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The new AUA PSA Testing Guidelines leave me scratching my head

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The fact that Otis Brawley describes the new PSA testing guidelines of the American Urological Association (AUA) as “wonderful”, should immediately raise a red flag at AUA headquarters. Dr Brawley, Chief Medical Officer of the American Cancer Society, and the most vocal anti-prostate cancer screening voice in the USA over the past decade, has enthusiastically welcomed the new document and “commended” the AUA for bringing its policy closer to that of his Society. The Guidelines have also been compared to those of the United States Preventative Services Task Force (USPSTF) which completely opposes PSA testing in any situation – a position which the AUA called “inappropriate and irresponsible” just a few months ago. Oh dear – where has it all gone wrong? ?

For those who haven’t yet seen the document, here are the five statements issued by the Guideline committee at the Annual Meeting of the AUA in San Diego this week along with some of my thoughts in italics:

  1. The Panel recommends against PSA screening in men under age 40 years. This appears reasonable.
  2. The Panel does not recommend routine screening in men between ages 40 to 54 years at average risk. I have some problems with this (as do many others). In addition to this statement, the AUA highlights its view that the likelihood of causing harm is high and that any benefit is marginal. It appears to have completely dismissed evidence (and its own previous view), that a baseline PSA in men in this age group is highly predictive of future prostate cancer, metastasis and death. In my view, there is considerable value in having a baseline PSA in this age group and I am disappointed that the AUA has not recognised the evidence to support this.
  3. For men ages 55 to 69 years the Panel recognizes that the decision to undergo PSA screening involves weighing the benefits of preventing prostate cancer mortality in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment. For this reason, the Panel strongly recommends shared decision-making for men age 55 to 69 years that are considering PSA screening, and proceeding based on a man’s values and preferences. I agree with the emphasis here on shared decision-making, although the concept can be somewhat nebulous and difficult to achieve in real-life. However, I think that this statement somewhat over-emphasises the harms associated with PSA testing in this group. Rather than portray the reduction in prostate cancer mortality as being very minor (1 in 1000), men should know that when compared with a man who chooses not to have PSA testing in this age group, those who do have regular PSA testing have a 44% reduction in prostate-cancer mortality over a 14 year period. Furthermore, the numbers needed to screen (293) and number needed to treat (12) to save one life stack up very well when compared with other screening modalities such as mammography (Hugosson et al). Why has the AUA instead chosen to over-emphasise the harms? This is disappointing.  
  4. To reduce the harms of screening, a routine screening interval of two years or more may be preferred over annual screening in those men who have participated in shared decision-making and decided on screening. As compared to annual screening, it is expected that screening intervals of two years preserve the majority of the benefits and reduce over-diagnosis and false positives. This appears reasonable.
  5. The Panel does not recommend routine PSA screening in men over age 70 years or any man with less than a 10 to 15 year life expectancy. Yes, but this strong advice not to offer PSA testing in men greater than 70 belies the fact that many men in this age group have a long life expectancy (eg in Australia a male who reaches 70 has a 15 year life expectancy (www.abs.gov.au), and an early diagnosis of prostate cancer may prevent their untimely death from this disease. Clearly, not all men in their 70’s are the same but following this advice to the letter could deny many men the option of avoiding death from prostate cancer in later life.

Therefore, it appears that the only circumstances under which the AUA currently recommend a PSA test be performed is for men between the age of 55 and 69 following a weekend seminar so they can be adequately informed (or thoroughly confused).

These statements have led to headlines such as these in the mass media today:

  • Urology Group Stops Recommending Routine PSA Test (USA Today)
  • Looser Guidelines Issued on Prostate Cancer Screening (New York Times)
  • Urologists No Longer Support Routine Prostate Cancer Screening (Minn Post)
  • Most men don’t need PSA test (Arizona Star)
  • AUA No Longer Recommend Routine PSA Testing For Prostate Cancer (Huff Post)

I think it is reasonable to say that this AUA document adds more confusion than clarity to the debate around prostate cancer testing. It has certainly provoked some anger among prominent members of the AUA who voiced their displeasure to the Committee during the plenary and also through social media. Dr Catalona was first to the microphone asking why AUA members were not more widely consulted prior to publication and in particular, challenging the guidance around men aged 40-54 (reported on Twitter):

 

 

Dr Stacy Loeb also voiced her concerns at various sessions during the day:

 

Much progress has been made in the last few decades with a 30% reduction in prostate cancer-specific mortality since the introduction of PSA testing. And while we accept that this has led to a large amount of over-treatment of less aggressive disease, it is clear that (at least outside the USA), active surveillance is being enthusiastically embraced for appropriate patients. Any return towards the pre-PSA era would likely lead to a reversal in these mortality gains and we would again see many more men presenting to our rooms with incurable disease.

