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April Editorial: The BJUI’s clinical trials initiative

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The BJUI supports clinical trials. Plain, simple, and with some new strategies.

Randomised clinical trials (RCTs) are the highest level of evidence-based medicine. We know this to be true, but we also know that RCTs are a challenge to fund, accrue patients, execute, and follow to endpoints. From a statistician’s point of view, RCTs provide unbiased estimates of the effects of different treatments. From a clinician’s point of view, RCTs provide the grandest of experiments in nature – a true test of option A vs option B. We are thrilled when one option beats the other. We can be satisfied if the options are equivalent, at least knowing the matter is settled and move on to the next question. Either way, the story lines can be rich with ongoing debate, drama, and analysis: were the cohorts truly equivalent? Was the study population generalisable? Were the treatments contemporary? Were there unintended harms/toxicities?

Allow us to illustrate some examples of what we propose to our readers. In 2003, Thompson et al. [1] published the famous Prostate Cancer Prevention Trial in the New England Journal of Medicine: ‘The influence of finasteride on the development of prostate cancer’. This landmark study has been cited 2541 times, according to Google Scholar. Looking further at impact, one can go to the www.swog.org site and query the protocol ‘SWOG-9217’ and see that over 150 publications have been produced using this dataset (16 in 2016!). Several publications pre-dated the primary endpoint paper and discussed trial design, the dilemma of chemoprevention, and updates to trial progress. Post primary endpoint, publications have looked at multiple strategies – costs, the high-grade findings, longer-term follow-up, biopsy findings from the placebo arm, etc. Just last year, the UK made its mark on the prostate cancer world with the landmark Prostate Testing for Cancer and Treatment (ProtecT) study [2]. Again, we see the primary endpoint paper in the New England Journal of Medicine, but secondary endpoint papers, such as the quality-of-life outcomes are in the BJUI [3], and a mortality outcome analysis for trial screen failures in European Urology [4].

The BJUI can support clinical trial efforts through multiple pathways. Certainly, we would love to receive a primary endpoint paper from an important RCT in urology. We can also have impact by featuring important secondary endpoint papers, trial design papers (preferably ones that read like a good review article, with the trial proposed as the ‘answer’ to the dilemma), as well as smaller/early phase I–II trials that are stand-alone pieces of key knowledge. Figure 1 shows a possible flow chart of a RCT with each box representing possible publication points. In addition to content in the BJUI, our webpage Blogs section has a ‘rapid response team’ to start immediate dialogue on important RCTs published in other journals. For example with the recent Yaxley et al. [5] trial in the Lancet, our blogs section, led by Declan Murphy, had over 10 000 views and over 50 follow-up comments. So clearly, our readers care about RCTs.

apr-ed

Figure 1. A possible flow chart of a randomised clinical trial (RCT) with each box representing possible publication points. QOL, quality of life; f/u, follow-up.

Finally, the BJUI can help with RCTs in two more ways. For the reader, we will highlight RCT-related papers in their native sections (i.e. oncology, functional, education) with a special ‘Trials’ headline, and will invite experts to comment on the significance of the study. For reviewers and authors, we will be critical on RCT design, such that flaws are identified, and papers not given inflated significance. It is frustrating to receive papers that lack adequate reporting on what researchers did, RCT-related papers submitted to the BJUI frequently fail to adhere to the 2010 Consolidated Standards of Reporting Trials (CONSORT) guidance for reporting RCTs, which potentially leads to major revisions, if not outright rejection. The CONSORT requirements are on our author submission guidelines, but ideally these are read and adhered to in advance, as many are not possible to correct after the fact. Recently, we have also added that all RCTs must be registered (i.e. clinicaltrials.gov or similar) before the first patient is enrolled.

John W. Davis, Associate Editor, Urological Oncology* and
Graeme MacLennan, Consulting Editor, Statistics and Trials†

*MD Anderson Cancer Center, Houston, TX, USA and †University of Aberdeen, Aberdeen, UK

References
1 Thompson IM, Goodman PJ, Tangen CM et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349: 215–24

 

2 Donovan JL, Hamdy FC, Lane A et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016; 375: 1425–37

 

3 Lane A, Metcalfe C, Young GJ et al. Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life. BJU Int 2016; 118: 869–79

 

4 Johnston TJ, Shaw GL, Lamb AD et al. Mortality among men with advanced prostate cancer excluded from the ProtecT trial. Eur Urol 2017; 71: 381–8

 

5 Yaxley JW, Coughlin GD, Chambers SK et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study. Lancet 2016; 388: 1057–66

 

How to Cite this article

Davis, J. W. and MacLennan, G. (2017), The BJUI‘s clinical trials initiative. BJU International, 119: 503. doi: 10.1111/bju.13837

 

Article of the Month: PROMs in the ProtecT trial of PCa treatments

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

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

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video discussing the paper.

