Prostate Cancer and Prostatic Diseases: From the Editor

08 August 2019

Radiotherapy is a mainstay of treatment for localized prostate cancer. Biochemical recurrence after radiotherapy, defined as a prostate-specific antigen (PSA) rise of ≥ 2 ng/mL above nadir, occurs in up to 40% of intermediate- and high-risk patients within 10 years of treatment (Eur. Urol. 67, 1009–1016 (2015). Patients with biochemical recurrence are at increased risks of metastases and death (J. Clin. Oncol. 23, 6992–6998 (2005)).

In patients with biochemical recurrence after radiation, biopsy-proven localized disease, and no evidence of metastases, salvage prostatectomy may potentially improve survival and delay initiation of androgen deprivation therapy. This National Cancer Institute-sponsored multi-institutional study, CALGB 9687 (Alliance), prospectively evaluated the efficacy and morbidity of salvage prostatectomy in 41 men between 1997 and 2006 (Prostate Cancer Prostatic Dis. 2019 May; 22(2):309-316). At a median follow-up 91 months, these investigators observed robust 2-, 5- and 10-year progression-free survival rates of 51%, 39%, and 33% respectively; and 2-, 5- and 10-year overall survival rates of 100%, 89%, and 52%, respectively.

11 July 2019

A pressing issue facing men with a rising PSA despite hormone therapy is whether to pursue more potent androgen receptor inhibition. While novel PET imaging such as PSMA scans are reducing the size of this M0 CRPC population, this setting remains fairly common in regions of the world where PSA screening is common and men are treated for initially localized prostate cancer. Relapsed disease is first manifested as a PSA rise, and many urologists and oncologists will utilize androgen deprivation therapy (ADT) prior to the onset of visible metastases on standard CT/MRI or technetium bone scans. We know that most of these men have metastases, but these metastases remain small and below the limit of detection of these scans. We also know that most of these men will likely die of metastatic prostate cancer over the next 4-8 years, and therapies that can delay or prevent prostate cancer-specific mortality are needed.

Recent phase 3 trials suggest that both apalutamide, enzalutamide, and darolutamide can delay metastasis-free survival (MFS) significantly in such men with M0 CRPC who have rapid PSA doubling times (<10 mo) and an elevated PSA of 2.0 or higher. These men may have disease in their prostates or regional nodal

06 June 2019

To speak with Bob Dylan, ‘’..times they are a changing..’’, particularly when it comes to our insight in the genetic changes in prostate cancer. In the early days of molecular genetics studies of prostate cancer, scientists often referred to prostate cancer as being very different from other cancers, e.g. mutations in TP53 were rarely found in this malignancy. With the large scale introduction of next-generation sequencing and the impressive SU2C initiative, focusing on metastatic/advanced cancers, it was shown that prostate cancer was not that of a ‘’cancer genetic outlier’’. TP53-, Rb mutations ánd a rather high frequency of aberrations in genes encoding DNA repair proteins were found in advanced prostate cancer (metastatic CRPC).

A straight forward hypothesis is that these mutations have prognostic significance, i.e. mutations in pivotal cancer pathways are associated with clinical-, pathological stage, and grade, which in turn are a good proxy/surrogate for the outcome of the disease. Marshall and colleagues¹ focussed on DNA repair gene mutations and ‘mined’ existing DNA sequencing information (TCGA, NatureGenetics via cBioportal) to test this hypothesis. There appeared to be a clear correlation between pathological stage (pT3/4 versus pT2) and Gleason Grade groups (GG ≥ 3 versus GG 1-2). In the cT≥3 ánd GG ≥3 tumors in >20% DNA repair gene mutations were identified. Interestingly there appeared

13 May 2019

It has now been over 20 years since holmium enucleation of the prostate was first described. Since then, several other energy sources have been described to perform endoscopic enucleation and more recently there has been a shift to performing the surgery using an enbloc resection technique instead of individual lobar resection. At the end of the day, it probably doesn’t make a great deal of difference as to which energy source is used to perform endoscopic enucleation of the prostate (EEP) and as to whether tissue removal was by individual lobes or enbloc. They are all achieving the same anatomical removal of tissue and are a basically similar principle of technique.

There have been systematic reviews and meta-analyses evaluating individual energy sources to perform EEP versus transurethral resection of the prostate (TURP). The study by Zhang and colleagues is novel in that for the first time, we have an analysis that takes the stance that all of the EEP techniques are essentially equivalent, and therefore creating a very powerful comparison with TURP.

