Role of PET/CT in Carcinoma of the Prostate

Introduction

Prostate cancer is the most commonly diagnosed malignancy in men and a leading cause of cancer death. It is also the tumour in which molecular imaging has most decisively changed practice.

Prostatic Adenocarcinoma

The great majority of prostate cancers are acinar adenocarcinomas arising in the peripheral zone of the gland. Behaviour ranges from indolent, clinically insignificant disease that never threatens life to aggressive, rapidly metastasising cancer, and a central task of both clinical assessment and imaging is to distinguish the two.

Risk Factors

Molecular Pathogenesis

Prostate carcinogenesis proceeds from prostatic intraepithelial neoplasia to invasive adenocarcinoma through a series of characteristic alterations, several of which are directly relevant to imaging and therapy.

• TMPRSS2-ERG gene fusion — the commonest early genomic event, placing ERG under androgen-responsive control.
• PTEN loss — associated with higher grade, metastasis and poorer outcome.
• Androgen receptor (AR) signalling — the central driver, and the target of androgen-deprivation and AR pathway therapy. AR also regulates PSMA expression, which has practical imaging consequences.
• DNA damage repair defects, notably BRCA2 — confer sensitivity to PARP inhibitors and platinum agents.
• RB1 and TP53 loss — drive transformation toward the aggressive, AR-independent neuroendocrine phenotype that loses PSMA expression.

The link between androgen receptor signalling and PSMA expression is clinically important. Androgen deprivation can transiently increase PSMA expression in hormone-sensitive disease — a potential flare — while long-term treatment resistance and neuroendocrine transformation reduce it. Interpreting a PSMA study therefore requires knowledge of the treatment context.

Anatomy and Pathology

Zonal Anatomy

• The prostate is described in zones: the peripheral zone, where 70–80% of cancers arise; the transition zone, the site of benign prostatic hyperplasia and a minority of cancers; the central zone; and the anterior fibromuscular stroma.
• The gland is encapsulated, and extracapsular extension, together with seminal vesicle invasion, defines locally advanced (T3) disease with direct prognostic and surgical implications.
• Lymphatic drainage is to the obturator, internal and external iliac, and presacral nodes, ascending to the common iliac and para-aortic chains — the anatomical basis for the pattern of nodal spread seen on PSMA PET.
• The prostatic venous plexus communicates with the vertebral venous plexus of Batson, explaining the predilection for axial skeletal metastasis.

Histopathology and Grading

The Gleason System and Grade Groups

Prostate cancer is graded by the Gleason system, which assigns a pattern from 1 to 5 to the most and second-most prevalent architectures, summed into a score. This has been reorganised into the more intuitive five-tier ISUP Grade Group system, which correlates strongly with outcome and with PSMA expression.

Grade Group correlates with PSMA avidity: higher-grade tumours generally express more PSMA and are more reliably detected, which is why PSMA PET performs best precisely in the high-risk population in whom accurate staging matters most.

Clinical Presentation and Tumour Markers

Clinical Presentation

Most prostate cancer is now detected through PSA testing while asymptomatic. Locally advanced disease may cause lower urinary tract symptoms, haematuria or haematospermia, while metastatic disease classically presents with bone pain, or occasionally with anaemia, spinal cord compression or renal impairment from nodal obstruction. Because the skeletal metastases are typically osteoblastic, they may cause pain without the lytic destruction seen in other cancers.

Prostate-Specific Antigen

PSA is the central biomarker of prostate cancer and the pivot around which imaging decisions turn. It is organ-specific but not cancer-specific — benign hyperplasia, prostatitis and instrumentation all raise it — so its greatest value lies not in a single measurement but in its kinetics after definitive treatment. Two derived parameters are particularly important for imaging:

• PSA level — the absolute value at the time of imaging is the single strongest predictor of whether a PSMA PET performed for recurrence will be positive.
• PSA doubling time — a short doubling time indicates aggressive, rapidly proliferating disease and independently predicts both PET positivity and poorer outcome.

The definitions of treatment failure are precise and worth stating, because they determine when imaging is indicated. After radical prostatectomy, biochemical recurrence is defined as a PSA of 0.2 ng/mL or above, confirmed on a second sample. After radiotherapy, the Phoenix definition applies: a rise of 2 ng/mL or more above the post-treatment nadir.

Screening

Population screening for prostate cancer rests on PSA testing, with the recognised trade-off that it reduces mortality at the cost of over-diagnosis of indolent disease. Contemporary pathways mitigate this with risk-adapted testing, multiparametric MRI before biopsy, and active surveillance for low-risk cancer. PET/CT has no role in screening or early detection; its contribution begins once a diagnosis of significant disease is established and the question becomes one of extent.

Staging of Prostate Cancer

Management is driven by risk stratification, which combines PSA, Grade Group and clinical T stage into low, intermediate, high and very-high-risk categories. The intensity of staging imaging is scaled to this risk, and it is in the high and very-high-risk groups that PSMA PET has become central.

Risk Stratification

TNM Framework

Primary Tumour (T)

Nodes (N) and Metastasis (M)

N0 denotes no regional nodal metastasis and N1 regional nodal metastasis. Distant metastasis is subclassified as M1a (non-regional lymph nodes), M1b (bone) and M1c (other sites, with or without bone disease).

Patterns of Tumour Spread

Prostate cancer spreads through direct extension, lymphatic dissemination and haematogenous metastasis:

Local extension

Direct extracapsular extension is seen in a substantial proportion of patients at diagnosis, particularly in clinically advanced disease. Overall, approximately 30–50% of patients with locally advanced prostate cancer show direct extension beyond the prostate capsule at staging, with higher rates in high-grade (Gleason ≥7) tumours. Tumour commonly extends through the prostatic capsule along the posterolateral neurovascular bundles, followed by invasion of the seminal vesicles. Advanced disease may involve the bladder neck, external sphincter, levator muscles or pelvic wall. Rectal invasion remains uncommon due to the protective Denonvilliers fascia.

