REVIEW

C URRENT
OPINION The role of prostate-specific membrane antigen
PET/computed tomography in the management of
prostate cancer patients: could we ask for more?
Riccardo Mei a,b, Andrea Farolfi a, Joshua James Morigi c and Stefano Fanti a,b

Purpose of review
Thanks to the development of novel PSMA-based peptides, molecular imaging, such as PET/CT paired with
theranostic-based approaches have recently been proposed for treatment of prostate cancer. Patient
selection, however, remains challenging because of the absence of strong prospective data to interpret and
translate imaging scans into effective and well tolerated treatment regimens.
Recent findings
In this review, we discuss the latest findings in PSMA imaging in prostate cancer patients. Particularly, we
go into detail into the impact of PSMA imaging on the treatment management in primary staging,
biochemical recurrence and in advanced prostate cancer.
Summary
For primary prostate cancer staging, PSMA PET/CT seems crucial for primary therapy assessment, being
able in some cases to detect lesions outside the surgical template, thus permitting a change in
management. Moreover, Nþ condition at PSMA has been correlated with a worse biochemical recurrence-
free and therapy-free survival. The early detection of PSMA-positive findings in recurrent prostate cancer is
associated with a better time to relapse survival. Similarly, for advanced prostate cancer patients, accurate
restaging with PSMA imaging is gaining importance for early prediction of response to systemic therapies
and to assure the best outcome possible. With regards to theranostics, appropriate selection of patients
eligible for 177Lu-PSMA requires PSMA imaging, whereas the role of added FDG-PET for discriminating
those with PSMA/FDG discordance needs to be further evaluated.
Keywords
androgen deprivation therapy, castrate-resistant prostate cancer, prostate cancer, prostate-specific membrane
antigen PET/CT/CT, radioligand therapy, staging

INTRODUCTION when compared with other conventional imaging

Prostate cancer is one of the most frequent malig- modalities or to other PET tracers (i.e. choline,
nancies in men. Although frequently indolent, FACBC, NaF). As a result of overwhelming data evi-
nearly 25% of prostate cancer patients present with dence, PSMA PET/CT was implemented within the
high-risk disease, potentially leading to poorer out- European Association of Urology (EAU) guidelines
comes [1]. Accurate staging of the extension of the
tumor is, therefore, pivotal for immediate or future a
Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria di Bolo-
treatment decisions. gna, bDIMES, University of Bologna, Bologna, Italy and cPET/CT Unit,
The recent introduction of fluoride or gallium- Department of Medical Imaging, Royal Darwin Hospital, Darwin, Australia
labelled prostate-specific membrane antigen (PSMA) Correspondence to Riccardo Mei, MD, Nuclear Medicine, IRCCS,
Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti, 9,
radiotracers in functional imaging with PET/CT
40138 Bologna, Italy. Tel: +39 512143194;
has added an important diagnostic tool, which e-mail: [email protected]
has revolutionized prostate cancer management. Curr Opin Urol 2022, 32:269–276
Firstly trialed in the setting of biochemical relapse
DOI:10.1097/MOU.0000000000000982
(BCR) prostate cancer, PSMA PET/CT has since
This is an open access article distributed under the Creative Commons
proven effective for primary staging and validated Attribution License 4.0 (CCBY), which permits unrestricted use, dis-
with strong prospective data [2,3]. PSMA PET/CT tribution, and reproduction in any medium, provided the original work is
demonstrated superior sensitivity and specificity properly cited.

0963-0643 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-urology.com
Treatment and patient selection for patients with metastatic prostate cancer

