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Importance of fundamental science as the cornerstone for translational research

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fwefwefResearch headlines that attract the most publicity are those that show success in benefitting patients, whether it is through new targeted drugs or new immunotherapies. Many funding bodies and charities have also changed their policy toward funding more translational research that has clear economic, clinical and patient benefit. We must remember, however, that the innovations for these transformative publications and translational research projects are imbedded in our fundamental understanding of the molecular and cellular biology of disease investigated at the basic science level. These investigations are the cornerstone of translational research.

 

The BJUI has continued its tradition of publishing fundamental research with translational insight, and this is exemplified in this month’s article by Liu et al. [1], which undertakes to explain the mechanistic and functional role of EZH2 in RCC. In this study the authors manipulate the expression of EZH2 by silencing it using short-hairpin EZH2, which targets the RNA. They also use a small molecule inhibitor of methyltransferase which has been shown to deplete the expression of EZH2. Both these approaches inhibit EZH2 expression, which was associated with reduced migration and invasion of the cancer cells, as assessed in in vitro models, as well as with slowing tumour growth and prolonging survival in an in vivo nude mouse model. These changes were mechanistically explained by a change in the mesenchymal epithelial transition phenotype of the tumour cells. The authors then went on to show that EZH2 is associated with E-cadherin suppression and poor survival in patients with RCC, demonstrating the translational importance of these findings.

 

This impo rtant fundamental and translational paper adds to the growing body of evidence that EZH2, which is a histone methyltransferase and regulator of gene expression, plays a key role in the development of a range of cancers including prostate, breast, lymphoma and colon [2]. 

 

The Translational Science section of the BJUI is looking for relevant and citable articles similar to the paper by Liu et al., which are imbedded in fundamental science and bring the concept into clinical investigation, either through its validation in clinical material or manipulation in clinically relevant in vivo model systems, and represent a clear translational step.

 

To facilitate our readers’ understanding and to familiarize them with often complicated and complex fundamental scientific concepts, in 2013 the BJUI introduced the ‘Science Made Simple’ review-type article section, in which various scientific concepts are explained so as to assist interactions between scientists and clinicians as they translate their ideas and findings into clinical utility.

 

References

 

1 Liu L, Xu Z, Zhong L et al. Enhancer of zeste homolog 2 (EZH2) promotes tumour cell migration and invasion via epigenetic repression of E-cadherin in renal cell carcinoma. BJU Int 2016; 117: 351–62

 

2 Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 2008; 647: 21–9

 

R. William Watson, BJUI Consulting Editor, Translational Science

 

UCD School of Medicine and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland

 

Editorial: Minimally invasive surgery or nephron preservation for small renal tumours?

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In the present issue of BJUI, there is an important study by Hadjipavlou et al. [1], summarizing radical (RN) and partial nephrectomy (PN) practice in the UK in 2012. Specifically, the authors reported the outcomes of ~1 800 patients undergoing either RN or PN for clinical T1 renal masses. Approximately 55% of the patients with cT1a tumours underwent PN, of whom 44% underwent minimally invasive PN. Conversely, in the cohort of patients with cT1b tumours, only ~19% received PN, of whom 33% underwent a minimally invasive procedure. Notably, whereas operating time, transfusion rate and the risk of intraoperative complications was similar for RN and PN, postoperative complications were approximately three times more common in patients who underwent PN, after adjusting for covariates. A sub-analysis comparing robot-assisted and laparoscopic PN failed to show any difference in peri-operative outcomes [1].

The study is important for several reasons. Firstly, it shows a fairly high adoption of PN for cT1a tumours. Although PN is recommended as the standard treatment for small renal masses [2], population-based studies have shown that there has been limited adoption of PN outside referral centres [3, 4], especially in the USA. Conversely, the present data from UK show more encouraging results, maximizing the benefit of nephron preservation; however, although PN might be more challenging in cT1b tumours and the available evidence in favour of PN in such a setting is less compelling, the adoption of PN was lower in such tumours. Efforts should be made to popularize such an approach whenever feasible.

Secondly, the study showed that a minority of the PN procedures were performed with a minimally invasive approach. Although we can agree that nephron preservation is more important than a minimally invasive approach in the long term for most patients, an increasing number of publications and growing clinical experience suggest that laparoscopic, and, above all, robot-assisted PN could represent the ideal solution. Although the number of minimally invasive PNs should increase with increased diffusion of DaVinci platforms, major efforts should be made to expand the number of patients in whom the morbidity of the traditional open PN approach can be avoided. In this context, regionalization of care for PN, as for other major oncological procedures, could be an excellent solution.

Thirdly, the significant rise in the risk of postoperative complications observed after PN could allow better selection of patients to undergo either PN or RN. For example, where surgery is indicated, frail comorbid patients, in whom the risk of perioperative complications should be minimized and who would benefit less from nephron preservation, could be better treated by laparoscopic RN or, probably, robot-assisted PN as performed by very experienced surgeons.

Finally, the study failed to show major differences between laparoscopic and robot-assisted PN. Although this finding is in line with data from systematic reviews of the literature [5], the present data from a large cohort of surgeons are more solid. The lack of data on patient selection, previous laparoscopic and robot-assisted surgery, annual surgical volume and tumour characteristics according to nephrometry scores, however, does not allow us to draw definitive conclusions on the issue. In our opinion, robot-assisted surgery might offer major significant benefits during PN in terms of quicker and more accurate tumour dissection, improved renorrhaphy with consequent shorter ischaemia time, lower risk of complications and a shorter learning curve as compared with pure laparoscopic PN.

Unfortunately, no analysis stratified by centre and/or surgeon volume was provided in the present paper. As with other major surgical procedures, some studies suggest that case volume may have a major impact on outcome [6]. It would have been interesting to see such a relationship analysed in the present cohort involving almost 300 surgeons from more than 100 institutions. Despite the large number of cases analysed, however, it is likely that these data depict the outcomes of RN and PN in a low-volume setting (an average of approximately six cases per year in total).

