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Editorial: Examining the role of centralisation of radical cystectomy for bladder cancer

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Despite the high risk of postoperative complications and/or death, radical cystectomy (RC) is currently considered as the standard of care for patients with muscle-invasive bladder cancer (MIBC) without clinical evidence of metastases at initial diagnosis. As an alternative, trimodality bladder-sparing therapy with a potentially more favourable toxicity profile has been developed over recent decades, but definitive surgery may provide better cancer control outcomes, especially in fit individuals. Consequently, efforts have been made recently to improve RC quality by introducing new concepts in the perioperative management of patients with MIBC. For example, the implementation of robot-assisted techniques and enhanced recovery protocols may help to reduce surgical stress and facilitate discharge after early rehabilitation. Nonetheless, such valuable interventions are more likely to be delivered at expert centres in MIBC management.

Interestingly, given that surgical experience mostly comes from surgical volume, numerous studies suggest that there is an inverse relationship between hospital as well as surgeon volume and morbidities for major surgeries including RC. Specifically, a recent meta-analysis showed that high-volume hospitals (odds ratio [OR] 0.55, 95% CI: 0.44–0.69; P < 0.001) and surgeons (OR 0.58, 95% CI: 0.46–0.73; P < 0.001) were significantly associated with a lower risk of death after RC [1]. As a result, centralisation of RC at high-output centres has been advocated worldwide to optimise perioperative management of patients with MIBC and improve short-term outcomes.

In this issue of the BJUI, Afshar et al. [2] eloquently show that such a healthcare policy can be effective at the population level. The authors impressively collected perioperative information on >15 000 RC patients from the Hospital Episode Statistics (HES) dataset in England, where the ‘Improving Outcomes Guidance’ (IOG) programme recommends since 2002 that RC should be performed by surgeons operating at least five cases per year at centres carrying out ≥50 procedures per year. Interestingly, they found that the proportion of RC performed in discordance with IOG guidelines decreased from 60.7% in 2003 to 12.4% in 2013. This resulted in a significant improvement in the overall 30-day crude mortality rate, with a reduction from 2.7% to 1.5% over the 11-year period (P = 0.02). After adjusting for available confounding, RC patients in the non-IOG-compliant group were more likely to die at 30 days (OR 1.41, 95% CI: 1.13–1.76) or 1 year (OR 1.31, 95% CI: 1.21–1.43) as compared to those in the IOG-compliant group. When analysing the incremental effect of hospital volume, each extra RC per year reduced the risk of death at 30 days and 1 year by 1.5% (OR 0.985, 95% CI: 0.977–0.992) and 1% (OR 0.990, 95% CI: 0.988–0.993), respectively. Although there was no significant difference in the odds of postoperative complications between the two groups (OR 0.96, 95% CI: 0.88–1.04), the risk of re-intervention was higher in the non-IOG-compliant group (OR 1.20, 95% CI: 1.12–1.30). It is noteworthy that, as observed for the risk of death, each extra RC decreased the risk of re-intervention (OR 0.99, 95% CI: 0.991–0.995). In conclusion, the findings by Afshar et al. [2] suggest that urologists have embraced centralisation of care for RC patients in England and this is likely to have positively affected the short-term outcomes.

Although, as acknowledged by the authors, many limitations related to the administrative nature of the HES dataset (e.g. missing data or coding errors) may have influenced the aforementioned results, other reports from the USA are consistent with this study. Specifically, it has been estimated that up to 40% of the decline in 30-day mortality after RC from 2000 to 2008 was attributable to centralisation of care [3]. In addition, other RC quality criteria, such as adequate pelvic lymph node dissection at the time of surgery, have improved after similar centralisation in the Netherlands between 2006 and 2012 [4]. As such, centralisation of RC offers many undisputable advantages, but given that travel distance to the treating facility may represent an important barrier for patients with MIBC seeking surgical care, concerns have been raised with regards to potential drawbacks, including increased time to definitive surgery. However, a recent report from the USA showed that, although centralisation of RC has led to a decrease overall access to the treating facilities, the process simultaneously improved access to high-volume centres [5]. It is noteworthy that hospital volume standards for centralisation of RC should not be set too high to avoid unreasonable travel burdens on patients with MIBC [6].

To summarise, centralisation of care is arguably the best way to go, to continue improving quality of RC and its associated short-term outcomes in the near future. Despite inherent limitations, virtually all available evidence, including the study by Afshar et al. [2], converge toward the general concept that RC patients should be managed by experienced urologists operating at expert centres with trained surgical teams.

