Prostate ...

[Michael Scally MD]

[OA] Association of Statin Use with Risk of Gleason Score-Specific Prostate Cancer

Background Conflicting evidence suggests that statins act chemopreventively against prostate cancer (PCa). Whether the association of statin use with PCa risk is Gleason score-dependent, time-, dose-respondent is not well studied.

Methods We conducted a cohort study at a tertiary hospital in the Southeastern US using longitudinal data of electronic medical records (EMR) from 1994 to 2016. Only cancer-free men aged >18 years at baseline with follow-up time of ≥12 months were included. Time-dependent Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs).

Results Among 13 065 men, 2976 were diagnosed with PCa over median follow-up of 6.6 years. Statin use was associated with lower risk of both Gleason low- (score <7: aHR, 0.85; 95% CI, 0.74-0.96) and high-grade PCa (score ≥7: aHR, 0.54; 95% CI, 0.42-0.69).

The protective association was observed only when statins had been used for a relatively longer duration (≥11 months) or higher dose (≥121 defined daily doses), and were more pronounced for PCa of higher Gleason score (<7: aHR, 0.85, 95% CI, 0.74-0.96; 7 [3 + 4]: aHR, 0.62, 95% CI, 0.43-0.90; 7 [4 + 3]: aHR, 0.49, 95% CI, 0.29-0.82; 8: aHR, 0.60, 95% CI, 0.37-0.96; 9-10: aHR, 0.24, 95% CI, 0.11-0.54). Lipophilic statins (aHR, 0.83; 95% CI, 0.72-0.95) might be more protective than hydrophilic statins (aHR, 0.91, 95% CI, 0.63-1.33) against PCa.

Conclusion Statin use might be associated with reduced PCa risk only when used for a relatively longer duration, and the risk reduction was higher for PCa of higher Gleason score.

Wang K, Gerke TA, Chen X, Prosperi M. Association of statin use with risk of Gleason score-specific prostate cancer: A hospital-based cohort study. Cancer Medicine 2019;0. Error - Cookies Turned Off

 

[Michael Scally MD]

[OA] Pursuing an Elusive Prostate Carcinoma: A Case Report Involving Multiparametric MR and CT-Guided Biopsy

Prostate cancer is usually diagnosed when elevated PSA levels lead to a TRUS biopsy. We present a case in which there were several negative biopsies and a rising PSA.

This led to a multiparametric MR (mpMRI) which demonstrated a large mass which originated in the anterior transition zone and had extended through the anterior fibromuscular stroma and prostate capsule with a significant extra-prostatic component.

The mass was successfully approached anteriorly with a CT-guided biopsy. The patient was subsequently successfully treated with radiotherapy utilizing MR in the planning process.

This case report summarizes the utility of mpMRI in this clinical setting. For patients with high suspicion of prostate malignancy despite prior negative biopsies, it can identify tumor in locations not amenable to TRUS biopsy. It also is critical for accurate radiation treatment planning, allowing for increased confidence in tumor targeting as well as sparing sensitive normal tissue.

Olson DO, Baisden JM, Groten DL, Talug C. Pursuing an Elusive Prostate Carcinoma: A Case Report Involving Multiparametric MR and CT-Guided Biopsy. Case reports in oncology 2019;12:737-41. Pursuing an Elusive Prostate Carcinoma: A Case Report Involving Multiparametric MR and CT-Guided Biopsy

 

[Michael Scally MD]

[OA] Non-nuclear AR Signaling in Prostate Cancer

Despite the key role played by androgen receptor (AR) in tumor cell aggressiveness and prostate cancer (PCa) progression, its function in the tumor microenvironment (TME) is still controversial. Increasing studies highlight the crucial role played by TME modulation in treatment outcome and tumor cell spreading.

In this context, targeting specific constituents of the TME could be considered an alternative approach to classic treatments directed against cancer cells. Currently, androgen deprivation therapy (ADT) is a routinely adopted strategy in the management of PCa, with initial success, and consecutive fail.

A possible justification to this is the fact that ADT aims to target all the transcription/translation-related activities of AR, which are typical of tumor epithelial cells. Less is still known about side effects of ADT on TME.

Cancer Associated Fibroblasts (CAFs), for example, express a classic AR, mostly confined in the extra-nuclear portion of the cell. In CAFs ADT exerts a plethora of non-transcriptional effects, depending by the protein partner linked to AR, leading to cell migration, proliferation, and differentiation.

