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Editorial: Tether your stents!

April 16, 2014/by Archana Fernando

Ureteric stents are commonly placed after ureteroscopy to protect the ureter and to facilitate subsequent stone fragment passage. They are known to be a cause of significant morbidity as judged by standardised validated questionnaires [1]. Whether placement of a stent is required at all is debatable, with randomised studies suggesting they are unnecessary after routine ureteroscopy [2]. The European Association of Urology (EAU) guidelines recommend stent insertion only ‘in patients who are at increased risk of complications’ and ‘in all doubtful cases to avoid stressful emergency situations’. Despite this, available evidence would suggest that we continue to commonly place stents [3].

If a stent is placed, the principal means of reducing morbidity is by minimising the stent dwell-time. One of the ways of doing this is to leave a stent with extraction strings/tether. This obviates the delay associated with scheduling cystoscopic extraction, the morbidity of cystoscopy and potentially reduces additional hospital visits if the patient is able to remove the stent at home.

Tethered stents are not widely used due to preconceptions about their tolerability, increased risk of complications (e.g. infection, migration) and accidental removal. Perhaps for this reason there have been few studies into the effectiveness of tethered stents in minimising stent-related morbidity to date, with only a handful in the past 30 years that have specifically addressed this issue.

In this issue of BJUI, Barnes et al. [4] report on the results of a prospective randomised trial analysing stented patients with or without the extraction strings attached, for both quality of life and postoperative complications after ureteroscopy for stone disease. This follows on from a retrospective series previously reported by the same group [5]. It is pleasing to see the authors, who originally concluded that randomised trials are needed in this area, actually get on and do the trial!

Two aspects of the trial methodology are worth highlighting: (i) the surgeons were not told that the patient was part of the study until they had made the decision to stent to minimise selection bias; (ii) patients completed the Ureteric Stent Symptom Questionnaire (USSQ) 6 weeks after stent removal as a control for their USSQ scores at postoperative days 1 and 6.

The headline results showed that there was no difference in quality of life and stent-related symptoms between patients with and without the extraction strings. There was also no difference in postoperative complications, emergency room visits or phone calls between the groups. What is surprising is that they found no difference in pain scores between self-removal and cystoscopic removal. This has not been our experience with tethered stents and may be due to the few men in the study. However, stent dwell-time was significantly less for patients with tethers compared with those without (10.6 vs 6.3 days, P < 0.001).

For urologists planning on using this technique it should be noted that the authors removed the original knot and shortened the string considerably to reduce the risk of accidental removal. For this reason the string was not attached to the patient’s skin.

This trial addresses many of the reservations urologists have about the use of tethered stents. Furthermore, reducing accidental removal and encouraging self-removal should be possible with improved patient education and selection. This was addressed by a study in New Zealand [6], which showed the feasibility of self-removal of stents.

The authors also acknowledged weaknesses in their study, which included failure to reach target enrolment, a 68% completion of trial surveys and a larger proportion of women in the study group due to male anxiety about self-removal of stents. In all, 15% of stents were inadvertently removed early and thus this technique should be used with caution in patients where early removal may be detrimental, e.g. in single kidneys. This does of course prompt the question: ‘If you are going to place a stent, how long does the stent need to stay for?’ and hopefully future trials may address this unanswered question.

Archana Fernando and Matthew Bultitude

Urology Department, Guy’s and St Thomas’ NHS Trust, London, UK

References

Joshi HB, Newns N, Stainthorpe A et al. Ureteral stent symptom questionnaire: development and validation of a multidimensional quality of life measure. J Urol 2003; 169: 1060–1064
Song T, Liao B, Zheng S, Wei Q. Meta-analysis of postoperatively stenting or not in patients underwent ureteroscopic lithotripsy. Urol Res 2012; 40: 67–77
Mangera A, Parys B. BAUS Section of Endourology national ureteroscopy audit: setting the standards for revalidation. J Clin Urol 2012; 6: 45–49
Barnes KT, Bing MT, Tracy CR. Do ureteric stent extraction strings affect stent-related quality of life or complications after ureteroscopy for urolithiasis: a prospective randomised control trial. BJU Int 2014; 113: 605–609
Bockholt N, Wild T, Gupta A et al. Ureteric stent placement with extraction strings: no strings attached? BJU Int 2012; 110: 1069–1073
York N, English S. Self-removal of ureteric JJ stents: analysis of patient experience. Presented at AUA 2013, May 7; San Diego, CA, USA. Abstract no. 1979. J Urol 2013; 189 (Suppl. 4): e812