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

Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life

Athene Lane*,†, Chris Metcalfe*,†, Grace J. Young*,†, Tim J. Peters‡,§, Jane Blazeby*, Kerry N. L. Avery*, Daniel Dedman, Liz Down*, Malcolm D. Mason**, David E. Neal††, Freddie C. Hamdy†† and Jenny L. Donovan*,§ for the ProtecT Study group

 

*School of Social and Community Medicine, University of Bristol, Bristol, †Bristol Randomised Trials Collaboration, University of Bristol, Bristol, ‡School of Clinical Sciences, University of Bristol, Bristol, §Collaboration for Leadership in Applied Health Research and Care West, United Hospitals Bristol, Bristol, Clinical Practice Research Datalink Group, Medicines and Healthcare Products Regulatory Agency, London, **School of Medicine, Cardiff University, Cardiff, and ††Nuffield Department of Surgery, University of Oxford, Oxford, UK
Read the full article

Objectives

To present the baseline patient-reported outcome measures (PROMs) in the Prostate Testing for Cancer and Treatment (ProtecT) randomized trial comparing active monitoring, radical prostatectomy and external-beam conformal radiotherapy for localized prostate cancer and to compare results with other populations.

Materials and Methods

A total of 1643 randomized men, aged 50–69 years and diagnosed with clinically localized disease identified by prostate-specific antigen (PSA) testing, in nine UK cities in the period 1999–2009 were included. Validated PROMs for disease-specific (urinary, bowel and sexual function) and condition-specific impact on quality of life (Expanded Prostate Index Composite [EPIC], 2005 onwards; International Consultation on Incontinence Questionnaire-Urinary Incontinence [ICIQ-UI], 2001 onwards; the International Continence Society short-form male survey [ICSmaleSF]; anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), generic mental and physical health (12-item short-form health survey [SF-12]; EuroQol quality-of-life survey, the EQ-5D-3L) were assessed at prostate biopsy clinics before randomization. Descriptive statistics are presented by treatment allocation and by men’s age at biopsy and PSA testing time points for selected measures.

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Results

A total of 1438 participants completed biopsy questionnaires (88%) and 77–88% of these were analysed for individual PROMs. Fewer than 1% of participants were using pads daily (5/754). Storage lower urinary tract symptoms were frequent (e.g. nocturia 22%, 312/1423). Bowel symptoms were rare, except for loose stools (16%, 118/754). One third of participants reported erectile dysfunction (241/735) and for 16% (118/731) this was a moderate or large problem. Depression was infrequent (80/1399, 6%) but 20% of participants (278/1403) reported anxiety. Sexual function and bother were markedly worse in older men (65–70 years), whilst urinary bother and physical health were somewhat worse than in younger men (49–54 years, all P < 0.001). Bowel health, urinary function and depression were unaltered by age, whilst mental health and anxiety were better in older men (P < 0.001). Only minor differences existed in mental or physical health, anxiety and depression between PSA testing and biopsy assessments.

Conclusion

The ProtecT trial baseline PROMs response rates were high. Symptom frequencies and generic quality of life were similar to those observed in populations screened for prostate cancer and control subjects without cancer.

Read more articles of the week

Editorial: ‘Killing Two Birds With One Stone’ – PROMS from the ProtecT Trial

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Very few areas of medicine generate more controversy than the management of clinically localised prostate cancer. This is in large part due to the somewhat conflicting nature of the scant level I evidence that exists on the subject. Whereas the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) demonstrated a clinically meaningful and durable survival advantage for surgery when compared to watchful waiting in a predominantly White Scandinavian population of patients with clinically palpable yet localised prostate cancer [1], the Radical Prostatectomy Versus Observation for Localized Prostate Cancer (PIVOT) trial reported a mostly null effect of surgery in a predominantly older, less healthy population of American patients with clinically indolent disease [2]. Neither trial addresses the effect of radiotherapy on prostate cancer survival and both may lack relevance in contemporary prostate cancer practice.

