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Using PSMA imaging for prognostication in localized and advanced prostate cancer

Nature Reviews Urology volume 20, pages 23–47 (2023)Cite this article

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Abstract

The use of prostate-specific membrane antigen (PSMA)-directed applications in modern prostate cancer management has evolved rapidly over the past few years, helping to establish new treatment pathways and provide further insights into prostate cancer biology. However, the prognostic implications of PSMA–PET have not been studied systematically, owing to rapid clinical implementation without long follow-up periods to determine intermediate-term and long-term oncological outcomes. Currently available data suggest that traditional prognostic factors and survival outcomes are associated with high PSMA expression (both according to immunohistochemistry and PET uptake) in men with localized and biochemically recurrent disease. Treatment with curative intent (primary and/or salvage) often fails when PSMA-positive metastases are present; however, the sensitivity of PSMA–PET in detecting all metastases is poor. Low PSMA–PET uptake in recurrent disease is a favourable prognostic factor; however, it can be associated with poor prognosis in conjunction with high 18F-fluorodeoxyglucose uptake in metastatic castration-resistant prostate cancer. Clinical trials embedding PSMA–PET for guiding management with reliable oncological outcomes are needed to support ongoing clinical use.

Key points

  • Prostate-specific membrane antigen (PSMA)–PET–CT is increasingly being used in clinical practice for prostate cancer staging and re-staging owing to improved accuracy and potential to change management. Improved oncological outcomes from improved accuracy are assumed, but yet to be conclusively proven.

  • PSMA is biologically associated with high-grade prostate cancer and advanced disease, and is altered by the use of systemic hormonal therapies. Higher PSMA expression according to immunohistochemistry has been associated with worse survival outcomes than patients with low PSMA expression.

  • Primary tumour PSMA ligand uptake on PET–CT has been associated with traditional prognostic factors, such as high Gleason scores or International Society of Uro-Pathology (ISUP) Grade Group and reduced progression-free survival after radical prostatectomy. PSMA–PET detection of index tumours also serves to improve accuracy of prostate biopsy and possibly enable safe omission of biopsy for men with suspected prostate cancer.

  • Detection of PSMA-positive lymph nodal metastases is associated with biochemical persistence and biochemical recurrence after surgery, as well as after salvage therapies (surgery and radiotherapy). However, small-sized lymph node metastases will be missed by PSMA–PET; thus, clinical factors remain an important consideration.

  • Biochemical recurrence prognostic factors, such as high Gleason score, high PSA levels and short PSA doubling time, are predictive of positive PSMA–PET results. Conversely, patients with post-prostatectomy biochemical recurrence and negative PSMA–PET might be a group of patients with the best oncological outcomes after salvage radiotherapy.

  • PSMA–PET has a high detection rate for metastasis in men with non-metastatic castration-resistant prostate cancer according to conventional imaging, enabling image-guided treatments (such as radiotherapy and radioligand therapy) in this context. High PSMA–PET radioligand uptake in men with castration-resistant prostate cancer does not necessarily confer a poor prognosis, with emerging data suggesting that low PSMA uptake with concurrent high 18F-fluorodeoxyglucose uptake might be the subgroup with a very poor prognosis, and least likely to benefit from radioligand therapy.

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Fig. 1: The influence of PSMA activation on cell pathways.
Fig. 2: 68Ga-PSMA-11–PET–CT images of two patients.
Fig. 3: Locally recurrent prostate cancer after initial primary radiotherapy (brachytherapy) 13 years earlier, subsequently treated with stereotactic body radiation therapy.
Fig. 4: Response to PSMA RLT using 177Lu-PSMA maximum intensity projection and axial PET–CT images before and after RLT.
Fig. 5: Current and potential future role of PSMA–PET in risk assessment, tumour localization, diagnosis and management of prostate cancer.