Thomas Seisen 
Department of Urology, Pitie Salpetriere Hospital, Assistance Publique des Hopitaux de Paris, Paris Sorbonne University, Paris, France

 

 

References

 

1 Goossens-Laan CA, Gooiker GA, van Gijn W et al. A systematic review and meta-analysis of the relationship between hospital/surgeon volume and outcome for radical cystectomy: an update for the ongoing debate. Eur Urol 2011; 59: 775–83

 

2 Afshar M, Goodfellow H, Jackson-Spence F et al. Centralisation of radical cystectomies for bladder cancer in England, a decade on from the ‘Improving Outcomes Guidance’: the case for super centralisation. BJU Int 2018; 121: 217–24 166

 

 3 Finks JF, Osborne NH, Birkmeyer JD. Trends in hospital volume and operative mortality for high-risk surgery. N Engl J Med 2011; 364: 2128–37

 

4 Hermans TJ, Fransen van de Putte EE, Fossion LM et al. Variations in
pelvic lymph node dissection in invasive bladder cancer: a Dutch

 

nationwide population-based study during centralization of care. Urol
Oncol 2016;34:532. e7–532.e12

 

5 Casey MF, Wisnivesky J, Le VH et al. The relationship between centralization of care and geographic barriers to cystectomy for bladder cancer. Bladder Cancer 2016; 2: 319–27

 

6 Birkmeyer JD, Siewers AE, Marth NJ, Goodman DC. Regionalization of high-risk surgery and implications for patient travel times. JAMA 2003; 290: 2703–8

 

Editorial: Selecting patients for PCa treatment: the role of comorbidity

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The risk of dying from prostate cancer is strongly influenced by competing causes related to age and comorbidity. In the past, indiscriminate screening and treatment of prostate cancer in men with limited life expectancy have been heavily criticized. In the SPCG-4 study, Bill-Axelson et al. [1] showed that patient age significantly modified the likelihood of benefit from radical prostatectomy: while patients aged <65 years at the time of treatment saw significantly decreased risk of overall mortality, prostate cancer mortality, and metastases, those aged >65 years did not have a significant improvement in survival, despite significantly decreased risk of metastases [1]. Significant progress has since been made with regard to treatment, in offering surveillance to men unlikely to die from their prostate cancer, either because of indolent disease or competing risks.

In this issue of BJUI, Crawley et al. [2] describe the association between type 2 diabetes and receipt of curative treatment for patients newly diagnosed with intermediate- and high-risk prostate cancer. Using the Prostate Cancer database Sweden (PCBaSE), the authors convincingly show us that patients who received oral therapies or insulin for type 2 diabetes were significantly less likely to undergo curative treatment after a prostate cancer diagnosis compared with men without diabetes. They also demonstrated a gradient of effect, as men treated with insulin (with presumably more severe diabetes) were even less likely to receive curative therapies than those treated with oral agents (odds ratios 0.62 and 0.91, respectively, both compared with men without diabetes). This could have been better assessed with more objective measures of disease severity including micro- and macrovascular complications or glycated haemoglobin levels. Interestingly, the authors found that men with diabetes had more aggressive disease, with higher Gleason scores, a greater proportion of biopsy cores involved with cancer, and higher PSA levels. We therefore must consider the question, is withholding curative therapy from these patients undertreatment or appropriate?

Mortality rates for men with diabetes are significantly higher than for those without. Among men aged ≥50 years, life expectancy is 7.5 years (95% CI: 5.5–9.5) shorter for those with diabetes [3]. The effect of diabetes on mortality is mediated through cardiovascular disease, the leading cause of mortality among men diagnosed with prostate cancer [4]. Thus, competing risks of mortality, rather than prostate cancer mortality, are likely to be the limiters of these patients’ life expectancy.

Interestingly, the authors found that men with diabetes who received pharmacotherapy for dyslipidaemia or cardiovascular disease had a similar likelihood of receiving treatment as men treated for diabetes alone [2].

The authors then assessed whether receipt of curative treatment was associated with overall survival among patients with diabetes. The authors conclude that curative treatment was associated with improved overall survival among these men [2], with differences in both prostate cancer and non-prostate cancer mortality. We should be sceptical of these findings, however, because of significant selection bias and confounding as the authors present only unadjusted results. The greater comorbidity and more aggressive cancers among men with diabetes in this cohort may explain a large portion of the differences in non-prostate cancer mortality and prostate cancer-mortality, respectively, separate from the effect of local treatment. This is supported by the authors’ observation that men with type 2 diabetes treated with curative intent had better overall survival than men with type 2 diabetes without prostate cancer [2]. In fact, non-prostate cancer causes contributed to the majority of deaths in these men with intermediate- and high-risk cancer, regardless of receipt of curative treatment. Lastly, with respect to survival, it should be noted that previous analyses have demonstrated a protective effect of metformin on overall and prostate cancer mortality among men with diabetes [5].

What are we to take from this paper? First, men with diabetes appear to present with more aggressive disease at the time of diagnosis. This may relate to decreased prostate cancer screening, lower PSA levels among screened men leading to a decreased index of suspicion [6], or a lower likelihood of biopsy at a given PSA level. Further, we believe that this paper shows that Swedish urologists are understandably providing curative prostate cancer treatment to men with the potential to benefit from these interventions, while sparing men with significant medical comorbidity the side effects of such therapies which are unlikely to benefit them. Caution should be applied in using these data to reflexively justify more aggressive screening and treatment in all men with diabetes. Individualized decision-making should be made on a case-by-case basis based on the best estimates of risks of prostate cancer and non-prostate cancer mortality.

