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Editorial: The BAUS consensus documents on andrology

May 30, 2018/by Prokar Dasgupta

In 2018, the BAUS returns to Liverpool and we have taken this opportunity to renew the lasting friendship between the BAUS and the BJUI. We also celebrate a monumental achievement for the city of Liverpool itself – the Knighthood of Sir Ringo Starr. This has finally happened, 50 years after his MBE and is richly deserved. We therefore decided to feature Liverpool and The Beatles on the front cover of your journal.

This year, Duncan Summerton, a well‐respected Urologist and Andrologist, starts his 2‐year term as the President of the BAUS. In our ‘Guidelines’ section, we have featured two BAUS consensus documents from the Andrology Section on priapism [1] and testicular trauma [2]. The former has an excellent flow chart on management of priapism with timelines of presentation, which every urologist will find clinically useful.

We have also included two excellent UK articles on renal trauma [3, 4], which BAUS members and beyond can learn from.

Finally, renal oncocytoma and its management may pose its own challenges as recorded by Neves et al. [5]. We also present the BAUS radical prostatectomy audit, which is publicly accessible and reassures readers (and the public) that the majority of these operations are being performed in high‐volume centres (164/centre) by high‐volume surgeons with good outcomes [6]. Nearly three in four operations are now performed robotically, which was certainly not the case when I started 15 years ago.

We look forward to meeting you at lunchtime on the Monday and Tuesday of the BAUS conference at the BJUI stand. I am particularly excited about the BJUI lecture and the National Clinical Entrepreneurship Programme, led by my friend Tony Young, on the second day of the meeting (https://www.baus.org.uk/agm/programme.aspx).

Prokar Dasgupta

MRC Centre for Transplantation, King’s College London, London, UK

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References

1 BAUS Section of Andrology Genitourethral Surgery, Muneer A, Brown G et al. BAUS consensus document for the management of male genital emergencies: priapism. BJU Int 2018; 121: 835–9
Wiley Online Library Web of Science®Google Scholar

2 Lucky M, Brown G, Dorkin T et al. British Association of Urological Surgeons (BAUS) consensus document for the management of male genital emergencies – testicular trauma. BJU Int 2018; 121: 840–4
Wiley Online Library Web of Science®Google Scholar

3 Wong KY, Jeeneea R, Healey A et al. Management of paediatric high‐grade blunt renal trauma: a 10‐year single‐centre UK experience. BJU Int 2018; 121: 923–7
Wiley Online Library Google Scholar

4 Hadjipavlou M, Grouse E, Gray R et al. Managing penetrating renal trauma: experience from two major trauma centres in the UK. BJU Int 2018; 121: 928–34
Wiley Online Library Google Scholar

5 Neves JB, Withington J, Fowler S et al. Contemporary surgical management of renal oncocytoma: a nation’s outcome. BJU Int 2018; 121: 893–9
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6 Khadhouri S, Miller C, Fowler S et al. The British Association of Urological Surgeons (BAUS) radical prostatectomy audit 2014/2015 – an update on current practice and outcomes by centre and surgeon case‐volume. BJU Int 2018; 121: 886–92
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Article of the Month: The Metabolic Syndrome & the Prostate

May 2, 2018/by admin Z.9

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

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

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

Association between metabolic syndrome and intravesical prostatic protrusion in patients with benign prostatic enlargement and lower urinary tract symptoms (MIPS Study)

Giorgio I. Russo*, Federica Regis*, Pietro Spatafora†, Jacopo Frizzi†, Daniele Urzı*, Sebastiano Cimino*, Sergio Serni†, Marco Carini†, Mauro Gacci† and Giuseppe Morgia*

*Urology Section, Department of Surgery, University of Catania, Catania, Italy, and †Department of Urology, University of Florence, Florence, Italy

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Abstract

Objective

To investigate the association between metabolic syndrome (MetS) and morphological features of benign prostatic enlargement (BPE), including total prostate volume (TPV), transitional zone volume (TZV) and intravesical prostatic protrusion (IPP).

