Prostate cancer is a challenging disease for both physicians and patients. It requires
a multidisciplinary team of urologists, medical oncologists, radiation oncologists,
radiologists, and pathologists. Current management options include radical prostatectomy
(RP), external beam therapy, brachytherapy, high-intensity focused ultrasound, cryotherapy,
or watchful waiting (1). Although initial management of prostate cancer is difficult,
there is even more uncertainty when patients have biochemical recurrence (BCR) prostate
cancer (BCRPCa), which is described as a rise in prostate-specific antigen (PSA) levels
in patients with prostate cancer who have undergone surgery or radiation (1). This
is because with BCRPCa, the site of recurrence can be elusive. The multidisciplinary
team needs the best data possible to ascertain treatment and management options, while
the patient deserves answers on the state of his disease.
After radical prostatectomy, up to a third of patients will experience BCRPCa (1).
BCRPCa has risen in recent years and now affects, by some estimates, 25,000 men annually
in the United States (2). Spratt et al. (2) reason that this rise is largely due to
the discouragement of routine PSA screening from the US Preventative Task Force, causing
an increase of men presenting with high-risk localized cancer (2, 3). This trend has
also been observed in Europe and was the impetus for the European Association of Urology
(EAU) latest policy statement to reevaluate PSA screening (4, 5). In addition, there
is <10% utilization of adjuvant radiation therapy despite support from the American
Urological Association (AUA), American Society for Radiation Oncology (ASRO), and
American Society of Clinical Oncology (ASCO) (2).
The definition of BCRPCa depends on the initial treatment strategy. Any strategy that
does not remove all prostate epithelial tissue will demonstrate a nadir in PSA values
instead of the expected undetectable PSA values seen with RP. The AUA as well as the
EAU guidelines define BCR after RP as an initial PSA value of ≥0.2 ng/ml confirmed
by subsequent PSA value of ≥0.2 ng/ml (1). To predict the probability of metastasis,
BCR must be taken with clinical factors such as initial PSA level, Gleason score,
pathological findings after surgery, and post-BCRPCa PSA kinetics.
After confirmation of BCRPCa, imaging is vital to supply the data needed by the multidisciplinary
team to direct management. Imaging can change management in up to 70% of patients
(1, 6). The determination of local salvage therapy, systemic therapy, surveillance,
or the addition of androgen deprivation depends on confident detection (or the lack
thereof) of recurrence and distinguishing between local recurrent and metastatic disease
(7). It should be noted that a change in management does not necessarily translate
to a change in morbidity or mortality. Current National Comprehensive Cancer Network
(NCCN) guidelines allow consideration of a multitude of imaging modalities (8). However,
it is our opinion that the recommendations should be streamlined to the most effective
imaging modalities available in answering the clinical question with the highest level
of confidence available. The imaging studies with the highest positive rate at the
lowest PSA can lead to early salvage radiation therapy.
Current Landscape of Imaging in Biochemical Recurrence Prostate Cancer
Transrectal ultrasound (TRUS) can only evaluate the prostate bed and detects <50%
of recurrence when PSA is <0.5 ng/ml (1). Computed tomography (CT) has poor anatomical
resolution in the treated prostate bed, and unless recurrence is of substantial size,
it is of limited use for local recurrence. CT can be helpful in evaluating for distant
metastasis; however, CT has been reported to be positive in only 14% of cases (9).
Any lesion seen on Tc-99m methyldiphosphonate (MDP) bone scintigraphy is highly non-specific.
In fact, bone scintigraphy with BCRPCa has a positive rate of <5% when PSA is <7.0
ng/ml (10). The other obvious limitation of bone scintigraphy is that it cannot detect
soft tissue recurrence.
