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Early Prostate Cancer Detection. One Canadian Urologist’s Perspective

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After seventeen years as a practicing urologist and a further six in training, it amazes me that we still regard prostate cancer as a mystical science and view the issue of screening through the opaque prism of controversy. For so long it seems that the advanced stage disease that I learned about in the mid 1980s in medical school was irreversibly altered by early detection and treatment. Of course we now know that much of this early detection was simply a lead-time bias and that many men who were treated required only observation and were left with many potential compromises to quality of life. “Doctor, my cancer is gone, why am I so miserable?”

At the recent annual meeting of the American Urological Association in San Diego, new guidelines on prostate cancer screening were unveiled. In the past, routine testing at age 50 was recommended with age 40 being the threshold for those at risk. Essentially they can be summarized as:

  • Avoid screening under 40
     
  • Do not routinely screen between 40 and 54 for average risk men. For those at risk screening should be individualized.
     
  • For those between age 55 and 69 there is possibly some benefit and shared decision-making with a patient should be the rule.
     
  • Finally no routine screening after 70.
     
  • PSA should be considered every two years

The motivation for this more cautious recommendation stems for the fact that many men have indolent disease. Many of these men don’t require treatment. Treatment brings with it the potential to harm and therefore casts into doubt the value of any treatment.

The problem of course is while that may represent a possible, cost-effective strategy across the wider population, there is little doubt in my mind that this will lead to many younger and even older men falling through the cracks. It will be justified as too high a number needed to treat to make sense to find these men. Policy makers and health economists may shrug. My own experience is that we have much to learn about risk factors and that many men present seemingly without warning with significant disease.

 

This email from a patient illustrates the concern. Identifiers of course are removed. Both men had disease beyond the capsule of the prostate. Neither man had risk factors. Our patients are very wise and quickly become experts in the disease.

In Canada, the Canadian Urological Association has taken the view for some time that we should look at multiple factors as we “build a case” for prostate biopsy. Its own guidelines reflect this. This paper that we published speaks to the use of nomograms to make better biopsy decisions. Many calculators are available on the web.

So what is shared, informed decision-making? The assumption after the AUA meeting is that somehow patients and their primary care doctors will somehow know. What sort of conversation is happening if urologists themselves don’t seem to provide clear guidance? I suspect it will go something like “PSA doesn’t work, prostate cancer is not lethal and you will likely die from something else” Many family doctors have much of their time rightfully diverted to treating important disease entities such as hypertension, depression and diabetes. A not insignificant number of primary care doctors don’t necessarily even do a DRE anymore. If the urological community conveys the message that prostate cancer is not worth the effort it will further fall down the priority list.

In my view I am a little dismayed by the rhetoric that has started since these guidelines were presented. Much of this is well intentioned and a reaction to years of potential over-treatment. This earlier 2012 piece from the highly respected @OtisBrawley of the American Cancer Society illustrates the false promise of screening message that is being told. It will only be amplified after San Diego. In my view PSA itself is a blood test. It is harmless. It is the treatment machinery that it often initiates that potentially gives it a bite and needs careful reflection.

To many, prostate cancer is simply a benign disease in aging males along the lines of male pattern baldness. This would be a disaster in my view. We have definitely shifted the curve to the left but in addition to lowering overall mortality have greatly lessened the burden of disease complications. Men presenting with hematuria, urinary retention and renal failure has significantly diminished. It is rare that we get asked to insert nephrostomy tubes for advanced disease. This was a common clinical scenario when I was a resident in the early 1990s. I think we will see much more of that if we massively abandon screening.

I think as urologists we have a big responsibility to lead within our local communities. This comment from Dr. A Partin speaks to this very well. In the absence of the perfect pre-test conditions that predict meaningful disease my view is that we have to cast a wide net. In doing so we will uncover disease that does not need to be treated. We must then be prepared to separate diagnosis from treatment and carefully counsel our patients in a way that takes much detail and effort. It is not a five-minute discussion you can have in the middle of a busy clinic. Active Surveillance does work for low-risk disease. Our patients are sophisticated and will not blindly ask for treatment out of overwhelming anxiety. In parallel, we must continue to improve. The risk of biopsy, which has greatly increased over fifteen years, must be modified. Biopsy accuracy to find “real” disease can perhaps be improved with technology such as MRI. Techniques that lessen quality of life issues need to be modified. Robotic surgery can’t be a marketing free-for-all. In other words the onus is on us experts to get it right and do better.