Urological Pathology (ISUP) grade 4–5] and clinical

KEY POINTS rectal examination of at least cT2c [1]. This group
 Fluoride and gallium-labelled PSMA radiotracers in represents about 25% of all prostate cancer cases and
functional imaging with PET/CT has added an typically reflects a more aggressive disease, with
important diagnostic tool, which has revolutionized shorter time to recurrence after primary treatment
prostate cancer management. and even worse overall survival [4].
Accurate disease primary staging with imaging is
 PSMA PET/CT is crucial for primary therapy
assessment, because of its capability to detect even crucial for treatment decisions. The localization of
small but PSMA-avid pelvic lymph node metastasis pelvic lymph node metastasis in a region outside the
outside the surgical template, thus leading to change in standard pelvic dissection template (e.g. para-rectal
management in a considerable number of high- and presacral regions) might significantly influence
risk patients. the surgical approach. Similarly, the detection of an
 PSMA PET/CT in restaging biochemical recurrence and extra-pelvic lymph node metastasis or a bone meta-
CRPC prostate cancer showed a considerable impact stasis yields a switch to oligometastatic disease and
on patient management, helping to clarify the site of in turn a change in treatment (from surgery to
the disease and to subsequently treat it by choosing the systemic therapy) (Fig. 1).
best therapeutic strategy (i.e. local vs systemic) for Up until recent years, conventional imaging
the patient. modalities (i.e. bone scan, CT and mpMRI) were
 PSMA PET/CT parameters have been preliminary considered standard-of-care for primary staging of
demonstrated to be predictors of systemic therapy and prostate cancer. These methods revealed poor sen-
RLT response, even if further studies are needed. sitivity and specificity and were gradually overtaken
by PET/CT with PSMA tracers. PSMA is a type II
trans-membrane glycoprotein, which is normally
expressed in some epithelia (salivary and lacrimal
glands, duodenum, liver and spleen) and highly
at staging for intermediate-to-high-risk patients and expressed on the cell surface of almost 90% of
in the setting of biochemical relapse when PSA prostate cancer [5]. Moreover, PSMA expression is
greater than 0.2 ng/ml if this can influence subse- also correlated with tumor grade, higher PSA values
quent treatment decisions [1]. and prognosis [6]. PET/CT with Ga or F-labeled
However, authors also highlight that there is still PSMA tracers provided a significant increase in pri-
a lack of data concerning patient outcomes related to mary staging of prostate cancer.
PSMA imaging-based management decisions. A recent comparison between mpMRI and PSMA
Although strong data exists with regards to PET/CT in primary index lesion, pelvic lymph node
sensitivity and specificity in the detection of either metastasis in staging intermediate-risk and high-risk
lymph nodes and bone metastasis with various Gal- prostate cancer patients has been studied by Szigeti
et al. [7 ]. A total of 81 patients were included; index
&
lium and Fluoride-labelled PSMA tracers, random-
ized controlled trials aimed to evaluate the real lesion was detected by PSMA PET/CT and mpMRI in
impact of the result of PSMA PET/CT the subsequent 87 and 98% of them, respectively. However, as
treatment choice and the related patient outcome regards N staging, 60% of patients with histology-
are lacking. proven pelvic lymph node metastasis were detected
The aim of this nonsystematic review is to provide by PSMA PET/CT, whereas only 50% on mpMRI.
an overview about the latest and most relevant data in Bone and distant lymph node metastasis were found
literature about the role of PSMA ligand PET tracers in by PSMA PET/CT in 17% of patients, of which 39%
the management of prostate cancer, exploring the of bone metastasis appeared without any morpho-
settings of staging, biochemical recurrence (BCR) and logical correlation on CT.
castrate-resistant prostate cancer (CRPC). The combination of PSMA PET/CT and MRI
seems to be superior to MRI alone in the diagnostic
performance for detecting clinical significant pros-
THE ROLE OF PROSTATE-SPECIFIC tate cancer (csPC), thus potentially allowing a better
MEMBRANE ANTIGEN IMAGING IN selection and even a reduction in the number of
PRIMARY STAGING OF PROSTATE prostate biopsies. In a recent prospective multicen-
CANCER ter phase II imaging trial by Emmett et al. almost 300
High-risk prostate cancer is defined accordingly to men underwent both PSMA PET/CT and MRI prior
EAU guidelines on the basis of several clinical fac- to biopsy. Combined PSMA and MRI imaging
tors, such as initial PSA levels, pathology grading improved NPV as compared with MRI alone [91
[Gleason Score >7 or International Society Of vs. 72%, test ratio ¼ 1.27 (1.11–1.39), P < 0.001].

270 www.co-urology.com Volume 32  Number 3  May 2022

 Role of PSMA positron emission tomography/CT in prostate cancer management Mei et al.

