High-risk prostate cancer (PCa) encompasses a wide spectrum of diseases, ranging from organ-confined cancer with high-risk features to locally advanced cancer which may or may not have spread to the pelvic nodes.¹ But when do you label your PCa patient as high-risk localized or locally advanced? Well, it depends on multiple factors—whether you stage your patients on the basis of clinical examination as suggested by the American Joint Committee on Cancer or use MRI, whether you classify your patients based on the European Association of Urology or the National Comprehensive Cancer Network^® stratification, and whether you use conventional imaging or next-generation imaging (NGI) for metastatic evaluation. These variations in clinical practice broaden the spectrum of high-risk PCa even further. The last criterion is also subject to the availability of NGI (the prostate-specific membrane antigen [PSMA] positron emission tomography [PET] scan) in one’s part of the world and is fast turning out to be the most impactful factor.

The PSMA PET scan is turning out to be a game-changer in staging PCa. We have level 1 evidence from the proPSMA study that the PSMA PET scan has significantly greater accuracy for nodal and distant metastasis compared to conventional imaging comprising of a bone scan plus a CT.² At the recent Advanced Prostate Cancer Consensus Conference 2022 congress at Lunago, Switzerland, 78% of experts vouched for the PSMA PET scan as their investigation of choice for metastatic staging. The PSMA PET scan has now found its way into guidelines, as well.³ However, we do not yet have data that tells us that using PSMA PET scans instead of conventional imaging to guide management decisions leads to a survival benefit; and the guidelines also caution us to be aware of the lack of these outcome data.

Figure. Bone scan and CT vs PSMA PET: possible case scenarios of change in the stage and alteration in the management plan and prognosis.

Within the heterogeneous group of locally advanced and oligometastatic patients, using a PSMA PET scan instead of a bone scan may lead to a change in the stage, usually an upstaging, and subsequently lead to an alteration in the management plan and prognostication.⁴ This means that certain locally advanced and low-volume metastatic patients on a bone scan would be upstaged to low-volume and high-volume metastatic cancer, respectively, on the PSMA PET (see Figure). This would lead to a change in the “intent” of treatment and would deprive these patients a chance at possible cure if we chose to not address the primary lesion in the prostate. We need to remember that all the evidence available today for deciding whether to treat the primary in the setting of metastatic PCa comes from studies which used bone scan and CT to stage the patients, and not PSMA PET CT.^5,6

Another point to consider is that in the setting of high-risk and locally advanced disease, we are moving towards intensification of systemic treatment in addition to the local treatment. Guidelines already recommend adding 2 years of abiraterone for such patients who are treated with radiation plus androgen deprivation therapy. Ongoing trials such as PROTEUS and ARNEO, amongst others, are evaluating the role of intensifying systemic treatment along with radical prostatectomy in these patients in the form of neoadjuvant apalutamide or docetaxel.^7,8 Quite contrastingly, while one of these trials is using conventional imaging, the other is using the PSMA PET scan for staging the patients. It would be interesting to see how the results of these trials would be applied to clinical practice in the near future. But, at this point in time, it doesn’t seem fair to deprive a patient with, for example, 5 metastatic lesions on a PSMA PET scan of treatment to his primary lesion in the prostate. Whether this primary treatment should be in the form of surgery or radiation therapy is another debate in itself. Another potential downside of treating a patient as per a higher risk category based on PSMA findings is the increased toxicity from the additional systemic therapies that may be prescribed.

The advent of NGI has only blurred further the “fine line” between high-risk, locally advanced, and oligometastatic PCa. It is the need of the hour to reach a consensus to demarcate these disease stages, for accurate and distinct risk stratification for our PCa patients, based on newer imaging. We need to identify patients who have “limited” metastatic burden on a PSMA PET scan and will benefit from treatment to their primary lesion. Inclusion of biomarkers in the decision algorithm will help better identify such patients in the near future.