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Fish Oil Causes Prostate Cancer: fact or fishy tale?

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Following the recent fish oil and prostate controversy (which BJUI Chairman Dr David Quinlan recently blogged about, the August International Urology Journal Club discussion on Twitter was based on the recent high-profile (and controversial) paper “Plasma Phospholipid Fatty Acids and Prostate cancer risk in the Select trial”, available by advance access from the Journal of the National Cancer Institute, June 10, 2013.

In the recent weeks, many concerned patients had attended urologist and GP clinics, enquiring about the reports that fish oil supplements increase the risk of prostate cancer. This has led to lengthy discussions between patients and their doctors during consultations, and even caused some clinics to run overtime.

So, does fish oil really lubricate prostate cancer growth, or is this all just a fishy tale?

In summary, this case–cohort study set out to examine the association between plasma phospholipid fatty acids and prostate cancer risk among participants in the Selenium and Vitamin E Cancer Prevention Trial. 834 men diagnosed with prostate cancer formed the prostate cancer group. 1393 men chosen at random, and matched according to age and race, formed the non-cancer group. The study reports that men in the lowest quartiles of LCω-3PUFA, compared with men in the highest quartile, had increased risks for low-grade (HR = 1.44, 95% CI = 1.08 to 1.93), high-grade (HR = 1.71, 95% CI = 1.00 to 2.94), and total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88). Similar associations were reported for individual long-chain ω-3 fatty acids. Higher linoleic acid (ω-6) was associated with reduced risks of low-grade (HR = 0.75, 95% CI = 0.56 to 0.99) and total prostate cancer (HR = 0.77, 95% CI = 0.59 to 1.01); however, there was no dose response. This study therefore concluded that increased prostate cancer risk among men with high blood concentrations of LCω-3PUFA was confirmed. The authors went on to say that the consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis, and that recommendations to increase LCω-3PUFA intake should consider these risks.

There has been a lot of media hype surrounding this paper, with the claim that fish oil supplements may increase one’s risk of prostate cancer. This has led to many anxious patients. It is not the first time that sensational claims of natural therapies either causing or preventing cancer has received a lot of media attention.

However, as doctors who have patients and colleagues asking us for sound advice on the matter, it is important that we don’t simply dismiss such hype (and questions from anxious patients) without looking into the matter more deeply, examining the evidence for ourselves, and forming a sensible opinion.


Early in the discussion, the methodology of the study was criticised as being observational by Kate Linton and Faisal Ahmed agreed. The study lacked a proper control group, and did not adequately address confounding factors. Associations were attributed to causation.


Stacy Loeb pointed out that the study did not record the amount of fish oil supplements ingested by any of the men in the study and instead on the basis of a single serum level. Yet the media extrapolates the study’s findings to make recommendations about fish oil supplements, which can be delivered in various formulations and doses.


There was also concern for the assay method used in measuring plasma lipids.


This study’s conclusions might have interesting commercial ramifications. I wonder whether there has been a drop in fish oil supplement sales this week?

However, it is worthwhile to note that there have been other prospective studies and metanalyses that have shown an inverse association between fish oil and prostate cancer. Helen Nicholson brought to our attention, a paper published in Cancer Epidemiology, Biomarkers and Prevention in 2007, which concluded that higher blood levels of long-chain n-3 fatty acids, mainly found in marine foods, and of linoleic acid, mainly found in non-hydrogenated vegetable oils, are associated with a reduced risk of prostate cancer.

To conclude the discussion, several participants stated

My take home message from the August #urojc discussion is;

1.Although interesting, this study is limited by its methodology – it was not a randomised controlled trial of fish oil supplements versus no fish oil supplements. Therefore it cannot answer this question.

2.This study does not provide sufficient evidence to confirm whether omega-3 fatty acids conclusively lead to increased risk of prostate cancer.

3.Media hype = anxious patients. But we can tell our patients the science.

The winner of the best tweet prize for the August #urojc was Kate Linton for the following tweet which highlighted a significant shortcoming of the paper.

 

 

The August #urojc prize was kindly supported by the Asian Journal of Andrology.

We thank everyone who participated in the August #urojc, and to the many other on-lookers.

We look forward to your input in the next great International Urology Journal Club discussion, in early September 2013. The topic will soon be announced. If you would like any specific papers to be discussed, please DM us @iurojc – we always welcome your suggestions and feedback.

 

Dr Amanda Chung is an Australian Urological Surgeon in Training, currently based at The Wollongong Hospital, New South Wales. @AmandaSJChung

Editorial: Fesoterodine is superior to extended-release tolterodine for OAB

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The treatment of overactive bladder (OAB) is still based on antimuscarinics, although the recent introduction of β3 agonists and botulinum toxin A has opened a window of new opportunities, the range of which is yet to be defined.

The clinical development of fesoterodine has taken the Urological community by surprise and raised levels of expectation. From a pharmacological standpoint fesoterodine is just a ‘smart drug’ because it is the pro-drug of 5-hydroxymethyl tolterodine (5-HMT) the active metabolite of tolterodine that is metabolised into 5-HMT by cytochrome P450 (CYP) enzymes, the activity of which is known to suffer significant genetic variability. Fesoterodine is transformed into 5-HMT by nonspecific esterase pathways. Pharmacokinetic studies of fesoterodine have shown highly predictable plasma levels of the 5-HMT after fesoterodine administration. Whether or not the better bioavailability offered by the esterase-related activation pathway translates into a larger clinic benefit for our patients with OAB was initially unclear. A phase II study showed a good safety profile and suggested that two different doses of fesoterodine could be proposed with a good balance between efficacy and adverse events. Results of the pivotal phase III study confirmed how the two different doses: 4 and 8 mg, tended to separate with a larger benefit observed with the larger dose, although a slightly larger incidence of adverse events was observed. As long as the comparison between 4 and 8 mg of fesoterodine was not part of the pre-planned analysis, the results of thepost hoc analysis had to be confirmed in a properly design prospective randomised trial.

