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Editorial: MRI with targeted fusion biopsy: is the time now?

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The current standard of performing TRUS‐guided systematic biopsy in men with a PSA of 4–10 ng/mL results in a considerable number of unnecessary prostate biopsies and overtreatment of clinically indolent disease, both of which are costly from the patient and healthcare system perspectives [1]. Two recent studies document that incorporating multiparametric (mp)MRI into prostate cancer screening has the potential to reduce overdiagnosis and overtreatment. Ahmed et al. [2] performed mpMRI followed by TRUS biopsy and template prostate mapping biopsy in 576 men with a PSA level of 4–14 ng/mL or an abnormal DRE. They found that using mpMRI to triage men would result in 27% fewer men undergoing biopsy while diagnosing 5% fewer clinically insignificant cancers. Furthermore, if subsequent TRUS biopsies were directed by mpMRI findings, 18% more cases of clinically significant cancer might be detected compared with traditional screening biopsies. Using a similar randomized study design, Kasivisvanathan et al. [3] found the use of mpMRI for screening reduced the biopsy rate by 28%, while lowering the rate of clinically insignificant cancer by 13% and improving the detection rate of clinically significant cancer by 12% [3]. While the addition of mpMRI to the screening armamentarium clearly provides clinical value, it also adds considerable increased costs, begging the question: is it worth it?

In the current issue of BJUI, Barnett et al. [1] evaluated the cost‐effectiveness of prostate MRI in a screening setting in order to determine whether MRI may be able to mitigate prostate biopsies in biopsy‐naïve men with a negative imaging study. They found that, when using the generally accepted threshold of $100 000/quality‐adjusted life year (QALY), the most cost‐efficient strategy consisted of obtaining prostate MRI in men with PSA >4 mg/mL. This was followed by either systematic and targeted fusion biopsy if the MRI showed a Prostate Imaging Reporting and Data System (PI‐RADS) score ≥3 lesion or continued observation if the MRI did not show a PI‐RADS score ≥3 lesion. Altogether, this strategy resulted in 5.9 prostate cancer deaths averted, 60.7 QALYs gained, and 72.6 life‐years gained for every 1000 patients screened. The number‐needed‐to‐treat to prevent one prostate cancer death with this approach was 169.

While the results are informative, the reader should interpret the study’s findings carefully as there is not agreement among policy makers on what is the optimal incremental willingness‐to‐pay threshold to determine what is truly cost‐effective. Furthermore, this study does not address the potential negative impact that detection of clinically insignificant prostate cancer may have on health‐state utilities and quality of life. Barnett et al. also predominantly obtained costs from Medicare data, but as previously reported, these costs are often rough estimates that are derived more from revenue or reimbursement than from the true cost of treating the disease process. The cost‐effectiveness estimates presented in this report, therefore, will probably vary from country to country. To examine the true cost, Laviana et al. [4] previously explored the cost of prostate MRI using time‐driven activity‐based costing and found the cost of MRI and mpMRI/TRUS to be $670 and $1,072 US dollars, respectively. These are significantly cheaper than the Medicare reported costs of $964.21 and $3,019.35 for MRI and mpMRI/TRUS, respectively. This implies that MRI and targeted biopsy may actually be even more cost‐effective than reported in the present study.

We must remember that, while the present study shows that MRI in prostate cancer screening may be cost‐effective, the base case population only included men with a PSA >4 mg/mL. This study does not address the cost‐effectiveness of a screening MRI in the larger population of all men at risk of prostate cancer, although previous data by Nam et al. [5] suggest MRI may be a potentially better primary screening tool than PSA. Of course, population‐wide prostate MRI screening would result in greatly increased upfront costs and, as such, the strategy would first need to be proven cost‐effective before MRI could replace PSA as the front‐line test in prostate cancer screening.

In conclusion, Burnett et al. elegantly demonstrate that an upfront MRI, in men with a PSA of >4 ng/mL, may ultimately be a cost‐effective approach depending on your willingness‐to‐pay threshold. Policymakers and payers worldwide should recognize that prostate MRI is here to stay and should be made more widely available to those with a PSA >4 ng/mL who are at risk of prostate cancer.

Aaron A. Laviana* and David F. Penson*†
*Department of Urological Surgery, Vanderbilt University, and †VA Tennessee Valley Geriatric Research, Education and Clinical Centre, Nashville, TN, USA

 

References
  1. Barnett C, Davenport M, Montgomery J et al. Cost‐effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer. BJU Int 2018; 122: 50–8
  2. Ahmed HU, El‐Shater BA, Brown LC et al. Diagnostic accuracy of multi‐parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017; 389: 815–22
  3. Kasivisvanathan V, Rannikko AS, Borghi M et al. MRI‐targeted or standard biopsy for prostate‐cancer diagnosis. N Engl J Med 2018; 378: 1767-77
  4. Laviana AA, Ilg AM, Veruttipong D et al. Utilizing time‐driven activity‐based costing to understand the short‐ and long‐term costs of treating localized, low‐risk prostate cancer. Cancer 2016; 122: 447–55
  5. Nam RK, Wallis CJD, Stojcic‐Bendavid J et al. A pilot study to evaluate the role of magnetic resonance imaging for prostate cancer screening in the general population. J Urol 2016; 192: 361–6

 

Editorial: Can we still recommend tension‐free vaginal tape for long‐term safety and efficacy?