08 April 2019

The Fountain of Youth is thought to be a mystical spring that restores youth upon its drinkers. It has been searched for dating back to before the ancient Romans. Many people spent their lives chasing it – just ask Ponce De Leon! We now know the Fountain of Youth does not exist. In more recent times, the Fountain of Youth has been replaced by various remedies such as elixirs, oils, ointments, and herbs. More recently, people have turned to pharmaceuticals, of which statins has been one of the most touted. Statins are currently the most widely prescribed class of medicines. However, unlike various treatments of the past, statins are very effective. Specifically, they acutely block cholesterol production thereby lowering serum cholesterol levels typically by ~25%. In turn, this leads to dramatic reductions in heart disease risk.

Given the presumed importance of cholesterol in cancer pathways (it is the precursor for androgens as well as important in cell signaling pathways), there are multiple reasons to believe statins have anti-prostate cancer properties. While multiple studies have examined the role of statins in prostate cancer, often with mixed results, no prior study has examined this relationship in men undergoing active surveillance.

11 March 2019

The Luminal Improvement Following Prostatic Tissue Approximation (L.I.F.T) study demonstrated the efficacy of prostatic urethral lift (PUL) to treat lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction (BOO)¹. One of the exclusion criteria for L.I.F.T. was the presence of an obstructing median or middle lobe (OML). The MedLift study was a non-randomized cohort analysis assessing the efficacy of PUL to improve symptoms of BOO in 45 patients with OML. 

Other than OML status, the inclusion criteria for MedLift were identical to L.I.F.T.: ≥ 50 years of age, International Prostate Symptom Score (I-PSS) ≥ 13, and Qmax ≤ 12 ml/s. The primary endpoints were an improvement in I-PSS over baseline and incidence of post-procedure complications. Outcomes were compared to the L.I.F.T. historical cohort.

13 February 2019

Androgen deprivation therapy (ADT) is the mainstay of systemic therapy for men with metastatic or recurrent hormone-sensitive prostate cancer (mHSPC), as well as localized and PSA recurrent prostate cancer when radiation is indicated for higher risk disease. ADT is also continued indefinitely in men with mCRPC, and thus many men with aggressive forms of prostate cancer will be treated with years of ADT and face the cumulative risks of low testosterone. 

08 November 2018

Cholesterol is a key building block of cells. It provides crucial support to cell membranes allowing signaling between the inside and outside of cells. Cholesterol makes up ~ 1/3 of the cell membrane. Also, cholesterol is the precursor for many hormones – including testosterone. Without cholesterol, life as we know it could not exist. However, there is such a thing as too much of a good thing. Specifically, high serum cholesterol levels have been linked with numerous conditions such as cardiovascular disease, stroke, and many cancers.

18 October 2018

This comprehensive review summarizes important clinical concepts in the rapidly advancing field of positron emission tomography/computed tomography (PET/CT) for prostate cancer. The authors reviewed 18F-NaF-, choline-, fluciclovine- and prostate-specific membrane antigen (PSMA)-based modalities in primary disease staging and assessment of biochemical recurrence. The most thoroughly studied modality to date is choline PET/CT.

11 September 2018

Prostate cancer is known to be an immune evasive tumor, often coexisting with areas of inflammation in the primary site, but without over-expression of the traditional PD-1/PD-L1 immune checkpoint, unlike many other cancer subtypes.  While certain prostate cancer subsets like microsatellite high (MSI high) and CDK12 deleted disease may respond well to single agent PD-1 pathway inhibitors, in most (>90%) of prostateadenocarcinomas, other immunosuppressive molecules and pathways are likely to be of greater importance and have yet to be adequately targeted.  Here is where B7-H3 may be relevant.

02 August 2018

The proof of concept for the utility of urinary biomarkers to predict biopsy outcome was published in 2003 by Hessels et al, which subsequently led to the launch of the PCA3 test in 2007.  The test was mostly used for repeat biopsy decisions, to which also the FDA approval in 2012 was confined. The potential utility in active surveillance settings was suggested by many and in their recent paper Tosoain et al study the value of a first PCA3 outcome (fPCA3) and a subsequent PCA3 test (sPCA3) to predict Grade Reclassification (GR) in men on active surveillance.

