imaging acquisition is recommended. Despite this, in some circumstances, high residual activity in the urinary system might lead to so called “halo-artefacts” in PET. Activity in ureters might lead to false positive findings. Furosemide administration (20 mg i.v, shortly before or after administration of 68Ga-PSMA) may be especially useful in these situations. Furosemide should not be administered in patients with medical contraindications to furosemide administration including allergies (e.g. sulfa allergies) [194]
The detailed recommendations are available in the EANM Oncology Guidelines
[18F]PSMA-1007, [18F]DCFPyL, [18F]CTT-1057, [18F]rh-PSMA-7, [18F]-JK-PSMA-7, [18F]AIF-PSMA-11
As for 68Ga-labelled tracers, these radiopharmaceuticals are inhibitors targeting the Prostate Specific Membrane Antigen (PSMA). PSMA is a glycoprotein, a membrane bound metallo-peptidase, encoded by FOLH1 gene on chromosome 11. The protein acts as a glutamate carboxypeptidase on different alternative substrates, including the nutrient folate and the neuropeptide N-acetyl-l-aspartyl-l-glutamate (NAAG) and is expressed in several tissues such as prostate, kidney salivary glands [210]. The upregulation of PSMA in prostate cancer (PCa) cells is well known and is used as an effective diagnostic marker for the presence of PCa. This over-expression is attested to be present in over 90% of PCa cells, making PSMA a reliable tissue biomarker for PCa functional imaging [211]. The current hypothesis concerning the function of PSMA is that it plays a role in folate transportation and metabolism. The extra-membrane part of PSMA potentially hydrolyses glutamated-folates released by dying tumour cells. The created folate may be taken up by healthy PCa cells, facilitating further cell proliferation [210]. There is a direct effect of the PSMA receptor on the AkT and PI3K growth pathways, and it likely has a strong role as a driver of cell growth in prostate cancer [211,212].
Glutamate-Phosporamidate Inhibitors: the identification of the hydrophobic accessory pocket using a series of phenylalkylphosphonamidate derivatives of glutamic acid as hydrophobic probes, inspired the exploration of substituted phosphoramidates as transition-state analogue inhibitors of PSMA [18F]CTT1057 is the most prominent tracer of this class, due to its optimal binding, tumour uptake and retention, and remarkable tumour-to-blood ratios [213].
Glutamate-Ureido-Based Inhibitors: glutamate-ureido (Glu-ureido) based inhibitors are by far the most explored class of PSMA agents. Several radioligands have already entered in clinical practice both in diagnosis and therapy. While [68Ga]Ga-HBED-PSMA (or [68Ga]Ga-PSMA-11) is the variant mostly used in clinical practice, several 18F-labelled compounds have been explored recently.
[18F]DCFBC was one of the first released and was synthesized in order to exploit the characteristics of fluorine-18 for clinical translation. Unfortunately, a relevant 18F-DCFBCdrawback is the strong binding with serum proteins, determining a long blood clearance time, which reduces tumour-to-background ratio [214]. [18F]DCFPyL (2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}ureido)-pentanedioic acid), was developed to overcome this limitation, demonstrating lower permanency in the blood pool and greater binding affinity for PSMA [215].
Recently, [18F]PSMA-1007 was developed basing its chemical structure to that of PSMA-617 (using DOTA chelator conjugated to the pharmacophore Glu-urea-Lys by a naphthalic spacer) [216]. The main advantage of [18F]PSMA-1007 is related to almost exclusively hepatobiliary excretion. The absence of radioactive urine in ureters and bladder might improve local detection of PCa.
PSMA-11 has been labelled with 18F as well, using a direct labelling procedure of PSMA ligands via aluminium fluoride [18F]AlF-complexation [8]. [18F]AlF-PSMA-11 demonstrated lower renal accumulation but demonstrated a time-dependent increase of radiotracer uptake in the bone, and such defluorination may influence the accuracy of lesion detection in the skeleton.
