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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5209_Библиотеки_им_академика_М_И_Перельмана.pdf
21 Diagnostic Performance ofPET-Based Targeted Fusion Biopsy inProstate Cancer
243
[39, 40]. Various compounds have been devel-
oped, from peptides to small molecules and antibodies; 68Ga-PSMA-11 and 18F-DCFPyL are the
two currently FDA-approved PSMA-targeting
radiopharmaceuticals. Both compounds have the
same urea motif as a binding structure for PSMA
and thus maintain the same high tumor specicity
and tumor uptake. They only differ in the physical
properties of the respective radioisotope. PSMA
expression positively correlates with disease
grade—aggressive cancers show higher uptake on
PSMA-PET [41–43]. Therefore, PSMA PET may
serve to differentiate clinically signicant PC
from indolent disease. Prior to prostatectomy,
PSMA-targeted PET has been shown to risk-stratify intermediate-risk or high- risk disease by
assessing the intensity of uptake in the prostate,
expressed as standard uptake value (SUV) [44].
Several studies have shown that PSMA-PET’s
preferential detection of clinically signicant PC
could improve the accuracy of index lesion identication for targeted prostate biopsy [45–49]. In
retrospective comparisons of 68Ga-PSMA-11
PET/CT [50, 51] or PET/MRI [52] with mpMRI
and post-prostatectomy histology, PSMA-PET
outperformed mpMRI in diagnostic accuracy.
Gallium-68 (68Ga)-Radiolabeled PSMA Ligands
In a prospective feasibility study, 31 patients with
prior negative standard template biopsy but persistent high clinical suspicion for PC underwent
standard re-biopsy with an additional
68
Ga-PSMA-617 PET/CT-TRUS fusion-targeted
biopsy [53]. PET/CT-TRUS fusion-guided
biopsy identied signicant disease in 39% compared to 32% with TRUS-guided biopsy. Despite
the similar yield of signicant PC for both
approaches, PSMA PET/CT-TRUS fusiontargeted biopsy utilized fewer needle samples,
reducing the risk for pain and complications after
biopsy. The combined approach of TRUS- and
PET/CT-TRUS fusion-targeted biopsy improved
detection rates to 67% in patients with positive
68
Ga-PSMA-617 PET/CT. Conversely, neither
targeted nor standard biopsy identied any clinically relevant cancers when 68Ga-PSMA-617
PET/CT was negative. This study demonstrated
that PET-guided biopsy is feasible and resulted in
a higher yield of clinically signicant PC compared to systematic biopsy alone.
The multicenter PRIMARY trial investigated
the benet of adding pelvic PSMA PET/CT to
mpMRI for the detection of clinically signicant
PC in a large cohort of 291 biopsy-naïve patients
[54]. The combination of PSMA PET and
mpMRI for biopsy guidance had the highest sensitivity and NPV (97% and 91%, respectively),
followed by PSMA PET (90% and 80%, respectively) and mpMRI alone (83% and 72%, respectively). In retrospect, the combined PET/CT and
mpMRI approach could have served as a triage
tool as 19% of men who were negative on both
scans could have been spared from biopsy.
As MRI has higher soft tissue contrast and
spatial resolution than CT [48], 68Ga-PSMA-11
PET/MRI-guided prostate biopsy was evaluated
against standard saturation biopsy in biopsynaïve patients [55]. PET/MRI showed high accuracy (90%), sensitivity (96%), and specicity
(81%) in detecting signicant PC.However, the
accuracy of PET-targeted biopsy at 71% with a
sensitivity of 65% indicates that some signicant
PC lesions identied on PET are missed by the
three targeted cores. A perilesional “focal saturation” of four additional needles was proposed in
the 4M trial to decrease the rate of missed signicant cancers at mpMRI-guided biopsy, which
seems to be related to the intratumor heterogeneity of PC [25]. A third of patients with negative
68
Ga-PSMA-11 PET/MRI could have been
spared from biopsy without missing any signicant disease. In line with a reported 5–10% of PC
that are PSMA-negative [56, 57], one participant
with an ISUP GG 2 tumor and PI-RADS 5 on
mpMRI was false negative on PSMA-PET, veried by negative PSMA immunohistochemistry.