Finally, alternative approaches such as percutaneous or laparoscopic cryoablation are gaining popularity for the treatment of small renal masses in selected cases [2]. Although long-term oncological outcomes of such procedures are lacking, the available evidence suggests good short-term efficacy and safety for cryoablation in patients with small renal masses. The presence of data on such treatments to compare with the surgery results reported in the present cohort would also have been of interest.

Read the full article
Giacomo Novara, and Alexander Mottrie†‡

 

Department of Surgery, Oncology, and Gastroenterology, Urology Clinic, University of Padua, Padua, Italy, †Department of Urology, Onze-Lieve-Vrouw Hospital and ‡OLV Vattikuti Robotic Surgery Institute, Aalst, Belgium

 

References

 

1 Hadjipavlou M, Khan F, Fowler S, Joyce A, Keeley FX, Sriprasad S on behalf of BAUS Sections of Endourology & Oncology. Partial versus radical nephrectomy for T1 renal tumours: an analysis from the british association of urological surgeons nephrectomy audit. BJU Int 2015; 117:62–71
2 Ljungberg B, Bensalah K, Canfield S et al. EAU Guidelines on Renal Cell Carcinoma: 2014 Update. Eur Urol 2015; 67: 913–24

 

3 Sun M, Becker A, Tian Z et al. Management of localized kidney cancer: calculating cancer-specific mortality and competing risks of death for surgery and nonsurgical management. Eur Urol 2014; 65: 235–41

 

4 Fedeli U, Novara G, Alba N, Ficarra V, Artibani W, Spolaore P. Trends from 1999 to 2007 in the surgical treatments of kidney cancer in Europe: data from the Veneto Region, Italy. BJU Int 2010; 105: 1255–9

 

5 Aboumarzouk OM, Stein RJ, Eyraud R et al. Robotic versus laparoscopic partial nephrectomy: a systematic review and meta-analysis. Eur Urol 2012; 62: 1023–33

 

6 Peyronnet B, Couapel JP, Patard JJ, Bensalah K. Relationship between surgical volume and outcomes in nephron-sparing surgery. Curr Opin Urol 2014; 24: 453–8

 

Editorial: Doubling our precision of risk stratification in early prostate cancer? Too good to be true?

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It is difficult to over-estimate the enormity of the revolution involved in transitioning away from an organ-based system of care in prostate cancer (prostatectomy or radiotherapy to prostate cancer of any grade, number, location or volume) to one in which the target condition is defined and verified, and then subsequently treated with a margin. Since Hugh Hampton-Young undertook the first radical prostatectomy more than 100 years ago, an organ-based system of care has been the only plausible strategy for men with early-stage prostate cancer. This is because our risk stratification methods could certainly tell us who had prostate cancer when it was indeed identified, but they could not tell us with any degree of precision how much cancer was present (number of foci and volume of cancer), what grade it was and where within the prostate the cancer resided. Surgery or radiotherapy to the whole gland, it was thought, was a reasonable mitigation (at the cost of over-treatment in a significant proportion of men) to the systematic under-estimation of risk to the patient. The degree to which our attempts at risk stratification failed our patients was emphasized in a recent UK report that showed an increase of >50% in histological grade (the most important determinant of risk) at radical prostatectomy compared with the risk the patient was told at the time of diagnosis[1]. ‘Upgrading’ is an inverse measure of the quality of our risk stratification.

With this background it should be of little surprise that there remains considerable skepticism about our ability to localize disease within the prostate, define its volume with some degree of precision and identify the worst histological grade within the tumour most of the time. These conditions, which most patients, quite reasonably, might expect of a modern cancer diagnostic programme, need to be fulfilled if we are to move away from an organ-based strategy for all towards a system of care that risk stratifies with precision, treats only those who are likely to benefit and tries to preserve tissue and function when we are able to do so.

The technologies and developments that have permitted a reduction in risk stratification error from 50 to ~5% are the subject of a paper by Tran et al. [2] in the present issue of BJUI. This group from Australia exploited a cohort of men that underwent a series of tests that culminated in a radical prostatectomy. These comprised: high-quality multiparametric MRI at a range of magnet strengths; formal scoring of the MRI using an ordinal scale of risk; a subsequent 5-mm transperineal template-guided biopsy modified from Winston Barzell’s original account; and additional sampling of prostate sectors that corresponded to a high likelihood of clinically significant cancer based on the MRI reading, a process otherwise known as ‘targeting’. The outputs of these tests were compared with the presence or absence of clinically significant prostate cancer in the 100 prostate lobes evaluated from the 50 eligible men who underwent surgery. The authors’ a priori threshold for declaring clinically significant disease in the tests was the presence or a PIRADS 4–5 MRI lesion (with or without concordant pathology) and/or the presence of exclusive Gleason pattern 3 amounting to ≥4 mm maximum cancer core length or the presence of any Gleason pattern 4 or 5 [3]. At radical prostatectomy slightly different criteria were employed. Clinically significant prostate cancer constituted an exclusive Gleason pattern 3 lesion provided it was ≥1.3 mL. The presence of patterns 4 and 5 within the lesion triggered ‘significance’, as did evidence of capsular invasion or extraprostatic extension.

