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Editorial: New Strategies for Treating RMC

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In the current issue of BJUI, Shah et al. [1] present a multi-institutional study of 52 patients with renal medullary carcinoma (RMC) collected over a 15-year period. This notoriously lethal and rare form of kidney cancer, associated with sickle cell trait and disease, usually affects young adults. In the study, the median age was 28 years, 94% of the patients presented with stage 3 or 4 disease, and the median overall survival was only 13 months. Nephrectomy, performed in 75% of patients, as opposed to systemic therapy alone, was associated with longer survival (16.4 vs 7.0 months). Of the 45 patients who received platinum- or carboplatinum-based systemic chemotherapy, 13 (29%) had an objective response, while there was no objective response in 28 patients treated with vascular endothelial growth factor-targeted agents, which are highly effective in conventional clear-cell carcinoma of the kidney. Only seven patients survived >2 years, with two long-term survivors at 5 and 9 years after nephrectomy and various combinations of systemic therapy.

Recent reports suggest new insight into this lethal form of kidney cancer, raising hope about the development of effective systemic agents. Calderaro et al. [2] used gene expression profiling, array genomic hybridization, and RNA and whole-exome sequencing to study frozen tissue in five patients with RMC. They reported an interchromosomal balanced translocation that disrupts the SMARCB1 gene, a tumour suppressor on chromosome 22 encoding BAF47 protein, which impairs the SWI/SNF complex regulating chromatin remodelling, which, in turn, leads to increased cyclin D transcription and downstream over-expression of the transcriptional regulator EZH2. EZH2 is the enzymatic subunit of the PRC2 complex and its histone methylation function. EZH2 also has a PRC2-independent role in transcriptional activation and can methylate a number of non-histone proteins. Over-expression of EZH2 can lead to cancer by changing expression of tumour suppressor (pRB) and DNA-damage repair genes. EZH2 over-expression and loss of function mutations are associated with a diverse group of cancers including liver, breast, prostate, endometrial, melanoma, bladder and lymphoma, none of which are as rare as RMC but in which targetable agents can be tested for their ability to disrupt this pathway [3]. Interestingly, SMARCB1 gene truncating and or deletion mutations have been reported in the equally rare and lethal paediatric rhabdoid tumour of the kidney [4] and loss of immunoexpression of SMARCB1 reported in the clinically aggressive collecting duct renal cancer, which is morphologically similar to and often difficult to distinguish from RMC [5].

A number of small-molecule compounds able to target both EZH2 and PRC2 complex are currently undergoing preclinical testing (i.e. DZNEP, E11, EP2005687), phase I trials (GSK126), and phase II trials (EPZ-648, Tazemetostat) [3]. A phase II multicentre study of tazemetostat, a selective small-molecule inhibitor of EZH2, is underway and accruing patients with rare tumours with abnormalities in this pathway, including synovial-cell sarcoma, RMC and rhabdoid tumour of the kidney, for which there are no standard therapies [6]. Contemporary genomic research has great potential to identify such critical oncogenic pathways, shared in both rare and more common malignancies, with the potential for effective drugs to be designed to improve the grave prognosis of RMC and related cancers.

Paul Russo
Weill Cornell School of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

 

 

References

 

1 Shah AY, Karam JA, Malouf GG et al. Management and outcomes of patients with renal medullary carcinoma: a multicentre collaborative study. BJU Int2017; 120: 782–92.

 

2 Calderaro J, Masliah-Planchon J, Richer W et al. Balanced translocations disrupting SMARCB1 are hallmark recurrent genetic alterations in renal medullary carcinomas. Eur Urol2016; 69: 1055–61.

 

3 Kim KH, Roberts CWM. Targeting EZH2 in cancer. Nat Med 2016; 22: 128– 34

 

4 Versteege I, Sevenet N, Lange J et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 1998; 394:203–6

 

5 Elwood H1, Chaux A, Schultz L et al. Immunohistochemical analysis of SMARCB1/INI-1 expression in collecting duct carcinoma. Urology 2011;78: 474

 

 

Editorial: Novel risk stratification nomograms for counseling patients on the need for prostate biopsy

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Contemporary recommendations for prostate screening incorporate the measurement of serum PSA levels into shared decision making [1]. PSA is limited by a low specificity for prostate cancer and exposes a certain number of men to unnecessary prostate biopsies. Moreover, it has been attributed to an over-diagnosis and over treatment of this disease, especially in indolent cancer that may never affect a man’s longevity [2].

Prostate cancer risk stratification and aggressiveness is necessary in both the pre-biopsy clinical counselling, as well as the decision-making process. It is clear that such an important approach cannot be accomplished based on PSA alone. In order to enhance prostate cancer screening and detection, other clinical variables such as PSA density, prostate volume, percentage free PSA, and DRE, are routinely considered in conjunction with PSA for determining the need for prostate biopsy.

Increasing evidence supports the use of MRI in prostate cancer detection when used as a localisation tool to guide MRI-targeted biopsy techniques such as MRI-ultrasonography fusion-targeted biopsy [3-5]. Pre-biopsy MRI not only allows accurate tumour localisation, but also provides an assessment of cancer suspicion using an MRI suspicion score, and thus provides accurate prediction of the likelihood of prostate cancer on prostate biopsy [6].

In this study, van Leeuwen et al. [7] developed and externally validated a set of nomograms predicting clinically significant prostate cancer by incorporating prostate MRI. The performance characteristics of the nomograms were maximised by inclusion of MRI results. The authors determined that clinical application of the model would reduce 28% of biopsies, while missing 2.6% of clinically significant prostate cancer. Ultimately incorporating these nomograms into the clinical decision-making process could result in a considerable reduction in unnecessary biopsies and reduction in the risk of over-detection of clinically insignificant disease at the cost of a small increase in the number of significant cancers missed.