As Dr Smith editorialized in the Journal of Urology following the publication of the ERSPC and PLCO trials in 2009, “Treatment or non-treatment decisions can be made once a cancer is found, but not knowing about it in the first place surely burns bridges”. It is clear that many urologists consider these new AUA PSA Guidelines to be in danger of burning these bridges. However, rather than burn bridges, it is likely that urologists and others will ignore these guidelines and continue to counsel men in a more balanced fashion about the pros and cons of PSA testing. The AUA will then need to consider whether ignored guidelines are failed guidelines.

 

Prof Tony Costello is a Director and Professor of Urology at the Royal Melbourne Hospital, Melbourne, Australia.

Twitter: @proftcostello

 

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Editorial: Incorporating prognostic grade grouping into Gleason grades

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The ‘Gleason Grading System’ first proposed by Donald Gleason in 1966 was a revolutionary system for its time. As it advocated the use of a sum score that combined the two most common patterns of prostate cancer seen in a radical prostatectomy specimen to predict the biological outcome of the tumour, rather than the worst pattern that was in common usage with other tumour types, it was truly innovative. Furthermore, although several other classification systems for prostate cancer have been proposed since then, none has stood the test of time as well as the Gleason system and certainly no other system is in widespread use internationally.

Gleason and Mellinger went on to make adjustments and modifications to this classification system in 1974 and 1977, as the series of cases examined was expanded from the original 270 patients to >1000 patients.

Since then, there have been further changes to the Gleason Grading System with the advent of immunocytochemistry and in terms of clarification of the size and spacing of individual acini that are seen in the various patterns originally illustrated by Gleason. A tertiary pattern of prostate cancer, mentioned in passing by Gleason, has also become more clearly identified in a proportion of cases.

Possibly the most important advance regarding the Gleason Grading System was the result of an International Consensus Conference of Urological Pathologists in 2005. This meeting, comprising >80 specialist pathologists from 20 countries, published the updated or ‘Modified Gleason Grading System’. These guidelines were based on the changes in practice that had taken place in the diagnosis and treatment of prostate cancer in the previous 40 years and included evidence for the confirmation that Gleason 1 and 2 patterns should not be assigned on prostatic needle biopsy specimens and that all cribriform areas of tumour were best regarded as Gleason pattern 4 rather than Gleason pattern 3.

Although these modifications have been useful for the surgeon and pathologist, they have not clarified the Gleason grading system for the patient. It is not easy to explain or to understand why a system that in theory could produce a range of Gleason sum scores from 2 to 10, is in practice actually limited on prostatic biopsy to Gleason sum score 6 to 10. Thus, rather confusingly, Gleason 6 is the most favourable category of prostatic carcinoma in terms of prognosis, rather than indicating a ‘middle-of-the-scale’ tumour.

The paper presented in this issue of BJUI, ‘Prognostic Gleason grade grouping: data based on the modified Gleason scoring system’, attempts to compensate for this by allowing the categorisation of prostatic carcinoma not only in terms of Gleason sum score, but also into prognostic groups I to V that correlate with the sum score and may be easier for the patient to appreciate.

This is an important next step in the development of the Gleason Grading System and hopefully one that will be embraced by surgeons and pathologists and more easily accepted by patients.

Alex Freeman
Department of Histopathology, University College London Hospital, London, UK

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Editorial: Prostate cancer families – predicting disease before and after the radical

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In this issue of BJUI, Borque et al. discuss a subject that is now very close to my heart. Aged 48 years, I am 6 weeks post radical prostatectomy for a Gleason 3 + 4 prostate adenocarcinoma measuring ~2 mL in volume, with a PSA level of 2.54 ng/mL. Histology reassures me it is organ confined and seminal vesicle negative. My father and his brother both died aged 63 years of Gleason 10 prostate cancer and my brother is awaiting his radical prostatectomy in a few weeks. I have two sons, one of whom has asked me when he should be tested. Any prognostic information is going to help me advise my family.

In all, 85% of prostate cancers appear to be sporadic. The incidence of all prostate cancers is 1 in 8500 under the age of 40 years, rising to 1 in 15 at 60–69 years and 1 in 8 after that. The lifetime risk in the UK for all men is 8–10%.

