Prostate Cancer and Prostatic Diseases: From the Editor

07 May 2020

It is now a decade ago that Provenge (sipuleucel-T), an autologous active cellular immunotherapy, was approved by the FDA. Many unanswered questions, still needed to be resolved. When to give this to which patient, i.e. timing and predictive patient characteristics are issues that need to be resolved.

03 March 2020

Much of the push to perform transperineal prostate biopsy has been driven by concerns about increasing rates of sepsis associated with the transrectal approach to needle biopsy.

Historically, the strategy to minimize the infective complications of prostate biopsy had relied upon using more and more potent antibiotic regimens to combat growing bacterial resistance. A more recent approach to mitigate the risk of sepsis has been to use the more potent antibiotics in a targeted manner guided by rectal swabs prior to biopsy. However, the concept of chasing increasing antibiotic resistance with increasingly powerful antibiotics is a strategy that will never win. 

The transperineal approach to prostate needle biopsy is a logical way forward given that the risk of biopsy sepsis is minimal. It should be the standard of care approach to prostate biopsy but there is a reluctance to change practice and much of this is based upon the arguments that expensive equipment is necessary and that a general anesthetic is necessary. Recent advances are seeing these issues overcome.

09 February 2020

In the past 10 years, the number of new treatment options for metastatic castration-resistant prostate cancer (mCRPC) has exploded. Prior to 2010, only one agent – docetaxel – had been shown to extend survival for mCRPC patients. Now, a decade later, we have many such agents beyond docetaxel, including abiraterone, enzalutamide, sipuleucel-T, radium-223, and cabazitaxel. In addition, two other agents have shown significant benefits in other disease settings prior to mCRPC – apalutamide and darolutamide. While all extend survival, in the mCRPC setting the added months of life, on average, range from ~2 to 5. Thus, if all the new agents are added together, it is well over a year of added life. However, can the survival months merely be added together? Alternatively, do you get the biggest bang with the first agents and subsequent agents add little? This is an important unanswered question.

13 January 2020

Multiparametric magnetic resonance imaging (mpMRI) is a robust staging modality for high-risk prostate cancer. Less clear is whether pre-operative mpMRI may potentially improve radical prostatectomy outcomes by providing actionable information for planning neurovascular bundle excision, bladder neck sparing, and extent of staging lymph node dissection.

To address this question, these investigators performed a novel, single-center survey study of six urologic oncologists. Study participants were given two surveys incorporating 41 case studies of patients with clinically localized prostate cancer who underwent pre-operative mpMRI prostate followed by robot-assisted laparoscopic prostatectomy and extended pelvic lymph node dissection.

02 December 2019

Many adverse events have been described in men receiving androgen deprivation therapy (ADT), ranging from loss of bone density, hot flushes, cardiovascular risk, metabolic syndrome, cognitive dysfunction, and even less common risks such as deep vein thrombosis and colorectal cancer development. In the January 2019 edition of PCAN, Liu and colleagues describe a novel potential decreased risk of autoimmune diseases with ADT. This is intriguing for several reasons:

28 October 2019

The dilemma that resulted from the widespread use of serum prostate-specific androgen (PSA) testing was the identification of a significant number of men with indolent pure red cell aplasia (PrCa). After a significant period of overtreatment, the implementation of active surveillance (AS) has partly solved that issue. However, 25-50 % of AS patients will undergo an intervention. The follow up is rather invasive including serum PSA and repeat biopsies.

Models based on clinical parameters can be used to predict repeat biopsy outcome, yet improved methods to asses the risk to predict adverse pathology are needed. Candidate tools are improved imaging and biomarkers. In the past decade, molecular urine biomarkers were introduced in clinical practice (i.e.Prostate Cancer Gene 3 (PCA3) and TMPRSS2 erg).

09 October 2019

This Australian study is the largest published experience of the use of Ga68 PSMA PET/CT imaging in the context of previous primary radiotherapy for prostate cancer. 

This study evaluated 276 men who had undergone a Ga68 PSMA PET/CT for which the majority had PSA biochemical failure (mean PSA 3.60 ng/mL, range 0.01–83 ng/mL). Overall, 86% (239/276) men had positive scans with morethan half having evidence of local disease recurrence. Clearly, there are some limitations given that in the relatively small number of 33 men who underwent a prostate biopsy, only 28 men (85%) were confirmed to histological recurrence. Lymph node metastases were identified in 122 men (44%) of which 49 men had positive lymph nodes that were located outside the template for an extended pelvic lymph node dissection. Bone metastases were documented in 50 men.

09 September 2019

Androgen deprivation therapy (ADT) is standard treatment for advanced and metastatic prostate cancer. While it is very effective for cancer control, it has many side effects. Commonly known side effects include loss of libido, fatigue, osteoporosis, and hot flashes. Additionally, ADT has metabolic side effects. Imagine a young athlete using steroids to have a competitive advantage. They gain muscle mass and lose fat. Now imagine the same man 50 years later undergoing ADT for his prostate cancer – it will have the exact opposite effects – gain of fat mass and loss of muscle mass.

These changes are coupled with a ~40% increased relative risk of diabetes. While exercise can help preserve muscle mass, to date, no treatment has been shown to prevent this metabolic sequela. Given one of the fundamental problems from ADT is problems with controlling sugar, what if people simply didn’t eat sugar?

There is tremendous growth in interest in the ketogenic diet, an extreme form on a low carbohydrate (i.e. sugar) diet. Proponents often tout it as the cure-all for diabetes, obesity, and possibly even cancer. Opponents argue that it is not sustainable, is bad for the environment, and it simply can’t be healthy to eat all that fat. Where

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.