The authors should be commended for their predictive nomograms, in that they may further aid in the decision to perform biopsy in men with clinical suspicion of prostate cancer. However, the findings of this study should be interpreted with caution. In formulating nomograms, the obvious clinical goal is the creation of a tool that improves the selection of men in need of biopsy. Unless nomograms are derived from general ‘at risk’ populations, including men with low- and high-risk of prostate cancer, the tool may be limited in its prediction. As an example, if all men in the training cohort have an elevated PSA level, the predictive value of PSA in the nomogram may be reduced. In this case, the training and validation cohort are not well described, but it seems to be a referral population, and the PSA range is relatively narrow. As such, it’s applicability to all men presenting for prostate cancer may be questionable.

We also have had difficulty modelling a nomogram from our MRI-targeted biopsy dataset because the power of MRI-suspicion score in predicting cancer tends to minimise the effect of other variables such as PSA, age, and gland size. The authors did not compare their multivariable predictive models to MRI alone, and this may have been the most relevant comparison. In this study, the gland size and PSA level contribute significantly to the nomogram score, but one might question the findings. For example, a man with a Prostate Imaging Reporting and Data System (PI-RADS) score of 4 or 5, a large gland and a low PSA level, has a similar or lower risk as a man with a PSA level of 15 ng/mL, a moderate gland, and a PI-RADS score of 3. This is not consistent with our clinical experience and draws concern in the reliability of the nomogram at extremes of PSA and age. Men with PI-RADS 5 have high rates of clinically significant prostate cancer, regardless of PSA or age. This also may reflect variability in the predictive accuracy of MRI depending upon MRI interpretation.

Another limitation of the study, as the authors cite, is that patients were biopsied using a transperineal mapping with a median of 30 cores. This biopsy strategy is not routinely used in most institutions, and consequently limits the generalisability of the nomograms.

Selective use of prostate biopsy among men with elevated PSA levels through further refinement of cancer risk is highly desirable. The novel risk stratification nomograms developed by van Leeuwen et al. [7] add to the tools we may use to counsel our patients on the need for prostate biopsy. Further evaluation of these nomograms on additional independent patient cohorts is warranted prior to implementation in clinical practice.

Marc A. Bjurlin* and Samir S. Taneja†
*Division of Urology, Department of Surgery, NYU Lutheran Medical Center, NYU Langone Health System, New York, NY, USA and †Division of Urologic Oncology, Department of Urology, NYU Langone Medical Center, New York, NY, US

 

References

 

1 Carter HB, Albertsen PC, Barry MJ et al. Early detection of prostate cancer: AUA Guideline. J Urol2013; 190: 419–26

 

2 Loeb S, Bjurlin MA, Nicholson J et al. Overdiagnosis and overtreatment of prostate cancer. Eur Urol
2014; 65: 1046–55

 

3 Mendhiratta N, Meng X, Rosenkrantz AB et al. Prebiopsy MRI and MRI-ultrasound fusion-targeted prostate biopsy in men with previous negative biopsies: impact on repeat biopsy strategies. Urology 2015; 86: 1192–8

 

 

5 Meng X, Rosenkrantz AB, Mendhiratta N et al. Relationship between prebiopsy multiparametric magnetic resonance imaging (MRI), biopsy indication, and MRI-ultrasound fusion-targeted prostate biopsy outcomes. Eur Urol 2016; 69: 512–17

 

 

7 van Leeuwen PJ, Hayan A, Thompson JE et al. A multiparametric magnetic resonance imaging-based risk model to determine the risk of significant prostate cancer prior to biopsy. BJU Int 2017; 120: 774–8

 

Editorial: Human development and its impact on genitourinary cancers

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Using the extensive data from the WHO International Agency for Research on Cancer and the United Nations Human Development Report, Greiman et al. [1] aimed to investigate how human development is associated with incidence and mortality of genitourinary cancers. Even though they generate some interesting descriptive findings, we have to remain critical of these descriptive statistics and carefully assess what needs to be investigated next.

Firstly, despite having highlighted the need for attention to indicators of longevity, education, and income per head when assessing human development, the human development index (HDI) is a rather crude measurement. As a geometric mean of normalised indices for each of these three domains, the HDI simplifies but only captures part of what human development entails. Important indicators of health care such as inequalities, poverty, human security, and empowerment are not reflected in the HDI (www.hdr.undp.org). In the context of cancer incidence and mortality this is an important limitation, as it has for instance been shown that socioeconomic status affects early phase cancer trial referrals, which can be considered as a proxy for access to health care [2]. This inequality has been hypothesised to be linked to more comorbidities and lower education in those who are most deprived – a complex interaction which may not be completely captured by the HDI.

Secondly, registration of incidence and mortality of cancers may vary substantially between countries based on both medical practice and governance. These differences are important when trying to generate hypotheses following the ecological study of Greiman et al. [1]. In the case of bladder cancer, for instance, mortality has been estimated to be 17% in the Netherlands, compared to 22% in the USA, and 50% in the UK. As cancer treatments are expected to be similar in these developed countries, it has been thought that a lower registration of non-muscle-invasive bladder cancer in the UK could explain this higher proportion [3]. Thus, discrepancies in cancer registration, even between developed countries, may limit our awareness of cancer burden.