Although it was a small study, the men included were exposed to the best diagnostic profile that it was possible to have and were subjected to a reference test which most of us would trust. What did they find? Just how well did a modern diagnostic panel rule in or rule out prostate cancer that exceeded a minimum threshold of 4 mm of Gleason pattern 3? Within the hundred lobes that were evaluated, 21 clinically significant cancers were identified in the diagnostic process. At radical prostatectomy two of these were at the midline and therefore attributed, within the rules, to both sides of the gland. In one of these cases there was a 5-mm diameter (0.1 mL) Gleason 3+4 lesion with 10% Gleason pattern 4 that was overlooked by the combined diagnostic process. A lesion of this volume can evade a well-applied sampling strategy based on a 5-mm sampling frame, especially if the lesion is non-spherical. The relatively low component of pattern 4 combined with the relatively low volume means that MRI would also have a hard time detecting it. Under the conditions described in the present paper, the authors concluded that combined MRI and intensive biopsy conferred a sensitivity of 97% and a negative predictive value of 91% for a fairly conservative definition of clinically significant disease. This level of accuracy, which is nearly twice as good as that of which we were previously capable, will result in major benefits for patients in terms of communicating risk with an order of precision that was hitherto not possible. This should translate to more appropriate treatment allocation, both avoiding unnecessary treatment and having treatment when it is likely to be beneficial. It should also result in a significant proportion of patients being offered the option of a tissue-preserving therapy when this is an option [4]. Most importantly, this new precision opens up an opportunity for greater involvement of the patient in the process of informed decision-making [5]. Something that was not really possible in the face of yesterday’s diagnostic uncertainty.

Read the full article
Mark Emberton
Division of Surgery and Interventional Science, University College London, London, UK

 

References

 

1 Shaw GL, Thomas BC, Dawson SN et al. Identification of pathologically insignificant prostate cancer is not accurate in unscreened men. Br J Cancer 2014; 110: 2405–11

 

2 Tran M, Thompson J, Bohm M et al. Combination of multiparametric magnetic resonance imaging and transperineal template-guided mapping biopsy of the prostate to identify candidates for hemi-ablative focal therapy. BJU Int 2015; 117: 48–54

 

3 Ahmed HU, Hu Y, Carter T et al. Characterizing clinically significant prostate cancer using template prostate mapping biopsy. J Urol 2011; 186: 458–64

 

4 Ahmed HU, Dickinson L, Charman S et al. Focal ablation targeted to the index lesion in multifocal localised prostate cancer: a Prospective Development Study. Eur Urol 2015; 25682339.

 

5 Agoritsas T, Heen AF, Brandt L et al. Decision aids that really promote shared decision making: the pace quickens. BMJ 2015; 350: g7624

 

Editorial: SRP – a few good men

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The current management of recurrent disease after definitive treatment of a localized prostate cancer with radiation therapy (RT) or cryotherapy remains debatable. A substantial portion of patients treated with RT (20–50%) will experience biochemical recurrence. Androgen deprivation therapy has been the mainstay of therapy for this patient population, especially if there was concern about metastatic spread. As the initial experience with salvage radical prostatectomy (SRP) was highly morbid with poor functional outcomes, this did not gain strong acceptance as a recommended treatment method; however, with improved functional outcomes and fewer complications reported in recent series, SRP has once again become a viable alternative in select cases.

The rarity of the procedure makes it difficult to generate large-volume prospective studies on SRP, requiring us to depend on retrospective series. Chade et al. [1] published the largest series of patients undergoing SRP through a multicentre collaborative effort, and were able to identify 404 patients treated between 1985 and 2009; other large series were limited to 50–200 patients. In their systematic review of studies published between 1980 and 2011, Chade et al. [2] reported 5- and 10-year biochemical recurrence-free survival rates of 47–82% and 28–53%, respectively. This broad range of outcomes hints at the variable response of patients to SRP. Identifying the subset of patients who are most likely to benefit from SRP will therefore help tailor therapies for patients who have failed RT, cryotherapy or high-intensity focused ultrasonography.

As described by Mandel et al. [3], there are three sets of guidelines currently addressing patient selection for SRP. The NICE guidelines are the least specific, essentially mentioning SRP as an option for management without specifying specific criteria [4]. The European Association of Urology (EAU) and National Comprehensive Cancer Network guidelines are more specific, and help narrow the patient population to men with clinically localized recurrence (cT1–2), life expectancy of at least 10 years and a preoperative PSA level <10 ng/mL[5, 6]. The EAU guidelines are even more restrictive, limiting selection to men with Gleason ≤7 on prostate biopsy, although they do not specify whether that is before or after RT [5].

In their retrospective analysis of 55 patients treated with SRP between 2007 and 2012, Mandel et al. [3] compare the oncological outcomes of patients treated according to the EAU criteria (n = 32) and those treated without meeting the EAU criteria (n = 23). The 5-year biochemical recurrence-free survival rate was 48.7%, consistent with previous studies, as was the 5-year cancer-specific survival rate of 89%. Importantly, however, after stratification based on EAU criteria, the 5-year biochemical recurrence-free survival rates were drastically different: 73.9% in patients who met the EAU criteria and 11.6% in patients who did not. Patients who did not meet the EAU criteria were more likely to have Gleason score ≥8 (P = 0.08) tumours and pN1 (nodal metastatic) disease at the time of SRP (P = 0.04), which shows the ability of these criteria to select patients with localized disease recurrence. They also established that overall functional outcomes were acceptable after this procedure, with a postoperative urinary continence rate of 74%; none of the patients recovered potency, however, which is not surprising considering the high rate of preoperative erectile dysfunction and the non-nerve-sparing nature of the procedure [3].

In terms of complications, 12.7% of the patients had Clavien ≥ III complications requiring additional intervention. When complications do occur, they can be severe: three of the patients (5.5%) developed rectovesical fistulae and failed conservative management, progressing to fistula repair with omental flap, and two of the patients required permanent urinary diversion. There was no specification, however, regarding which subset of patients experienced these complications. The complication rate was acceptable, and consistent with recent reports of decreased complication rates with SRP [3].

While the study has its limitations as a retrospective review of a relatively small cohort, it is the first to analyse outcomes based on published guidelines criteria, and thereby helps to validate the subset of patients that will benefit from surgical intervention. Based on their findings, appropriately selected patients, those with evidence of truly localized recurrent disease after RT or high-intensity focused ultrasonography, can have significant oncological benefit with acceptable functional outcomes and without significant morbidity. The goal is not to perform SRP indiscriminately, rather to wait for a few good men.