The genetics of prostate cancer are confused by case clustering; the family members of men with a prostate cancer diagnosis seek out early advice from their physician resulting in detection of some clinically questionable cancers and an apparent higher incidence in certain families. These families do not necessarily have genetically determined prostate cancer.

The lifetime risk is altered dramatically by having two or more first-degree relatives with a diagnosis of prostate cancer; if the disease in the relative is identified before the age of 65 years the risk is increased further. Bratt suggests the risk rises from 15 to 20% when a single first-degree relative is diagnosed aged < 60 years. Zeegers et al., in a meta-analysis, have shown that diagnosing prostate cancer in a relative aged < 65 years increases the relative risk of having prostate cancer by 3.3, and having two first-degree relatives increases the relative risk by a factor of 5.1.

Analysis of a huge database from Sweden including data on 182 000 fathers and 3700 sons with prostate cancer suggest a standardised incidence ratio of 9.4 in men with a father and brother diagnosed with prostate cancer, with further analysis also showing unsurprisingly that the risk increases as an individual ages. Some true ‘prostate cancer families’ have been identified. These families have three or more relatives with prostate cancer often associated with a diagnosis at a young age, possibly with an increased tendency to an aggressive
phenotype; my uncle was 18 months from diagnosis to death from his disease, my father 4 years. In these families, the relative risk in male family members is 3.39 in those where the diagnosis of identified sufferers was made aged > 65 years, and 7.33 where the diagnosis is in men aged < 65 years. These risks which effectively give a lifetime risk in the individual of 45–50% are associated with carriage of a gene identified as increasing the prostate cancer risk. The best identified of these genes is the BRCA2 (breast cancer type 2 susceptibility protein) gene, which is associated with an increased risk of other cancers including breast, ovarian, gallbladder and pancreatic cancer, as well as malignant melanoma. This gene, carried in 1% of
Ashkenazi Jewish families, is associated with prostate cancer families in this population.

Now my prostate has been removed, I need to determine my chance of treatment failure. It would be interesting to know whether my genes and my single nucleotide polymorphisms (SNPs), which have almost certainly been responsible for me developing prostate cancer, can also predict my chance of developing early biochemical recurrence (EBCR) and the possibility of needing further treatment. In the Borque et al. article, I would appear on the first model (Fig. 1) to have a chance of ECBR of between 1 and 5%. This risk, according to this study, could increase to up to 30%, if I was to have four SNPs associated with prostate cancer (Fig. 2). Furthermore, we need to know whether identification of SNPs is any better than other possible predictors of EBCR and disease progression, such as the identification of lymphovascular invasion and tumour volume in the final specimen and the presence of extraprostatic extension, data not included in this study. Incidentally, I had no evidence of lymphovascular invasion.

The authors identify that this study needs repeating, particularly in a more ethnically diverse group (this study included Caucasian origin as an entry criterion), and we await longer term data to see how SNPs predict metastasis and prostate cancer-related death.

Jonathan M. Glass
Department of Urology, Guys & St Thomas’ Hospital Trust, London, UK

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Video: Genetic predisposition to early recurrence in clinically localized prostate cancer

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Genetic predisposition to early recurrence in clinically localized prostate cancer

Ángel Borque, Jokin del Amo†, Luis M. Esteban*, Elisabet Ars§, Carlos Hernández**, Jacques Planas, Antonio Arruza††, Roberto Llarena‡, Joan Palou§, Felipe Herranz**, Carles X. Raventós, Diego Tejedor†, Marta Artieda†, Laureano Simon†, Antonio Martínez†, Elena Carceller, Miguel Suárez, Marta Allué, Gerardo Sanz* and Juan Morote

‘Miguel Servet’ University Hospital, *University of Zaragoza, Zaragoza, Spain, †Progenika Biopharma S.A., ‡University Hospital of Cruces, Bilbao, §Puigvert Foundation, ‘Vall d’Hebron’ University Hospital, Barcelona, **‘Gregorio Marañón’ University Hospital, Madrid, and ††Hospital of Txagorritxu, Vitoria, Spain

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• To evaluate genetic susceptibility to early biochemical recurrence (EBCR) after radical prostatectomy (RP), as a prognostic factor for early systemic dissemination.

• To build a preoperative nomogram to predict EBCR combining genetic and clinicopathological factors.