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Traditional retropubic tension‐free vaginal tape (TVT) has been in widespread use for over 20 years. It has been estimated that 10 million women worldwide have received mid‐urethral tapes, and that at least half of these have been traditional retropubic TVTs. So, why have TVTs suddenly fallen into disrepute? Surely, so many women and their healthcare advisors can’t all be wrong? With this in mind, Braga et al. [1] are to be congratulated on their study in this issue of BJUI, in which they evaluate the efficacy and adverse effects of TVT for treatment of pure urodynamic stress urinary incontinence (SUI), with a 17‐year follow‐up.

Women’s reproductive health has been very well established compared to decades ago. Nowadays, women have options and opportunity to take care of themselves. After pregnancy, some women opt to tighten to vaginal walls. You can read more on that topic on vtightensafely.com. Reasons may vary for doing so, but the point is we’ve come a long way.

Whilst there have been other publications detailing relatively long‐term follow‐up of this procedure, as referenced in Braga et al. in their paper, the only study reported to date with a 17‐year follow‐up is that by Nillson et al. [2], who are from the three centres in Scandinavia where the mid‐urethral retropubic tape procedures were originally developed and undertaken. In the present study from Italy and Switzerland, however, Braga et al. have managed to follow up 46 out of 52 (88.4%) women who had a traditional TVT inserted between 1998 and 2000 [1]. The remaining patients were lost to follow‐up or had died in the intervening period. The patients were assessed using both subjective and objective outcome measures. At 17 years, 41 out of 46 patients (89.1%) were cured subjectively and 42 out of 46 (91.3%) were cured objectively on a stress test. The only long‐term adverse outcome was de novo overactive bladder (OAB) symptoms, which were reported by 15 out of 46 (32.6%) women at 17‐year follow‐up. This is not surprising, as it is well known that the prevalence of OAB increases with age [3], and obviously these women were significantly older when assessed at 17‐year follow‐up than when their TVTs were inserted. Unfortunately, despite the use of quality‐of‐life outcome measures (Patient Global Impression of Improvement and patient satisfaction scores), the authors have not reported the overall change in quality of life. This could be important when considering cure of SUI at the possible expense of developing OAB symptoms in later life. Most importantly, there were no reported TVT‐associated complications requiring release or resection of the TVT, nor were there any erosions into the vagina, bladder or urethra.

Although the use of all mid‐urethral tapes for urinary incontinence and meshes for pelvic organ prolapse was suspended by the Scottish Health Minister in 2014, because of concerns regarding a perceived high complication rate, brought about by a group of vocal campaigners and fuelled by the press, the final report published in 2017 recommended that women choosing surgery for SUI should be offered all available options including mesh and non‐mesh procedures [4]. Similarly, the final NHS England mesh report in 2017 [5] supported the use of retropubic mid‐urethral tapes rather than the trans‐obturator route, and the European (SCENIHR) Report [6] concluded that mesh for SUI is safe and should continue to be offered as a choice for women seeking surgery for their SUI.

Obviously, a wide range of options is available for the management of SUI, and conservative measures including pelvic floor muscle training should be offered first. For those women who do not desire a surgical solution, duloxetine is available and can be very effective when adequately tolerated. For those women who wish to undergo surgery, however, the main choices are a bulking agent, mid‐urethral tape, colposuspension or an autologous fascial sling. From all the reports and published literature to date the TVT would appear to be as, if not more, effective than all other procedures without having a higher complication rate. The data in the present paper by Braga et al. [1] should reassure healthcare providers that TVT continues to be a safe and effective surgical strategy for the management of SUI in women.

 

Linda Cardozo
Department of Urogynaecology, King’s College Hospital, London, UK

 

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References
  • 1 Braga A, Caccia G, Sorice P, et al. Tension‐free vaginal tape for treatment of pure urodynamic stress urinary incontinence: efficacy and adverse effects at 17‐year follow‐up. BJU 2018; 122: 113–7

 

  • 2 Nilsson CG, Palva K, Aarnio R, et al. Seventeen years’ follow‐up of the tension free vaginal tape procedure for female stress urinary incontinence. Int Urogynaecol J. 2013; 24: 1265–69

 

  • 3 Milsom I, Abrams P, Cardozo L, et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population based prevalence study. BJU Int 2001; 88: 807

 

  • 4 The Scottish Independent Review of the Use, Safety and Efficacy of Transvaginal Mesh Implants in the Treatment of Stress Urinary Incontinence and Pelvic Organ Prolapse in Women: Final Report March 2017

 

 

  • 6 European (SCENIHR) Report Opinion on the Safety of Surgical Meshes Used in Urogynecological Surgery. December 2015

 

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Editorial: The trials of doing trials: will the prostatic stent rise from the dead?

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A further re‐engineering of the prostatic stent (temporary implantable nitinol device [TIND®, Medi‐Tate Ltd., Israel]) is reported by Porpiglia et al. 1 in this edition of the BJUI. Enthusiasm for novel ‘minimally invasive’ treatments for BPH/LUTs has surged recently, with new options supported by strong data becoming available 2, 3. That interest reflects the continuing desire of our patients to seek alternatives to the standard drug or surgical therapies.

