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Editorial: The metabolic syndrome and the prostate

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The metabolic syndrome has been known for ~80 years 1 and is important to both urologists and their patients because of a two‐fold increase in the relative risk of atherosclerotic cardiovascular disease‐related events and a five‐fold increase for developing Type 2 diabetes as compared to people without the syndrome. Abdominal obesity is well known to be an important underlying risk factor for precipitating the syndrome and obesity is also known to markedly increase the risk for developing BPH and its symptoms 2. There are other associations that may be relevant here including an association between a lack of physical activity and the severity of LUTS 3, and a close correlation between the degree of prostatic and systemic inflammation and the degree of LUTS 4. Systemic inflammation is implicated in the metabolic syndrome with pro‐inflammatory cytokines due to the adipose tissue load, such as C‐reactive protein, tumour necrosis factor α and interleukin 6, being involved in causing the insulin resistance, which is a diagnostic feature of this condition 5.

The current study connects the metabolic syndrome with an anatomical feature of benign prostatic enlargement (BPE), namely intravesical prostatic protrusion (IPP) 6. Each of the diagnostic features of metabolic syndrome was examined separately such as reduced high‐density lipoprotein (HDL)‐cholesterol and raised triglycerides. Hypertriglyceridaemia is due to an overproduction of very‐low‐density lipoprotein (VLDL) by the liver and a reduction of lipoprotein lipase in peripheral tissues, and reflects the insulin resistant condition responsible for the metabolic syndrome 5. In this study, high triglyceride levels were an independent predictor of a total prostatic volume (TPV) of >40 mL. The other major lipoprotein abnormality in metabolic syndrome is a reduction in HDL‐cholesterol levels, which is due to both a decrease in the cholesterol content of this lipoprotein and an increase in its clearance from the circulation. In this study by Russo et al. 6, HDL levels were negatively associated with IPP and both total and transition zone volumes, and they postulate that these associations may be mediated by the effect of dyslipidaemia on prostate cells and prostatic inflammation.

Hypertension is another diagnostic feature that the authors address. There is increased renal sodium reabsorption, increased activity of the sympathetic nervous system, and vasoconstriction related to an increase in fatty acids in this syndrome. Hypertension, defined as systolic ≥135 mmHg, diastolic ≥85 mmHg or on current treatment, was positively associated with IPP and also associated with a TPV of ≥40 mL and a transitional zone volume of ≥20 mL in this study 6. Waist circumference and fasting glucose were not as strongly related to the features of BPH but ultimately are key drivers of the metabolic syndrome and management of these features is a cornerstone of the management of the whole condition.

Lifestyle and dietary interventions can address many of the aspects of this insulin‐resistant state with medical management of the metabolic features being used to supplement these. The same interventions are also successful in decreasing LUTS 3, which should not be surprising given the above. The longstanding aphorism that ‘heart healthy is prostate healthy’ appears to not only apply to the treatment of prostate cancer but also to that of BPH and urologists remain in an important position to identify men at significant risk.

Peter J. Gilling
Urology, Bay of Plenty District Health Board Clinical School, Tauranga, New Zealand

 

References
  • 1 Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus Group. The metabolic syndrome–a new worldwide definition. Lancet 2005; 366: 1059–62

 

  • 2 Parsons JK, Sarma AV, McVary K, Wei JT. Obesity and benign prostatic hyperplasia: clinical connections, emerging etiological paradigms and future directions. J Urol 2013; 189 (Suppl.): S102–6.

 

  • 3 Fowke JH, Phillips S, Koyama T et al. Association between physical activity, lower urinary tract symptoms (LUTS) and prostate volume. BJU Int 2013; 111: 122–8

 

  • 4 Burris MB, Cathro HP, Kowalik CG et al. Lower urinary tract symptom improvement after radical prostatectomy correlates with degree of prostatic inflammation. Urology 2014; 83: 186–90

 

  • 5 Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365: 1415–28

 

  • 6 Russo GI, Regis F, Spatafora P et al. Association between metabolic syndrome and intravesical prostatic protrusion in patients with benign prostatic enlargement and lower urinary tract symptoms (MIPS Study). BJU Int 2018; 121: 799–804.

 

Editorial: Well‐being beyond the bladder. How do we improve the overall health of patients with bladder cancer?

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Declines in quality of life and physical function are commonly associated with all cancers 1, and in this month’s issue of BJUI, Smith et al. 2 describe the changes in quality of life that occur specifically in patients with bladder cancer. The authors examine 535 individuals with bladder cancer (of whom 77 [14%] had invasive disease) and matched them to 2770 non‐cancer controls using propensity scores. The Surveillance, Epidemiology and End Results (SEER) registry was linked with the Medicare Health Outcomes Survey. This dataset represents linkages of population‐based SEER data with survey data for Medicare‐managed enrollees. In this study, patients were surveyed at different times with respect to their diagnosis and the authors identified all patients who were surveyed some time before and after their diagnosis. By harnessing this dataset, the authors describe changes that occur in mental and physical function. The authors should be commended for conducting an analysis that seeks to quantify the impact of a bladder cancer diagnosis on multiple dimensions affecting quality of life.

A few findings are worth highlighting. First, the quality of life of a patient with bladder cancer declines more between a pre‐diagnosis and post‐diagnosis assessment as compared with matched, non‐cancer controls. As any urological oncologist can attest, a bladder cancer diagnosis causes permanent changes to a patient’s life. Second, people with bladder cancer have deficits in multiple domains of well‐being and not just in physical function. Third, people with bladder cancer have impairments in well‐being whether they have non‐invasive or invasive disease. Fourth, decrements were more pronounced in those with invasive disease. In fact, patients who underwent cystectomy had statistically significant declines in nearly all physical domains and similar declines in mental health‐related quality of life across several domains, including emotional, vitality and social functioning. Lastly, a predictor of a significant decrease in both the physical component and mental component score included a diagnosis of recent depression. This insightful study shows the potential impact of a bladder cancer diagnosis on mental and physical health‐related quality of life.