Read the full article
Thenappan Chandrasekar , and Christopher P. Evans
Department of Urology, University of California, Sacramento, CA, USA

 

References

 

1 Chade DC, Shariat SF, Cronin AM et al. Salvage radical prostatectomy for radiation-recurrent prostate cancer: a multi-institutional collaboration. Eur Urol 2011; 60: 205–10

 

2 Chade DC, Eastham J, Graefen M et al. Cancer control and functional outcomes of salvage radical prostatectomy for radiation-recurrent prostate cancer: a systematic review of the literature. Eur Urol 2012; 61: 961–71

 

3 MandelP, Steuber T, Ahyai S et al. Salvage radical prostatectomy for recurrent prostate cancer: verification of European Association of Urology guideline criteria. BJU Int 2015; 117: 55–61

 

4 Prostate cancer: diagnosis and treatment. NICE clinical guideline 175: Hearing before the National Institute for Health and Care Excellence (January 2014).

 

5 Heidenreich A, Bastian PJ, Bellmunt J et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014; 65: 467–79

 

6 Mohler JL, Kantoff PW, Armstrong AJ et al. Prostate cancer, version 2.2014. JNCCN 2014; 12: 686–718.

 

 

Editorial: Frozen section during partial nephrectomy: an unreliable test that changes nothing

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A core goal of oncological surgery is complete removal of the neoplastic mass. Conventional wisdom with regards to partial nephrectomy (PN) is that a minimal tumour-free margin is sufficient to achieve adequate cancer clearance, minimises loss of normal renal parenchyma and avoids local tumour recurrence [1]. Does this maximisation of nephron preservation and reported positive surgical margin rates after PN ranging from 0% to 7% [2] make intraoperative frozen sections a prerequisite? The results of the paper by Gordetsky et al. [3] in this month’s issue of BJU International suggest that frozen section results from the tumour bed of patients undergoing a PN may be both unreliable and result in subsequent inconsistent management decisions by the operating surgeon.

A recent survey of 197 American urologists revealed that up to 69% (‘always’ or ‘sometimes’) undertake a frozen section during PN [4]. In view of such high penetrance of this test with a resulting high workload for the uro-pathologist, it is critical that the test is reliable and the results are positively and consistently acted upon by the operating urologist.

Gordetsky et al. [3] present interesting data from an expert uro-pathology service, on a consecutive cohort of patients undergoing PN. Reassuringly the pathologist’s skill at making the correct call on the frozen-section specimen was extremely high with a 98% concordance between the actual frozen section and the subsequently created formalin-fixed paraffin-embedded tissue block from the very same piece of tissue. However, despite this high level of accuracy, the sensitivity of the tumour bed frozen section in predicting the actual presence of a positive surgical margin in the resected tumour was only 30% (in other words, of all the patients who actually had positive surgical margins only 30% were identified by frozen section analysis of the tumour bed). As tumour bed biopsies only represent a small fraction of the resection margin this is perhaps unsurprising.

The second issue addressed by Gordetsky et al. [3] is the matter of an inconsistent response of the surgeon to a positive frozen section. In five cases no action was taken, in three cases the tumour bed was re-resected and in a single case a subsequent radical nephrectomy was performed. These results can be compared with those of Sidana et al. [4], where there was a similar inconsistency of management strategies. This inconsistency can be explained by the controversy surrounding the oncological importance of a positive surgical. There is evidence that a positive margin may be associated with an increased risk of recurrence; however, it does not appear to infer a poorer long-term oncological outcome for the patient [5]. It is intriguing that at the time of a completion nephrectomy following a positive surgical margin, residual malignant cells were not found in any of the patients who underwent a re-resection or nephrectomy in this and other studies [3, 6]. It should, however, be noted that published series of conservative management of positive margins are few with only medium-term follow-up. As we know that the natural history of the small renal mass is one of slow growth, any microscopic residual disease may take several years to become clinically apparent and these studies are therefore underpowered.

We think there are several practical arguments against routine use of frozen section. Whilst waiting for the frozen section result some surgeons have been known to keep the kidney ischaemic (16%) resulting in consequent loss of renal function [4]. To avoid this many urologists will undertake the renorrhaphy whilst waiting for the result, a practice becoming increasingly more common with the move towards laparoscopic and robot-assisted PN, where tumour extraction is usually the final step. This practice inevitably influences the subsequent enthusiasm of the surgeon to go back and perform a re-resection and re-do renorrhaphy. It is known that the surgeons’ gross interpretation of the surgical margin approaches the sensitivity of the permanent section and has low false-negative rates, apparently superior to tumour bed frozen section [7]. Routine cautery of the resection bed may also provide an additional safety margin and render any microscopic positive margin clinically insignificant.

It is our opinion that this work by Gordetsky et al. [3] adds credence to the stand that there is no need for a routine tumour bed frozen section in PN and that careful examination of the resected tumour with selected frozen section analysis of suspicious areas is a safe strategy, saves time and provides adequate information for intraoperative decision making.

Read the full article
Grant D. Stewart, *† and Grenville Oades, ‡

 

*Clinical Senior Lecturer, Edinburgh Urological Cancer Group, University of Edinburgh,†Honorary Consultant in Urological Surgery, Department of Urology, NHS Lothian, Edinburgh, and ‡Consultant Urological Surgeon, Department of Urology, NHS Greater Glasgow and Clyde, Glasgow, UK

 

References

 

1 Sutherland SE, Resnick MI, Maclennan GT, Goldman HB. Does the size of the surgical margin in partial nephrectomy for renal cell cancer really matter? J Urol 2002; 167: 61–4

 

2 Marszalek M, Carini M , Chlosta P et al. Positive surgical margins after nephron-sparing surgery. Eur Urol 2012; 61: 757–63

 

3 Gordetsky J, Gorin M, Canner J et al. Frozen section during partial nephrectomy: does it predict positive margins? BJU Int 2015; 116: 868–72

 

4 Sidana A, Donovan JF, Gaitonde K. Surgeons’ preferences and practice patterns regarding intraoperative frozen section during partial nephrectomy. Urol Oncol 2014; 32: 864–8

 

5 Bensalah K, Pantuck AJ, Rioux-Leclercq N et al. Positive surgical margin appears to have negligible impact on survival of renal cell carcinomas treated by nephron-sparing surgery. Eur Urol 2010; 57: 466–71

 

6 Raz O, Mendlovic S, Shilo Y et al. Positive surgical margins with renal cell carcinoma have a limited influence on long-term oncological outcomes of nephron sparing surgery. Urology 2010; 75: 277–80

 

7 Timsit MO, Bazin JP, Thiounn N et al. Prospective study of safety margins in partial nephrectomy: intraoperative assessment and contribution of frozen section analysis. Urology 2006; 67: 923–6

 

Editorial: How Can We Improve Surgical Outcomes?