Patients and Methods

Between January 2015 and January 2017, 224 consecutive men aged >50 years presenting with lower urinary tract symptoms (LUTS) suggestive of BPE were recruited to this multicentre cross‐sectional study. MetS was defined according to International Diabetes Federation criteria. Multivariate linear and logistic regression models were performed to verify factors associated with IPP, TZV and TPV.

Results

Patients with MetS were observed to have a significant increase in IPP (P < 0.01), TPV (P < 0.01) and TZV (P = 0.02). On linear regression analysis, adjusted for age and metabolic factors of MetS, we found that high‐density lipoprotein (HDL) cholesterol was negatively associated with IPP (r = −0.17), TPV (r = −0.19) and TZV (r = −0.17), while hypertension was positively associated with IPP (r = 0.16), TPV (r = 0.19) and TZV (r = 0.16). On multivariate logistic regression analysis adjusted for age and factors of MetS, hypertension (categorical; odds ratio [OR] 2.95), HDL cholesterol (OR 0.94) and triglycerides (OR 1.01) were independent predictors of TPV ≥ 40 mL. We also found that HDL cholesterol (OR 0.86), hypertension (OR 2.0) and waist circumference (OR 1.09) were significantly associated with TZV ≥ 20 mL. On age‐adjusted logistic regression analysis, MetS was significantly associated with IPP ≥ 10 mm (OR 34.0; P < 0.01), TZV ≥ 20 mL (OR 4.40; P < 0.01) and TPV ≥ 40 mL (OR 5.89; P = 0.03).

Conclusion

We found an association between MetS and BPE, demonstrating a relationship with IPP.

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Editorial: The metabolic syndrome and the prostate

May 2, 2018/by Peter Gilling

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

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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
Google Scholar

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.
Google Scholar

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
Google Scholar

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
Google Scholar

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

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.
Google Scholar

Video: The Metabolic Syndrome & the Prostate

May 2, 2018/by admin Z.9

Association between metabolic syndrome and intravesical prostatic protrusion in patients with benign prostatic enlargement and lower urinary tract symptoms (MIPS Study)

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Abstract

Objective

Patients and Methods

Results

Conclusion

We found an association between MetS and BPE, demonstrating a relationship with IPP.

Read more articles of the week

Article of the Month: MEAL Study – Effects of Diet in PCa Patients on AS

March 28, 2018/by admin Z.9

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

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

J. Kellogg Parsons*†‡ , John P. Pierce§, James Mohler¶, Electra Paskett**, Sin-Ho Jung††, Michael J. Morris‡‡, Eric Small§§, Olwen Hahn¶¶, Peter Humphrey***, John Taylor††† and James Marshall†††

*Division of Urologic Oncology, UC San Diego Moores Comprehensive Cancer Center, La Jolla, CA, USA, †Department of Urology, UC San Diego Health System, La Jolla, CA, USA, ‡VA San Diego Healthcare System, La Jolla, CA, USA, §Department of Family Medicine and Public Health and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA, ¶Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA, **Department of Medicine, College of Medicine, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA, ††Alliance Statistics and Data Center, Duke University, Durham, NC, USA, ‡‡Memorial Sloan Kettering Cancer Center, New York, NY, USA, §§UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA, ¶¶Alliance Central Protocol Operations, University of Chicago, Chicago, IL, USA, ***Department of Pathology, Yale University Medical School, New Haven, CT, USA, and †††Department of Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY, USA J. Protocol Operations, University of Chicago, Chicago, IL, USA, ***Department of Pathology, Yale University Medical School, New Haven, CT, USA, and †††Department of Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY, USA

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Abstract

Objective

To assess the most recommended books on keto and the feasibility of performing national, randomized trials of dietary interventions for localized prostate cancer.

Methods

The Men’s Eating and Living (MEAL) study (CALGB 70807 [Alliance]) is a phase III clinical trial testing the efficacy of a high‐vegetable diet to prevent progression in patients with prostate cancer on active surveillance (AS). Participants were randomized to a validated diet counselling intervention or to a control condition. Chi‐squared and Kruskal–Wallis analyses were used to assess between‐group differences at baseline.