Thirdly, the study design suffers from ‘ecological fallacy’. The latter refers to the inability to draw causal inference about the effect of the HDI on genitourinary cancer at the individual level, in conjunction with the underlying problem of heterogeneity of exposure levels [4]. This limitation was not mentioned by Greiman et al. [1], but affects their conclusions. The lack of information on, for instance, smoking data, comorbidities, and ethnicity make it difficult to understand how development is affecting cancer incidence or mortality. It would have been interesting to also investigate cancers other than genitourinary cancers because a comparison of different tumour types might have shed light on differences in medical practice or risk factors across countries and help tease out the ecological effect of human development.

Despite the aforementioned limitations, the descriptive analysis by Greiman et al. [1] can be helpful for generating hypotheses – as also outlined by the authors. This ecological effect of human development on incidence and mortality rates of genitourinary cancers is particularly relevant when evaluating the impacts of prevention and intervention programmes for these cancers. Their findings suggest that further investigation is required to examine the hypothesis regarding human development and incidence/mortality of genitourinary cancers. To further elucidate this association, methodological challenges will need to be overcome, as HDI assessment has been criticised for being too crude. Nevertheless, it should be possible to collect more detailed information to allow for an understanding of which components of a country’s collective resources affect cancer incidence and mortality the most, e.g. differences in resources used for cancer detection and treatment.

Mieke Van Hemelrijck
Division of Cancer Studies, Translational Oncology and Urology Research (TOUR), King’s College London, London, UK

 

References

 

1 Greiman AK, Rosoff JS, Prasad SM. Association of Human Development Index with global bladder, kidney, prostate and testis cancer incidence and mortality. BJU Int2017; 120: 799-807

 

2 Mohd Noor A , Sarker D, Vizor S et al. Effect of patient socioeconomic status on access to early-phase cancer trials. J Clin Oncol 2013; 31: 224– 30.

 

3 Boormans JL, Zwarthoff EC. Limited funds for bladder cancer research and what can we do about it. Bladder Cancer 2016; 2: 49–51

 

4 Morgenstern H . Ecologic studies in epidemiology: concepts, principles, and methods. Annu Rev Public Health 1995; 16: 61–8

 

Editorial: NICE guidance and the BJUI

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As the year comes to an end, one cannot help but reflect on the successes of 2017. The impact factor of the BJUI has gone up to 4.439. Our infographics have introduced an entirely different level of interaction with our readers, some of whom are hard pressed for time. We have simply relied on the age old idiom – ‘a picture is worth a thousand words’. And we have credited our reviewers for giving up their valuable time, through Publons and the entirely new Four Seasons, where we will recognise the best reviewers each quarter through BJUI blogs.

Figure 1. Tower Bridge, London. ©John W. Davis 2017.

But perhaps the greatest accomplishment this year has been the publication of National Institute of Health and Care Excellence (NICE) Guidance for the very first time in the BJUI. Guidelines in general are now regarded as perhaps the highest level of evidence, which is obvious from the many hundred citations attracted by guidelines from the EAU and AUA. An absolute classic is the American Cancer Society Breast Cancer Screening Guideline from 2003, which was updated in 2015. In keeping with modern times and shorter attention spans, JAMAenhanced the guideline with an amazing infographic of a digital hand and pen drawing across a white paper! Whilst admiring such stunning quality, the team at the BJUI became acutely aware of our major weakness of being an international journal – we do not have society guidelines to publish. Until now…

NICE guidelines are based not just on the highest level of evidence; every effort is made to eliminate bias as far as possible. Every committee has at least two lay members. The processes and methods are based on internationally accepted criteria of quality, as detailed in the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrumen ns are clear and unambiguous, making them easier to implement and understand.

A unique feature of NICE Guidance is not just ‘clinical effectiveness’ but engagement with economists to make clear statements on ‘cost effectiveness’. It is no wonder that although NICE is based mainly in London, these guidelines are now popular worldwide and not just for the NHS.

We have earlier published NICE Guidance on the GreenLight XPS laser for BPH avoiding high risk patients such as those with risk of bleeding, prostate volume >100 mL, and urinary retention [1]. This technology would be cost effective if used on a day case basis.

NICE have also weighed the evidence for enzalutamide in hormone-relapsed prostate cancer before chemotherapy [2], in patients with mild symptoms, provided it is made available by the manufacturer on the agreed discounted price. Although expensive, it is regarded as an effective treatment amongst the new emerging therapies to prolong the lives of patients with prostate cancer.

In this issue of the BJUI, we feature the NICE Guidance on diagnosis and management of bladder cancer [3]. Not only is smoking cessation important in these patients, but perhaps somewhat controversially, NICE recommend discharge to primary care of patients with low-risk non-muscle-invasive bladder cancer with no recurrence within 12 months. They make a number of research recommendations on biomarkers that are increasingly becoming important with next generation sequencing but also patient satisfaction, which is what ultimately matters in this cancer that can adversely affect quality of life of those who suffer with it.

Wishing you all Greetings of the season!

Prokar Dasgupta

Editor in Chief, BJUI

References

1 National Institute of Health and Care Excellence (NICE). GreenLight XPS for treating benign prostatic hyperplasia: ©NICE (2016) GreenLight XPS for treating benign prostatic hyperplasia. BJU Int2017; 119: 823–30

 

2 National Institute of Health and Care Excellence (NICE). Enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated: ©NICE (2016) Enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated. BJU Int 2017; 120: 168–84

 

3 National Institute of Health and Care Excellence (NICE). Bladder cancer: diagnosis and management of bladder cancer: ©NICE (2015) Bladder cancer: diagnosis and management of bladder cancer. BJU Int2017; 120: 755–6

 

Editorial: Stereotactic radiotherapy for primary renal cell carcinoma: time for larger-scale prospective studies

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A number of important trends in kidney cancer diagnosis have emerged in recent decades, including the increasing detection of renal tumours in older patients with more comorbidities. In the UK in 2012–2014, 50% of new cases were diagnosed in people aged 70 years and over. Whilst many of these lesions are incidental small renal masses suitable for active surveillance, the dilemma of how to manage the higher-risk lesion (rapid growth kinetics, larger size, symptomatic lesion) is increasingly encountered. Surgical management may pose an unacceptable risk of morbidity, mortality or dialysis, yet these patients may live long enough to experience the consequences of disease progression. Thermal ablation is an option for small cortical tumours (≤3 cm), but there are limitations for larger or centrally located tumours.

