Prostate ...

[Michael Scally MD]

No Mortality Differences Among Localized Prostate Cancer Treatments

Compared with active monitoring, radical treatment of localized prostate cancer does not improve disease-specific or overall survival at 10 years, a multicenter UK trial in Health Technology Assessment found. Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT - NCBI Bookshelf

After prostate-specific antigen testing, 1643 men with localized prostate cancer were randomized to receive active monitoring, radical prostatectomy, or radical radiotherapy.

No statistically significant differences occurred regardless of treatment among 17 men who died of prostate cancer and 169 who died of other causes. At a 10-year median follow-up, almost all the men in each group were alive. Radical treatment, however, reduced disease progression by approximately 50% compared with active monitoring; 55% of men receiving active monitoring eventually received radical treatment.

Surgery resulted in greater urinary incontinence and erectile symptoms, and radiotherapy caused erectile and bowel symptoms. Men in the active monitoring group had a general decline in their urinary and sexual function with age and subsequent radical treatments. Quality of life, anxiety, and depression were similar among all groups. The study will observe the men for a median of 15 years total to determine the treatments’ longer-term effects.

Slomski A. No Mortality Differences Among Localized Prostate Cancer Treatments. JAMA. 2020;324(16):1599. No Mortality Differences Among Localized Prostate Cancer Treatments

 

[Michael Scally MD]

[OA] Prostate-Specific Antigen Concentrations in Response to Testosterone Treatment of Severely Hypogonadal Men

Context: Clinical guidelines recommend measurement of the serum prostate-specific antigen (PSA) concentration during testosterone treatment of hypogonadal men to determine whether the increase is sufficiently high to warrant urologic referral. Prior studies of the effect of testosterone treatment on PSA concentrations have been conducted in men who were mildly to moderately hypogonadal.

Objective: The objective of this work is to determine the PSA response to testosterone treatment of men who are severely hypogonadal.

Design and setting: This retrospective cohort study was conducted at a single academic medical center.

Participants: Eighty-five men participated who were severely hypogonadal as a result hypothalamic-pituitary or testicular disease.

Main outcome measure: Changes in serum PSA concentrations were measured during testosterone treatment for up to 18 months.

Results: Testosterone treatment increased the median serum testosterone concentration from 36 ng/dL (interquartile range [IQR], 20-91 ng/dL) at baseline to 395 ng/dL (IQR, 266-542 ng/dL) at 6 to 18 months. This treatment resulted in a median increment in PSA above baseline of 0.70 ng/mL (IQR, 0.10-1.85 ng/mL) at 6 to 18 months. Apropos current Endocrine Society clinical guidelines, 31% of the men experienced a PSA increase above baseline greater than 1.4 ng/mL, and 13% reached an absolute PSA concentration of greater than 4.0 ng/mL. Four men were diagnosed with prostate cancer.

Conclusions: The PSA response to testosterone replacement in men who are severely hypogonadal as a result of pituitary or testicular disease is greater than that previously reported in men with mild to moderate hypogonadism. These results suggest the magnitude of the PSA response to testosterone replacement is related to the degree of hypogonadism.

Sachdev S, Cucchiara AJ, Snyder PJ. Prostate-Specific Antigen Concentrations in Response to Testosterone Treatment of Severely Hypogonadal Men. J Endocr Soc. 2020 Sep 25;4(11):bvaa141. doi: 10.1210/jendso/bvaa141. PMID: 33134766; PMCID: PMC7584115. Prostate-Specific Antigen Concentrations in Response to Testosterone Treatment of Severely Hypogonadal Men

 

[Michael Scally MD]

Wilkins LJ, Tosoian JJ, Sundi D, Ross AE, Grimberg D, Klein EA, Chapin BF, Nyame YA. Surgical management of high-risk, localized prostate cancer. Nat Rev Urol. 2020 Nov 10. doi: 10.1038/s41585-020-00384-7. Epub ahead of print. PMID: 33173205. Surgical management of high-risk, localized prostate cancer

Key points

High-risk prostate cancer is a heterogeneous disease that varies in its clinical aggressiveness and associated oncological outcomes.

Effective staging of high-risk prostate cancer is limited by the poor diagnostic performance of conventional imaging; however, novel imaging modalities are being developed.

Level I data on the role of radical prostatectomy in the management of high-risk, localized prostate cancer are currently scarce.

Clinical, pathological and genomic markers of tumour responsiveness to hormonal therapy, resistance to radiation and risk of metastatic progression will also improve the stratification of patients with high-risk prostate cancer.


High-risk prostate cancer is a heterogeneous disease that lacks clear consensus on its ideal management. Historically, non-surgical treatment was the preferred strategy, and several studies demonstrated improved survival among men with high-risk disease managed with the combination of radiotherapy and androgen deprivation therapy (ADT) compared with ADT alone.

However, practice trends in the past 10-15 years have shown increased use of radical prostatectomy with pelvic lymph node dissection for primary management of high-risk, localized disease. Radical prostatectomy, as a primary monotherapy, offers the potential benefits of avoiding ADT, reducing rates of symptomatic local recurrence, enabling full pathological tumour staging and potentially reducing late adverse effects such as secondary malignancy compared with radiation therapy.

