Biopsy-free radical prostatectomy for prostate cancer—modern reality or pipe dream?

Current role of prostate biopsy

Treatment for localised prostate cancer generally results in effective local control at the expense of local side effects. A histopathological diagnosis, prior to treatment, has been mandatory according to the World Health Organisation (1), in order to justify radical treatment and potential morbidity (2). Additional information from pathology assists with risk stratification, prognosis estimation and management selection [e.g., use of androgen deprivation therapy (ADT) with radiotherapy, use of pelvic lymph node dissection during surgery] (2). Diagnosis by prostate needle biopsy has changed over time, with use of imaging [e.g., multiparametric magnetic resonance imaging (MRI)] and transperineal prostate biopsy shown to reduce over-biopsying and related side effects (e.g., sepsis) (3,4). Despite these benefits of a biopsy based diagnostic paradigm, some patients and clinicians seek a biopsy free approach (5). Besides avoiding biopsy related risks and side effects, spread of cancer from biopsy-related manipulation as a concept with some supportive data (6,7), is a major concern for some patients.

Biopsy-free radical prostatectomy—data so far

The advent of prostate specific membrane antigen (PSMA) positron emission tomography (PET) has improved staging (8) and intra-prostatic characterization of prostate cancer (9,10). Additionally, PSMA PET serves to improve diagnostic accuracy of prostate biopsy and may translate to a reasonable biopsy avoidance rate in patients with two negative imaging studies (11). Conversely, patients with highly suspicious imaging on both MRI and PSMA PET have a very high likelihood of harbouring a significant prostate cancer (12). Through this unprecedented diagnostic accuracy obtained noninvasively through imaging, a biopsy free treatment approach has gained enthusiasm in recent years (13). This approach has been used for renal, testicular and other tumours for many years. Preliminary, small retrospective studies have reported on patients proceeding to surgery without biopsy on the basis of imaging parameters with encouraging results (Figure 1) (5,14,15). However, in these previous series, several cases of discordant radiology and pathology have been reported—resulting in prostatectomy without significant cancer, thankfully with good functional outcomes (16). A small prospective study using a diagnostic prediction model combining prostate specific antigen (PSA) density with MRI and PSMA PET confirmed insignificant prostate cancer in only 1.8% of patients (1/57) (17).

Figure 1 Comparison of histological outcomes following biopsy-free radical prostatectomy within available studies. ISUP, International Society of Urological Pathology.

Potential downfalls of biopsy-free prostatectomy

A pervading concern is whether a biopsy-free paradigm is opening the flood gates without reliable tools and high level evidence to justify safety for patients (18). The study by Tang and colleagues “Benign Prostatic Hyperplasia-Related False-Positive of Prostate-Specific Membrane Antigen-Positron Emission Tomography in the Diagnosis of Prostate Cancer: The Achilles’ Heel of Biopsy-Free Radical Prostatectomy?” (19) provides valuable data to inform this treatment paradigm. They considered patients who had undergone prostate MRI, PSMA PET and prostate biopsy with subsequent negative histology [benign prostatic hyperplasia (BPH) group] or positive histology that preceded to radical prostatectomy (cancer group). Within their study, they reported a 30% false positive rate (PET score 3–5) in the BPH group, with requisite immunohistochemical staining confirming moderate to strong intensity so biopsy sampling error was less likely. Within the cancer cohort, a maximum standardized uptake value (SUVmax) of 9.8 showed a 100% specificity and 60% sensitivity. When considered relative to the BPH cohort, in order to definitely confirm significant cancer (100% specificity), a SUVmax of 15 was required. This confidence was maintained but sensitivity increased by 8% (41% to 49%) if MRI findings were incorporated [Prostate Imaging-Reporting and Data System (PIRADS) ≥4 and PET ≥4].

The findings from this study indicate that a biopsy free treatment pathway is only obtainable for patients with very high SUVmax values on PSMA PET. The available small series have a large proportion of patients below this cut off. While in the PRIMARY trial a SUVmax off of 12 resulted in 100% specificity for significant prostate cancer (12), the study by Tang as well as others (20) necessitate that a very high cut off is required, which means many patients still require biopsy. Furthermore, specific MRI and PSMA quantitative cut-offs are difficult to define due to heterogeneity in MRI and PSMA machines, acquisition parameters tracers used (21). Interobserver variability is also a well-known limitation of MRI (22) and evolving for PSMA PET (23). Such heterogeneity limits reliability and diagnostic accuracy of specific parameters to recommend that biopsy can be safely avoided. Additionally, health system considerations are important, such as cost and access. PSMA PET needs to be used in combination with MRI to guide treatment decisions, which increases cost for patients and health systems of varying degrees depending on the setting (e.g., PSMA PET more expensive and inaccessible in North America compared to Australia, inverse for tissue molecular testing).

While side effects of prostate biopsy can cause harm, they are generally infrequent and minor, particularly using MRI triage to reduce biopsy numbers and a transperineal biopsy approach (3,4). Oncological concerns regarding prostate biopsy have merit, however the majority of low-intermediate risk patients (lowest risk of cancer-mediated metastasis), all of whom undergo biopsy prior to treatment, remain cured at 20-year follow-up (24).

For the small proportion that may be eligible for a biopsy free pathway, they will be deprived of the additional information provided by the biopsy that influence evidence-based management plans. Further to traditional prognostic measures, such as Gleason score and variant morphology (e.g., intraductal carcinoma), molecular classifiers (e.g., Decipher^TM) and artificial intelligence image processing (e.g., ArteraAI) serve to improve on prognostication (25) and treatment selection to further personalise treatment. Absence of tissue for these tests would deprive patients of this information for decision-making. Additionally, it is likely that biopsy-free pathway will limit patient choice for local treatment, such as radiotherapy and/or ADT. It would be unlikely that a radiation oncologist would commit to biopsy-free radiotherapy with curative intent without histological diagnosis and grade, much like a medical oncologist is unlikely to give chemotherapy without a tissue diagnosis. So this leaves surgery as the only option, as histopathology is obtained post-operatively, which is inconsistent with shared-decision making principles that underpin prostate cancer management (2).

Future directions

While it is conceivable that clinicians and patients may eventually transition to a biopsy-free pathway for prostate cancer for some patients, improvements in current tools or introduction of new tools are needed before this is a reliable approach that can be widely practised.

Acknowledgments

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-2025-8/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-8/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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