The assumption that a higher drug dose brings a larger therapeutic effect is very often just wishful thinking and clinical pharmacology has often disproved such a belief. What is instead clear, from the paper of David Ginsberg et al., which pools data from two randomised trials (BJU Int 2010, BJU Int 2011), is that the flexible dosage available with fesoterodine brings a clinically relevant advantage in our daily practice.

The question is whether there is a real need for dose flexibility in the management of OAB. After a couple of decades in this area, I strongly believe that flexible dosing is crucial, in general, and even more so in functional urology. This is in fact an area where storage and voiding function needs to be rebalanced; a too weak or too strong effect may easily lead to a therapeutic failure. Reaching the right balance between therapeutic effect and adverse events is crucial while using antimuscarinics. If 40% of patients who withdraw from anticholinergic medications do so because of insufficient benefit, another large proportion (22%) discontinues treatment because of side-effects.

The question in real-life practice, provided treatment should be initiated with a 4 mg dose because of regulatory issues, is whether the dose should be upgraded and when, should this be left to the individual patient’s decision or should it be guided by the treating physician? There is no ‘golden’ rule and in my opinion is a matter of patient expectations. Most patients expect drugs to cure the conditions they are prescribed for, although we know this is rarely the case. When patients are properly informed about the effect of antimuscarinics treatment they will often choose their goal, some patients will look for reducing OAB symptoms while avoiding dry mouth and constipation as much as possible, others will want to become dry and accept higher levels of adverse events. Furthermore, because of body distribution, different doses of drugs may be required in a 45 kg lady and in a 90 kg man, although this may depend on the drug bioavailability at the target organ. The same applies to patients with normal detrusor contractility and patients with a weak bladder, such as patients with multiple sclerosis. The ‘one dose fits all’ approach does not seem to be the way to go.

The larger therapeutic effect achieved in the 8 mg fesoterodine group is obtained at the expense of almost doubling the incidence of dry mouth (from 15% to 28%), although the increase in the constipation rate is just 1%. Whether or not the observed differential improvement between tolterodine 4 mg and fesoterodine 8 mg is clinically relevant is matter for discussion for the investigators but looking at the parallel improvement in all patients reported outcomes, the difference seems to be of importance from the patient perspective.

The therapeutic area of storage disorders, e.g. OAB, is experiencing a number of paradigm changes, including the availability of flexible dosing of antimuscarinics, β3 agonists and botulinum toxin A. What once used to be a neglected area of functional urology is now an exciting area of basic and clinical research.

Andrea Tubaro and Cosimo De Nunzio*
Urology Unit, Department of Clinical and Molecular Medicine, Faculty of Health Sciences, Sapienza University, and *Urology Unit, Sant’Andrea Hospital, Rome, Italy

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The Melbourne Consensus Statement on Prostate Cancer Testing

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The final, peer-reviewed version of this Consensus Statement has now been published in BJUI. You can find it here. The full citation is Murphy, D. G., Ahlering, T., Catalona, et al. (2014), The Melbourne Consensus Statement on the early detection of prostate cancer. BJU International, 113: 186–188. doi: 10.1111/bju.12556

A consensus view on the early detection of prostate cancer, led by experts at the Prostate Cancer World Congress, Melbourne, 7–10th August 2013

Recent guideline statements and recommendations have led to further confusion and controversy regarding the use of Prostate Specific Antigen (PSA) testing for the early detection of prostate cancer. Despite high-level evidence for the use of PSA testing as a screening tool, and also for its role as a predictor of future risk, the U.S. Preventive Services Taskforce (USPSTF) has called for PSA testing to be abandoned completely [1], and many men are therefore not given the opportunity for shared decision-making. Other groups such as the American Urological Association, National Comprehensive Cancer Network , and European Association of Urology support a role for PSA screening but with somewhat conflicting recommendations. The majority of guideline statements have endorsed the role of shared decision-making for men considering PSA testing.

To address these somewhat conflicting and confusing positions, a group of leading prostate cancer experts from around the world have come together at the 2013 Prostate Cancer World Congress in Melbourne and have generated the following set of consensus statements regarding the use of PSA testing. The goal of these statements is to bring some clarity to the confusion that exists with existing guidelines, and to present reasonable and rational guidance for the early detection of prostate cancer today.