Retrospective studies have reported wide variability in short-term (pathological) and long-term (oncological) outcomes of radical prostatectomy. Surgical monotherapy continues to be appropriate for selected patients, whereas in others the best treatment strategy probably involves a multimodal approach.

Appropriate risk stratification utilizing clinical, pathological and potentially also genomic risk data is imperative in the initial management of men with prostate cancer. However, data from ongoing and planned prospective trials are needed to identify the optimal management strategy for men with high-risk, localized prostate cancer.

 

[Michael Scally MD]

Schulze A, Christoph F, Sachs M, Schroeder J, Stephan C, Schostak M, Koenig F. Use of the Prostate Health Index and Density in 3 Outpatient Centers to Avoid Unnecessary Prostate Biopsies. Urol Int. 2020;104(3-4):181-186. doi: 10.1159/000506262. Epub 2020 Mar 30. PMID: 32224611. https://www.karger.com/Article/Abstract/506262

Objectives: We investigated the diagnostic efficacy of the prostate health index (PHI) and PHI density (PHID) to avoid unnecessary prostate biopsies in 3 urological practices.

Methods: In 122 patients, total prostate-specific antigen (PSA), free PSA (f-PSA), the quotient from total PSA and f-PSA (f-PSA%), and [-2]pro-PSA were measured in the serum; PHI, PHID, and PSA density (PSAD) were calculated prior to prostate biopsy. Tissue sampling via transrectal biopsy was indicated in case of suspicious PSA (progression and/or elevation of PSA) and/or suspicious digital rectal examination. PSAD, PHI, and PHID were not used for biopsy indication. The diagnostic efficacy was determined with receiver-operating characteristic (ROC)and decision curve analyses.

Results: Based on prostate biopsies, 38% (n = 46) of the cases had no prostate carcinoma (PCa), 21% (n = 26) no clinically significant (insignificant) PCa, and 41% (n = 50) had clinically significant PCa. ROC analyses of the PSA parameters showed higher diagnostic efficacy for PHI and PHID (AUC 0.722 and 0.739) than for f-PSA%, PSA, and PSAD (AUC 0.612, 0.595, and 0.698, respectively) regarding carcinoma diagnosis. With a combined use of PHI and PHID (cutoff >40 and >0.9, respectively), only 1 clinically significant PCa would have been missed (sensitivity 98%); in 24 (20%) patients, biopsy could have been avoided.

Conclusion: The integration of PHI and PHID could improve the diagnostic efficacy of risk calculators to avoid unnecessary prostate biopsies. However, as a prerequisite, validation of cutoff values in prospective studies is urgently required.


Barisiene M, Bakavicius A, Stanciute D, et al. Prostate Health Index and Prostate Health Index Density as Diagnostic Tools for Improved Prostate Cancer Detection. Biomed Res Int. 2020;2020:9872146. Published 2020 Jul 21. doi:10.1155/2020/9872146 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396080/

Background - To evaluate the diagnostic potential of [-2] proPSA (p2PSA), %p2PSA, Prostate Health Index (phi), and phi density (PHID) as independent biomarkers and in composition of multivariable models in predicting high-grade prostatic intraepithelial neoplasia (HGPIN) and overall and clinically significant prostate cancer (PCa).

Methods - 210 males scheduled for prostate biopsy with total PSA (tPSA) range 2-10 ng/mL and normal digital rectal examination were enrolled in the prospective study. Blood samples to measure tPSA, free PSA (fPSA), and p2PSA were collected immediately before 12-core prostate biopsy. Clinically significant PCa definition was based on Epstein's criteria or ISUP grade ≥ 2 at biopsy.

Results - PCa has been diagnosed in 112 (53.3%) patients. Epstein significant and ISUP grade ≥ 2 PCa have been identified in 81 (72.3%) and 40 (35.7%) patients, respectively. Isolated HGPIN at biopsy have been identified in 24 (11.4%) patients. Higher p2PSA and its derivative mean values were associated with PCa. At 90% sensitivity, PHID with cut-off value of 0.54 have demonstrated the highest sensitivity of 35.7% for overall PCa detection, so PHID and phi with cut-off values of 33.2 and 0.63 have demonstrated the specificity of 34.7% and 34.1% for ISUP grade ≥ 2 PCa detection at biopsy, respectively. In univariate ROC analysis, PHID with AUC of 0.77 and 0.80 was the most accurate predictor of overall and Epstein significant PCa, respectively, so phi with AUC of 0.77 was the most accurate predictor of ISUP grade ≥ 2 PCa at biopsy. In multivariate logistic regression analysis, phi improved diagnostic accuracy of multivariable models by 5% in predicting ISUP grade ≥ 2 PCa.

Conclusions - PHID and phi have shown the greatest specificity at 90% sensitivity in predicting overall and clinically significant PCa and would lead to significantly avoid unnecessary biopsies. PHID is the most accurate predictor of overall and Epstein significant PCa, so phi is the most accurate predictor of ISUP grade ≥ 2 PCa. phi significantly improves the diagnostic accuracy of multivariable models in predicting ISUP grade ≥ 2 PCa.