So, with these detriments in mind, can urologists do anything to address these declines in quality of life for patients with bladder cancer?

In clinical practice, urologists may be able to play an active role in mitigating the negative consequences of therapy, be it for invasive or non‐invasive disease. If a urologist is following a patient with non‐muscle‐invasive bladder cancer, then there are clinical visits for cystoscopy, intravesical instillation and follow‐up, during which a provider can regularly check in with a patient and offer recommendations. If a patient has muscle‐invasive bladder cancer, they are typically seen a few times before surgery and there is an incentive to address potentially modifiable sources of morbidity before a major operation plagued by complications.

While encouraging healthy behaviours is common sense and may help some patients, understanding the difference between motivating self‐care (e.g. coaching our patients) and recommending programmes that are scientifically established and effective (e.g. recommending a programme proven in a randomized controlled trial) are different. One major challenge in promoting healthy behaviours in our patients is understanding their mindset, i.e. their motivation to make meaningful change. The Transtheoretical Model is a biopsychosocial model that conceptualizes intent for changing behaviour: pre‐contemplation, contemplation, preparation, action, maintenance and termination 3. Based on a continuum of patient activation and knowledge of these stages, interventions can be designed more effectively and focused on individuals. Conversation content, clinician effort and clinical resources can be judiciously allotted instead of offering all options to all patients.

The presence of validated interventions that have been determined to consistently improve quality of life is evolving. A new area of preoperative care known as prehabilitation, is being studied in patients with cancer and seeks to optimize preoperative factors, such as increasing fitness, improving nutritional status, encouraging smoking cessation and decreasing anxiety 4. Although studies vary in quality, content and outcomes measured 5, there is still an opportunity to exercise common sense and make practical suggestions.

For busy urologists who manage patients with bladder cancer, any patient can benefit from:

  1. Mindful conversations: having open and regular communication about quality of life.
  2. Measurements: tracking patient‐reported outcome measures longitudinally to follow well‐being systematically and identify detrimental changes early.
  3. Multidisciplinary resources: offer support (Fig. 1) based on conversations (#1) and scores (#2).

Conversations only require a little provider time, monitoring patient‐reported outcomes can be facilitated by the use of technology such as the electronic health record, and most institutions have previously established resources that patients can use during their care. Strategies may be low‐cost, quick and capable of helping patients or caregivers. Also, data show that routine assessment of patient‐reported outcome measures in patients with advanced cancers may be associated with improved overall survival 6.

Figure 1

Open in figure viewerPowerPoint
Potential targets to improve patient well‐being during bladder cancer care.

Acknowledging that other dimensions of health are affected after a bladder cancer diagnosis may allow us to track, address and ultimately improve the health of our patients. When we care for patients with bladder cancer, focusing cancer treatment is paramount; however, we can also extend this treatment by being cognisant of quality of life. Complementing oncological care with efforts to promote health in other ways allows us to promote well‐being and treat these patients beyond the bladder.

 

Matthew Mossanen*†, Justin C. Brown† and Deborah Schrag†
*Division of Urology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA and †Dana Farber Cancer Institute, Boston, MA, USA

 

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References

 

  • 1 Petrick JL, Reeve BB, Kucharska‐Newton AM et al. Functional status declines among cancer survivors: trajectory and contributing factors. Journal of Geriatric Oncology 2014; 5: 359–67

 

  • 2 Smith AB, Jaeger B, Pinheiro LC et al. Impact of bladder cancer on health‐related quality of life. BJU Int 2018; 121: 549–57

 

 

  • 4 Silver JK, Baima J. Cancer prehabilitation: an opportunity to decrease treatment‐related morbidity, increase cancer treatment options, and improve physical and psychological health outcomes. Am J Phys Med Rehabil 2013; 92: 715–27

 

 

  • 6 Basch E, Deal AM, Dueck AC et al. Overall survival results of a trial assessing patient‐reported outcomes for symptom monitoring during routine cancer treatment. JAMA 2017; 318: 197–8

 

“Is radiotherapy the work of the Devil?” – why we chose this title.

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With the recent electronic publication of our editorial written for the BJUI USANZ supplement, we have been somewhat surprised with the Twitter response our title has generated with some very strong opinions expressed. Why would a radiation oncologist, who happens to be the Chair of their National Genito-Urinary group (“FROGG”) propose such a provocative title? The BJUI editorial board wisely suggested that we explain the origin of this title which would be lost on many outside Australia.

In mid-2014, a leading Australian urologist quipped that adjuvant post-prostatectomy radiotherapy was “the work of the Devil” when referring to some of the severe complications that can occur following post-prostatectomy radiation. This comment has become “infamous” in Australian Radiation Oncology circles leading to extensive discussions and interactions between our specialties with urologists stating that radiotherapy complications can occur late and be very challenging to treat and radiation oncologists stating that these complications are relatively uncommon and that overall quality of life is as good if not better when going down the radiotherapy pathway. This is the climate that the article by Ma et al was submitted to the BJUI describing the impact of radiotherapy complications on a tertiary urology service in Melbourne Australia over a 6 month period.

 

 

I was impressed that the BJUI approached a radiation oncologist to provide balance on such a paper. We provocatively titled the editorial “Is Radiotherapy the work of the Devil?” and were hoping the response to anyone reading the editorial would be a resounding “No”.  However, many have only seen “the headline” and not read the editorial itself which appears to have created offence especially from some of our international Radiation Oncology colleagues. The aim of such a title is that it will encourage people to read both the original article and the editorial which we feel provides a balanced view on the impact of radiotherapy complications in contemporary practice. We hope that in future, the response to our title: “Is Radiotherapy the work of the Devil” is “No – the Devil is in the detail”.

 

A/Prof Andrew Kneebone

Department of Radiation Oncology, Royal North Shore Hospital and Chair of the Faculty Of Radiation Oncology Genito-Urinary Group (FROGG)

 

 

 

Editorial: Low rates of bone density testing in prostate cancer survivors on androgen‐deprivation therapy: where do we go from here?