1.        Consensus Statement 1: For men aged 50–69, level 1 evidence demonstrates that PSA testing reduces prostate cancer-specific mortality and the incidence of metastatic prostate cancer. In the European Randomized Study of Screening for Prostate Cancer (ERSPC), screening reduced metastatic disease and prostate cancer-specific mortality by up to 30% and 21% respectively in the intent-to-treat analysis, with a greater reduction after adjustment for noncompliance and contamination[2,3]. In addition, the Goteborg randomized population-based randomized trial showed a reduction in metastatic disease and prostate cancer mortality with screening starting at age 50 [4]. The degree of over-diagnosis and over-treatment reduces considerably with longer follow-up, such that the numbers needed to screen and numbers needed to diagnose compare very favourably with screening for breast cancer. The boob reduction in Tri-Cities procedures are one among the very best rated and most valued cosmetic procedures among woman (and some men) within the Tri-Cities, TN area.  High patient satisfaction ratings for this procedure should come as no surprise, given the quantity of relief the operation provides to those that suffer from heavy or large breasts. With years of experience, and a diary of positive patient outcomes, Dr. Jim Brantner, M.D. can help improve your overall wellness, comfort, and confidence through a secure and effective breast reduction procedure. Breast reductions, otherwise referred to as Reduction Mammoplasties, are often a relief for thousands of men and ladies . If your breasts are causing pain or other health issues, then you’ll wish to think about a breast reduction. In a breast reduction, our surgeon improves a patient’s health by removing a predetermined amount of breast tissue, skin, and fat. This reduces the patient’s breast size overall and helps improve their neck, shoulder, back, and overall health. If you would like to understand what the procedure evolves in additional detail, please read subsequent paragraph. If you discover you are feeling squeamish, be happy to scroll to subsequent section. To remove the surplus breast tissue, your surgeon will make an incision around your nipple then downward over your breast — consider a keyhole. Our expert team will remove excess skin, tissue, and fat before adjusting your nipple for cosmetic purposes. Your surgeon may have to use drainage tubes before your incision site is sutured. Our team will then wrap your breasts during a special gauze; your doctor may recommend a surgical bra, as well. While routine population-based screening is not recommended, healthy, well-informed men in this age group should be fully counseled about the positive and negative aspects of PSA testing to reduce their risk of metastases and death. This should be part of a shared decision-making process. According to a study, it is also revealed that not every time you need a surgery, breast cancer can be also be treated easily. With the advancement of the technology, Botox injection and dermal filler injection can be used by patient of breast cancer. But for this an expert recommendation is required.  Visit the dermal fillers melbourne expert to know more.

 2.        Consensus Statement 2: Prostate cancer diagnosis must be uncoupled from prostate cancer intervention. Although screening is essential to diagnose high-risk cases within the window of curability, it is clear that many men with low-risk prostate cancer do not need aggressive treatment. Active surveillance protocols have been developed and have been shown to be a reasonable and safe option for many men with low-volume, low-risk prostate cancer [5,6]. While it is accepted that active surveillance does not address the issue of over-diagnosis, it does provide a vehicle to avoid excessive intervention. Active surveillance strategies need standardization and validation internationally to reassure patients and clinicians that this is a safe strategy.

 3.        Consensus Statement 3: PSA testing should not be considered on its own, but rather as part of a multivariable approach to early prostate cancer detection. PSA is a weak predictor of current risk and additional variables such as digital rectal examination, prostate volume, family history, ethnicity, risk prediction models, and new tools such as the phi test, can help to better risk stratify men. Prostate cancer risk calculators such as those generated from the ERSPC ROTTERDAM, the Prostate Cancer Prevention Trial (PCPT) , and from Canada , are useful tools to help men understand the risk of prostate cancer in these populations. Further developments in the area of biomarkers, as well as improvements in imaging will continue to improve risk stratification, with potential for reduction in over-diagnosis and over-treatment of lower risk disease.

4.        Consensus Statement 4: Baseline PSA testing for men in their 40s is useful for predicting the future risk of prostate cancer. Although these men were not included in the two main randomized trials, there is strong evidence that this is a group of men who may benefit from the use of PSA testing as a baseline to aid risk stratification for their likely future risk for developing prostate cancer [7], including clinically significant prostate cancer. Studies have shown the value of PSA testing in this cohort for predicting the increased likelihood of developing prostate cancer 25 years later for men whose baseline PSA is in the highest centiles above the median [8,9]. For example, those men with a PSA below the median could be spared regular PSA testing as their future risk of developing prostate cancer is comparatively low, whereas those with a PSA above the median are at considerably higher risk and need closer surveillance. The median PSA for men aged 40–49 ranges from 0.5–0.7 ng/ml, with the 75th percentile ranging from 0.7–0.9ng/ml. The higher above the median, the greater the risk of later developing life-threatening disease. We recommend that a baseline PSA in the 40s has value for risk stratification and this option should be discussed with men in this age group as part of a shared decision-making process.

 5.        Consensus Statement 5: Older men in good health with over ten year life expectancy should not be denied PSA testing on the basis of their age. Men should be assessed on an individual basis rather than applying an arbitrary chronological age beyond which testing should not occur. As life expectancy improves in many countries around the world (men aged 70 in Australia have a 15 year life expectancy), a small proportion of older men may benefit from an early diagnosis of more aggressive forms of localised prostate cancer, just as it is clear that men with many competing co-morbidities and less aggressive forms of prostate cancer are unlikely to benefit irrespective of age. Likewise, a man in his 70s who has had a stable PSA at or below the median for a number of years previously is at low risk of developing a threatening prostate cancer and regular PSA screening should be discouraged.

An important goal when considering early detection of prostate cancer today, is to maintain the gains that have been made in survival over the past thirty years since the introduction of PSA testing, while minimizing the harms associated with over-diagnosis and over-treatment. This is already happening in Australia where over 40% of patients with low-risk prostate cancer are managed with surveillance or watchful waiting [10], and in Sweden where 59% of very low risk patients are on active surveillance. This is also reflected in current guidelines from the EAU, NCCN and other expert bodies, and in a comment from AUA Guideline author Dr Bal Carter in the BJU International.

Abandonment of PSA testing as recommended by the USPSTF, would lead to a large increase in men presenting with advanced prostate cancer and a reversal of the gains made in prostate cancer mortality over the past three decades.