In recent years, substantial progress in the structure-function relationships of AR, identification of its binding partners and function of protein complexes including AR have improved our knowledge of its signaling axis. Important AR non-genomic effects and lots of its cytoplasmatic binding partners have been described, pointing out a fine control of AR non-genomic pathways.

Accordingly, new AR inhibitors have been designed and are currently under investigation. Prompt development of new approaches to target AR or block recruitment of its signaling effectors, or co-activators, is urgently needed. The present review takes an in-depth look at current literature, furnishing an exhaustive state-of-the-art overview of the non-genomic role of AR in PCa, with particular emphasis on its involvement in TME biology.

Zamagni A, Cortesi M, Zanoni M, Tesei A. Non-nuclear AR Signaling in Prostate Cancer. Frontiers in chemistry 2019;7:651. Non-nuclear AR Signaling in Prostate Cancer

 

[Michael Scally MD]

Aging, Fat Mass, and Prostate Cancer: Is It the Time to Reconsider Testosterone?

The rising epidemic of obesity and metabolic syndrome leads to an ever-growing attention by the public health systems. It is well known that these conditions are associated with the development of metabolic and cardiovascular diseases, such as type 2 diabetes (T2D), heart failure and stroke, requiring chronic therapies, hospitalizations and invasive procedures.

However, the burden of obesity is related not only with cardio-metabolic complications but also with the risk of developing some forms of cancer. In fact, obesity and metabolic syndrome are now recognized as risk factors for several types of cancers, … with high BMI being associated with higher cancer invasiveness and mortality.

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In the light of the increasing demand for testosterone replacement therapy in obesity, metabolic syndrome and aging, which can no longer be neglected, the overall risk profile of hormonal replacement therapy has to be reconsidered, properly balancing the negative and the beneficial effects.

Future studies have to be provided to confirm the anti-inflammatory, well-aging, and anti-neoplastic potential of testosterone, together with its long-term complications. Furthermore, considering the lack of a standardized approach in clinical practice for testosterone measurement in patients diagnosed with PCa, future works could also assess how many clinicians evaluate testosterone at the diagnosis, and how often the determination of testosterone plasma levels should be performed over time.

Di Vincenzo A, El Hadi H, Vettor R, Rossato M. Aging, fat mass, and prostate cancer: is it the time to reconsider testosterone? Aging Clinical and Experimental Research 2019. https://doi.org/10.1007/s40520-019-01372-7

 

[Michael Scally MD]

Sex Hormones and Prostate Cancer

The prostate is an androgen-dependent organ that develops only in male mammals. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer deaths.

Metastatic prostate cancer initially retains its androgen dependence, and androgen-deprivation therapy often leads to disease control; however, the cancer inevitably progresses despite treatment as castration-resistant prostate cancer, the lethal form of the disease.

Although it was assumed that the cancer became androgen independent during this transition, studies over the last two decades have shown that these tumors evade treatment via mechanisms that augment acquisition of androgens from circulating precursors, increase sensitivity to androgens and androgen precursors, bypass the androgen receptor, or a combination of these mechanisms.

This review summarizes the history of prostate cancer research leading to the contemporary view of androgen dependence for prostate cancers and the current treatment approaches based on this modern paradigm.

Auchus RJ, Sharifi N. Sex Hormones and Prostate Cancer. Annual review of medicine 2019. https://www.annualreviews.org/doi/10.1146/annurev-med-051418-060357

 

[Michael Scally MD]

Association of Long-Term Dynamics in Circulating Testosterone with Serum PSA in Prostate Cancer-Free Men with Initial-PSA < 4 ng/mL

We previously reported that an accelerated decline in circulating testosterone level is associated with a higher risk of prostate cancer (PCa). This study is to examine whether testosterone change rate is related to serum prostate-specific antigen (PSA) concentration among PCa-free men.

Longitudinal data were derived from electronic medical records at a tertiary hospital in the Southeastern USA. PCa-free men with initial-PSA < 4 ng/mL and >/= 2 testosterone measurements were included (n = 632). Three PSA measures (peak, the most recent, and average PSA) during the study period (from first testosterone measurement to the most recent hospital visit) were examined using multivariable-adjusted geometric means and were compared across quintiles of testosterone change rate (ng/dL/month) and current testosterone level (cross-sectional).