PATIENTS AND METHODS

• We evaluated 670 patients from six University Hospitals who underwent RP for clinically localized prostate cancer (PCa), and were followed-up for at least 5 years or until biochemical recurrence.

• EBCR was defined as a level prostate-specific antigen >0.4 ng/mL within 1 year of RP; preoperative variables studied were: age, prostate-specific antigen, clinical stage, biopsy Gleason score, and the genotype of 83 PCa-related single nucleotide polymorphisms (SNPs).

• Univariate allele association tests and multivariate logistic regression were used to generate predictive models for EBCR, with clinicopathological factors and adding SNPs.

• We internally validated the models by bootstrapping and compared their accuracy using the area under the curve (AUC), net reclassification improvement, integrated discrimination improvement, calibration plots and Vickers’ decision curves.

RESULTS

• Four common SNPs at KLK3, KLK2, SULT1A1 and BGLAP genes were independently associated with EBCR.

• A significant increase in AUC was observed when SNPs were added to the model: AUC (95% confidence interval) 0.728 (0.674–0.784) vs 0.763 (0.708–0.817).

• Net reclassification improvement showed a significant increase in probability for events of 60.7% and a decrease for non-events of 63.5%.

• Integrated discrimination improvement and decision curves confirmed the superiority of the new model.

CONCLUSIONS

• Four SNPs associated with EBCR significantly improved the accuracy of clinicopathological factors.

• We present a nomogram for preoperative prediction of EBCR after RP.

Who let the Dogs Out?

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Or

Let’s Paws for a Second!

Or

Lets paws for a second before we all start howling about nothing!

 

Recently while driving to a Day Surgery list at Heatherwood hospital in Ascot, I happened to listen to BBC Radio 4. There was a report regarding high accuracy for the detection of stomach cancer by a simple breath test. This reminded me of a study published some time ago in European Urology on the ability of a dog to detect prostate cancer by smelling a sample of urine. For a skeptic like me, reading that article in the platinum journal had indeed brought a sarcastic chuckle. Pondering over the paper and the report on the radio, it just dawned on to me as to why I would instantly believe a high-tech nanosensor detecting stomach cancer but not a mortal Belgian Malinois shepherd! This formed my basis of my blog.

It is well known that when someone is afflicted by a disease or cancer, there is a change that occurs in the internal milieu. In the vast majority, before this change can be manifested clinically, there is definite change seen biochemically.  There is emerging evidence that volatile organic compounds (VOC) that are exhaled either in the breath or in bodily fluids can indicate these changes reflecting the underlying pathology.  This is where the humble mongrel comes into play. Olfactory bulb in dogs is forty times bigger than of humans relative to total brain size. Having 125 to 220 million smell-sensitive receptors, their olfactory sense is up to one hundred thousand to one million times more sensitive than a human’s. So, there may be some sense and science in the paper that I had initially chuckled at. The earliest report is a letter to the Lancet reporting the diagnosis of melanoma made after the dog sniffed at a suspicious mole of its owner. Since then, there have been several reports on the ability for the trained dogs to detect various cancers and chronic illness, urological diseases. One of the earliest attempts to detect prostate cancer can be dated back to 2002. Further attempts were made to initiate trials in 2003 but no published results on Medline were found. Earliest published paper can be traced back to 2008, wherein the study did not support the concept of dogs being able to detect prostate cancer. This was recently challenged by the article by Cornu J et al that revealed a sensitivity and specificity of 91% for biopsy proven prostate cancer! In fact, one of the three patients who was wrongly classified as prostate cancer, was found to have cancer on a re-biopsy! The potential VOC that may be found in the urine of a patient with prostate cancer can be found in this letter to the editor. Indeed, to carry out more research, “Medical Detection Dogs” is aiming to recruit prostate cancer patients within the UK!

One would obviously think that if we can diagnose prostate cancer, why not bladder cancer? This is precisely what led to a “proof of principle” study headed by Carolyn Willis and findings were published in the BMJ. The dogs had a mean success rate of 41%, compared with 14% expected by chance alone. Multivariate analysis suggested that the dogs’ capacity to recognise a characteristic bladder cancer odour was independent of other chemical aspects of the urine detectable by urinalysis. What was astonishing about this study was on one occasion during training, all dogs unequivocally indicated as positive a sample from a participant recruited as a control on the basis of negative cystoscopy and ultrasonography. The consultant responsible for the patient was sufficiently concerned to bring forward further tests, and transitional cell carcinoma of the right kidney was discovered! The same group further reported specificity that ranged from 92% for urine samples obtained from healthy, young volunteers down to 56% for those taken from older patients with non-cancerous urological disease.