However, any discussion about surveillance is predicated on having a diagnosis of early prostate cancer in the first instance. As Dr Joseph Smith editorialized in the Journal of Urology following the publication of the ERSPC and PLCO trials, “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” [11]. A key strategy therefore is to continue to offer well-informed men the opportunity to be diagnosed early, while minimizing harms by avoiding intervention in those men at low risk of disease progression. This consensus statement provides some guidance to help achieve these goals.

 
Signatories:

A/Professor Declan G Murphy, University of Melbourne, Peter MacCallum Cancer Centre, Melbourne, Australia

Professor Tony Costello, University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia

Dr Patrick C Walsh, The James Buchanan Brady Urological Institute, Johns Hopkins University, USA

Dr Thomas Ahlering, University of California, Irvine, School of Medicine, USA

Dr William C Catalona, Northwestern University Feinberg School of Medicine, USA

Dr Oliver Sartor, Tulane University School of Medicine, USA

Dr Tom Pickles, British Columbia Cancer Agency, Canada

Dr Jane Crowe, Australian Prostate Cancer Research Centre, Australia

Dr Addie Wootten, Royal Melbourne Hospital, Australia

Ms Helen Crowe, Royal Melbourne Hospital, Australia

Professor Noel Clarke, Manchester University, The Christie Hospital, Manchester, UK

Dr Matthew Cooperberg, University of California San Francisco, Helen Diller Family Comprehensive Cancer Centre, USA

Dr David Gillatt, University of Bristol, Bristol Urological Institute, Bristol, UK

Dr Martin Gleave, University of British Columbia, The Vancouver Prostate Centre, Vancouver, Canada

Dr Stacy Loeb, New York University, USA

Dr Monique Roobol, Erasmus University Medical Centre, Rotterdam, The Netherlands

Footnote:

The median PSA for men aged 40–49 ranges from 0.5–0.7ng/ml. The 75th percentile ranges from 0.7–0.9ng/ml.

This blog was originally published on 7th August 2013 and was updated on 13th August 2013.

References:

[1] Moyer VA, Force USPST. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157:120–34.

[2] Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366:981–90.

[3] Schroder FH, Hugosson J, Carlsson S, Tammela T, Maattanen L, Auvinen A, et al. Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Eur Urol. 2012;62:745–52.

[4] Hugosson J, Carlsson S, Aus G, Bergdahl S, Khatami A, Lodding P, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11:725–32.

[5] Bul M, Zhu X, Valdagni R, Pickles T, Kakehi Y, Rannikko A, et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur Urol. 2013;63:597–603.

[6] Bangma CH, Bul M, van der Kwast TH, Pickles T, Korfage IJ, Hoeks CM, et al. Active surveillance for low-risk prostate cancer. Crit Rev Oncol Hematol. 2012.

[7] Loeb S. Use of baseline prostate-specific antigen measurements to personalize prostate cancer screening. Eur Urol. 2012;61:875–6.

[8] Vickers AJ, Ulmert D, Sjoberg DD, Bennette CJ, Bjork T, Gerdtsson A, et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ. 2013;346:f2023.

[9] Lilja H, Cronin AM, Dahlin A, Manjer J, Nilsson PM, Eastham JA, et al. Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50. Cancer. 2011;117:1210–9.

[10] Evans SM, Millar JL, Davis ID, Murphy DG, Bolton DM, Giles GG, et al. Patterns of care for men diagnosed with prostate cancer in Victoria from 2008 to 2011. Med J Aust. 2013;198:540–5.

[11] Smith JA, Jr. What would you do, doctor? J Urol. 2009;182:421–2.

Surgeon Responsibility

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In an outstanding editorial in the current issue of the Journal of Urology (https://dx.doi.org/10.1016/j.juro.2013.05.031) my friend and colleague Jay Smith (who has accompanied us when we climbed Mt Kinabalu in Borneo and on cycle challenges in Malawi and Madagascar to raise funds for The Urology Foundation) asks the important question as to who decides when a surgeon has the requisite skills and experience to subject a patient to an operative procedure? He points out that a patient entrusting his or her quality of life, and indeed very survival, to a surgeon creates an ethical bond that has few parallels in society. Certification by the Royal College of Surgeons, American Board of Urology, or equivalent bodies elsewhere, does not imply competence in the operating theatre, or for a particular surgical procedure.

The question becomes even more pertinent in an era when new technologies such as the da Vinci surgical robot are becoming increasingly available and many clinicians, like Jay and myself, have had to become proficient robotic surgeons in the midst of their careers. Having the necessary case numbers for training, as well as expert help and mentoring in the early stages, has not always been easy. Becoming safely proficient with the robot has been compared to learning to fly a helicopter, where 40 hours mentored flying time is considered a minimum requirement.

Financial incentives, for both industry and the surgeon, and motives related to pride and practise promotion, can certainly conspire to cloud a clinician’s judgement. In the end it has to be the individual surgeon’s conscience that should be the prime determinant of whether he or she is qualified to perform any given operation. The patient trusts that the surgeon is not unduly influenced to attempt to perform a procedure beyond his or her competence. That is a truly essential covenant, as no regulatory body or oversight committee can truly know how qualified an individual surgeon may be for a particular procedure.

Patient-related outcome measurements (PROMS) and the publication of the results of individual surgeons seem set to play an important role in the future.

While some of us may view this negatively, from a patient safety viewpoint is it almost certainly the way ahead.

 

Roger Kirby, BJUI Associate Editor, The Prostate Centre, London

Functional urology in the BJUI

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Although urological oncology is by far our largest section, it has increasingly become evident to us that the most cited part of the BJUI is functional urology. While this may come as a surprise, it is a reflection of the high quality of submissions that appear in this section. For your reading pleasure here are three “functional” articles in this issue worthy of attention. The paper from David Ginsberg also appears on the web journal as an article of the week.