Editorial: Nationwide prostatectomy practice

April 9, 2014/1 Comment/by Henk G. van der Poel

Surgical management of prostate cancer is one of the most frequently performed urological procedures [1]. Available data suggests that surgeons’ experience is correlated with both oncological and functional outcome [2]. These initial observations stress the importance of concentration of prostatectomy in high-volume institutes. This centralisation could improve documentation and monitoring of outcome. The data presented by Røder et al. [1] from Denmark show a rapid increase in registered prostatectomy procedures in recent years in six institutes. It remains to be studied whether this is caused by centralisation and better registration or the results of an increased overtreatment. For that, data on the incidence of low-risk disease over time in their series needs analysis.

At least one-third of the population was treated since 2008. The relatively short follow-up and associated few events, and high number of low-risk patients (47% had biopsy Gleason ≤6) make outcome analysis of less value. It is therefore not surprising that in their analysis low- and intermediate-risk tumors had similar outcome. On the other hand, despite prostatectomy, one-third of deaths during follow-up were prostate cancer related in their population. Consistent with reported data at 15 years after prostatectomy more patients died from prostate cancer than from other causes [3]. But still a considerable number of men died from prostate cancer. This also seems the case in the group of men often soothed for having indolent, low-risk disease. At 15 years Røder et al., reported 8.9% of these men with low-risk disease still dying from prostate cancer in Denmark, despite prostatectomy. And although this percentage was lower than that of the prostatectomy group in the Scandinavian Prostate Cancer Group Study Number 4 (SCPG-4) study (14.6%) [4], most men will still find it disturbingly high and it is three-times higher than the 3% life-time risk of dying from prostate cancer for all men. In other words, it may be perceived that prostatectomy does only partly reverse the risk of dying from prostate cancer, even in men with low-risk disease.

The data from Røder et al. [1] can, with longer follow-up, set the standard for oncological outcome on a national level. Of interest is the observation that, although not significant in the multivariate analysis, variation among institutes for outcome seems to exist but not clearly dependent on institutes volume. Variations of case-mix and patient selection could be topics of further study. With the short follow-up available we are also looking forward to data on functional outcome and perioperative complications that may be more mature. Comparison with now also available registries in Belgium and the Netherlands would be of interest.

It always strikes me that prostate cancer seems to be a systemic disease from the start even in assumed ‘low-risk’ disease, yet surgical management is only focused at loco-regional control. Perhaps the mortality improvement shown in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial by prostatectomy is merely caused by disease delay provided by local control even in the presence of systemic disease. Initial encouraging data from an ongoing study evaluating the role of radiotherapy to the prostate in the presence of bone metastases seem supportive of this notion. Is prostatectomy a debulking management of a systemic disease at most, and an unneeded cure for many, or is there this sub-sub group of men that is eventually fully benefiting from the intervention reversing not only death but also the debilitating effects of androgen ablation.

Henk G. van der Poel

Department of Urology, Netherlands Cancer Institute, Amsterdam, the Netherlands

Read the full article

References

Røder MA, Brasso K, Christensen IB et al. Survival after radical prostatectomy for clinically localised prostate cancer: a population-based study. BJU Int 2014; 113: 541–547
Vickers A, Savage C, Bianco F et al. Cancer control and functional outcomes after radical prostatectomy as markers of surgical quality: analysis of heterogeneity between surgeons at a single cancer center. Eur Urol 2011; 59: 317–322
Shikanov S, Kocherginsky M, Shalhav AL, Eggener SE. Cause-specific mortality following radical prostatectomy. Prostate Cancer Prostatic Dis 2012; 15: 106–110
Bill-Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708–1717

Editorial: Do live case demonstrations have a future in surgical education?