 

[Michael Scally MD]

Circulating Insulin-Like Growth Factor-I, Total and Free Testosterone Concentrations and Prostate Cancer Risk

Insulin‐like growth factor‐I (IGF‐I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full‐cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF‐I, sex hormone‐binding globulin (SHBG), total and calculated free testosterone concentrations with prostate cancer incidence and mortality.

For prospective analyses, risk was estimated using multivariable‐adjusted Cox regression in 199,698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. 2‐sample Mendelian randomization (MR) analysis of IGF‐I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79,148 cases and 61,106 controls). We used cis‐ and all (cis and trans) SNP MR approaches.

5,402 men were diagnosed with and 295 died from prostate cancer (mean follow‐up 6.9 years). Higher circulating IGF‐I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment=1.09, 95% CI 1.05‐1.12) and mortality (HR per 5 nmol/L increment=1.15,1.02‐1.29). MR analyses also supported the role of IGF‐I in prostate cancer diagnosis (cis‐MR odds ratio per 5 nmol/L increment=1.34,1.07‐1.68).

In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment=1.10,1.05‐1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment=0.95,0.94‐0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF‐I and free testosterone in prostate cancer development and/or progression.

Watts EL, Fensom GK, Smith Byrne K, Perez-Cornago A, Allen NE, Knuppel A, Gunter MJ, Holmes MV, Martin RM, Murphy N, Tsilidis KK, Yeap BB, Key TJ, Travis RC. Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank. Int J Cancer. 2020 Nov 30. doi: 10.1002/ijc.33416. Epub ahead of print. PMID: 33252839. https://onlinelibrary.wiley.com/doi/10.1002/ijc.33416

 

[Michael Scally MD]

Hypogonadism and Its Treatment Among Prostate Cancer Survivors

Adult-onset hypogonadism (AOH) is associated with sexual dysfunction, poor bone mineralization, decreased muscle mass, metabolic syndrome disorder, and cognitive suppression.

Historically, testosterone has been contraindicated in men with a history of prostate cancer. However, there has been a modern resurgence in re-evaluating this belief.

Not only can testosterone be safely utilized to alleviate AOH symptoms in prostate cancer survivors, it has been also touted as a treatment option for aggressive prostatic cancer.

While much work remains in understanding the relationship between testosterone and prostate cancer, those who survive this disease should not be automatically turned away from an opportunity to be treated and restored.

Choi, E.J., Xu, P., el-Khatib, F.M. et al. Hypogonadism and its treatment among prostate cancer survivors. Int J Impot Res (2020). https://doi.org/10.1038/s41443-020-00387-3

 

[Michael Scally MD]

Aurilio G, Cimadamore A, Mazzucchelli R, et al. Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications. Cells. 2020 Dec 10;9(12):E2653. doi: 10.3390/cells9122653. PMID: 33321757. https://www.mdpi.com/2073-4409/9/12/2653/htm

Around 80-90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient's response to androgen ablation therapy is variable, and 20-30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs.



Roggero CM, Jin L, Cao S, et al. A detailed characterization of stepwise activation of the androgen receptor variant 7 in prostate cancer cells. Oncogene. 2020 Dec 15. doi: 10.1038/s41388-020-01585-5. Epub ahead of print. PMID: 33323969. https://www.nature.com/articles/s41388-020-01585-5

Expression of the androgen receptor splice variant 7 (AR-V7) is frequently detected in castrate resistant prostate cancer and associated with resistance to AR-targeted therapies. While we have previously noted that homodimerization is required for the transcriptional activity of AR-V7 and that AR-V7 can also form heterodimers with the full-length AR (AR-FL), there are still many gaps of knowledge in AR-V7 stepwise activation. In the present study, we show that neither AR-V7 homodimerization nor AR-V7/AR-FL heterodimerization requires cofactors or DNA binding. AR-V7 can enter the nucleus as a monomer and drive a transcriptional program and DNA-damage repair as a homodimer. While forming a heterodimer with AR-FL to induce nuclear localization of unliganded AR-FL, AR-V7 does not need to interact with AR-FL to drive gene transcription or DNA-damage repair in prostate cancer cells that co-express AR-V7 and AR-FL. These data indicate that AR-V7 can function independently of its interaction with AR-FL in the true castrate state or "absence of ligand", providing support for the utility of targeting AR-V7 in improving outcomes of patients with castrate resistant prostate cancer.



Wang, Y.A., Sfakianos, J., Tewari, A.K. et al. Molecular tracing of prostate cancer lethality. Oncogene 39, 7225–7238 (2020). https://doi.org/10.1038/s41388-020-01496-5

Prostate cancer is diagnosed mostly in men over the age of 50 years, and has favorable 5-year survival rates due to early cancer detection and availability of curative surgical management. However, progression to metastasis and emergence of therapeutic resistance are responsible for the majority of prostate cancer mortalities. Recent advancement in sequencing technologies and computational capabilities have improved the ability to organize and analyze large data, thus enabling the identification of novel biomarkers for survival, metastatic progression and patient prognosis. Large-scale sequencing studies have also uncovered genetic and epigenetic signatures associated with prostate cancer molecular subtypes, supporting the development of personalized targeted-therapies. However, the current state of mainstream prostate cancer management does not take full advantage of the personalized diagnostic and treatment modalities available. This review focuses on interrogating biomarkers of prostate cancer progression, including gene signatures that correspond to the acquisition of tumor lethality and those of predictive and prognostic value in progression to advanced disease, and suggest how we can use our knowledge of biomarkers and molecular subtypes to improve patient treatment and survival outcomes.