More trials are being carried out for detection of cancers affecting the lung, breast, ovary, bowel and others, a review of which can be found in this article. We may need to wait for a few more years to find out whether we are dealing with real science or we are going in circles like the dog chasing its own tail!

On the lighter note, if you hear an old male dog bark for no apparent reason, think prostate cancer!! Dog is the only other mammal that can be afflicted by prostate cancer and fortunately the doggie world will not be affected by the USPSTF recommendations, as canine prostate cancers do not secrete PSA!

Amrith Rao is a Consultant Urological Surgeon at Wexham Park Hospital, Wexham, UK

Tweet: @urorao

 

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Editorial: Robot-assisted radical prostatectomy: getting your ducks in a row!

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Robot-assisted radical prostatectomy (RARP) has become the technique of choice for clinically localised prostate cancer. However, marked inter-surgeon heterogeneity and an obvious lack of standardisation exist for the indications and technique of the procedure. In this issue of the BJUI, Ficarra et al. conducted a multinational survey seeking opinion from 145 robotic surgeons about individual practices during RARP. These opinions can be compared against the benchmark set by the Pasadena Consensus and can help gauge the impact of its recommendations.

Responses from 116 (79.4%) invited surgeons were analysed. The authors acknowledge the limited participation of non-European surgeons (17.1%), which may limit validity and application of its results at a global level. Most surgeons were in consensus with the Pasadena recommendations for transperitoneal access (88%), antegrade approach (76%) and bladder neck preservation (77%). The opinions on cautery use for the seminal vesicle/vas deferens dissection (51% athermal; 21% bipolar), athermal nerve-sparing approach (90%) and the use of the running suture technique for urethrovesical anastomosis (96.6%) were also in agreement.

Despite wide surgeon and institutional variability regarding the definition of bladder neck preservation and its role in the return of urinary continence, most preferred to preserve the bladder neck. This may pose difficulty in the interpretation of the results in view of the ambiguity about the definition and technique adopted under the term ‘bladder neck preservation’ (Eur Urol, BJU Int).

Most of the participating surgeons were using anterolateral prostatic fascia dissection (Veil of Aphrodite) towards preserving the cavernous nerves by using an athermal approach. Over the last decade the evolution of robot-assisted surgery, with excellent three-dimensional visualisation, depth perception, and EndoWrist® technology has made working in the confines of the pelvis both ubiquitous and a desired skill.

The present study found that 33% of surgeons omitted the internal iliac lymph nodes (LNs) and removed only obturator, with or without the external iliac LNs. The Pasadena Consensus recommends a template that includes the internal iliac, external iliac and obturator LNs. Mattei et al. in an attempt to map primary prostatic lymphatic ‘landing’ zones found that after performing a standard limited LN dissection (dorsal to and along the external iliac vein; medially along the obturator nerve) only 38% of LNs were removed. They recommended a template that retrieves LNs extending up to the ureteric crossing of the common iliac vessels. Meanwhile, Menon et al. evaluated the role of only internal iliac LN dissection (limited) in patients with a low probability of nodal disease (Partin table prediction 0–1%), and surprisingly found positive LNs in the internal iliac/obturator region 13.7 times more often than in the external iliac/obturator region. One of the issues that could be addressed in future surveys would be to evaluate how surgeons view and adapt to changes in the proposed LN template. The Pasadena Consensus further recommends considering performing LN dissection for the low-risk category based on the D’Amico risk stratification. The surgeon’s indications for pelvic LN dissection were not addressed in this survey.

Despite significant studies, including two randomised controlled trials (RCTs), published in the peer-reviewed literature reporting minimal advantage for early recovery of urinary continence with posterior reconstruction, a significant number of the surveyed surgeons still preferred to perform it. Responses to other questions about the posterior/anterior reconstruction also showed marked variability reflecting the controversial opinion about the value of these surgical steps.

On the other hand, future surveys should gather opinions about the role of RARP for high-risk disease, standardised evaluation of surgical complications; while addressing continence and potency status along with methods of their measurement. These topics were already addressed in the Pasadena Consensus and obtaining opinions of surgeons will further provide insight as to how surgeons adapt to the ever-changing advances in this field.

Over the last decade RARP has gained acceptance despite the absence of high-quality RCTs in robot-assisted surgery. The Pasadena Consensus was meant to meet the need for uniformity and this study educates us on how the surgeons really perform ‘in the trenches’. Until further evidence is available, surgeon experience and institutional volume will remain the main force driving the use of these surgical techniques and their outcomes.