April 2, 2014/by Walter Artibani

The ever increasing desire for instant access to information is a reflection of our times facilitated by social networks and by video and information technology. Nowadays, sport events are dissected and quantified from every possible perspective. We know almost real-time any detail of a soccer match: how many miles each player runs, how many good or bad passages of play, how many faults and so on, including if needed the details of heart rate and weight loss. The same and even more is available for example in formula one racing. Theoretically the same could easily be applied to surgical performance and it is foreseeable it will be applied, as a self-performance improvement method and as a development of one of the most popular ‘scientific and educational’ activities during surgical meetings, live case demonstrations (LCDs). All this, together with simulation, could in the near future have a tremendous impact on surgical performance and training. Twitter and Instagram show the power of the immediate real-time diffusion of events, as condensed as possible, so that the tweet or the instantaneous image can be visible and digested without losing time. Video clips follow the same concept and certainly BJUI is pioneering the use of short surgical video clips that are easily accessible and usable at any spare time of a busy day.

The core issue about LCDs is that at present there is no solid scientific evidence of their educational value, and this is outlined in the paper by Elsamra et al. [1] published in this issue of BJUI, which commendably attempts to evaluate the educational benefit of LCDs in terms of perception, clearly not a very strong criterion.

Data about the outcomes of live surgery operations are scant. Clearly patient’s safety is the first goal of any surgical activity, and this applies to LCDs. As mentioned in the paper, the European Association of Urology (EAU) Executive felt the urgent need to establish procedures and regulations in order to endorse live surgery events. The reader can find all related information on the EAU website. These regulations are meant to be in the best interest of patients, surgeons and organisers. Among others, one important innovation is the requisite of a ‘patient advocate’ present during the LCD, being an experienced medical doctor, independent from the organising committee of the educational event, in charge of advising in case of unexpected events, which can endanger patient’s safety.

Moreover, the EAU has established a prospective database of all endorsed live surgery events. This will hopefully allow in a few years an answer, with solid data, to the question of whether an intervention performed during a live surgery event has the same outcome compared with the same intervention executed by the same surgeon in his usual environment. The more challenging goal is to quantify the educational value of a live surgical event and the jump from perception to scientific evidence is far from being an easy task.

Walter Artibani
Urologia – Azienda Ospedaliero Universitaria Integrata di Verona, Verona, Italy

Read the full article

Reference

Elsamra SE, Fakhoury M, Motato H et al. The surgical spectacle: a survey of urologists viewing live case demonstrations. BJU Int 2014; 113: 674–678

Quality matters most where the BJUI and stone disease are concerned

April 1, 2014/1 Comment/by Daron Smith

Size (and shape) is important and sometimes strings should be attached, but quality matters most where the BJUI and stone disease are concerned …

The Editor-in-chief of the BJUI has consolidated the journal’s commitment to accepting only the highest quality papers, and this is certainly evident in the upper urinary tract section of this edition, where two studies demonstrate what it takes to be published in the journal nowadays.

In the first article, Kerri Barnes and colleagues from University of Iowa Department of Urology [1] have followed their own department’s earlier retrospective analysis of the benefit of “tethered stents” [2], by analysing the safety and effectiveness of this approach in a prospective, randomised controlled trial. It is often stated that randomised controlled trials are difficult in surgical disciplines, but this study affirms the proverb that “where there’s a will, there’s a way”. Although there was a substantial drop out in the number of patients that could have been included (three quarters of the patients approached for the study declined to be involved as they wished to determine the nature of the stent left in situ), statistical significance was not approached for any of the key concerns that leaving a stent on a string might cause for either the patient or their surgeon.