The benefit of PET/CT is that it combines functional data ascertained by the radiotracer
with limited anatomical data from the CT portion. 18F-NaF PET/CT is a bone imaging
study that detects areas of increased bone turnover similar to Tc-99m MDP, allowing
it to detect osseous metastases (11). Although 18F-NaF PET/CT has been shown by Jadvar
et al. (12) to outperform 18-FDG PET/CT in the detection of occult osseous metastases,
it has a similar constraint as bone scintigraphy in that it is confined to detecting
osseous recurrence where other modalities can detect both osseous and soft tissue
recurrence. The true-positive detection rate for occult osseous metastases by 18F-NaF
PET/CT is 16.2%, and the median PSA levels for positive vs. negative PET/CT scans
is reported as 4.4 and 2.9 ng/ml, respectively (12). 18F-FDG PET/CT, making use of
glucose metabolism with a radiolabeled glucose analog, has a low sensitivity for BCRPCa,
with only 28% detection of recurrence when PSA is <1.5 ng/ml (1). 11C-choline leverages
the function of choline in cell membranes and lipid biosynthesis. 18F- or 11C-choline
PET/CT is only of utility when PSA is >2.0 ng/ml (1). It has been observed that when
PSA is <0.4 ng/ml, 11C-choline PET shows a dismal positive rate of only 21% (2). 18F-fluciclovine
is a leucine amino acid analog and a novel PET radiotracer recently Food and Drug
Administration (FDA) approved for use. Prostate cancer upregulates amino acid metabolism,
giving 18F-fluciclovine its effectiveness as a radiotracer. At low PSA levels, it
has a substantial positive detection rate. At PSA values of <1.0 ng/ml, 1.0–2.0 ng/ml,
and ≥2.0 ng/ml, detection rates are reported as 72.0, 83.3, and 100%, respectively
(13). Additionally, Lovec et al. (14) reported a positive rate above 50% with men
with PSA values below or equal to 0.3 ng/ml. Although the NCCN guidelines report only
a marginally better sensitivity and specificity range for 18F-fluciclovine compared
to 11C-choline, studies comparing them head-to-head have shown that 18F-fluciclovine
is superior (8, 15). Furthermore, Nanni et al. (15) reported the true positives at
all PSA levels were generally higher with 18F-fluciclovine than 11C-choline.
Multi-parametric magnetic resonance imaging (mpMRI) is highly sensitive for local
recurrence with its superior anatomic and tissue resolution. A positive rate of up
to 94% has been reported with median PSA of 0.59 ng/ml (1). With respect to its application
in prostate cancer imaging, mpMRI sequences involve various advanced sequences. The
two most important sequences include diffusion-weighted imaging (DWI), which measures
Brownian motion of water molecules within a voxel of tissue, and dynamic contrast
enhancement (DCE) T1 imaging, which highlights vascular perfusion to tissue. DWI signal
may be degraded secondary to the blooming artifact caused by surgical metallic clips
or retained rectal air (16). Additionally, with short tau inversion recovery (STIR)
imaging and DCE T1 imaging, osseous lesions are readily detected. In fact, MRI can
detect changes in bone marrow prior to osteoblastic response which is needed for other
types of bone-specific imaging (17). Post-therapy scar and fibrosis either does not
enhance or demonstrates late enhancement. Malignancy, however, demonstrates early
enhancement (18). The added benefit of mpMRI is that it can tease out local disease
from focal treatment change that often occurs from focal therapies such as cryoablation
and high-intensity focused ultrasound (18). Diagnostic CT or the CT portion of a PET/CT
cannot provide the same level of anatomical detail of the treatment-altered prostate
bed as mpMRI of the prostate.
In patients with BCRPCa, it is imperative to deliver salvage radiation therapy (RT)
as early as possible (ideally PSA <0.5 ng/ml). This means that finding recurrence
with the lowest possible PSA is invaluable. Of the imaging modalities available, the
ones that detect disease with the lowest PSA value are 18F-fluciclovine PET/CT and
mpMRI. 18F-fluciclovine is effective in detecting both local recurrence and distant
metastatic disease, while mpMRI has very high utility in detecting local recurrence.
In fact, a whole-body MRI would obviate the need for bone-specific imaging modalities
given its superiority to both bone scintigraphy and 18F-NaF PET/CT (17). Hence, it
is our opinion that there is no need for any other imaging modality except 18F-fluciclovine
PET/CT combined with mpMRI, including a whole-body sequence, for BCRPCa, and ideally,
18F-fluciclovine PET/MRI, if available, for the added benefit of superior osseous
detection (Figure 1). This approach will give the multidisciplinary team the structural
and functional information to make early management decisions with high confidence.