Christopher J.D. Wallis,*† Raj Satkunasivam,*† and Bimal Bhindi‡
*Division of Urology, Department of Surgery, University of Toronto, †Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada and ‡Department of Urology, Mayo Clinic, Rochester, MN, USA

 

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References

 

1 Bill-Axelson A, Holmberg L, Garmo H et al. Radical prostatectomy or watchful waiting in early prostate cancer. New Engl J Med 2014; 6: 932–42

 

2 Crawley D, Garmo H, Rudman S et al. Association between type 2 diabetes, curative treatment and survival in men with intermediate and high risk localized prostate cancer. BJU Int 2018; 121: 209–16

 

3 Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder W. Associations of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease. Arch Intern Med 2007; 167: 1145–51

 

4 Ketchandji M, Kuo YF, Shahinian VB, Goodwin JS. Cause of death in older men after the diagnosis of prostate cancer. J Am Geriatr Soc 2009;57: 24–30

 

5 Margel D, Urbach DR, Lipscombe LL et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol 2013; 31: 3069–75

 

6 Werny DM, Saraiya M, Gregg EW. Prostate-specific antigen values in diabetic and nondiabetic US men, 2001–2002. Am J Epidemiol 2006; 164: 978–83

 

Editorial: Even ‘low-dose’ cabazitaxel requires careful and meticulous patient selection

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In the present issue of BJUI, Clèment-Zhao et al. [1] have evaluated the safety profile of a 2-weekly regime of cabazitaxel (CBZ) at a dose of 16 mg/m2 in 43 patients with progressing, metastatic castration-resistant prostate cancer (mCRPC). Treatment was planned to have been delivered for a total of six cycles, with each cycle consisting of two 2-weekly applications of CBZ. The majority of patients had already received two life-extending systemic therapies, such as docetaxel and abiraterone acetate. Despite the prophylactic use of granulocyte colony-stimulating factor (G-CSF), 11.6% and 4.7% of patients developed grade ≥3 neutropenia or febrile neutropenia, respectively, and one patient even died from treatment-related toxicities. Only 75% of the scheduled six cycles could be delivered, although dose reduction of 20% was carried out in 37.2% of the patients. The authors recommend this type of treatment for elderly and frail patients and they provide the reader with the impression that the delivery of such a toxic regime in elderly and frail patients is accordance with the guidelines [2].

Based on the International Society of Geriatric Oncology (SIOG) guidelines [2], it is evident that the term ‘frailty’ requires a dedicated and sophisticated geriatric assessment using, for example, the G8 questionnaire. If a score <14 is calculated on this questionnaire, and the patients have been identified as having irreversible impairment, an intensive geriatric intervention might be undertaken to correct the underlying comorbidities. Only in the presence of correctable comorbidities should an adapted cancer therapy be initiated, while in their absence best supportive care seems to be the optimal approach. Of the 43 patients in the present phase II trial, none underwent a geriatric assessment and three-quarters of the patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; therefore, only a minority of the treated patients represented frail patients, and conclusions should be drawn with great caution, also considering the relatively low number of patients recruited.

The frequency of 11.6% and 4.7% of grade 3/4 neutropenia and neutropenic fever, respectively, and an overall frequency of 34.9% grade 3/4 treatment-emergent adverse events is still quite high compared with the data from studies on the German Early-Access Programme (EAP) and the European EAP on CBZ, which included 111 and 746 patients with similar disease characteristics, of whom 7.2% and 15%, respectively, developed grade ≥3 neutropenia, despite non-regular use of G-CSF [3, 4].

Several factors might have contributed to the relatively high frequency of treatment-emergent adverse events in the present study. Firstly, the cumulative CBZ dose was 144 mg/m2 in the present study as compared with 100 mg/m2 in the European EAP and 162.5 mg/m2 in the German EAP, so that there was not a significant reduction in dose despite the lower dose delivered at each cycle. This might have contributed to impairment of bone marrow function over time. Secondly, bone marrow reserve appeared to differ among treated patients: ~50% of patients already had neutrophil counts below the normal values. As we have shown recently, neutrophil counts <4 000/mm3 were associated with an odds ratio of 1.73 (95% CI 1.25–2.39; P < 0.001) for developing grade 3/4 neutropenia [4]. Thirdly, age ≥75 years, but not age <75 years or ECOG performance status ≥2, was associated with a 1.66-fold (95% CI 1.09–5.52; P = 0.018) increased risk of significant neutropenia in the above-mentioned studies [3, 4]; however, it is unclear how many patients were aged >75 years in the present study.

As a result of these factors, it is still necessary to carefully select elderly patients with mCRPC prior to the recommendation of cytotoxic CBZ therapy, even at a reduced dose. Despite the fact that there is some weak evidence that severe neutropenia might be associated with a survival benefit, we need to bear in mind that this evidence is from post hoc analysis of fit and non-elderly patients recruited in the TROPIC trial [5]. We have no meaningfuldata from a cohort of elderly and vulnerable/frail patients and we have no data at all on quality of life in these patients; therefore, we should not overtreat and we should only consider frail and elderly patients with mCRPC for CBZ treatment if they have undergone geriatric assessment that has shown correctable comorbidities. Otherwise, there are numerous other treatment options in addition to chemotherapy, including best supportive care [6].

With regard to therapeutic efficacy, we always find it difficult to report median overall survival times of 15.2 months when the median follow-up time is only 12.9 months.

