To see clear is not enough; it is the action that counts

In 2020, professor Hofman and coworkers published the proPSMA trial (1). The trial is a prospective randomized controlled trial (RCT) of patients with high-risk prostate cancer (PCa). It compared staging with [⁶⁸Ga]Ga-prostate specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) of 150 patients against conventional staging of 152 patients. 87 of 295 patients had metastases in lymph nodes or bones. Staging with [⁶⁸Ga]Ga-PSMA PET/CT had a higher accuracy than conventional imaging (92% vs. 65%). A recent study has reproduced the findings in staging with PSMA PET/CT (2). Now international guidelines recommend the new staging modality.

However, the annual European Association of Urology (EAU) conference in Milan 2023 led to the warning regarding the implications for treatment: treatment should not be changed based on PSMA PET/CT findings (3). Gelardi and coworkers supported the recommendation and commented: “Therapeutic decision should be made with caution until we have more data from prospective studies that incorporate upfront staging PSMA-ligand PET/CT”.

The statement seems like a paradox. Three findings favor staging with PSMA PET/CT. The scans have an impressively high sensitivity and specificity (1). PSMA PET/CT detects positive sites in lymph nodes and bones that are not detected with conventional imaging. Up to half of the patients with PCa have staging with PSMA PET/CT that motivates changes in treatment (4). Our editorial uses miN1/miM1 for positive N/M findings with PSMA PET/CT according to a classification based on staging PET/CT, PROMISE, now version 2, to differentiate against standard TNM staging that is based on staging with conventional imaging modalities.

Our editorial comments on a recent multicenter prospective phase 3 study by Djaïleb and coworkers (protocol registered in ClinicalTrials.com, NCT03368547/02611882/02919111) (5). Indirectly the study elucidated the paradox. The study reported 240 patients who underwent staging with [⁶⁸Ga]Ga-PSMA PET/CT before radical prostatectomy (RP) and pelvic lymph node dissection and who were followed up clinically. None of the patients had undergone neoadjuvant treatment before RP or adjuvant treatments after the RP. Eighty patients (33%) had prostate biopsies with the International Society of Urological Pathology (ISUP) grade 5. Staging PSMA PET/CT showed that 199 patients (83%) did not have metastases (miN0/miM0), and 41 patients (17%) had miN1/miM1 PCa.

None of the patients had a change in treatment due to the preoperative staging PSMA PET/CT. The patients were followed median 32.4 (interquartile range, 23.3–42.9) months. Ninety-one patients (38%) developed prostate-specific antigen (PSA) relapse [PSAR; previously denoted biochemical recurrence (BCR), as in the Djaïleb publication] (5).

The study had an overall relatively high frequency of PSAR. It reflected the patient selection with intermediate- and high-risk PCa as the largest subgroup of patients (80 patients, 33%) in the preoperative setting who had prostate biopsy results with ISUP grade 5 (5). The authors state that miN1/miM1 was a significant predictor of PSAR on a univariate basis. Djaïleb et al. concluded that preoperative PSMA PET was a strong predictive biological indicator that increased PSAR risk assessment (5).

Other studies reported that staging PSMA PET/CT gave a similar or slightly higher frequency of patients with miN1/miM1 (6-14). Zheng et al. showed that staging PSMA PET/CT gave pathological upgrading for 27% of the patients and a downgrading for 23% of the patients (6). In a study by Donswijk and coauthors, an upstaging for N/M status was found in 23%/13% while downstaging was found in 9%/23% (15). Comparison with histopathology, apart from correct staging, PSMA PET/CT also has a few patients with false positive findings and slightly more patients with false negative findings (16).

The high frequency of patients with PSAR in patients with staging PSMA PET/CT before the initial treatment pointing to metastatic lesions is a strong counterargument against the recent EAU recommendation of not to treat patients based on PSMA PET/CT. The recommendation is based on a concern of a (supposed) risk for overtreatment, and supports a doctor’s delay for treatment. But in real life, the implicit delay looks like a preplanned undertreatment, especially of patients who have positive metastatic lesions on PSMA PET/CT that conventional imaging has not detected.

Staging PSMA PET/CT transfers some N0/M0 and miN1/miM1 patients from the non-metastatic group of patients to the group of patients with metastatic lesions. Thereby the survival for both the non-metastatic and the metastatic group of patients will increase, despite the survival for the whole cohort remains unchanged. Feinstein called the consequence of the stage migration for a Will-Rogers phenomenon (17). Nevertheless, the Djaïleb study showed that the ignoring of the metastatic sites of PCa detected with staging PSMA PET/CT dominated for the risk of PSAR (5).