Results

Between 2011 and 2015, 478 (103%) of a targeted 464 patients were randomized at 91 study sites. At baseline, the mean (sd) age was 64 (6) years and mean (sd) PSA concentration was 4.9 (2.1) ng/mL. Fifty‐six (12%) participants were African‐American, 17 (4%) were Hispanic/Latino, and 16 (3%) were Asian‐American. There were no significant between‐group differences for age (P = 0.98), race/ethnicity (P = 0.52), geographic region (P = 0.60), time since prostate cancer diagnosis (P = 0.85), PSA concentration (P = 0.96), clinical stage (T1c or T2a; P = 0.27), or Gleason sum (Gleason 6 or 3+4 = 7; P = 0.76). In a pre‐planned analysis, the baseline prostate biopsy samples of the first 50 participants underwent central pathology review to confirm eligibility, with an expectation that <10% would become ineligible. One of 50 participants (2%) became ineligible.

Conclusion

The MEAL study shows the feasibility of implementing national, multi‐institutional phase III clinical trials of diet for prostate cancer and of testing interventions to prevent disease progression in AS.

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Editorial: PCa Prevention – Proof is Elusive

March 28, 2018/by Laurence Klotz

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, 1^st 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

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References

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
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
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
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.
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
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.
Cooperberg MR, Carroll PR, Klotz L: Active surveillance for prostate cancer: progress and promise. J Clin Oncol 29 (27): 3669-76, 2011. [PubMed]
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.

Article of the Month: Comparing survival after RN vs NSS in RCC

February 28, 2018/by admin Z.9

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

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

Firas Abdollah, * Sohrab Arora, * Nicolas von Landenberg, †Philipp Gild, ‡Akshay Sood, * Deepansh Dalela, * Quoc-Dien Trinh, §Mani Menon, * and Craig Rogers, *

*Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA, †Department of Urology, Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany, ‡Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg,Germany and §Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

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The European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904 reported that for solitary renal masses ≤5 cm, radical nephrectomy (RN) was associated with a higher overall survival (OS; primary endpoint): 81%, compared with 76% for nephron-sparing surgery (NSS) at a median follow-up of 9.3 years (P = 0.03). The difference in cancer-specific mortality, however, was not significant. For histologically proven RCC, and after exclusion of patients with positive surgical margins, NSS was associated with equivalent OS compared with RN [1]. It is noteworthy that the renal function outcomes of the two groups in the trial have been reanalysed, showing that renal function does not decline over time after RN, as was expected [2].

The EORTC 30904 trial had difficulty recruiting and randomizing patients, and was criticized for not meeting the accrual goal of 1300 patients. Additionally, the generalizability of the study findings to ‘real-world’ patients has been questioned. Despite the criticism, and more than 20 retrospective studies [3, 4] showing better OS and cancer-specific survival with NSS, this randomized clinical trial (RCT) remains the only available level 1 evidence on this subject. Notably, no study to date has formally examined the external validity [5] of the trial.

For any RCT to be externally valid, its supposedly randomly selected sample must be representative of the general population seen in clinical practice. In this context, we studied patients with localized RCC treated with NSS or RN within the National Cancer Database (NCDB), in an effort to test the external validity of the EORTC 30904. Our objective was not to compare survival outcomes between the two treatment arms, as this is beyond the scope of examining the external validity of an RCT, and such analysis is already available in literature. Instead, our aim was to ascertain if the trial patients were representative of contemporary patients with RCC in the USA, using the NCDB, which captures ~70% of all incident cancer diagnoses in the USA [6].

We identified patients who met the clinical and pathological inclusion criteria of the EORTC 30904 within the NCDB from 2004 to 2013: histologically confirmed RCC; tumour size ≤5 cm; clinically node-negative, non-metastatic disease; no positive surgical margins; and no pT3/4 disease. After exclusions, there were 90 844 assessable patients within the NCDB, of whom 41 588 (45.78%) underwent RN and 49256 (54.22%) underwent NSS. The demographic characteristics, namely, age, gender (percentage of men), presence of comorbidities (yes/no), histology (clear cell/non-clear cell), Fuhrman grade (1, 2, 3 or 4) and surgical approach (open/robotic/laparoscopic) were then compared with the patients enrolled in the EORTC 30904. The statistical significance of differences in categorical variables was tested using the chi-squared test. Unfortunately, the trial did not provide measures of variance (such as standard deviation, or interquartile range) for continuously coded variables; we were therefore unable to test for the statistical significance of differences in these variables. All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA), with a P value <0.05 taken to indicate statistical significance.