PI-RADS 3 lesions on mpMRI are seen in
approximately 17% of cases and present a diagnostic dilemma as they are considered equivocal
for PC, making it difcult for clinicians to make
denitive decisions regarding subsequent patient
management [58]. Biopsy of PI-RADS 3 lesions
results in comparable rates of clinically signicant PC (19%) and insignicant disease (17%)
[58]. PSMA PET showed a PPV of 60% for
aggressive cancers in these equivocal lesions
[59]. It could increase specicity from 59% when
244
H. Duan et al.
using mpMRI-guided biopsy to 86% when adding PSMA PET/MRI-guided biopsy [60]. In the
decision curve analysis for signicant PC,
PSMA-PET increased the net benet, i.e., the
overall positive outcome, of PI-RADS 3 lesions;
however, its impact was minimal for lesions classied as PI-RADS 4 and 5.
Fluorine-18 (18F)-Radiolabeled PSMA Ligands
68
Ga requires in-house production. This has both
advantages and disadvantages. An advantage is that
no cyclotron is needed, and the radiolabeling process is easily managed in a hospital hot lab. The disadvantage lies in the short half-life of 68min. The
generator is expensive and provides only a small
yield of 2–4 patient doses per synthesis. Newer
18
F-radiolabeled PSMA compounds stand out as 18F
has more favorable physical properties. Its lower
kinetic energy results in a higher spatial resolution,
providing better image quality. The longer half-life
of 110 min allows for delayed imaging with an
improved tumor-to-background ratio as the background organs have time to clear. The longer halflife facilitates commercial distribution over longer
distances, making it widely and readily available.
The DeTeCT trial was the rst prospective study
to assess the diagnostic performance of
18
F-DCFPyL PET/CT for primary PC and its ability to discern the index lesion for targeted prostate
biopsy guidance [61]. Two readers used a vepoint scale to rate whether lesions seen on
18
F-DCFPyL PET/CT were benign (1, 2), equivocal (3), or positive (4, 5) for PC.They then delineated two segments that should be targeted for
biopsy using a 12-core prostate-mapping model
that is commonly used for TRUS-guided biopsy.
Comparing these annotated segments to postprostatectomy histopathology, a detection rate of
93% for clinically signicant disease would have
been achieved. In comparison, index lesion identication was projected at 87% when using a prostate-mapping model. However, dening the
prostate segments was difcult as anatomical landmarks are lacking to clearly delineate the different
segments within the prostate. In a subsequent study,
the same group compared 18F-DCFPyL PET/
CT-targeted prostate biopsy to standard 12-core
template biopsy in biopsy-naïve men at high risk
for PC based on an elevated PSA of 20–50ng/mL
[62]. PSMA-targeted biopsy identied clinically
signicant PC in 82% of patients versus 77% for
TRUS-guided biopsy. Nearly half of the patient
cohort (45%) demonstrated metastatic disease on
18
F-DCFPyL PET/CT.The combination of PSMAtargeted and systematic biopsy yielded the highest
detection rate for aggressive disease at 87%. The
authors conclude that in this cohort with high suspicion for (metastatic) PC, biopsy could be limited
to PSMA-targeted (conrmatory) biopsy. In metastatic disease, mpMRI could be avoided in most
cases, while in localized disease, mpMRI could
provide added benet for evaluation for local treatment and secondary local staging.
In a cohort of 55 patients with a solitary positive intraprostatic lesion on 18F-DCFPyL PET/CT
or PET/MRI, the performance of PET/CT-US and
PET/MRI-US fusion-targeted prostate biopsy was
investigated [63]. Overall, PET-US fusion-guided
biopsies showed a high detection rate of PC at
93%, of which 86% were clinically signicant.
Interestingly, PSMA PET/CT-US- guided biopsies
showed a slightly higher detection rate of signicant disease at 88% compared to 83% for PET/
MRI-US-guided biopsies. A small subset of participants underwent both PET/CT and PET/MRI
scans; PET-positive lesions correlated with abnormal MRI signal in 78% of cases, as validated by
biopsy. The performance of 18F-DCFPyL PET/
MRI was evaluated in a large cohort of biopsynaïve men and compared to standard prostate
biopsy [64]. Lesions were scored according to the
standardized molecular imaging PSMA
(miPSMA) score [65]. Sensitivity and specicity
were calculated according to the miPSMA score:
If the highest score of 4 was considered positive
on 18F-DCFPyL PET/MRI, the specicity was
100%, with all positive lesions proven to have
PC.If the lowest score of 1 was considered negative, the sensitivity was 100%, meaning these
patients were truly negative and could have been
spared an unnecessary biopsy. If a score of 3 or 4
was considered positive, high sensitivity at 94%
and specicity at 75% were seen. Applying these
denitions, only 5% of patients would have
avoided biopsy. The location of the index lesion
21 Diagnostic Performance ofPET-Based Targeted Fusion Biopsy inProstate Cancer
245
was 100% accurate, thus patients with positive
PET might benet from targeted biopsy only,
sparing additional needle sampling.