Mean (standard deviation, SD) age at baseline was 59.3 (10.5) years; mean study period was 93.0 (55.3) months. After adjusting for covariates including baseline testosterone, the three PSA measures all significantly increased across quintile of testosterone change rate from increase to decline (peak PSA: quint 1 = 1.09, quint 5 = 1.41; the most recent PSA: quint 1 = 0.85, quint 5 = 1.00; average PSA: quint 1 = 0.89, quint 5 = 1.02; all Ptrend < 0.001). But current testosterone level was not associated with PSA levels.

Stratified analyses indicated men with higher adiposity (body mass index > 24.1 kg/m(2)) or lower baseline testosterone (</= 296 ng/dL) were more sensitive to testosterone change in regard to PSA. Among PCa-free men, accelerated testosterone decline might correlate with higher serum PSA concentration. It will help to elucidate the mechanisms relating aging-accompanying testosterone dynamics to prostate carcinogenesis.

Wang K, Chen X, Cheng TD, Qiu P, Bird VY, Prosperi M. Association of Long-Term Dynamics in Circulating Testosterone with Serum PSA in Prostate Cancer-Free Men with Initial-PSA < 4 ng/mL. Hormones & cancer 2019. Association of Long-Term Dynamics in Circulating Testosterone with Serum PSA in Prostate Cancer-Free Men with Initial-PSA < 4 ng/mL

 

[Michael Scally MD]

[OA] Risk of Dementia and Depression in Young and Middle-aged Men Presenting with Nonmetastatic Prostate Cancer Treated with Androgen Deprivation Therapy

BACKGROUND: Previous studies have found an association between androgen deprivation therapy (ADT) and an increased risk of dementia and depression in elderly men. This association remains controversial, and little is known about the effects of ADT in younger men.

OBJECTIVE: To examine the association between the receipt of ADT and these outcomes in young men aged 40-64 yr presenting with nonmetastatic prostate cancer (PCa).

DESIGN, SETTING, AND PARTICIPANTS: For this observational study, we identified 9117 men aged 40-64 yr diagnosed with localized PCa between 2007 and 2014, without a pre-existing neurocognitive diagnosis, using the TRICARE military database.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier curves were fitted to compare ADT versus no ADT. We also performed a subgroup analysis in patients undergoing ADT for >/=12 mo. The association between ADT and new-onset dementia or depression was evaluated using inverse-probability-of treatment-weight-adjusted Cox proportional hazards regression analysis.

RESULTS AND LIMITATIONS: Patients receiving ADT had a significantly higher incidence of depression (30.2 vs 15.8 per 1000 person years) and dementia (17.9 vs 7.5 per 1000 person years). The risk of developing either outcome was higher in the ADT cohort (depression: hazard ratio

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2.07, p < 0.001; dementia: HR 1.70, p = 0.052). Additionally, there was a dose-response relationship between the duration of ADT and either outcome.

CONCLUSIONS: In our cohort of young men with PCa, the receipt of ADT was associated with an increased risk of developing dementia and depression. Long-term use of ADT was associated with the highest risk of neurocognitive outcomes.

PATIENT SUMMARY: In this study, we looked at the risk of dementia and depression in patients <65 yr of age undergoing androgen deprivation therapy (ADT) for prostate cancer. We found that these patients had a higher risk of dementia and depression than those who did not undergo ADT.

Tully KH, Nguyen DD, Herzog P, et al. Risk of Dementia and Depression in Young and Middle-aged Men Presenting with Nonmetastatic Prostate Cancer Treated with Androgen Deprivation Therapy. European urology oncology 2019. https://euoncology.europeanurology.com/article/S2588-9311(19)30129-4/fulltext

 

[Michael Scally MD]

Testosterone Therapy in Relation to Prostate Cancer in A US Commercial Insurance Claims Database

Background: We conducted a study assess whether testosterone therapy (TT) alters prostate cancer risk using a large US commercial insurance research database.

Methods: From the HealthCore Integrated Research Database (HIRDSM), we selected men aged 30 years or greater who were new users of TT during 2007-2015.

We selected two comparison groups:
1) unexposed (matched 10:1);
2) new users of phosphodiesterase type 5 inhibitor (PDE5i).