FIGURE 1. A 75-year-old man with prostate adenocarcinoma (iPSA ¼ 26 ng/ml; GS 4þ3). Primary staging 68Ga-PSMA PET/CT
(a, MIP) showed several lymph node metastasis with increased PSMA uptake in the pelvis (b, fused images with a large left internal
iliac node) and in the abdomen (c, fused image, red circle showing some small retroperitoneal nodes with PSMA uptake). Patients
was excluded from surgery and subsequentley treated with ADT. 68Ga-PSMA PET/CT in primary staging of high-risk patients can
easily detect sites of metastasis outside the surgical template, thus excluding those patients with M disease. ADT, androgen
deprivation therapy; CT, computed tomography; MIP, maximum intensity projection; PSMA, prostate-specific membrane antigen.

Sensitivity also improved, despite a slightly reduced 108 patients. Overall, PSMA PET/CT led to a change
specificity [8]. of disease stage in 36% of the patients (45% in the
The performance of PSMA PET/CT in the detec- subgroup of primary radiation and 26% in patients
tion of lymph node metastasis in primary staging of intended for salvage radiation therapy). Upstaging
prostate cancer patients is highlighted in a recent and downstaging resulted in 22 and 14%, respec-
review by Stabile et al. [9]. They found a moderate
&
tively [11 ].
heterogeneity among the studies. The sensitivity, While staging prostate cancer, the assessment
specificity, PPV and NPV of PSMA PET/CT for LNI of regional pelvic lymph node metastasis is crucial
were, respectively, 58% [95% confidence interval for surgery and subsequent clinical decisions (e.g.
(CI) 50–66%], 95% (95% CI 93–97%), 79% (95% whether to perform PLND is pelvic lymph node
CI 72–85%) and 87% (95% CI 84–89%), with overall dissection (PLND) or extended pelvic lymph node
moderate heterogeneity between studies. Similar dissection (ePLND), subsequent salvage therapy,
results were confirmed by Moreira et al. [10], with etc.). To better predict the risk of regional lymph node
specificity and accuracy of 75, 96 and 91%, respec- metastasis, validated nomograms (i.e. Briganti, Memo-
tively, for lymph node involvement, and 91, 50 and rial Sloan Kettering Cancer and Winter) have been
76%, respectively for metastatic bone lesions. created to better select candidates for PLND. According
A recent study by Al-Ibraheem et al. explored the to these nomograms, PLND should be performed in
impact of 68Ga PSMA PET/CT on prostate cancer patients with lymph node metastasis risk higher than
staging and definitive radiation therapy planning in 2% (MSKCC), 5% (Briganti) and 7% (Winter) [12–14].

0963-0643 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-urology.com 271
Treatment and patient selection for patients with metastatic prostate cancer