Lymphatic spread

The initial nodal stations are usually the obturator (≈20–30%), internal iliac (≈25–35%) and external iliac nodes (≈20–30%), followed by the presacral and common iliac nodes. Further progression may involve para-aortic and other non-regional lymph nodes.

Haematogenous spread

The skeleton is the predominant metastatic site, particularly the spine, pelvis and ribs; metastases are typically osteoblastic. In a population-based study of 74,826 patients with metastatic prostate cancer, metastases involved the bones in 84%, distant lymph nodes in 10.6%, liver in 10.2% and thoracic organs in 9.1%; 18.4% had multiple metastatic sites.

Lung, liver, pleural and adrenal metastases generally occur in advanced or castration-resistant disease.

Imaging of Prostate Cancer

The Modern Imaging Pathway

Multiparametric MRI localises and locally stages the primary and guides biopsy; PSMA PET assesses nodal and distant disease in higher-risk patients; and conventional CT and bone scintigraphy are increasingly relegated to situations where PSMA PET is unavailable. Guidelines now accept that PSMA PET need not be preceded by conventional imaging, since it is at least as effective as a front-line staging tool.

Multiparametric MRI

MRI combining T2-weighted, diffusion-weighted and dynamic contrast-enhanced sequences is the reference standard for intraprostatic disease. It localises significant cancer, guides targeted biopsy and assesses extracapsular extension and seminal vesicle invasion with an accuracy PET cannot match at the local level.

Conventional CT and Bone Scintigraphy

Contrast-enhanced CT detects only bulky nodal and visceral disease and relies on size criteria that miss small metastatic nodes. ⁹⁹ᵐTc bone scintigraphy images the osteoblastic reaction rather than tumour, giving limited sensitivity for early marrow disease and frequent equivocal findings from degenerative change.

Comparative Summary

Treatment of Prostate Cancer

Localised Disease

• Active surveillance for low-risk and selected favourable intermediate-risk disease, avoiding the morbidity of radical treatment.
• Radical prostatectomy, with pelvic lymph node dissection in higher-risk cases.
• Radiotherapy — external beam or brachytherapy — often with androgen-deprivation therapy in higher-risk disease.
• Focal therapy in carefully selected patients.

Advanced and Metastatic Disease

• Androgen-deprivation therapy (ADT) is the backbone of systemic treatment.
• Androgen receptor pathway inhibitors — abiraterone, enzalutamide, apalutamide, darolutamide — in hormone-sensitive and castration-resistant disease.
• Taxane chemotherapy (docetaxel, cabazitaxel) for metastatic disease.
• PARP inhibitors for tumours with DNA-repair defects such as BRCA2.
• Metastasis-directed therapy — stereotactic radiotherapy or surgery to a limited number of lesions — for oligometastatic disease identified on PSMA PET.
• ¹⁷⁷Lu-PSMA-617 radioligand therapy for PSMA-positive metastatic castration-resistant disease, the therapeutic arm of the theranostic pairing.

Radiopharmaceuticals for prostate cancer

PSMA Radiopharmaceuticals

The PSMA Molecule

• Prostate-specific membrane antigen is a type II transmembrane glycoprotein with enzymatic activity as glutamate carboxypeptidase II (also called folate hydrolase).
• The monomer has three parts: a short intracellular domain of 19 amino acids, a single transmembrane region, and a large extracellular domain of 707 amino acids that carries the catalytic site. The functional, enzymatically active form is a homodimer.
• 7E11 binds the intracellular N-terminal domain and therefore only labels cells with a disrupted membrane
• J591 binds the extracellular domain of intact, viable cells — the reason later imaging and therapeutic ligands are all directed at the external face.

Cellular Localisation and Malignant Change

• PSMA is expressed on the apical side of the duct epithelium and within the cytoplasm in benign prostatic tissue. It is not expressed on basal epithelial cells, neuroendocrine cells or stromal cells.
• With dysplastic and neoplastic transformation, PSMA expression is relocated from the apical to the luminal surface and is markedly upregulated, so that it becomes accessible to a circulating radioligand.
• This apical-to-luminal shift, together with the increase in expression with grade, is the cellular basis for the high tumour-to-background contrast of PSMA PET. It also explains a key exception: neuroendocrine and stromal cells do not express PSMA, so the neuroendocrine-dedifferentiated phenotype is PSMA-negative.

Where the Tracer Binds

PSMA radioligands are small molecules that bind the catalytic pocket of the extracellular domain, at or adjacent to the active site targeted by the PSMA-inhibitor class. This active site contains two zinc (Zn) ions, and the chemistry of binding is defined by how the ligand engages them. Three chemical classes have been developed:

• Phosphorus-based inhibitors (for example GPI-3, and phosphoramidate compounds) — bind the two zinc atoms at the outer part of the PSMA active site. Their practical limitation is that endogenous phosphate competes for the same site, reducing target binding.
• Urea-based inhibitors — built on a glutamate-urea-lysine or glutamate-urea-glutamate motif (the latter also known as DUPA, dicarboxy-peptidyl-ureido-pentanedioic acid). This is the dominant class in current clinical use, underlying ⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL and ¹⁸F-PSMA-1007. The urea group anchors the glutamate-sensing pocket with high affinity and is not displaced by physiological phosphate.
• Thiol-based inhibitors — a third class engaging the zinc site through a sulphur moiety.

The targeting molecule is joined to the radionuclide through a linker and a chelator or prosthetic group. For radiometals such as ⁶⁸Ga and ¹⁷⁷Lu, a chelator holds the metal: common chelators include DOTA, NOTA and HBED-CC (hydroxy-carboxy-ethyl-benzyl-ethylenediamine-diacetic acid). DOTA is versatile and, importantly, binds both ⁶⁸Ga (diagnostic) and ¹⁷⁷Lu (therapeutic), which is what makes a single ligand scaffold usable as a theranostic pair. For ¹⁸F-labelled ligands the fluorine is incorporated through a covalent prosthetic group rather than a metal chelator.