Dierent Biopsy Trajectories
To increase the diagnostic accuracy of signicant
disease, in-bore, 68Ga-PSMA-11 PET/
CT-targeted, trans gluteal prostate biopsy was
performed using robotic arms to support the navigation of biopsy needles [66]. This technique was
not only feasible and safe but also showed a high
detection rate of PC in 96% of patients, of whom
44% had clinically signicant disease. The inbore procedure, however, is constrained by higher
costs due to extended scanning time and the associated learning curve for the interventionist. This
approach might be more useful in patients with
prior negative or equivocal mpMRI and negative
prior biopsy.
a
Gastrin-Releasing Peptide Receptor (GRPR)
PC is characterized by high intertumor and intratumor heterogeneity [67]; therefore, targeting
one molecular marker might not be sufcient to
image all stages of PC. Gastrin-releasing peptide
receptor (GRPR) is overexpressed in many
human cancers, including PC [68]. It has been
reported to be complementary to PSMA
(Fig.21.1) [69, 70], thus presenting as an alterna-
tive for the detection of the 10% of PC that are
PSMA-negative [57]. Conversely, despite the
high specicity, false positive lesions are a known
pitfall of PSMA-targeted imaging, particularly in
benign prostatic hyperplasia [71–77].
Imaging of GRPR has been explored for initial staging [69, 70] and biochemical recurrence
[78, 79]. The overexpression of GRPR is particularly pronounced in the early stages of PC, making it an attractive target for initial staging
b
Fig. 21.1 64-year-old man with suspected prostate cancer and PSA 8.8 ng/mL: 68Ga-PSMA-11 PET/MRI (a,
axial PET, axial fused PET/MRI, and maximum intensity
projection [MIP]) shows focal uptake in the right prostate
anterior (red arrow), which is less intense in 68Ga-RM2
PET/CT (blue arrow) (b, axial PET, axial fused PET/MRI,
and MIP). 68Ga-RM2 PET also demonstrates two additional lesions bilaterally in the prostate (blue arrows).
Histopathology after radical prostatectomy revealed bilateral Gleason score 3+4 prostate cancer
246
H. Duan et al.
[80–83]. The most widely used radiopharmaceutical is 68Ga-RM2, which acts as an antagonist at
the GRPR.However, multiple other compounds
are being developed and investigated to further
improve tumor-to-background contrast.
The PSMA-targeting 68Ga-PSMA-617 and the
GRPR-targeting 68Ga-RM26 were evaluated
alongside mpMRI for targeted biopsy guidance
and compared to systematic biopsy in a pilot
study [84]. Despite the large study cohort of 112
men with suspected PC, only 35% had clinically
signicant PC and 4% indolent disease. Using the
dual-tracer approach of PSMA and GRPR PETtargeted biopsy, a detection rate of 77% was seen
in patients with PSMA- and GRPR-positive scans
(41/53 patients) without missing any signicant
cancers. Single radiotracer, 68Ga-PSMA-617- and
68
Ga-RM26-targeted biopsy yielded detection
a
rates for PC of 70% (in 30/43 patients) and 56%
(in 22/40 patients), respectively. In contrast,
mpMRI-guided and standard template biopsy
showed comparably low detection rates of only
36% (in 30/83 patients) and 35% (in 39/112
patients), respectively. The authors reason that the
low mpMRI detection rate might be due to the
overall low PC incidence rate in China and low
PSA in the study participants. Half of the study
cohort (53%) could have avoided prostate biopsy
when dual-tracer PET was negative without missing any signicant cancers.