In the first of our functional urology articles this month, Sjostrom et al. once again confirm the value of PFMT for the treatment of questionnaire and interview diagnosed SUI. Further, they show that an Internet-based program, which is more detailed and requires more contact (see Table 2 in the article), is more effective than a postal-based program in this regard after 3 months of usage (follow up at 4 months). What does more effective mean? For the ICIQ-UI SF scores, minimal difference in mean score is seen in the group scoring 1–5 (slight) and 6–12 (moderate) at baseline, a difference of 8.1 to 11 seen in the group scoring 13–21 (severe and very severe) at baseline (Figure 2). I like the PGI-I as a subjective patient global assessment. The largest difference was in the “very much better” group with minimal differences elsewhere (Figure 3). It would be interesting to know whether the larger difference occurred primarily in the severe and very severe groups as well. My take away is that PFMT is effective for SUI management. One can quibble about the lack of a physical exam here, but I suspect there would have been little difference. The real question is how best to apply this concept, keeping in mind the balance between results and efficient use of healthcare resources. My hypothesis would be that of the 3 methods of post, Internet and face-to-face therapy, there would be a preferred grouping based on the level of incontinence severity and education with the confounding factors of ages, socioeconomic class and desire for treatment, the latter associated with QOL impairment. A follow up at 6 and 12 months after treatment cessation would be helpful, and I am sure this is planned by the authors.

The article by Volpe et al. shows that the same indications can be used for recommending outlet reduction via TURP in the post renal transplant as in the general population. The only issue not specified was whether the pre-TUR serum creatinine in the 5/32 patients requiring catheterization (measured before catheterization), was higher than the others and, if so, may have skewed the group results. Nevertheless, it is important to acknowledge that renal transplant patients have the same LUT issues as “normals” and, for these fragile men it may be especially important to be cognizant of LUT obstruction as a potential adverse but correctible factor for decreased renal function.

Regarding the article by Ginsberg et al. on the differences in efficacy and tolerability between 8 mg of fesoterodine, 4 mg of ER tolterodine and placebo in patients with OAB, the authors are to be commended, in my opinion, for publishing this article, which is bound to generate much controversy among those who carefully read it. It is true that this is probably the first large study to compare antimuscarinic efficacy separately in women and men. The article begins by pointing out the pharmacokinetic issues with the drug that the sponsor previously promoted as the gold standard of antimuscarinic therapy. It does show that the higher (double) dose of active agent produces a ‘better” efficacy result albeit with an increase in dry mouth frequency but not in other adverse events. A useful result of the article is to make one consider the questions of what constitutes a clinically significant result as opposed to a statistically significant one and what the mechanism is of the profound placebo effect, especially with reference to the objective parameters recorded (Fig 2). Almost 50% of women and 60% of men become diary dry on placebo. It would also be interesting to reconcile the greater (but not large) differences between the subjective or QOL measures and the objective ones. As a take home, if both drugs were similarly priced, or available through health care benefits, the choice would be obvious. If not, what would the difference be worth?

Alan J. Wein, MD, FACS, PhD(hon)
Associate Editor – Functional Urology
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA

 

Original publication of this editorial can be found at: doi: 10.1111/bju.12326. BJUI 2013; 112: 277. 

Fish Oils and Prostate Cancer

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If a Blog can be a call for help, then this is it! Since the recent high-profile paper in JNCI (https://jnci.oxfordjournals.org/content/early/2013/07/09/jnci.djt174.abstract) suggesting that Omega 3 supplements increase the risk of Prostate Cancer and induce high grade prostate cancer, I am plagued by patient and colleague concerns about whether or not men should stop taking Omega 3 supplements! I know that health care providers all over the world have been similarly inundated. What are we to say to our patients?

Let us first look at the paper. The authors used data collected as part of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) to determine whether men with high levels of plasma phospholipid fatty acids (high levels of which are present in fish oil supplements), namely long-chain ω-3 polyunsaturated fatty acids ([LCω-3PUFA], were at higher risk of developing prostate cancer. The case subjects in the study were 834 men diagnosed with prostate cancer, of whom 156 had high-grade cancer. The comparison cohort consisted of 1393 men selected randomly at baseline and matched to case subjects on age and race. Proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between fatty acids and prostate cancer risk overall and by grade. The results? Compared with men in the lowest quartiles of LCω-3PUFA, men in the highest quartile had increased risks for low-grade (HR = 1.44, 95% CI = 1.08 to 1.93), high-grade (HR = 1.71, 95% CI = 1.00 to 2.94), and total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88). These results are strong enough for the authors to conclude that there is increased prostate cancer risk among men with high blood concentrations of these plasma phospholipid fatty acids, and that “the consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis”.

Crikey! Fish oil supplements increase risk of prostate cancer! Is it really so?? Is the study methodology robust enough to change practice? Undoubtedly, there are a lot of patients taking these supplements, some prescribed by medical practitioners; even my lovely ophthalmologist wife tells me that nearly every patient with macular degeneration worldwide is on it! My knowledge of antioxidants is somewhat pedestrian and I feel like an amateur in advising whether or not men should discontinue Omega 3 supplements.

What should we tell those who ask us? All comments gratefully received.