Incident prostate cancer was defined as diagnosis of prostate cancer within four-weeks following prostate biopsy. Propensity scores and inverse probability of treatment weights were used in Poisson regression models to estimate adjusted incidence rates, incidence rate ratios (IRRs) and 95% confidence intervals (CI). Subgroup analyses included stratification by prostate cancer screening, hypogonadism, and follow-up time.

Results: The adjusted prostate cancer IRR was 0.77 (95%CI: 0.68, 0.86) when comparing TT with the unexposed group and 0.85 (95%CI: 0.79, 0.91) in comparison with the PDE5i group. Inverse associations between TT and prostate cancer were observed in a majority of subgroup analyses, although in both comparisons estimates generally attenuated with increasing time following initial exposure. Amongst TT users, duration of exposure was not associated with prostate cancer.

Conclusions: Men who received TT did not have a higher rate of prostate cancer compared with the unexposed or PDE5i comparison groups. The inverse association between TT and prostate cancer could be the result of residual confounding, contraindication bias, or undefined biologic effect. Impact: This study suggests that limited TT exposure does not increase risk of prostate cancer in the short-term.

Cook MB, Beachler DC, Parlett LE, et al. Testosterone therapy in relation to prostate cancer in a US commercial insurance claims database. Cancer Epidemiology Biomarkers & Prevention 2019. Testosterone therapy in relation to prostate cancer in a US commercial insurance claims database

 

[Michael Scally MD]

Should We Even Talk About a PSA?
Should We Even Talk About a PSA?

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Although the PSA test was not developed to screen asymptomatic men for prostate cancer, primary care physicians were persuaded by expert opinion to use it for nearly two decades in this way before the publication of the only US trial testing its efficacy. That study, and its subsequent reports, found that the test did not decrease prostate cancer deaths and there was clear evidence of harm to the screening group. It has appropriately led to less PSA screening being performed in the United States, ensuring that fewer patients suffer from a needless test.

In contrast to the USPSTF's current recommendation to discuss the pros and cons of PSA-based screening, the best evidence indicates that routine use of a decision aid does not improve clinical outcomes. My practice, therefore, follows the lead of the AAFP. I do not recommend prostate cancer screening. If patients ask me about it, I tell them, "The PSA test is unlikely to help you and is much more likely to cause harm." If they still want the test, I will order it. These patients, at least, know what they are getting themselves into rather than being stranded with millions of other men on the shores of SDM.

 

[Michael Scally MD]

Huynh LM, Ahlering TE. Challenging beliefs of testosterone therapy and prostate cancer. Nature Reviews Urology 2019. https://doi.org/10.1038/s41585-019-0253-8

The relationship between testosterone therapy and prostate cancer continues to challenge historic and current beliefs. A new cohort analysis revealed a ~33% reduction in prostate cancer incidence in men with increased testosterone use. The mechanisms underlying this protective effect are unclear, but these findings challenge current paradigms and warrant further investigation.

 

[Michael Scally MD]

[OA] Performance and Inter-Observer Variability of Prostate MRI

Objective: Despite the growing trend to embrace pre-biopsy MRI in the diagnostic pathway for prostate cancer (PC), its performance and inter-observer variability outside high-volume centres remains unknown. This study aims to evaluate sensitivity of and variability between readers of prostate MRI outside specialized units with radical prostatectomy (RP) specimen as the reference standard.

Materials and methods: Retrospective study comprising a consecutive cohort of all 97 men who underwent MRI and subsequent RP between January 2012 and December 2014 at a private hospital in Sweden. Three readers, blinded to clinical data, reviewed all images (including 11 extra prostate MRI to reduce bias).

A tumour was considered detected if the overall PI-RADS v2 score was 3–5 and there was an approximate match (same or neighbouring sector) of tumour sector according to a 24 sector system used for both MRI and whole mount sections.

Results: Detection rate for the index tumour ranged from 67 to 76%, if PI-RADS 3–5 lesions were considered positive and 54–66% if only PI-RADS score 4–5 tumours were included. Detection rate for aggressive tumours (GS ≥ 4 + 3) was higher; 83.1% for PI-RADS 3–5 and 79.2% for PI-RADS 4–5. The agreement between readers showed average κ values of 0.41 for PI-RADS score 3–5 and 0.51 for PI-RADS score 4–5.