 

[Michael Scally MD]

Endogenous Testosterone as A Predictor of Prostate Growing Disorders

Objective: To investigate the associations of endogenous testosterone with prostate growing disorders (PGD) including benign prostatic hyperplasia (BPH) and prostate cancer (PCA).

Methods: The study population was composed by 1176 cases including 371 BPH subjects (31.5%) without cancer who underwent prostate transurethral resection from January 2017 to November 2019 and 805 patients (68.5%) with PCA who underwent surgery from November 2014 to December 2019. The association of endogenous testosterone, which was measured before surgery, with the risk of PGD was evaluated by statistical methods.

Results: In the study population, endogenous testosterone levels were significantly lower in PCA cases compared to BPH patients who were older with larger prostates but lower prostate-specific antigen (PSA) levels.

On multivariate analysis, the risk of PCA decreased by endogenous testosterone (odds ratio, OR = 0.957; 95% CI 0.930-0.984; p = 0.002) as by age (OR = 0.955; 95% CI 0.933-0.984; p < 0,0001) and prostate volume (OR = 0.930; 95% CI 0.919-0.940; p < 0.0001) but increased by PSA (OR = 1.652; 95% CI 1.542-1.769; p < 0.0001).

On multivariate linear regression analysis, endogenous testosterone inversely associated with body mass index (BMI) (regression coefficient, b = - 0.279; p = 0.002) and PCA (b = - 2.935; p < 0.0001).

Conclusions: In the aging male, endogenous testosterone independently predicted malignant prostate disorders, which associated with decreased hormone levels along BMI categories. Endogenous testosterone is a further marker for evaluating prostate growing disorders in clinical practice; however, controlled studies are required.

Porcaro AB, Amigoni N, Tafuri A, et al. Endogenous testosterone as a predictor of prostate growing disorders in the aging male. Int Urol Nephrol. 2021 Jan 3. doi: 10.1007/s11255-020-02747-w. Epub ahead of print. PMID: 33389506. https://link.springer.com/article/10.1007/s11255-020-02747-w

 

[Michael Scally MD]

[OA] Updated Review of Testosterone Replacement Therapy in the Setting of Prostate Cancer

Since the 1940s, elevated serum testosterone (T) levels have been infamously suggested as a causal factor in the development of prostate cancer (PCa); this time was also the dawn of both surgically and pharmacologically induced castration. However, men suffering from primary or secondary hypogonadism and who are concomitantly paradoxically at risk for developing PCa cited the adverse effects of T deficiency.

In the past 25 years, researchers have published on the genetic, biochemical, and clinical outcomes of testosterone replacement therapy (TRT) in hypogonadal men. The longstanding dogma of the deleterious effects of TRT has recently been challenged, and it now appears that TRT may have an important therapeutic role in the treatment of hypogonadism in those men with either low-risk, active, or previously treated PCa.

This review summarizes the latest findings on the treatment of hypogonadal men with a history of PCa, emphasizing results of clinical research studies.

Polchert M, Voznesensky I, Soubra A, Hellstrom WJG. Updated Review of Testosterone Replacement Therapy in the Setting of Prostate Cancer. Androgens: Clinical Research and Therapeutics 2021;2:36-45. https://doi.org/10.1089/andro.2020.0013

 

[Michael Scally MD]

Hormonal Therapy for Prostate Cancer

Huggins and Hodges demonstrated the therapeutic effect of gonadal testosterone deprivation in the 1940s and therefore firmly established the concept that prostate cancer is a highly androgen-dependent disease.

Since that time, hormonal therapy has undergone iterative advancement, from the types of gonadal testosterone deprivation, to modalities that block the generation of adrenal and other extragonadal androgens, to those that directly bind and inhibit the androgen receptor (AR).

The clinical states of prostate cancer are the product of a superimposition of these therapies with non-metastatic advanced prostate cancer, as well as frankly metastatic disease. Today's standard of care for advanced prostate cancer includes gonadotropin-releasing hormone agonists (e.g. leuprolide), 2 nd-generation non-steroidal AR antagonists (enzalutamide, apalutamide, and darolutamide) and the androgen biosynthesis inhibitor abiraterone.

The purpose of this review is to provide an assessment of hormonal therapies for the various clinical states of prostate cancer. The advancement of today's standard of care will require an accounting of an individual's androgen physiology that also has recently recognized germline determinants of peripheral androgen metabolism, which include HSD3B1 inheritance.

Desai K, McManus J, Sharifi N. Hormonal Therapy for Prostate Cancer. Endocr Rev. 2021 Jan 22:bnab002. doi: 10.1210/endrev/bnab002. Epub ahead of print. PMID: 33480983. https://academic.oup.com/edrv/advance-article/doi/10.1210/endrev/bnab002/6106550

 

[Michael Scally MD]

Testosterone Therapy After Prostate Cancer Treatment: A Review of Literature

Introduction: Although testosterone therapy (TTh) is the standard practice in otherwise healthy hypogonadal men, this therapy has historically been contraindicated in men with a history of prostate cancer. Recent evidence suggests that there is minimal or no prostate cancer growth in the setting of TTh administration in men definitively treated for non-metastatic prostate cancer.

