World Journal of Medical Innovations - New generation prostate cancer imaging (PET/SPECT): systematic review of di

UROLOGY, RADIOLOGY, ONCOLOGY

New generation prostate cancer imaging (PET/SPECT): systematic review of diagnostic and therapeutic roles

Mytsyk Yulian1,2,3,4, Dutka Ihor4, Matskevych Viktoriya5

WJMI 2025; 5(1):5-18

Published online: 2025.08.17

DOI: https://doi.org/10.5281/zenodo.16889723

Citation: Mytsyk, Y., Dutka, I., & Matskevych, V. (2025). New generation prostate cancer imaging (PET/SPECT): systematic review of diagnostic and therapeutic roles. World Journal of Medical Innovations, 5(1), 5–18. https://doi.org/10.5281/zenodo.16889723

Affilations

1Voxel Diagnostic Center, Gliwice, Poland

2Department of Radiology, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

3Department of Urology, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

4Medical center “Euroclinic”, Lviv, Ukraine

5Department of Radiology and Radiation Medicine, Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine

Corresponding author. Mytsyk Yulian, mytsyk.yulian@gmail.com

Abstract

Objectives: To systematically evaluate the role and clinical application of nuclear imaging in contemporary prostate cancer (PCa) management across all disease phases, including initial staging, detection of biochemical recurrence (BCR), assessment of oligometastatic disease, and guidance of theranostic treatment.

Material and methods: A systematic literature search was performed in MEDLINE, Web of Science, and Scopus for English-language human studies published from January 2013 to August 2025. Studies evaluating nuclear imaging techniques—including conventional modalities (bone scintigraphy, SPECT) and new-generation PET tracers (e.g. PSMA ligands, 18F-fluciclovine, choline)—were included. Outcomes analyzed included diagnostic performance, impact on management, and clinical utility across the disease spectrum. The review followed PRISMA guidelines and used structured methods based on a predefined protocol.

Results: A total of 6,854 records were identified (2,310 in MEDLINE, 2,478 in Web of Science, and 2,066 in Scopus), with 1,432 duplicates removed. After screening, 312 full-texts were reviewed, and 34 studies met inclusion criteria. PSMA PET/CT demonstrated superior diagnostic accuracy in high-risk staging and BCR settings compared to conventional imaging, with detection rates exceeding 85% in some studies and management changes reported in 30–75% of cases. In oligometastatic PCa, PET-guided metastasis-directed therapy prolonged progression-free survival. Nuclear imaging also enabled patient selection for radioligand therapy, notably 177Lu-PSMA-617, with demonstrated survival benefit in the VISION trial.

Conclusions: Nuclear imaging, especially PSMA-targeted PET, has revolutionized prostate cancer management by enhancing diagnostic precision and enabling personalized treatment. Integration into clinical practice is justified by strong evidence of improved staging, recurrence detection, therapeutic planning, and patient outcomes.

Introduction

Prostate cancer is one of the most prevalent malignancies among men worldwide, with significant morbidity and mortality especially in advanced stages [1]. Accurate imaging is critical across all phases of prostate cancer management, including initial staging, detection of disease recurrence, and guiding therapy for metastatic or recurrent disease. For decades, conventional nuclear imaging such as 99mTc bone scintigraphy (bone scan) and computed tomography (CT) have been standard for staging and monitoring. However, these modalities have important limitations in sensitivity and specificity, particularly for detecting small metastases and nodal disease. Novel nuclear medicine techniques have emerged in the last ten years that dramatically improve diagnostic performance. In particular, positron emission tomography (PET) using cancer-specific radiotracers has transformed prostate cancer imaging. Tracers targeting prostate cancer metabolism or cell-surface markers—such as radiolabeled choline, radiolabeled amino acid analogues, and the prostate-specific membrane antigen (PSMA)—enable visualization of disease with much higher accuracy than conventional imaging.

Research over the past decade has demonstrated that next-generation nuclear imaging can detect prostate cancer lesions at lower tumor burden, improve staging accuracy, and impact clinical decision-making. For example, a multicenter randomized trial in high-risk patients showed that PET/CT with a PSMA-targeted tracer had markedly greater sensitivity (around 85% vs 38%) for metastatic disease than traditional CT and bone scan, with a higher diagnostic specificity as well [2]. These advances have led to rapid adoption of PET imaging in practice and incorporation into clinical guidelines. Both “standard” tracers (like fluoride or choline for PET, or gamma-emitting bone agents) and new-generation tracers (such as 68Ga-PSMA-11 and 18F-PSMA derivatives) now play a role in prostate cancer care. Nuclear imaging is utilized in all phases of management, from initial staging of high-risk localized disease, through identification of sites of biochemical recurrence after local treatment, to selection of patients for targeted systemic therapies (theranostics) in advanced metastatic castration-resistant prostate cancer (mCRPC).

This systematic review provides a comprehensive overview of the role and applications of nuclear imaging in contemporary prostate cancer management. We follow the standard structure for medical systematic reviews, summarizing current evidence on diagnostic performance and clinical impact of nuclear imaging modalities. We include both established techniques and emerging imaging approaches over the past 10 years, focusing only on human studies in English. The findings will highlight how nuclear imaging is integrated into current practice and its contribution to improved patient outcomes.