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How to improve surgical outcomes for all is a long-standing health policy/services research question. There are generally two perspectives to the debate. One reasonable approach would be to regionalise, or centralise, the performance of a procedure, in this case radical prostatectomy (RP), to ‘specialised’ surgeons or institutions. Data from the USA show that regionalisation of prostate cancer care initially occurred in the late 1990s and even further more recently after the introduction of robotic surgery. The improvement of surgical outcomes after RP in the USA has been partially attributed to such phenomena [1]. Conversely, it may be impossible to centralise a common procedure, such as RP, to a small number of hospitals, concerns that were raised in an review on improving surgical care by Hollenbeck et al. [2]. Alternatively, large state or national quality improvement initiatives, with incremental advances in process-of-care adoption/compliance, may improve the care of prostate cancer for all. This collaborative and inclusive approach is, for example, employed by the Michigan Urological Surgery Improvement Collaborative (MUSIC). However, one has to factor in that this type of approach demands funding, collaboration and patience. Regardless, there is little doubt that both approaches, enforced by health policy or not, are needed in large and diverse countries such as the USA.

In this issue of BJU International, Novara et al. [3] examine the trends in RP utilisation within Italy. The authors have to be commended for their efforts to raise awareness of the need for concerted cancer registries and centralised treatments. They corroborated previous studies on the relationship between hospital volume and perioperative outcomes, such as in-hospital mortality, complications and length of stay [4]. They also found an improvement in perioperative outcomes over time. Although their study design may only allow us to speculate on the reasons for these improvements, they are likely to be the result of many factors, such as improved surgical technique, improved perioperative medical/anaesthetic care and regionalisation of care. For surgical technique, the only significant advance over the past decade was the introduction of robot-assisted RP. Given the late adoption of robotic surgery in Italy and the controversy about its benefits, this is unlikely to be the major driver behind the recorded trends. On perioperative medical/anaesthetic care, the past decade has seen major advances and standardisation of thromboembolic prevention, perioperative care of patients with pre-existing heart conditions and significant comorbidities. Finally, centralisation of care may have played an important role in the decreasing rates of adverse outcomes after RP. Although the authors specify that there was no policy-driven regionalisation of RP care in Italy (relative to the UK, for example), the increase in average hospital volume should translate into better outcomes, as discussed above [4]. Further regionalisation should be expected in Italy with the adoption of robotic surgery, as only a few centres have the means and logistics to support a da Vinci system [5].

Read the full article
Julian Hanske *†, Christian P. Meyer†‡ and Quoc-Dien Trinh†

 

*Department of Urology, Marien Hospital, Ruhr-University Bochum, Herne, Germany, †Division of Urologic Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA and ‡Department of Urology, University Medical Centre Hamburg–Eppendorf, Hamburg, Germany

 

References

 

1 Kowalczyk KJ, Levy JM, Caplan CF et al. Temporal national trends of minimally invasive and retropubic radical prostatectomy outcomes from 2003 to 2007: results from the 100% Medicare sample. Eur Urol 2012; 61: 803–9

 

2 Hollenbeck BK, Miller DC, Wei JT, Montie JE. Regionalization of care:centralizing complex surgical procedures. Nat Clin Pract Urol 2005; 2: 461

 

3 Novara G, Ficarra V, Zattoni F, Fedeli U. Recourse to radical prostatectomy and associated short-term outcomes in Italy: a country- wide study over the last decade. BJU Int 2015; 116: 862–7

 

4 Trinh QD, Bjartell A, Freedland SJ et al. A systematic review of the volume–outcome relationship for radical prostatectomy. Eur Urol 2013; 64: 786–98

 

5 Makarov DV, Yu JB, Desai RA, Penson DF, Gross CP. The association between diffusion of the surgical robot and radical prostatectomy rates. Med Care 2011; 49: 333–9

 

The British Association of Urological Surgeons nephrectomy audit for T1 renal tumours

/2 Comments/by
It is hard to believe that 3 years have elapsed since my new team took over publishing the BJUI, aiming to make it ‘the most read surgical journal on the web’. Many of our readers believe that we have achieved that and a number of web statistics indicate that we are not far away. Complacency is not in our DNA and this year you will notice a number of subtle changes to www.bjui.org to make it even more attractive and user friendly. Of course we rely heavily on feedback from o ur authors and readers. The January 2016 issue includes our ‘Thank you to reviewers’ online, listing all 785 people who have reviewed for us in 2015. We just cannot achieve our high standards without you. Each reviewer is entitled to Continuing Professional Development (CPD) points as a recompense for the time they spend helping us select only the very best papers. 
Last year, we published a fantastic selection of ‘Articles of the Month’. If you missed any, you can find them collected together in our free online virtual issue (https://bit.ly/ZrWA6q). The end of 2015 was dominated by falling PSA testing and prostate cancer detection rates, as highlighted in David Penson’s editorial in JAMA [1]. In the UK and many other parts of the world we have already been through this. I remember during my training years that the majority of men presented with locally advanced or metastatic disease. And while we look towards ‘smart’ screening of high-risk groups, particularly those with a relevant family history of prostate and breast cancer, I urge you again to look at the summary table of our ‘Guideline of Guidelines’ by Loeb [2] on this thorny subject.
The BAUS has taken the lead on public reporting of surgical outcomes. The BJUI is proud to publish our nephrectomy audit [3], which has >6000 patients. Radical nephrectomy (RN) was performed mostly for T1b and partial nephrectomy (PN) for T1a tumours. Over 90% of RNs were minimally invasive – an established standard of care. Only 43% of PNs were minimally invasive of which one-third were robotic, with no obvious difference between the robotic and laparoscopic arms. As expected, the complication rates of PN were higher than RN. All of us as surgeons can learn a lot from large national datasets such as this and, more importantly, strive to improve continuously. I hope you enjoy reading this important paper and look forward to interacting with many of you in 2016.