Dr David Quinlan
Consultant Urologist, St Vincent’s Hospital,
Senior Lecturer, University College Dublin
Chairman, BJUI

Twitter: @daithiquinlan

Editorial: Accepting the positive results of unconventional methods

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It is sometimes difficult to accept the results of a study based on a concept that is unfamiliar, involves unknown physiological mechanisms, or shows results that defy rational explanation. Remote ischaemic preconditioning (RIPC) is probably not a familiar topic to most urologists and, admittedly, was not familiar to this reviewer until now. Yet the authors, based on animal models and clinical data from non-urological literature, conducted a prospective, surgeon and patient ‘blinded’, randomised controlled trial to evaluate the potential benefit of RIPC in minimising ischaemic damage. By most available factors affecting postoperative renal function (warm ischaemia time, tumour complexity as measured by Preoperative Aspects and Dimensions Used for an Anatomical [PADUA] scores, preoperative renal function, tumour stage, etc.), no difference existed between the control and study groups. The authors found that patients undergoing RIPC had a lower change in estimated GFR (eGFR) at 1 month and appeared to have less ischaemic damage based on urinary marker levels (retinol binding protein) and functional imaging parameters. Unfortunately, the short-term benefit of RIPC did not translate to improvements over a longer period, with no differences at 6 months or in absolute eGFR between the two groups.

The authors should be congratulated for conducting such an elegant trial, unfamiliar and unconventional as the concept may be. Strengths of this study include its randomised ‘blinded’ design, correlation with metabolite, urinary marker and imaging findings, 6-month follow-up, and due diligence for assessing most pre-analytic factors. Limitations include the absence of data on residual functioning renal parenchyma, which arguably is the single best predictor of function in an operated kidney; additionally, this population with outstandingly good renal function (≈120 mL/min/1.73 m2 in both groups) with very few comorbidities (<5–10% incidence of hypertension and diabetes) may not translate equally to the less healthy, more renally impaired Western population. The results may appear to be underwhelming, but I agree with the authors that further study is needed, and in particular for the Western population. The major impact from this reviewer’s perspective is for the patient with baseline renal compromise, whose risk for short- and long-term ischaemic renal injury is greater, and who could most benefit from a simple protective measure. Should we now enter unfamiliar territory and accept that the results of a randomised, ‘blinded’, prospective trial of a simple but unconventional method provide sufficient justification for testing this strategy in a higher risk population?

Surena F. Matin
Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Editorial: Equivalent outcomes for monopolar and bipolar TURP; but are we overlooking the potential for improvement in sexual function after surgery?

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Both BPH and sexual function (SF) have a major impact on quality of life in older men. Sexual dysfunction is a complex process encompassing both erectile and ejaculatory dysfunction, as well as reduced libido and difficulty achieving orgasm. Whilst retrograde ejaculation is an almost inevitable consequence of TURP, the evidence that TURP causes erectile dysfunction is conflicting. This is probably attributable, at least in part, to a lack of high-quality historical data. Studies now show that LUTS is a risk factor for sexual dysfunction, and we are becoming increasingly aware of the relationship that exists between LUTS, depression and sexual dysfunction.

Given the favourable safety profile of bipolar TURP (b-TURP), it is perhaps a surprise that this latest study from Mamoukalis et al. has failed to demonstrate any difference in outcomes with regard to the deterioration in SF after surgery. The authors should be praised for their attempts to examine in fine detail (using the International Index of Erectile Function [IIEF]-15 in this case) any potential differences between b-TURP and monopolar TURP (m-TURP).

The design of the bipolar system is such that tissue is removed at a lower temperature and therefore the likelihood of damage to surrounding tissues and nerves is reduced. Several randomized trials have compared b-TURP with m-TURP, but only a small number have looked specifically at sexual variables in a randomized setting. This multicentre study by Mamoukalis et al. randomized 279 men to one of the two resection techniques, looking specifically at overall SF quantified by the IIEF-15. No differences were detected in any aspect of SF; erectile function (EF) improved in 26.4% of patients in the m-TURP group compared with 19.6% in the b-TURP group, and remained stable in 60.9 and 60.8% of patients, respectively. A deterioration in EF was apparent in 12.7% of the m-TURP group compared with 19.6% of the b-TURP group (P = 0.323). These results mirror those of a similar randomized study by Akman et al. comparing a quasi-bipolar system with m-TURP. They demonstrated equivalence for all measured variables except for operating time and a 1.4% incidence of TUR syndrome in the m-TURP group. In their study, the EF domain of the IIEF-15 was measured before and after surgery. EF worsened in 17% of men, improved in 28.2% and was unchanged in 54.8%. A comparative evaluation of EF was performed in a sub-group of 188 sexually active non-catheterized men of whom 18.2% developed de novo erectile dysfunction.

The explanation for the equivalent outcomes is unclear and further investigation is required. Does the failure of bipolar TURP to demonstrate a benefit with regard to SF leave the door open for the competing minimally invasive laser technologies? The overall impact of the holmium laser compared with that of TURP appears to be equivalent, with a mean of 7.5 and 7.7% of patients reporting decreased erectile function, and 7.1 and 6.2% of patients reporting increased function after each surgery. From the data available thus far, it would also appear that photoselective vaporization of the prostate similarly has no overall deleterious impact on SF when compared with TURP in a randomized trial. Further randomized data are pending and are of course of great importance if we are to understand better how the procedures we perform for symptomatic BPH affect our patients. As technological advances are made the hope is that the ‘damaging’ effects of BPH surgery on overall SF (particularly EF) will reduce further, but it may indeed be that we are searching for small margins when our attention might be better focused on maximizing the likelihood of a positive outcome, facilitated by considering the preoperative status (general health as well as urinary and sexual function), aided by the use of validated questionnaires. A better appreciation and understanding of the factors that may increase the risk of ED after surgery (age, diabetes, metabolic syndrome, obesity, cardiovascular disease and psychological factors) will enable us to manage expectations more effectively. A shorter hospital stay with minimal postoperative discomfort and an early return to normal activities, coupled with good symptomatic improvement in the longer term can only serve to be of benefit with regard to improving SF outcomes.