The success of UroLift® (Neotract, Pleasanton, CA, USA) in satisfying the rigour of the regulatory bodies (especially the Food and Drug Administration [FDA] in the USA and National Institute for Health and Care Excellence [NICE] in the UK) and the recent merger/acquisition of Neotract by Teleflex Inc. for a sum potentially exceeding 1 billion dollars, indicates the rewards available for a novel treatment with convincing data. Not surprisingly, this has stimulated innovators, so there is a veritable tsunami of new treatments approaching us. The rewards are certainly encouraging, but it is worth remembering that the difficulties and cost of reaching market and the point of sale are now enormous.

The TIND stent is implanted endoscopically and then gradually distends to cause three linear pressure necrosis effects within the prostatic urethra and bladder neck tissues, before it is removed at approximately 5–7 days by a second, minor and office‐based procedure.

However, this report is simply a repeat of the initial case series from 2015 4, just with follow‐up to 36 months. An initial report is legitimate in order to show primarily safety and with effectiveness as a secondary outcome measure. I see limited value in a follow‐up report of a device that has already been superseded by a second version, which is currently being assessed in the more rigorous studies that we, our patients, and regulators require.

Even so, there are some important messages and some inconsistencies. Porpiglia et al. 1 are, firstly, to be commended for successfully following their patients out to 3 years with essentially complete data sets. That is remarkable. Although the TIND seems safe, there was one serious complication (a prostatic abscess associated with arrhythmia, sepsis and hyperglycaemia, which required 10 days of inpatient care). About 10% of men restarted medical therapy, but are not ‘failures’, as failures are defined only as those requiring surgical treatment. The prostate size in this small cohort is also surprisingly small compared to the initial studies of other novel devices (29.5 vs 50 mL for UroLift in the initial report) 5. It is also surprising that even though all were on α‐blockers and a substantial proportion were taking 5α‐reductase inhibitors that there is no sexual or especially ejaculatory dysfunction in any of the 19 sexually active men before or after TIND implantation. They appear to have surprisingly resilient ejaculatory function and one wonders why or how? The population studied may therefore not be representative of men we meet in our clinics. Nevertheless, the safety and effectiveness of the original TIND stent do seem reasonable and many of us will await the definitive ‘pivotal’ randomised controlled studies of the successor device with great interest.

For the TIND to find a place in our range of treatments, we urologists, our patients, and regulators of healthcare, now need to see proper randomised controlled trials, preferably incorporating a sham arm and eventually comparisons with TURP. Ideally, the TIND should also be compared to UroLift and to steam injection (Rezūm®; NxThera, Inc., Maple Grove, MN, USA). But who will pay for these studies, even if the regulators insist on them? Funding the required studies is now a major financial challenge to any new device in development. Those studies cost more than we think. A survey of >200 MedTech companies in 2010 suggested device development costs up to 100 million dollars (the majority spent on FDA‐dependent or related activities) but for UroLift total development spend was nearly 240 million. Unfortunately, even innovative and potentially useful devices will struggle to overcome the double jeopardy of regulatory hurdles and obtaining the finance required to clear them. I wish the developers of TIND well and hope there is adequate funding. Today, developers need deep pockets to perform the proper studies correctly.

 

Tom McNicholas
Pinehill Hospital, Hitchin, Herts, UK

References

 

  • 1 Porpiglia F, Fiori C, Bertolo R et al. 3‐Year follow‐up of temporary implantable nitinol device implantation for the treatment of benign prostatic obstruction. BJU Int2018; 122: 106–12

 

  • 2 Roehrborn CG, Barkin J, Gange SN et al. Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study. Can J Urol 2017; 24: 8802–13

 

  • 3 McVary KT, Roehrborn CG. Three‐year outcomes of the prospective, randomized controlled Rezūm System study: convective radiofrequency thermal therapy for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia. Urology 2018; 111: 1–9

 

  • 4 Porpiglia F, Fiori C, Bertolo R, Garrou D, Cattaneo G, Amparore D. Temporary implantable nitinol device (TIND): a novel, minimally invasive treatment for relief of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH): feasibility, safety and functional results at 1 year of follow‐up. BJU Int 2015; 116: 278–87

 

  • 5 Woo HH, Chin PT, McNicholas TA et al. Safety and feasibility of the prostatic urethral lift: a novel, minimally invasive treatment for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). BJU Int 2011; 108: 82–8

 

Editorial: Systematic transperineal and MRI‐targeted biopsies: the resolution of uncertainty

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The paper published in this issue of the BJUI titled ‘Multicentre evaluation of magnetic resonance imaging supported transperineal biopsy in biopsy‐naïve men with suspicion of prostate cancer’ is timely and helps to resolve some of the uncertainty inherent within the diagnostic pathway 1.

The publication of the PROstate MRI Imaging Study (PROMIS) study, although demonstrating that 25% of patients might avoid prostate biopsy with a normal MRI (Prostate Imaging Reporting and Data System [PI‐RADS] 1–2) and that MRI could identify 90% of patients with high‐risk disease (PI‐RADS 5), did not resolve the issue of what to do with equivocal PI‐RADS 3 scans, uncertainty remained 2. The recent publication of the PRECISION trial (Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or Not?) has only contributed to the uncertainty of systematic TRUS biopsy and has shown that targeted biopsies resolve the issue for <50% of the patients overall and only 12% of those with PI‐RADS 3 lesions had a diagnosis of cancer on targeted biopsy only 3. The study has shown that in the face of an identifiable lesion a MRI‐targeted biopsy is non‐inferior to a blind systematic TRUS biopsy, which was positive in only 28% and implies that a systematic biopsy may be unnecessary, so where does that leave us? The uncertainty within MRI remains at the PI‐RADS 3 level, and particularly with a TRUS biopsy that is not a systematic biopsy of the peripheral zone. The authors of the paper highlighted in this issue of the BJUI 1 help to resolve the issue because they describe a more systematic biopsy.