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In this month’s issue of the BJU International, Kirk et al. 1 describe their findings regarding an important issue in the care of prostate cancer survivors on androgen‐deprivation therapy (ADT): the underuse of bone density testing (BDT) to screen for osteoporosis. ADT is the commonest systemic therapy in patients with prostate cancer, used in both metastatic and localised settings. Whilst it has clear survival benefits, ADT is also associated with harms including cardiovascular, cognitive, and metabolic side‐effects, as well as an increased risk of osteoporosis and fractures. These bone‐related complications are costly from a quality‐of‐life and financial perspective, especially given the critical importance of mobility in maintaining performance status and cardiovascular health during cancer treatment 2, 3. Consequently, most clinical practice guidelines include osteoporosis screening as a recommendation for men undergoing ADT.

In their study, ‘The implications of baseline bone health assessment at initiation of androgen‐deprivation therapy for prostate cancer’, the authors describe patterns of use of BDT and diagnosis of osteoporosis amongst men treated for prostate cancer in the USA Veterans Affairs (VA) system within a 3‐year period following ADT initiation. There was a statistically significant increase in the BDT rate throughout the study period; however, overall BDT remains uncommon amongst patients with prostate cancer on ADT, used in only 15% of men in their cohort. Unsurprisingly, patients who received BDT were more likely to be diagnosed with osteoporosis, be diagnosed with a fracture, and receive treatment with vitamin D, calcium and bisphosphonates. The authors acknowledge an important limitation about the applicability of their VA study to the civilian health population. However, given that the VA and military health systems perform as well, if not better, on several important metrics in prostate cancer care 4, 5, these results should not be ignored simply because they were obtained in the military health system.

The increase in BDT screening throughout the study may be attributable to increased awareness of guidelines published during the study period. However, the overall BDT rate remains low. This may be explained by insufficient access, lack of information technology, as well as more nebulous aspects of care such as physician culture, beliefs, and habits 6.

Studies such as this are vital to identify opportunities for improving care delivery. What are needed next are innovations to optimise the delivery of care for patients treated with ADT. Whilst improving BDT adherence may lack the cachet of next‐generation targeted therapies, this is an example of the kind of simple, measurable area where improvement in care delivery systems may yield large benefits.

There are many possible avenues for success: quality improvement collaboratives are one well‐known innovation, which may be applicable to this area: examples, such as the Michigan Urological Surgery Improvement Collaborative (MUSIC) and the AUA Quality Registry (AQUA) are success stories, but to our knowledge there are no published studies specifically attempting to improve adherence to BDT guidelines within these cohorts. Other practice‐based innovations include navigators and multidisciplinary cancer teams, either of which may yield improvements in guideline adherence. Online patient support groups can raise awareness. And although we all know how electronic reminders have frustrated countless physicians, electronic reminders about recommended tests and interventions may be an important tool. At our institution, a Prostate Cancer Foundation grant is funding the development of a mobile health app, which is targeted exclusively at men receiving ADT for prostate cancer. This app will encourage physical activity and healthy eating, which can both support bone health.

In our view, the issue of bone screening is a clear example of where innovative strategies to improve care delivery and guideline adherence may make a big difference for men living with prostate cancer. We look forward to seeing more in the years to come.

 

Sabrina S. Harmouch, Alexandra J. Berger, and Alexander P. Cole

 

Center for Surgery and Public Health, Division of Urological Surgery, Brigham and Wo men’s Hospital, Harvard Medical School, Boston, MA, USA

 

References
  • 1 Kirk PS, Borza T, Shahinian VB et al. The implications of baseline bone‐health assessment at initiation of androgen‐deprivation therapy for prostate cancer. BJU Int2018; 121: 558–64

 

 

 

  • 4 Cole AP, Jiang W, Lipsitz SR et al. The use of prostate specific antigen screening in purchased versus direct care settings: data from the TRICARE® military database. J Urol 2017; 198: 1295–300

 

  • 5 Cullen J, Brassell SA, Chen Y et al. Racial/Ethnic patterns in prostate cancer outcomes in an active surveillance cohort. Prostate Cancer 2011; 2011: 234519

 

 

Editorial: Sexual function in patients undergoing combination treatment with α1‐adrenoceptor antagonists and 5α‐reductase inhibitors – a step forward in a still‐open debate

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Combination treatment with α1‐adrenoceptor antagonists and 5α‐reductase inhibitors (5ARIs) is recommended in men with moderate‐to‐severe LUTS and risk of disease progression 1, 2. These drugs can improve symptoms as well as urodynamic markers of BOO 3, 4. Despite the clinical benefits, the potential negative impact of these drugs on sexual function is of major concern, and may be cause for treatment discontinuation. Additionally, in everyday clinical practice, the incidence of sexually‐related adverse events is often perceived to be higher than that reported in clinical trials, and clinicians may consequently be reluctant to prescribe these drugs in younger, sexually active patients 5. Evidence from the literature in this area, however, is low‐level, controversial and inconclusive. Notably, in most clinical studies on combination treatment, assessment of sexual function is based only on the reported incidence of sexually‐related adverse events; a non‐quantitative method that can be biased by the subjective burden of suffering, by a patient’s misinterpretation of symptoms and his propensity to mention them during follow‐up visits.