The unifying theme is the theranostic scaffold: a urea-based targeting molecule on a DOTA or DOTAGA chelator accepts a diagnostic radiometal (⁶⁸Ga) or a therapeutic one (¹⁷⁷Lu beta-emitter, ²²⁵Ac alpha-emitter) with essentially identical biodistribution, so that the imaging scan faithfully predicts where the therapy will deposit its dose.

¹⁸F-FDG

• FDG has a limited but specific role.
• Typical PSMA-expressing adenocarcinoma is frequently not FDG-avid, so FDG is insensitive for routine staging.
• It becomes valuable in dedifferentiated, aggressive and neuroendocrine disease, where PSMA expression is lost but glycolytic activity is high.
• In advanced castration-resistant disease, discordant imaging — FDG-positive but PSMA-negative lesions — identifies disease unsuitable for PSMA radioligand therapy and carries adverse prognostic weight.
• FDG and PSMA are therefore complementary at the aggressive end of the disease spectrum.

Role of PET/CT in the Diagnosis of Prostate Cancer

• Diagnosis of prostate cancer rests on prostate-specific antigen (PSA), multiparametric magnetic resonance imaging (mpMRI) and histological confirmation by biopsy.
• mpMRI, not PET, is the modality for intraprostatic localisation and local (T) staging.
• Benign prostatic hyperplasia and prostatitis can show increased uptake with both FDG and PSMA tracers, so an avid prostate on PET cannot be equated with cancer.
• Incidental Prostatic Uptake on PET/CT: Reported rates of focal incidental prostatic FDG uptake are of the order of 1–2% of male scans, and a substantial minority of investigated cases prove malignant. Focal incidental prostatic uptake in FDG PET/CT should be investigated with PSA, DRE and urological referral. Diffuse uptake, by contrast, is more often benign (hyperplasia or prostatitis).

Situations Where PET/CT Contributes to Diagnosis

• Guiding biopsy after a negative or equivocal work-up. In men with a persistently rising PSA and negative systematic or mpMRI-targeted biopsies, PSMA PET can identify an occult intraprostatic focus and direct repeat targeted biopsy.
• Equivocal lesion on mpMRI: PSMA PET/CT can increase confidence that the lesion represents clinically significant cancer.

Suspected aggressive or unusual cancer: Low PSMA uptake with high FDG uptake may indicate dedifferentiated or neuroendocrine prostate cancer and prompts targeted biopsy.

Role of PET/CT in Primary Staging

Which Patients Should Undergo Staging PET/CT

PSMA PET/CT is indicated for initial staging in high-risk group of prostate cancer

The yield of staging PSMA PET rises steeply with risk group, and this drives the guideline indications. A comprehensive 2024 meta-analysis found that PSMA PET was positive outside the prostate in 23% of patients overall, with a marked difference between high-risk (31%) and intermediate-risk (12%) subgroups. Detection of such occult disease is the principal reason to scan.

The evidence for PSMA PET in primary staging of high-risk disease is stronger than for almost any other application of PET in oncology, because it rests on a randomised trial with a histological and follow-up reference standard.

Diagnostic Accuracy: The proPSMA Randomised Trial

The strongest evidence comes from the proPSMA study, a prospective multicentre randomised trial of 300 men with high-risk prostate cancer scheduled for curative-intent surgery or radiotherapy, randomised to conventional imaging (CT and bone scan) or ⁶⁸Ga-PSMA-11 PET/CT, with a composite reference standard and crossover. The results established the superiority of PSMA PET across every metric:

The 27% absolute difference in accuracy (92% versus 65%), together with fewer equivocal findings and lower radiation exposure, led the investigators to conclude that PSMA PET/CT is a suitable replacement for conventional imaging in high-risk staging — a conclusion now reflected in international guidelines.

Local (T) Staging Accuracy

• For local staging against the radical prostatectomy specimen, PSMA PET is inferior to MRI.
• MRI still remains the standard for T staging.

Nodal (N) Staging Accuracy

• PSMA PET for nodal disease is characterised by high specificity but limited sensitivity.
• A meta-analysis of 51 studies (7,713 patients) reported sensitivity of 54%, specificity of 94% and high positive predictive value on a per-patient basis. PSMA PET reliably detects macroscopic nodal disease but misses micrometastatic deposits below approximately 3–5 mm.
• A positive node is reliable, but a negative pelvis does not exclude microscopic nodal disease, and PSMA PET therefore does not permit omission of pelvic lymph node dissection in high-risk patients where it is otherwise indicated.
• Its advantage over CT is the detection of disease in normal-sized nodes that fail size criteria, and of nodal disease outside the standard dissection template.

Interpretation and Pitfalls

Physiological Uptake

• Lacrimal and salivary glands, and the liver, spleen and small bowel — expected physiological PSMA expression.
• Kidneys and urinary tract — intense uptake and excretion with renally cleared tracers, potentially obscuring the prostatic bed.
• Coeliac and other ganglia — a classic mimic of retroperitoneal nodal disease, distinguished by their characteristic linear or teardrop configuration and location.

Benign and Non-Prostatic Uptake

• Benign bone lesions — fibrous dysplasia, healing fractures, Paget disease, and haemangiomas can show uptake; unexplained solitary rib uptake is a recognised pitfall, particularly with ¹⁸F-PSMA-1007.
• Ganglia and nerve structures, as above.
• Inflammatory and granulomatous disease — sarcoidosis, tuberculosis and reactive nodes.
• Other malignancies — PSMA is expressed in the neovasculature of many tumours (renal, thyroid, hepatocellular, glioma), so an avid lesion in an atypical site may not be prostatic.
• Degenerative and post-therapeutic change.

The PSMA-Negative Tumour

• The most important interpretive principle is that a proportion of prostate cancers do not express PSMA, either intrinsically or through dedifferentiation.
• A PSMA-negative scan in the presence of a rising PSA does not exclude disease, and should prompt consideration of FDG PET to identify a neuroendocrine or dedifferentiated phenotype.
• Conversely, PSMA uptake can transiently change with androgen-deprivation therapy, so timing relative to treatment must be known.

