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Is Gleason 6 really cancer?

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The recently published Viewpoint of the National Cancer Institute working group on “Overdiagnosis and Overtreatment in Cancer” by Esserman and colleagues [1] raises continued discussion as to whether some lesions currently classified as carcinomas should have the designation of “cancer” removed, based on low rates of progression, death, and other adverse outcomes. Pertinent to those interested in urology, a central example in the article is prostatic adenocarcinoma.

One simple answer to this question is that to a small extent, a subgroup of prostatic lesions has already been reclassified as not cancer: In current practice, needle biopsy or radical prostatectomy specimens with an overall Gleason score (GS) of 5 or less are now quite rare in current practice. This shift is due in part to modern updates to the Gleason grading system [2], under which many tumors now reach thresholds for GS6 or above. However, at least some lesions previously considered adenocarcinoma with a low overall GS would now be categorized as atypical adenomatous hyperplasia or adenosis in the era of immunohistochemistry for markers of prostatic basal cells. Nonetheless, the current and more controversial debate surrounds whether some (or all?) tumors currently classified as GS6 could be recategorized as not “cancer”.

Arguments against removing the cancer designation from some prostatic adenocarcinomas:

A major difficulty from the pathologic standpoint in adopting a non-cancer nomenclature for some tumors (such as GS6 adenocarcinomas) is that the Gleason pattern 3 component of a GS 3+3=6 tumor (small, round prostatic glands that lack a basal cell layer and infiltrate between benign glands) is for all intents and purposes identical to the Gleason pattern 3 component of a GS 3+4=7 or higher prostate cancer. These similarities are not limited exclusively to the microscopic appearance but also include a number of immunohistochemical and molecular features, as summarized in a recent article addressing this question [3]. Therefore, no pathologic features are as yet defined that ideally predict whether Gleason pattern 3 glands in a biopsy specimen represent a pure GS6 tumor or a component of higher-grade tumor in which the high-grade component is not represented. Not surprisingly, it is not unusual for tumors with GS6 on needle biopsy to be upgraded to GS7 at radical prostatectomy [3], particularly when a high tumor volume is present in the needle biopsy.

Gleason pattern 3 glands from a GS7 tumor, identical to those of a GS6 tumor.

To compare to other cancers with low risk of aggressive behavior, basal cell carcinoma and squamous cell carcinoma of the skin similarly show locally infiltrative properties, supporting their classification as carcinomas by a classical pathologic definition. Despite that the word “carcinoma” continues to be used for these tumors, most patients are not concerned that they have a life-threatening disease and these lesions are even excluded from the American Cancer Society statistics regarding cancers [4]. In the same way, Gleason pattern 3 glands exhibit infiltrative growth by extending between benign glands, invading nerves, and sometimes extending outside of the prostate. This difference in mindset regarding some types of “cancers” could be considered supportive evidence for the assertion in the recent Melbourne Consensus Statement that uncoupling prostate cancer diagnosis from intervention may be more appropriate than removing its “cancer” nomenclature.


This small GS6 adenocarcinoma was an incidental finding in a radical cystoprostatectomy specimen for bladder cancer but surprisingly extended into periprostatic fat via this focus of perineural invasion.

Supporting removal of the cancer designation from some prostatic adenocarcinomas:

A valid argument of the NCI Viewpoint is that a neoplasm should have a substantive rate of progression and patient death if it is to be considered a cancer. Likewise, others have questioned whether low-volume GS6 tumors fulfill other molecular and pathogenetic hallmarks of cancer, such as unlimited replicative potential and other features [5].

In general, benign and malignant neoplasms can be regarded as having some prototypical gross and microscopic pathologic characteristics, such as a circumscribed vs infiltrative growth and homogeneous vs pleomorphic cell population. However, differentiating benign from malignant lesions also relies heavily on parameters specific to the organ involved. Clear cell renal cell carcinoma, another genitourinary tract tumor, often does not possess these prototypical features of malignancy. Tumors often form a well-circumscribed mass without an “invasive” growth pattern and they often are composed of a uniform population of cells. However, based on known behavior of these tumors, their status as a malignancy is not in doubt. Conversely, renal oncocytoma is a benign neoplasm that shares some of these general features (a round mass composed of a homogeneous population of renal tubular cells). Occasionally oncocytomas appear infiltrative by extending into the perinephric fat or renal vein, yet their status as benign is also not the subject of debate. If some prostate cancers do not have a substantial likelihood of resulting in progression and death, they may not meet an important criterion for a diagnosis of cancer, despite that other features, such as infiltration of tissues, invasion of nerves, and loss of the basal cell layer are characteristic of a malignant neoplasm.

Since a diagnosis of GS6 by needle biopsy is not always predictive of a radical prostatectomy overall GS6, a major challenge to such an approach would be to determine where such a cutoff could be drawn between “cancer” and “not cancer” [5]. If based on tumor volume, it would be difficult to conceptualize that a small amount of GS6 glands would be regarded as a benign lesion, whereas a large amount of identical glands would represent a malignant lesion. Alternatively, the presence of Gleason pattern 4 could used as the point of differentiation (GS7 or above). In the endometrium, a disorganized proliferation of crowded glands with some cytologic features of cancer is regarded as complex atypical hyperplasia. Diagnosis of adenocarcinoma is then reserved for proliferations with a confluent growth of these glands, similar to the threshold for recognizing a component of cribriform glands as Gleason pattern 4. A limitation to such an approach, however, is that a substantial fraction of patients with a needle biopsy GS6 are upgraded to GS7 at radical prostatectomy, as discussed above. Likewise, the ability to treat and monitor GS6 adenocarcinoma nonsurgically is not quite analogous to that of endometrial hyperplasia.