Methods

Eligibility Criteria

We defined a review question using a broad PICO framework to capture all relevant studies on nuclear medicine imaging in prostate cancer. Population: men with prostate cancer at any disease phase (initial diagnosis, staging, biochemical recurrence, metastatic disease). Intervention: nuclear imaging modalities used in prostate cancer, including standard techniques (bone scintigraphy, SPECT) and newer PET imaging with various radiotracers (e.g. choline, fluciclovine, PSMA-targeted agents). Comparator: conventional reference standards or alternate imaging when applicable (for diagnostic accuracy studies) or prior management plan (for impact studies). Outcomes: diagnostic performance metrics (sensitivity, specificity, detection rates), management changes due to imaging, and patient outcomes (e.g. progression-free survival) when reported. We included original studies published in the last 10 years (January 2013 onward) that reported on the use of nuclear imaging in prostate cancer. Both prospective and retrospective human studies were eligible. We excluded case reports, small case series (<10 patients), non-English articles, preclinical/animal studies, and publications that were purely reviews, commentaries, or editorials without original data.

Information Sources and Search Strategy.

A systematic literature search was performed in three databases: MEDLINE (PubMed), Web of Science, and Scopus. The final search was conducted on August 1, 2025. We used search terms combining prostate cancer with imaging keywords and specific radiotracers. The search strategy included terms such as: “prostate cancer” AND (imaging OR scan OR PET OR scintigraphy OR bone scan) AND (PSMA OR choline OR fluciclovine OR acetate OR fluorodeoxyglucose OR radionuclide OR nuclear). We applied filters to restrict results to studies in humans, published in English, and from 2013 onward. Additional references were identified by hand-searching bibliographies of relevant articles and major conference abstracts in the field.

Selection Process.

All titles and abstracts retrieved were screened independently by two reviewers to identify potentially eligible studies. After initial screening, full-text articles were obtained for those studies meeting inclusion criteria or for which eligibility was uncertain. The two reviewers then independently assessed full-texts for final inclusion, with any disagreements resolved by discussion and consensus. A PRISMA flow diagram was used to document the study selection process.

Data Collection and Data Items.

For each included study, data were extracted on study design, sample size, patient population (disease setting and phase), imaging modality (type of scan and radiotracer), reference standard (if any), and key outcomes. For diagnostic accuracy studies, we recorded sensitivity, specificity, and positive/negative predictive values when available. For studies assessing management impact or therapeutic outcomes, we extracted the proportion of patients with management changes due to imaging and any relevant clinical outcome data (e.g. recurrence-free survival differences). We also noted any reported adverse events related to imaging. Data extraction was performed by one reviewer and verified by a second for accuracy.

Quality Assessment.

We assessed the methodological quality of included studies using appropriate tools. Diagnostic accuracy studies were evaluated with the QUADAS-2 criteria, examining risk of bias in patient selection, index test, reference standard, and flow/timing. For interventional studies or trials, we assessed risk of bias based on randomization (if applicable), blinding, and completeness of follow-up. We did not exclude studies on the basis of quality, but findings are interpreted with consideration of each study’s limitations.

Synthesis of Results.

Given the heterogeneity of study designs and outcomes, a quantitative meta-analysis was not performed. We conducted a qualitative synthesis of the evidence. Results are organized by clinical context: initial staging of high-risk prostate cancer, detection of recurrent disease after local therapy (biochemical recurrence), imaging in oligometastatic disease management, and imaging in advanced metastatic disease including theranostic applications. Within each section, findings of individual studies are summarized and compared. We highlight how nuclear imaging modalities influence diagnostic accuracy and patient management in each scenario.

This systematic review is reported in accordance with PRISMA guidelines. The review protocol was not registered in PROSPERO.

Study Selection.

Our search strategy identified a total of 6,854 records (2,310 in MEDLINE, 2,478 in Web of Science, and 2,066 in Scopus). After removal of 1,432 duplicates, 5,422 unique records remained for screening. We screened titles and abstracts of these records, of which 312 were considered potentially relevant and retrieved for full-text evaluation. After full-text review, 34 articles met all inclusion criteria and were included in the qualitative synthesis. These studies span a range of designs including prospective trials, retrospective analyses, and systematic reviews. The selection process is summarized in the PRISMA flow diagram (Figure 1). The 34 included studies were published between 2014 and 2024, reflecting the recent surge in advanced imaging research.

Study Characteristics.

In aggregate, the studies encompassed over 7,000 prostate cancer patients across different disease states. Twelve studies evaluated imaging in the initial staging of high-risk or newly diagnosed prostate cancer. Fifteen studies focused on imaging for biochemical recurrence (BCR) after surgery or radiotherapy, including diagnostic accuracy and impact on salvage therapy planning. Four studies addressed imaging-guided management of oligometastatic recurrent disease (limited metastases), and three studies examined imaging in advanced metastatic castration-resistant prostate cancer (mCRPC), particularly for selecting or monitoring systemic radioligand therapy. The majority of included papers (n ≈ 20) were prospective studies or trials, while others were retrospective cohort studies or systematic reviews/meta-analyses synthesizing smaller studies. Most studies evaluated PET/CT using specific radiotracers, whereas a few addressed planar bone scintigraphy or SPECT/CT and compared them to newer modalities. The radiotracers studied included: radiolabeled PSMA ligands (the most common, evaluated in ~20 studies), radiolabeled choline (C-11 or F-18; ~5 studies), 18F-fluciclovine (AXUMIN™; several studies, including trials), and traditional 18F-FDG (few studies, usually in advanced disease context). Some emerging tracers like 68Ga-RM2 (gastrin-releasing peptide receptor antagonist) were represented in single-center investigations.

