SPECIALTY SOCIETIES Paradigm Shifts in the Diagnostic Pathway for Prostate Cancer in Accordance With Evolving Technology
By: Timothy K. O’Rourke Jr, MD, Wake Forest University School of Medicine, Winston-Salem, North Carolina, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, North Carolina; Parth U. Thakker, MD, MS, Wake Forest University School of Medicine, Winston-Salem, North Carolina, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, North Carolina; Ashok K. Hemal, MD, MCh, FACS, FRCS (Glas), Wake Forest University School of Medicine, Winston-Salem, North Carolina, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, North Carolina | Posted on: 04 May 2023
The diagnostic evaluation of prostate cancer (PCa) has evolved significantly in the last century. For perspective, consider this: In the early 1900s, the only modality used to screen for PCa was the digital rectal examination (DRE). Refinements in the diagnostic algorithm have vastly improved over time.
Transrectal ultrasound (TRUS) has permitted image-guided, systematic prostate biopsy and has been utilized in practice since the latter half of the 20th century. PSA, first implemented in clinical practice in the early 1990s, was investigated in a study at our institution in 1994, where men with PSA 4-10 ng/mL or abnormal DRE underwent TRUS-guided prostate biopsy. Volumetric analysis was obtained by ultrasound; PSA density was calculated and demonstrated to be significantly different among those with and without cancer.1 Novel high-resolution micro-US has significantly optimized the diagnostic capabilities for PCa. The OPTIMUM trial is ongoing, which has randomized 3 cohorts into micro-US-only biopsy, MRI/micro-US “FusionVu” biopsy, and MRI/US biopsy with conventional fusion system.2
Transperineal prostate biopsy has gained traction over the last 5-10 years with advantages including lower rates of infection and, especially in larger glands, optimized anterior prostatic cancer detection.3 The Figure simplifies the overarching pathways in modern prostate biopsy.
Pros for performing TRUS-guided biopsy include broad familiarity among all urologists, optimized sampling of the peripheral zone, facility, efficiency, and commonality in performing under local anesthesia. The increased risk of sepsis relative to transperineal biopsy is well documented; however, this can be minimized through approaches including rectal swabs to identify antibiotic resistance, periprocedural antibiotics, and augmented antibiotic prophylaxis at the time of biopsy. Transperineal biopsy has gained significant momentum; however, limitations include lack of familiarity with all urologists, especially with regard to comfort performing the procedure under local anesthesia, increased cost, decreased efficiency, and perhaps an increased risk of urinary retention post-biopsy.4 We have found that there seems to be a steeper learning curve in transperineal biopsy relative to transrectal biopsy, particularly among urology trainees. Taking all the available data, both approaches are viable and the decision to proceed will depend on clinical factors, patient-related factors, and surgeon experience. A strong niche for transperineal biopsy in our practice includes persistently elevated PSA with prior negative transrectal biopsy, large prostate with inability to access the anterior prostate via transrectal biopsy, in those with anterior lesions on MRI to be targeted, and in confirmatory biopsy for patients who elect active surveillance for PCa 12-18 months from initial biopsy.
MRI has become an important adjunct to the workup of PCa. Studies including PROMIS and PRECISION have helped clarify the ideal utility of MRI in PCa diagnosis. In PROMIS, the concept of pre-biopsy screening MRI was evaluated and found to be of value; the authors suggested that approximately 27% of patients could defer biopsy in the setting of a negative MRI. While the sensitivity for detection of Grade Group 2 PCa was 88% (range 84%-91%), it is important to consider the negative predictive value was 76% (69%-82%).5 While a negative MRI can be reassuring to patients and urologists alike, a negative MRI should be interpreted with caution and biopsy should still be advised with shared decision-making. PRECISION demonstrated superior diagnosis of clinically significant prostate cancer (csPCa) in those who underwent MRI prior to biopsy with MRI-targeted biopsies obtained vs standard 12-core TRUS prostate biopsy. Lower rates of clinically insignificant PCa were detected via this modality and optimization of positive core identification was noted.6 The PRIME study (NCT04571840) has been proposed to clarify detection of csPCA with biparametric MRI (T2 weighted and diffusion weighted, no dynamic contrast enhanced [DCE]) vs standard multiparametric magnetic resonance imaging (mpMRI) to assess whether IV contrast is required for prostate MRI. Patients will undergo standard mpMRI; however, radiologists will be blinded to the DCE phase. Biopsies in both biparametric MRI and mpMRI will undergo MRI-targeted prostate biopsies and the primary outcome will be proportion of men with csPCa. Benefits of deferring DCE would include faster MRI and risk mitigation of allergic and other contrast-related reactions.7
Pre-biopsy MRI in our practice is utilized primarily in patients with elevated PSA (<10 ng/mL) with negative DRE and clinical suspicion for PCa prior to biopsy. In patients with a palpable nodule and clinical concern for PCa we find it logical to proceed with transrectal prostate biopsy directly in most cases to optimize efficiency in diagnosis. We routinely favor cognitive fusion transrectal and transperineal prostate biopsy for larger lesions, predominantly peripheral zone lesions, and palpable lesions to improve diagnostic efficiency and avoid a backlog for software-assisted MRI/US fusion. We typically reserve software-assisted grid-based transperineal fusion biopsy for patients with small anterior lesions in large prostates that would otherwise be quite challenging to localize with cognitive fusion alone. In our practice, TRUS-guided biopsy is generally performed under local anesthesia, whereas transperineal biopsy is performed under general anesthesia to optimize patient comfort.