PET/CT in Response Assessment

Assessment of treatment response in prostate cancer is challenging because metastatic disease is frequently bone-predominant. Sclerotic bone lesions may remain visible or become more conspicuous despite successful therapy, while many nodal and skeletal deposits are not measurable using conventional RECIST 1.1 criteria. Serum PSA is useful but may not accurately reflect heterogeneous or dedifferentiated disease. PET/CT provides functional information regarding tumour viability and enables whole-body assessment of treatment response.

PSMA PET/CT is the most important molecular imaging modality for response assessment in advanced prostate cancer. Serial imaging can evaluate:

• disappearance or reduction of PSMA-avid lesions;
• changes in intensity of PSMA uptake;
• changes in whole-body PSMA-positive tumour volume;
• development of new lesions;
• response at individual metastatic sites;
• heterogeneous or mixed treatment response; and
• emergence of disease progression despite biochemical response.

Baseline PSMA PET/CT should ideally be performed before treatment initiation, and follow-up scans should use the same radiopharmaceutical, uptake interval, scanner and reconstruction protocol to permit reliable comparison.

Clinical applications

1. Response to systemic therapy

PSMA PET/CT can demonstrate response following androgen-deprivation therapy, androgen-receptor pathway inhibitors, chemotherapy and other systemic treatments. Reduction in lesion uptake and total PSMA-positive tumour volume generally indicates response, whereas increasing tumour burden or new lesions suggests progression.

However, hormonal manipulation may alter PSMA expression independently of changes in tumour-cell number. Early after ADT or androgen-receptor inhibition, increased PSMA expression may produce an apparent PSMA flare. Conversely, suppression of PSMA expression in hormone-sensitive disease may underestimate residual tumour burden. Therefore, very early changes in uptake should not be interpreted as progression or response without correlation with PSA, symptoms and anatomical imaging. Follow-up imaging at approximately 3 months after androgen-receptor pathway inhibitor initiation has shown greater reliability than very early assessment.

2. Response to PSMA radioligand therapy

PSMA PET/CT is particularly valuable in patients undergoing ¹⁷⁷Lu-PSMA radioligand therapy. It can quantify reduction in total tumour volume, identify responding and nonresponding lesions, detect early progression and assess whether sufficient PSMA-expressing disease remains for further treatment.

Response assessed on PSMA PET/CT at approximately 12 weeks has demonstrated prognostic value for progression-free and overall survival. Combining PSMA PET response with PSA response provides better prognostic stratification than either parameter alone.

Post-treatment ¹⁷⁷Lu-PSMA SPECT/CT may also provide information regarding tracer distribution and changes in tumour burden during successive cycles, although PSMA PET/CT remains more sensitive and quantitatively robust.

3. Response to local and metastasis-directed therapy

After surgery, radiotherapy or stereotactic body radiotherapy, PET/CT can determine whether the treated lesion has lost tracer uptake and can detect residual disease or progression elsewhere.

Nevertheless, inflammatory uptake and treatment-related tissue changes may occur after radiotherapy. Imaging should therefore be performed at an appropriate interval and correlated with CT, MRI and PSA kinetics.

Role of ¹⁸F-FDG PET/CT

FDG PET/CT has limited sensitivity in well-differentiated, androgen-sensitive prostate cancer but becomes more useful in aggressive, poorly differentiated, neuroendocrine or treatment-resistant disease. It can:

• evaluate dedifferentiated tumour;
• identify FDG-positive/PSMA-negative discordant lesions;
• provide prognostic information in metastatic castration-resistant disease.

Dual-tracer PSMA and FDG PET/CT is particularly useful before or during PSMA-targeted radioligand therapy because FDG-positive/PSMA-negative disease represents tumour heterogeneity and is generally associated with an unfavourable prognosis.

PET/CT in Biochemical Recurrence

Biochemical recurrence is defined as rising PSA level following definitive treatment for localised prostate cancer, in absence of radiographic evidence of disease on conventional imaging.

Approximately 20-40% of patients experience BCR within 10 years of primary treatment.

Biochemical recurrence criteria

• Following radical prostatectomy, BCR is defined as PSA level ≥ 0.2ng/ml or higher, which is confirmed by second measurement
• After definitive radiotherapy, BCR is defined as PSA rise ≥ 2ng/ml above post treatment nadir

Conventional CT and bone scintigraphy have limited sensitivity in patients with low PSA levels. In post-prostatectomy BCR, bone scintigraphy is positive in fewer than 5% of patients when PSA is <7 ng/mL, while CT detects recurrence in only approximately 11–14%. Molecular imaging, particularly PSMA PET/CT, can detect small-volume local, nodal and distant metastatic disease at substantially lower PSA levels.

PSMA PET/CT is currently the most sensitive whole-body imaging technique for localising recurrent prostate cancer. Commonly used tracers include ⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL and ¹⁸F-PSMA-1007.

The probability of detecting recurrent disease increases with the serum PSA level. In an influential early series, ⁶⁸Ga-PSMA-11 PET/CT detected recurrence in 58% of patients with PSA 0.2 to < 0.5 ng/mL, 73% at 0.5 to < 1.0, 93% at 1.0 to < 2.0, and 97% at ≥ 2.0 ng/mL. A systematic review by Perera and colleagues confirmed the same PSA-dependence, with positivity around 45–55% in the 0.2–1.0 ng/mL range rising above 90% beyond 2.0 ng/mL.

Detection is also influenced by PSA doubling time, pathological grade, disease stage, androgen-deprivation therapy and the interval from primary treatment.

Clinical applications

PSMA PET/CT helps determine whether recurrence is:

• confined to the prostate bed or residual prostate;
• limited to pelvic lymph nodes;
• present as oligometastatic disease; or
• disseminated to extrapelvic nodes, bones or visceral organs.

This distinction directly influences treatment selection. A localised recurrence may be treated with salvage radiotherapy or another local salvage procedure, whereas pelvic nodal disease may require expansion of radiotherapy fields and nodal dose escalation. Limited metastatic disease may be considered for stereotactic body radiotherapy or other metastasis-directed treatment, while extensive disease generally favours systemic therapy.