Conclusions: Prostate MRI evidenced a moderate detection rate for clinically significant PC with a rather large variability between readers. Clinics outside specialized units must have knowledge of their performance of prostate MRI before considering omitting biopsies in men with negative MRI.

Kohestani K, Wallström J, Dehlfors N, et al. Performance and inter-observer variability of prostate MRI (PI-RADS version 2) outside high-volume centres. Scandinavian Journal of Urology 2019:1-8. https://doi.org/10.1080/21681805.2019.1675757

 

[SaneDog]

I've been needing some more information on this, thank you for providing.

 

[Michael Scally MD]

[OA] How do we define "castration" in men on androgen deprivation therapy?

Androgen deprivation therapy (ADT) is the mainstay for the treatment of advanced prostate cancer. Since the clinical evolution from surgical orchiectomy, we have typically used ADT and orchiectomy to be synonymous terms for castration.

The goal of this study is to determine if, in contemporary medical practice, surgical and chemical castration provide for similar levels of diminishment of total and free testosterone. Further, what approaches should be used to most accurately measure testosterone levels in men with advanced prostate cancer and what cutoff values, for example for total testosterone 50 ng dl-1 or 20 ng dl-1, should be utilized.

Studies available in the literature have been analyzed and compiled to address these questions. Finally, evidence is provided that free testosterone, the biologically active component, should be utilized to provide clinically relevant state of castration.

Itty S, Getzenberg RH. How do we define "castration" in men on androgen deprivation therapy? [published online ahead of print, 2020 Jan 21]. Asian J Androl. 2020;10.4103/aja.aja_139_19. http://www.ajandrology.com/preprintarticle.asp?id=276306

 

[MR10X]

I was on ADT for 3 months before seed implants and radiation treatments. about 9 months after i started the ADT and implants and radiation my TT was 32 (348-1197) and FT was .02 (6.6-18.1). my TT only returned to 132 by itself. I did HCG and Nolvadex cycle a couple of times and it came back to the mid 500..that was 2012,my latest TT was tested at 553 natural in july 2019......

 

[MR10X]

Also my PSA tested last year was 0.1,thats 7 years since treatments

 

[Michael Scally MD]

All change in the Prostate Cancer Diagnostic Pathway

Following detection of high levels of serum prostate-specific antigen, many men are advised to have transrectal ultrasound-guided biopsy in an attempt to locate a cancer. This nontargeted approach lacks accuracy and carries a small risk of potentially life-threatening sepsis. Worse still, it can detect clinically insignificant cancer cells, which are unlikely to be the origin of advanced-stage disease.

The detection of these indolent cancer cells has led to overdiagnosis, one of the major problems of contemporary medicine, whereby many men with clinically insignificant disease are advised to undergo unnecessary radical surgery or radiotherapy. Advances in imaging and biomarker discovery have led to a revolution in prostate cancer diagnosis, and nontargeted prostate biopsies should become obsolete.

In this Perspective article, we describe the current diagnostic pathway for prostate cancer, which relies on nontargeted biopsies, and the problems linked to this pathway. We then discuss the utility of prebiopsy multiparametric MRI and novel tumour markers. Finally, we comment on how the incorporation of these advances into a new diagnostic pathway will affect the current risk- stratification system and explore future challenges.

Lomas DJ, Ahmed HU. All change in the prostate cancer diagnostic pathway [published online ahead of print, 2020 Feb 28]. Nat Rev Clin Oncol. 2020;10.1038/s41571-020-0332-z. doi:10.1038/s41571-020-0332-z All change in the prostate cancer diagnostic pathway | Nature Reviews Clinical Oncology

 

[Michael Scally MD]

Targeted, Systematic, and Combined Biopsy for Prostate Cancer Diagnosis

BACKGROUND - The use of 12-core systematic prostate biopsy is associated with diagnostic inaccuracy that contributes to both overdiagnosis and underdiagnosis of prostate cancer. Biopsies performed with magnetic resonance imaging (MRI) targeting may reduce the misclassification of prostate cancer in men with MRI-visible lesions.

METHODS - Men with MRI-visible prostate lesions underwent both MRI-targeted and systematic biopsy. The primary outcome was cancer detection according to grade group (i.e., a clustering of Gleason grades).

Grade group 1 refers to clinically insignificant disease; grade group 2 or higher, cancer with favorable intermediate risk or worse; and grade group 3 or higher, cancer with unfavorable intermediate risk or worse.