Results.

Initial Staging of High-Risk Prostate Cancer.

For men with high-risk localized prostate cancer (typically defined by PSA >20, high Gleason score, or advanced T-stage), accurate initial staging is crucial to detect occult metastatic disease (especially in bone or lymph nodes) before curative treatment. Conventional staging with CT and bone scintigraphy has relatively poor sensitivity for small metastases. Several studies in the past decade demonstrate that PSMA PET/CT provides far superior staging accuracy in this setting. The landmark proPSMA randomized trial by Hofman et al. compared 68Ga-PSMA-11 PET/CT against conventional imaging (CT plus bone scan) in 302 high-risk patients prior to surgery or radiotherapy [2]. PSMA PET/CT detected a significantly higher number of metastatic lesions and had an 85% sensitivity for pelvic nodal or distant metastases, compared to only 38% sensitivity with CT and bone scan [2]. The specificity of PSMA PET was also higher (98% vs 91%), and importantly, PSMA imaging led to changes in clinical management in 28% of patients [2]. This high-level evidence established PSMA PET as a more accurate staging modality in high-risk disease.

Subsequent prospective studies reinforced these findings. In the multicenter OSPREY trial, 18F-DCFPyL (a PSMA-targeted PET tracer) was evaluated against histopathology in high-risk patients undergoing initial radical prostatectomy with lymph node dissection [3]. The specificity of PSMA PET for detecting pelvic lymph node metastasis was excellent (~98%), while sensitivity was modest (~40% for nodes <5 mm, improving to 60% for larger nodes) [3]. Although some microscopic nodal metastases evade PET detection, the high specificity means that a PSMA PET-positive node is almost certainly true disease. Another trial by Hope et al. focused on Ga-68-PSMA-11 PET for preoperative nodal staging, and reported sensitivity around 64–66% and specificity ~95–98% for nodal metastases, using surgical pathology as gold standard [4]. These results indicate that PSMA PET, while not 100% sensitive for the smallest metastases, greatly outperforms conventional imaging and approaches the accuracy of surgical lymph node dissection for detecting clinically significant nodal spread.

In terms of distant metastases (bone or visceral), PSMA PET/CT has shown near-perfect specificity and very high sensitivity in initial staging. A comprehensive meta-analysis by Zhou et al. compared various imaging modalities for bone metastasis detection in prostate cancer [5]. On a per-patient basis, PSMA PET had the highest pooled sensitivity (97%) and specificity (100%) for bone metastases, outperforming whole-body MRI (91% sensitivity) and traditional bone scan (86% sensitivity) [5]. This aligns with clinical observations that PSMA PET can reveal small skeletal lesions that bone scans (which rely on osteoblastic activity) might miss, while avoiding many false positives from degenerative changes that can plague bone scans. Taken together, the evidence strongly supports that new-generation PET imaging, especially with PSMA-targeted radiotracers, is a more effective tool for initial staging in high-risk prostate cancer. As a result, many centers have adopted PSMA PET in lieu of CT and bone scan for staging high-risk patients, and guidelines now include PSMA PET/CT as a recommended option for this group. It is important to note that a negative PSMA PET does not absolutely rule out microscopic metastases, so clinical judgement (and in some cases surgical nodal sampling) remains relevant [2][4]. Nonetheless, the ability of PSMA PET to accurately upstage disease has important therapeutic implications—for example, identifying patients who would benefit from systemic therapy or avoidance of futile local treatment.

A distinct but related application in initial management is the detection of intraprostatic tumor extent for guiding biopsy or focal therapy. Multi-parametric MRI is standard for local prostate imaging, but recent studies have explored adding PSMA PET to MRI for primary tumor detection. The prospective PRIMARY trial (Emmett et al.) found that combining PSMA PET with MRI increased sensitivity for clinically significant prostate tumors from 83% (MRI alone) to 97% (combined), at the cost of some specificity [5]. In that study, a limited-field PSMA PET added incremental value especially in MRI-equivocal cases, and could potentially reduce unnecessary biopsies [5]. While MRI remains first-line for local tumor visualization, PSMA PET/MRI hybrid imaging or sequential imaging is an emerging strategy that may further refine initial diagnostic accuracy.

Detection of Biochemical Recurrence (Post-Treatment).

One of the most significant impacts of modern nuclear imaging has been in the evaluation of biochemical recurrence (BCR) of prostate cancer. BCR refers to a rising PSA after definitive treatment (radical prostatectomy or radiotherapy) when no disease is visible on conventional imaging. Historically, locating the source of recurrent PSA rise was challenging; bone scans and CT often fail to detect lesions at low PSA levels, and salvage therapies (like targeted radiation or surgery) were guided mostly by clinical assumptions. PET imaging now provides a means to localize recurrence at PSA levels as low as 0.2–0.5 ng/mL in many cases. This has enabled more personalized salvage treatment and, in some patients, potentially curative intervention for oligorecurrence.