For these reasons and a myriad of others, the medical community eagerly awaits the results of the Prostate Testing for Cancer and Treatment (ProtecT) trial [3]. With a fastidiously designed protocol that involves 337 primary care centres across nine cities in the UK, the use of dedicated study nurses, the successful enrolment of pre-specified sample size targets, and the inclusion of patient-reported quality-of-life measures, the ProtecT trial is poised to make enormous inroads for men with prostate cancer and the providers who care for them.

In this issue of the BJUI, the investigators from the ProtecT trial publish baseline patient-reported outcome measures (PROMs) from the ProtecT trial [4]. While others have previously reported baseline PROMs in large comparative effectiveness studies [5], the findings from this study are notable for several reasons. First, this is the first randomised trial comparing the effect of surgery, radiation, and active monitoring on PROMs. While several high-quality prospective observational cohort studies have reported long-term quality-of-life outcomes after prostate cancer treatment [6, 7], ProtecT will offer randomised comparisons that minimise confounding and selection bias from the outset. Second, the ProtecT trial will not only measure disease-specific health-related quality of life through the use of psychometrically validated survey instruments, such as the Expanded Prostate Index Composite, but also general health-related quality of life through the use of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C-30 (as well as depression and anxiety through the use of the Hospital Anxiety and Depression Scale). Finally, and perhaps most importantly, the investigators collected baseline PROMs at the time of the first biopsy before cancer diagnosis, which will offer distinct advantages when modelling patient-reported function over time, as well as avoiding recall bias associated with retrospective collection of baseline patient-reported outcomes.

In the absence of the long-term survival data from randomised trials comparing surgery and radiation, previous studies have rightly focused on understanding how the effect of prostate cancer treatments differ with respect to PROMs. With the ProtecT trial, we will not only start to have answers to longstanding questions about how surgery, radiation and active surveillance compare with respect to clinical outcomes, such as survival and cancer control, but also with respect to PROMs. By addressing both of these domains, the ProtecT investigators are in position to ‘kill two birds with one stone’ and in so doing will undoubtedly make large strides in facilitating data-driven decision-making for patients with prostate cancer worldwide.

Read the full article
Mark D. Tyson* and David F. Penson*,†,‡

 

Departments of *Urologic Surgery and †Health Policy, Vanderbilt University Medical Center, and‡ Geriatric, Research, and Educational Center, Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, USA

 

References

 

1 Bill-Axelson A, Holmberg L, Garmo H et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 2014; 370: 932–42

 

2 Wilt TJ, Brawer MK, Jones KM et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203–13

 

3 Lane JA, Donovan JL, Davis M et al. Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet Oncol 2014; 15: 1109–18

 

4 Lane A, Metcalfe C, Young GJ et al. Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life. BJU Int 2016; 118: 869–79

 

5 Resnick MJ, Barocas DA, Morgans AK et al. Contemporary prevalence of pretreatment urinary, sexual, hormonal, and bowel dysfunction: defining the population at risk for harms of prostate cancer treatment. Cancer 2014; 120: 1263–71

 

6 Sanda MG, Dunn RL, Michalski J et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008; 358: 1250–61

 

7 Resnick MJ, Koyama T, Fan KH et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 2013; 368: 436–45

 

Randomised Controlled Trials in Robotic Surgery

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PDGSep16It has been nearly 15 years since one of the first ever randomised controlled trials (RCT) in robotic surgery was conducted in 2002. The STAR-TRAK compared telerobotic percutaneous nephrolithotomy (PCNL) to standard PCNL and showed that the robot was slower but more accurate than the human hand [1].

In the 24 h since the much anticipated RCT of open vs robot-assisted radical prostatectomy was published in The Lancet [2], our BJUI blog from @declangmurphy was viewed >2500 times, receiving >40 comments, making it one of our most read and interactive blogs ever. It is a negative trial showing no differences in early functional outcomes between the two approaches.

And it is not the only negative trial of its kind as a number of others have matured and reported recently. The RCT of open vs robot-assisted radical cystectomy and extracorporeal urinary diversion showed no differences in the two arms [3], and likewise a comparison of the two approaches to cystectomy as a prelude to the RAZOR (randomised open vs robotic cystectomy) trial showed no differences in quality of life at 3-monthly time points up to a year [4]. The only RCT comparing open, laparoscopic and robotic cystectomy, the CORAL, took a long time to recruit and yet again showed no differences in 90-day complication rates between the three techniques [5].