Objective: To review the evidence supporting the safety and efficacy of TTh in patients previously treated for localized prostate cancer.

Methods: A literature review of the PubMed database was performed to identify studies evaluating the safety and efficacy of TTh in patients with a history of prostate cancer. Search terms included Testosterone Therapy, Testosterone Replacement Therapy and Radical Prostatectomy, Radiotherapy, External Beam Radiation Therapy, EBRT, Brachytherapy; Prostate Cancer and Hypogonadism, Low Testosterone; Bipolar Androgen Therapy.

Results: Available literature provides evidence for the safe application of TTh in patients previously treated for prostate cancer with either radical prostatectomy or radiotherapy. Furthermore, there exists evidence that severely hypogonadal levels of testosterone may lead to worse oncological outcomes. More recent research has begun to elucidate the effectiveness of bipolar androgen deprivation therapy in the treatment of prostate cancer.

This mechanism of action increases the level of evidence indicating that the traditional management of maintaining testosterone levels at low levels may no longer be standard of care. TTh likely has a role in improved erectile function and other quality-of-life concerns in patients developing testosterone deficiency after being treated for prostate cancer.

Conclusions: TTh should be offered to select hypogonadal patients who have a history of definitively treated prostate cancer. Adequately designed randomized controlled trials are necessary to confirm the safety and efficacy of TTh in this population.

Natale C, Carlos C, Hong J, Khera M, Baum N, Raheem OA. Testosterone Therapy After Prostate Cancer Treatment: A Review of Literature. Sex Med Rev. 2021 Jan 27:S2050-0521(20)30141-4. doi: 10.1016/j.sxmr.2020.12.003. Epub ahead of print. PMID: 33516741. https://www.sciencedirect.com/science/article/abs/pii/S2050052120301414?via%3Dihub

 

[Michael Scally MD]

View: https://twitter.com/daviesbj/status/1357651494141628416?s=20

 

[Michael Scally MD]

Comparison of Multiparametric Magnetic Resonance Imaging–Targeted Biopsy With Systematic Transrectal Ultrasonography Biopsy for Biopsy-Naive Men at Risk for Prostate Cancer

Key Points

Question Is magnetic resonance imaging (MRI) with targeted biopsy only noninferior to systematic biopsy for the diagnosis of clinically significant prostate cancer (PCa)?

Findings In this prospective phase 3 randomized clinical trial of 453 men, clinically significant cancer was found in 35% vs 30% in the MRI and systematic biopsy arms, respectively, which demonstrated noninferiority. A total of 79 participants in the MRI arm (37%) avoided a biopsy, and diagnosis of grade group 1 PCa was reduced by more than 50%.

Meaning Magnetic resonance imaging with targeted biopsy alone resulted in similar detection rates of clinically significant PCa while avoiding biopsy in more than one-third of men and reducing the diagnosis of clinically insignificant cancer.

Klotz L, Chin J, Black PC, et al. Comparison of Multiparametric Magnetic Resonance Imaging–Targeted Biopsy With Systematic Transrectal Ultrasonography Biopsy for Biopsy-Naive Men at Risk for Prostate Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. Published online February 04, 2021. https://jamanetwork.com/journals/jamaoncology/article-abstract/2775932

Importance Magnetic resonance imaging (MRI) with targeted biopsy is an appealing alternative to systematic 12-core transrectal ultrasonography (TRUS) biopsy for prostate cancer diagnosis, but has yet to be widely adopted.

Objective To determine whether MRI with only targeted biopsy was noninferior to systematic TRUS biopsies in the detection of International Society of Urological Pathology grade group (GG) 2 or greater prostate cancer.

Design, Setting, and Participants This multicenter, prospective randomized clinical trial was conducted in 5 Canadian academic health sciences centers between January 2017 and November 2019, and data were analyzed between January and March 2020. Participants included biopsy-naive men with a clinical suspicion of prostate cancer who were advised to undergo a prostate biopsy.

Clinical suspicion was defined as a 5% or greater chance of GG2 or greater prostate cancer using the Prostate Cancer Prevention Trial Risk Calculator, version 2. Additional criteria were serum prostate-specific antigen levels of 20 ng/mL or less (to convert to micrograms per liter, multiply by 1) and no contraindication to MRI.

Interventions Magnetic resonance imaging–targeted biopsy (MRI-TB) only if a lesion with a Prostate Imaging Reporting and Data System (PI-RADS), v 2.0, score of 3 or greater was identified vs 12-core systematic TRUS biopsy.

Main Outcome and Measures The proportion of men with a diagnosis of GG2 or greater cancer. Secondary outcomes included the proportion who received a diagnosis of GG1 prostate cancer; GG3 or greater cancer; no significant cancer but subsequent positive MRI results and/or GG2 or greater cancer detected on a repeated biopsy by 2 years; and adverse events.

Results The intention-to-treat population comprised 453 patients (367 [81.0%] White, 19 [4.2%] African Canadian, 32 [7.1%] Asian, and 10 [2.2%] Hispanic) who were randomized to undergo TRUS biopsy (226 [49.9%]) or MRI-TB (227 [51.1%]), of which 421 (93.0%) were evaluable per protocol.