Ahmed A. Aboumohamed and Khurshid A. Guru
Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA

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A Tale of Four Prostates

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There was a time when doctors were reluctant to tell patients the truth about a diagnosis of cancer, and even more unwilling to discuss any illness from which they themselves suffered.  John Anderson broke the mould last year when he made a public announcement about his newly diagnosed liver metastases, which subsequently turned out to be the result of secondary spread of adenocarcinoma of the prostate.

John was President Elect of the British Association of Urological Surgeons (BAUS) at the time, so sadly had to resign his presidency (the best president we never had!) and subsequently his trusteeship of the Prostate Cancer UK charity. John’s energy and drive are legendary, he is a true surgeon’s surgeon. The stoicism and determination that he has displayed throughout a year in which he has received hormonal treatment, followed by chemotherapy, is awe-inspiring.

My admiration for John, in addition to my own recent diagnosis of localised prostate cancer, requiring robot-assisted radical prostatectomy (https://moreintelligentlife.co.uk/content/ideas/simon-garfield/prof-roger-kirby) led me to approach Sean Vesey and Damian Hanbury, whom I knew were similarly afflicted by a disease that carries a 1 in 9 lifetime risk. It occurred to me that there was a great deal to be gained from frank disclosure and discussion, as opposed to treating this problem as some dark, furtive secret. Women suffering from breast cancer are generally much more open about their problem and consequently receive much more support from friends, relatives and others who have been touched by the disease. This empowers them to make the difficult but smarter choices about their health by opting in to breast cancer treatment. Men need this kind of social encouragement and support so that we can be within reach to them as well.

The result was a publication entitled “a Tale of Four Prostates” in the upcoming issue of Trends in Urology and Men’s Health (www.trendsinurology.com) and a short accompanying video.

In this John, Damian and myself discuss the impact of our respective diagnoses and treatment. We sincerely hope that, by being frank, honest and transparent about our own situation, we can help other patients to help themselves by seeking advice and treatment earlier, and by sharing information about their diagnosis with others in order to mobilize support from their family and friends.

 

Sadly, John Anderson has since died. You can read an obituary by Roger Kirby here. 

 

 

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Does Michelangelo’s David have an increased risk of prostate cancer?

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Recently when researching on the Italian Renaissance master Michelangelo and his suffering with kidney stones, I stumbled upon a project on his famous masterpiece David. At the precise time, I was browsing BJUI and came across the article by Motofei et al, on the sexual side effects of finasteride as related to hand preference (right-handed or left-handed) for men undergoing treatment of male pattern baldness. This manuscript reminded me of several articles that measured different parts of the male body and correlated with the risk of prostate cancer. With this paper on my mind and at the same time looking at David, it just occurred to me whether I could predict the possibility him getting prostate cancer!

Let’s start from the beginning. Being born as a male, he had acquired a 1 in 6 chance of being diagnosed with prostate cancer and 1 in 36 chance that he would have died from it. The moment David stood erect as a toddler; the risk of getting prostate cancer became a reality. Indeed, the authors of the study go on to claim the link of erect posture of humans with BPH and infertility. For those interested, the theoretical aspects of erect posture and its effects on the male reproductive tract can be found in this review.

It is worth analyzing the David’s anthropometric measurements and bodily features from head to toe and correlate them to the current available evidence. David’s height has been calculated at being 497 cm. This, in real life would probably make him around 5’ 8” to 6’. According to the findings of the PLCO trial, being tall increased his risk of developing more aggressive prostate cancer and at a younger age. This is supported also by the findings of the ProtecT trial, which demonstrated that for high-grade tumours, there was a 23% increase in risk per 10 cm increase in height. The study group’s meta-analysis of published literature also support the increased risk of prostate cancer with increasing height.

Let us start from his head. Fortunately, David is not bald. Recent evidence suggests a strong correlation between vertex pattern androgenic alopecia and significant risk of prostate cancer. Looking at the elegance of the face, it is quite obvious that he is a clean-shaven man. Fortunately, being white, the age at which he started shaving indicating early or delayed adolescence, does not seem make his chances of getting prostate cancer worse.