Choline PET was one of the first tracers used widely for BCR detection. Studies around 2010–2015 indicated that 11C- or 18F-choline PET/CT could detect recurrent disease in roughly 30–40% of patients with PSA <1 ng/mL and in >70% of those with PSA >2 ng/mL, outperforming conventional imaging. However, the new PSMA-targeted PET tracers have substantially higher performance. A head-to-head comparison in 2014 by Afshar-Oromieh et al. showed that 68Ga-PSMA-11 PET/CT identified more metastatic lesions than 18F-fluorocholine PET in the same cohort of recurrent prostate cancer patients, particularly at low PSA levels [6]. Subsequent meta-analyses directly comparing choline versus PSMA PET confirmed superior sensitivity of PSMA PET for BCR. For instance, a meta-analysis by Treglia et al. found that the detection rate of PSMA PET/CT was significantly higher than that of choline PET/CT in the restaging setting (pooled detection 79% vs 62%) [7]. The advantage of PSMA PET is most pronounced when PSA is low (<1 ng/mL), where choline PET often fails. PSMA PET can detect recurrence in approximately 40–50% of patients with PSA in the 0.2–0.5 range, which was nearly unachievable with previous techniques [7][8]. This remarkable sensitivity is clinically important – it means that PSMA PET can trigger earlier localization of recurrence and guide early salvage therapy, which is associated with better outcomes.

Another tracer approved for biochemical recurrence is 18F-fluciclovine (an amino acid analog). Fluciclovine PET/CT was widely adopted in the United States after FDA approval in 2016 for men with rising PSA post-prostatectomy or radiotherapy. Fluciclovine has moderate sensitivity, particularly in the range of PSA >1 ng/mL. In men with low PSA (<0.5), its detection rates are relatively modest (~30–40%) but improve as PSA increases. Several prospective trials have evaluated fluciclovine PET’s impact. The LOCATE trial (2019) enrolled 213 men with biochemical recurrence after initial treatment and negative or equivocal conventional imaging [12]. 18F-fluciclovine PET detected at least one site of recurrence in 57% of these patients, and importantly led to a change in clinical management in 59% (with changes considered “major” in 78% of those) [12]. Common management changes included altering radiation plans or switching between salvage local therapy and systemic therapy based on the PET findings [12]. Similarly, the FALCON trial in the UK reported fluciclovine PET positivity in about 63% of BCR cases, resulting in management modifications in approximately 64% [13]. These studies underscore that advanced PET imaging frequently changes the salvage treatment approach – for example, detecting oligometastatic spread that might prompt targeted radiation instead of blind local therapy, or conversely confirming disease confined to the prostate bed to justify localized salvage radiation.

Notwithstanding its utility, fluciclovine PET has generally been shown to be less sensitive than PSMA PET. A direct comparative trial by Calais et al. demonstrated that 68Ga-PSMA-11 PET/CT identified recurrent lesions in significantly more patients than fluciclovine PET/CT did in the same population [11].

In that single-center study of men with early biochemical recurrence (median PSA ~0.5 ng/mL), PSMA PET had a detection rate of 67% versus 37% for fluciclovine PET [11]. Likewise, a systematic review and meta-analysis by Tan et al. pooled data from multiple studies and found that PSMA PET/CT was markedly superior to fluciclovine PET in BCR detection, especially at lower PSA levels (for PSA <0.5 ng/mL, pooled detection ~45% with PSMA vs ~35% with fluciclovine) [8]. Given these findings, PSMA PET is increasingly considered the new gold standard for imaging biochemical recurrence where available, although fluciclovine remains a valuable option in regions where PSMA PET is not yet accessible.

The improved diagnostic reach of PET imaging in recurrence directly influences patient management. Several studies illustrate this point beyond the LOCATE/FALCON trials mentioned. In a German study by Morawitz et al., men with biochemical recurrence after prostatectomy underwent PSMA PET/CT vs conventional CT imaging [14]. PSMA PET detected recurrence in a majority of patients even when CT was negative, and as a result, therapeutic plans were changed in a significant proportion (for example, directing metastasis-targeted therapy or expanding radiation fields based on PSMA findings) [14]. Overall, across studies, PSMA PET has been reported to lead to management changes in approximately 30–75% of patients with BCR [2][12][14]. Changes include tailoring of salvage radiotherapy volumes (e.g. inclusion of PET-positive nodes), avoidance of futile local salvage if distant metastases are seen, or initiation of systemic therapy when widespread disease is identified. As an example, Calais et al. (2018) noted that 68Ga-PSMA PET results altered the treatment approach in about half of patients compared to pre-PET plans [38].

In summary, for biochemical recurrence after primary treatment, modern nuclear imaging provides a means to accurately localize disease at PSA rises that were previously un-localizable. Both PSMA PET and fluciclovine PET improve detection compared to conventional imaging, with PSMA PET offering the highest yield. This has enabled more personalized salvage treatments. It should be noted that even the most sensitive PET scans have detection limits; extremely small or micro-metastatic disease may remain occult. Nonetheless, by shifting the detection threshold downward, PET imaging increases the opportunity for potentially curative interventions and better patient stratification.

Figure 1. PSMA PET/CT scan demonstrating multiple metastatic lesions in common and external iliac lymph nodes in a patient with recurrent prostate cancer

Oligometastatic Disease and Metastasis-Directed Therapy.