The transperineal (TP) biopsy approach for systematic and targeted biopsy they use is that which was adopted by the Ginsburg Study Group on Enhanced Prostate Diagnostics 4. It is a systematic biopsy that preferentially targets the peripheral zone in a sectoral fashion. It avoids the oversampling inherent in template‐mapping biopsy and the under‐sampling of the non‐systematic transrectal biopsy. Their paper evaluates the combination of an MRI‐targeted biopsy with a systematic TP biopsy. It confirms, as suggested by the PROMIS study, that patients with PI‐RADS 1 or 2 prostates on MRI with a low PSA density <0.1 ng/mL/mL could safely avoid biopsy, based upon a negative predictive value of 0.91 on systematic biopsy. However, in 418 patients with PI‐RADS 4–5 lesions, it was the combination of a targeted and systematic TP biopsy that achieved an overall cancer detection rate of 71%, but that MRI‐targeted biopsies alone had a detection rate of 59% vs 61% for systematic TP biopsies. In the PI‐RAD 3 equivocal group the combined biopsy identified 30% with Gleason score 7–10, whereas targeted biopsy only was positive in 21% vs 27% with systematic biopsies.

The message is clear.

An appropriate systematic biopsy targeted to the peripheral zone remains an essential component of prostate diagnosis even in the MRI era, as indeed it did before MRI was available. In the pre‐MRI days, about one‐third of patients that had negative TRUS biopsies had cancer on TP biopsies and a third of those thought suitable for AS on TRUS biopsy had more significant disease. I suspect in the modern era that figure remains unchanged for those with PI‐RADS 1, 2 or 3, particularly with a PSA density >0.15 ng/mL/mL. As urologists we have always been criticised for over diagnosing and over treating prostate cancer but I suspect that the more heinous crime is that of under treatment of significant disease, it is the very reason why I started doing TP biopsies, to resolve uncertainty. I consider that MRI, for all its benefits in the diagnostic algorithm, cannot yet resolve that uncertainty.

Probably the only patients that merit a target‐only biopsy are those with the high‐PSA, large‐volume disease, easily visible on MRI and usually palpable. Prostate biopsy can be avoided or at least deferred in the PI‐RADS 1–2 group with low PSA density; the rest should be offered a systematic biopsy along with a targeted biopsy. This may be less important in those proceeding to whole gland treatment or surgical extirpation but remains essential in those considering active surveillance, brachytherapy, or any one of the myriad of unproven focal treatments becoming available. The authors should be congratulated for bringing some certainty to uncertainty.

Rick Popert
Urology Centre, Guy’s Hospital, London, UK

 

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References
  • 1 Hansen NL, Barrett T, Kesch C et al. Multicentre evaluation of magnetic resonance imaging supported transperineal prostate biopsy in biopsy‐naïve men with suspicion of prostate cancer. BJU Int 2018; 122: 40–9

 

  • 2 Ahmed HU, El‐Shater Bosaily A, Brown LC et al. Diagnostic accuracy of multi‐parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017; 389: 815–22

 

 

  • 4 Kuru TH, Wadhwa K, Chang RT et al. Definitions of terms, processes and a minimum dataset for transperineal prostate biopsies: a standardization approach of the Ginsburg Study Group for Enhanced Prostate Diagnostics. BJU Int 2013; 112: 568–77

 

Editorial: β3‐adrenoceptor agonists inhibit calcium oscillations in bladder detrusor

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The β3‐adrenoceptor (β3‐AR) agonist mirabegron has now been used clinically for the treatment for overactive bladder (OAB) for 5 years, but it is still not clear either exactly where the β3‐ARs are located within the bladder wall or entirely how they work. β3‐AR agonists can reduce detrusor contractions after cholinergic stimulation, but the concentrations of mirabegron required for this effect suggest that this is unlikely to be the main therapeutic route, which may instead involve an indirect pathway or a combination of pathways.

In this issue of BJUI, Griffin et al. 1 show that β3‐AR agonists can reduce the rise in calcium and calcium waves observed after muscarinic receptor activation with carbachol in murine detrusor smooth muscle. They convincingly demonstrate that this effect is mediated by β3‐AR rather than by β1‐AR or β2‐AR and is not mediated by an effect on L‐type calcium channels or depletion of calcium stores; however, although they use BRL37344 and CL316,243, which have a higher potency in rodents than mirabegron, the concentrations of these agents needed are in the micromolar range, significantly higher than the values of ~100 nM measured in plasma following therapeutic dosing with mirabegron 2. It will be interesting to see when these experiments are repeated with, these effects on calcium are also seen in the therapeutic dosing range.