In this issue of BJUI, Siva and colleagues [1] report promising early efficacy and toxicity data using stereotactic ablative body radiotherapy (SABR) for the treatment of primary RCC in this difficult cohort. SABR is a non-invasive treatment that delivers very high doses of radiation over one to five outpatient sessions. It uses advanced motion management, radiation planning and image guidance techniques to ensure delivery of an ablative dose with millimetre precision. Survival benefits with stereotactic radiosurgery have been demonstrated in patients with solitary brain metastases [2], and SABR is now an accepted standard of care for patients with medically inoperable early-stage lung cancer [3]. Randomized phase III trials are currently under way, testing SABR against standard of care in primary prostate (clinicaltrials.gov ID NCT01584258) and liver cancer (NCT01730937) and in the oligometastatic setting (NCT02759783). Historically considered radio-resistant, both pre-clinical and clinical data now support the sensitivity of RCC to high-dose per fraction radiotherapy, as used in SABR [4].

The study by Siva and colleagues is one of the largest, early-phase, prospective studies of SABR for primary RCC to date, accruing 37 patients with cT1a–cT2a RCC not suitable for other therapies. Importantly, this was not a cohort of incidentally detected small renal masses. The majority (65%) of tumours were >4 cm (median 4.8 cm), were growing on surveillance or symptomatic, and were biopsy-proven. The inclusion of enlarging T1a tumours is not unreasonable. A recent analysis of patients with localized T1a kidney cancer from the Surveillance, Epidemiology and End Results (SEER) Medicare data reported an excess of kidney cancer deaths for non-surgically managed patients aged >75 years, highlighting how difficult it can be to find the right balance between active and expectant management in this group [5]. Indeed 11% of patients in the present study by Siva et al. developed distant metastases by 2 years.

In the present study, tumours <5 cm received a single 26-Gy fraction of SABR, whilst tumours >5 cm received 42 Gy over three fractions. Whilst acknowledging a number of uncertainties in modelling, this should equate to an equivalent biological dose in excess of 100 Gy. The authors found that delivering this SABR regimen was feasible and well tolerated with one grade 3 toxicity (transient fatigue) and no grade 4–5 toxicities. Most patients sustained only transient minor side effects (78%) or no treatment-related side effects (18%). The mean baseline estimated GFR was 55 mL/min, which decreased to 44 mL/min at 1 year, and was maintained for those with 2 years follow-up.

Similarly, short-term efficacy appears promising. With a median follow-up of 24 months, freedom from local progression at 2 years was 100%, with one patient subsequently progressing locally with concurrent distant metastases 28 months after treatment. Local progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. This is a pragmatic definition and takes into account the challenges in interpreting standard imaging after SABR and the difficulties in obtaining and interpreting repeat biopsies in this cohort. Similarly to the study by Sun et al. [6] it appears that stable or partial radiological responses will predominate in the early years after SABR and, unlike thermal ablation, changes in enhancement patterns can be very slow to evolve.

Longer-term follow-up is required to confirm these promising tumour control and nephron preservation rates, in addition to evaluating longer-term late effects. To that end, the present study has provided a platform for the authors to launch an international phase II clinical trial under the auspices of the TransTasman Radiation Oncology Group (TROG 15.03 FASTRACK, clinicaltrials.gov ID NCT02613819). Larger-scale prospective studies are essential to confirm the efficacy and safety of this non-invasive, nephron-sparing, ablative technique and provide further information to help refine patient selection and develop better biomarkers of response.

Read the full article
David I. Pryor *† and Simon Wood†‡

 

*Department of Radiation Oncology, Princess Alexandra Hospital, Wooloongabba, †School of Medicine, University of Queensland, Brisbane, and ‡Department of Urology, Princess Alexandra Hospital, Wooloongabba, Qld, Australia

 

References

 

1 Siva S. Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial. BJU Int 2017; 120: 623–30
 

 

2 Andrews DW, Scott CB , Sperduto PW et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with  one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet (London, England) 2004; 363: 1665–72

3 Chang JY, Senan S, Paul MA et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol 2015; 16: 630–7

 

4 De Meerleer G, Khoo V, Escudier B et al. Radiotherapy for renal-cell carcinoma. Lancet Oncol 2014; 15: e170–7

 

5 Patel HD, Kates M, Pierorazio PM et al. Survival after diagnosis of localized T1a kidney cancer: current population-based practice of surgery and nonsurgical management. Urology 2014; 83: 126–32

 

6 Sun MR, Brook A, Powell MF et al. Effect of stereotactic body radiotherapy on the growth kinetics and enhancement pattern of primary renal tumors. AJR Am J Roentgenol 2016; 206: 544–53

 

Editorial: Getting to the right biopsy in the right patient at the right time

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Guidelines now recommend performing multiparametric MRI (mpMRI) and targeted prostate biopsies in men with a history of prior negative biopsy and continued concern for significant cancer. This new approach to prostate re-biopsy is aimed at improving prostate cancer detection. However, several important clinical factors may help clinicians’ fine-tune the process of repeated prostate biopsy. In this month’s issue of the BJUI, Hansen et al. [1] present a multicentre study of patients with prior negative TRUS biopsy undergoing MRI/TRUS-fusion transperineal biopsy.