Axel Heidenreich and David Pfister
Department of Urology, Uro-Oncology, Robot-Assisted and Reconstructive Urological Surgery, University of Cologne, Cologne, Germany

 

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References

 

1Clement-Zhao A, Auvray M, Aboudagga H et al. Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer. BJU Int 2018; 121: 203–8

 

2 Droz JP, Aapro M, Balducci L et al. Management of prostate cancer in older patients: updated recommendations of a working group of the International Society of Geriatric Oncology. Lancet Oncol 2014; 15: e404–14

 

3 Heidenreich A, Scholz HJ, Rogenhofer S et al. Cabazitaxel plus prednisone for metastatic castration-resistant prostate cancer progressing after docetaxel: results from the German compassionate-use programme. Eur Urol 2013; 63: 977–82

 

4 Heidenreich A, Bracarda S, Mason M et al. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: results of the European compassionate-use programme. Eur J Cancer 2014; 50: 1090–9

 

5 Meisel A, von Felten S, Vogt DR et al. Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): a post-hoc analysis of the TROPIC phase III trial. Eur J Cancer 2016; 56: 93–100

 

6 Fitzpatrick JM, Bellmunt J, Fizazi K et al. Optimal management of metastatic castration-resistant prostate cancer: highlights from a European Expert Consensus Panel. Eur J Cancer 2014; 50: 1617-27

 

The challenge with systematic reviews of non-randomised studies in urology

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In this issue, BJU International has made the conscious decision to publish a systematic review (SR) and meta-analysis (MA) by Guo et al. [1]to inform the question of whether patients undergoing nephrouretectomy for upper tract urothelial carcinoma are at increased risk of worse oncological outcomes. This question was also the topic of a similar review by Marchioni et al. [2] published earlier this year in this journal. Both studies were submitted around the same time and underwent independent, parallel peer review that resulted in different editorial decisions. Given their similarity in methodological quality they both deserved similar consideration for publication, which the journal is hereby honouring.

At the same time, this provides the unique opportunity to reflect on methodological developments in the field and BJU International‘s efforts to raise the bar of the methodological quality of SRs, which include the provision of an Assessment of Multiple Systematic Reviews (AMSTAR) rating [3]. AMSTAR is a validated tool to assess the components of a SR on an 11-point scale (0–11), with higher scores reflecting higher methodological rigor. An updated version of this tool has recently been provided, which offers greater clarity in interpretation [4]. Another related instrument that has become available is the Risk of Bias in Systematic Reviews (ROBIS), which assesses the study limitations in SRs (i.e., the relevance of the review, concerns with the review process, and potential bias introduced during the review) [5]. Meanwhile, while it would be premature to claim success, it is our impression that BJU International’s initiative to provide AMSTAR ratings is making a valuable contribution in raising awareness for such methodological issues and improving the transparency of published reviews.

As BJU International takes a lead in promoting high-quality SRs in urology, the journal has seen a considerable increase in the number of submissions, including SRs of non-randomised studies (NRS). Whilst much of what we practice on a day-to-day basis is based on evidence from NRS, studies of those designs have infrequently been included in the Cochrane Library, which has pioneered much of the underlying methodology. This is for a few reasons: First, the ‘garbage in–garbage out’ phenomenon; if the underlying individual studies only provide very low-quality evidence, combining these studies will rarely enhance the confidence we place in their results. Second, the need for methodological advances in the assessment and analyses of NRS. Third, when high-quality evidence from randomised controlled trials (RCTs) is available, it may be inefficient to review the NRS literature.

However, progress is being made on the methodology front. Members of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group are credited with having developed an approach for rating the quality or certainty of evidence from randomised and NRS to inform decision making [6]. While a body of evidence from RCTs, which starts as high-quality evidence, may be downgraded for study limitations, a body of evidence from NRS, which starts as low-quality evidence, may be upgraded for one of three reasons, most commonly for large magnitude of effect [7]. The underlying assumption is that, whilst we have to assume that bias is likely to be present in these studies, it is unlikely to explain the entire observed effect.

It nevertheless remains critical to assess the risk of bias of NRS. While the Newcastle-Ottawa scale (as used in both of these SRs) is a widely used instrument to evaluate risk of bias in NRS, it has critical limitations that the recently developed Risk Of Bias In Non-randomised Studies – of Interventions (ROBINS-I) seeks to overcome [8]. ROBINS-I evaluates NRS by using a standardised comparison to an RCT (i.e. target trial) [9]. In this way, ROBINS-I captures the bias inherent to studies without proper randomisation or allocation concealment, namely the lack of a balance of known and unknown confounders and selection of participants. ROBINS-I allows users to fundamentally start all studies at the same quality level, providing the transparency requested by some SR authors conducting SRs of NRS.

While ureterorenoscopy before nephroureterectomy may indeed increase the risk of intravesical recurrence as the authors suggest, additional exploration would be needed to make a statement about the causality of the relationship. Guo et al. [1] conducted sensitivity analyses to describe the potential for bias introduced by confounders of previous bladder tumour history and bladder-cuff management, thereby increasing our confidence that the observed effect may be closer to the truth. It seems equally important to note that Guo et al. found no increased risk in cancer-specific, recurrence-free or overall survival, which are other outcomes of potentially greater patient importance.

Understanding the inherent limitations of NRS, and placing their findings into appropriate clinical context are critical to the conduct of SRs. Moving forward, BJU International will continue to seek out the highest quality reviews that make use of the best, up-to-date methodology. We hope that these efforts will both serve as a beacon for the research community, but more importantly, result in improved evidence-based care for our patients.