Despite this, more than 36% of intermediate-risk and these occur, re-staging and subsequent appropriate
high-risk prostate cancer patients present with nonre- management is indicated. This may be with cura-
gional pelvic lymph node metastasis (i.e. out of the tive intent in case of local relapse (e.g. salvage
PLND template) or with nonregional extra-pelvic radiotherapy) or with palliative and tumor control
lymph node metastasis [15]. For these patients, stand- intent in case of systemic therapy for diffuse disease
ard PLND might, therefore, be unnecessary as they spread. Restaging of these patients with PSMA
already have disseminated disease outside the surgical imaging has become pivotal. Its superior perform-
template (e.g. presacral or pararectal lymph node ance compared with standard imaging [17] and to
metastasis) or even M1a disease. other PET tracers, is well established by a number of
In a recent study, Jiao et al. aimed to evaluate a studies in literature, even for low PSA values [18]
threshold for current clinical PLND-validated nomo- (Fig. 2).
grams to predict nonregional pelvic and extrapelvic In a recent review, the positive-predictive value
lymph node metastasis in 57 high-risk prostate cancer of 68Ga-PSMA PET/CT according to PSA values
patients studied with 68Ga-PSMA PET/CT. They over- in patients with BCR before salvage lymph node
all observed extrareolar spread in nearly 35% of the dissection ranged from 11.3 to 50% for PSA values
lymph node metastasis with PSMA uptake. According less than 0.2 ng/ml, 20% to 72.7% with PSA 0.2–
to Briganti, MSKCC and Winter nomograms, 70–72% 0.49 ng/ml and 25–87.5% for PSA 0.5 to less than
of the patients resulted in candidates to ePLND 1.0 ng/ml [19].
(according to EAU and NCCN guidelines). Positive Baas and colleagues retrospectively evaluated
lymph node metastasis on PSMA PET/CT led to a the predictive value for biochemical persistence
change in management in 70% of these patients. (BCP) and early BCR of metastatic lymph node on
Moreover, patients with a nomogram score greater PSMA PET/CT in 213 intermediate-risk and high-risk
than 64, 75 and 67% according to Briganti, MSKCC prostate cancer patients prior to radical treatment
and Winter, respectively were more likely to have (RARP with ePLND). PSMA PET/CT resulted positive
nonregional lymph node metastasis. Authors con- for lymph node metastasis in 19% of the patients,
cluded that these nomograms are able to predict whereas pN1 was found in 23%. Sensitivity, specif-
nonregional lymph node metastasis. Interestingly, icity, PPV and NPV on a per-patient analysis for the
PSMA PET/CT may provide an additional benefit to detection of pN1 was 29, 84, 35 and 80%, respec-
nomograms-based clinical decision-making in more tively. BCP was observed in 12%, whereas early BCR
than two-third of patients for reducing unnecessary in 21%. Authors concluded that a positive PSMA
&&
PLND [16 ]. PET/CT prior to radical treatment was a significant
To summarize, PSMA PET/CT is at present the prognostic tool for early relapse of the disease [odds
best diagnostic tool for intermediate and high-risk ratio (OR) for BCP: 0.71, 95% CI 2.9-17.1; OR for
prostate cancer patients, demonstrating excellent early BCR: 8.1, 95% CI 2.9–22.6). Interestingly, of
diagnostic performance for both N and M staging the 173 patients with negative PSMA PET/CT, pN1
and likely superior to mpMRI in the detection of was found in 20%, thus suggesting the importance
locoregional lymph node metastasis. On the basis of of performing ePLND in intermediate-risk and high-
latest data in literature, PSMA PET/CT might be risk prostate cancer patients, even with a negative
&&
crucial for primary therapy assessment, because of PSMA PET/CT scan [20 ].
its capability to detect even small but PSMA-avid Moreover, the role of PSMA PET/CT in restaging
pelvic lymph node metastasis outside the surgical BCR showed a considerable impact on patient man-
template, thus leading to change in management in agement. Amiel et al. studied the impact of preop-
a considerable number of patients. Moreover, PSMA erative PSMA PET/CT on BCR and time to adjuvant
positivity for pelvic lymph nodes is associated with a or salvage treatment in 230 intermediate-risk and
worse prognosis in terms of BCR-free and therapy- high-risk prostate cancer patients. Overall sensitiv-
free survival, suggesting a potential role in predict- ity, specificity, PPV and NPV of PSMA PET/CT for
ing the patient outcome and thus improving the pN1 disease was around 49, 96, 82 and 82%, respec-
decision about subsequent treatment, such as PLND, tively. Biochemical recurrence-free and therapy-free
salvage radiotherapy and ADT. survival was worse with patients with pN1 and
PSMA PET/CT-positive lymph node, followed by
pN1 patients with negative PSMA PET/CT (median
THE ROLE OF IMAGING IN PATIENT WITH BCR-free survival 1.7 vs. 7.5 vs. >36 months, median
BIOCHEMICAL RECURRENT PROSTATE therapy-free survival 2.6 vs. 8.9 vs. >36 months).
CANCER According to Baas and colleagues, authors con-
Patients with PSA persistence or recurrence are at cluded that patients with lymph node metastasis
increased risk to have metastasis. When either of on staging PSMA PET/CT have an increased risk of

272 www.co-urology.com Volume 32  Number 3  May 2022

 Role of PSMA positron emission tomography/CT in prostate cancer management Mei et al.