In the study, 487 men undergo mpMRI and transperineal biopsy with detection of clinically significant (Gleason score 7–10) cancer as the primary outcome. Several factors are evaluated to compare cancer detection rates, including systematic biopsies, targeted biopsies, PSA density (PSAD), and Prostate Imaging Reporting and Data System (PI-RADS) version 1 score. From their cohort, a suspicious lesion (PIRADS 3–5) was identified in 343 (70%) patients. Prostate cancer was detected in 249 (51%), with 149 (31%) having Gleason score 7–10 cancer. Potentially missed significant cancers from the anterior prostate were found in 27% (40/149). Cancer was detected in 28% (40/144) of patients with PI-RADS 1–2 lesions, with 8% (11/144) being Gleason score 7–10. For patients with PI-RADS 3–5 lesions, cancer was identified in 61% (209/343) with 40% (138/343) being Gleason score 7–10. For patients with PI-RADS 3–5 lesions, systematic biopsies alone failed to detect 13/138 significant cancers, while targeted biopsies missed 24/138 cancers. The combination of systematic and targeted biopsies was significantly better for Gleason score 7–10 prostate cancer detection than either alone. The addition of a PSAD threshold of 0.15 ng/mL/mL for the detection of Gleason score 7–10 resulted in a significant improvement in the area under the curve (0.846) of the receiver operating characteristic curve for PSAD groups and PI-RADS score.

Getting the right biopsy: In this study [1], patients with a prior negative TRUS biopsy underwent TRUS-fusion transperineal biopsy. Having two approaches to prostate biopsy can be advantageous when evaluating men with prior negative biopsies. Historical studies have found comparable prostate cancer detection between transrectal and transperineal biopsies for men undergoing both initial biopsy [2] and saturation re-biopsy [3]. However, the detection of anterior lesions has remained a persistent challenge from the transrectal approach. As in the current study [1], use of transperineal biopsy can detect cancer in up to 30% of tumours that would otherwise be missed on extended template TRUS biopsy [4]. Although attempts to reach anterior lesions from the transrectal approach may be feasible [5], the transperineal approach is felt to provide better sampling in comparison [6].

Getting the right patient: Patient-specific factors such as PI-RADS lesions 3–5 and PSAD have become increasing utilised for stratifying patients who may benefit from additional biopsies using image guidance. As the authors suggest, patients with negative imaging may consider deferring repeat biopsy, particularly those with reassuring PSADs (<0.15 ng/mL/mL). In their study [1], only 4% (6/144) of men with negative mpMRI and a PSAD of <0.15 ng/mL/mL harboured clinically significant cancer (five Gleason score 3 + 4 and one Gleason score 8). Patients with concerning PSAD, but negative mpMRI and those with lesions identified in the peripheral zone could have the option to undergo repeated, fusion-directed TRUS or transperineal biopsy. For patients with lesions identified in the anterior prostate, a transperineal prostate biopsy may provide the highest detection rate.

At the right time: Now that high quality prostate MRI is becoming more widely available; men with a prior negative biopsy should strongly consider the benefit of repeated biopsy after prostate imaging. In addition to identifying suspicious lesions, calculating PSAD has been found to improve the likelihood of detecting clinically significant prostate cancer. Without additional testing, a personalised biopsy plan can be created.

A thorough discussion of the prescribed biopsy approach and the likelihood of detecting a significant cancer is the final step to the right biopsy in the right patient at the right time.

Kelly Stratton

 

Department of Urology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA

 

Read the full article

 

1 Hansen NL, Kesch C, Barrett T et al. Multicentre evaluation of target and systematic biopsies using magnetic resonance and ultrasound image-fusion guided transperineal prostate biopsy in patients with a previous negative biopsy. BJU Int 2016; 120: 631–8

 

2 Hara R, Jo Y, Fujii T et al. Optimal approach for prostate cancer detection as initial biopsy: prospective randomized study comparing transperineal versus transrectal systematic 12-core biopsy. Urology 2008; 71: 191–5

 

3 Abdollah F, Novara G, Briganti A et al. Trans-rectal versus trans- perineal saturation rebiopsy of the prostate: is there a difference in cancer detection rate? Urology 2011; 77: 921–5

 

4 KomaiY, Numao N, Yoshida S et al. High diagnostic ability of multiparametric magnetic re onance imaging to detect anterior prostate cancer miss ed by transrectal 1 2-core biopsy. JUrol2013; 190: 867– 7

 

5 Volkin D, Turkbey B, Hoang AN et al. Multiparametric magnetic resonance imaging (MRI) and subsequent MRI/ultrasonography fusion-guided biopsy increase the detection of anteriorly located prostate cancers. BJU Int 2014; 114: E43–9

 

6 Borkowetz A, Platzek I, Toma M et al. Direct comparison of multiparametric magnetic resonance imaging (MRI) results with final histopathology in patients with proven prostate cancer in MRI/ ultrasonography-fusion biopsy. BJU Int 2016; 118: 213–20

 

Urolithiasis around the world

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Stone disease is a highly prevalent condition that unites all countries around the world, although surgical management will depend on many factors including availability of different technologies. However, percutaneous nephrolithotomy (PCNL) remains the cornerstone for the management of larger renal stones in all parts of the world, and Rizvi et al. [1] report on a huge cohort of PCNL procedures – 3 402 to be precise from Karachi. This is a single-centre series, over an 18-year period, reporting real-life data and showing a stone clearance rate of ~80%, as assessed by plain abdominal radiograph of the kidneys, ureters and bladder, and ultrasonography (US). Whilst the definition of stone-free and imaging modality used to judge it remains a contentious issue, this paper reflects the excellence of high-volume surgery in specialist centres.