The median age of the NCDB cohort was 60.0 years, compared with 62.0 years in the EORTC 30904. The median clinical tumour size in the NCDB was 30 mm, similar to the 30-mm tumour size observed in the trial. The percentage of men was 59.4% in the NCDB vs 65.8% in EORTC 30904 trial (P < 0.001). The NCDB cohort was healthier, with 70.03% patients having no comorbidity vs 62.8% in the trial (P < 0.001). The percentage of patients with clear-cell histology was 81.9% in the NCDB vs 62.9% in the trial (P < 0.001). The trial did not report data on race, while the NCDB had 15.6% non-white patients. Finally, the percentage of patients with high-grade disease (Fuhrman grade ≥3) was 21.1% in the NCDB vs 11.2% in the EORTC 30904 (P < 0.001; Table 1). Notably, in the EORTC 30904 trial, there was no central pathology review.

Table 1. Descriptive statistics of 391 clinically and pathologically eligible patients randomized to nephron-sparing surgery (NSS) or radical nephrectomy (RN) in the European Organization for Research and Treatment of Cancer randomized trial 30904 compared with 40 762 patients within the National Cancer Database with similar inclusion/exclusion criteria, who underwent NSS vs RN, between 2004 and 2013
Variable	EORTC 30904 trial	NCDB	P
EORTC 30904, European Organization for Research and Treatment of Cancer randomized trial 30904; IQR, interquartile range; NCDB, National Cancer Database.
Study period	1992–2003	2004–2013	–
Number of patients clinically and pathologically eligible	391	90 844	–
Median (IQR) age, years	62 (not provided)	60 (51–69)	–
Median (IQR) clinical tumour size, mm	30 (not provided)	30 (21–40)	–
Men, %	65.8	59.44	<0.001
Race	Not provided	Non-white 15.6%	–
Free of comorbid disease, %	62.8	70.03	<0.001
Clear cell histology, %	62.9	81.9	<0.001
Tumour grade, %
1	22.30	18.08	<0.001
2	66.60	60.78
3	10.50	19.63
4	0.70	1.51
Surgical approach (recorded in NCDB since 2010, n = 15 604), %
Open	100	39.4	<0.001
Robotic	0	34.6
Laparoscopic	0	23.5

Several important observations emerge from these results. First, age and tumour size were similar in the EORTC 30904 trial and the NCDB. These two variables are the most important determinants of mortality and stage of disease, respectively, which implies that the trial was able to recruit patients representative of those seen in ‘real-world’ clinical practice.

Second, there was a higher incidence of high-grade disease and clear-cell histology in the NCDB cohort compared with the EORTC 30904 trial. In other words, patients in the NCDB had more aggressive tumours as compared with patients in the trial. Arguably, such patients are better served with RN, which has a higher probability of completely eradicating the tumour. The survival benefit of RN observed in the trial might therefore be even more evident in clinical practice, where a higher proportion of patients harbour unpredictable aggressive disease.

Finally, the EORTC seems to have recruited patients with a higher comorbidity burden than is generally observed in clinical practice. The significance of this finding is controversial. On the one hand, it might be argued that the higher background mortality of the cohort could have masked the potential OS benefit of NSS by offering this treatment method to sicker patients with limited life expectancy [7]. On the other hand, preserving renal function might be even more important in sicker patients, who have the burden of other comorbidities [8].