The term “oligometastatic” prostate cancer generally refers to an intermediate state with a limited number of metastatic lesions (often defined as 3 or fewer), usually identified after primary therapy failure. The advent of sensitive imaging, especially PSMA PET, has led to more frequent identification of patients with only a few metastases. This, in turn, has spurred interest in metastasis-directed therapy (MDT)—such as stereotactic body radiotherapy (SBRT) or surgical removal of metastases—to potentially improve outcomes in these patients. Nuclear imaging is integral in this context to accurately confirm the extent of metastatic spread. Two key prospective trials provide evidence on MDT in oligometastatic recurrence, both relying on advanced imaging to select patients.

The STOMP trial (Ost et al. 2018) was a randomized Phase II study that enrolled men with biochemical recurrence after local therapy who had up to 3 metastatic lesions detected on 11C-choline PET/CT [15]. Patients were randomized to either surveillance or MDT to all detected lesions (mostly SBRT). After a median follow-up, those who received MDT had a significantly prolonged androgen-deprivation therapy (ADT)-free survival (median 21 months vs 13 months for surveillance) [15]. This trial demonstrated a clinical benefit to treating limited metastatic disease, delaying the need for systemic hormonal therapy. It also underscored the importance of imaging—patients were included only if choline PET showed ≤3 metastases. It is likely some patients had additional unseen lesions (given choline PET’s limits), but nonetheless the concept was validated.

The ORIOLE trial (Phillips et al. 2020) further investigated MDT, but with PSMA PET/CT for patient selection [14]. ORIOLE randomized men with recurrent oligometastatic prostate cancer (defined as 1–3 metastases) to observation vs SBRT to all PET-detected lesions. In this study, imaging was done with 18F-DCFPyL PSMA PET in the SBRT arm (though blinded for the observation arm). ORIOLE found that progression at 6 months occurred in only 19% of men who received MDT, compared to 61% in the observation group [14]. This was a significant improvement in progression-free survival with MDT. Notably, on post-hoc analysis, patients in the MDT arm who had all PSMA-PET-positive lesions successfully treated had better outcomes than those in whom PET showed additional unseen metastases outside the treated field [14]. This emphasizes that the thoroughness of imaging (and treatment of all PET-visible disease) correlates with efficacy of MDT. In ORIOLE, PSMA PET identified occult lesions in some patients that were not initially detected by conventional imaging; untreated lesions were the harbinger of earlier recurrence. Thus, PSMA PET is extremely valuable to define the true extent of “oligometastatic” disease—some patients presumed oligometastatic on conventional scans are found to have more extensive metastases on PSMA PET and would be triaged to systemic therapy instead of futile local MDT.

Imaging is also being applied in the context of metastatic hormone-sensitive disease with low volume (often discovered by PSMA PET). For example, subgroup analyses from the STAMPEDE trial suggested a survival benefit to treating the prostate primary tumor in men who had few metastases (defined as <4 bone lesions and no visceral mets) [35]. This finding, made in an era prior to routine PSMA imaging, has led to ongoing trials of aggressive treatment of the primary and metastases in oligometastatic settings (e.g. the TRoMbone and IP2-ATLANTA trials). As PSMA PET becomes commonplace, it may better identify candidates for such approaches. It should be noted that while evidence is still evolving, these studies collectively indicate that when advanced imaging finds only limited metastases, focal therapies can be beneficial. Nuclear imaging enables a more confident identification of truly oligometastatic patients and helps guide ablative treatments to those lesions. At the same time, if PET reveals extensive disease, patients can be spared localized treatments and moved directly to systemic therapy. This paradigm of imaging-guided stratification is a growing theme in prostate cancer management.

Advanced Metastatic Disease and Theranostics

In advanced metastatic prostate cancer, particularly castration-resistant prostate cancer (CRPC), nuclear imaging plays a dual diagnostic and therapeutic role. Fluorodeoxyglucose (FDG) PET/CT has a limited routine role in typical prostate adenocarcinoma due to low glucose uptake in many tumors; however, in advanced disease with neuroendocrine differentiation or very aggressive phenotype, FDG PET can identify lesions that may not be PSMA-avid. Studies have shown that a subset of mCRPC lesions are FDG-positive and PSMA-negative, and these patients tend to have poorer prognosis [40]. Thus, in advanced CRPC, FDG PET is sometimes used in conjunction with PSMA PET to comprehensively assess disease biology – PSMA PET for the bulk of adenocarcinoma lesions and FDG PET for dedifferentiated components [40]. This complementary use is especially relevant when evaluating eligibility for PSMA-targeted radionuclide therapy, as discussed below.

Theranostics, the combination of diagnostic imaging and therapy using the same molecular target, has become a reality in prostate cancer through the PSMA pathway. After the success of PSMA PET in imaging, the logical extension was to use PSMA ligands labeled with therapeutic radionuclides to treat metastatic disease. 177Lu-PSMA-617 is a beta-emitting radioligand that delivers targeted radiation to PSMA-expressing tumor cells. Nuclear imaging is vital here: patients are selected for 177Lu-PSMA therapy based on demonstrating sufficient PSMA expression on a diagnostic PET scan (typically 68Ga-PSMA-11 or similar). Two pivotal trials have cemented this theranostic approach. The TheraP trial (Australia, 2021) compared 177Lu-PSMA-617 therapy to chemotherapy (cabazitaxel) in mCRPC patients who had progressed after androgen receptor targeted therapy [19]. All patients underwent PSMA PET and FDG PET for selection – those with high PSMA uptake and no FDG-dominant disease were treated. TheraP showed a higher PSA response rate with 177Lu-PSMA (66% vs 37% had ≥50% PSA decline) and less toxicity than chemotherapy [19].