Recently, the BJUI became the affiliated journal for the International Alliance of Urolithiasis (IAU), whose annual meeting takes place in Shaoxing this month. To celebrate this, we are proud to publish a ‘Best of Urolithiasis’ issue, which features some of the top stone papers published in the BJUI over the last few years [2]. Choosing articles for this was quite a task given the quality and whilst we have attempted to recognise submissions that potentially change practice, the geographical diversity of the work shows not only the global nature of stone disease but also the excellent research that is being done worldwide and in different healthcare systems to improve care and outcomes. Of particular importance are randomised trials that are often lacking in surgical areas. One such paper from China addressed the question of US vs fluoroscopy for PCNL access during mini-PCNL [3]. Whilst the truth is that surgeons should use whatever gives the best outcomes, the authors in a very high-volume centre were able to demonstrate the effectiveness of US-only punctures, although a combination may be better in complex stone burdens. Another randomised controlled trial (RCT) of clinical importance was from the USA, where the authors conducted a good quality double-blind RCT of NSAID use before ureteric stent removal under local anaesthesia [4]. Whilst a small study, the incidence of severe pain in the 24 h after stent removal was 55% in the placebo group vs 0% in the NSAID group – as such this simple study should have changed practice for all who perform this procedure.

Other papers worthy of inclusion include a single-centre experience of the conservative management of staghorn calculi, which challenges the dogma that all staghorn stones should be treated [5]. This single-centre series showed a conservative policy could be adopted in highly selected patients. Is this practice changing? Maybe … but it certainly gives an evidence base for stone surgeons in making decisions in very high-risk patients. Manoj Monga and his group recently reported on the accuracy of US for the detection of renal stones [6]. This again is a very important topic and a question that commonly arises. In a series of >500 patients with US-detected stones who subsequently underwent CT scanning, 22% of patients would have been inappropriately counselled about their stone based on US alone. Again, the message is clear … US is a good screening tool but do not rely on it for treatment decisions.

I hope you take the time to check out the virtual issue on urolithiasis and read the other papers I could not mention here. Please continue to send your high-quality stone papers to the BJUI and maybe your submission will feature in our next ‘Best of Urolithiasis’ issue.

Matthew Bultitude, BJUI Associate Editor

 

Guy’s and St Thomas’ NHS Foundation Trust, London, UK

 

References

 

1 Rizvi SA, Hussain M, Askari SH, Hashmi A, Lal M, Zafar MN. Surgical outcomes of percutaneous nephrolithotomy in 3402 patients and results of stone analysis in 1559 patients. BJU Int 2017; 120: 702–9

 

2 BJU International. Virtual Issues Page. Available at: https://bit.ly/BJUI-VIs. Accessed September 2017

 

3 Zhu W, Li J, Yuan J et al. A prospective and randomised trial comparing fluoroscopic, total ultrasonographic, and combined guidance for renal access in mini-percutaneous nephrolithotomy. BJU Int 2017; 119: 612–8

 

4 Tadros NN, Bland L, Legg E, Olyaei A, Conlin MJ. A single dose of a non-steroidal anti-inflammatory drug (NSAID) prevents severe pain after ureteric stent removal: a prospective, randomised, double-blind, placebo-  controlled trial. BJU Int 2013; 111: 101–5

 

5 Deutsch PG, Subramonian K. Conservative management of staghorn calculi: a single-centre experience. BJU Int 2016; 118: 444–50

 

6 Ganesan V, De S, Greene D, Torricelli FC, Monga M. Accuracy of ultrasonography for renal stone detection and size determination: is it good enough for management decisions? BJU Int 2017; 119: 464–9

 

Editorial: Should we care more about SPARE?

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Huddart et al. [1] report the results of a phase III clinical trial (SPARE) evaluating the feasibility of randomising participants with cT2/T3 muscle-invasive bladder cancer (MIBC) to either radiation or radical cystectomy (RC) following neoadjuvant chemotherapy. Whilst attempting to address an important, in fact crucial ongoing point of debate, due to poor patient accrual (45 participants recruited in 30 months) the study was terminated early. Additionally, compliance with study assignment was low, with as many as 24% of participants electing to proceed with a treatment arm that was the opposite of what they were randomised to. This underscores the problems with obtaining randomised data in an era where patient and clinician preference drive clinical decision-making.

Whilst well-performed prospective studies show acceptable results with bladder-sparing approaches (69% complete response and 71% 5-year disease-specific survival [2]), no randomised clinical trials comparing bladder sparing with RC have demonstrated equivocal results. As non-randomised studies are subject to selection bias [many patients with large bulky T3 tumours or those with carcinoma in situ (CIS) or hydronephrosis have not met inclusion criteria for trials of bladder sparing], it is often debated as to whether bladder sparing is appropriate for the entire population of patients with MIBC or a selected subset. This is especially important in a deadly disease such as bladder cancer, where we often have only one chance to get it right and hence recent guidelines state that bladder sparing and radical options should be discussed with the patient.