Philipp Dahm*, Jae Hung Jung† and Rebecca L. Morgan‡
*Department of Urology, Minneapolis VA Medical Center, University of Minnesota, Minneapolis, MN, USA, †Department of Urology, Yonsei University Wonju College of Medicine,
Wonju, Korea and ‡Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada

 

References

 

1 Guo RQ, Hong P, Xiong GY et al. Impact of ureteroscopy before radical nephroureterectomy for upper tract urothelial carcinomas on oncological outcomes: a meta-analysis. BJU Int 2018; 121: 184-93

 

2 Marchioni M, Primiceri G, Cindolo L et al. Impact of diagnostic ureteroscopy on intravesical recurrence in patients undergoing radical nephroureterectomy for upper tract urothelial cancer: a systematic review and meta-analysis. BJU Int 2017; 120: 313–9

 

3 Dahm P. Raising the bar for systematic reviews with Assessment of Multiple Systematic Reviews (AMSTAR). BJU Int 2017; 119: 193

 

4 Shea BJ, Reeves BC, Wells G et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017; 358: j4008

 

5 Whiting P, Savovic J, Higgins JP et al. ROBIS: a new tool to assess risk of bias in systematic reviews was developed. J Clin Epidemiol 2016; 69: 225–34

 

6 Guyatt GH, Oxman AD, Vist GE et al. GRADE: what is “quality of evidence” and why is it important to clinicians? BMJ 2008; 336: 995–8

 

7 Guyatt GH, Oxman AD, Sultan S et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol 2011; 64: 1311–6

 

8 Deeks JJ, Dinnes J, D’Amico R et al. Evaluating non-randomised intervention studies. Health Technol Assess 2003; 7: iii–x, 1–173

 

9 Sterne JA, Hernan MA, Reeves BC et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016; 355: i4919

 

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

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

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

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

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

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

Matteo Soligo, Vidit Sharma and R. Jeffrey Karnes
Mayo Clinic Urology, Rochester, MN, USA

 

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References

 

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

 

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

 

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

 

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

 

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

 

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

 

Editorial: The new frontier of prostate biopsy: determining the role of image-guidance in moving the needle

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One of the most pressing topics in urological oncology concerns the role of MRI/ultrasonography (US)-fusion guided biopsies in detecting prostate cancer. The literature on this emerging technology is permeated by questions regarding when it should be used, how it should be performed, and which patients stand to benefit. The stakes are high to figure this out, as real patients will continue to suffer from missteps made in diagnosis and treatment of prostate cancer whilst we seek to improve our detection methods.

In this issue of BJUI, Borkowetz et al. [1] compare prostate cancer detection rates between MRI/US-fusion targeted and conventional systematic biopsies. They prospectively enrolled a cohort of biopsy-naïve men who had an elevated PSA level and/or an abnormal DRE. All men received both a transperineal MRI/US-fusion biopsy and a systematic TRUS-guided biopsy. They found that combining both approaches led to improved detection rates for clinically significant and overall prostate cancer compared to either method alone.

A strength of this study [1] is its focus on biopsy-naïve men, for which data on the comparison of biopsy techniques is relatively limited. Siddiqui et al. [2] were instrumental in demonstrating that targeted MRI/US-fusion biopsy, compared to the systematic TRUS biopsy, was associated with improved diagnostic accuracy for higher-risk tumours and decreased detection of low-risk disease. However, the large majority of men in the study had received a prior biopsy, making it difficult to generalise the results to biopsy-naïve men. Focusing on biopsy-naïve men is of great importance – men referred for a biopsy after an elevated PSA level or abnormal DRE increasingly face conflicting opinions about the next best step in diagnostic evaluation, especially given the recent influx of imaging and biomarker tests that aim to guide this decision point.

One group previously compared MRI-guided and systematic TRUS biopsy in a large group of biopsy-naïve of men and found the MRI-guided in-bore technique to be superior in detecting significant cancers and avoiding insignificant cancers [3]. However, that study was limited by both its definition of ‘significant cancer’ (it included Gleason 3 + 3 disease) and the variance in the definition of ‘low-risk’ cancer between MRI-guided and TRUS biopsies. By contrast, the present authors uniformly defined significant cancer as Gleason ≥3 + 4. This is just one example highlighting the widespread disagreement over the parameters used to measure the efficacy of targeted-biopsy techniques in cancer detection. Continued incorporation of standardised scales such as the Prostate Imaging Reporting and Data System (PI-RADS), which was also used in the accompanying article, will help to mitigate some of this disagreement in future studies. Of course, these standardised scales are still subject to inter- and intra-observer variability, which may decrease with further clarification of the grading systems, as well as appropriate reader training [4].

Whilst Borkowetz et al. [1] helped to fill important gaps in the literature, their study was not without limitations. They included PI-RADS 2 scores for targeted biopsies although many urologists would consider these lesions insignificant and not worth targeting. Furthermore, comparing a transperineal MRI/US-fusion with a transrectal systematic approach makes it difficult to separate the true effect of the targeted approach from that of the anatomical approach. Using both methods in each patient also precludes any comparison of complication rates between the biopsy approaches, an important clinical endpoint for both the urologists administering the biopsies and the patients enduring the complications.