Our group evaluated 68Ga-PSMA-11 and 68GaRM2 PET fusion-targeted prostate biopsy against
standard template biopsy in a selected cohort of
men with high clinical suspicion of PC but
negative or equivocal mpMRI and/or negative
prior biopsy (Figs. 21.2 and 21.3) [85]. 68Ga-
b
Fig. 21.2 69-year-old man with suspected prostate cancer, PSA 20.9ng/mL, PSA velocity 5.4ng/mL/year, and
PSA density 0.68ng/mL2. 68Ga-PSMA-11 (a) (red arrow)
and 68Ga-RM2 (b) (blue arrow) axial PET, axial fused
PET/MRI, and MIP show congruent focal uptake in the
left anterior mid prostate. This lesion correlated with a
PI-RADS 3 lesion on mpMRI and was negative in prior
standard template biopsy. PET-targeted prostate biopsy
revealed a Gleason score of 4+5 cancer, while standard
template biopsy undergraded with a Gleason score of
3+4. 68Ga-RM2 PET/MRI showed an additional left lateral lesion (blue arrow) that correlated with a Gleason
score 4+4 cancer on PET-targeted biopsy
21 Diagnostic Performance ofPET-Based Targeted Fusion Biopsy inProstate Cancer
a
b
247
Fig. 21.3 A 54-year-old man presents with suspected
prostate cancer and PSA 5.09ng/mL. 68Ga-PSMA-11 (a)
axial PET, axial fused PET/MRI, and MIP images show
focal uptake in the left lateral prostate (red arrow), correlating with a PI-RADS 5 lesion on mpMRI, while 68Ga-
RM2 was able to detect all clinically signicant
cancers with a high sensitivity of 83%, while
68
Ga-PSMA-11 missed signicant disease in
29% with a sensitivity of 63%. The difference in
diagnostic performance between GRPR-targeted
and PSMA-targeted PET might be attributed to
the high tumor heterogeneity of PC [53]; as
GRPR is particularly overexpressed in earlier
stages of PC [80], GRPR-targeting radiopharmaceuticals may be more suitable in this specic
clinical scenario. This cohort represents a small
proportion of patients who are clinically difcult
to manage and are more likely to be subjected to
serial imaging and repeat biopsy, thereby impacting quality of life and increasing healthcare costs.
The higher costs of additive PET might remunerate when contrasted to costs of repeat conventional imaging and biopsy. However, this needs
to be validated by further larger-scale studies.
RM2 (b) axial PET, axial fused PET/MRI, MRI, and MIP
demonstrate a lesion on the contralateral side (blue arrow).
PET-targeted prostate biopsy reveals a Gleason score
4+4 tumor in the right prostate while standard template
biopsy undergraded with Gleason score 3+3
Future Outlook
Several ongoing clinical trials are evaluating the
benet of additive PSMA PET fusion-targeted
prostate biopsy on the clinical management of
PC patients. The DEPROMP trial (German
Clinical Study Register [DRKS] 00024134) was
designed to assess the proportion of men with
suspected PC for whom added 68Ga-PSMA-11
PET/CT-targeted biopsy changed subsequent
management plans [86]. Participants enrolled in
this trial underwent standard saturation biopsy
along with mpMRI- and PSMA PET-targeted
biopsy. The interim analysis, including 100 participants, showed that PSMA PET/CT-targeted
biopsies increased the detection of signicant
disease by 4% compared to standard of care
(mpMRI-targeted and standard biopsy) while
performing PET-targeted biopsy instead of
248
H. Duan et al.
mpMRI-targeted biopsy, an increase of 3% was
seen. The addition of PSMA PET/CT-targeted
biopsies affected subsequent treatment decisions
in 53%, particularly in the 48 patients with
aggressive disease for whom therapy decisions
changed in 85% (41/48 patients). These preliminary results showed that PSMA PET/CT-targeted
biopsies improved the detection of signicant,
treatment-worthy PC and inuenced subsequent
management. Furthermore, PSMA PET-targeted
biopsy was not inferior to mpMRI fusion biopsy.
Final results are anticipated as enrollment has
been closed for this study.
A challenging cohort are men with high suspicion of PC but negative standard template and/or
mpMRI-targeted biopsy. These patients are subjected to serial imaging and re-biopsy. The
PROSPET-BX trial is a prospective imaging trial
that is currently comparing transrectal or transperineal PSMA PET/TRUS fusion-guided prostate biopsy with mpMRI/TRUS fusion-guided
biopsy in the same subset of patients with suspected PC but at least one prior negative biopsy
(NCT05297162). The primary outcome is to
assess the diagnostic performance of PSMA
PET/TRUS fusion-guided prostate biopsy for
clinically signicant disease. Secondary outcomes are to determine the relationship between
PSMA PET/TRUS fusion-guided prostate biopsy
and histopathological characteristics to validate
optimal cut-off points for SUVmax and SUVratio
that can reliably detect intraprostatic malignancy
and differentiate clinically relevant PC lesions.