Going on to his chest, it is apparent that David did not suffer from Gynaecomastia. There is considerable controversy in the literature regarding the association of gynaecomastia and future risk of prostate cancer. A cohort study following men with histologically proven gynaecomastia did not find any increased risk of prostate cancer but surprisingly showed an increased risk of testicular cancer. David’s chest, abdomen and back lack excess dense body hair. A Japanese study has shown that dense body hair raises the risk of prostate cancer!

A lot of research has gone into determining whether David is a right-handed or a left-handed man. If you take a closer look at the statue, the sling is held by the left hand and a rock on the right, suggesting that he could indeed be left handed, like his creator Michelangelo! Although no specific research has been carried out in prostate cancer, it has been shown in a few studies that women who are left handed are more prone to get breast cancer as compared to those who are right handed. The authors claim the effect of prenatal hormones on the foetus that determines the dominance of the side can also have effects on the breast tissue. A study found that men who were exposed to DES in utero were more likely to be left-handed. Similarly mouse experiments have shown an increased risk of prostate cancer in those exposed to DES. So, there may be a connection between left-handedness and risk of prostate cancer!

Coming to his fingers: The ratio of second to fourth digit length (2D:4D) would allow us to further assess the risk. It is now understood that the 2D:4D ratio is determined by Homeobox (Hox) a and d genes that also regulate urogenital system. What is even more interesting is the study that showed the patients with a lower 2D:4D ratio have higher risks of undergoing prostate biopsy and prostate cancer. The same group indeed went on to prove that a lower digit ratio was related to high percentage core cancer volume and higher Gleason score!

Fortunately, David’s waist circumference (WC) is within reasonable limits, thereby reducing his risk of prostate cancer. A recent study has shown that increased WC seems to be associated with high-grade disease at the time of biopsy.

It is obvious looking at David that he was not circumcised. Although aesthetically pleasing for many, there is considerable debate in the medical as well as philosophical literature whether David was circumcised or not?! Not being circumcised unfortunately increases his risk for prostate cancer.

There is a huge controversy about the size of David’s flaccid penis. Penis size has not (yet) been shown to correlate with risk of prostate cancer. Although, indirectly you conclude that because the 2D:4D digit ratio has been correlated with penis size and as shown above 2D:4D ratio has been correlated with prostate cancer. Therefore, the smaller the penis, greater the risk of prostate cancer! With so many manuscripts being published on 2D:4D ratio, I decided to research more on it and landed up on the Wikipedia page. I was astonished to find the various conclusions that have been reached with the curious case of 2D:4D ratio, including a recent study in Germany that found its correlation with male to female transsexuals!

Although not possible, but of interest would have been to measure David’s anogenital distances from anus to upper penis and from anus to scrotum. A study published in BJUI showed that a higher measurement between the anus and the penis was associated with lower risk of prostate cancer. As you may have guessed, yes there is research going on finding a relationship between anogenital distance and the 2D:4D ratio!

My interest then turned to David’s feet. Looking at it, it does seem that he would have been wearing a shoe size of 10 or 11 at least. Does it matter? Comparing his shoe size and the length of his flaccid penis, I was just reminded of the seminal paper by Jyoti Shah et al, which disproved that shoe size has got to do anything with the size of the penis. However, contrary to this paper, a study confirmed significant evidence of older age at the maximal shoe size (20.1 versus 17.6 years, P <0.05) was associated with increased risk of prostate cancer. Yes, as you may have guessed by now, there is a relationship between the 2D:4D to your penis size!

To conclude on the observations, there are several factors that increased David’s risk and several others that are protective, as shown in Table 1. I would leave it to the reader’s judgment, whether you would recommend a PSA test for David or indeed climb on to him and measure the most important parameter, the 2D:4D ratio!

Amrith Rao is a Consultant Urological Surgeon at Wexham Park Hospital, Wexham, UK. His views are his own. @urorao

 

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On the Receiving End!

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It was weird, having spent a career looking after men with prostate problems, to discover that my own PSA was raised to 4.3ng/mL. A 3 Tesla MRI with gadolinium enhancement revealed a lesion in the right peripheral zone, which a biopsy confirmed as a Gleason 3+4=7 adenocarcinoma. The decision wasn’t difficult for me: I opted for a robot-assisted radical prostatectomy (RARP), to be performed by the Editor-in-Chief of this journal, Professor Prokar Dasgupta, ably assisted by Ben Challacombe and Krishna Patil. Details of my whole journey are available here for those who are interested.

The key point for discussion in this blog is the availability of the latest technology for the care of patients with prostate cancer who are less in the know than me. Shouldn’t we be lobbying for greater access for all to the latest pieces of high tech gear?