Currently, the only effects of mirabegron reported in the therapeutic dosing range are a reduction in detrusor contractions when elicited by field stimulation and a reduction in acetylcholine release from detrusor strips 3, 4. The similarly of the concentrations required for these two effects have led to the suggestion that the reduction in contractions may be mediated by the reduction in acetylcholine release; however, there is still disagreement as to whether β3‐ARs are located in the cholinergic nerve terminals or not, as different groups have obtained different patterns of β3‐adrenoreceptor staining, even when using the same antibodies 4–6. It is therefore still unclear if this involves a direct inhibition of acetylcholine release or not, although a predominantly neural source of acetylcholine is indicated by sensitivity to the sodium channel blocker, tetrodotoxin 3.

There is evidence that the reduction may be at least partially mediated via adenosine, such that increased adenosine formed post‐junctionally from breakdown of cAMP following β3‐AR stimulation, acts as a retrograde transmitter to inhibit acetylcholine release by acting at pre‐junctional A1 receptors 4. In support of this, Silva et al. 4 showed that A1 antagonists can reverse the increase in voiding seen with isoprenaline in an anaesthetized rat cystoscopy model.

The reduction in calcium rise reported by Griffin et al. 1 also suggests a post‐junctional site of action and the likely possibility that multiple pathways are activated following the binding of the β3‐AR agonists to post‐junctional receptors. A multiple pronged mechanism may be one of the reasons why mirabegron is successful at reducing the symptoms of OAB whilst sparing normal voiding.

The potency of β3‐AR agonists shows differences depending on the method of stimulation of the muscle, with higher potency seen for inhibition of contraction induced by field stimulation than carbachol stimulation, for example 1, 3, 4. This may reflect differences in the combinations of pathways and receptors activated, with carbachol stimulating only the muscarinic receptors themselves, but field stimulation activating more widely. It would therefore be interesting to see whether the potency of mirabegron to affect calcium release in human tissue is higher when field stimulation is used rather than carbachol, and hence help to evaluate if this pathway is involved in the mechanism of action of mirabegron in the clinic.

L. M. McLatchie
Department of Urology, Guy’s Hospital, London, UK

 

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References
  • 1 Griffin CS, Bradley E, Hollywood MA, McHale NG, Thornbury KD, Sergeant GP. B3‐adrenoceptor agonists inhibit carbachol‐evoked Ca2+ oscillations in murine detrussor myocytes. BJU Int 2018; 121: 959–70

 

  • 2 Krauwinkel W, van Dijk J, Schaddelee M et al. Pharmacokinetic properties of mirabegron, a beta(3)‐adrenoceptor agonist: results from two phase I, randomized, multiple‐dose studies in healthy young and elderly men and women. Clin Ther 2012; 34: 2144–60

 

  • 3 D’Agostino G, Condino AM, Calvi P. Involvement of beta(3)‐adrenoceptors in the inhibitory control of cholinergic activity in human bladder: direct evidence by H‐3‐acetylcholine release experiments in the isolated detrusor. Eur J Pharmacol 2015; 758: 115–22

 

  • 4 Silva I, Costa AF, Moreira S et al. Inhibition of cholinergic neurotransmission by beta(3)‐adrenoceptors depends on adenosine release and A(1)‐receptor activation in human and rat urinary. Am J Physiol‐Renal Physiol 2017; 313: F388–403

 

  • 5 Coelho A, Antunes‐Lopes T, Gillespie J, Cruz F. Beta‐3 adrenergic receptor is expressed in acetylcholine‐containing nerve fibers of the human urinary bladder: an immunohistochemical study. Neurourol Urodyn 2017; 36: 1972–80

 

  • 6 Limberg BJ, Andersson KE, Kullmann FA, Burmer G, de Groat WC, Rosenbaum JS. beta‐Adrenergic receptor subtype expression in myocyte and non‐myocyte cells in human female bladder. Cell Tissue Res 2010; 342: 295–306

 

Editorial: RARP and a Parachute

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Radical prostatectomy is probably the most scrutinized, debated and re‐invented procedure in the field of urology. This is with good reason. Dr Hugh Hampton Young gave the first formal account of a radical treatment for prostate cancer in 1905. It was a procedure performed perineally with the prime intention of total cancer extirpation. The oncological results were tremendous given the nascency of the procedure. Functional outcomes, however, were less so, with only ~25% of the patients achieving urinary continence and almost none achieving potency 1. Seminal studies undertaken by Drs Patrick C. Walsh and Pieter J. Donker in the 1980s led to the next major advance in technique: nerve‐sparing. It lead to dramatic improvements in sexual and urinary function preservation, with urinary continence achieved in upwards of 90% and potency in upwards of 60% of patients 2, 3. Nerve‐sparing retropubic radical prostatectomy was rapidly adopted by urologists across the world. No randomized trial was conducted as the operation ‘made sense’, and it would have been unethical to offer patients an alternative, inferior operation. Retropubic radical prostatectomy, however, remained a morbid operation that was difficult to master; 1 200 mL blood loss and 20% incontinence, 15% stricture and 60–90% erectile dysfunction rates were the norm. Robot‐assisted surgery changed much of this. This surgery was perfected and popularized by Dr Mani Menon and his team at the Henry Ford Hospital. Blood loss dropped to ~100 mL, and incontinence and stricture rates today are ~1–5% with potency rates between 70% and 80% 4.