Methodology aside, the new frontier of prostate biopsy technique still relies on a basic triad of efficacy: (i) improved accuracy of cancer detection, (ii) reduced complication rates, and (iii) manageable cost and practicality of widespread implementation. For the first tenet, the recently published PROstate MRI Imaging Study (PROMIS) trial cemented the ability of multi-parametric MRI to detect clinically significant prostate cancer with greatly improved sensitivity and negative predictive value over TRUS [5]. The ongoing randomised PRostate Evaluation for Clinically Important Disease: Sampling Using Image-guidance Or Not? (PRECISION) trial will hopefully add to the step taken by Borkowetz et al. [1], by comparing MRI-targeted and systematic TRUS biopsies on the outcomes of accuracy in cancer detection, adverse events, patient health-related quality of life, and cost [6]. Continued investigation in all of these areas will be crucial to guiding how we move the needle in prostate cancer diagnostics.

Sean A. Fletcher, Sebastian Berg and Quoc-Dien Trinh

 

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

 

References

 

1 Borkowetz A, Hadaschik B, Platzek I et al. Prospective comparison of transperineal magnetic resonance imaging/ultrasonography fusion biopsy and transrectal systematic biopsy in biopsy-naive patients. BJU Int 2018;121: 53–60

 

2 Siddiqui MM, Rais-Bahrami S, Turkbey B et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA2015; 313: 390–7

 

3 Pokorny MR, de Rooij M, Duncan E et al. Prospective study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasound-guided biopsy versus magnetic resonance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate biopsies. Eur Urol 2014; 66: 22–9

 

 

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

 

6 ClinicalTrials.gov. PRostate Evaluation for Clinically Important Disease: Sampling Using Image-guidance or Not? (PRECISION), Identification No. NCT02380027 (2017). Available at: https://clinicaltrials.gov/ct2/show/NCT02380027. Accessed October 2017.

 

Editorial: Impact of warm ischaemia time during partial nephrectomy on renal function – is it really a matter of time?

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In the latest edition of the BJUI, Lee et al. [1] have revisited the question of defining the ideal limit of warm ischaemia time (WIT) and its impact on postoperative renal function in patients undergoing partial nephrectomy (PN).

Partial nephrectomy has replaced radical nephrectomy as the preferred treatment for T1 renal masses. This publication challenges the theory that ischaemic nephropathy is inevitable if the renal vessels are clamped beyond 30 min, leading to a long-term decline in renal function.

The authors in this series are to be commended for analysing a prospectively collected database on 1 816 patients in two institutions who underwent PN for clinical T1 renal tumours. Their primary endpoint was to investigate the impact of prolonged WIT on long-term renal function focusing on two clinical endpoints; chronic kidney disease, as estimated by an estimated GFR of <60 mL/min/1.73 m2, and major renal function deterioration defined as an increase in creatinine of >25% of the preoperative value.

Warm ischaemia time using a threshold of 30 min created two comparative groups. Patients were followed for up to 40 months after surgery. In addition to this, patients were further sub-stratified into five subgroups, critiquing the effect of WIT up to 50 min. A key feature of this paper [1] is the use of propensity score matching to adjust for any potential preoperative confounders affecting postoperative renal function, a technique also allowing matching of the two groups.

The authors correctly emphasise the direct relationship between tumour size and duration of WIT, with larger tumours requiring excision of more renal parenchyma and adding to ‘on-clamp’ time. Tumour size and renal function are vital determinants of suitability for PN [2]. This publication [1] clearly demonstrates that although large tumour size equated with prolonged clamp time, this was not the sole determinant of impaired long-term renal function.

The importance of other independent variables such as preoperative renal function, patient age and preserved renal parenchyma have been highlighted here as potentially playing a greater role than was previously appreciated.

The second and possibly more remarkable finding from this paper is that ischaemic time was not an independent predictor of ultimate renal function after PN. This contrasts with most other reports to date. Although not recommending using a WIT of up to 50 min, the results here suggest this may not be relevant to future renal function. It appears that long-term renal function after PN is primarily determined by the quantity and quality of renal parenchyma preserved, although the type and duration of ischaemia remain the most important modifiable factors, and warrant further evaluation [3].

When discussing this topic, it is interesting to refer to the initial bench work on this issue. The current approach to WIT is extrapolated from data derived from the histological changes occurring in nephrons during operative stone cases. From the data presented in this and other studies, it seems more relevant than ever to conduct clinical trials to assess this appropriately. Traditionally the time threshold for WIT is taken as 30 min, an arbitrarily placed time-point based on the above laboratory data. Beyond this value in the setting of room temperature renal ischaemia creates an array of injury centred on cellular adaptations beginning ~20 min after clamping and persisting beyond 60 min. This indicates that the traditional 30-min limit of WIT is a somewhat subjective time point and was not based on clinical outcomes.

Previous evidence suggests a 5% increase in risk for acute renal failure for every additional minute of WIT [4]. It is hard to ignore such data in exchange for this a contemporary study when so much is at stake for patient longevity. Advocators of zero-ischaemia PN have shown that those who benefit most from a zero-ischaemia technique are those with the poorest baseline renal function [5]. Most of these studies have shown that the renal functional outcomes are either equivalent or superior in zero-ischaemia cases involving small renal tumours [6].