[18F]-Rh-PSMA-7 has been recently proposed [217]. This PSMA inhibitor is based on Silicon-Fluoride-Acceptor (SiFA) and a chelator to improve hydrophilicity. Such rhPSMA-ligands can be labelled with 18F, or with radiometal (e.g. 68Ga, 177Lu, 225Ac), making this compound a “real” theranostics agent.
Finally, [18F]-JK-PSMA-7 is another compound that drawn clinical interest, and it was obtained by the combination of 2,3,5,6-tetrafluorophenyl-6-([18F]fluoro)-2-methoxy-nicotinate ([18F]FPy-OMe-TFP) with ((S)-5-amino-1-carboxypentyl)-carbamoyl)-L-glutamic-acid (LYS-GLU) to obtain the final product (JK-PSMA-7), after purification [218].
As for 68Ga-labelled PSMA tracers, the clinical application for 18F-labelled PSMA inhibitors is mainly the biochemical recurrence after radical therapy. At present, the most updated guidelines released by the European Association of Urology recommends performing PSMA PET (without specifying the type of PSMA ligands) in any case of biochemical recurrence after either radical prostatectomy or primary radiotherapy, or biochemical persistence after surgery [219]. More in detail, EAU guidelines suggest performing PSMA if the results will influence subsequent treatment decisions.
Currently, no clinical guidelines support the use of PSMA PET to stage the disease in intermediate to high-risk patient prior to radical prostatectomy. Few data are available at present for 18F-labelled PSMA inhibitors in this clinical setting. Thus, no specific recommendations can be proposed at present. However, recently a prospective, randomized, multi-centre study investigated whether [68Ga]Ga-PSMA-11 PET/CT might improve accuracy and affect management in high-risk PCa, compared to standard of care (cross-sectional CT and bone scan) [196]. This study demonstrated a significantly higher accuracy, less incidence of equivocal findings, greater management effect and less radiation exposure for [68Ga]Ga-PSMA-11 PET/CT compared to standard of care. These results will support in the near future the replacement for conventional imaging with PSMA-labelled PET.
Considering advanced settings of PCa and the condition of castration-resistance PCa (CRPC), at present, few data regarding 18F-labelled PSMA are available. [68Ga]Ga-PSMA-11 PET/CT proved its superior accuracy to detect PCa metastasis in patients with negative conventional imaging (m0 CRPC) [203]. However, confirmatory data are needed, thus no recommendation in this setting can be offered at present.
The efficacy of radio-ligand therapy with [177Lu]Lu-PSMA-617 in mCRPC is currently under investigation in a randomized phase 3 trial (NCT03511664), and [68Ga]Ga-PSMA-11 PET/CT is used as diagnostic procedure to enrol patients. However, at present there are not enough data regarding the application of 18F-labelled PSMA compounds to investigate patients prior to 177Lu-labelled or [225Ac]Ac-PSMA-617 therapy.
Since PSMA PET is generally performed in male patient with prostate cancer, contra-indications such as pregnancy and breastfeeding are not applicable. Administration of contrast media and diuretic (furosemide) might be indicated. PSMA PET can be performed in patients with hyperthyroidism and kidney failure. However, if intravenous iodinated CT contrast is being considered for the CT protocol, thyroid and renal function should be considered. Furosemide should not be administered in patients with medical contraindications to furosemide administration including allergies (e.g. sulfa allergies).
18F-DCFPyL has been tested in a head-to-head comparison with [68Ga]Ga-PSMA-11 PET/CT [218]. In14 patients with biochemically recurrent PCA, [18F]DCFPyLPET/CT identified more locations in three patients, showing also and those findings higher SUVmax values and more favourable tumour-to background ratios. Recently the efficacy of [18F]DCFPyL PET/CT has been evaluated in a population of 248 PCa patients affected by PSA recurrence after curative therapy [15]. The positivity rate of [18F]DCFPyLPET/CT was 86.3% [220]. The positivity rate of 18F-DCFPyLPET/CT was 86.3%. Namely, with PSA values <0.5 ng/ml the positivity rate was 59%, while resulted 69% with PSA comprised between 0.5 and 1.0 ng/ml. At present, the phase 2/3 OSPREY trial (NCT02981368) investigating 385 patients in staging setting prior to surgery has been recently completed [221]. Preliminary results showed high specificity to detect PCa locations (96-99%), with optimal PPV (78-91%) and NPV (81-84%), while sensitivity resulted suboptimal (31-42%), as already observed for [68Ga]Ga-PSMA-11 PET/CT.