10 July 2018

A large number of studies on ⁶⁸Ga PSMA PET/CT are coming out of Australia due to the ready access to this technology.  To give some background, PET/CT imaging has long been registered with the Australian Therapeutic Goods Administration (TGA) and with this has come the approval to use any radionuclide tracer.  With it being unnecessary to apply for additional registration to use new tracers, this has allowed uptake of 68Ga PSMA PET/CT into routine clinical practice throughout Australia and to the extent that it is rapidly replacing conventional radionuclide bone scans and CT scan of the abdomen and pelvis as imaging for the staging of prostate cancer. 

08 June 2018

Obesity is all around us.  Over 30% of all Americans are obese. We know obesity is linked with many medical problems – heart disease, diabetes, hypertension, and of course cancer. Indeed, over a dozen different cancers have been linked with obesity. In regards to prostate cancer, while obesity may lower the risk of low-grade indolent cancer, it unequivocally increases the risk of high-grade aggressive disease. Many explanations have been put forward: alterations in insulin levels, changes in sex steroid hormone levels, higher cholesterol,

14 May 2018

This compelling study revisits the concept of neoadjuvant adjuvant deprivation therapy (ADT) prior to radical prostatectomy. A small series of randomized clinical trials (RCTs) performed almost 20 years ago failed to demonstrate substantial benefits in patients with localized prostate cancer who received ADT before surgery. Based on these data, the American Urological Association and the European Association of Urology recommend against ADT prior to prostatectomy outside the setting of a clinical trial.

02 April 2018

Molecular risk tools are being increasingly utilized in men with localized prostate cancer to help in clinical decision making around the need for surgery or radiation vs. active surveillance, and for the need for salvage radiation after surgery.  The Decipher Genomic Classifier has recently been demonstrated to predict distant metastases in men undergoing radical prostatectomy, using biopsy or surgical tissue, and may provide a greater level of prognostic discrimination than current NCCN or CAPRA risk groups. 

01 February 2018

Urethral strictures do not tend to be at the forefront of most clinicians’ minds when considering the adverse effects of radiotherapy for prostate cancer. Quite correctly, the first considerations would be for those associated with any collateral damage to the rectum or bladder. But all urologists are well aware of radiation-related urethral strictures because the great majority would have these patients in their clinical workload. They are ‘heavy’ patients in that they need a lot of counseling and often require a lot of work to ‘manage’ their disease.  It is often a case of where a few patients as such can

02 January 2018

Race, family history, and age.  Those are the three classic risk factors for prostate cancer that are etched in stone in every textbook and course taught. While absolutely true, the challenge is that none of these are modifiable.  We can’t change our race.  We can’t grow younger and as much as some of us would like, we can’t change our parents. As such, we are stuck.  Our risk is our risk.  Or is it?  Are there modifiable risk factors for prostate cancer? It is now clear that obesity and smoking are modifiable risk factors for fatal prostate cancer. While avoiding obesity and not smoking sound like overall good advice, is there more specific advice we can give to our patients or to men at risk who don’t want to become patients in the first place. 

11 December 2017

Active surveillance (AS) provides a safe management option for men with low-risk and selected men with intermediate-risk prostate cancer. However, concerns persist that African American (AA) men pursuing AS are at increased risk of adverse clinical outcomes relative to other races. 

These investigators undertook a systematic review of studies of AA men with low-risk prostate cancer and AS. They identified eleven studies focused on pathologic features at time of surgery and five on other clinical outcomes. Further, they reviewed genetic characteristics of prostate cancer and the AA population. They did not

17 November 2017

Enzalutamide is a second generation AR inhibitor that engages AR through the ligand binding domain, inhibiting DNA binding and AR activity. In the PREVAIL study, enzalutamide improved overall survival in chemotherapy naïve men with mCRPC, and enzalutamide is presently a standard of care for these men, with greater activity observed when used prior to docetaxel as compared to following docetaxel.  While most men respond to enzalutamide in this setting, all men develop treatment resistance between 1-3 years. This present article explores how men progress on enzalutamide, using data from the PREVAIL trial.

17 October 2017

PSA screening has allowed for the detection of prostate cancer at curable clinical stages, and accordingly, there has been a reduction in prostate cancer-specific mortality in the PSA era.  Criticisms of PSA based screening and its utilization for decision making regarding biopsy have focused on its sensitivity, and lack of specificity for prostate cancer.  Use of PSA alone can lead to unnecessary initial and repeat biopsies, and to the detection of indolent prostate cancer, all of which cause health and economic burdens.