Furthermore, they have shown that that leaving the strings in place allowed patients to remove their stents significantly earlier (and in the convenience of their own home), than if they had to return to hospital for cystoscopic removal a week or so post-operatively. Despite the established knowledge that stents contribute to postoperative morbidity and can adversely affect quality of life, and the increasing evidence that stents are not required in “uncomplicated” ureteroscopy, it is clear that most urologists continue to leave a stent for a sense of security after performing ureteroscopic stone surgery. Shorter stent dwell times may help reduce the overall burden of stent related symptoms, and it is worth emphasising that none of the patients whose stent was removed at 7 days post operatively had any adverse consequences; neither did the 15% of this group whose stents fell out even earlier. As Fernando and Bultitude [3] comment in the associated editorial, the next question is: “If you are going to place a stent, how long does the stent need to stay for?” Perhaps, in order to emphasise that, where stent bother is concerned, shorter is better, this should be re-phrased as “how little time is enough time for a stent to stay in”…

In the second, Will Finch, from Norfolk and Norwich University Hospital, and his colleagues from Addenbrooke’s Hospital, Cambridge [4], have shown that stone size assessments from CT are most reliably calculated by a 3D-reconstructed stone volume. They have demonstrated that the maximum diameter of a stone tends to predict its overall shape such that a rugby ball-shaped stone (a “prolate ellipsoid”) has the polar diameter as the major axis, whereas a disc-shaped stone (an “oblate ellipsoid”) has the equatorial diameter as its major axis. Stones less than 9mm in diameter tended to be prolate, whilst those of 9–15 mm in diameter tended to be oblate; stones larger than 15 mm in diameter approach the more “random” shape of a scalene ellipsoid, for which the formula used to calculate stone volume (length (l) × width (w) × depth (d) × π × 0.167, which is often simplified to (l × w × d) / 2 in clinical practice) can be used.

However, if this is used for all stones regardless of their size and shape, rugby-ball and disc-like stones of less than 15mm in size are likely to have their volume over-estimated. Accordingly, the authors challenge the guidance of the EAU regarding stone volume calculations [5] to recommend that formulae based on the shape of the stone (π/6*a*a*c* for an oblate and π/6*a*b*b* for a prolate stone – see the paper itself to make sense of this) offer a more accurate assessment of stone volume.

Whilst these formulae are recommended for day-to-day calculations to guide treatment choices, they emphasise that 3D-reconstructed stone volumes should be used to report stone volume in research papers. In an age of stone surgery where CTKUB is so widely used in patients’ imaging assessment, and accepting that stone volume is the key determinant of achieving a stone free patient, this would allow the most accurate comparisons between the effectiveness of different surgical treatments.

Both articles are simple, straightforward, and well conducted studies that apply to the every-day practice of stone surgery. High quality papers are, of course, only really of benefit if they change practice for the better. So why not speak to your radiologist today about adding stone volume assessments to CTKUB reports (and point them to Finch et al. for the evidence) or even do it yourself! And the next time you put in a stent, reassure yourself, and the patient,

that there is no harm, and many benefits, in having some strings attached …

Daron Smith
University College Hospital, London, United Kingdom

Read the April issue

References

Barnes KT, Bing MT, Tracy CR. Do ureteric stent extraction strings affect stent-related quality of life or complications after ureteroscopy for urolithiasis: a prospective randomised control trial. BJU Int 2014; 113: 605–609
Bockholt N, Wild T, Gupta A, Tracy CR. Ureteric stent placement with extraction strings: no strings attached? BJU Int 2012; 110 (11 Pt C): E1069–1073
Fernando A, Bultitude M. Tether your stents! BJU Int 2014; 113: 517–518
Finch W, Johnston R, Shaida N, Winderbottom A, Wiseman O. Measuring stone volume – three-dimensional software reconstruction or an ellipsoid algebra formula? BJU Int 2014; 113: 610–614
Tiselius HG, Alken P, Buck C et al. European Association of Urology 2008 Guidelines on Urolithiasis. Available at: https://www.uroweb.org/fileadmin/user_upload/Guidelines/Urolithiasis.pdf. Accessed 17 June 2012

Editorial: Radical cystectomy: how do blood transfusions affect oncological outcomes?

March 26, 2014/by Shamim Khan

Kluth et al. [1] have conducted a large retrospective study from several institutions in North America and Europe to assess the impact of blood transfusion on oncological outcomes after radical cystectomy (RC) for bladder cancer. The hypothesis for a negative impact of transfusion on oncological outcomes stems from the observation that renal allograft survival is prolonged after pre-transplant blood transfusions because of its immuno-modulatory effects [2]. This finding prompted Gantt [3] to express concern about the possible adverse effects of transfusions in patients being treated for cancer. Since then, there have been numerous publications addressing this issue in various surgical journals including those of urology with conflicting messages.