A head-to-head comparison study between [18F]DCFPyLPET/CT and [18F]PSMA-1007PET/CT [222]. In the twelve selected, treatment-naïve patients, no significant differences were recorded regarding visual or SUVmax of putative sites of disease. [18F]-PSMA-1007PET/CT efficacy in recurrent setting has been recently explored [223]. In a population of 251 patients presenting with a high median PSA value of 10.9 ng/mL, the overall positivity rate was 81.3%. Namely, the positivity rate was 61.5% with PSA<0.5 ng/mL and 74.5% with PSA comprised between 0.5 and 1 ng/mL.
[18F]-rh-PSMA-7 has been recently tested in cohort of 261 hormone-sensitive PCa patients presenting biochemical recurrence, with a median PSA value of 0.96 ng/mL [224]. The overall positivity rate was 81%, while resulted 71% with PSA with PSA<0.5 ng/mL and 86% with PSA comprised between 0.5 and 1 ng/mL.
Scant information is currently available for 18F]CTT-1057, [18F]-JK-PSMA-7 and [18F]AIF-11, thus at present conclusion regarding their efficacy to explore PCa patients affected by biochemical recurrence cannot be drawn.
No specific recommendations have been published so far. Below are reported the doses and uptake times used in the few studies published in the literature:
Flushing of the administration syringe with at least 10 mL of normal saline (NaCl 0.9 %) and subsequent emptying into the i.v. access is recommended to maximize use of dispensed activity.
18F-DCFPyL mean effective dose for the whole body is 0.017 ± 0.002 mSv/MBq [225]. The effective dose from [18F]-JK-PSMA-7 for the whole body was calculated to be 1.09E-02 mGy/MBq [226].
Caveat
:“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
As for [68Ga]Ga-PSMA-11 PET, 18F-labeled PSMA PET should be interpreted as suggested by the EANM standardized reporting guidelines v1.0 for PSMA PET (E-PSMA). The expression of PSMA can predominantly be found in PCa, but benign and other malignant tissues are known to express PSMA and have extensively been described [227] Although the positive predictive value and specificity of PSMA-PET are known to be high [228], cautious reading and knowledge of common pitfalls should be considered while interpreting PSMA PET images and drafting the medical report. Potential pitfalls for 18F-labeled PSMA are similar to that of [68Ga]Ga-PSMA-11 PET as reported in the E-PSMA guidelines. However, [18F]-PSMA-1007 has been described as expressing increased PSMA expression in benign bone lesions compared to [68Ga]Ga-PSMA-11 PET, but also in non-trauma related PSMA uptake [229].
As for [68Ga]Ga-PSMA-11 PET, patients do not need to fast and are allowed to take all their medications. Androgen receptor (AR) inhibition is believed to increase PSMA expression in PCa [230]. This upregulation and its exact timing are not completely understood but must be considered in order to prevent falsely defining disease progression shortly after initiation of AR-targeted therapies. This increase in PSMA uptake appears transient, since it is more visible during first weeks of hormonal-blockade, with a tendency to decrease over time [194]. However, PSMA upregulation may not be transient, but PSMA uptake goes down due to treatment response rather than down regulation of PSMA.
Patients should be well hydrated before the study and during the uptake time (e.g. oral intake of 500 mL of water during a 2 h period prior to acquisition). Voiding immediately before imaging acquisition is recommended. Despite this, in some circumstances, high residual activity in the urinary system can be observe, especially for [18F]DCFPyL. Furosemide administration (10 to 20 mg i.v, shortly before or after administration of the radiotracer) may be especially useful in these situations.
