Prostate cancer remains one of the most frequently diagnosed malignancies in men worldwide, with outcomes strongly influenced by disease stage at diagnosis. While survival is high in localised disease, prognosis worsens markedly once metastases develop, underlining the need for effective systemic therapies and accurate tools to guide their use. Radioligand therapy targeting prostate-specific membrane antigen, commonly referred to as 177Lu-PSMA therapy, has become an established option for men with metastatic castration-resistant prostate cancer following regulatory approvals in the early 2020s. As clinical use expands, imaging has taken on a central role across the treatment pathway, supporting patient selection, early response assessment and longer-term follow-up. Evidence highlights how PSMA-PET/CT forms the foundation of this approach, while additional imaging modalities provide complementary information that can refine clinical decision-making.
PSMA-PET/CT as the Foundation for Patient Selection
PSMA-PET/CT is widely recognised as the principal imaging modality for selecting patients for 177Lu-PSMA therapy. Compared with conventional imaging such as CT and bone scintigraphy, it offers higher sensitivity for detecting metastatic disease in bone, lymph nodes and soft tissues. Accurate identification of PSMA-avid lesions is essential, as sufficient PSMA expression is required for effective delivery of targeted radioligand therapy.
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Beyond lesion detection, PSMA-PET/CT provides quantitative and semi-quantitative imaging biomarkers that have been associated with treatment outcomes. Measures related to tracer uptake intensity, overall PSMA-avid tumour burden and inter-lesional heterogeneity have shown value in predicting biochemical response and survival. However, some of these metrics require time-consuming whole-body segmentation, limiting their routine use in clinical practice. To address this, visually assessed scores derived from standard workstations have been proposed, offering a more pragmatic way to capture tumour heterogeneity and intensity while retaining prognostic relevance.
Standardised reporting frameworks further support consistent interpretation of PSMA-PET/CT. Systems incorporating lesion distribution and PSMA expression intensity aim to ensure that patients with clearly PSMA-positive disease are selected, while also linking imaging features to response and survival patterns. Despite this structured approach, variability in treatment response persists, with a substantial proportion of patients failing to achieve meaningful biochemical responses even after imaging-based selection. This highlights the limitations of relying on PSMA-PET/CT alone and provides the rationale for incorporating additional imaging strategies.
Complementary Imaging Identifies Discordant and Resistant Disease
Several adjunctive imaging modalities can reveal biological features of disease that are not fully captured by PSMA-PET/CT. Among these, 18F-FDG PET/CT has emerged as a useful tool for identifying aggressive tumour components characterised by increased glucose metabolism. The presence of lesions that are FDG-positive but show low or absent PSMA expression has been associated with poorer outcomes and has been used as an exclusion criterion in some clinical trials. Comparative analyses indicate that stricter imaging selection, including assessment of discordant disease, is associated with higher response rates and improved progression outcomes.
Alternative PSMA radiotracers labelled with fluorine-18 also play a role in clinical practice. These tracers offer logistical advantages related to production and distribution and, in some studies, have demonstrated higher tumour-to-background contrast. Differences in tracer clearance can improve lesion detection in certain anatomical regions but may also introduce challenges, such as non-specific uptake in bone. As a result, guidance emphasises consistency in tracer choice across serial scans and careful interpretation to avoid overestimating disease extent.
In settings where PET/CT is not readily available, technetium-labelled PSMA SPECT/CT provides a more accessible alternative. The research describes comparable diagnostic performance in selected contexts, particularly for assessing bone-dominant disease. Beyond baseline assessment, SPECT/CT is widely used after therapy administration, enabling verification of radiotracer delivery and supporting dosimetry. Its broader availability makes it particularly relevant in resource-constrained environments, where access to PET infrastructure may be limited.
Imaging-Based Response Assessment Beyond PSA
Monitoring response to 177Lu-PSMA therapy has traditionally relied on prostate-specific antigen measurements combined with CT and bone scintigraphy, using established response criteria. However, PSA changes do not always align with true disease activity, and bone-related imaging findings can be difficult to interpret due to treatment-related changes. PSMA-PET/CT offers a more sensitive approach to response assessment, detecting small-volume disease and providing functional information that may precede anatomical change.
Several PET-based response frameworks have been proposed, focusing on the appearance of new PSMA-avid lesions and changes in overall tumour burden. While fully quantitative approaches depend on specialised software, visually assessed criteria have shown good agreement with quantitative methods and strong inter-reader consistency. Early interim scans during treatment cycles have demonstrated prognostic value, with persistent PSMA-avid disease or limited reduction in tumour burden associated with less favourable outcomes.
Post-therapy SPECT/CT adds another dimension to response evaluation. Because it uses the therapeutic radionuclide, it allows assessment of tumour burden and lesion evolution without additional diagnostic tracers. Early changes in SPECT-derived tumour volume and the emergence of new lesions have been linked to progression and survival, and imaging findings have been reported to influence management decisions in a substantial proportion of patients.
For longer-term follow-up, PSMA-PET/CT remains a key tool for detecting progression or recurrence, although no standardised schedule for repeat imaging has been established. Whole-body diffusion-weighted MRI is also highlighted as a radiation-free alternative that provides both anatomical and functional assessment, with standardised reporting systems supporting evaluation across different disease sites.
The evidence underscores the central role of PSMA-PET/CT in selecting patients for 177Lu-PSMA therapy, while also highlighting its limitations when used in isolation. Complementary imaging modalities, including FDG PET/CT, post-therapy SPECT/CT and whole-body diffusion-weighted MRI, provide additional insight into tumour biology, treatment response and disease evolution. Together, these approaches support a more nuanced and individualised imaging strategy, helping clinicians identify patients most likely to benefit, detect early non-response and optimise follow-up in metastatic prostate cancer care.
Source: Insights into Imaging
Image Credit: iStock