One recent study reporting both the short-, medium- and long-term effects of TURP on SF highlighted the high incidence of LUTS before treatment with 57% overall reporting ED before surgery. Those with severe LUTS were much more likely to have significant sexual dysfunction before surgery. This study also demonstrated a 15% improvement in pre-existing ED which was related to the improvement in LUTS after TURP.

On reflection, therefore, it would seem reasonable to conclude from the evidence presented that, although retrograde ejaculation frequently occurs after outflow surgery, erectile function is as likely to improve as it is to deteriorate. By focusing on the specific patient characteristics for each individual case before surgery it is possible we can improve the proportion of patients achieving a favourable outcome. When counselling patients before surgery regarding SF we should therefore remember to include the potential benefits as well as the risks. Furthermore, for those patients particularly anxious about the possibility of worsening SF, a ‘lesser’ surgical procedure, which might not achieve a transurethral resection-like cavity should perhaps be considered as a compromise. However, a surgical alternative which is not equivalent to TURP may indeed reduce the likelihood of improving erectile function, given the interrelationship that appears to exist between LUTS and SF.

Richard Hindley
Department of Urology, Hampshire Hospitals NHS Foundation Trust, Basingstoke, Hampshire, UK.

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Urologists up in arms? ….Diclofenac no longer indicated in high risk groups

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This blog is an update form the originally published comment article in BJU International, 110: 607–608.
DOI: 10.1111/j.1464-410X.2012.11330.x

On the 23rd June 2013 the MHRA (The Medicines and Healthcare products Regulatory Agency) issued a press release stating that ‘patients with serious underlying heart conditions, such as heart failure, heart disease, circulatory problems or a previous heart attack or stroke should no longer use diclofenac’. The MHRA is responsible for regulating all medicines and medical devices in the United Kingdom (UK) by ensuring they work and are acceptably safe.

 

 

The new guidelines in the UK state:

  • Diclofenac is now contraindicated in patients with established:
    – ischaemic heart disease
    – peripheral arterial disease
    – cerebrovascular disease
    – congestive heart failure (New York Heart Association [NYHA] classification II–IV)

Patients with these conditions should be switched to an alternative treatment at their next routine appointment

  • Diclofenac treatment should only be initiated after careful consideration for patients with significant risk factors for cardiovascular events (e.g., hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Now for urologists in the UK this has wider implications. What else are we to use for acute renal colic, chronic pelvic pain, prostatitis, urethritis and any other type of..-itis?

We are treating an ever aging population and the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, will increase. NSAIDs have been the cornerstone of pain relief in patients with first presentation of renal and ureteric lithiasis. The British Association of Urological Surgeons (BAUS) and the European Association of Urology (EAU) guidelines for the acute management of renal and ureteric lithiasis state the first line analgesia is an NSAID e.g. diclofenac [1][2]. There have been a number of clinical trials which have clearly shown that NSAIDs provide effective relief in patients who have acute stone colic [3][4][5].

Controversies of NSAID use

Rofecoxib (trade name Vioxx ®), was approved by the Food and Drug Administration (FDA) in May 1999. The drug was heavily promoted by the global pharmaceutical and chemical company Merck as safer than older generation NSAIDs. The increased risk of stroke was highlighted in a large study, the Vioxx gastrointestinal outcomes research (VIGOR) study, published in the New England Journal of Medicine in 2000. Merck voluntarily took rofecoxib off of the market on 30 September 2004 after research showed that it almost doubled the risk of myocardial infarction and stroke when taken for 18 months or longer. In 2007 Merck paid $4.85bn to settle about 26 000 lawsuits in the United States relating to the drug in state and federal courts.

What are the alternatives suggested?

Naproxen and low-dose ibuprofen are considered to have the most favourable thrombotic cardiovascular safety profiles of all non-selective NSAIDs. There is limited evidence for the use of naproxen and low-dose ibuprofen in the management of acute renal colic. We do not know if the efficacy is equivalent to diclofenac. There are a lot of unanswered questions since the press release, but the key questions remain: Is this guidance applicable to us as urologists? And will this change my practice?

This topic is an important area for urologists to be aware of as NSAIDs are prescribed daily in urological practise to a wide range of patients. There is some caution that has to be exercised when reviewing the published data. In a recently published meta-analysis by the Coxib and traditional NSAID Trialists’ (CNT) Collaboration group their data provides further evidence that the vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs.

The majority of trials evaluating the cardiovascular risk of NSAIDs have looked at a group of patients with predominately arthritis or Alzheimer’s disease; not a typical urological cohort of patients. None of the studies in the meta-analysis looked at the short term use of NSAIDs, in particular diclofenac. Some may argue that absolute rates of events were low and clinically irrelevant as the event rates in the included trials are considerably lower than in routine clinical settings.

The options for the treatment of acute urological pain have not changed in the past 15 years. COX-2 selective inhibitors and diclofenac are associated with an increased risk of thrombotic events. Naproxen is associated with a lower thrombotic risk and low doses of ibuprofen (1.2 g daily or less) have not been associated with an increased risk of myocardial infarction. The lowest effective dose of NSAIDs should be prescribed for the shortest period of time to control the symptoms and the need for long term treatment should be reviewed periodically. As we treat an ever aging population with increasing medical co-morbidities the widespread use of NSAIDs has to be evaluated and urologists need to keep up to date with current prescribing guidelines and long term cardiovascular risk factors. 