Sadeghi et al. [4] queried the Columbia University Urologic Oncology Database. This included 638 patients undergoing RC between 1989 and 2010. Of these, 209 (32.8%) received perioperative blood transfusions. On univariate analysis, the number of units transfused was inversely related to overall and cancer-specific survival. However, on multivariate analysis, it did not prove to be an independent predictor of cancer-specific survival.

As the authors highlighted in this paper, Linder et al. [5] reported a large series of patients from the Mayo Clinic, which included 2060 patients undergoing RC over 25 years. Of this large cohort, 1279 (62%) received perioperative blood transfusion with adverse outcomes, not only in terms of overall and cancer-specific mortality, but also postoperative tumour recurrence.

RC is one of the most major surgical procedures performed in urological surgery. The vast majority of patients with bladder cancer requiring RC are in their mid-sixties, overweight and have several co-morbidities. Some of these patients present late and are anaemic at presentation.

Blood loss during open RC varies depending upon surgeons’ experience, patients’ body mass index, disease stage and availability of modern equipment, e.g. LigaSure™ or stapling devices. Blood transfusion may be required because of pre-existing anaemia or excessive blood loss during surgery. Variations exist in thresholds of anaesthesiologists and the surgeons for transfusions. All of these factors account for variation in reported frequency of transfusion rates for this operation and this is well reflected in many large series of RC.

As there are many confounding factors that may influence overall and cancer-specific survival in patients undergoing RC including stage of the disease, histological nature of the tumour, lymph node status and competing co-morbidities, it is very challenging to control for these factors in retrospective series. Hence, prospective well-controlled multicentre studies are the only way forward to answer this question.

While we await robust evidence on the influence of perioperative transfusion on oncological outcomes, several potential options could be explored to avoid homologous blood transfusion. These include preoperative optimisation of haemoglobin levels through iron infusions, administration of erythropoietin where appropriate, and preoperative autologous-banking. Intraoperatively meticulous surgical technique, use of modern devices, e.g. LigaSure/stapler and Cell Savers, could be used to avoid homologous blood transfusion.

Fortunately, these studies aimed at raising awareness of potential risks of transfusions are appearing in the urological literature at a time when urologists are moving away from open to minimally invasive oncological surgery with a steady decline in the need for perioperative blood transfusion. This is one of the important steps in the right direction and will have a major impact on the need for blood transfusion in foreseeable future.

Muhammed S. Khan
Department of Urology, Guy’s Hospital and King’s College London School of Medicine, London, UK

Read the full article

References

Kluth LA, Xylinas E, Rieken M et al. Impact of perioperative blood transfusion on the outcome of patients undergoing radical cystectomy for urothelial carcinoma of the bladder. BJU Int 2014; 113: 393–398
Opelz G, Sengar DP, Mickey MR, Terasaki PI. Effect of blood transfusions on subsequent kidney transplants. Transplant Proc 1973; 5: 253–259
Gantt CL. Red blood cells for cancer patients. Lancet 1981; 2: 363
Sadeghi N, Badalato GM, Hruby G, Kates M, McKiernan JM. The impact of perioperative blood transfusion on survival following radical cystectomy for urothelial carcinoma. Can J Urol 2012; 19: 6443–6449
Linder BJ, Frank I, Cheville JC et al. The impact of perioperative blood transfusion on cancer recurrence and survival following radical cystectomy. Eur Urol 2013; 63: 839–845

Editorial: mTOR-related non-infectious pneumonitis: a potential biomarker of clinical benefit?

March 19, 2014/by Simon Chowdhury

The study by Atkinson et al. [1] published in the present issue of the BJUI is the largest study to date to address the role of non-infectious pneumonitis (NIP) as a predictive biomarker in patients with RCC who are treated with mammalian target of rapamycin (mTOR) inhibitors. It is also the first article to correlate mTOR-related NIP with improved overall survival (OS). Until now, only radiological response as measured by RECIST and progression-free survival (PFS) had been correlated to the onset of NIP in two small retrospective studies [2, 3], but the results obtained in those studies were contradictory and, therefore, this correlation remains controversial.