PSMA PET/CT changes intended management in approximately 40–76% of patients. In the prospective CONDOR trial, ¹⁸F-DCFPyL PET/CT changed intended management in 63.9%, while prospective studies using ⁶⁸Ga-PSMA-11 reported major management changes in approximately 53% of patients.

Role in salvage radiotherapy

Before salvage radiotherapy, PSMA PET/CT can:

• confirm disease confined to the prostate bed;
• identify pelvic nodes requiring inclusion in the treatment volume;
• detect lesions outside standard radiotherapy fields;
• guide focal dose escalation; and
• identify distant metastases that may make prostate-bed-only radiotherapy inadequate.

However, a negative PSMA PET/CT does not exclude microscopic recurrent disease, particularly at low PSA levels. Therefore, salvage prostate-bed radiotherapy should not be withheld or unnecessarily delayed solely because the PSMA PET/CT is negative.

Other PET tracers: When PSMA PET/CT is unavailable, ¹⁸F-fluciclovine or radiolabelled choline PET/CT may be considered, particularly when PSA is ≥1 ng/mL and imaging results would alter management. However, PSMA PET/CT is generally more sensitive at low PSA levels. In a prospective comparison involving patients with PSA <2 ng/mL, the patient-level detection rate was 56% with ⁶⁸Ga-PSMA-11 compared with 26% using ¹⁸F-fluciclovine. [22]

The European Association of Urology recommends PSMA PET/CT after radical prostatectomy when PSA is >0.2 ng/mL, provided the result will influence treatment decisions. After radiotherapy, PSMA PET/CT is strongly recommended in patients suitable for potentially curative salvage treatment. The AUA/ASTRO/SUO guideline permits PSMA PET in place of conventional imaging or following negative conventional imaging in patients with BCR.

To conclude, PSMA PET/CT is the imaging modality of choice for localising biochemical recurrence of prostate cancer. It provides high detection rates at relatively low PSA levels, accurately differentiates local, nodal and distant recurrence, modifies radiotherapy planning and frequently changes overall treatment strategy.

Theranostics: PSMA Radioligand Therapy

PSMA PET is a selection tool and response-assessment tool for therapy.

¹⁷⁷Lu-PSMA-617 and the VISION Trial

The pivotal VISION trial randomised 831 men with PSMA-positive metastatic castration-resistant prostate cancer, previously treated with an androgen receptor pathway inhibitor and taxane chemotherapy, to ¹⁷⁷Lu-PSMA-617 plus standard care or standard care alone. Radioligand therapy prolonged median overall survival from 11.3 to 15.3 months (HR 0.62, p < 0.001) and median radiographic progression-free survival from 3.4 to 8.7 months (HR 0.40, p < 0.001), with benefit across key secondary endpoints and without detriment to quality of life. Eligibility required a PSMA-positive scan, and 87% of screened patients qualified — establishing PSMA PET as the gatekeeper to therapy.

The TheraP trial (ANZUP) compared ¹⁷⁷Lu-PSMA-617 with cabazitaxel and found superior PSA response and lower toxicity, using dual PSMA and FDG PET for selection — requiring PSMA-avid disease and excluding patients with FDG-positive, PSMA-negative lesions. This dual-tracer selection embodies the principle that the target must be present on imaging for target-directed therapy to succeed.

Imaging-Based Patient Selection

• PSMA-positivity above a threshold uptake identifies disease likely to respond.
• FDG-positive, PSMA-negative disease identifies dedifferentiated clones unlikely to respond and carrying adverse prognosis — the rationale for dual-tracer screening.
• Whole-body PSMA SUVmean is quantitatively predictive of ¹⁷⁷Lu-PSMA-617 efficacy: in a VISION analysis, higher SUVmean correlated with better survival, each unit increase associated with a measurable reduction in the risk of progression and death.

Response Assessment After Radioligand Therapy

PSMA PET performed during and after treatment assesses response, and PSMA-based response frameworks such as PPP (PSMA PET Progression) criteria and adaptations of RECIST/PERCIST are used to distinguish response from progression. Interpretation is combined with PSA trajectory, and discordance between the two prompts consideration of dedifferentiation and a role for FDG imaging.

Prognostic Role of PET/CT

Quantitative PSMA PET parameters carry independent prognostic information across the disease spectrum. In the metastatic castration-resistant setting, whole-body PSMA tumour volume and SUVmean predict survival and response to radioligand therapy. In localised disease, PSMA PET-based local staging has been associated with biochemical recurrence-free survival after radical prostatectomy, adding prognostic value to MRI and pathological staging.

• PSMA-derived tumour volume — higher volume predicts poorer outcome across disease states.
• Whole-body SUVmean — higher mean uptake predicts better response to ¹⁷⁷Lu-PSMA-617, reflecting greater target availability.
• FDG-positive, PSMA-negative disease — an adverse prognostic pattern indicating dedifferentiation.
• Extent and site of disease — visceral and high-volume disease carry worse prognosis than oligometastatic nodal or bone disease.

Guideline Recommendations

Guideline positions on PSMA PET have converged rapidly since the proPSMA trial, and the direction of travel is consistently toward wider use. There is now broad international consensus that PSMA PET is a valuable staging tool in newly diagnosed high-risk disease and in biochemical recurrence, with residual differences chiefly concerning intermediate-risk disease and whether conventional imaging must precede it.

EAU

• PSMA PET/CT recommended for metastatic screening in high-risk disease, in preference to — or at least alongside — CT and bone scan.
• In biochemical recurrence, PSMA PET/CT recommended once PSA exceeds 0.2 ng/mL where the result will influence management.
• Strong recommendation to perform PSMA PET/CT in patients fit for curative salvage treatment.
• MRI used alongside PSMA PET to localise disease for salvage local therapy.