The present study has some limitations. An inherent limitation of the NCDB is the lack of information on the performance status of patients. Second, the comparison was between two cohorts separated in time. The mode of treatment and thus, patient selection might have changed over time. The NCDB provides information about surgical approach starting in 2010, and indeed open surgery was performed in only 39.4% of the cases compared with 100% in the trial. More than 15% of patients in the NCDB had missing tumour grade compared with 4% in the trial; however, this proportion was equally distributed between patients undergoing RN and PN in the NCDB (data not shown). Despite the limitations, these findings are significant in the context of the recent debate on contemporary guidelines recommending NSS ‘wherever possible’ in patients with a normal contralateral kidney [9].

In conclusion, our results indicate that, although the EORTC 30904 cohort had somewhat different baseline characteristics than ‘real-world’ patients with small renal masses, none of these differences seem to have the potential to significantly alter the outcomes of the trial. The latter should therefore be considered generalizable to contemporary North American patients with renal masses ≤5 cm.

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

February 28, 2018/by Hein Van Poppel

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.

Article of the Month: Does RARP benefit patients with oligometastatic PCa?

January 31, 2018/by admin Z.9

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

Does robot-assisted radical prostatectomy benefit patients with prostate cancer and bone oligometastases?

Won Sik Jang, Myung Soo Kim, Won Sik Jeong, Ki Don Chang, Kang Su Cho, Won Sik Ham, Koon Ho Rha, Sung Joon Hong and Young Deuk Choi

Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea

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Abstract

Objective

To investigate the peri-operative and oncological outcomes of robot-assisted radical prostatectomy (RARP) in patients with oligometastatic prostate cancer (PCa).

Patients and Methods

We retrospectively reviewed the records of 79 patients with oligometastatic PCa treated with RARP or androgen deprivation therapy (ADT) between 2005 and 2015 at our institution. Of these 79 patients, 38 were treated with RARP and 41 were treated with ADT without local therapy. Oligometastatic disease was defined as the presence of five or fewer hot spots detected by preoperative bone scan. We evaluated peri-operative outcomes, progression-free survival (PFS), and cancer-specific survival (CSS). We analysed data using Kaplan–Meier methods, with log-rank tests and multivariate Cox regression models.

Results

Patients treated with RARP experienced similar postoperative complications to those previously reported in RP-treated patients, and fewer urinary complications than ADT-treated patients. PFS and CSS were longer in RARP-treated compared with ADT-treated patients (median PFS: 75 vs 28 months, P = 0.008; median CSS: not reached vs 40 months, P = 0.002). Multivariate analysis further identified RARP as a significant predictor of PFS and CSS (PFS: hazard ratio [HR] 0.388, P = 0.003; CSS: HR 0.264, P = 0.004).

Conclusions

We showed that RARP in the setting of oligometastatic PCa is a safe and feasible procedure which improves oncological outcomes in terms of PFS and CSS. In addition, our data suggest that RARP effectively prevents urinary tract complications from PCa. The study highlights results from expert surgeons and highly selected patients that cannot be extrapolated to all patients with oligometastatic PCa; to confirm our findings, large, prospective, multicentre studies are required.

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Editorial: Is it time for a more ‘proactive’ approach to metastatic prostate cancer?

January 31, 2018/by admin Z.9

In this issue of BJU International, Jang et al. [1] investigate the perioperative and oncological outcomes of robot-assisted radical prostatectomy (RARP) in oligometastatic prostate cancer. The authors evaluated a retrospective cohort of 79 patients with oligometastatic prostate cancer, defined as up to five bony metastases on bone scan without visceral metastasis on conventional CT, treated either with RARP (n = 38, 48%) or androgen-deprivation therapy (ADT: n = 41, 52%). They found that cytoreductive RARP was associated with longer progression-free survival (PFS) and cancer-specific survival (CSS) relative to the ADT cohort at a median follow-up of 40 months.

The authors exclusively use the robotic approach for RP in the metastatic prostate cancer setting. Overall, they should be commended for demonstrating the feasibility of RARP in the metastatic setting, with a median operating room time of 147 min and complication rate of ~15%. This is in the same range as the 164 min operative time and 20% complication rate reported in a recent multi-institutional cytoreductive RP (cRP) series, consisting of both open and robotic approaches [2]. However, it is important to note that Jang et al. [1] had a 79% positive margin rate compared to 54% for Sooriakumaran et al. [2]. Furthermore, Jang et al. [1] had a median hospital stay of 5 days compared to 2–3 days in the USA centres [2]. These findings underscore the significant difficulty often encountered in metastatic cases, despite robotic assistance. Thus, we believe the age-old debate of open vs robotic prostatectomy is perhaps less relevant in the cytoreductive setting, where surgeon experience and expertise may be more critical drivers of outcome.