In the systematic review by Ilic et al. 5 trials that compared open with minimally invasive radical prostatectomy were evaluated. The authors are commended for combing through vast quantities of data to arrive at the final sample of two clinical trials (one laparoscopic, one robot‐assisted). The authors found no data on oncological endpoints. With respect to functional outcomes, the data reported in their systematic review are essentially from the recent Yaxley trial. It is true that randomized controlled trials form the backbone of medical progress, but they must be interpreted with care. The Yaxley trial has been criticized for comparing surgeons of vastly varying surgical expertise (1 500‐case experience for open prostatectomies, 200‐case experience for robot‐assisted prostatectomies), having a small sample size (~150 patients in each arm) and having a limited follow‐up (3 months). In line with this, Dr Gordon Smith has eloquently argued about the judicious use of randomized trials in evidence‐based medicine in his classic paper on parachutes and gravitational challenge 6. It is our sincere belief that robot‐assisted radical prostatectomy is a procedure in the service of the patients, and we believe that anyone who has performed both an open radical prostatectomy and a robot‐assisted radical prostatectomy would agree. Operating deep in the pelvis and being able to visualize the anatomy up‐close with robotic assistance ‘makes sense’, much like the anatomical radical prostatectomy did in the 1980s 2, 3.

‘If it ain’t broke, don’t fix it’, the old saying goes. In case of radical prostatectomy, the converse has been true, for the most part. The procedure is still not perfect, and nuances need to be worked out. Nonetheless, over the last century, radicalprogress has been made in the surgery for prostate; the two issues that now remain to be solved are: improving potency and improving cost‐effectiveness. With the potential arrival of competing robotic systems and improvements in technology, the costs associated with robotic surgery may become less of an issue in the future. With regard to potency, focal therapies, whether surgical or otherwise, hold promise.

Akshay Sood, Firas Abdollah, and Mani Menon
Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA

 

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References
  • 1 Young HH. The cure of cancer of the prostate by radical perineal prostatectomy (prostato‐seminal Vesiculectomy): History, Literature and Statistics of Young’s Operation1. J Urol 1945; 53: 188–252

 

 

 

  • 4 Menon M, Dalela D, Jamil M et al. Functional recovery, oncologic outcomes and postoperative complications after robot‐assisted radical prostatectomy: an evidence‐based analysis comparing the Retzius sparing and standard approaches. J Urol 2018; 199: 1210–7

 

  • 5 Ilic D, Evans SM, Allan CA, Jung JH, Murphy D, Frydenberg M. Laparoscopic and robot‐assisted vs open radical prostatectomy for the treatment of localized prostate cancer: a Cochrane systematic review. BJU Int 2018; 121: 845–53

 

  • 6 Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003; 20: 1459–61

 

Editorial: The BAUS consensus documents on andrology

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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

 

Read the full article

 

References

 

 

  • 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

 

  • 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

 

  • 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

 

  • 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

 

  • 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

 

Editorial: Has tailored, tissue‐selective tumour ablation in men with prostate cancer come of age?

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There are two principal challenges that face the growing number of clinical investigators that are evaluating tissue‐preserving therapies in men with prostate cancer.

The first is that every man’s prostate is different. So different and so unique are the personal attributes of a man’s prostate that it would, just like the iris or fingerprint, qualify as a unique identifier. It is just a few practical considerations that prevent it from doing so. This is a challenge that the clinician treating the liver, kidney or brain does not face – as these organs do not exhibit the between patient variability that we see in the prostate.

The second relates to within‐patient (or within‐prostate) differences. The nature of the tissue being treated will depend on which part of the prostate is being treated – peripheral, transition or central zone. Each of these zones will, in turn, be dependent on the age of the prostate, the extent of BPH, exhibit calcification and or cysts, and may or may not be infiltrated by acute and/or chronic inflammation.

These two sets of variability present considerable challenges to investigators that seek to selectively ablate a given zone of tissue, given that the nature of the target volume will be different in every man treated and exist in a context that is specific to the that man.

Add to this challenge the variability in prostate cancer tumour attributes – volume, location, heterogeneity (genetic, radiological, and histological), degree of immune infiltrate, and the extent of microscopic extension, we begin to get the picture 1.

The paper in this issue of the BJUI by van den Bos et al. 2 describes a modern attempt to overcome these challenges and attempt and achieve personalised care to individuals, their prostate glands, and their cancer.

The team used irreversible electroporation (IRE) to create a selective ablation zone around a given tumour volume, embracing a margin of 5–10 mm. This method of ablation has certain attributes that lend itself to the task. It can be applied to any zone of the prostate. It is not limited by the size of the prostate. It can create lesions of variable volume. The treatment is quick and therefore not overly affected by prostate gland swelling. Because the treatment uses an interstitial approach (needle based) the effectors of the treatment move with the prostate during respiration and changes in rectal fullness. These attributes mitigate most of the challenges generated by between‐patient variability.

The authors describe the methods by which they manage tumour‐specific differences. These important but rather technical constraints (to the non‐expert) comprise: tumour‐volume dependent variable needle load; individualised tissue impedance‐based energy adjustment; minimising variability in needle–needle distance; application of a 10‐mm margin; and near term verification of tissue change with post‐treatment MRI.

These conditions seem to have paid off. Although every patient underwent a treatment that was bespoke to both their prostate and their prostate cancer, the results were most promising for this truly personalised sub‐specialty of uro‐oncology.

The treatment was safe. There were no high‐grade adverse events reported in the 63 men included in the analysis. The disease‐specific and generic quality of life was not compromised by the range of interventions administered except in relation to the sexual quality of life domain that was marginally affected – a median score of 66 prior to therapy diminished to 54 when measured again 6‐months after treatment.