NCCN

• PSMA PET accepted for initial staging of unfavourable-intermediate, high and very-high-risk disease.
• Conventional imaging is not a required prerequisite; PSMA PET may serve as a front-line staging tool.
• PSMA PET endorsed for evaluation of biochemical recurrence after definitive local therapy.
• PSMA-positive imaging required to select patients for ¹⁷⁷Lu-PSMA-617.

AUA/SUO and ASCO

• Both ⁶⁸Ga-PSMA-11 and ¹⁸F-DCFPyL indicated for suspected metastasis before local therapy and for suspected recurrence with rising PSA.
• PSMA PET recommended preferentially where available in PSA recurrence after local therapy, given greater sensitivity.
• Somewhat more conservative than EAU and NCCN in requiring, in certain settings, that conventional imaging be negative or indeterminate first.

SNMMI and EANM Perspective

The nuclear medicine societies provide procedure standards and appropriate-use criteria delineating the situations in which PSMA PET is and is not indicated, and emphasise standardised acquisition, structured reporting with PSMA-RADS or miTNM, and quantification to support both staging and therapy selection. They also underpin the theranostic pathway with guidance on patient selection and dosimetry for ¹⁷⁷Lu-PSMA therapy.

Guideline Comparison

Standardised Reporting and Response Criteria

• Staging and reporting systems - (PROMISE V2/ miTNM and PSMA-RADS)
• Response-assessment systems - RECIP 1.0, PPP and the composite PSA + RECIP

PROMISE V2 (miTNM)

miTNM — the molecular imaging TNM classification — is the whole-body staging notation that sits at the heart of the PROMISE framework (Prostate Cancer Molecular Imaging Standardised Evaluation). It was proposed by Eiber and colleagues in 2018 as version 1.0 and substantially revised within PROMISE V2 (2023). Its purpose is to provide a single, standardised language for describing the extent of prostate cancer on PSMA-ligand PET/CT or PET/MRI, so that findings are communicated consistently between physicians and institutions and are reproducible in clinical trials. [18]

The prefix “mi” (molecular imaging) deliberately distinguishes it from the conventional clinicopathological TNM system. This distinction is important: the two systems answer different questions. Clinicopathological TNM records what is known from examination, conventional imaging and histopathology; miTNM records what is seen on PSMA-PET, a far more sensitive modality that detects disease invisible to conventional staging. A patient may therefore be, for example, cN0 on CT but miN1 on PSMA-PET.

miTNM organises findings into four elements: the local tumour (miT), regional nodes (miN), distant metastases (miM), and a superimposed miPSMA expression score capturing uptake intensity.

Local tumour - miT

The miT category describes the primary tumour within the prostate, or recurrent disease within the prostate bed after treatment. Notably, in keeping with the deliberate avoidance of a miT1 category, miT begins at miT0 (no local disease) and proceeds through organ-confined and locally advanced categories that parallel the clinicopathological T stage.

In PROMISE V2, assessment of the intraprostatic lesion was strengthened by integrating the PRIMARY score, a five-point scale combining the intraprostatic pattern and intensity of PSMA uptake. PRIMARY scores 1–2 are treated as negative and reported as miT0, while scores 3–5 are positive and assigned to miT2, miT3 or miT4 according to the presumed extent of disease.

Regional nodes - miN

The miN category describes pelvic (regional) lymph node involvement. It is deliberately confined to the pelvis; nodes above the pelvis are classed as distant disease (miM1a), not regional.

Some applications further distinguish the burden of nodal disease (for example single versus multiple pelvic nodes), and the number of findings per region is recorded.

Distant metastasis - miM

The miM category describes disease beyond the pelvis and is divided, in parallel with the clinicopathological system, into three principal subcategories.

miM1c liver disease is a red flag for dedifferentiation and short survival — consider FDG imaging.

mi-PSMA expression score

Superimposed on the anatomical miTNM categories is the miPSMA expression score, which grades the intensity of PSMA uptake against physiological reference organs. It is scored per lesion or region and, at a whole-body level, informs selection for ¹⁷⁷Lu-PSMA radioligand therapy, since higher expression predicts response.

The reference organ is tracer-dependent: the liver is used for most tracers, but for ¹⁸F-PSMA-1007, which has hepatobiliary excretion and high liver background, the spleen is used instead, with the right parotid gland as the agreed high-reference organ

Key changes in PROMISE V2

The PRIMARY Score

The PRIMARY score, derived from the prospective PRIMARY trial, grades the intraprostatic pattern and intensity of ⁶⁸Ga-PSMA uptake on a five-point scale to estimate the probability of clinically significant cancer, and is now folded into the miT assessment of PROMISE V2. It is a diagnostic / local tool rather than a response tool. [16,17]

In the PRIMARY trial, combining PSMA PET with mpMRI raised sensitivity for clinically significant cancer from 83% (MRI alone) to 97%, and negative predictive value from 72% to 91%, at some cost to specificity. Scores 1–2 are treated as negative and scores 3–5 as positive. [16]

PSMA-RADS

PSMA-RADS — the Prostate-Specific Membrane Antigen Reporting and Data System — is a structured framework for classifying individual lesions on PSMA-PET according to their likelihood of representing a site of prostate cancer. It is conceptually parallel to PI-RADS on MRI: it standardises reporting, improves inter-reader agreement, and translates each finding into a management implication. [19,24]

Each lesion is assigned to one of the following categories, reflecting the probability that it represents prostate cancer, together with the recommended action:

Overall reader score (ORS)

PSMA-RADS 2.0 emphasises an overall reader score (ORS) at the patient level, defined as the highest PSMA-RADS category of any single target lesion. This provides a single categorised result for the whole scan and is the basis on which detection rates are calculated in practice — categories 3–5 are treated as positive for malignancy and 1–2 as negative. [19]

One important exception applies: a lesion scored 3C (intense uptake at a highly atypical site) does not automatically set the overall score, because it most likely reflects non-prostatic disease. In a patient with multiple lesions, the highest score other than an isolated 3C determines the patient-level category. The framework thus offers both lesion-level and patient-level classification, with confidence and probability scores to support decision-making.