Higher magnification of image 2 shows Gleason pattern 3 glands invading a nerve with ganglion cells.

Other points of discussion

The NCI Viewpoint also suggests that high-grade prostatic intraepithelial neoplasia (HGPIN) no longer be considered cancer or even neoplasia.  A comparison to ductal carcinoma in situ (DCIS) of the breast for this argument is somewhat flawed, as HGPIN neither contains the word “carcinoma” nor is justification for treatment in and of itself. Its status as a risk factor for a future cancer even remains debated. The proposal to remove “neoplasia” from HGPIN is also a confusing one, particularly as cervical cancer is noted as an example of the successful application of screening, in which “cervical intraepithelial neoplasia” is the preferred term for precancerous lesions. The authors suggest the designation “indolent lesions of epithelial origin” (IDLE) for cancers in this category to convey their low likelihood of aggressive behavior. However, would recognizing the status of these lesions as at least premalignant neoplasms be more appropriate?

Likely a typographical error in the Viewpoint is that the authors also cite reclassification of urothelial papilloma as papillary urothelial neoplasm of low malignant potential [1]. Since urothelial papilloma has never been considered a malignant neoplasm, the authors likely meant reclassifying “grade 1 urothelial carcinoma” to papillary urothelial neoplasm of low malignant potential.

References
[1]        Esserman LJ, Thompson IM, Reid B. Overdiagnosis and Overtreatment in Cancer: An Opportunity for Improvement. JAMA. 2013 Jul 29:

[2]        Epstein JI, Allsbrook WC, Jr., Amin MB, Egevad LL. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005 Sep: 29:1228-42

[3]        Carter HB, Partin AW, Walsh PC, et al. Gleason score 6 adenocarcinoma: should it be labeled as cancer? J Clin Oncol. 2012 Dec 10: 30:4294-6

[4]        Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 Jan: 63:11-30

[5]        Ahmed HU, Arya M, Freeman A, Emberton M. Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy? Lancet Oncol. 2012 Nov: 13:e509-17

 

Sean Williamson is Senior Staff Pathologist in the Department of Pathology and Laboratory Medicine, Henry Ford Health System, Detroit MI, USA. @Williamson_SR

Editorial: Time to raise the bar in localised prostate cancer

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In this issue of BJUI, Ficarra et al. present the long-term (mean 81.3 months) follow-up of a case series of 183 men that underwent robot-assisted radical prostatectomy (RARP) at a single academic medical centre in Europe. To the authors’ credit, they report both cancer control and patient-reported outcomes, using well-known validated and reliable instruments to assess both urinary and sexual function. Like others before them, Ficarra et al. demonstrate that RARP is a safe and effective way to treat localised prostate cancer.

However, the question the study raises is not so much about the operation’s success rate but rather how success is defined in the first place. Throughout the prostate cancer literature, we have loosened definitions of successful urinary and sexual function to make RP more palatable to patients. In the present study, potency is effectively defined as a Sexual Health Inventory for Men (SHIM) score of >17 with or without the use of a phosphodiesterase type 5 (PDE5) inhibitor. Similarly, continence is defined as either no pad use or the use of a single pad ‘for security’. This approach certainly has face validity to us as clinicians. After all, PDE5 inhibitors are effective therapies for erectile dysfunction and the use of a single urinary liner certainly does not seem like a big deal. However, we need to consider this from the patient’s perspective. Both urinary pads and PDE5 inhibitors are costly to the patient and may represent an inconvenience and a potential embarrassment to many men. Is it really fair to tell men that they will be potent and/or continent after the operation, if they are going to require these additional interventions to achieve the desired state? I think not.

Going forward, we must set the bar higher if we are to be truly honest with our patients and optimise outcomes after RP. We must effectively ‘leave patients the way we found them’ with the critical difference being that they are now cancer-free. In other words, if a man was able to achieve an erection sufficient for intercourse preoperatively without the use of PDE5 inhibitors, he should only be considered potent postoperatively if he is in the same state, i.e. able to achieve an erection sufficient for intercourse without the use of a PDE5 inhibitor. The same holds true for urinary continence and the use of urinary liners. This will certainly make it more difficult to achieve the ‘trifecta’ but the reader should remember that the term is meant to imply ‘triple perfection’ and needing to use a PD5 inhibitor for sexual activity or having to wear a urinary pad, while acceptable to many patients, is certainly not perfect.

Some will say that I am insisting that the bar be set too high, that patients are willing to accept these reasonable but less than perfect definitions of success to be cured of their cancer. I acknowledge that there may be some validity to this argument in men with higher risk disease, where we know that cancer control and cure is necessary. However, I do not think the argument holds up in the case of men with low-risk disease, many of whom will never experience any symptoms of prostate cancer in their lifetimes and will not die of their disease if it were left untreated. In these patients, setting the bar higher would not only be more honest but it would probably increase the uptake of active surveillance and decrease overtreatment. In summary, while the use of more stringent definitions of success after RP may make our operations look ‘worse’, it will help our patients to set more realistic expectations, make more informed choices about treatment and ultimately to have better outcomes.

David F. Penson
Department of Urologic Surgery, Vanderbilt University, 2525 West End Avenue, Suite 1200, Nashville, TN, 37203, USA

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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

What’s the diagnosis?

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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

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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

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