Prostate cancer is a very significant disease and the source of pain and suffering for men and their families. We must continue to be vigilant of its implications, respectful of patient desires and hopeful ultimately of a cure. A benign disease it most certainly is not.

Dr. Rajiv K Singal is a Urologist at Toronto East General Hospital and Assistant Professor in the Department of Surgery at the University of Toronto.

Follow him on Twitter at @DrRKSingal

 

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Article of the week: ADT increases fracture in high-risk men

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of Grace Lu–Yao discussing her paper.

If you only have time to read one article this week, it should be this one.

Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications

Yu-Hsuan Shao*†, Dirk F. Moore*‡, Weichung Shih*‡, Yong Lin*‡, Thomas L. Jang* and Grace L. Lu-Yao*†

*The Cancer Institute of New Jersey, †Department of Medicine, The Robert Wood Johnson Medical School, New Brunswick, and ‡Department of Biostatistics, UMDNJ School of Public Health, Piscataway, NJ, USA

Read the full article
OBJECTIVE

• To quantify the impact of androgen deprivation therapy (ADT) in men with a high baseline risk of skeletal complications and evaluate the risk of mortality after a fracture.

PATIENTS AND METHODS

• We studied 75 994 men, aged ≥66 years, with localized prostate cancer from the Surveillance, Epidemiology and End Results–Medicare linked data.

• Cox proportional hazard models were employed to evaluate the risk.

RESULTS

• Men with a high baseline risk of skeletal complications have a higher probability of receiving ADT than those with a low risk (52.1% vs 38.2%, P < 0.001).

• During the 12-year follow-up, more than 58% of men with a high risk and 38% of men with a low risk developed at least one fracture after ADT.

• The dose effect of ADT is stronger among men who received ADT only compared to those who received ADT with other treatments.

• In the high-risk group, the fracture rate increased by 19.9 per 1000 person-years (from 52.9 to 73.0 person-years) for men who did not receive ADT compared to those who received 18 or more doses of gonadotropin-releasing hormone agonist among men who received ADT only, and by 14.2 per 1000 person-years (from 45.2 to 59.4 person-years) among men who received ADT and other treatments.

• Men experiencing a fracture had a 1.38-fold higher overall mortality risk than those who did not (95% CI, 1.34–1.43).

CONCLUSIONS

• Men with a high baseline risk of skeletal complications developed more fractures after ADT.

• The mortality risk is 40% higher after experiencing a fracture.

• Consideration of patient risk before prescribing ADT for long-term use may reduce both fracture risk and fracture-associated mortality.

 

Read Previous Articles of the Week

 

Editorial: Androgen deprivation therapy: further confirmation of known harms

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Androgen deprivation therapy (ADT) has been an established and effective treatment for men with asymptomatic metastatic prostate cancer for decades. Randomized trials have shown significant survival benefits when ADT is used, coupled with radiotherapy, for patients with locally advanced disease; however it is often used in patients where the benefits are less clear, such as for a rising serum PSA level after radical prostatectomy, and among patients who elect to take a more conservative approach to treatment for low-risk disease. In addition to the absence of data proving benefit, there are a number of adverse consequences attached to androgen deprivation which should be given serious consideration before beginning treatment. Most of the side effects of ADT are linked to its induced hypo-androgenic, and consequently hypo-oestrogenic, state. These include fatigue, vasomotor flushing, loss of muscle mass, weight gain, hyperlipidaemia and insulin resistance.

Osteoporosis and fracture are additional known consequences of ADT with a trend toward greater fracture risk with a higher number of doses of a GnRH agonist and/or longer duration of use. Studies indicate that men with non-metastatic prostate cancer treated with ADT experience an annual loss in bone mineral density of up to nine times that of men in the general population. The use of intermittent ADT, as opposed to continuous use, as a strategy to reduce the negative cardiometabolic and osteoporotic effects is unresolved; however, a report indicating that more recent treatment was associated with a greater risk of fracture, irrespective of cumulative dose, suggests the potential for some reversibility in bone loss post-treatment.