FIGURE 2. A 80-year-old man with prostate cancer (GS 4þ4), previously treated with RT. At the time of the scan, PSA value
was 6.4 ng/ml, with ongoing ADT. At the 68Ga-PSMA PET/CT scan (a, MIP) a single bone lesion in the left scapula (b, fused
image) was found without any alterations on low-dose CT images (c). 68Ga-PSMA PET/CT can clarify the site of the disease
with unprecedent accuracy and even by detecting lesions without any alteration on CT, thus helping to choose the best
therapeutic strategy. ADT, androgen deprivation therapy; CT, computed tomography; MIP, maximum intensity projection;
PSMA, prostate-specific membrane antigen.

early BCR, and are therefore, expected to undergo radiotherapy for lymph node recurrence in terms of
early adjuvant or salvage therapy [21]. BCR-free survival (BRFS) and distant metastasis-free
Fendler et al. retrospectively studied with PSMA survival (DMFS). Overall, 100 patients consecutively
PET/CT 635 patients with recurrent prostate cancer. received sRT [with or without androgen deprivation
They overall observed a change in management for therapy (ADT)], according to PSMA PET/CT scan
PSA values of 0.5 to less than 2.0 ng/ml in nearly 70% results, with a median follow-up of 37 months.
of them, of which approximately 50% with major The following factors were predictors of better prog-
changes intended as active surveillance for unknown nosis: concomitant ADT, longer ADT duration (12
disease site (27%), local treatment for locoregional vs. <12 months) and lymph node localization (pel-
disease (33%) or systemic therapy for metastatic vic vs. paraaortic). However, no association was
disease (40%). In summary, PSMA PET/CT helps to observed with the number of PSMA-positive lymph
clarify the site of the disease and to subsequently treat nodes [24].
it by choosing the best therapeutic strategy (i.e. local Generally, patients with either locally advanced
&&
vs. systemic) for the patient [22 ]. (combined with radiotherapy) or metastatic disease
Patients who present prostate cancer relapse with high risk of progression (i.e. with PSA doubling
may benefit from different treatment modalities, time <6 to 12 months) may benefit from ADT [1].
whose decision needs to be well balanced by con- When patients after initial treatment with ADT
sidering both the burden of the disease and the experience biochemical progression, they require
potential treatment side effects and their implica- further re-staging PSMA PET/CT to assess the pro-
tions on quality of life, thus avoiding inappropriate gression of the disease and eventually switch to
treatments [23]. other lines of therapy. The influence of ADT on
A recent study by Rogowski et al. aimed to the expression of PSMA is so far not well understood.
explore the outcome of PSMA PET/CT-based salvage Generally, a short period of ADT treatment seems to

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Treatment and patient selection for patients with metastatic prostate cancer