Roehrborn et al. 1 investigated the impact of a fixed‐dose combination of the 5ARI dutasteride 0.5 mg and the α1‐adrenoceptor antagonist tamsulosin 0.4 mg therapy on sexual function in sexually active men with LUTS, secondary to BPH 1. The authors designed a prospective, randomized, placebo‐controlled study and adopted, for the first time in this setting, the Men’s Sexual Health Questionnaire (MSHQ). Overall, 489 patients, with a mean age of 65.5 years, an IPSS ≥12 and a prostate volume ≥30 mL were randomized to receive combination therapy (n = 243) or placebo (n = 246) for 12 months. Change in sexual function from baseline to month 12, as measured by a change in total MSHQ score, was the primary endpoint of the study. Change from baseline in the MSHQ erection, ejaculation and satisfaction domain scores were among the secondary endpoints. The authors found a statistically significant decrease in the total MSHQ score in the active treatment group compared with placebo at all post‐treatment visits (months 1,3, 6, 9 and 12), indicating a worsening of sexual function 1. The magnitude of the total MSHQ reduction was greater at month 6 and remained substantially unchanged beyond this time point. This change was driven largely by the change in the score for the ejaculatory domain, which showed a similar temporal trend. Changes in terms of the overall satisfaction domain, although statistically significant, were judged to be numerically small and therefore unlikely to be clinically relevant. Changes in terms of erectile domain score were not statistically significant.

The major methodological strength of this study was the adoption of the MSHQ, a clinically validated questionnaire designed to assess quantitatively multiple domains of sexual function, namely erectile function, ejaculatory function and sexual satisfaction. Findings are relevant from both a pathophysiological and clinical viewpoint. Indeed, the temporal trend that characterizes the deterioration of ejaculatory function and therefore the total MSHQ score implies the involvement of both drugs in this process. From a clinical point of view the study provides additional data to counsel patients requiring combination therapy about the deleterious effects on sexual function and particularly on ejaculatory function. The main limitations of the study, as acknowledged by the authors, is the lack of long‐term follow‐up. Indeed, a recent meta‐analysis showed a positive correlation between duration of therapy with 5ARIs and incidence of sexual dysfunction, with long‐term exposure (≥1 year) being associated with a significantly higher risk 6. Consequently, conclusive data about erectile function cannot be drawn based on the results from the present 1‐year‐long study. Additionally, the authors do not report on possible changes in sexual desire. This aspect deserves future investigation as the risk of decreased libido has been reported to be statistically significant in patients assuming therapy with 5ARIs 6. Finally, results from clinical trials do not always correspond to everyday clinical practice, as patient selection for therapies in the real world is often different with respect to inclusion criteria adopted in clinical trials. Specifically, patients who receive therapy with 5ARIs (alone or in combination) in everyday clinical practice are often older than the patients who were enrolled in the present study and in other clinical trials and therefore may have comorbidities that could contribute to the development of sexual side effects during treatment 5.

Ferdinando Fusco and Massimiliano Creta
Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples Federico II, Naples, Italy

 

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References

 

  • 1 Roehrborn CG, Manyak MJ, Palacios‐Moreno JM et al. A prospective randomised placebo‐controlled study of the impact of dutasteride/tamsulosin combination therapy on sexual function domains in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). BJU Int 2018; 121: 647–58

 

  • 2 Gratzke C, Bachmann A, Descazeaud A et al. EAU guidelines on the assessment of non‐neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol2015; 67: 1099–109

 

  • 3 Fusco F, Creta M, Imperatore V et al. Benign prostatic obstruction relief in patients with lower urinary tract symptoms suggestive of benign prostatic enlargement undergoing endoscopic surgical procedures or therapy with alpha‐blockers: a review of urodynamic studies. Adv Ther2017; 34: 773–83

 

  • 4 Matsukawa Y, Takai S, Funahashi Y et al. Effects of withdrawing α1‐blocker from combination therapy with α1‐blocker and 5α‐reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics. J Urol 2017; 198: 905–12

 

  • 5 Fusco F, Arcaniolo D, Creta M et al. Demographic and comorbidity profile of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia in a real‐life clinical setting: Are 5‐alpha‐reductase inhibitor consumers different? World J Urol 2015; 33: 685–9

 

  • 6 Liu L, Zhao S, Li F et al. Effect of 5α‐reductase inhibitors on sexual function: a meta‐analysis and systematic review of randomized controlled trials. J Sex Med 2016; 13: 1297–310

 

Editorial: PCa Prevention – Proof is Elusive

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Prevention is so much better than cure because it saves the labor of being sick. Thomas Adams, 1618

Inferior doctors treat the full blown disease; mediocre doctors treat the disease before evident; superior doctors prevent disease.   Nai Ching, 1st Chinese Medical Text, 2600 BC. 

Enthusiasm for prevention is hundreds, even thousands of years old.  In the field of prostate cancer, profound differences in the regional variation of prostate cancer around the world (highest in Americans and Scandinavians, lowest in Asians) despite the similar incidence of histologic occult prostate cancer, and shifts in the incidence in mortality amongst immigrant populations moving from low to high prostate cancer regions, led to a firm belief that clinical disease was preventable.   This belief was supported by the known long initiation phase for prostate cancer, providing an opportunity over decades for diet and micronutrient intake to influence the likelihood of disease progression.

In addition, many epidemiologic studies pointed to the benefits of fruits and vegetable intake high in Vitamin E, Selenium, Beta Carotene, Lycopene, and other micronutrients, and a diet low in animal fat.

However, recently several pivotal studies have taken the bloom off the rose of prevention.  In particular, the SELECT study demonstrated a 17% increased rate of prostate cancer in men on Vitamin E, and an increase in DM in men on Selenium (1).  The study was resoundingly negative.  In addition, both high intake of multivitamins, and high dairy and calcium intake, have been associated with an increased risk of fatal prostate cancer (2).   Folic acid intake results in an increased incidence of prostate cancer.  Despite the positive PCPC and Reduce trials, the 5 ARIs were not approved for prevention by the FDA due to concerns about an increased risk of high grade prostate cancer, despite the reduction in positive biopsies in men on the drug (mostly due to  a decrease in low grade cancer).

Further, studies of the association between dietary intake of fruits and vegetables and PCa are inconsistent.  For example, one large study of 130,544 men found no significant association between fruit or vegetable intake, including cruciferous vegetables, and prostate cancer. (3)  Another study showed dietary modification, reducing fat and increasing fruits, vegetables, and fiber, had no impact on PSA.  (4).