Adjunct tests including tissue, blood, and urine-based assays have been developed for clinical practice (see Table).8 Tissue-based tests utilize multigene footprints and can be used to risk stratify patients diagnosed with low- and intermediate-risk PCa, especially those considering additional information to decide on active surveillance or radical treatment. Head-to-head comparisons for tissue- and blood-based tests are lacking, however, and their utility is nuanced.
Table. Biomarkers in the Prostate Cancer Diagnostic Algorithm
|4k Score||Blood||Pre-biopsy||Risk of csPCa on biopsy||Initial or repeat biopsy|
|PHI||Blood||Pre-biopsy||Risk of csPCa on biopsy||Initial or repeat biopsy|
|SelectMDx||Post-DRE urine||Pre-biopsy||Risk of csPCa on biopsy||Initial biopsy|
|ExoDx||Urine||Pre-biopsy||Risk of csPCa on biopsy||Initial or repeat biopsy|
|MiPS||Post-DRE urine||Pre-biopsy||Risk of csPCa on biopsy||Initial or repeat biopsy|
|PCA3||Post-DRE urine||Prior negative biopsy||Risk of csPCa on biopsy||Repeat biopsy|
|ConfirmMDx||Tissue||Prior negative biopsy tissue||Risk of csPCa on biopsy||Repeat biopsy|
|STHLM3||Serum||Pre-biopsy||Risk of detecting Gleason ≥7 PCa on biopsy||Initial biopsy|
|epiCaPture||Urine||Pre-biopsy||Risk of detecting high-risk PCa on biopsy||Initial biopsy|
|Decipher||Tissue||Post-biopsy||Risk of pT3 or Gleason grade 4 or N+ PCa||High-grade disease|
|Oncotype DX||Tissue||Post-biopsy||Risk of pT3 or Gleason grade 4 PCa||Aggressive disease|
|Prolaris||Tissue||Post-biopsy||PCa-specific mortality, BCR, metastasis||Aggressive disease and PCa-specific mortality|
|PTEN||Tissue||Post-biopsy||Risk of harboring aggressive PCa||Aggressive disease|
|ProMark||Tissue||Post-biopsy||Risk of pT3 or Gleason grade 4 PCa||Aggressive disease|
|Ki67||Tissue||Post-biopsy||Risk of BCR, metastatic disease, RFS||PCa-specific mortality|
|Abbreviations: BCR, biochemical recurrence; csPCa, clinically significant prostate cancer; DRE, digital rectal examination; PCa, prostate cancer; RFS, recurrence-free survival.|
Artificial Intelligence (AI) is developing at a swift pace. AI applications have been applied to mpMRI to assist radiologists in assigning a PI-RADS (Prostate Imaging–Reporting and Data System) score and have shown promise previously for detection of suspicious lesions in the peripheral zone.9 In prostate histopathology, AI models with acceptable accuracy may have a role in minimizing inter-rater variability and improving diagnostics, reducing cost, and improving efficiency.10
We have come a long way from the early days of open incisional prostate biopsy based solely on DRE. We look forward to continued technological improvements as we continue to push for optimized diagnostic precision in men at risk for PCa.
- Bare R, Hart L, McCullough DL. Correlation of prostate-specific antigen and prostate-specific antigen density with outcome of prostate biopsy. Urology. 1994;43(2):191-196.
- Klotz L, Andriole G, Cash H, et al. Optimization of prostate biopsy-micro-ultrasound versus MRI (OPTIMUM): a 3-arm randomized controlled trial evaluating the role of 29 MHz micro-ultrasound in guiding prostate biopsy in men with clinical suspicion of prostate cancer. Contemp Clin Trials. 2022;112:106618.
- Wilcox Vanden Berg RN, George AK, Kaye DR. Should transperineal prostate biopsy be the standard of care?. Curr Urol Rep. 2023;24(3):135-142.
- Berry B, Parry MG, Sujenthiran A, et al. Comparison of complications after transrectal and transperineal prostate biopsy: a national population-based study. BJU Int. 2020;126(1):97-103.
- Ahmed HU, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017;389(10071):815-822.
- Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med. 2018;378(19):1767-1777.
- Ng A, Khetrapal P, Kasivisvanathan V. Is it PRIME time for biparametric magnetic resonance imaging in prostate cancer diagnosis?. Eur Urol. 2022;82(1):1-2.
- Duffy MJ. Biomarkers for prostate cancer: prostate-specific antigen and beyond. Clin Chem Lab Med. 2020;58(3):326-339.
- Gaur S, Lay N, Harmon SA, et al. Can computer-aided diagnosis assist in the identification of prostate cancer on prostate MRI? A multi-center, multi-reader investigation. Oncotarget. 2018;9(73):33804-33817.
- Marginean F, Arvidsson I, Simoulis A, et al. An artificial intelligence-based support tool for automation and standardisation of Gleason grading in prostate biopsies. Eur Urol Focus. 2021;7(5):995-1001.