Version 1.0 vs Version 2.0

RECIP 1.0

Response Evaluation Criteria in PSMA PET/CT (RECIP 1.0, Gafita et al., 2022) is the principal response framework for metastatic castration-resistant prostate cancer. It combines the change in whole-body PSMA-positive tumour volume (PSMA-VOL) with the appearance of new lesions, with asymmetric thresholds: a 30% fall defines response, a 20% rise with new lesions defines progression. It can be applied quantitatively (software segmentation) or visually, with excellent agreement between the two. [20]

RECIP-PD is associated with significantly shorter overall survival and is the strongest single imaging predictor of outcome after ¹⁷⁷Lu-PSMA therapy.

PPP — PSMA PET Progression Criteria

The PSMA PET Progression (PPP) criteria (Fanti et al., 2020) define progression without requiring volumetric software, making them readily applicable in routine practice. Progression is met by any one of three conditions: [21]

PPP is suited to the biochemical-recurrence and routine clinical setting, whereas RECIP, being volume-based, is oriented to high-volume metastatic disease and trials. In comparative studies RECIP-PD best predicts overall survival while PPP is most consistently associated with PSA progression-free survival — the two are complementary.

Important discrepancy: A patient with a marked overall reduction in PSMA tumour volume but two new lesions would be classified as progressive disease by PPP. Under RECIP 1.0, the patient may be classified as stable disease, because partial response requires no new lesions, while progression requires both new lesions and a ≥20% increase in total tumour volume.

PSA + RECIP: Composite Response

Recognising that biochemistry and imaging each capture part of the picture, PROMISE V2 and the RECIP developers proposed a composite classification combining serum PSA response with imaging response:

This composite improves prognostic accuracy over PSA response alone. It also embodies the central principle of advanced-disease imaging: discordance — between PSA and PSMA, or between PSMA and FDG — is itself informative, flagging clonal heterogeneity or neuroendocrine dedifferentiation that any single measure would miss.

Pro-PET score

The Pro-PET score is a proposed dual-tracer PET/CT prognostic system combining PSMA PET/CT and ¹⁸F-FDG PET/CT in metastatic castration-resistant prostate cancer, particularly before PSMA radioligand therapy. The score is assigned according to the lesion showing the greatest FDG uptake relative to its PSMA uptake—the most discordant lesion. [23]

Prognostic interpretation: Lower scores indicate predominantly PSMA-expressing disease and a more favourable likelihood of response to PSMA-targeted radioligand therapy. Increasing scores indicate greater FDG dominance, tumour heterogeneity and dedifferentiation. Pro-PET 4–5, particularly FDG-positive/PSMA-negative disease, is associated with poorer treatment response and survival.

How the Frameworks Fit Together

Emerging Tracers and Applications

Next-Generation PSMA Ligands

• Radiohybrid PSMA ligands (rhPSMA) — designed for favourable biodistribution and low urinary activity, aiding pelvic assessment.
• Albumin-binding PSMA ligands — prolong tumour residence and increase delivered dose in the therapeutic setting.
• Bivalent and optimised ligands — seeking higher tumour uptake and faster clearance from salivary glands and kidneys.

FDG and Dual-Tracer Imaging

As the dedifferentiated and neuroendocrine phenotype gains clinical prominence with prolonged survival, the role of dual PSMA and FDG imaging is expanding — for selecting radioligand therapy, for identifying discordant disease, and for prognostication. This complementary use of the two tracers, rather than reliance on either alone, is likely to become standard in advanced disease.

Emerging PET Tracers and Theranostic Radionuclides in Prostate Cancer

Frequently Asked Questions

Q Is PSMA PET used to diagnose prostate cancer?

No. Diagnosis is by MRI-guided biopsy, and local staging is by multiparametric MRI. PSMA PET assesses nodal and distant disease and localises recurrence; it does not establish the diagnosis or replace MRI for local staging.

Q When is PSMA PET indicated for primary staging?

Principally in high and very-high-risk disease, where it detects extraprostatic disease in up to about a third of patients and changes management in roughly one in four. Its yield in low-risk disease is negligible, and its role in intermediate-risk disease is selective.

Q Why is PSMA PET better than CT and bone scan?

The proPSMA trial showed a 27% absolute accuracy advantage over conventional imaging, from both higher sensitivity and higher specificity, with fewer equivocal findings and lower radiation. PSMA PET detects disease in normal-sized nodes and in marrow before an osteoblastic reaction develops.

Q At what PSA level should PSMA PET be performed for recurrence?

Guidelines support imaging once PSA exceeds 0.2 ng/mL after prostatectomy, where the result will change management. Detection rates are meaningful even below 0.5 ng/mL and exceed 90% above 2 ng/mL, and imaging at low PSA enables curative-intent salvage.

Q What does a negative PSMA PET mean if the PSA is rising?

It does not exclude disease. The recurrence may be below the resolution of the scan at very low PSA, or the tumour may not express PSMA. A negative scan with a convincingly rising PSA should prompt short-interval repeat imaging or FDG PET to look for a dedifferentiated phenotype.

Q Why would a prostate cancer not show on PSMA PET?

Because a proportion of tumours, particularly dedifferentiated and neuroendocrine cancers, express little or no PSMA. These are often FDG-avid instead, which is why dual-tracer imaging is used in advanced disease.

Q What is the theranostic principle in prostate cancer?

The same PSMA target is used for both imaging and therapy. A diagnostic radionuclide on a PSMA ligand images the disease; a therapeutic radionuclide, ¹⁷⁷Lutetium, on the same ligand treats it. PSMA PET both selects patients for therapy and monitors their response.

Q How are patients selected for ¹⁷⁷Lu-PSMA therapy?

By demonstrating adequate PSMA expression on PET. In VISION a PSMA-positive scan was required, and in TheraP dual PSMA and FDG imaging excluded patients with FDG-positive, PSMA-negative disease. Whole-body PSMA SUVmean also predicts the degree of benefit.

Q What are the main pitfalls in reading a PSMA PET?