And yet, despite the negative intervention studies, a lingering spark of hope exists that the many positive population, epidemiologic, and pre- clinical studies supporting dietary prevention will be vindicated.  The study in the current issue of BJU Int on the MEAL study is therefore a laudable and ambitious initiative (5).   Remarkably, 478 men have been randomized to validated dietary counseling intervention vs no intervention.  This paper reports the initial demographics and eligibility data.  It is undoubtedly the first of many publications that will arise from this important trial.

Will this study prove its’ ambitious goal, to demonstrate that prostate cancer progression can be influenced by dietary modification?   While the initiative is laudable, I suspect the hurdles are insurmountable given the sample size and conceptual basis for the study.  The study is being performed in men on active surveillance, and the primary end point will be the risk of disease ‘progression’.  The study references the Redeem study, which showed a 44% reduction in disease ‘progression’ with dutasteride compared to placebo (6).

What we have learned since the Redeem study was initiated more than a decade ago was that the major limitation of conservative management in men diagnosed with low grade prostate cancer on systematic biopsy is not disease progression as it is usually defined (ie, developing worse disease over time); it is grade misattribution, based on sampling and pathologic miss of co-existent higher grade cancer (7).  Higher grade cancer is present in about 30% of men with Gleason 6 cancer on systematic biopsy.  Finding this on subsequent systematic biopsy is largely a matter of luck, location of the cancer, and biopsy strategy and number.    In contrast, true grade progression (from Gleason pattern 3 to pattern 4 or 5) is uncommon, estimated to occur in only 1-2% of patients per year (8).  The adoption of MRI and targeted biopsy into the surveillance algorithm has reduced the misattribution problem.   Thus, the true ‘event rate’ (exclusive of misattribution) is likely to be in the 15% range at 10 years.   A study with the power to detect a 20% relative difference in these events, ie a 3% absolute difference, would require more than a thousand patients followed for 10 years.

In the Redeem study, the reduction in ‘progression’ was entirely related to a decrease in the volume of low grade cancer.  Indeed, the rate of upgrading was 13% in both arms in Redeem.  Therefore the decrease in progression in that study likely reflected the cytoreduction effect of 5 ARIs, and not a real biological effect on cancer progression.

Thus, to be meaningful, prevention studies in men on surveillance should identify, at the very least, a real reduction in grade progression, based on state of the art evaluation at baseline with MRI and targeted biopsies as warranted, and long term follow up.    A decrease in the rate of volume progression of Gleason 6, a major end point of this study, is not meaningful.   In the study as described, which does not explicitly incorporate MRI, an imbalance in the number of patients having off protocol MRI and targeted biopsies between the two arms could significantly bias the outcome.

A further problem with long term studies of dietary intervention relates to the well-known methodological limitations in this area—ensuring long term compliance, recall bias of food intake, and contamination of the control arm.

Nonetheless, the authors deserve strong congratulations for pursuing this major initiative.  We will follow the course of this study with interest.

 

Dr. Laurence Klotz C.M.

Division of Urology, Sunnybrook Health Sciences Centre, 2075 Bayview Ave. #MG408 

Toronto, Ontario M4N 3M5

 

Read the full article

 

References

  1. Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011
  2. Lawson KA, Wright ME, Subar A, et al.: Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J Natl Cancer Inst 99 (10): 754-64, 2007
  3. Key TJ, Allen N, Appleby P, et al.: Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 109 (1): 119-24, 2004
  4. Shike M, Latkany L, Riedel E, et al.: Lack of effect of a low-fat, high-fruit, -vegetable, and -fiber diet on serum prostate-specific antigen of men without prostate cancer: results from a randomized trial. J Clin Oncol 20 (17): 3592-8, 2002.
  5. BJU-2016-1793.R2 – The Men’s Eating and Living (MEAL) Study (CALGB 70807 [Alliance]): Recruitment Feasibility and Baseline Demographics of a Randomized Trial of Diet in Men on Active Surveillance for Prostate Cancer
  6. Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. 2012;379(9821):1103-1111.
  7. Cooperberg MR, Carroll PR, Klotz L: Active surveillance for prostate cancer: progress and promise. J Clin Oncol 29 (27): 3669-76, 2011. [PubMed]
  8. Lurdes Y.T. Inoue, Bruce J. Trock, Alan W. Partin, H. Ballentine Carter, Ruth Etzioni Modeling Grade Progression In An Active Surveillance Study Stat Med. Author manuscript; available in PMC 2015 Mar 15. Published in final edited form as: Stat Med. 2014 Mar 15; 33(6): 930–939.

 

Editorial: Nerve wrapping with biomaterials during radical prostatectomy to improve potency recovery

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Radical prostatectomy is one of the standard treatment options for localized prostate cancer. The functional outcomes of radical prostatectomy are steadily improving along with better understanding of the surgical anatomy involved. Technological and technical advancements have helped improve continence outcomes significantly. High‐volume centres have consistently reported continence rates of >95% 1; however, potency recovery is the major limiting factor in achieving trifecta, even with full nerve‐sparing. Neuropraxia secondary to surgical dissection is one of the factors delaying potency recovery. We were the first to introduce the concept of protecting the neurovascular bundle using a wrap. In 2015, we first published our work on dehydrated human amnion‐chorion membrane (dHACM) nerve wrapping, a potential means of improving functional outcomes after radical prostatectomy 2.

Clinical applications of biomaterials are increasingly being explored. Their biological and physiochemical properties influence their role in peripheral nervous system regenerative therapy 3. Amniotic membrane graft has multiple growth factors including epidermal growth factor, vascular endothelial growth factor and anti‐inflammatory chemokines and cytokines including interleukin (IL)‐1, IL‐10 and IL‐1ra. In vitro and in vivo studies have reported that dHACM minimizes the surgical trauma‐induced inflammation and peri‐neural adhesions. These membranes are commercially available in various sizes for clinical use.