Among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens were recorded.

Secondary outcomes were the detection of cancers of grade group 2 or higher and grade group 3 or higher, cancer detection stratified by previous biopsy status, and grade reclassification between biopsy and radical prostatectomy.

RESULTS - A total of 2103 men underwent both biopsy methods; cancer was diagnosed in 1312 (62.4%) by a combination of the two methods (combined biopsy), and 404 (19.2%) underwent radical prostatectomy.

Cancer detection rates on MRI-targeted biopsy were significantly lower than on systematic biopsy for grade group 1 cancers and significantly higher for grade groups 3 through 5 (P<0.01 for all comparisons). Combined biopsy led to cancer diagnoses in 208 more men (9.9%) than with either method alone and to upgrading to a higher grade group in 458 men (21.8%).

However, if only MRI-target biopsies had been performed, 8.8% of clinically significant cancers (grade group ≥3) would have been misclassified. Among the 404 men who underwent subsequent radical prostatectomy, combined biopsy was associated with the fewest upgrades to grade group 3 or higher on histopathological analysis of surgical specimens (3.5%), as compared with MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%).

CONCLUSIONS - Among patients with MRI-visible lesions, combined biopsy led to more detection of all prostate cancers. However, MRI-targeted biopsy alone underestimated the histologic grade of some tumors. After radical prostatectomy, upgrades to grade group 3 or higher on histopathological analysis were substantially lower after combined biopsy.

Ahdoot M, Wilbur AR, Reese SE, et al. MRI-Targeted, Systematic, and Combined Biopsy for Prostate Cancer Diagnosis. New England Journal of Medicine 2020;382:917-28. https://doi.org/10.1056/NEJMoa1910038

 

[Michael Scally MD]

[OA] Detection of Individual Prostate Cancer Foci via Multiparametric Magnetic Resonance Imaging

Background: Multiparametric magnetic resonance imaging (mpMRI) undoubtedly affects the diagnosis and treatment of localized prostate cancer (CaP). However, clinicians need a better understanding of its accuracy and limitations in detecting individual CaP foci to optimize management.

Objective: To determine the per-lesion detection rate for CaP foci by mpMRI and identify predictors of tumor detection.

Design, setting, and participants: We carried out a retrospective analysis of a prospectively managed database correlating lesion-specific results from mpMRI co-registered with whole-mount pathology (WMP) prostatectomy specimens from June 2010 to February 2018. Participants include 588 consecutive patients with biopsy-proven CaP undergoing 3-T mpMRI before radical prostatectomy at a single tertiary institution.

Outcome measurements and statistical analysis: We measured mpMRI sensitivity in detecting individual CaP and clinically significant (any Gleason score ≥7) CaP foci and predictors of tumor detection using multivariate analysis.

Results and limitations: The final analysis included 1213 pathologically confirmed tumor foci in 588 patients with primarily intermediate- (75%) or high-risk (12%) CaP. mpMRI detected 45% of all lesions (95% confidence interval [CI] 42-47%), including 65% of clinically significant lesions (95% CI 61-69%) and nearly 80% of high-grade tumors. Some 74% and 31% of missed solitary and multifocal tumors, respectively, were clinically significant.

The majority of missed lesions were small (61.1% ≤1cm); 28.3% were between 1 and 2cm, and 10.4% were >2cm. mpMRI missed at least one clinically significant focus in 34% of patients overall, and in 45% of men with multifocal lesions.

On multivariate analysis, smaller, low-grade, multifocal, nonindex tumors with lower prostate-specific antigen density were more likely to be missed. Limitations include selection bias in a prostatectomy cohort, lack of specificity data, an imperfect co-registration process, and uncertain clinical significance for undetected lesions.

Conclusions: mpMRI detects less than half of all and less than two-thirds of clinically significant CaP foci. The moderate per-lesion sensitivity and significant proportion of men with undetected tumor foci demonstrate the current limitations of mpMRI.

Patient summary: Magnetic resonance imaging of the prostate before surgical removal for prostate cancer finds less than half of all individual prostate cancer tumors. Large, solitary, aggressive tumors are more likely to be visualized on imaging.