 

References

1 Penson DF. The pendulum of prostate cancer screening. JAMA 2015; 314: 2031–3

 

2 Loeb S. Guideline of guidelines: prostate cancer screening. BJU Int 2014; 114: 323–5

 

3 Hadjipavlou M, Khan F, Fowler S et al. Partial vs radical nephrectomy for T1 renal tumours: an analysis from the British Association of Urological Surgeons Nephrectomy Audit. BJU Int 2015; 117: 62–71

 

Prokar Dasgupta, Editor-in-Chief, BJUI

 

King’s College London, Guy’s Hospital, London, UK

 

Editorial: Is the modified sliding technique the way forward in Peyronie’s surgery?

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The old goal of prosthetic surgery, which aimed to guarantee a hard and straight penis good enough for penetrative intercourse, is likely to have now become obsolete. Various authors have reported that patients with Peyronie’s disease (PD) and severe corporal fibrosis who undergo penile prosthesis implantation tend to report the lowest satisfaction rates, mainly because of significant penile length loss [1, 2]. In particular, according to Kueronya et al. [3], ~80% of patients affected by PD perceive a degree of penile shortening before surgery, and any further loss of length attributable to the surgical correction leads to bother among all the affected patients. All attempts at penile length restoration during prosthetic surgery should therefore be welcomed in order to achieve higher patient satisfaction.

Initial attempts at penile length restoration involved a full disassembly of the penis and the use of a circumferential graft [4]. Then, in 2012, Rolle et al. [5] described the sliding technique, a modification of the circumferential graft that consists of a double dorsal-ventral patch and should therefore provide more stability to the corpora cavernosa than a circumferential graft.

The present series by Egydio et al. [6] describes a modified sliding technique without grafting the defect of the tunica albuginea. This reduces the operating time and theoretically infection rates should therefore be reduced.

Although leaving a defect in the tunica albuginea should, in theory, lead to a haematoma formation and potentially infection of the device, in the present series, no penile prosthesis infections were reported.

Although we believe that cutting corners in surgery is not the way forward, the authors of the present paper should be congratulated because the postoperative results in their series are very encouraging. In fact, the mean penile length gain in their series was 3.1 cm, with no reported infections requiring the explantation of the penile prosthesis and with an average increase in International Index of Erectile Function score of 36.

Certainly, if the results of the present series can be confirmed in the future, this technique will revolutionize the concept that any tunical defect >1 cm in size needs to be grafted to prevent aneurysmal dilatation of the cylinders of an inflatable penile prosthesis [7], as none of the inflatable cylinders in the series developed aneurysms.

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Giulio Garaffa, and David J. Ralph
St Peter’s Andrology and the Institute of Urology, University College London Hospitals, London, UK

 

References

 

1 Akin-Olugbade O, Parker M, Guhring P, Mulhall J. Determinants of patients satisfaction following penile prosthesis surgery. J Sex Med 2006; 3: 743–8

 

2 Zacharakis E, Garaffa G, Raheem AA, Christopher AN, Muneer A, Ralph DJ. Penile prosthesis insertion in patients with refractory ischemic priapism: early versus delayed insertion. BJU Int 2014; 114: 576–81

 

3 Kueronya V, Miernik A, Stupar S et al. International multicenter psychometric evaluation of patient reported outcome data for the treatment of Peyronie’s disease. BJU Int 2015; 115: 822–8

 

4 Sansalone S , Garaffa G, Djinovic R et al. Simultaneous penile lengthening and penile prosthesis implantation in patients with Peyronie’s Disease, refractory erectile dysfunction and severe penile shortening. J Sex Med 2012; 9: 316–21

 

5 Rolle L, Ceruti C, Timpano M et al. A new, innovative, lengthening surgical procedure for Peyronie’s Disease by penile prosthesis implantation with double dorsal-ventral patch: the sliding technique. J Sex Med 2012; 9: 2389–95

 

6 Egydio P, Kuehhas F. Penile lengthening and widening without grafting according to a modified sliding technique. BJU Int 2015; 116: 965–72

 

7 Ralph D, Gonzalez-Cadavid N, Mirone V et al. The management of Peyronie’s Disease: 2010 guidelines. J Sex Med 2010; 7: 2359–74

 

 

Editorial: Are men who are biopsied without prior prostate magnetic resonance imaging getting substandard care?

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The article by Borkowetz et al. [1], published in this issue, by a multi-disciplinary group from Dresden who have been offering MRI to their patients since 2012, would suggest so. In their hands, an image-guided biopsy resulted in 29 patients with Gleason scores of 7 or 8 being identified, who had been overlooked by an optimised 12-core systematic biopsy taken at the same sitting. Dedicating a minimum of two cores to a ‘target’ conferred an increase in detection of clinically significant prostate cancer, as defined by Gleason pattern ≥4, of 43% compared with systematic biopsy alone.

There is reason to think that, if anything, this might be an underestimate of the utility of sampling a target of high propensity for clinically significant prostate cancer vs a strategy that tries to spread the needle around the posterior limits of the gland. The reason for this is that the operator was aware of the location of the target during the systematic biopsy, as these were done after the targeted biopsy. The resulting incorporation bias should not trouble us too much, as its effect will be to make systematic biopsy ‘better’ and therefore diminish any difference between the two strategies. The fact that the patients had their systematic biopsy under anaesthesia and were in lithotomy (non-standard conditions) might add further to both bias and direction.