A lesion with a PI-RADS score of 3 or greater was detected in 138 of 221 men (62.4%) who underwent MRI, with 26 (12.1%), 82 (38.1%), and 30 (14.0%) having maximum PI-RADS scores of 3, 4, and 5, respectively. Eighty-three of 221 men who underwent MRI-TB (37%) had a negative MRI result and avoided biopsy. Cancers GG2 and greater were identified in 67 of 225 men (30%) who underwent TRUS biopsy vs 79 of 227 (35%) allocated to MRI-TB (absolute difference, 5%, 97.5% 1-sided CI, −3.4% to ∞; noninferiority margin, −5%).

Adverse events were less common in the MRI-TB arm. Grade group 1 cancer detection was reduced by more than half in the MRI arm (from 22% to 10%; risk difference, −11.6%; 95% CI, −18.2% to −4.9%).

Conclusions and Relevance Magnetic resonance imaging followed by selected targeted biopsy is noninferior to initial systematic biopsy in men at risk for prostate cancer in detecting GG2 or greater cancers.


Rouvière O. Choosing the Right Diagnostic Pathway in Biopsy-Naive Patients With Suspected Prostate Cancer. JAMA Oncol. Published online February 04, 2021. https://jamanetwork.com/journals/jamaoncology/article-abstract/2775928

In the prospective multicenter Prostate Evaluation for Clinically Important Disease: Sampling Using Image-Guidance or Not? (PRECISION) trial,1 500 biopsy-naive patients with suspected prostate cancer were randomly assigned to either classical 10- to 12-core systematic biopsy or to magnetic resonance imaging (MRI) and targeted biopsy without systematic biopsy if MRI was suggestive of cancer.

The detection rate for cancers with an International Society of Urological Pathology (ISUP) grade 2 or higher was significantly higher in men assigned to MRI and targeted biopsy (38%) than in those assigned to systematic biopsy (26%; P = .005). In addition, overdiagnosis of ISUP grade 1 cancer was reduced in the MRI-targeted biopsy group (9% vs 22%, P < .001), and 28% of men in this group avoided biopsy.

 

[Michael Scally MD]

[OA] Low Serum Testosterone and Prostate Cancer Behaviour - Any Correlation

Background and Objective: Prostate cancer is one amongst the most common medical diseases affecting elderly men. Carcinoma of the prostate is being the most common non-cutaneous cancer diagnosed.

The lifetime risk of prostatic carcinoma is 16.7 % and the risk of death during the entire lifetime is around 2.6% for men but the overall lifetime risk of death due to prostate malignancy is low in comparison to lifetime risk of diagnosis.

Prostate cancer is a hormone dependant cancer and the clinical course of prostate cancer varies with individual and again it varies within the individual in relationship to serum testosterone levels.

The present study is to find out the role of low serum testosterone level in predicting prostate cancer behaviour in comparison with normal serum testosterone level patients and to find out the relationship between low serum testosterone level and serum PSA levels in TRUS biopsy proven cancer prostate patients.

The primary aim and objective of our study is to determine the association of low serum testosterone and prostate cancer behaviour and with a Secondary objective to determine the relationship of serum PSA level in cancer prostate patients with low serum testosterone.

Methodology: Informed consent was obtained from all patients. All TRUS biopsy proven caner prostate patients were enrolled to a maximum number of 100. All details were recorded. Blood investigations like serum PSA, serum testosterone and other baseline investigations were obtained. The serum determinations of Testosterone obtained between 7 – 9.30 am.

The serum Testosterone levels measured by appropriate standard protocols. Patients were divided into two groups based on the serum testosterone levels. Patients with low serum testosterone levels (< 250 ng/dl) were categorized as Group A and patients with normal serum testosterone levels (> 250 ng/dl) were categorized as Group B and the findings between two groups will be compared.

Results: Total of 106 patients with cancer prostate were taken into our study of which 5 patients on 5 alpha reductase inhibitors and 1 patient on testosterone replacement therapy were excluded from our study and finally 100 patients were enrolled in our study of which patients with low testosterone level (<250 ng/dl) were categorized as group A and the remaining patients with normal testosterone level (> 250 ng/dl) were categorized as group B.

The majority (74%) of patients in low testosterone group has got a serum PSA of more than 20 values compared with only 34% of patients in the corresponding group. P value is found to be statistically significant. Most of the patients (82.6%) in low testosterone group had a higher Gleason grade (8-10) compared to the normal testosterone group. P value is found statistically significant.

Conclusion: Low total serum testosterone is associated with higher proportion of predominant Gleason pattern 4, an indicator of aggressive prostate cancer. Patients with low serum testosterone levels were associated with an increased serum PSA levels compared with patients in normal serum testosterone levels.

Patients with low testosterone who were managed by radical prostatectomy had a higher proportion of positive surgical margin, extra capsular extension and seminal Vesical invasion suggesting an aggressive prostate cancer behaviour. Preoperative total testosterone should be routinely added to serum prostate specific antigen estimation to improve prostate cancer management.