Most importantly, the phase III VISION trial (FDA registration trial) demonstrated improved survival with 177Lu-PSMA-617 in mCRPC. In VISION, over 800 patients with PSMA PET-positive mCRPC were randomized to receive 177Lu-PSMA-617 plus standard care vs standard care alone[16]. Radiographic progression-free survival and overall survival were both significantly prolonged in the 177Lu-PSMA group [16]. This led to regulatory approval of 177Lu-PSMA-617 (Pluvicto™), establishing a new treatment for advanced prostate cancer. It is noteworthy that approximately 87% of screened patients in VISION were PSMA PET-positive and eligible; the remainder had insufficient PSMA expression and were not offered the therapy [16]. This underscores how nuclear imaging (PSMA PET) is now an essential biomarker to select appropriate candidates for radioligand therapy. Imaging also continues to be used during therapy to monitor response (PSMA PET SUV changes, though still investigational) and to ensure critical organs are not at risk (e.g. verifying no unexpected uptake in end organs).

Beyond PSMA, other radionuclide therapies and their imaging companions exist. Radium-223 (223Ra) dichloride is a bone-seeking alpha emitter used for bone metastases in mCRPC. While its use is based on the presence of bone metastases typically confirmed by bone scan, newer PET agents like 18F-NaF (sodium fluoride) PET can more sensitively quantify bone tumor burden. In clinical practice, bone scan remains the workhorse for assessing response to 223Ra therapy, but NaF PET is sometimes employed in trials and has higher sensitivity for bone lesions than planar scans [5]. Moreover, novel targets like fibroblast activation protein (FAP) in the tumor stroma are being explored: FAP inhibitor (FAPI) PET tracers have shown uptake in prostate cancer lesions including bone mets, and could serve both imaging and potential therapy roles in the future (though as of 2025, these remain investigational).

Finally, it is worth mentioning that the improved accuracy of nuclear imaging is influencing advanced disease management beyond therapy selection. For example, detecting progression sites earlier on PSMA PET can guide timely switches in systemic therapy. There is also interest in using PSMA PET as an efficacy endpoint in trials (e.g. molecular response evaluation) and in artificial intelligence applications to prognosticate outcomes based on whole-body tumor quantification. All these rely on the imaging advances achieved in recent years.

Discussion.

This systematic review highlights the transformative impact of nuclear imaging advancements on prostate cancer management over the past decade. We synthesized evidence from 34 studies encompassing initial staging, recurrent disease localization, oligometastatic therapy, and theranostic applications. Overall, the literature consistently shows that PET imaging with specific tracers (notably PSMA-targeted radiotracers) outperforms conventional imaging in sensitivity and specificity across all stages of disease. The ability to accurately detect nodal and distant metastases at much lower tumor volumes has improved staging and restaging, which in turn allows more appropriately tailored treatments. Nuclear imaging has directly led to changes in management in a large proportion of patients in multiple studies (ranging from about 30% to over 60%, depending on the scenario) [2][12]. Furthermore, there is emerging evidence from randomized trials that these imaging-driven changes can translate into improved patient outcomes, such as prolonged progression-free survival when oligometastatic lesions are ablated [14][15] or prolonged overall survival when radioligand therapy is applied in advanced disease [16].

Initial Staging Implications: For high-risk patients at diagnosis, the paradigm is shifting away from blind systemic therapy or extensive lymph node dissection for all, towards a more nuanced approach guided by PET findings. If PSMA PET/CT is negative for extraprostatic disease, patients can proceed with local curative therapy with more confidence; if PET reveals occult metastases, plans can change to include systemic therapy or broader radiation fields. One interesting debate is whether an extended pelvic lymph node dissection (ePLND) is needed if PSMA PET is negative in high-risk cases. Some studies have found that ePLND can still uncover microscopic metastases missed by PET (hence PET cannot yet completely replace pathological staging) [4]. However, other analyses suggest that a negative PSMA PET in the context of other low-risk features might safely omit ePLND in selected patients [4]. Ongoing trials are addressing this question. In any case, the improved nodal staging with PSMA PET helps refine risk stratification. Another point is cost-effectiveness: performing a single PSMA PET for staging might be more cost-effective than doing both CT and bone scan (and then follow-up procedures for equivocal findings). Economic analyses in various health systems are underway to confirm this.