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Authors and Affiliations

  1. Department of Urology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

    Matthew J. Roberts

  2. University of Queensland Centre for Clinical Research, Faculty of Medicine, Brisbane, Queensland, Australia

    Matthew J. Roberts

  3. Department of Urology, Redcliffe Hospital, Brisbane, Queensland, Australia

    Matthew J. Roberts

  4. Martini-Klinik Prostate Cancer Center, Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Tobias Maurer

  5. Department of Surgery, Austin Health, Heidelberg, Victoria, Australia

    Marlon Perera

  6. Department of Nuclear Medicine, Technical University of Munich, Munich, Germany

    Matthias Eiber

  7. Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA

    Thomas A. Hope

  8. Department of Radiation Oncology, Iridium Network, GZA Ziekenhuizen, Antwerp, Belgium

    Piet Ost

  9. Department of Human Structure and Repair, Ghent University, Ghent, Belgium

    Piet Ost

  10. Peter MacCallum Cancer Centre, Radiation Oncology, Parkville, Victoria, Australia

    Shankar Siva

  11. Sir Peter MacCallum Department of Oncology, Melbourne University, Parkville, Victoria, Australia

    Shankar Siva, Michael S. Hofman & Declan G. Murphy

  12. Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Michael S. Hofman

  13. Prostate Cancer Theranostics and Imaging Centre of Excellence, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Michael S. Hofman & Declan G. Murphy

  14. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Declan G. Murphy

  15. Department of Theranostics and Nuclear Medicine, St Vincent’s Hospital, Sydney, New South Wales, Australia

    Louise Emmett

  16. Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia

    Louise Emmett

  17. Department of Nuclear Medicine, University of Duisburg-Essen, Essen, Germany

    Wolfgang P. Fendler

  18. PET Committee of the German Society of Nuclear Medicine, Goettingen, Germany

    Wolfgang P. Fendler

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Contributions

M.J.R., T.M., M.P., S.S. and W.P.F. researched data for the article. All authors contributed substantially to discussion of the content. M.J.R., T.M., M.P., S.S., L.E. and W.P.F. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Matthew J. Roberts.

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Competing interests

M.J.R. is supported by a Clinician Research Fellowship from the Metro North Office of Research, Queensland Health, and a Doctor in Training Research Scholarship from Avant Mutual Group Pty Ltd. W.P.F. received financial support from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, grant FE1573/3-1 / 659216), IFORES (D/107-81260, D/107-30240) and Wiedenfeld-Stiftung/Stiftung Krebsforschung Duisburg. The other authors declare no competing interests.

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Related links

Decipher: https://decipherbio.com

Memorial Sloan Kettering Cancer Centre: https://www.mskcc.org/nomograms/prostate/pre_op

OncotypeDX: https://precisiononcology.exactsciences.com/healthcare-providers/treatment-determination/prostatecancer/oncotype-dx-genomic-prostate-score

Prolaris: https://prolaris.com

Supplementary information

Glossary

Index lesion or tumour

Tumour focus displaying the highest International Society of Uro-Pathology (ISUP) Grade Group, or largest diameter for the same ISUP Grade Group, according to radical prostatectomy histopathology.

Partial volume effect

A concept in cross-sectional imaging in which limited imaging resolution is unable to detect small structures or tissues.

PI3K–AKT–mTOR pathway

Key signalling pathway that is central to cell growth and survival in both physiological and pathological conditions.

PSA doubling time

(PSADT). A unit of measurement (ng/ml/year) that estimates the rate of change for a PSA level to increase twofold from the original measurement.

Response Evaluation Criteria in Solid Tumors

(RECIST). Guidelines for evaluation of the efficacy of cancer treatments according to change in tumour burden detected by imaging.

Standardized uptake value

(SUV). A semiquantitative measure of tracer uptake in a region of interest that normalizes the lesion activity to the injected activity and a measure of the volume of distribution.

Stereotactic

Used in techniques for precise treatment, usually radiotherapy, to targets that are localized with 3D imaging.

Stereotactic ablative radiotherapy

(SABR). A radiotherapy technique that delivers high doses with high accuracy, enabling high-dose delivery with fewer effects on surrounding tissues.

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Roberts, M.J., Maurer, T., Perera, M. et al. Using PSMA imaging for prognostication in localized and advanced prostate cancer. Nat Rev Urol 20, 23–47 (2023). https://doi.org/10.1038/s41585-022-00670-6

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