Porpiglia et al. 4 have reported their work on chitosan membrane application on the prostatic neurovascular bundle. Their phase II study is a step towards finding an ideal biomaterial favouring peripheral nerve healing. Chitosan is another potential biomaterial made of glucosamine and N‐acetyl glucosamine polymer which are natural components of mammalian tissues 5. Chitosan is hypoallergenic and only transiently stimulates the immune system and ultimately becomes bio‐tolerated and metabolized. It is not possible to develop specific antibodies against it because there are no proteins and lipids in its structure. Chitosan has inherent antimicrobial activity as its positive loads destabilize the membrane integrity of microorganisms. The inherent haemostatic and antimicrobial action of chitosan favour its application in wound healing. Chitosan has been extensively researched as a carrier molecule for biologically active particles and a scaffold in tissue engineering. Porpiglia et al. 4 have reported the safety and feasibility of its application for neurovascular bundle wrap during radical prostatectomy. In their non‐comparative study, they observed 96.4% continence and 68.6% potency recovery within 6 months. Comparative clinical trials are recommended to study its advantages in both partial and full nerve‐sparing settings. Membranes were manufactured from chitosan solution and sterilized for the purposes of the study. Pending approval by the regulators, study in other centres using chitosan membrane may be challenging.

The urological community has long been searching for ways to optimize functional outcomes after radical prostatectomy. Even for an ideal candidate with full nerve‐sparing, potency recovery is not assured. Several technical and technological modifications are being explored to address this concern. Bio-materials hold potential, and further exploration is warranted in the form of multicentre and randomized trials.

Hariharan Palayapalayam Ganapathi, Fikret Onol, Travis Rogers and Vipul Patel
Global Robotics Institute at Florida Hospital, University of Central Florida College of Medicine, Celebration, FL, USA

 

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References

 

  • 1 Patel VR, Abdul‐Muhsin HM, Schatloff O et al.Critical review of ‘pentafecta’ outcomes after robot‐assisted laparoscopic prostatectomy in high‐volume centres. BJU Int2011; 108: 1007–17

 

  • 2 Patel VR, Samavedi S, Bates AS et al.Dehydrated Human Amnion/Chorion membrane allograft nerve wrap around the prostatic neurovascular bundle accelerates early return to continence and potency following robot‐assisted radical prostatectomy: propensity score‐matched analysis. Eur Urol2015; 67: 977–80

 

  • 3 Dalamagkas K, Tsintou M, Seifalian A. Advances in peripheral nervous system regenerative therapeutic strategies: a biomaterials approach. Mater Sci Eng C Mater Biol Appl2016; 65: 425–32

 

  • 4 Porpiglia F, Bertolo R, Fiori C, Manfredi M, De Cillis S, Geuna S. Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study. BJU Int2018; 121: 473–9

 

  • 5 Rodríguez‐Vázquez M, Vega‐Ruiz B, Ramos‐Zúñiga R, Saldaña‐Koppel DA, Quiñones‐Olvera LF. Chitosan and its potential use as a scaffold for tissue engineering in regenerative medicine. Biomed Res Int2015; 2015: 821279

 

Editorial: To drain or not to drain after RARP? That is the question

/1 Comment/by

In the current issue of BJUI, the article by Chenam et al. [1] from the City of Hope Hospital clarifies an important surgical issue that most major uro-oncology centres face every day, but it also raises several other important surgical issues. The objective of the study was to determine if eliminating the routine placement of a pelvic drain after robot-assisted radical prostatectomy (RARP) affects the incidence of early (90-day) postoperative adverse events. RARP has become the new ‘gold standard’ approach for the surgical treatment of localized prostate cancer, and now comprises the majority of radical prostatectomies performed in the USA and the UK, with >80% of cases using this technique [2].

In this parallel-group, blinded, non-inferiority trial, patients who were planned to undergo RARP were randomized to one of two arms: no drain placement or pelvic drain placement. The primary endpoint was incidence of 90-day complications which, based on standard treatment using pelvic drain retrospectively, was estimated at 13%. The non-inferiority margin was set at 10%, and the planned sample size was 312. Despite stopping short of the intended number of patients to reach the accrual goal, it was impressive to read that the study was still well conducted, with robust statistical evidence that the no drain placement group was not inferior to the pelvic drain group. As a result, the authors conclude that pelvic drain can be safely omitted based on a clinical decision according to the surgeon’s discretion.

It has previously been demonstrated that the need for pelvic drain placement in RARP may be significantly less than in open prostatectomy techniques [3], and the concept of omitting the drain was initially presented more than 10 years ago [4]. But in any radical prostatectomy the rationale for placing a pelvic drain is potentially complex. Firstly, an anastomotic urine leak and subsequent urinoma or urinary peritonitis are the key historical concerns. The current reliable continuous running anastomosis now routinely possible with the robotic approach is far superior to the five to seven interrupted sutures inserted with the open or laparoscopic techniques, and hence the integrity is far more robust. Anastomotic leak rate is therefore generally very low at ~0.5–1% [2], and other non-randomized studies have previously shown that omission of pelvic drains is potentially safe [5].

Secondly, a drain may also assist with drainage of lymphatic leak after pelvic lymphadenectomy, preventing symptomatic lymphocele. The incidence of symptomatic lymphocele is ~2.5% in those undergoing RARP and extended pelvic lymph node dissection, as most lymphoceles are asymptomatic, but those that present late may be more at risk of infection in people with diabetes [6]. Another aspect that a small randomized controlled trial will not evaluate is the impact of the very occasional disaster, such as significant anastomotic disruption by a pelvic haematoma or a postoperative haemorrhage, and how that might be adverted by prior placement of a pelvic drain.

One of the few relevant problems with small randomized controlled trials in single centres is generalizability; results potentially only relate to very similar patient populations, i.e. those treated at high-volume and experienced centres, and cannot necessarily be extrapolated to other situations, such as RARPs performed by surgeons early on their learning curve or by those on fellowship/training programmes, or complex cases such as salvage RARP or when the anastomosis is technically challenging. This may include cases with significant bladder neck reconstruction, RARPs performed after TURP, or even cases with patients on steroids or other immunosuppressants. How necessary a pelvic drain is to the rapidly emerging Retzius-sparing RARPs remains to be seen, but judicious placement initially during the learning curve at least seems very sensible. Thus it would be wrong to conclude from the present study that pelvic drains are never indicated, as the authors also specify. Perhaps future larger studies may indicate more clearly those populations which do require pelvic drains in the form of an algorithm or decision-making tool.