Whilst we acknowledge the limitations based on the number of participants analysed, these data show some interesting trends [1]. There appears to be more local recurrence with radiation therapy (69%) compared to RC (15%), this despite confirmation of ≤cT1 disease after neoadjuvant chemotherapy. And while most of the local failures are attributed to non-muscle-invasive recurrences; additional treatments, patient anxiety, and potential salvage RC, as well as the cost of surveillance, must be considered in reflecting on these results. It is unclear whether these factors are outweighed by the perceived lower toxicity in these patients.

It is our opinion that until randomised studies show equivalency, radiation-based approaches should definitely be discussed with all patients but patients should also be guided as to who are ideal candidates. Ideal candidates are those who have non-variant histology (pure urothelial carcinoma), non-bulky (minimal) invasive T2 cancer, absence of CIS, absence of a three-dimensional mass on imaging or examination, absence of hydronephrosis, and have an adequate bladder capacity [3]. The role of multidisciplinary care is paramount, maximal transurethral resection is a critical initial step, as incomplete resections can potentially double the odds of eventual RC in bladder-sparing protocols [4]. Additionally, concomitant chemotherapy has shown improved survival and should be considered standard of care based on a randomised control trial [5]. The addition of neoadjuvant chemotherapy is unknown and needs to be further evaluated. In addition to the treatment itself, it is clear that vigilant surveillance is critical in identifying patients at highest risk of failure and requires a combination of both cystoscopy and imaging, with expedient salvage RC.

Beyond the challenges of treating patients with MIBC, this report from Huddart et al. [1] reflects the larger issue of clinical trial accrual. As mentioned, patients and clinicians often have predetermined notions about the ‘best’ course of action, even in the context of a randomised clinical trial. These limitations have plagued early closure of other trials in bladder cancer as well. Similarly in prostate cancer, comparative treatment trials of radiation and surgery are limited as patients are reluctant to relinquish decisions about their treatment. Clearly, an intensive effort is necessary to create clinical trials that are palatable to a multi-disciplinary treatment team committed to answering tough therapy questions. MIBC is no different, where we often offer differing treatment modalities without having quality comparative data, which is a disservice to our patients who look to us to guide their treatment approaches based on best available hard evidence. We again commend the authors for their well-designed clinical trial and presenting their results and challenges from the SPARE trial.

Eugene K. Lee* and Ashish M. Kamat†

 

*University of Kansas Medical Center, Kansas City, KS and † Department of Urology, MD Anderson Cancer Center, Houston, TX, USA

 

Read the full article

References

1 Huddart RA, Birtle A, Maynard L et al. Clinical and patient-reported outcomes of SPARE – a randomised feasibility study of selective bladder preservation versus radical cystectomy. BJU Int 2017; 120: 639–50

 

2 Mak RH, Hunt D, Shipley WU et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 2014; 32: 3801–9

 

3 Smelser WW, Austenfeld MA, Holzbeierlein JM, Lee EK. Where are we with bladder preservation for muscle-invasive bladder cancer in 2017? Indian J Urol 2017; 33: 111–17

 

4 Efstathiou JA, Spiegel DY, Shipley WU et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol 2012; 61: 705–11

 

5 James ND, Hussain SA, Hall E et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012; 366: 1477–88

 

Editorial: Management of urolithiasis in South Asia

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The article by Rizvi et al. [1] makes a great read. The authors deserve credit for their work and the data presented. A few points merit mention to summarise and put the article in perspective.

First, the authors present a mammoth database from a public sector hospital in Pakistan. In the initial era, as noted by the authors, they adopted extracorporeal shockwave lithotripsy (ESWL) as their mainstay for treating stones. ESWL as the least invasive, safe and readily available method remained the preferred option initially. However, stones seen in South Asia differ from those in the West. In this geographical area, the stone bulk is large and often not amenable to ESWL. In the subsequent period, the authors changed to percutaneous surgery. The reason for this shift, apart from large stone burden, may also have been influenced by local facto required to be travelled by patients to reach a healthcare facility and the lack of resources and infrastructure in remote locations. In such situations, the treatment option that offers rapid, safe, and efficacious results would be preferred. These criteria are fulfilled with the percutaneous approach to renal stones and this is what the authors did!

Second, it is worthwhile noting that that the need for embolisation and/or nephrectomy is a miniscule number in this series [1]. This emphasises the importance of the basic tenet in percutaneous renal surgery that a perfect initial access is the secret to successful percutaneous removal of stones. It should be noted that in this large series the complications across all Clavien–Dindo complication grades reduced as the authors ascended the learning curve.

Third, we feel the major limitation of this study [1] was the means of assessing the stone-free rate. The authors used a combination of ultrasonography and plain abdominal radiograph of the kidneys, ureters and bladder. As acknowledged by the authors this could have possibly overestimated the stone-free rates and skewed the data and interpretation. The authors can substantiate these findings in further prospective studies.

Fourth, the paper exemplifies that stone composition, choice of approach, and patient preferences vary from region to region globally. The findings in the study [1] are similar to the results of Desai et al. [2] from India.

Last but not the least, the AUA guidelines [3] state that the optimal strategy for stone management must take into consideration patient health and economic outcomes. Stone-free requirement is global but economic implications are regional. In this context, the treatment options for similar sized stones may vary for a particular patient located in Europe or Asia. Hence, we feel this paper could be considered as a benchmark for future multicentre trials investigating treatment options and strategies for urolithiasis in South Asia.