Preetam Penumatcha, Krishna Rao. Low serum testosterone and prostate cancer behaviour - any correlation. Int J Surg Sci 2021;5(1):128-135. DOI: Low serum testosterone and prostate cancer behaviour - any correlation / Low serum testosterone and prostate cancer behaviour - any correlation

 

[Michael Scally MD]

[OA] Is serum PSA a predictor of male hypogonadism?

Objective: Male hypogonadism (MH) is common among infertile men. Besides testosterone, limited MH biomarkers are available, while researchers have suggested the use of prostate-specific antigen (PSA) to help diagnose MH. Hence, we sought to evaluate the potential use of PSA to predict MH among relatively young men with infertility in Nigeria.

Methods: The study included 707 male partners (35-44 years) in infertile couples seeking infertility evaluation at a third-level care center in Nigeria. MH was diagnosed using standard guidelines. Receiver operating characteristic (ROC) and regression analyses explored the potential of serum free PSA (fPSA) and total PSA (tPSA) in predicting MH and MH-related clinical features.

Results: In all, 29.7% of the patients had MH (MH+ve). The MH+ve group had lower mean values of fPSA and tPSA than the group without MH (MH-ve). The best fPSA threshold of < 0.25 μg/L compared with the best tPSA threshold of < 0.74 μg/L had higher accuracy (area under the curve [AUC] 0.908 versus 0.866, respectively), sensitivity (87% versus 83%, respectively), and specificity (42% versus 37%, respectively) for MH diagnosis. After adjustment for confounders, fPSA level ≤ 0.25 μg/L was more likely to predict MH-related decreased libido (odds ratio [OR] 2.728, p<0.001) and erectile dysfunction (OR 3.925, p<0.001) compared with tPSA ≤ 0.74 μg/L in the MH+ve group.

Conclusion: For MH diagnosis, fPSA and tPSA had good sensitivity but very poor specificity, although fPSA had better potential for MH diagnosis and association with MH-related clinical features than tPSA. Hence, fPSA could complement other biomarkers for MH diagnosis in men 35-44 years, although we recommend further studies to confirm these findings.

Amadi C, Green KI, Odum EP. Is serum PSA a predictor of male hypogonadism? Testing the hypothesis. Arch Endocrinol Metab. 2021 Feb 15:2359-3997000000326. doi: 10.20945/2359-3997000000326. Epub ahead of print. PMID: 33587836. https://www.aem-sbem.com/media/uploads/2020-0214.pdf

 

[Michael Scally MD]

[OA] Serum Prostate-Specific Antigen Testing for Early Detection of Prostate Cancer: Managing the Gap between Clinical and Laboratory Practice

Background: Current clinical practice guidelines (CPGs) for early detection of prostate cancer recommend for clinical decision-making a personalized prostate-specific antigen (PSA)-based management to improve the risk-benefit ratio of the screening strategy. Some important critical issues regarding the PSA determination in the clinical framework are, however, still neglected in current guidelines and a major focus of recommendations on those aspects would be needed to improve their effectiveness.

Content: Evidence sources in the available literature concerning the interchangeability of total PSA results measured with different commercial methods were critically appraised. We discuss how the heterogeneity of the measurand, the intermethod bias, and the design and selectivity of immunoassays may affect the diagnostic accuracy of selected PSA thresholds, and how knowledge of the analytical characteristics of assays in service, such as the recognized PSA circulating forms and the cross-reactivity with PSA homologs, is basic for improving both clinical decision-making in cancer screening and the reliability of the clinical interpretation of results at the individual level.

Summary: Current CPGs ignore the poor interchangeability of PSA results obtained from different assays and the substantial role of laboratory issues in clinical performance of PSA testing.

Involved stakeholders should contribute to fill the existing gap by:

(a) preparing commutable reference materials for immunoassay calibration;

(b) providing analytical characteristics that may explain the different performance of assays;

(c) deriving outcome-based analytical performance specifications for PSA measurement; and

(d) giving more focus on laboratory items when CPGs are prepared.

Ferraro S, Bussetti M, Panteghini M. Serum Prostate-Specific Antigen Testing for Early Detection of Prostate Cancer: Managing the Gap between Clinical and Laboratory Practice. Clin Chem. 2021 Feb 23:hvab002. doi: 10.1093/clinchem/hvab002. Epub ahead of print. PMID: 33619518. Serum Prostate-Specific Antigen Testing for Early Detection of Prostate Cancer: Managing the Gap between Clinical and Laboratory Practice

 

[Michael Scally MD]

[OA] Endocrinology of the Aging Prostate

Benign prostate hyperplasia (BPH), one of the most common diseases in older men, adversely affects quality-of-life due to the presence of low urinary tract symptoms (LUTS). Numerous data support the presence of an association between BPH-related LUTS (BPH-LUTS) and metabolic syndrome (MetS). Whether hormonal changes occurring in MetS play a role in the pathogenesis of BPH-LUTS is a debated issue.

Therefore, this article aimed to systematically review the impact of hormonal changes that occur during aging on the prostate, including the role of sex hormones, insulin-like growth factor 1, thyroid hormones, and insulin. The possible explanatory mechanisms of the association between BPH-LUTS and MetS are also discussed.