It is clear that, as the emphasis shifts to enhanced recovery in the RARP population, pelvic drain placement may delay discharge and have a negative impact on the patient, such as increased anxiety and potential morbidity. In a public healthcare system such as the NHS, in which length of stay is an important cost variable, the present study empowers urologists to dispense with drains in the majority of cases. We believe the study was very well conducted and raises an important and a controversial topic. Overall, as we are all so much more familiar with standard RARP, it seems the time has come to omit the routine pelvic drain.

Salma Ghanem, Benjamin Namdarian and Ben Challacombe
Urology Centre, Guy’s Hospital, London, UK

 

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References

 

1 Chenam A, Yuh B, Zhumkhawala A et al. Prospective randomized non-inferiority trial of pelvic drain placement vs no pelvic drain placement after robot-assisted radical prostatectomy. BJU Int 2018; 121: 358–65

 

2 BAUS UK Radical Prostatectomy Audit 2016. Available at: https:// www.baus.org.uk/_userfiles/pages/files/Publications/Audit/Radical% 20Prostatectomy%202016%20final%20analysis.pdf. Accessed November 2017

 

3 Danuser H, Di Pierro GB, Stucki P, Mattei A. Extended pelvic lymphadenectomy and various radical prostatectomy techniques: is pelvic drainage necessary? BJU Int 2013; 111: 963–9

 

4 Sharma S, Kim HL, Mohler JL. Routine pelvic drainage not required after open or robotic radical prostatectomy. Urology 2007; 69: 330–3

 

5 Musser JE, Assel M, Guglielmetti GB et al. Impact of routine use of surgical drains on incidence of complications with robot-assisted radical prostatectomy. J Endourol 2014;28:1333–7

 

6 Keskin MS, Argun OB, Obek C et al. The incidence and sequela of lymphocele formation after robot-assisted extended pelvic lymph node dissection. BJU Int 2016; 118: 127–31

 

Editorial: PCa BCR after SRT – first look into risk stratification and prognosis

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As salvage radiation therapy (SRT) is commonly offered as a treatment option to select patients with prostate cancer who have biochemical recurrence (BCR) after radical prostatectomy (RP), the uro-oncology community is in strong need of tangible data regarding patients who have a ‘second’ BCR after such therapy. The multi-institution team led by Tumati and Jackson [1] provides new insight into the outcomes of second biochemical failures, offering a novel risk stratification system with the help of prognostic factors. Their analysis of 286 patients offers retrospective prognostic clues that could guide further work trying to better understand the natural history and management of such patients.

At the core of their findings is two risk stratification grouping systems predicting event rates for freedom from distant metastases (FFDM) and for prostate cancer-specific survival (PCSS), both based on multivariate analysis. Variables such as interval from RP to second BCR, Gleason score, and concurrent androgen-deprivation therapy (ADT) proved to be of significance. Of note, their cohort also allowed them to establish an overall survival from time of second BCR diagnosis of 13 years, a surprisingly hopeful figure for such treatment-resistant disease.

Whilst the classification proposed by Tumati et al. [1] brings valuable numbers to this poorly understood patient group, some questions remain about parts of the analysis performed. First, it came as a surprise to our team that, on multivariate analysis, FFDM and PCSS did not significantly correlate with clinical staging or nodal involvement, two well-established predictors of poor outcomes after RP [2]. Although both risk factors either reached or approached statistical significance on univariate analysis, we have difficulty explaining why such clear prognosticators would not reach significance with other factors controlled. Maybe the lack of systematic, complete lymph node sampling could partially explain the lack of significant correlation with N staging. Also, whilst some may find it surprising that positive surgical margins were insignificantly associated with better long-term outcomes, other published studies have actually shown similar results, sometimes with statistical significance [3, 4]. This could have very important implications, as it suggests that treatment options for patients with positive margins might be applied more selectively, and that systematic SRT might not be necessary in most cases.

We also would like to question the risk grouping proposed in the article to predict FFDM after 6 years (6-year FFDM). By combining patients with no risk factors (6-year FFDM = 75.8%) to those with either Gleason score 8–10 (6-year FFDM = 54.3%) or concurrent ADT (6-year FFDM = 64.0%) in a single group, the favourable prognosis of patients without any risk factor seems inappropriately merged with the two poorer-outcome risk factors, leading to an overall 6-year FFDM of 71% in that group. Based on the tables presented, separating patients with no risk factors from those with a high Gleason score or with concurrent ADT to create a separate risk group seems essential to optimise stratification given the striking difference in FFDM rates. We are also wondering why a similar weighted-risk grouping was not performed for PCSS, given that hazard ratios for the same variables were similar between FFDM and PCSS.

Another important limitation, as acknowledged by the authors, lies in the lack of analysis based on the period of treatment over their 27-year review (1986–2013). Although they provide second BCR rates for every decade, they do not to perform complete subgroup analyses for separate periods. As discussed in the article, 2004 marked an important change in the technique of RT at their institutions (three-dimensional planning vs intensity-modulated RT) and could have been used as a threshold to stratify patients based on era, which would have removed this possible confounder. Other important factors, also mentioned by the authors (e.g. increase in CT sensitivity over the years, problems with older ADT records, new therapies for castration-resistant prostate cancer since 2010), may have significantly influenced outcomes in the sample. We understand that most of these subgroupings, even if theoretically necessary, would probably have made analyses underpowered. Furthermore, as discussed in the paper, it would have been relevant to study PSA doubling time, as it is a well-recognised surrogate for clinical progression and PCSS in primary BCR [5]; maybe similar results could have been expected in second BCR.