On balance, the authors are to be credited with tackling such a controversial matter and highlighting the lack of good quality laboratory data. Clearly, factors other than WIT contribute to postoperative renal function but for now we must conclude that every minute ‘on-clamp’ does count.

Eva M. Bolton and Thomas H. Lynch
St. James’s Hospital, Dublin, Ireland
Read the full article

References

1 Lee H, Song BD, Byun SS, Lee SE, Hong SK. Impact of warm ischaemia time on postoperative renal function after partial nephrectomy for clinical T1 renal cell carcinoma: a propensity score-matched study. BJU Int 2018; 121: 46–52

 

2 Volpe A, Blute ML, Ficarra V et al. Renal ischemia and function after partial nephrectomy: a collaborative review of the literature. Eur Urol 2015; 68: 61–74

 

3 Lane BR, Russo P, Uzzo RG et al. Comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys reveals predominant role of nonmodifiable factors in determining ultimate renal function. J Urol 2011; 185: 421–7

 

4 Thompson RH, Lane BR, Lohse CM et al. Every minute counts when the renal hilum is clamped during partial nephrectomy. Eur Urol 2010;58: 340–5

 

5 Porpiglia F, Bertolo R, Amparore D et al. Evaluation of functional outcomes after laparoscopic partial nephrectomy using renal scintigraphy: clamped vs clampless technique. BJU Int 2015; 115: 606–12
 
6 Salami SS, George AK, Rais-Bahrami S, Okhunov Z, Waingankar N, Kavoussi LR. Off-clamp laparoscopic partial nephrectomy for hilar tumors: oncologic and renal functional outcomes. J Endourol 2014; 28: 191–5

 

Editorial: Viewpoint – Rationing and Surgical Care

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Limitation in the provision of surgical care has many causes. In a nationalised healthcare system, this often reflects lack of funds, leading to rationing of clinical services. Rationing itself takes a number of forms. Deliberate exclusion of specific operations (usually elective) or specific patient groups (smokers, obese) are the most common examples, but strategic extension of waiting times by the removal of ‘target’ times can also be used as a rationing tool.

Many surgeons are dismayed by these decisions. They feel that the surgical patient is unfairly targeted as the clinical and cost-effectiveness of many planned surgical interventions have been well characterised. Surgeon and institutional outcomes are freely available – unlike the situation in many non-surgical specialties, so how can it be fair to pick on the surgical patient?

The idea that non-urgent elective surgery falls into neat categories where delay has no adverse consequences for the patient mystifies many surgeons. Whilst all would advocate a healthy diet, exercise, weight loss and smoking cessation, decisions to withhold surgery from the obese or those who smoke is rarely evidence-based. Rationing based on such prejudice soon becomes illogical. Why should the obese cancer patient receive an operation when the obese incontinent patient cannot?

In the long term, the absence of a substantial volume of ‘routine’ surgery damages training as exposure to such procedures is limited. Surgery has become the soft target for rationing clinical services. Surgeons should make their patients aware of how this process will affect them. Healthcare planners need to hear a public voice as well as that of the clinicians.

Just occasionally, an apparent limitation can be beneficial. In this issue of the BJUI, the National Institute for Health and Care Excellence (NICE) provides clear guidance on preoperative testing. This is based on sensible recommendations such as: avoiding routine urine dipstick testing, routine chest X-rays, and glycated haemoglobin (HbA1c) in non-diabetic patients. All surgeons irrespective of their specialty would benefit from paying close attention to these important guidelines [1].

Derek Alderson

President of the Royal College of Surgeons of England; Emeritus Professor of Surgery, University of Birmingham; Editor-in-chief of BJS Open.

Read the full article

Reference

1 National Institute of Health and Care Excellence (NICE). Routine preoperative tests for elective surgery: © NICE (2016) Routine preoperative tests for elective surgery. BJU Int 2018; 121: 12–6

 

Editorial: LDR prostate brachytherapy in younger men

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Langley et al.1 report on the oncological and functional outcomes of men treated with low dose rate (LDR) prostate brachytherapy in men 60 years old or younger. 597 patients with a median (range) age of 57 (44-60) years had a median follow-up of 8.9 (1.5-17.2) years. The 10- year post-implant relapse free survival using the Phoenix definition for biochemical failure (nadir plus 2 ng/ml) was 95%, 90% and 87% for low, intermediate and high-risk disease, respectively. Potency was preserved in 75% of men potent before treatment. The authors concluded that LDR brachytherapy is an efficacious treatment with excellent long-term control of prostate cancer in men ≤60 years at time of treatment. While the results from this investigation are encouraging, enthusiasm should be tempered given the short follow up, long natural history of prostate cancer and the long-life expectancy for these younger patients.