In all likelihood, despite the level 1 evidence provided in The Lancet paper showing no superiority of the robotic over the open approach, the Brisbane study may not change the current dominance of robotic prostatectomy in those countries who can afford this technology. Why is this? Apart from the inherent limitations that the BJUI blog identifies, there are other factors to consider. In particular, as observed previously in a memorable article ‘Why don’t Mercedes Benz publish randomised trials?’ [6], there may be reasons why surgical technique is not always suited to the RCT format.

A few additional reflections are perhaps appropriate at this time:

  1. Despite the best statistical input many of these and future studies are perhaps underpowered.
  2. Many have argued that the RCTs have shown robotics to be as good, although not better than open surgery, even in the hands of less experienced surgeons.
  3. Patient reported quality of life should perhaps become the primary outcome measure because that in the end that is what truly matters.
  4. Cost-effectiveness ratios should feature prominently, as otherwise there is much speculation by the lay press without any hard data.
  5. Industry has a role to play here in keeping costs manageable, so that these ratios can become more palatable to payers.
  6. Surgery is more of an art than a science. The best surgeons armed with the best technology that they are comfortable with will achieve the best outcomes for their patients.

While this debate will continue and influence national healthcare providers and decision makers, the message looks much clearer when it comes to training the next generation of robotic surgeons. A cognitive- and performance-based RCT using a device to simulate vesico-urethral anastomosis after robot-assisted radical prostatectomy (RARP) showed a clear advantage in favour of such structured training [7]. In this months’ issue of the BJUI, we present the first predictive validity of robotic simulation showing better clinical performance of RARP in patients [8]. This is a major step forward in patient safety and would reassure policy makers that investment in simulation of robotic technology rather than the traditional unstructured training is the way forward.

Most of our patients are knowledgeable, extensively research their options on ‘Dr Google’ and decide what is good for them. It is for this reason that many did not agree to randomisation in other robotic vs open surgery RCTs, like LopeRA (RCT of laparoscopic, open and robot assisted prostatectomy as treatment for organ-confined prostate cancer) and BOLERO (Bladder cancer: Open vs Lapararoscopic or RObotic cystectomy). Many of them continue to choose robotic surgery without necessarily paying heed to the best scientific evidence. Perhaps what patients will now do is select an experienced surgeon whom they can trust to use their best technology to deliver the best clinical outcomes.

Prokar Dasgupta @prokarurol
Editor-in-Chief, BJUI 

@declangmurphy
Associate Editor BJUI

References

1 Challacombe B, Patriciu A, Glass J et al. A randomized controlled trial of human versus robotic and telerobotic access to the kidney as the first step in percutaneous nephrolithotomy. Comput Aided Surg 2005; 10: 165–71
2 Yaxley JW, Coughlin GD, Chambe rs SK et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study. Lancet 2016 [Epub ahead of print]. doi: 10.1016/S0140-6736(16)30592-X
3 Bochner BH, Sjoberg DD, Laudone VP, Memorial Sloan Kettering Cancer Center Bladder Cancer Surgical Trials Group. A randomized trial of robot-assisted laparoscopic radical cystectomy. N Engl J Med 2014; 371:389–90

4

Messer JC, Punnen S , Fitzgerald J et al. Health-related quality of life from a

prospective randomised clinical trial of robot-assisted laparoscopic vs open radical cystectomy. BJU Int 2014; 114: 896–902

5

Khan MS, Gan C, Ahmed K et al. A single-centre early phase randomised controlled three-arm trial of open, robotic, and laparoscopic radical cystectomy (CORAL). Eur Urol 2016; 69: 613–21

6 O’Brien T, Viney R , Doherty A, Thomas K. Why don’t Mercedes Benz publish
randomised trials? BJU Int 2010; 105 : 293–5
7 Chowriappa A, Raza SJ, Fazili A et al. Augmented-reality-based skills training for robot-assisted urethrovesical anastomosis: a multi- institutional randomised controlled trial. BJU Int 2015; 115: 336–45
8 Aghazadeh MA, Mercado MA, Pan MM , Miles BJ, Goh AC. Performance of
robotic simulated skills tasks is positively associated with clinical robotic surgical performance. BJU Int 2016; 118: 4 75 –81

 

Editorial: Cost-effectiveness of robotic surgery; what do we know?