Additional outcomes are to determine the clinical
utility of PSMA PET/TRUS fusion-guided prostate biopsy compared to the standard mpMRI/
TRUS fusion-guided biopsy based on the proportion of patients that could have been spared from
unnecessary biopsy, patient-friendliness, time
involvement of the procedure, reading, and contouring, as well as cost-effectiveness [87]. Studies
evaluating advanced imaging-guided prostate
biopsy in prior biopsy-negative men remain
scarce. With the reported higher sensitivity and
specicity of PSMA PET, it is anticipated that
this trial will show the superiority of PSMA PET/
TRUS fusion-guided prostate biopsy and thus
spare patients from painful and potentially futile
standard re-biopsies. The higher costs of an
upfront PET might become less of a concern as a
growing body of literature supports the inclusion
of PSMA PET earlier in the imaging sequence of
PC.The proPSMA trial showed that PSMA PET
is far more accurate (93%) than conventional
imaging (CT and bone scintigraphy) for the
detection of pelvic lymph nodes and distant
metastases at the initial staging of high-risk PC
and altered the disease management strategy in a
third of cases [88]. While current guidelines do
not include PET-targeted prostate biopsy, the
recent update to the NCCN guidelines endorses
PSMA-PET as a rst-line imaging tool, acknowledging its effectiveness, which is deemed
“equally effective, if not more effective than conventional imaging” for both initial staging and
detecting biochemical recurrence [89].
Another important cohort are men on active
surveillance. Patients with low-risk PC and also
some intermediate-risk Gleason score 3+4 cancers with low disease volume and low percentage
of Gleason pattern 4 may be managed with active
surveillance to avoid unnecessary radical treatment with its related adverse effects [90]. The
role of imaging is to detect the progression from
indolent to clinically signicant PC and thus
reduce the frequency of repeat prostate biopsies
and associated morbidity. This holds particular
signicance as 85% of active surveillance protocols require a conrmatory untriggered biopsy
within a year [90]. Currently, a multicenter clinical trial (Australian New Zealand Clinical Trials
Registry [ANZCTRN] 12622000188730) is
investigating the additive value of PSMA PET to
mpMRI to detect or exclude clinically signicant
disease in newly diagnosed PC deemed suitable
for active surveillance [91]. Similarly, the
CONFIRM trial (ANZCTRN 12621001648819)
is evaluating the role of additive PSMA PET/CT
to the standard of care (prostate biopsy and repeat
mpMRI) for risk stratication in patients with
newly diagnosed PC meeting the criteria for
active surveillance [92]. The goal is to identify
21 Diagnostic Performance ofPET-Based Targeted Fusion Biopsy inProstate Cancer
249
the men who are at high risk of developing unfavorable outcomes while on active surveillance
and, on the other end of the spectrum, whether a
negative PSMA PET might replace repeat biopsies. With the added information provided by
PET and other clinical data (PSA) and imaging
(mpMRI), the group aims to develop a nomogram to predict the likelihood of failure of active
surveillance in men with high-risk features.
A recently published study showed that PSMA
PET/CT can accurately detect advanced disease
without prior prostate biopsy in elderly patients
with suspected PC [93]. With worse clinical status and co-morbidities, the elderly patient is at
higher risk of post-biopsy complications than
younger patients and would benet from the
potential of PSMA PET to avoid invasive biopsy
and stratify for subsequent treatment. As more
long-term data become available, consensus
guidelines are anticipated to address when to
incorporate PET and PET-targeted prostate biopsies in men with suspected PC, newly diagnosed
PC, and on active surveillance.
Conclusion
PET-targeted prostate biopsies have shown better
diagnostic performance for clinically signicant
disease than standard TRUS-guided and mpMRItargeted biopsies. Particularly in equivocal,
PI-RADS 3 lesions, PET offers added value in
identifying aggressive cancers, risk stratication,
and change in disease management. Further prospective studies with larger cohorts are needed to
address the fundamental question of which
patients may benet from advanced imagingtargeted biopsy instead of systematic TRUSguided 12-core template biopsy while keeping
costs in check. Finally, PET offers a one-stopshop for local disease classication and wholebody assessment for potential disease extent
beyond the prostate gland.
Disclosure Statement The authors have nothing to
disclose.
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