Biochemical Recurrence and Salvage Therapy: Perhaps the area of greatest clinical uptake for new imaging is biochemical recurrence. Conventional imaging often fails to locate recurrence until PSA is quite high, at which point disease may be widespread. Early localization with PET allows for personalized salvage therapy—for example, directing radiation to a PET-positive pelvic nodal relapse rather than treating the whole pelvis empirically, or deciding on systemic therapy if PET shows distant spread beyond a local region. The clinical benefit of this personalized approach is strongly supported by non-randomized data (management changes and some improved biochemical control) [12][13], and a randomized trial (EMPIRE-1) provides level I evidence that PET-guided salvage radiotherapy is superior to standard imaging guidance [29]. In EMPIRE-1, patients whose post-prostatectomy salvage radiotherapy was planned with the help of 18F-fluciclovine PET had significantly higher progression-free survival at 3 years than those planned with conventional imaging alone [29]. This result validates that modern imaging can improve patient outcomes by optimizing treatment targeting and patient selection. It is likely that trials with PSMA PET guidance (e.g. the ongoing EMPIRE-2 using PSMA vs fluciclovine) will show even greater benefit, given PSMA’s higher lesion detection.

One challenge in BCR imaging is how to manage patients with very low PSA (<0.2 ng/mL) who cannot yet be imaged reliably. There is interest in ultrasensitive detection—some studies are exploring whether PSMA PET could be positive even before PSA rises, for instance in patients with adverse pathology but undetectable PSA; initial reports show limited yield in that context. Therefore, PSA remains the trigger for imaging, and most guidelines recommend waiting for PSA to reach a certain threshold (commonly 0.2–0.5 ng/mL after prostatectomy) before doing a PSMA PET, to maximize the chance of a true positive result.

Oligometastatic Disease: The concept of oligometastatic prostate cancer was largely theoretical until imaging advances allowed us to actually identify low-volume metastatic states. Now, with PSMA PET, it is not uncommon to find a patient with a rising PSA who has, say, a single tiny lymph node or one bone lesion. This has led to an expansion of focal therapies in the recurrent setting—metastasis-directed SBRT, nodal salvage surgery, etc. The STOMP and ORIOLE trials offer proof that if you treat what you see, patients benefit in the intermediate term by delaying systemic therapy [14][15]. Notably, ORIOLE also taught us that what you don’t see (i.e., occult disease) can limit the benefit of MDT; this underscores the value of the most sensitive imaging available (PSMA) in selecting patients. Moving forward, the integration of advanced imaging with novel systemic treatments (e.g., second-generation hormonal agents) for oligometastatic disease is an area of active research. For instance, trials are examining if combining MDT with systemic therapy in PET-staged oligometastatic patients yields additive benefit.

Advanced Disease and Therapeutic Monitoring: In metastatic CRPC, the use of nuclear imaging goes beyond diagnosis to therapy guidance. One important application is patient selection for PSMA radioligand therapy (RLT). Both the TheraP and VISION studies required confirmation of PSMA expression via PET imaging before administering 177Lu-PSMA [16][19]. Patients with “PSMA-negative” disease (often neuroendocrine-transformed lesions) were excluded because they are unlikely to respond. Some centers perform dual-tracer imaging (PSMA and FDG PET) to more thoroughly characterize advanced disease; those with mismatched FDG-positive, PSMA-negative lesions might be directed to alternate treatments (such as platinum chemotherapy for neuroendocrine differentiation) instead of RLT [40]. This exemplifies precision medicine: using imaging phenotypes to triage therapy. Additionally, after a course of 177Lu-PSMA, doing a follow-up PSMA PET can help assess treatment response (e.g., decrease in SUV or disappearance of lesions) and potentially prognosticate survival, although standardized criteria for molecular response are still being developed.

Safety and Radiation Considerations: All nuclear imaging involves radiation exposure, but the doses from diagnostic PET tracers are generally modest and comparable to or lower than a CT scan. The newer PET tracers do not appear to carry significant safety issues; for example, PSMA PET tracers have low toxicity (some mild transient dry mouth with certain compounds, due to salivary gland uptake). The therapeutic isotopes like 177Lu have more substantial side effects (e.g., dry mouth, bone marrow suppression), but these are managed clinically and were acceptable in trials [16]. From a patient perspective, the introduction of these scans means additional visits and sometimes out-of-pocket costs (depending on healthcare systems), but most would argue the benefit outweighs these factors when imaging results can markedly change management.

Guideline Recommendations: Reflecting the evidence, professional guidelines have rapidly evolved. The European Association of Urology (EAU) 2023 guidelines endorse PSMA PET/CT as a new standard for staging high-risk patients and for imaging biochemical recurrence, where available. They note that PSMA PET can detect disease not seen on conventional imaging and can guide salvage therapy decisions[24][25]. The EANM/SNMMI also released procedure standards for PSMA PET to ensure quality and consistency in its use[33]. In the United States, NCCN guidelines were updated to prefer PSMA PET over conventional scans for most indications in prostate cancer after the FDA approvals of PSMA PET agents. One point of caution in guidelines: they advise that management decisions should be made judiciously, as the impact on long-term outcomes, though logical, still needs more validation in some scenarios. An example is the EAU recommendation that patients with PSMA-only metastases (M1 detected by PET but M0 on conventional imaging) should not automatically be escalated to systemic therapy outside of a trial, because the survival benefit of acting on PET-detected micrometastases remains under investigation [35]. Such recommendations are likely to be refined as more outcome data (like the EMPIRE and other trials) emerge.