Right anterior prostate bed recurrence as seen on multi-parametric MRI (mpMRI) with
18F-fluciclovine PET/CT. There is diffusion signal on calculated b-1400 diffusion-weighted
imaging (DWI) (red arrow) (A) with corresponding low apparent diffusion coefficient
(ADC) values (red arrow). (B) Anatomical correlation is noted on T2 Half-Fourier acquisition
single-shot turbo spin echo (HASTE) imaging (red arrow). (C) Lesion is confirmed to
contain upregulated amino acid transport, seen in prostate cancer, in the 18F-fluciclovine
image (red arrow) (D).
Future Directions in Biochemical Recurrence Prostate Cancer Imaging
Molecular imaging approaches applied in the management of BCRPCa management include
prostate-specific membrane antigen (PSMA) radiotracers bound either to gallium (68Ga-PSMA)
or to fluoride (18F-DCFPyL). PSMA is a membrane glycoprotein that is overexpressed
by prostate cancer cells. Ga-PSMA PET is currently undergoing Phase III trials in
the US and appears to outperform 18F-fluciclovine with a positive rate of 73% at a
PSA range as low as 0.5 to 1.0 ng/ml and a positive rate of >50% at the remarkably
low PSA range of 0.20–0.29 ng/ml (1). It should be noted that 68Ga-PSMA is already
clinically available in Europe and outperforms 18F-fluciclovine (19). 18F-DCFPy is
a PSMA radiotracer that produces images with higher resolution and is currently in
phase II trials (2). It has been shown to successfully identify recurrent disease
and lead to a change in management in 60% of patients and in up to 28% of patients
who had negative CT or MR findings (20). It has been shown to detect bone metastases
as accurately as 18F-NaF PET/CT but is superior to the latter given its ability to
detect non-osseous disease at low PSA values, making it a more useful study overall
BCRPCa as well as primary prostate cancer is ripe for quantitative imaging biomarker
development using radiomics as a methodology. Radiomics may be defined as a process
of extracting quantified data from medical images as single-order (histogram-based)
and second-order (texture analysis-based) features, which are then classified into
clusters (or signatures) that best align with an underlying pathophysiologic process
(Figure 2). Radiomic analysis performed on pretreatment mpMRI has been shown to predict
BCRPCa, which has implications for predicting response to adjuvant therapy (22, 23).
In addition, radiomic texture analysis has been shown to predict biochemical relapse
as well as BCRPCa-free survival after prostatectomy [area under the curve (AUC) 0.76]
(24). Furthermore, MR radiomic signatures [using T2W and apparent diffusion coefficient
(ADC) images] can accurately predict the response to carbon ion radiotherapy (CIRT)
for prostate cancer as well (25). Recently, radiomics has been shown to predict Decipher
score (an mRNA-based genomic test that predicts the occurrence of prostate cancer
metastasis after radical prostatectomy) by differentiating between low and intermediate/high
scores (with an AUC of 0.92) (26, 27).
Graphical schema of the radiomics process that involves lesion identification, drawing
regions of interest, image preprocessing followed by radiomic feature extraction and
classification that provides the imaging biomarker for predicting biochemical recurrence.
Reused from Fernandes et al. (28) under the Creative Commons License.
Imaging is central to BCRPCa treatment decisions. Current practice in the US should
be reformed to use 18F-fluciclovine and moving to a PSMA-based radiotracer as currently
approved in Europe once FDA approved in the USA in conjunction with mpMRI or as PET/MR
where available. The future is bright in the fight against BCRPCa with growing research
in imaging-based precision medicine practices including radiomics-based imaging biomarkers.
FS contributed to manuscript writing, focusing on PET/CT and radiomics. DD-R, JD,
and OK contributed to manuscript writing and provided technical input. MQ contributed
to manuscript writing focusing on clinical, PET/CT, and MRI. All authors contributed
to the article and approved the submitted version.
Conflict of Interest
FS, DD-R, JD, and OK are employees of Image Analysis Group, Philadelphia, PA, USA.
The remaining author declares that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential conflict