The authors managed to get a high proportion of men to undergo verification biopsy after treatment. From this they derived two oncological outcomes. These comprised freedom from clinically significant prostate cancer (high‐volume exclusive Gleason pattern 3 and/or any Gleason pattern 4 or 5) within and on the edge of field on the one hand and out of field on the other.

In patients who were free of any technical failure in relation to the administration of IRE and had a 10‐mm margin incorporated, the results were very promising with most of the patients evaluated free of disease both within (97% [38/39 men]) and out of field (87% [34/39 men]).

Although the numbers of patients reported upon are relatively small, the overall results represent a welcome improvement on previously published phase I clinical trial data using IRE, probably as a result of better patient selection and optimisation of energy delivery 3. The results, however, are reassuringly similar to previous case‐series that used alternative energy sources but were predicated on an anatomical‐based approach to tissue preservation 4. The tumour‐based approach reported upon by van den Bos et al. 2 is much more challenging as it exposes any subtle deficiencies in the base‐line risk‐stratification and imposes exacting constraints on the reliability of the energy source in creating irreversible cell kill where cell kill is intended.

Mark Emberton
Division of Surgery and Interventional Science, UCL, London, UK

 

Read the full article
References
  • 1 Linch M, Goh G, Hiley C et al. Intratumoural evolutionary landscape of high‐risk prostate cancer: the PROGENY study of genomic and immune parameters. Ann Oncol2017; 28: 2472–80

 

  • 2 van den Bos W, Scheltema MJ, Siriwardana AR et al. Focal irreversible electroporation as primary treatment for localized prostate cancer. BJU Int 2018; 121: 716–24

 

  • 3 Valerio M, Dickinson L, Ali A et al. Nanoknife electroporation ablation trial: a prospective development study investigating focal irreversible electroporation for localized prostate cancer. J Urol 2017; 197: 647–54

 

  • 4 Ahmed HU, Hindley RG, Dickinson L et al. Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study. Lancet Oncol 2012; 13: 622–32

 

Editorial: Growth spurts of small renal masses correlate with pathology

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A rapid growth rate has long been known to be a harbinger of aggressive tumour pathology and clinical behaviour of small renal masses (SRMs) 1. However, this association has not been confirmed in prospective studies of patients with SRMs on active surveillance (AS) 2. Jewett et al. 2, in a multicentre prospective phase 2 clinical trial of 209 patients with a SRM, found that despite an average growth rate of 0.13 cm/year, pathology did not impact growth. Clinically, the growth rates of SRMs are most commonly variable, rather than the assumed steady slow growing rate that is often reported 3. Due to the discrepancies in the literature, the use of average growth rate for a SRM can be misleading. Finding a clinically effective tool to identify potentially aggressive cancers remains an important (and unmet) need for patients undergoing AS.

Jang et al. 4 provide insight into this need by evaluating the number of growth periods over time as a risk factor for renal masses under surveillance. They retrospectively reviewed renal masses that were initially <4 cm at diagnosis and were followed for a variable time period before undergoing surgical therapy. Two cohorts were grouped into ‘favourable‐’ (benign tumours, chromophobe RCC and low grade, pT1–2 RCC) and ‘unfavourable’‐risk tumours (high‐grade RCC of any stage and low‐grade, pT3–4 RCC), finding no difference in the amount of interval imaging between the two groups. There was a significant difference in the number of positive growth periods between the ‘favourable’ and ‘unfavourable’ pathology groups (P = 0.02) for the entire cohort (all pT stages) and a similar finding when examining only pT1a tumours (P < 0.05). Additionally, there was a positive association between increased number of positive growth periods and unfavourable pathology (odds ratio 0.15, 95% CI 0.02–0.29).

Active surveillance is considered an acceptable initial option for the management of all patients with SRMs, not just those with limited life expectancy or poor performance, as highlighted in the 2017 AUA guidelines 5. Optimal management of patients on AS would appear to require a good understanding of growth kinetics, pathological details, and risk–benefit analysis. The previously held dogma of using linear growth rate as a guide for the aggressiveness of a tumour has been challenged recently 6 and again put into question by this study 4. The Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) study showed that there was a higher growth rate in patients who had delayed intervention compared with those on AS, but there was no significant association (P = 0.15) 6. However, in the same study, the proportion of patients who had a positive growth rate (>0 cm/year) or a recorded ‘growth spurt’ were significantly more likely to have delayed intervention than AS patients (P < 0.01) 6.

Growth spurts, rather than growth rate over time, as a marker for malignancy, correlates best with clinical experience. Average growth rate can be artificially high with one large growth and multiple stable imaging intervals. One of the important elements of AS is regular interval imaging. The development of protocols that can be evaluated to determine the optimal type, interval, and duration of follow‐up imaging is a clinical need in this space. Whilst the cohort from Jang et al. 4 did not have regular intervals for imaging, there were an equal number of studies performed on patients with ‘favourable’ and ‘unfavourable’ pathology. Without clear protocols, using growth spurts rather than growth rate, also provides a simplified message for patients and will aid in counselling.

The identification of growth spurts as a risk factor for potentially aggressive features of SRMs under surveillance provides a useful tool when determining the need for intervention of a SRM. The uniform reporting of pathological data for patients under study is a strength, but several weaknesses limit the generalisability of the findings including the retrospective study design and inconsistent manner in which AS was performed. The clinical impact of growth spurts in the AS population warrants further investigation before definitive conclusions can be drawn.