Coeliac and other ganglia mimicking nodes, benign bone uptake (especially solitary ribs with ¹⁸F-PSMA-1007), PSMA expression in non-prostatic tumours and inflammatory conditions, urinary activity obscuring the prostatic bed, and the effect of recent androgen-deprivation therapy on uptake.

Q Does FDG PET have any role in prostate cancer?

Yes, but a specific one. It is insensitive for typical PSMA-expressing adenocarcinoma and is reserved for dedifferentiated, aggressive and neuroendocrine disease, and for identifying PSMA-discordant lesions that will not respond to PSMA-directed therapy.

Selected References

1. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet 2020;395(10231):1208–1216. doi:10.1016/S0140-6736(20)30314-7

2. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer (VISION). New England Journal of Medicine 2021;385(12):1091–1103. doi:10.1056/NEJMoa2107322

3. Hofman MS, Emmett L, Sandhu S, et al. ¹⁷⁷Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet 2021;397(10276):797–804.

4. Perera M, Papa N, Roberts M, et al. Gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: updated diagnostic utility, sensitivity, specificity, and distribution of PSMA-avid lesions — a systematic review and meta-analysis. European Urology 2020;77(4):403–417.

5. 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. Journal of Nuclear Medicine 2015;56(5):668–674.

6. Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective comparison of ¹⁸F-fluoromethylcholine versus ⁶⁸Ga-PSMA PET/CT in prostate cancer patients with early biochemical recurrence. Journal of Nuclear Medicine 2015;56(8):1185–1190.

7. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic performance of ¹⁸F-DCFPyL-PET/CT in men with biochemically recurrent prostate cancer (CONDOR). Clinical Cancer Research 2021;27(13):3674–3682.

8. Sprute K, Kramer V, Koerber SA, et al. Diagnostic accuracy of ¹⁸F-PSMA-1007 PET/CT imaging for lymph node staging of prostate carcinoma in primary and biochemical recurrence. Journal of Nuclear Medicine 2021;62(2):208–213. doi:10.2967/jnumed.120.246363

9. Fendler WP, Calais J, Eiber M, et al. Assessment of ⁶⁸Ga-PSMA-11 PET accuracy in localizing recurrent prostate cancer: a prospective single-arm clinical trial. JAMA Oncology 2019;5(6):856–863.

10. Kuo PH, Benson T, Messmann R, et al. Quantitative ⁶⁸Ga-PSMA-11 PET and clinical outcomes in metastatic castration-resistant prostate cancer following ¹⁷⁷Lu-PSMA-617 (VISION trial). Radiology 2024. PMC11366674

11. Carll T, et al. Guideline of guidelines: PSMA PET in staging newly diagnosed intermediate-risk prostate cancer. BJU International 2025. doi:10.1111/bju.16872

12. Sweere V, Bruins Slot A, Hermsen R, et al. Prognostic value of PSMA PET/CT-based local staging in predicting biochemical recurrence after radical prostatectomy. European Journal of Nuclear Medicine and Molecular Imaging 2025. doi:10.1007/s00259-025-07455-0

13. Rowe SP, Pienta KJ, Gorin MA, et al. PSMA-RADS version 1.0: a step toward standardizing the interpretation and reporting of PSMA-targeted PET imaging studies. European Urology 2018;73(4):485–487.

14. Eiber M, Herrmann K, Calais J, et al. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE): proposed miTNM classification for the interpretation of PSMA-ligand PET/CT. Journal of Nuclear Medicine 2018;59(3):469–478.

15. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer, 2025 update. European Association of Urology.

16. Emmett L, Buteau J, Papa N, et al. The additive diagnostic value of prostate-specific membrane antigen positron emission tomography computed tomography to multiparametric magnetic resonance imaging triage in the diagnosis of prostate cancer (PRIMARY): a prospective multicentre study. European Urology 2021;80(6):682–689.

17. Emmett L, Papa N, Buteau J, et al. The PRIMARY score: using intraprostatic ⁶⁸Ga-PSMA PET/CT patterns to optimise prostate cancer diagnosis. Journal of Nuclear Medicine 2022;63(11):1644–1650. doi:10.2967/jnumed.121.263448

18. Seifert R, Emmett L, Rowe SP, et al. Second version of the Prostate Cancer Molecular Imaging Standardized Evaluation framework including response evaluation for clinical trials (PROMISE V2). European Urology 2023;83(5):405–412. doi:10.1016/j.eururo.2023.02.002

19. Werner RA, Hartrampf PE, Fendler WP, et al. Prostate-specific Membrane Antigen Reporting and Data System version 2.0. European Urology 2023;84(5):491–502. doi:10.1016/j.eururo.2023.06.008

20. Gafita A, Rauscher I, Weber M, et al. Novel framework for treatment response evaluation using PSMA PET/CT in patients with metastatic castration-resistant prostate cancer (RECIP 1.0): an international multicenter study. Journal of Nuclear Medicine 2022;63(11):1651–1658. doi:10.2967/jnumed.121.263072

21. Fanti S, Hadaschik B, Herrmann K. Proposal for systemic-therapy response-assessment criteria at the time of PSMA PET/CT imaging: the PSMA PET progression criteria. Journal of Nuclear Medicine 2020;61(5):678–682. doi:10.2967/jnumed.119.233817

22. Calais J, Ceci F, Eiber M, et al. ¹⁸F-fluciclovine PET-CT and ⁶⁸Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncology 2019;20(9):1286–1294. doi:10.1016/S1470-2045(19)30415-2

23. Adnan A, Basu S. Concept proposal for a six-tier integrated dual tracer PET-CT (⁶⁸Ga-PSMA and FDG) image scoring system (“Pro-PET” score) and examining its potential implications in metastatic castration-resistant prostate carcinoma theranostics and prognosis. Nuclear Medicine Communications 2021;42(5):566–574. doi:10.1097/MNM.0000000000001371

24. Rowe SP, Pienta KJ, Pomper MG, Gorin MA. Proposal for a structured reporting system for prostate-specific membrane antigen-targeted PET imaging: PSMA-RADS version 1.0. Journal of Nuclear Medicine 2018;59(3):479–485.