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The introduction of the daVinci robotic surgical system (Intuitive Surgical, Sunnyvale, CA, USA) has led to a continuous discussion about the cost-effectiveness of its use. The capital costs and extra costs per procedure for robot-assisted procedures are well known, but there are limited data on healthcare consumption in the longer term. In this issue of BJUI, a retrospective study investigated the NHS-registered, relevant care activities up to three years after surgery comparing robot-assisted, conventional laparoscopic, and open surgical approaches to radical prostatectomy and partial nephrectomy [1].

The robotic system is particularly useful in difficult to perform laparoscopic surgeries, which are easier to perform with the daVinci system due to improved three-dimensional vision, ergonomics, and additional dexterity of the instruments. Because the use of the robotic system is more costly, to justify its use the outcomes for patients should be improved. Therefore, more detailed information about the clinical and oncological outcomes, as well as the incidence of complications after surgery with the daVinci system, is needed.

Lower rates of positive surgical margins for robot-assisted radical prostatectomy (RARP) vs open and laparoscopic RP have been reported [2]. There also is evidence of an earlier recovery of functional outcomes, such as continence. RARP is associated with improved surgical margin status compared with open RP and reduced use of androgen-deprivation therapy and radiotherapy after RP, which has important implications for quality of life and costs. Ramsay et al. [3] reported that RARP could be cost-effective in the UK with a minimum volume of 100–150 cases per year per robotic system.

Centralisation of complex procedures will not only result in better outcomes, but also facilitate optimal economical usage of expensive medical devices. Furthermore, the skills learned to perform the RARP procedure can be used during other procedures, such as robot-assisted partial nephrectomy (RAPN) and radical cystectomy (RARC). The recent report by Buse et al. [4] confirms that RAPN is cost-effective in preventing perioperative complications in a high-volume centre, when compared with the open procedure. Minimally invasive techniques for complex procedures, such as a RC, take more time to perform, but result in less blood loss. A systematic review by Novara et al. [5] showed a longer operation time for RARC, but fewer transfusions and fewer complications compared with open surgery. However, there is no solid evidence about the cost-effectiveness of this technique to date. The RAZOR trial (randomised trial of open versus robot assisted radical cystectomy, DOI: 10.1111/bju.12699) is likely to provide some answers about differences in cost, complications, and quality of life when the results of the study become available later this year.

Additionally, the robotic system has been shown to shorten the learning curve of complex laparoscopic procedures in simulation models [6]. Recently, a newly structured curriculum to teach RARP has been validated by the European Association of Urology-Robotic Urology Section [7]. The effect of the shorter learning curve on the cost of the procedures has not yet been well studied for cost-effectiveness. However, due to the shorter learning curves, patients have lower risks of complications, which from the patients’ perspective is more important than any increased costs.

The study reported in this issue [1]; however, does not include the ‘out of pocket’ expenses of patients, it does not report on the differences in patient and tumour characteristics, and outcomes such as complications and oncological safety. These issues are all challenges to be addressed in a thorough prospective (randomised) trial on the cost-effectiveness of the use of robot-assisted surgery, including quality-of-life measurements and complications of the surgical procedures. In the Netherlands the RACE trial (comparative effectiveness study open RC vs RARC, www.racestudie.nl) started in 2015 and the results are expected in 2018–2019.

Read the full article
Carl J. Wijburg
Department of Urology, Robotic Surgery , Rijnstate Hospital, Arnhem, The Netherlands

 

References

 

1 Hughes D, Camp C, O’Hara J, Adshead J. Health resource use after robot-assisted surgery vs open and conventional laparoscopic techniques in oncology: analysis of English secondary care data for radical prostatectomy and partial nephrectomy. BJU Int 2016; 117: 940–7

 

2 HuJC, Gandaglia G, Karakiewicz PI et al. Comparative effectiveness of robot-assisted versus open radical prostatectomy. Eur Urol 2014; 66: 666–72

 

3 Ramsay C, Pickard R , Soomro N et al. Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer. Health Technol Assess 2012; 16: 1–313

 

4 Buse S, Hach CE, Klumpen P et al. Cost-effectiveness of robot-assisted partial nephrectomy for the prevention of perioperative complications. World J Urol 2015; [Epub ahead of print]. DOI:10.1007/s00345-015-1742-x

 