Conrad M. Tobert* and Brian R. Lane†‡
*Department of Urology, University of Iowa, Iowa City, IA, USA, †Division of Urology, Spectrum Health Medi cal Group, Grand Rapids, MI, USA and ‡Michigan State University College of Human Medicine, Grand Rapids, MI, USA

 

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References
  • 1 Lee SW, Sung HH, Jeon HG et al. Size and volumetric growth kinetics of renal masses in patients with renal cell carcinoma. Urology 2016; 90: 119–24

 

 

  • 3 Chawla SN, Crispen PL, Hanlon AL, Greenberg RE, Chen DY, Uzzo RG. The natural history of observed enhancing renal masses: meta‐analysis and review of the world literature. J Urol 2006; 175: 425–31

 

  • 4 Jang A, Patel HD, Riffon M et al. Multiple growth periods predict unfavourable pathology in patients with small renal masses. BJU Int 2018; 121: 732–6

 

 

 

Editorial: PLND during RP for PCa: extending the template in the right patients without increasing complications

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It took long time and consistent evidence to endorse the staging role of extended pelvic lymph node dissection (PLND) in prostate cancer (PCa). The poor performance of both conventional and functional imaging in identifying preoperative nodal status has contributed to making extended PLND the most accurate nodal staging procedure in PCa 1.

Current available guidelines recommend a standard extended PLND template that includes external, internal iliac and obturator lymph nodes 2–4; however, where does the need for a more extended template originate? Observational data suggest that a standard extended PLND template intercepts ~75% of all anatomical landing sites 4. Extending the anatomical template by adding nearby nodal stations would further minimize the risk of missing positive lymph nodes; however, it has previously been shown that a more accurate staging (i.e. a more extended template) might come at the price of longer operating time and a higher risk of procedure‐related complications 1.

According to the study by Maderthaner et al. 5, in the current issue of BJUI, an experienced academic surgical team is able to further extend the PLND template (including common iliac and the fossa of Marcille lymph nodes) without significantly increasing the risk of complications. In their study, 17% and 7% of the included men with pN+ disease had positive common iliac and fossa of Marcille lymph nodes, respectively.

Before celebrating this super‐extended template as safe and effective, however, at least three points need to be considered. First, these results were obtained by a group of skilled surgeons with longstanding experience in anatomical pelvic nodal dissection. It should not be taken for granted that this template in the hands of other surgeons would result in no additional complications, especially during the learning curve.

Second, >80% of men submitted to the super‐extended template did not have positive nodes outside the standard extended template boundaries, indicating possible overtreatment in a substantial proportion of men. Notably, extended PLND in this study was offered apparently without upfront preoperative lymph node invasion risk stratification.

Third, as a consequence, patient selection has a role to play. In other words, is super‐extended PLND appropriate for every patient? The use of available risk stratification tools in everyday clinical practice allows a more accurate decision process; this is the case for the Briganti nomogram concerning the need to perform an extended PLND 6. Could a similar approach be used in the setting of a super‐extended template to identify the best candidates? Recently, Gandaglia et al. 7 analysed data from 471 men with high‐risk PCa treated with radical prostatectomy and a super‐extended PLND including common iliac and pre‐sacral nodes in order to identify those men who really require such a super‐extended PLND. Interestingly, although not specifically designed for this task, the Briganti nomogram was able to provide a patient selection strategy: only 5% of patients with a nomogram‐derived N+ risk of <30% had positive common iliac and pre‐sacral nodes, indicating that the super‐extended PLND template should perhaps be considered exclusively in men with an N+ risk ≥30%.

In conclusion, a critical assessment of super‐extended staging PLND template would be welcome, allowing selection of the proper candidates, and a proper balance between accurate staging and the risk of treatment‐related complications.

 

Eugenio Vent imiglia, *†Alberto Briganti,*† and Francesco Montorsi,*†
*University Vita-Salute San Raffaele, Milan, Italy and †Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy

 

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References

 

  • 1 Fossati N, Willemse P‐PM, Van den Broeck T et al. The benefits and harms of different extents of lymph node dissection during radical prostatectomy for prostate cancer: a systematic review. Eur Urol 2017; 72: 84–109

 

  • 2 Santis D, Henry A, Joniau S et al. Prostate Cancer EAU ESTRO SIOG Guidelines on 2017.

 

  • 3 Mattei A, Fuechsel FG, Bhatta Dhar N et al. The template of the primary lymphatic landing sites of the prostate should be revisited: results of a multimodality mapping study. Eur Urol 2008; 53: 118–25

 

 

  • 5 Maderthaner L, Furrer MA, Studer UE, Burkhard FC, Thalmann GN, Nguyen DP. More extended lymph node dissection template at radical prostatectomy detects metastases in the common iliac region and in the fossa of Marcille. BJU Int 2018; 121: 725–31

 

  • 6 Briganti A, Larcher A, Abdollah F et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. Eur Urol 2012; 61: 480–7

 

  • 7 Gandaglia G, Zaffuto E, Fossati N et al. Identifying the candidate for super extended staging pelvic lymph node dissection among patients with high‐risk prostate cancer. BJU Int 2018; 121: 421–7

 

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