We hypothesize that adequate treatment based on the PSMA PET/CT improves survival compared with standard treatment based on conventional imaging. The ongoing Danish RCT PRISMA-PET (NCT05123300, ClinicalTrials.gov) evaluates the hypothesis (18). The trial aims to recruit 448 patients with high-risk PCa and will randomize 1:1 for staging with [¹⁸F]PSMA-1007 against conventional imaging. The trial plans a follow-up for 20 years. The trial intends to report the impact of staging on stage migration and treatment, the diagnostic accuracy of [¹⁸F]PSMA PET/CT, and the impact of the treatment on PSAR and progression-free survival. Another endpoint is the OS (18).

¹⁸F-based PSMA is a valid alternative to ⁶⁸Ga-based PSMA PET/CT (14).

Many studies, described in a PSMA-specific review, show that patients benefit from treatment based on PSMA PET/CT-positive metastatic lesions such as salvage radiation therapy (19). As illustration, a patient with PSAR underwent a restaging PET/CT. The scan showed a metastatic lymph node lesion, so treatment was changed from surveillance to metastasis-directed therapy (MDT). At a new relapse, restaging PSMA PET/CT showed positive metastatic lesions (20), so the patient, still taxane-naïve, fulfilled the criterion for PSMA-based radioligand therapy (PRLT).

PRLT has also been used as first-line treatment of oligometastatic PCa detected with PSMA PET/CT. Other patients with oligometastatic recurrent PCa detected with PET/CT have been treated with MDT (21). Two RCTs (TheraP and VISION) evaluated the outcome after third-line PRLT for patients with PSMA PET/CT-positive metastatic castration-resistant PCa (mCRPC) (22,23). The trials excluded patients with heterogeneous PSMA expression in the PCa lesions. For 98 and 529 patients treated with third-line treatment with PRLT, PSA more often was reduced >50% than PSA was for 85 and 205 patients in the control groups given the alternative treatments, cabazitaxel or best standard of care. In the TheraP trial, the rates of PSA reductions were 65% vs. 37%. Both trials prospectively documented the survival after treatment based on restaging PSMA PET/CT in a setting of preplanned treatment (22,23). In consequence, the US Federal Drug Agency (FDA) and the European Medical Agency (EMA) have approved PRLT as third-line treatment of patients with mCRPC.

An ongoing RCT, PSMAddition, an international, prospective, open-label, randomized, phase 3 trial (NCT04720157) (24), plans to include 1,100+ PSMA-PET/CT positive patients with metastatic hormone-sensitive PCa. The study evaluates a doublet of androgen deprivation therapy (ADT) + androgen receptor pathway inhibitor (ARPI) with or without PRLT. The result of the trial may further contribute to integration of nuclear medicine in multidisciplinary teams for the management of PCa.

Before PSMA PET/CT, D’Amico developed a risk classification based on initial PSA, cancer grade, and extent of the primary PCa. Many subsequent studies have validated the prognostic value of the risk score. In the Djaïleb and coworkers study, multivariate statistical analyses might be undertaken to evaluate whether staging PSMA PET/CT has an added value to this well-known risk score (5).

In conclusion, PSMA PET/CT is the best imaging modality to point to positive sites of PCa. Staging PSMA PET/CT of high-risk PCa patients detects lymph node metastases for almost a third of the patients and bone metastases for a sixth of the patients, as reported in a recent review (25). The estimates fit with recent literature (6-14). So staging PSMA shows metastatic PCa for half of the high-risk patients. This large subgroup of patients needs a more aggressive treatment than only local treatment of the primary PCa.

Acknowledgments

The authors thank Matthias Krapick from Koblenz for technical support.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-23-582/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-582/coif). The authors have no conflicts of interest to declare.