5 Novara G, Catto JW, Wilson T et al. Systematic review and cumulative analysis of perioperative outcomes and complications after robot-assisted radical cystectomy. Eur Urol 2015; 67: 376–401

 

6 Moore LJ, Wilson MR, Waine E, Masters RS, McGrath JS, Vine SJ. Robotic technology results in faster and more robust surgical skill acquisition than traditional laparoscopy. J Robot Surg 2015; 9: 67–73

 

7 Ahmed K, Khan R, Mottrie A et al. Development of a standardised training curriculum for robotic surgery: a consensus statement from an international multidisciplinary group of experts. BJU Int 2015; 116: 93–101

 

Article of the Week: Indoor cold exposure and nocturia

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

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

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

Indoor cold exposure and nocturia: a cross-sectional analysis of the HEIJO-KYO study

Keigo Saeki, Kenji Obayashi and Norio Kurumatani
Department of Community Health and Epidemiology, Nara Medical University School of Medicine, Nara, Japan

 

Read the full article

Objectives

To investigate the association between indoor cold exposure and the prevalence of nocturia in an elderly population.

Subjects and Methods

The temperature in the living rooms and bedrooms of 1 065 home-dwelling elderly volunteers (aged ≥60 years) was measured for 48 h. Nocturia (≥2 voids per night) and nocturnal urine production were determined using a urination diary and nocturnal urine collection, respectively.

MayAOTW4ResultsImage

Results

The mean ± sd age of participants was 71.9 ± 7.1 years, and the prevalence of nocturia was 30.8%. A 1 °C decrease in daytime indoor temperature was associated with a higher odds ratio (OR) for nocturia (1.075, 95% confidence interval [CI] 1.026–1.126; P = 0.002), independently of outdoor temperature and other potential confounders such as basic characteristics (age, gender, body mass index, alcohol intake, smoking), comorbidities (diabetes, renal dysfunction), medications (calcium channel blocker, diuretics, sleeping pills), socio-economic status (education, household income), night-time dipping of ambulatory blood pressure, daytime physical activity, objectively measured sleep efficiency, and urinary 6-sulphatoxymelatonin excretion. The association remained significant after adjustment for nocturnal urine production rate (OR 1.095 [95% CI 1.042–1.150]; P < 0.001).

Conclusions

Indoor cold exposure during the daytime was independently associated with nocturia among elderly participants. The explanation for this association may be cold-induced detrusor overactivity. The prevalence of nocturia could be reduced by modification of the indoor thermal environment.

Read more articles of the week

Editorial: Does cold exposure cause nocturia?

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We have all experienced that changing from a warm environment to a colder external temperature may provoke a sudden compelling desire to void. This feeling fits quite well with part of the definition of urgency following the International Continence Society definition. Consequently, it is logical to suspect that cold exposure during daytime may influence bladder behaviour and hence contribute to nocturia episodes. These Japanese authors [1] performed a cross-sectional analysis as part of a community based cohort study in 1127 home-dwelling volunteers aged ≤60 years. Living room and bedroom temperatures were measured for 48 h and the participants completed voiding charts and nocturnal urine collection, but were excluded if >12 h were spent outside their house. The mean age of the participants was ≈72 years and nocturia was present in 30.8%. A decrease in daytime indoor temperature of 1 °C was associated with a higher odds ratio for nocturia and this was independent of outdoor temperature and other potential confounders. Furthermore, the association was independent of nocturnal urine production and hence reflect a direct effect on bladder behaviour, probably due to detrusor overactivity. However, a change of indoor temperature modified nocturia in only 29.3% of participants, and varied significantly in individuals. Nevertheless, these findings could be used as a population approach to reduce the prevalence of nocturia and hence the eventual impact on quality of life and morbidity that is known to go together with nocturia.

Read the full article
Philip Van Kerrebroeck, Professor of Urology
Department of Urology, Maastricht University Medical Centre, Maastricht, The Netherlands

 

References
1 Saeki K, Obayashi K, Kurumatani N. Indoor cold exposure and nocturia: a cross-sectional analysis of the HEIJO-KYO study. BJU Int 2016; 117: 829–35

 

 

Article of the Month: Cabazitaxel Improves QoL in mCRPC

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

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

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

Final Quality of Life and Safety Data for patients with mCRPC treated with Cabazitaxel in the UK Early Access Programme (NCT01254279)