Although the overall median follow-up was 8.9 years, the calculation of PSA-free failure was derived from a median follow-up of 5.9 years. As this investigation did not identify men who may also be at risk of failure because of a rising PSA and who have not yet reached the Phoenix threshold, I anticipate longer-follow up will further reduce their favorable results. Of the 597 men, 6 (1%) died from prostate cancer. The low incidence of prostate cancer mortality, while impressive, also reflects the short follow-up. Our group has previously reported that PCSM substantially increases between the 10th and 15th year post treatment. The experience of these physicians in prostate brachytherapy is demonstrated in their favorable dosimetry outcomes-the median D90 was 106.4% of the prescription (145 Gy). These results (median D90 154.3 Gy), which were determined and computed on the day of the implant would be 10-15% higher had the CT scans been done on day 30 as most centers do. We and others have reported that patients receiving higher dose implants have improved biochemical and cancer-specific outcomes. While these data help explain their favorable oncological outcomes, they should also serve as a guide to other brachytherapy programs where implant quality should be a primary objective. Erectile function was preserved in 75% of men. These data are consistent with other reports of younger men who were treated for prostate cancer with surgery or radiation. Because this was not a randomized study, it is not possible to make direct comparisons between surgery and brachytherapy. The selection of an IIEF score of > 11 as potent might be challenged as the 12-16 group is considered to have mild to moderate ED. Nonetheless, these data are still encouraging for younger men who are considering treatment for localized prostate cancer where sexual function preservation is important.

Nelson Stone

Mount Sinai Medical Center – Urology 350 E 72nd Street, New York, New York 10021 United States

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Reference

  1. Langley SM, Soares R, Uribe J, et al. Long-term oncological outcomes and toxicity in 597 men ≤60 years of age at time of low dose rate brachytherapy for localised prostate cancer. BJU Int 2017

 

Editorial: Prostate cancer biomarkers: new scenarios in the multi-parametric magnetic resonance imaging era

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The management of prostate cancer poses difficult challenges, which is largely because we lack the necessary tools to predict its presence, and discern between indolent disease with a small chance of clinical manifestation and aggressive tumours that are more likely to be lethal.

Despite the fact that novel blood and urine tests are available, which may predict aggressive disease better than PSA; they are not routinely used due to a lack of clinical validity studies.

Tosoian et al. [1] in the present study explored the utility of prostate health index (PHI) density for detection of clinically significant prostate cancer in a contemporary cohort of men presenting for diagnostic evaluation of prostate cancer. Very interestingly the authors hypothesised that, similar to PSA density, PHI density could further improve upon the discriminative ability of PHI to detect prostate cancer. The PHI density calculation was performed using prostate volume, as determined by TRUS. Logistic regression was used to assess the ability of serum markers to predict clinically significant prostate cancer, defined as any Gleason score ≥7 cancer or Gleason score 6 cancer in >2 cores or >50% of any positive core.

They showed, albeit in a small sample size, that PHI density could further improve upon the discriminative ability of PHI and appears to be superior to PSA and other PSA derivatives for the identification of clinically significant disease [1].

However, it is noteworthy that in all studies on urine or serum biomarkers such as this, the ‘gold standard’ for cancer detection is pathological examination of multiple non-targeted systematic TRUS-guided prostate biopsies, not radical prostatectomy specimens. Intrinsically, this approach implies that no cancer predicted by the biomarker may still mean cancer missed by the biopsy.

Recently, the European Association of Urology Guidelines have introduced multi-parametric MRI (mpMRI) as a strongly recommended examination before repeating biopsy when clinical suspicion of prostate cancer persists [2]. Indeed, mpMRI is very accurate in detecting clinically significant prostate cancer, with a positive predictive value of 82% and a negative predictive value of >95% for excluding high-risk prostate cancer [3, 4].

Introducing mpMRI before prostate biopsy has the potential to improve prostate cancer sampling ink that is the most practical way to make mpMRI before biopsy economically viable for universal NHS adoption.

The aim should be the development of a clinical decision support system based on mpMRI and circulating biomarkers, as in this case PHI density evaluation, to stratify patients according to their risk of prostate cancer progression, using pathological assessment after prostatectomy as the reference standard.

Francesco Porpiglia and Stefano De Luca
Division of Urology, San Luigi Gonzaga Hospital and University of Torino, Orbassano, Italy

 

Read the full article

 

References

 

1 Tosoian JJ, Druskin SC, Andreas D et al. Prostate health index density improves detection of clinically significant prostate cancer. BJU Int2017; 120: 793–8.

 

2 Mottet N, Bellmunt J, Bolla M et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: Screening, diagnosis, and local treatment with curative intent.  Eur Urol 2016; pii: S0302-2838(16)30470-5. [Epub ahead of print]. doi: 10.1016/j.eururo.2016.08.003.

 

3 Russo F, Regge D, Armando E et al. Detection of prostate cancer index lesions with multiparametric magnetic resonance imaging (mp-MRI) using whole-mount histological sections as the reference standard. BJU Int 2016; 118: 84–94.

 

 

5 Porpiglia F, Manfredi M, Mele F et al. Diagnostic pathway with multiparametric magnetic resonance imaging versus standard pathway: results from a randomized prospective study in biopsy-naıve patients with suspected prostate cancer. Eur Urol 2016; pii: S0302-2838(16)30509-7. [Epub ahead of print]. doi: 10.1016/j.eururo.2016.08.041

 

6 Wegelin O, van Melick HH, Hooft L et al. Comparing three different techniques for magnetic resonance imaging-targeted prostate biopsies: a systematic review of in-bore versus magnetic resonance imaging- transrectal ultrasound fusion versus cognitive registration. Is there a preferred technique?. Eur Urol 2016; pii: S0302-2838(16)30446-8. [Epub ahead of print]. doi: 10.1016/j.eururo.2016.07.04

 

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