The detailed recommendations are available in the EANM Oncology Guidelines [229]. Further information regarding images interpretation and acquisition protocols can be found in the EANM standardized reporting guidelines v1.0 for PSMA PET (E-PSMA) [225].
[64Cu]Cu-PSMA-617, [64Cu]Cu-NODAGA-PSMA
[64Cu]Cu-PSMA-617 has been recently proposed as possible diagnostic radiotracer in prostate cancer PCa. PSMA-617 theragnostic ligand, in which the chelator DOTA was conjugated to the pharmacophore Glu-urea-Lys by a naphthalic spacer PSMA-617 seems to be more suitable for radioligand-therapy because of its higher tumour uptake at later time points, lower spleen accumulation, and highly efficient clearance from the kidneys [231]. Accordingly, the main advantage seems to be related to a lower radioactive urine excretion. It is generally labelled to 177Lu, but can be labelled to 225Ac or to 64Cu for diagnostic purposes. However, some studies have demonstrated a generally lower tumour uptake, mainly if compared with HBED-CC chelated agents.
Recently, there is growing interest in NOTA chelator and its derivatives, since64Cu chelating agents owing high in vivo stability, favourable impact on tracer pharmacokinetics, and ability to generate high contrast images. One derivative, 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), has been tested for 64Cu labelling of peptides providing promising results [232].
Clinical indication for 64Cu-labelled PSMA reflect the same indications applied to other 68Ga or 18F-PSMA ligands. Thus, biochemical recurrence after radical therapy is currently the approved clinical setting by the European Association of Urology (EAU) Guidelines [219]. Staging procedures prior to radical prostatectomy in high-risk PCa and castration resistant PCa (CRPC) are two scenarios where 64Cu-labelled PSMA inhibitors might be tested in the near future.
Contra-indication for 64Cu-labelled PSMA reflect the same indications applied to other 68Ga or 18F-PSMA ligands.
In the biochemical recurrent setting, the diagnostic efficacy of [64Cu]Cu-PSMA-617PET/CT has been recently compared to 18F-Choline PET/CT in a cohort of 43 patients retrospectively enrolled (median PSA 0.8ng/mL) [233]. The overall positivity rate for [64Cu]Cu-PSMA-617PET/CT resulted 74.4%, while resulted significantly lower for [18F]F-Choline (44.2%). Namely, the positivity rate was 57.1% with PSA<0.5 ng/mL (14.3% for 18F-choline PET/CT) and 60% with PSA comprised between 0.5 and 1 ng/mL (30% for 18F-choline PET/CT)
There is no data in literature about the performance of [64Cu]Cu-NODAGA-PSMA in recurrent setting. This radiotracer has been tested in clinical practice in a heterogeneous population of 23 patients with biochemical recurrence after radical therapy, or with progressive disease at primary staging. The calculated overall positivity rate was 79.2%, showing 24 PSMA positive lesions in 19 patients [234].
Suggested activities to administer are:
Flushing of the administration syringe with at least 10 mL of normal saline (NaCl 0.9 %) and subsequent emptying into the i.v. access is recommended to maximize use of dispensed activity.
As for [68Ga]Ga-PSMA-11 PET and 18F-labeled PSMA PET, 64Cu-labeled PSMA PET scan should be interpreted as suggested by the EANM standardized reporting guidelines v1.0 for PSMA PET (E-PSMA). Potential pitfalls for 64Cu-labeled PSMA are similar to that of [68Ga]Ga-PSMA-11 and for 18F-labeled PSMA inhibitors
As for other 68Ga and 18F, also for 64Cu-PSMA ligands patients do not need to fast and are allowed to take all their medications and similar preparation procedures can be applied to these 64Cu labelled radiotracers.
The detailed recommendations are available in the EANM Oncology Guidelines [194]. Further information regarding images interpretation and acquisition protocols can be found in the EANM standardized reporting guidelines v1.0 for PSMA PET (E-PSMA).