Johnson DC, Raman SS, Mirak SA, et al. Detection of Individual Prostate Cancer Foci via Multiparametric Magnetic Resonance Imaging. Eur Urol. 2019;75(5):712–720. doi:10.1016/j.eururo.2018.11.031 https://www.europeanurology.com/article/S0302-2838(18)30930-8/fulltext

 

[Michael Scally MD]

[OA] Inappropriate Use of Progression-Free Survival in Cancer Drug Approvals

New drugs should be judged on overall survival or quality of life, preferably both.

The aim of cancer drugs is to prolong life or improve its quality. Yet only a third of cancer drugs entering the market in Europe and the US have evidence of overall benefits in survival or quality of life. Instead, regulators now routinely approve new cancer drugs on the basis of surrogate endpoints that measure disease progression or tumour shrinkage.

This was not always the case. Historically, regulators had little appetite to accept surrogate measures for approving cancer drugs. In the mid-1980s, the US Food and Drug Administration required (with some exceptions) that clinical trials to support new cancer drug approvals show an improvement in patient survival, symptoms, or quality of life. This requirement was based on evidence that the correlation between tumour response and clinical benefit was weak.

Nevertheless, in 1996 the Clinton administration’s “reinventing government” initiative—which aimed to cut red tape for the benefit of business—announced that the FDA would begin to accept trials using “non-validated” surrogate endpoints such as tumour shrinkage for accelerated approval of new cancer drugs. It was expected that evidence of improved survival or quality of life would be demonstrated later, once drugs were on the market and being prescribed to patients.

Since then, progression-free survival, defined as time to death or disease progression, has replaced tumour response as the preferred surrogate endpoint in oncology drug trials. Both endpoints were developed to identify early signals of drug activity in phase II studies. They were not intended to measure patient benefit.

Yet progression-free survival is now the most commonly used efficacy endpoint in trials of treatments for advanced or metastatic solid tumours. Moreover, European medicines regulators now claim that progression-free survival is not a surrogate for patient relevant outcomes but reflects an intrinsic clinical benefit if a sufficient effect is observed.

...

Naci H, Davis C. Inappropriate use of progression-free survival in cancer drug approvals. BMJ 2020;368:m770. Inappropriate use of progression-free survival in cancer drug approvals

 

[Michael Scally MD]

Reconsidering Prostate Cancer Mortality — The Future of PSA Screening

Since PSA screening and the treatment that may follow result in trading off one cause of death for another, rather than extending life, providers who support such screening should offer patients a better deal by protecting them from overdiagnosis and overtreatment.

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So why not advocate for PSA screening? Unfortunately, the decrease in prostate cancer mortality has been achieved at enormous human cost: incidence soared to over 200 per 100,000, and more than a million men were diagnosed with a clinically insignificant “cancer” and received treatment for pathologic findings not destined to cause symptoms or death.18 PSA screening represents a textbook case of overdiagnosis and overtreatment in medical care. On that basis alone, we believe that the U.S. Preventive Services Task Force was right not to recommend it.

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On balance, we would continue to argue against contemporary PSA screening, particularly in light of our volume-driven health care system. But we acknowledge that our position reflects a value judgment. A few people receive a substantial benefit (avoiding death from prostate cancer), while many more are exposed to needless biopsies, operations, and another source of financial stress. We have no common metric for comparing these benefits and harms — they are like apples and oranges. Thus, there is no calculus or decision model that can produce a single “right” answer.

We believe that providers who arrive at the opposite value judgment and support PSA screening must offer patients a better deal by protecting them from overdiagnosis and overtreatment. Doing so requires an incidence target — a “not to exceed” incidence benchmark. Currently, prostate cancer incidence is about where it was in 1975: roughly 100 per 100,000. That should be the incidence target.

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From our mistakes with PSA screening, clinicians have learned about issues that are relevant to all cancer-screening efforts. We have learned that the conventional goal of screening — to maximize cancer detection — is wrong. The appropriate goal is more complex: identify the few cancers that matter, while not disturbing the rest of the population. Fortunately, the population signals are now positive: prostate cancer mortality has declined substantially, as has the number of men diagnosed with the disease. We will never have perfect data on the effectiveness of various screening approaches in reducing cancer-specific mortality — the trials required are too big and take too long. What we can have, however, is feedback on how many people are adversely affected by our actions.

Welch HG, Albertsen PC. Reconsidering Prostate Cancer Mortality — The Future of PSA Screening. New England Journal of Medicine 2020;382:1557-63. https://doi.org/10.1056/NEJMms1914228