Amit Bahl*, Susan Masson*, Zafar Malik†, Alison J. Birtle‡, Santhanam Sundar§, Rob J. Jones¶, Nicholas D. James**, Malcolm D. Mason††, Satish Kumar††, David Bottomley‡‡, Anna Lydon§§, Simon Chowdhury¶¶, James Wylie*** and Johann S. de Bono†††

 

*Bristol Haematology and Oncology Centre, Bristol, †Clatterbridge Centre for Oncology, Wirral, ‡Rosemere Cancer Centre, Royal Preston Hospital, Preston, §Nottingham University Hospitals NHS Trust, Nottingham, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, **School of Cancer Sciences, University of Birmingham, Birmingham, ††Velindre Hospital, Cardiff, ‡‡St James’s University Hospital, Leeds, §§South Devon Healthcare NHS Foundation Trust, Torquay, ¶¶Guy’s and St. Thomas’ NHS Foundation Trust, London, ***The Christie NHS Foundationm Trust, Manchester, and †††The Institute for Cancer Research and Royal Marsden Hospital, Sutton, UK

 

Read the full article
OBJECTIVE

To compile the safety profile and quality of life (QoL) data for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel in the UK Early Access Programme (UK EAP).

PATIENTS AND METHODS

A total of 112 patients participated at 12 UK cancer centres. All had mCRPC with disease progression during or after docetaxel. Patients received cabazitaxel 25 mg/m2 every 3 weeks with prednisolone 10 mg daily for up to 10 cycles. Safety assessments were performed before each cycle and QoL was recorded at alternate cycles using the EQ-5D-3L questionnaire and visual analogue scale (VAS). Thesafety profile was compiled after completion of the UK EAP and QoL measures were analysed to record trends. No formal statistical analysis was carried out.

RESULTS

The incidences of neutropenic sepsis (6.3%), grade 3 and 4 diarrhoea (4.5%) and grade 3 and 4 cardiac toxicity (0%) were low. Neutropenic sepsis episodes, though low, occurred only in patients who did not receive prophylactic granulocyte-colony stimulating factor. There were trends towards improved VAS and EQ-5D-3L pain scores during treatment.

CONCLUSIONS

The UK EAP experience indicates that cabazitaxel might improve QoL in mCRPC and represents an advance and a useful addition to the armamentarium of treatment for patients whose disease has progressed during or after docetaxel. In view of the potential toxicity, careful patient selection is important.

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

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

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

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

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

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

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

 

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

 

References

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

Article of the Month: Comparing health-related QoL outcomes for robotic cystectomy with those of traditional open radical cystectomy

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

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

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Dipen Parekh discussing his paper. 

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

Health-related quality of life from a prospective randomised clinical trial of robot-assisted laparoscopic vs open radical cystectomy

Jamie C. Messer, Sanoj Punnen*, John Fitzgerald, Robert Svatek and Dipen J. Parekh

Department of Urology, University of Texas Health Sciences Center at San Antonio, San Antonio, TX and *Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, USA

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Objective

To compare health-related quality-of-life (HRQoL) outcomes for robot-assisted laparoscopic radical cystectomy (RARC) with those of traditional open radical cystectomy (ORC) in a prospective randomised fashion.

Patients and Methods

This was a prospective randomised clinical trial evaluating the HRQoL for ORC vs RARC in consecutive patients from July 2009 to June 2011. We administered the Functional Assessment of Cancer Therapy–Vanderbilt Cystectomy Index questionnaire, validated to assess HRQoL, preoperatively and then at 3, 6, 9 and 12 months postoperatively. Scores for each domain and total scores were compared in terms of deviation from preoperative values for both the RARC and the ORC cohorts. Multivariate linear regression was used to assess the association between the type of radical cystectomy and HRQoL.

Results

At the time of the study, 47 patients had met the inclusion criteria, with 40 patients being randomised for analysis. The cohorts consisted of 20 patients undergoing ORC and 20 undergoing RARC, who were balanced with respect to baseline demographic and clinical features. Univariate analysis showed a return to baseline scores at 3 months postoperatively in all measured domains with no statistically significant difference among the various domains between the RARC and the ORC cohorts. Multivariate analysis showed no difference in HRQoL between the two approaches in any of the various domains, with the exception of a slightly higher physical well-being score in the RARC group at 6 months.

Conclusions

There were no significant differences in the HRQoL outcomes between ORC and RARC, with a return of quality of life scores to baseline scores 3 months after radical cystectomy in both cohorts.

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