While the predictive relationship between NIP and OS needs to be further investigated in well-designed prospective clinical trials, the implications of such a relationship may be significant because no predictive biomarkers for mTOR inhibitors have been validated to date. In the era of targeted therapies, the detection of biomarkers of treatment efficacy is crucial to differentiate the subpopulations of patients who are most likely to benefit from treatment. Several biomarkers, such as the development of arterial hypertension and hypothyroidism, have been correlated with improved outcomes in patients with advanced RCC treated with vascular endothelial growth factor pathway inhibitors [1]; however, there are currently very limited data regarding the potential predictors of the clinical efficacy of mTOR inhibitors. A recent study by Lee et al. [4] showed that greater increases in serum cholesterol levels from baseline in patients with advanced RCC treated with temsirolimus were significantly associated with longer PFS and OS. Interestingly, temsirolimus-related hypertriglyceridemia and hyperglycaemia were not associated with improved clinical outcomes. Although NIP or hypercholesterolaemia must still be validated prospectively to ascertain whether they are true surrogate biomarkers of pharmacodynamic effect or just confounding epiphenomena, these promising findings may be the first steps in the identification of predictive biomarkers in mTOR inhibitor therapy.

Other important aspects addressed by Atkinson et al. [1] are the uncertainty of the pathogenesis of mTOR-related NIP and the lack of clinical predictive factors. Older age and treatment with everolimus were the only significant predictive factors of onset of NIP in their multivariate analysis. Similarly, a retrospective study by Dabydeen et al. [2] showed a statistically nonsignificant higher incidence of NIP in patients with RCC treated with everolimus compared to those treated with temsirolimus. Interestingly, in a randomized phase II study testing three different dose levels of temsirolimus (25,75 and 250 mg/week) in patients with advanced RCC, none of the six patients diagnosed with NIP were in the highest dose group of 250 mg/week [5], suggesting that mTOR-related NIP might have a non-dose-dependent pathogenesis. Similarly, a meta-analysis of 2233 patients affected by different tumours including RCC treated with an mTOR inhibitor failed to show any relationship between median treatment duration and incidence of NIP [6]. Finally, underlying respiratory conditions before treatment, such as the presence of lung metastases [6], chronic obstructive pulmonary disease or smoking habit [2], were not shown to be predictive factors of development of mTOR-related NIP. Another study by White et al. [3] showed that the development of pneumonitis in patients with RCC treated with everolimus was not associated with more impaired baseline pulmonary function tests, indicating that pulmonary function tests may not help identify patients with an increased risk of pneumonitis nor predict its severity. At present, there are therefore very few pretreatment clinical predictive factors to help clinicians identify patients at higher risk of developing mTOR-related NIP.

In conclusion, given the potential value of NIP as a predictive biomarker of survival in patients with RCC treated with mTOR inhibitors, Atkinson et al. [1] suggest that efforts should be made to avoid dose reductions and treatment discontinuation whenever possible. However, predictive factors of the severity of lung toxicity are needed to identify those patients at risk of developing life-threatening NIP as the maintenance of dose intensity may be crucial for maximizing clinical benefit.

Read the full article

Alejo Rodriguez-Vida, Noan-Minh Chau and Simon Chowdhury
Department of Medical Oncology, Guy’s Hospital, London, UK

References

Atkinson BJ, Pharm D, Cauley DH et al. mTOR inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: management, predictors, and outcomes. BJU Int 2014; 113: 376–382
Dabydeen DA, Jagannathan JP, Ramaiya N et al. Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcome. Eur J Cancer 2012; 48:1519–1524
White DA, Camus P, Endo M et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 2010; 182: 396–403
Lee CK, Marschner IC, Simes RJ et al. Increase in cholesterol predicts survival advantage in renal cell carcinoma patients treated with temsirolimus. Clin Cancer Res 2012; 18: 3188–3196
Atkins MB, Hidalgo M, Stadler WM et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004; 22: 909–918
Iacovelli R, Palazzo A, Mezi S, Morano F, Naso G, Cortesi E. Incidence and risk of pulmonary toxicity in patients treated with mTOR inhibitors for malignancy. A meta-analysis of published trials. Acta Oncol 2012; 51: 873–879