In the present issue of the BJU International, Lu-Yao et al. add to the literature in this area. In a study of nearly 76 000 men with prostate cancer, using data gathered as part of the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) cancer registry linked to Medicare claims data, the authors reported that patients at high risk for skeletal complications were, not surprisingly, more likely to experience a fracture associated with ADT use over a 12-year period compared with patients receiving ADT but at low risk for developing such complications. Furthermore, men who experienced a fracture were 40% more likely to die during follow-up than those without fracture. Patients were sorted into risk groups using an index which summed the number of known risk factors for incident fracture identified from Medicare claims in the 12 months before their prostate cancer diagnosis. Unfortunately, owing to the relatively small number of patients with more than one risk factor, the study was limited in its ability to establish a dose – response relationship between the baseline index and fracture risk. SEER-Medicare is an excellent resource to investigate both outcomes and treatment-related expense associated with cancer diagnoses in the USA; however, in this particular study, the reliability of behaviours included in the baseline index (i.e. smoking) is questionable as it would require both patient report of tobacco use as well as physician documentation as a billable claim. Still, one might argue that the heaviest smokers, whose behaviour would most likely be captured as part of a claim, would also be the most important group to capture in an index intended to predict fracture risk.

Interestingly, it was reported that patients at high risk for skeletal complications were significantly more likely to receive ADT than patients at low risk. This was driven in part by the use of primary ADT among elderly men (aged ≥80 years) with prostate cancer and consistent with the notion that when curative treatment is contraindicated (i.e. older patients and those with pre-existing comorbidities) treatment with ADT is more common. Lastly, these findings do not suggest any modification of fracture risk associated with ADT according to baseline risk index, which is consistent with reports of the impact of comorbid conditions and ADT on the risk of incident diabetes and cardiovascular events. This is an important observation in that it says, there is no group that is immune to the adverse effects of ADT – all men are at risk. In absolute terms, however, the men at the greatest risk of an ADT side effect (i.e. a fracture or diabetes) are the men who are at greatest risk of having that side effect even if they were not receiving ADT. The findings of Lu-Yao et al. reinforce the need for careful monitoring of all men receiving ADT. Moreover, when these data are combined with an earlier study that showed that primary ADT was associated with poorer survival than that for men with low-risk prostate cancer who were managed conservatively with observation alone, it should be a wake-up call for us to stop treating non-lethal cancer with lethal and toxic treatments, including ADT.

Jennifer L. Beebe-Dimmer*† and Stephen J. Freedland‡§
*Wayne State University School of Medicine, †Karmanos Cancer Institute, Detroit, MI, ‡Durham VA Medical Center, and §Duke University School of Medicine, Durham, NC, USA

Read the full article

Video: Androgen deprivation therapy in men with high fracture risk

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Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications

Yu-Hsuan Shao*†, Dirk F. Moore*‡, Weichung Shih*‡, Yong Lin*‡, Thomas L. Jang* and Grace L. Lu-Yao*†

*The Cancer Institute of New Jersey, †Department of Medicine, The Robert Wood Johnson Medical School, New Brunswick, and ‡Department of Biostatistics, UMDNJ School of Public Health, Piscataway, NJ, USA

Read the full article
OBJECTIVE

• To quantify the impact of androgen deprivation therapy (ADT) in men with a high baseline risk of skeletal complications and evaluate the risk of mortality after a fracture.

PATIENTS AND METHODS

• We studied 75 994 men, aged 66 years, with localized prostate cancer from the Surveillance, Epidemiology and End Results–Medicare linked data.

• Cox proportional hazard models were employed to evaluate the risk.

RESULTS

• Men with a high baseline risk of skeletal complications have a higher probability of receiving ADT than those with a low risk (52.1% vs 38.2%, P < 0.001).

• During the 12-year follow-up, more than 58% of men with a high risk and 38% of men with a low risk developed at least one fracture after ADT.