Mahesh R. Desai and Arvind P. Ganpule
Department of Urology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India

 

Read the full article

 

References

 

1 Rizvi SA, Hussain M, Askari SH, Hashmi A, Lal M, Zafar MN. Surgical outcomes of percutaneous nephrolithotomy in 3402 patients and results of stone analysis in 1559 patients from a single centre in Pakistan. BJUInt 2017; 120: 702–9

 

2 Desai M, Jain P, Ganpule A, Sabnis R, Patel S, Shrivastav P. Developments in technique and technology: the effect on the results of percutaneous nephrolithotomy for staghorn calculi. BJU Int 2009; 104:542–8

 

3 Assimos D, Krambeck A, Miller NL et al. Surgical management of stones: American Urological Association/Endourological Society Guideline. Available at: https://www.auanet.org/guidelines/surgical-management-of-stones-(aua/endourological-society-guideline-2016). Accessed August 2017

 

Editorial: Anomalous observation with regard to PCa in cancer research

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In science, reports showing data deviating from what is expected are called anomalous observations. Metabolic syndrome (MetS) is a promoter of cancer at almost all sites [1]; however, when it comes to prostate cancer (PCa), a series of reports have been published showing an inverse relationship between MetS and its aspects and incident PCa. This lack of coherence in cancer research seriously hampers efforts to fight cancer disorders. It is therefore crucial to find an explanation for this incoherence.

In the search for a reasonable explanation for this anomalous observation, a hypothesis has been formulated, based on the study by Häggström et al. [2], and stating that the PSA-driven diagnostic procedure in PCa, which creates low-stage incident PCa material, is the culprit. The PSA-driven diagnostic procedure introduces several bias mechanisms, which tend to protect men with MetS from being diagnosed with PCa. Thus, men with MetS and its aspects are under-represented in PCa populations generated by PSA-driven diagnostics, thereby creating a distorted incident PCa population. This hypothesis also predicts that high-stage PCa, as well as non-localized and lethal PCa, are not subject to these bias mechanisms, as a minor reduction in the PSA level is of no importance for the PCa diagnosis at these high PSA levels. Finally, the hypothesis predicts that the link between MetS and incident PCa is stage-dependent. A study testing this hypothesis is now in progress.

Several studies have reported that men with MetS had lower PSA levels compared with men without MetS. Zhao et al. [3] address this specific question in this issue of BJUI and confirm that the presence of MetS was independently associated with a lower PSA level and that the enlarged prostate gland, which is an aspect of MetS, partly concealed an even greater PSA level reduction [3]. The findings indicate that a bias mechanism inverses the link between MetS and incident PCa and support the above-mentioned hypothesis.

In short, the following bias mechanisms have been described. MetS is associated with greater body fat with increased aromatase activity, resulting in a reduced testosterone level, which, in turn, is related to a reduced PSA level, as the production of PSA is under androgen control. Another possible bias mechanism, leading to men with MetS being diagnosed less often with PCa, is that these men are more likely to be obese. It is well established that men with a higher BMI also have larger plasma volumes and therefore have greater haemodilution of the PSA production, resulting in a lower PSA level. This means that incident PCa is diagnosed less often in men with MetS, as their PSA level is lower. MetS is also associated with an enlarged prostate gland volume, which means that fewer incident PCas are diagnosed, given the same tumour volume and the same number of biopsies. Another bias mechanism is that a high proportion of men with high socio-economic status undergo PSA testing in the PSA era. It is well established that men with a high socio-economic status have a lower prevalence of MetS and therefore have higher PSA levels, as indicated by the present report in the BJUI [3], and an elevated risk of PCa. Thus, multiple bias mechanisms seem to conceal low-stage PCa in the PSA era.

If it could be confirmed that the negative relationship between MetS and incident PCa is a spurious observation as a result of bias mechanisms, this would open the door for the MetS hypothesis regarding the promotion of multiple cancer disorders. This door has previously been closed by findings in a series of reports of an inverse relationship between MetS and its aspects and incident prostate cancer. Furthermore, this could lead to increased efforts to fight the metabolic aberrations of MetS. It is now well established that MetS and its aspects could be reduced by changes in lifestyle, including physical activity and diet. The most convincing evidence of the effect of diet on MetS comes from studies involving decreased intake of carbohydrates and increased intake of unsaturated fats. Recently, leading authorities in nutrition, endocrinology and metabolism presented a critical review and concluded that carbohydrate restriction is the single most effective intervention to reduce all features of MetS [4]. Another review concluded that carbohydrate restriction is one of the few common interventions that target all features of MetS [5]. This conclusion has recently been confirmed in a meta-analysis by Mansoor et al. [6].

In conclusion, new knowledge challenges the anomalous observation of PCa showing a negative relationship between MetS and PCa. The credibility of the hypothesis that MetS is an important promoting factor for cancer at almost all sites is strengthened. MetS could be treated effectively with a low carbohydrate and high fat diet.

Jan Hammarsten, MD, PhD
Department of Urology, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden

 

Read the full article

 

References

 

1 Esposito K, Chiodini P, Colao AM et al. Metabolic syndrome and risk of cancer. Diabetes Care 2012; 35: 2402–11 

 

2Haggstrom C, Stocks T, Ulmert D et al. Prospective study on metabolic factors and risk of prostate cancer. Cancer 2012; 118: 6199–206

 

3 Zhao S, Xia M, Tang J et al. The actual lowering effect of metabolic syndrome on serum prostate-specific antigen levels is partly concealed by enlarged prostate: results from large-scale population-based study. BJU Int 2017; 120: 482–9

 

4 Feinman RD, Pogozelski WK, Astrup A et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition 2015;31: 1–13

 

5 Accurso A, Bernstein RK, Dahlqvist A et al. Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for critical appraisal. Nutrition & Metabolism 2008; 5: 9

 

6 Mansoor N, Vinknes UJ , Veierod MB et al. Effects of low-carbohydrate diets v. low fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomized controlled trials. Br J Nutrition 2016; 115: 466–7

 

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