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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;395:1208-16. [Crossref] [PubMed]
2. Surasi DS, Eiber M, Maurer T, et al. Diagnostic Performance and Safety of Positron Emission Tomography with (18)F-rhPSMA-7.3 in Patients with Newly Diagnosed Unfavourable Intermediate- to Very-high-risk Prostate Cancer: Results from a Phase 3, Prospective, Multicentre Study (LIGHTHOUSE). Eur Urol 2023;84:361-70. [Crossref] [PubMed]
3. Gelardi F, Briganti A, Pini C, et al. European guidelines update on PSMA PET/CT for prostate cancer staging-snap back to reality. Eur J Nucl Med Mol Imaging 2023;50:2572-5. [Crossref] [PubMed]
4. Mena E, Lindenberg L, Choyke P. The Impact of PSMA PET/CT Imaging in Prostate Cancer Radiation Treatment. Semin Nucl Med 2022;52:255-62. [Crossref] [PubMed]
5. Djaïleb L, Armstrong WR, Thompson D, et al. Presurgical (68)Ga-PSMA-11 Positron Emission Tomography for Biochemical Recurrence Risk Assessment: A Follow-up Analysis of a Multicenter Prospective Phase 3 Imaging Trial. Eur Urol 2023;84:588-96. [Crossref] [PubMed]
6. Zheng A, Wang Z, Luo L, et al. The prognostic value of (18)F-PSMA-1007 PET/CT in predicting pathological upgrading of newly diagnosed prostate cancer from systematic biopsy to radical prostatectomy. Front Oncol 2023;13:1169189. [Crossref] [PubMed]
7. Hermsen R, Wedick EBC, Vinken MJM, et al. Lymph node staging with fluorine-18 prostate specific membrane antigen 1007-positron emission tomography/computed tomography in newly diagnosed intermediate- to high-risk prostate cancer using histopathological evaluation of extended pelvic node dissection as reference. Eur J Nucl Med Mol Imaging 2022;49:3929-37. [Crossref] [PubMed]
8. Ingvar J, Hvittfeldt E, Trägårdh E, et al. Assessing the accuracy of [18F]PSMA-1007 PET/CT for primary staging of lymph node metastases in intermediate- and high-risk prostate cancer patients. EJNMMI Res 2022;12:48. [Crossref] [PubMed]
9. Hope TA, Eiber M, Armstrong WR, et al. Diagnostic Accuracy of 68Ga-PSMA-11 PET for Pelvic Nodal Metastasis Detection Prior to Radical Prostatectomy and Pelvic Lymph Node Dissection: A Multicenter Prospective Phase 3 Imaging Trial. JAMA Oncol 2021;7:1635-42. [Crossref] [PubMed]
10. Klingenberg S, Jochumsen MR, Ulhøi BP, et al. (68)Ga-PSMA PET/CT for Primary Lymph Node and Distant Metastasis NM Staging of High-Risk Prostate Cancer. J Nucl Med 2021;62:214-20. [Crossref] [PubMed]
11. Onal C, Ozyigit G, Oymak E, et al. Clinical parameters and nomograms for predicting lymph node metastasis detected with (68) Ga-PSMA-PET/CT in prostate cancer patients candidate to definitive radiotherapy. Prostate 2021;81:648-56. [Crossref] [PubMed]
12. Wondergem M, van der Zant FM, Broos WAM, et al. (18)F-DCFPyL PET/CT for primary staging in 160 high-risk prostate cancer patients; metastasis detection rate, influence on clinical management and preliminary results of treatment efficacy. Eur J Nucl Med Mol Imaging 2021;48:521-31. [Crossref] [PubMed]
13. Yaxley JW, Raveenthiran S, Nouhaud FX, et al. Risk of metastatic disease on (68) gallium-prostate-specific membrane antigen positron emission tomography/computed tomography scan for primary staging of 1253 men at the diagnosis of prostate cancer. BJU Int 2019;124:401-7. [Crossref] [PubMed]
14. Hoffmann MA, Müller-Hübenthal J, Rosar F, et al. Primary Staging of Prostate Cancer Patients with [18F]PSMA-1007 PET/CT Compared with [68Ga]Ga-PSMA-11 PET/CT. J Clin Med 2022;11:5064. [Crossref] [PubMed]
15. Donswijk ML, van Leeuwen PJ, Vegt E, et al. Clinical impact of PSMA PET/CT in primary prostate cancer compared to conventional nodal and distant staging: a retrospective single center study. BMC Cancer 2020;20:723. [Crossref] [PubMed]
16. von Eyben FE, Picchio M, von Eyben R, et al. (68)Ga-Labeled Prostate-specific Membrane Antigen Ligand Positron Emission Tomography/Computed Tomography for Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol Focus 2018;4:686-93. [Crossref] [PubMed]
17. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985;312:1604-8. [Crossref] [PubMed]
18. Buch-Olsen KM, Poulsen MH, Hansen S, et al. A randomised trial of [18F]PSMA-1007-PET/CT versus NaF-PET/CT for staging primary prostate cancer: A trial protocol. BJUI Compass 2023;4:513-22. [Crossref] [PubMed]
19. Hoffmann MA, Wieler HJ, Baues C, et al. The Impact of 68Ga-PSMA PET/CT and PET/MRI on the Management of Prostate Cancer. Urology 2019;130:1-12. [Crossref] [PubMed]
20. von Eyben FE, Kiljunen T, Joensuu T, et al. (177)Lu-PSMA-617 radioligand therapy for a patient with lymph node metastatic prostate cancer. Oncotarget 2017;8:66112-6. [Crossref] [PubMed]
21. Ost P, Reynders D, Decaestecker K, et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin Oncol 2018;36:446-53. [Crossref] [PubMed]
22. Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet 2021;397:797-804. [Crossref] [PubMed]
23. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2021;385:1091-103. [Crossref] [PubMed]
24. Tagawa ST, Sartor AO, Saad F, et al. PSMAddition: A phase 3 trial to compare treatment with 177Lu-PSMA-617 plus standard of care (SoC) and SoC alone in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2023;41:TPS5116. [Crossref]
25. Jochumsen MR, Bouchelouche K. PSMA PET/CT for Primary Staging of Prostate Cancer - An Updated Overview. Semin Nucl Med 2024;54:39-45. [Crossref] [PubMed]