Overall, our team thinks that the study led by Tumati et al. [1] reached its primary objective of describing the natural history of second BCR following SRT after RP, whilst providing new, multi-centric data on this poorly explored topic. Moreover, the proposed risk stratification system for FFDM and PCSS after 6 years provides much needed prognostic insight for treatment-resistant disease. In addition, such data can help design future trials assessing new treatment options or novel diagnostic techniques and improve clinical management of second BCR.

Felix Couture * Come Tholomier *† and Kevin C. Zorn
**Section of Urology, Department of Surgery, University of Montreal Health Center (CHUM), Universite de Montreal, Montreal, Quebec, Canada and †Department of Surgery, Division of Urology, McGill University, Health Centre, Montreal, Quebec, Canada

 

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References

 

1 Tumati V, Jackson WC, Abugharib AE et al. Natural history of ‘second’ biochemical failure after salvage radiation therapy for prostate cancer: a multi-institution study. BJU Int 2018; 121: 366–73.

 

2 Eggener SE, Scardino PT, Walsh PC et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol 2011; 185: 869–75

 

3 Tendulkar RD, Agrawal S, Gao T et al. Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy. J Clin Oncol 2016; 34: 3648–54

 

4 Wadhwa H, Terris MK, Aronson WJ et al. Long-term oncological outcomes of apical positive surgical margins at radical prostatectomy in the Shared Equal Access Regional Cancer Hospital cohort. Prostate Cancer Prostatic Dis 2016; 19: 423–8

 

5 Freedland SJ, Humphreys EB, Mangold LA et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 2005; 294: 433–9

 

Editorial: Is overall survival not influenced by PN vs RN?

/by

In this issue of the BJUI, Abdollah et al. [1] have for the first time tested the external validity of the only randomized clinical trial, 30904, run by the European Organization for the Research and Treatment of Cancer Genito-Urinary Group (EORTC GU) in the early 1990s, comparing cancer-specific survival and overall survival in patients with solitary renal masses of ≤5 cm and stage T1 and T2 in the TNM classification (in use at that time). The trial showed, as expected, that renal function was worse after radical nephrectomy (RN) and that the complication rate was higher after partial nephrectomy (PN) [2]. However, unexpectedly, overall survival after PN was not better than after RN [3], as was suggested or claimed in many non-randomized studies and also in a meta-analysis that included the EORTC 30904 trial as the only randomized clinical trial [4].

Despite a couple of limitations in the randomized trial, and it’s premature closure because of slow accrual, we performed a second analysis looking at the estimated GRF in the vast majority of the included patients and, most importantly, showed that kidney function did not progressively deteriorate after RN when the contralateral kidney was normal, and that only exceptionally did patients developed chronic kidney disease (CKD) necessitating dialysis [5].

Whilst it was anticipated that decreased kidney function should induce cardiovascular disease and increase cardiovascular death, this was separately investigated by Capitanio et al. [6] in a multicentre study where this suggestion was confirmed. However, looking at their Kaplan–Meier curves, it is clear that, although the negative impact on cardiovascular disease should become more and more obvious and accumulate over time, the split of the curves in favor of PN occurred very early after surgery. This indicates that the patients included in these non-randomized studies were different from the start, meaning that those selected for PN were ‘better’ patients who obviously had less cardiovascular disease and therefore had better cardiovascular outcomes. Another study confirmed that both PN and RN impact on cardiovascular disease [7], whilst another meta-analysis showed no difference for cardiovascular outcomes [8]. Obviously patients with preoperative CKD will benefit from nephron-sparing surgery [9], as well as those who have concomitant conditions, e.g. hypertension, diabetes, and a worse Charlson’s Comorbidity Index [10].

The authors, who tested the external validity of the EORTC 30904 trial in contemporary North American patients, need to be congratulated for the effort undertaken to show that the EORTC 30904 cohort was not significantly different from the National Cancer Database cohort in a manner that could influence the reported trial outcomes.

Hein Van Poppel* and Richard Sylvester†
*UZ Leuven – Urology, Leuven, Belgium and †EAU Guidelines Office, Brussels, Belgium

 

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References

 

1 Rogers C, Abdollah F, Arora S, et al. Testing the external validity of the EORTC randomized trial 30904 comparing overall survival after radical nephrectomy vs nephron-sparing surgery in contemporary North American patients with renal cell cancer. BJU Int 2018; 345–8

 

2 Van Poppel H, Da Pozzo L, Albrecht W et al. A prospective randomized EORTC intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal carcinoma. Eur Urol 2007; 51: 1606–15

 

3 Van Poppel H, Da Pozzo L, Albrecht W et al. A prospective, randomized EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011; 59: 543–52.

 

4 Kim SP, Thompson RH, Boorjian SA et al. Comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta-analysis. J Urol 2012; 188: 51–7.

 

5 Scosyrev E, Messing EM, Sylverste R et al. Renal function after nephron- sparing surgery versus radical nephrectomy; results from EORTC randomized trial 30904. Eur Urol 2014; 65: 372–7.

 

6 Capitanio U, Terrone C, Antonelli A et al. Nephron-sparing techniques independently decrease the risk of cardiovascular events relative to radical nephrectomy in patients with a T1a-T1b renal mass and normal preoperative renal function. Eur Urol 2015; 67: 683–9

 

7 Shuch B, Hanley J, Lai J et al. Overall survival advantage with partial nephrectomy: a bias of observational data? Cancer 2013; 15: 2981–9

 

8 Wang Z , Wang G, Xia Q et al. Partial nephrectomy vs radical nephrectomy for renal tumors: a meta-analysis of renal function and cardiovascular outcomes. Urol Oncol 2016; 34: 533. e11-533. e19

 

9 Woldu SL , Weinberg AC, Korets R et al. Who really benefits from nephron-sparing surgery? Urology 2014; 84: 860–7

 

10 Larcher A, Capitanio U, Terrone C et al. Elective nephron sparing surgery decreases other cause mortality relative to radical nephrectomy only in specific subgroups of patients with renal cell carcinoma. J Urol 2016; 196: 1008–13.

 

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