3 Tesla MRI imaging, together with the expertise to interpret the findings of diffusion-weighted images, for example, offers the possibility of a “prostate mammogram” which facilitates the targeting of the biopsy and holds the promise of avoiding biopsies in those in whom the MRI images appear blameless.

Da Vinci robotic technology undoubtedly facilitates the surgical procedure, especially the preservation of the neurovascular bundles and the very precise vesico-urethral anastomosis. It certainly was an interesting experience to sit and watch the DVD of my own operation at home, with a catheter still draining my bladder, wondering about my future continence and sexual function, as well as the histopathology report! After an operation like this anybody is going to need assistance to move around the house just to do basic activities like go to the bathroom or even change clothes. That’s why it is very important to check into a nursing home where they offer their professional service. In some cases these nurses don’t work professionally and often neglect their patients needs, so that is why it’s recommended to contact a nursing home neglect attorney for situations like this for legal help.

Am I discombobulated by this experience? Not especially, I genuinely found being on the receiving end of prostate surgery a truly educational experience and I now feel energised to help others get through their journey. In the upcoming issue of Trends in Urology three other of our urological colleagues share their own experiences of prostate cancer, as well as the lessons that can be learned from them. Check out the Trends in Urology website from mid-March onwards.

In the meantime we would be interested in your own thoughts on these issues. Do add a comment or question to this blog.

Roger Kirby
The Prostate Centre, London W1G 8GT

 

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Editorial: Valuing interventions for localised prostate cancer

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Robert Pickard and Luke Vale

Governments of all nations struggle to work out how best to use the limited resources available for health care. One key area of uncertainty is long term conditions with multiple therapeutic options including no active treatment, where relative merits of different treatments are unclear and there is associated unexplained variation in use of often expensive interventions such as surgery. The management of localised prostate cancer typifies this situation. The problem is how to decide the relative worth of options especially as this judgement might differ between patients, clinicians, providers and funders. The best way is to perform well designed randomised trials between competing interventions with sufficient follow-up to identify any differences. For localised prostate cancer the ProTect trial is due to report in 2014. In the meantime, health care agencies commission Health Technology Assessments (HTA) to comparatively value interventions usually on the basis of the monetary cost of the added benefit they give in terms of better outcomes. This is commonly measured as the extra cost of each additional quality-adjusted life year (QALY) they give. The well laid out paper by Cooperberg et al. certainly adds to previous similar work  that is available on relevant health agency websites (HTA 2003, CADTH 2011, HTA 2011, HTA 2012), but was interestingly funded by an industrial stakeholder, Intuitive Surgical. Given its perspective focusing predominantly on Medicare tariffs, it is perhaps most relevant to the US Government who pays these rates, but careful reading by all will at the very least give a flavour of the use of predictive statistical and economic modelling of the possible benefits to patients, and costs to funders of the treatments advised by clinicians.

It is important to highlight that the methods of meta-analysis of the existing literature used by Cooperberg et al. are unclear – this makes it hard to critique whether the best data have been used in the model. Furthermore, the data analyses are unusual. A more typical presentation would have been to explore the likelihood that each treatment would be considered cost-effective. The method used does not really illustrate whether the conclusion should be that there are no differences between treatments or whether there is insufficient evidence to determine whether there are differences. Furthermore, although baseline characteristics of patients included in the meta-analysis are not given it is likely that some would differ between men undergoing surgery or radiotherapy leading to bias in outcome. The linear Markov model used is also perhaps an inadequate reflection of reality since it does not appear to calculate QALYs for repeated transit through further cancer treatment/remission/recurrence states and between incontinent/continent and sexual dysfunction/no sexual dysfunction states which men would value specifically and independently. In terms of costs the have included costs of patient recovery time. Arguably recovery should be captured within the QALY measure and to include it again under costs might be an element of double counting. In addition they showed that the results were sensitive to certain assumptions that may be questioned such as the four year shorter time to metastasis after biochemical recurrence for radiotherapy.

Cooperberg et al. have certainly provided a useful example of how different treatments supervised by clinicians may be valued by those that pay the bills. A parting thought is if only clinicians of differing specialties could collaborate on large definitive RCTs we would not need to rely on predictive models based on imperfect data.

 

Robert Pickard is a Professor of Urology at the Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. email: [email protected]

Luke Vale is Health Foundation Chair in Health Economics at the Institute of Health & Society, Newcastle University, Newcastle upon Tyne, UK. email: [email protected]

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