This study [1], like many before, incorporates a mixed population that comprises men who were biopsy-naïve (around one-quarter of the population) and those men who had undergone at least one previous biopsy. Again, this probably does not matter for our purposes, as the two groups were identical for overall cancer detection (52%) and very similar in terms of the proportion of patients with Gleason pattern ≥4 (80% for biopsy-naïve men vs 72% for those who had undergone a previous biopsy). The two groups had a similar number of lesions, around two lesions/subject were declared. The two groups did differ in PSA level; men undergoing repeat biopsy had a median PSA level twice that of men having a biopsy for the first time (12.2 vs 6.1 μg/L).

These results appear to be consistent with those summarised in a recent systematic review of studies that compared a targeted sampling strategy with another [2], but they do differ substantially from a recent study of >1000 biopsy-naïve men who were randomised to MRI vs a standard systematic TRUS biopsy approach [3]. In this large randomised controlled trial from Rome, the overall detection rate in MRI-positive individuals who underwent targeted sampling was 93% (410/440) vs the 52% (137/263) achieved in this study [1].

Both studies show higher detection rates compared with a standard systematic approach, and both show that targeting increases the proportion of men with clinically significant disease. However, exploring the differences between the studies might provide us with insight on how best to refine this new intervention. At present, the detection rate of clinically significant cancer (the generally agreed desired outcome of a biopsy when clinically significant disease is indeed present) is contingent on several variables [4]. They comprise the following: the population sampled; the target condition employed (definition of clinical significance); quality of the imaging; quality of the reporting; the threshold used for declaring a ‘lesion’ a target; the accuracy of the needle placement; the number of cores deployed to the target; and the efficiency of tissue capture. All these differed between the two studies, either explicitly or implicitly.

However, it is likely that the one with the greatest influence on the outcome is the level of certainty attributed to the lesion by the radiologist. There are several scales currently in use and this study used the Prostate Imaging Reporting and Data System (PI-RADS), which comprises an ordinal scale, range 1–5, derived from conditions being either met or unmet [5]. Ideally, a risk stratification system should influence clinical practice. A PI-RADS score of 1–2 should result in avoidance of a biopsy, because of the low probability of finding clinically significant disease. A PI-RADS score of 4–5 should result in a targeted biopsy, because of the high probability of underlying clinically significant disease. A PI-RADS 3 score should prompt a repeat assessment after a given interval, reflecting the indeterminate nature of the prediction.

In the study by Borkowetz et al. [1], PI-RADS scores of 2 and 3 were both associated with a 10% rate of Gleason pattern ≥4, suggesting poor discriminant ability between the two. On the other hand, PI-RADS scores of 4 and 5 were associated with a 24% and 60% detection rate, respectively, of Gleason pattern ≥4. From this we can say that lesions with PI-RADS scores of 4–5 should be targeted, are positively associated with risk, and will confer a high targeting yield. I think we can also say that more work is needed in relation to the inputs that generate PI-RADS 2–3 scores. This, fortunately, is in hand, as a new version of PI-RADS is soon to replace the one used in this article. Hopefully, it will improve the discriminant quality at the lower limits of PI-RADS and, as a result, should allow us to avoid incorporating a PI-RADS score of 2 into our targeting schedule.

Despite issues with the finessing of PI-RADS and other scoring systems, a task that will never be fully complete, this study adds to the burden of proof. What we can say, quite emphatically (based on this study, the systematic review and other studies published since), is that if patients want to maximise the chances of finding clinically significant prostate cancer, if it is indeed present, they should insist on an MRI before biopsy, so that targeting can be incorporated into the sampling strategy. To do otherwise would, according to this study, just about halve the chances of detecting clinically significant prostate cancer, if it were present.

Read the full article
Mark Emberton
UCL Division of Surgery and Interventional Science, UCL, London, UK

 

References

 

1 Borkowetz A, Platzek I, Toma M et al. Comparison of systematic transrectal biopsy to transperineal MRI/ultrasound-fusion biopsy for the diagnosis of prostate cancer. BJU Int 2015; 116: 873–9

 

2 Moore CM, Robertson NL, Arsanious N et al. Image-guided prostate biopsy using magnetic resonance imaging-derived targets: a systematic review. Eur Urol 2013; 63: 125–40.

 

3 Panebianco V, Barchetti F, Sciarra A et al. Multiparametric magnetic resonance imaging vs standard care in men being evaluated for prostate cancer: a randomized study. Urol Oncol 2015; 33: 17.e1–7.

 

4 Moore CM, Kasivisvanathan V, Eggener S et al. Standards of reporting for MRI-targeted biopsy studies (START) of the prostate: recommendations from an international working group. Eur Urol 2013; 64: 544–52.

 

5 VacheT, Bratan F, Mege-Lechevallier F, Roche S, Rabilloud M, Rouviere O. Characterization of prostate lesions as benign or malignant at multiparametric MR imaging: comparison of three scoring systems in patients treated with radical prostatectomy. Radiology 2014; 272: 446–55.

 

 

Editorial: Cabazitaxel for the therapy of mCRPC in the aftermath of CHAARTED

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In this issue of BJUI, Bahl et al. [1] describe clinical outcomes amongst 112 patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel 25 mg/m2 in the UK Early Access Programme (EAP). Patients also received daily oral corticosteroids in a fashion consistent with the phase III TROPIC study and had experienced disease progression during or after docetaxel [2]. The study suggests that improved quality of life and only modest toxicity are achieved with cabazitaxel. Moving forward, the key challenge will be translating these data to clinical practice in the context of a rapidly changing therapeutic landscape.