 

Jonathan Makanjuola is a Urology Trainee, Innovator and techie based at King’s College Hospital, London, United Kingdom. @jonmakUrology

References

  1. EAU guidelines on urolithasis. European Association of Urology; 2011. https://www.uroweb.org/gls/pdf/18_Urolithiasis.pdf. Accessed 12 December 2011.
  2. Guidelines for acute management of first presentation of renal/ ureteric lithiasis (excluding pregnancy). British Association of Urological Surgeons; 2008. https://www.baus.org.uk/AboutBAUS/publications/stones-guidelines. Accessed 12 December 2011.
  3. Phillips E, Kieley S, Johnson EB, et al. Emergency room management of ureteral calculi: current practices. J Endourol 2009; 23: 1021–1024.
  4. Micali S, Grande M, Sighinolfi MC, et al. Medical therapy of urolithiasis. J Endourol 2006; 20: 841–847.
  5. Engeler DS, Schmid S, Schmid HP. The ideal analgesic treatment for acute renal colic–theory and practice. Scand J Urol Nephrol 2008; 42: 137–142.

 

 

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Editorial: Impact of ERSPC study on PSA testing in the Netherlands

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General practitioner (GP)’s view on screening for prostate cancer in the Netherlands: the impact of a randomized trial

I am grateful to be given the opportunity to provide an editorial comment on a so-far unique publication investigating the impact of results of the European Randomized study of Screening for Prostate Cancer (ERSPC) on the attitude of Dutch GPs in requesting a serum determination of PSA in men aged >40 years. Access to data from one of the major health insurance companies and the structure and data acquisition of regional laboratories in the Netherlands provided an opportunity to carry out the project. This included the differentiation of age groups, of primary as opposed to repeat PSA testing and, in the case of the hospital database, of repeat PSA testing within 1 year, which provided the opportunity to address the primary goal of the study: the evaluation of the difference in primary PSA testing rates as well as follow-up testing before and after the 2009 publication of interim data from the ERSPC study. The fact that a Dutch translation of this publication and a recommendation by the Dutch Association of General Practitioners (Nederlands Huisartsen Genootschap, NHG) were mailed at the same time and the fact that GP guidelines had not been changed since 2005 in the Netherlands provided an important basis for the reported study.

Two different databases were used and PSA testing was evaluated 1 year before and 1 year after March 2009 (excluding the month March 2009). An overview of the data acquisition and results is given in Table 1. In brief, the data based on insurance claims show a significant decrease in PSA use before and after the 2009 publication. This decrease was less pronounced or not seen at all in men aged 70–80 or >80 years. The study selectively identified men in the ERSPC region of Rotterdam after exclusion of those assigned for re-testing in the screening arm. In line with earlier investigations, the PSA testing rate in the Rotterdam region was considerably higher then in the rest of the Netherlands. This effect was blamed on increased awareness and possibly on the motivation of men randomized into the control group of the study. The so-called ‘hospital database’ refers to a regional GP laboratory. It remains unexplained why only 2098 men of the total of 9766 men who were identified as having undergone primary PSA testing (Tables 1 and 2 in the study) were included in the analysis. These data show that there was no overall difference in testing before and after the ERSPC publication, but the proportion of re-testing decreased significantly between the two periods.

Table 1: Data acquisition and results.

Several comments can be made on this study. First, information provided on the insurance claims database allows an estimate of the proportion of men in whom PSA is evaluated (123 996/715 000 = 17.3%) and of those who undergo primary PSA testing for early diagnostic purposes (66 848/715 000 = 9.4%). The overall figure contrasts sharply with the results of a study by the Central Bureau of Statistics in the Netherlands, published in 2006. The study shows PSA use of 30–40% for the age groups 60–70 years or older.

Second, as the authors acknowledge, the differentiation between primary PSA tests for the purpose of early diagnosis and for other purposes may not be entirely reliable; however, the bias resulting from possibly incorrect assumptions is likely to be small.

Third, the sub-analysis of data coming from the Rotterdam region is likely to show the impact of greater awareness resulting from written informed consent before randomization and the effect of randomization into a control group. The data confirm an earlier evaluation of this subject (reference 7 in Van der Meer et al.) and at the same time provide a rough estimate of the level of contamination which may take place in the ERSPC study, Rotterdam region.

Fourth, it is interesting to see how age and previous PSA values influence the request for repeat PSA studies. It is counterintuitive (Table 3 in Van der Meer et al.) that even in the critical PSA range 4–10 ng/mL a significant decrease of PSA use within 1 year was seen. The multivariate analysis shows that study period before and after 2009, PSA categories and age groups are all significantly related to the decrease of PSA re-testing within 1 year.

Finally, as one of the initiators of the ERSPC study, I should like to refer to two important follow-up publications (Schröder et al., Heijnsdijk et al.) that point to the over-diagnosis and over-treatment of prostate cancer as the main reasons why the almost 30% reduction in prostate cancer mortality in screened men cannot (yet) be used for establishing population-based screening. For these reasons, the authors fully agree with the viewpoint of the Dutch GP Association and the recommendation against routine use of PSA-driven screening for prostate cancer; however, as pointed out in the last sentences of their paper instruments are now available to decrease over-diagnosis and the rate of unnecessary biopsies. In addition to that, it should be realized that men who are well informed and wish to be tested for prostate cancer cannot be refused PSA testing. To assist this process, the International Society of Urology (SIU) and the international movement ‘Movember’ have recently made available on their websites a validated decision aid for men who wish to be tested, their GPs and their treating urologists.

Fritz H. Schröder
Erasmus Medical Center, Rotterdam, The Netherlands.

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