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Editorial: Androgen deprivation therapy: further confirmation of known harms

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

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The new AUA PSA Testing Guidelines leave me scratching my head

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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This image is taken from the article by Pfalzgraf et al. in the BJUI recently reporting results on a modified Barbagli technique.

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Editorial: Incorporating prognostic grade grouping into Gleason grades

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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Patient presents 6 weeks after a renal transplant with a rise in creatinine.

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Reference
1. Donor type does not influence the incidence of major urologic complications after kidney transplantation. Transplantation. 2010; 90(10):1085-1090

 

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