In particular, the presence of a male polycystic ovarian syndrome (PCOS)-equivalent may represent a possible hypothesis to support this link. Male PCOS-equivalent has been defined as an endocrine syndrome with a metabolic background, which predisposes to the development of type II diabetes mellitus, cardiovascular diseases, prostate cancer, BPH and prostatitis in old age. Its early identification would help prevent the onset of these long-term complications.

Cannarella R, Condorelli RA, Barbagallo F, La Vignera S, Calogero AE. Endocrinology of the Aging Prostate: Current Concepts. Front Endocrinol (Lausanne). 2021 Feb 22;12:554078. doi: 10.3389/fendo.2021.554078. PMID: 33692752; PMCID: PMC7939072. Endocrinology of the Aging Prostate: Current Concepts

 

[Michael Scally MD]

[OA] Prostate Cancer Screening-The Need for and Clinical Relevance of Decision Analytical Models

Prostate cancer affects men’s health worldwide, being the second most common cancer in Western countries, surpassed only by nonmelanoma skin cancers. Prostate cancer is a localized disease that rarely exhibits symptoms, and its aggressiveness varies significantly between indolent disease to highly aggressive cancer. Moreover, risk factors for prostate cancer differ for every individual, based on family history, race/ethnicity, and other factors.

The diagnostic strategies using prostate-specific antigen (PSA) screening have been controversial since the PSA protein was identified more than 4 decades ago. Frequent, opportunistic PSA screening is initiated by the patient or physician for reasons specific to each individual patient, which is a strategy that entails the risk of either overdiagnosis or undertreatment. However, recent advances in diagnostic imaging and therapy argue for more timely diagnostic strategies based on a risk-stratified approach.

Borre M. Prostate Cancer Screening-The Need for and Clinical Relevance of Decision Analytical Models. JAMA Netw Open. 2021 Mar 1;4(3):e212182. doi: 10.1001/jamanetworkopen.2021.2182. PMID: 33704471. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777398

 

[Michael Scally MD]

[OA] Benefit, Harm, and Cost-effectiveness Associated with Magnetic Resonance Imaging Before Biopsy in Age-based and Risk-stratified Screening for Prostate Cancer

Importance: If magnetic resonance imaging (MRI) mitigates overdiagnosis of prostate cancer while improving the detection of clinically significant cases, including MRI in a screening program for prostate cancer could be considered.

Objective: To evaluate the benefit-harm profiles and cost-effectiveness associated with MRI before biopsy compared with biopsy-first screening for prostate cancer using age-based and risk-stratified screening strategies.

Design, setting, and participants: This decision analytical model used a life-table approach and was conducted between December 2019 and July 2020. A hypothetical cohort of 4.48 million men in England aged 55 to 69 years were analyzed and followed-up to 90 years of age.

Exposures: No screening, age-based screening, and risk-stratified screening in the hypothetical cohort. Age-based screening consisted of screening every 4 years with prostate-specific antigen between the ages of 55 and 69 years. Risk-stratified screening used age and polygenic risk profiles.

Main outcomes and measures: The benefit-harm profile (deaths from prostate cancer, quality-adjusted life-years, overdiagnosis, and biopsies) and cost-effectiveness (net monetary benefit, from a health care system perspective) were analyzed. Both age-based and risk-stratified screening were evaluated using a biopsy-first and an MRI-first diagnostic pathway. Results were derived from probabilistic analyses and were discounted at 3.5% per annum.

Results: The hypothetical cohort included 4.48 million men in England, ranging in age from 55 to 69 years (median, 62 years). Compared with biopsy-first age-based screening, MRI-first age-based screening was associated with 0.9% (1368; 95% uncertainty interval [UI], 1370-1409) fewer deaths from prostate cancer, 14.9% (12 370; 95% UI, 11 100-13 670) fewer overdiagnoses, and 33.8% (650 500; 95% UI, 463 200-907 000) fewer biopsies.

At 10-year absolute risk thresholds of 2% and 10%, MRI-first risk-stratified screening was associated with between 10.4% (7335; 95% UI, 6630-8098) and 72.6% (51 250; 95% UI, 46 070-56 890) fewer overdiagnosed cancers, respectively, and between 21.7% fewer MRIs (412 100; 95% UI, 411 400-412 900) and 53.5% fewer biopsies (1 016 000; 95% UI, 1 010 000-1 022 000), respectively, compared with MRI-first age-based screening.

The most cost-effective strategies at willingness-to-pay thresholds of £20 000 (US $26 000) and £30 000 (US $39 000) per quality-adjusted life-year gained were MRI-first risk-stratified screening at 10-year absolute risk thresholds of 8.5% and 7.5%, respectively.

Conclusions and relevance: In this decision analytical model of a hypothetical cohort, an MRI-first diagnostic pathway was associated with an improvement in the benefit-harm profile and cost-effectiveness of screening for prostate cancer compared with biopsy-first screening. These improvements were greater when using risk-stratified screening based on age and polygenic risk profile and may warrant prospective evaluation.

Callender T, Emberton M, Morris S, Pharoah PDP, Pashayan N. Benefit, Harm, and Cost-effectiveness Associated with Magnetic Resonance Imaging Before Biopsy in Age-based and Risk-stratified Screening for Prostate Cancer. JAMA Netw Open. 2021 Mar 1;4(3):e2037657. doi: 10.1001/jamanetworkopen.2020.37657. PMID: 33704474. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777401