A veritable game of leapfrog has been ongoing in metastatic prostate cancer. In 2010, two agents were approved by the US Food and Drug Administration, sipuleucel-T and cabazitaxel. Sipuleucel-T, a dendritic cell vaccine, remains largely applied in the pre-docetaxel setting in patients who are either asymptomatic or minimally symptomatic. By contrast, the phase III TROPIC trial leading to the approval of cabazitaxel exclusively included patients who had previously received docetaxel. These approvals made for a relatively straightforward approach to mCRPC, with docetaxel therapy flanked by sipuleucel-T and cabazitaxel. Within 2 years, two novel endocrine therapies emerged, abiraterone and enzalutamide, initially approved in the post-docetaxel space and subsequently in the pre-docetaxel space. A fifth agent, radium-223, was approved for mCPRC in 2013 based on a trial conducted in symptomatic patients with bone metastases who were either post-docetaxel or unfit for or refused docetaxel.

Although editorials and position papers abound, there is actually little consensus regarding the sequencing of these agents. Furthermore, the classification of these therapies as pre- or post-docetaxel may be rendered obsolete in the aftermath of the recently reported CHAARTED trial [3]. In that study, a total of 790 patients with mostly extensive (defined as presence of visceral disease or ≥4 bone lesions with ≥1 lesion beyond the spine or pelvis) newly diagnosed metastatic castration-sensitive prostate cancer were randomized to receive either androgen deprivation therapy (ADT) alone or ADT with six cycles of docetaxel (without daily corticosteroids). The study was closed after a planned interim analysis showed a significant survival advantage in the experimental arm; median overall survival was 57.6 months with docetaxel with ADT vs 44.0 months with ADT alone (hazard ratio 0.49, 95% CI 0.37–0.65; P < 0.001). Furthermore, recent data from the phase III STAMPEDE trial corroborate the robust increment provided by combining docetaxel with ADT in patients with metastatic or high-risk non-metastatic castration-sensitive disease [4]. Thus, for many patients, docetaxel may leap to the fore.

If this is the case, where will cabazitaxel be applied? In patients with mCRPC who have received docetaxel in the castration-sensitive setting, either reinstitution of docetaxel or one of the new agents approved since 2010 may be appropriate. The report by Bahl et al. provides useful data to suggest that cabazitaxel would be reasonably tolerated in this setting, and reports quality-of-life benefits in conjunction with a low incidence of neuropathy and no toxic deaths. Conversely, despite the fact that 79.5% of patients received prophylactic G-CSF from cycle 1 and an additional 5.3% received G-CSF with subsequent cycles, 6.3% experienced neutropenic sepsis, which attests to the substantial myelosuppression caused by this agent. The optimum sequencing of all of the available agents for mCRPC is unclear and there is an absence of validated predictive biomarkers to deploy personalized therapy. Hence, eligibility criteria employed in the landmark trials, and clinical factors such as Gleason score and duration of prior ADT and comorbidities have been used to select agents, although these strategies remain unvalidated. There are published retrospective clinical experiences that address sequencing, which are not definitive. Since the advent of abiraterone and enzalutamide, the use of cabazitaxel has declined. Intriguingly, some but not all retrospective studies suggest that cabazitaxel followed by androgen axis inhibitors might lead to improved outcomes compared with androgen axis inhibitors followed by cabazitaxel [5, 6]. Another piece in the puzzle is provided by retrospective studies suggesting that cabazitaxel may retain substantial activity even after docetaxel and novel androgen inhibitors, while docetaxel appears to show poorer activity after androgen inhibitors [7].

In summary, the EAP data from Bahl et al. [1] characterizes the activity and safety of cabazitaxel in a real-world population. Furthermore, the use of prophylactic G-CSF in accordance with guidelines appeared to eliminate the deaths from neutropenic sepsis observed in the TROPIC trial, which did not use routine prophylactic G-CSF. The ongoing three-arm phase III FIRSTANA trial compares cabazitaxel with docetaxel as first-line chemotherapy for mCRPC and also attempts to refine dosing by investigating both the 25 and 20 mg/m2 doses. Similarly, the PROSELICA phase III trial attempts to show the non-inferiority of the 20 mg/m2 dose of cabazitaxel compared with the 25 mg/m2 dose in the post-docetaxel setting. Randomized phase II trials are investigating the impact of early switching of the taxane (docetaxel or cabazitaxel) in the absence of PSA decline ≥30% within 3 months and the impact of switching to cabazitaxel vs a different androgen inhibitor in those progressing on a first-line androgen inhibitor within 6 months.

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Sumanta K. Pal, Associate Professor and Guru Sonpavde, *Associate Professor

 

Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, and *Department of Medicine, Hematology- Oncology division, University of Alabama School of Medicine, Birmingham, AB, USA

 

References

 

1 Bahl A, Masson S, Malik Z et al. Final quality of life and safety data for patients with mCRPC treated with cabazitaxel in the UK early access programme (NCT01254279). BJU Int 2015; 116: 880–7

 

2 de Bono JS, Oudard S, Ozguroglu M et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147–54

 

3 Sweeney CJ, Chen YH , Carducci M et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. New Engl Med 2015; 20: 737–46

 

4 James ND, Snyder M, Mason MD et al. Docetaxel and/or zoledronic acid for hormone-naïve prostate cancer: first overall survival results from STAMPEDE (NCT 00268476). J Clin Oncol 2015; 33:5s; (suppl Abstr 5001)

 

5 Caffo O, De GiorgiU, Fratino L et al. Clinical outcomes of castration- resistant prostate cancer treatments administered as third or fourth line following failure of docetaxel and other second-line treatment: results of an Italian Multicentre Study. Eur Urol 2014; [Epub ahead of print]

 

6 Sonpavde G, Bhor M, Hennessy D et al. Sequencing of Cabazitaxel and Abiraterone Acetate After Docetaxel in Metastatic Castration-Resistant Prostate Cancer: Treatment Patterns and Clinical Outcomes in Multicenter Community-Based US Oncology Practices. Clinical genitourinary cancer 2015; 13: 309–18

 

7 Pezaro CJ, Omlin AG, Altavilla A et al. Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents. Eur Urol 2014; 66: 459–65

 

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