Limitations and Future Directions: Our review is qualitative and relies on the available studies, which have some limitations. Many included studies are single-arm or retrospective, and thus prone to selection biases. There is heterogeneity in patient populations and imaging protocols. However, the consistency of findings across different contexts strengthens the conclusions. Future research directions include: head-to-head comparisons of different new tracers (e.g., 18F-PSMA-1007 vs 68Ga-PSMA-11, or PSMA PET vs whole-body MRI), the role of imaging in active surveillance (can PSMA PET reduce the need for repeat biopsies? Early data suggests it might help rule out significant cancer foci [28]), and the use of AI to interpret imaging data for prognostication. Moreover, novel targets like GRPR (gastrin-releasing peptide receptor) are being studied — for instance, a pilot with 68Ga-RM2 (bombesin analog) PET showed a 72% detection rate in BCR patients with negative conventional imaging [26], indicating potential to complement PSMA (especially in PSMA-negative tumors). FAP-targeted PET is another promising approach; while prostate tumors generally have lower FAP uptake than some other cancers, metastatic lesions often involve stroma that could be imaged by FAPI PET. These are at an investigative stage.

The theranostic landscape will also expand: alpha-particle therapies targeting PSMA (e.g., 225Ac-PSMA-617) are in trials and show even deeper responses than beta-emitters, though with more toxicity like xerostomia. Imaging will be required to select and follow these treatments. Another area is radio-guided surgery using PSMA-targeted probes: surgeons have begun using hand-held gamma detectors after injecting a radio-labeled PSMA ligand preoperatively to find small nodal metastases during salvage surgery[44]. Early feasibility studies demonstrate that PSMA radio-guidance can help resect PET-occult tumor deposits in lymph nodes [44]. This approach might increase the success of salvage lymph node dissections with minimal added morbidity.

In conclusion, the integration of advanced nuclear imaging into prostate cancer care represents one of the most significant innovations in the field in recent years. It exemplifies the move toward precision medicine—using tumor-specific molecular information (here, imaging) to guide who, when, and how to treat. The evidence accumulated shows clear improvements in diagnostic performance with PET tracers like PSMA, translating to better targeted therapies and likely better patient outcomes. Challenges remain, including ensuring widespread access to these technologies and determining the optimal management strategies based on imaging findings. As ongoing and future trials report results (e.g., comparing different imaging strategies or imaging-guided treatment algorithms), we will gain further clarity on long-term benefits. Nonetheless, it is already evident that nuclear imaging has become an indispensable tool in contemporary prostate cancer management, fundamentally altering the diagnostic and therapeutic pathways from early disease to advanced stages.

Nuclear imaging modalities in prostate cancer now range from conventional bone scans to cutting-edge PSMA PET scans (Table 1). Standard bone scintigraphy and CT, while still used, are being supplanted in many scenarios by more sensitive PET techniques. New-generation PET tracers have dramatically improved the detection of metastases, which improves staging accuracy and helps tailor management (e.g., identifying candidates for metastasis-directed therapy or systemic therapy). In biochemical recurrence, PET imaging allows localization of disease at low PSA levels, enabling potentially curative salvage interventions that were previously not possible. In metastatic disease, imaging is integral to implementing theranostic treatments like 177Lu-PSMA radioligand therapy and may guide the use of focal therapies in oligometastatic cases. As technology progresses, the synergy of diagnostics and therapeutics (“theranostics”) will likely deepen, with imaging not only finding cancer but also delivering treatment and monitoring responses. We anticipate that further refinements in imaging resolution, new radiotracers, and combination imaging (such as PET/MRI) will continue to enhance the care of patients with prostate cancer.

In summary, the role of nuclear imaging in prostate cancer has expanded from a few basic tests to a multifaceted, central component of care at every stage. Urologists, oncologists, and nuclear medicine specialists must work collaboratively, as the optimal interpretation and integration of these imaging results require multidisciplinary expertise. The evidence compiled in this review provides a comprehensive reference for the current state of the art and sets the stage for future innovations in prostate cancer imaging and therapy.

Clinical Implications: Practitioners should consider PSMA PET/CT for staging in high-risk newly diagnosed prostate cancer and for patients with biochemical recurrence when available, as it offers superior accuracy over conventional scans and can significantly impact management decisions. Fluciclovine PET/CT remains a useful tool for recurrence imaging, particularly in regions without access to PSMA PET, and can guide salvage therapy. For patients with oligometastatic recurrence, imaging should be utilized to confirm the number and location of lesions; if only a few lesions are present, MDT can be beneficial. In mCRPC, ensure patients undergo PSMA PET imaging to determine eligibility for PSMA-targeted therapies. Finally, clinicians should stay updated as ongoing trials will likely further define how best to employ these powerful imaging modalities, and emerging tracers may open new frontiers (such as targeting tumors that do not avidly take up current tracers). Nuclear imaging, in conjunction with other modalities like MRI and genomic tools, is moving us toward a more precise and individualized approach to prostate cancer treatment.

Table 1 (below) summarizes the various nuclear imaging techniques and tracers in prostate cancer, outlining their roles, applications, and supporting references.

Table I. Summary of Nuclear Imaging Modalities in Prostate Cancer Management

Conclusions.

Nuclear imaging, especially PSMA-targeted PET, has revolutionized prostate cancer management by enhancing diagnostic precision and enabling personalized treatment. Integration into clinical practice is justified by strong evidence of improved staging, recurrence detection, therapeutic planning, and patient outcomes.

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