• The dose effect of ADT is stronger among men who received ADT only compared to those who received ADT with other treatments.

• In the high-risk group, the fracture rate increased by 19.9 per 1000 person-years (from 52.9 to 73.0 person-years) for men who did not receive ADT compared to those who received 18 or more doses of gonadotropin-releasing hormone agonist among men who received ADT only, and by 14.2 per 1000 person-years (from 45.2 to 59.4 person-years) among men who received ADT and other treatments.

•Men experiencing a fracture had a 1.38-fold higher overall mortality risk than those who did not (95% CI, 1.34–1.43).

CONCLUSIONS

• Men with a high baseline risk of skeletal complications developed more fractures after ADT.

• The mortality risk is 40% higher after experiencing a fracture.

• Consideration of patient risk before prescribing ADT for long-term use may reduce both fracture risk and fracture-associated mortality.

 

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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Article of the week: Nomogram helps the preoperative prediction of early biochemical recurrence after radical prostatectomy

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of Ángel Borque discussing his paper.

If you only have time to read one article this week, it should be this one.

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

Read the full article
OBJECTIVES

• 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.

 

Read Previous Articles of the Week

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

Read the full article

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

Read the full article

• 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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Article of the week: The survey says: surgeon preferences during robot-assisted radical prostatectomy

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

The European Association of Urology Robotic Urology Section (ERUS) survey of robot-assisted radical prostatectomy (RARP)

Vincenzo Ficarra1, Peter N. Wiklund2, Charles Henry Rochat3, Prokar Dasgupta4, Benjamin J. Challacombe4, Prasanna Sooriakumaran5, Stefan Siemer6, Nazareno Suardi7, Giacomo Novara1 and Alexandre Mottrie8

1Oncological and Surgical Sciences, Urology Clinic, University of Padua, Padua, Italy; 2Urology Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 3Multidisciplinary Centre of Robot-Assisted Laparoscopic Surgery, Générale-Beaulieu Clinic, Geneva, Switzerland; 4Department of Urology, Guy’s Hospital, London, UK; 5Department of Urology, Royal Surrey County Hospital, Guildford, UK; 6Department of Urology, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; 7Department of Urology, Vita-Salute University San Raffaele, Milan, Italy; and 8Department of Urology O.L.V. Clinic Aalst, Aalst, Belgium; EAU Robotic Urologic Section (ERUS) Scientific Working Group

Read the full article
OBJECTIVE

• To evaluate surgeons adherence to current clinical practice, with the available evidence, for robot-assisted radical prostatectomy (RARP) and offer a baseline assessment to measure the impact of the Pasadena recommendations. Recently, the European Association of Urology Robotic Urology Section (ERUS) supported the Pasadena Consensus Conference on best practices in RARP.

SUBJECTS AND METHODS

• This survey was performed in January 2012. A specific questionnaire was sent, by e-mail, to 145 robotic surgeons who were included in the mailing-list of ERUS members and working in different urological institutions.

• Participating surgeons were invited to answer a multiple-choice questionnaire including 24-items evaluating the main RARP surgical steps.

RESULTS

• In all, 116 (79.4%) invited surgeons answered the questionnaire and accepted to participate to the ERUS survey.

• In all, 47 (40.5%) surgeons performed >100 RARPs; 41 (35.3%) between 50 and 100, and 28 (24.1%) <50 yearly.

• The transperitoneal, antegrade technique was the preferred approach.

• Minimising bladder neck dissection and the use of athermal dissection of the neurovascular bundles (NVBs) were also popular.

• There was more heterogeneity in the use of energy for seminal vesicle dissection, the preservation of the tips of the seminal vesicle and the choice between intra- and interfascial planes during the antero-lateral dissection of the NVBs. There was also large variability in the posterior and/or anterior reconstruction steps.

CONCLUSIONS

• The present study is the first international survey evaluating surgeon preferences during RARP.

• Considering that the results were collected before the publication of the Pasadena recommendations, the data might be considered an important baseline evaluation to test the dissemination and effects of the Pasadena recommendations in subsequent years.

 

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