Although there is some evidence in favour of cRP compared to the standard of care, selection bias, limited collection and analysis of much clinical data, and short follow-up often plague most series. Understandably, the current manuscript by Jang et al. [1] also suffers from some of these limitations and leaves some questions unanswered. For instance, did the number of bone metastases, PSA doubling time at diagnosis, and distribution of lymphadenopathy (pelvic vs extra-pelvic) differ between cRP and ADT groups and thus confound the impact of cRP on survival? In addition, the authors may wish to report overall survival, so that their series can be more readily compared to the existing literature. Moreover, the median CSS was only 40 months in the ADT group, whereas it was not even reached in the low-volume arm of the ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) [3], suggesting that the control group in the current manuscript may have had higher volume metastatic disease. Lastly, there is no evaluation of the impact of adjuvant ADT and radiation therapy on CSS, and further studies may wish to explore if such multi-modal approaches may yield a benefit in the cytoreductive setting.

The existing literature on cRP remains in the nascent stage and is conflicting. The first large studies to suggest a benefit for cRP were retrospective series based on large cancer databases. Subsequently, Heidenreich et al. [4] explored the role of cRP in a case-control study, which found a significantly longer PFS and CSS in a group of 23 men undergoing neoadjuvant ADT + cRP compared to 38 men treated with ADT alone. On the other hand, a prospective investigation comparing 43 men with low-volume bone metastasis treated with cRP to 38 men treated with ADT did not show a benefit for time-to-castration-resistance or overall survival [5]. Moschini et al. [6] also found no survival benefit for cRP with 5-years of follow-up relative to a cohort of ADT patients with CSS more consistent with randomised data from the CHAARTED [3]. The present study by Jang et al. [1] adds to the growing body of retrospective series advocating cRP in select patients.

Whilst a full discussion of the putative biological mechanisms proposed to explain a potential survival benefit of cRP is beyond this editorial, they can be broadly grouped into the following: removal of the primary source of circulating tumour cells, reducing the number of cells that can develop resistant mechanisms for systemic therapy, removal of immunosuppressive cytokines, abscopal effects, and decreasing tumour-growth promoting factors. Ultimately, the ‘proof is in the pudding’, and the results of several randomised trials (Testing radical prostatectomy in men with oligometastatic prostate cancer that has spread to the bone [TRoMbone], NCT01751438, and NCT02454543) are eagerly awaited to determine if cRP can benefit patients.

Matteo Soligo, Vidit Sharma and R. Jeffrey Karnes

Mayo Clinic Urology, Rochester, MN, USA

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References

1 Jang WS, Kim MS, Jeong WS et al. Does robot-assisted radical prostatectomy beneﬁt prostate cancer patients and bone oligometastases? BJU Int 2018; 121: 225–31

2 Sooriakumaran P, Karnes J, Stief C et al. A multi-institutional analysis of perioperative outcomes in 106 men who underwent radical prostatectomy for distant metastatic prostate cancer at presentation. Eur Urol 2016; 69:788–94

3 Sweeney CJ, Chen YH, Carducci M et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737–46

4 Heidenreich A, Pﬁster D, Porres D. Cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study. J Urol 2015; 193: 832–8

5 Steuber T, Budaus L, Walz J et al. Radical prostatectomy improves progression-free and cancer-speciﬁc survival in men with lymph node positive prostate cancer in the prostate-speciﬁc antigen era: a conﬁrmatory study. BJU Int 2011; 107: 1755–61

6 Moschini M, Morlacco A, Kwon E, Rangel LJ, Karnes RJ. Treatment of M1a/M1b prostate cancer with or without radical prostatectomy at diagnosis. Prostate Cancer Prostatic Dis 2017; 20: 117–21