increase the PSMA uptake in some patients and in sensitivity has been also observed as compared
some prostate cancer lesions. On the counterpart, with conventional imaging [29,30].
lower PSMA uptakes have been observed in long- The detection rate of PSMA PET/CT in early
term treatment. As the influence between ADT and CRPC with low PSA values has been studied by
PSMA expression is thus not fully understood, the Weber et al. in a cohort of 55 patients with PSA less
decision whether to interrupt or not ADT before than 3 ng/ml. PSMA PET/CT resulted positive in 75%
PSMA PET/CT is equivocal. Moreover, data in liter- of patients and in 45% of them M1 disease was
ature are limited and biased because of the lack of detected. For higher PSA values, PSMA PET/CT
direct comparison of PSMA PET/CT detection rate was positive in almost all the 200 patients studied
between homogeneous population of under-ADT by Fendler et al. with 55% cases with M1 disease
&
patients vs. treatment-naive patients [25]. At the despite conventional imaging [31 ].
time of this review, we found a recent study with Interestingly, Vlachostergios et al. evaluated the
direct comparison of the detection between two prognostic utility of PSMA uptake value in more
balanced groups with and without treatment. The than 200 CRPC patients who were subsequently
main finding of this study is that, with comparable treated with systemic therapies (chemotherapy,
PSA values, the detection rate of PSMA PET/CT is ADT, sipuleucel-T, 223-Ra-Dichloride). They overall
significantly higher in patients on ADT than in found higher PSMA uptakes in 75% of the patients;
patients off therapy. A possible explanation of these moreover, they demonstrated that PSMA uptake
results might be more related to the advanced dis- higher than liver parenchyma is an independent
ease stage (i.e. to a higher tumor burden) rather than prognostic factor for overall survival (OS) (hazard
an effective influence of ADT on PSMA expression. ratio 1.7; 95% CI 1.2–2.2; P ¼ 0.003) [32].
Authors conclude that the withdrawal of ADT before Furthermore, the role of PSMA PET/CT param-
&
PSMA PET/CT cannot be recommended [26 ]. eters in predicting the response to systemic thera-
However, the main limitations of PSMA PET/CT pies in 43 mCRPC patients has been assessed
is the lack of correlation between PSMA-positive by Grubmuller et al. Each patient received two
findings and histopathology, and the lack of any PET-PSMA scans prior and 6 weeks after systemic
correlation with the patient’s outcome. For this therapy scans. The delta values of PET parameters
reason, prospective studies with long median follow were significantly associated with PSA response
time are required. (dTTV P ¼ 0.003, dSUVmean P ¼ 0.003, dSUVmax
P ¼ 0.011, dSUVpeak P < 0001, dRECIST P ¼ 0.012),
whereas neither PSA values of PET parameters were
THE ROLE OF IMAGING IN PATIENT WITH &&
associated with OS [33 ].
CASTRATE-RESISTANT PROSTATE As regard of the impact of PSMA PET/CT in the
CANCER management of CRPC patients, Fourquet et al.
Patients with CRPC may benefit from a large treat- restaged 30 nmCRPC patients and observed a 100%
ment landscape aimed to delay the progression positivity rate for high PSA values (>2 ng/ml) and
of the disease as far as possible. These therapies 70% for PSA less than 2 ng/ml; impact of PSMA
range from antiandrogen drugs (bicalutamide, PET/CT on the management resulted in 70 and
&
enzalutamide, apalutamide and daroluatamide) 60% for high and low PSA values, respectively [34 ].
for men with nonmetastatic CRPC (nmCRPC) to PSMA PET/CT has also demonstrated a crucial
taxane-based chemotherapy (docetaxel, cabazi- impact on MDT assessment in oligometastatic CRPC
taxel), stereotactic radiotherapy (i.e. metastasis- patients. A systematic review by Rogowski et al.
directed therapy, MDT), 223Ra-dichloride, PARP enlightens that PSMA PET/CT is increasingly used
inhibitors for metastatic CRPC patients (mCRPC) for staging and defining the treatment plan. How-
[27]. More recently, PSMA-targeted radioligand ever, we lack randomized data related to a better
therapy (PSMA-RLT) have been also developed, clinical outcome by using PSMA PET/CT for oligo-
according to the theranostic principles [28]. In metastatic disease patients [24].
177
these patients, it is therefore, crucial to identify Lu-PSMA RLT shows antitumor activity with
the ideal moment for a change in therapy early an acceptable safe profile in men with mCRPC. Very
enough to ensure the best outcome possible. This recently, the TheraP trial has demonstrated a supe-
clinical aspect generates in turn the need for accu- rior response in terms of PSA decrease and progres-
rate prediction and monitoring of response. The sion-free survival in patients receiving Lu-PSMA as
role of PSMA PET/CT in CRPC patients is becoming compared with cabazitaxel [35]. Moreover, phase 3
predominant. Several studies demonstrated PSMA VISION trial compared Lu-PSMA plus standard of
PET/CT high diagnostic performance for accurate care versus standard of care alone and demonstrated
tumor staging and patient management. Higher an improved overall survival and imaging-based

274 www.co-urology.com Volume 32  Number 3  May 2022

 Role of PSMA positron emission tomography/CT in prostate cancer management Mei et al.

progression-free survival [36]. Patients candidates to Financial support and sponsorship

such therapy are preliminarily screened with PSMA None.
PET/CT for PSMA expression assessment of each
tumor lesion. Dual tracer PET imaging with both Conflicts of interest
PSMA and FDG-PET seems to further improve There are no conflicts of interest.
patient selection for Lu-PSMA RLT, by excluding
those with lower PSMA uptake or with significant
PSMA-/FDGþ discordances. However, there is a lack REFERENCES AND RECOMMENDED
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