Editorial: Renal functional recovery after radical nephrectomy

March 12, 2014/by Ithaar Derweesh

In their publication ‘Trends in renal function after radical nephrectomy: a multicentre analysis’, Chung et al. [1] suggest that after radical nephrectomy (RN), renal functional recovery in patients who have RCC occurs even in states of baseline renal functional compromise (pre-existing stage III chronic kidney disease, CKD). These findings bolster other recent reports, which suggest that surgically induced CKD may not be associated with the same degree of renal functional decline as CKD that may be caused by medical factors [2, 3]. While the incidence of de novo stage III CKD (36.1%) and delta estimated GFR between preoperative and postoperative values are lower than reported by most other groups, which may be attributable to national and demographic trends that are different from North American and European trends [2-4], the findings are nonetheless important and show that in the short-to-intermediate term (median follow up of 33 months) continued renal functional stabilisation and recovery occurs after RN. Also, performing a RN in a patient does not sentence him or her to invariable or inevitable renal functional decline in the short-to-intermediate term. Furthermore, they establish, in the short-to-intermediate term at least, a reasonable timeline of renal functional recovery for patient counselling and physician expectations in the postoperative follow-up period. Interestingly, and perhaps more disturbingly, the authors noted minimal and no functional recovery in the elderly and diabetic groups, underlying the importance for consideration of nephron-sparing approaches in these higher risk subgroups, even in the setting of normal renal function, and particularly with a lower risk lesion, e.g. a clinical T1a renal mass [5]. What we are missing from this analysis are longer term data, and a more thorough analysis of the incidence and impact of potential metabolic and cardiovascular sequelae during this period [4, 6], and a comparative analysis that examines the timeline of renal functional recovery after partial nephrectomy. Because of these reasons, the reader should be cautioned not to over-interpret these findings, and to conclude that because RN is associated with renal functional recovery, performing a RN may not pose increased long-term risk compared with a nephron-sparing method, particularly in a patient with pre-existing medical drivers towards CKD (diabetes, obesity, hyperlipidaemia, etc.). These findings are nonetheless important and provocative, and should spur further investigation and may provide an important adjunct in the counselling of patients about the functional impact of RN.

Read the full article

Ithaar H. Derweesh
Department of Urology, University of California San Diego Health System, La Jolla, CA, USA

References

Chung JS, Son NH, Byun SS et al. Trends in renal function after radical nephrectomy: a multicentre analysis. BJU Int 2014; 113:408–415
Van Poppel H, Da Pozzo L, Albrecht W et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011; 59:543–552
Lane BR, Campbell SC, Demirjian S, Fergany AF. Surgically induced chronic kidney disease may be associated with a lower risk of progression and mortality than medical chronic kidney disease. J Urol 2013; 189: 1649–1655
Sun M, Bianchi M, Hansen J et al. Chronic kidney disease after nephrectomy in patients with small renal masses: a retrospective observational analysis. Eur Urol 2012; 62: 696–703
Campbell SC, Novick AC, Belldegrun A et al. Guideline for management of the clinical T1 renal mass. J Urol 2009; 182:1271–1279
Woldrich J, Mehrazin R, Bazzi WM et al. Comparison of rates and risk factors for development of anaemia and erythropoiesis-stimulating agent utilization after radical or partial nephrectomy. BJU Int 2012; 109: 1019–1025

Radiation within urology: challenges and triumphs

March 6, 2014/by Nathan Lawrentschuk

As gatekeepers urologists remain at the frontline of urological oncology in a position of trust that they have held since Charles Huggins, Nobel Laureate in Urology, pioneered the use of hormone manipulation to treat prostate cancer. However, radiation within urology is an important adjunctive, palliative and even primary treatment method for many urological malignancies. However, within many spheres, particularly internationally regarding prostate cancer, tensions appear to have been simmering between urologists and radiation oncologists. Fortunately, this does not appear to be the case in Australia and New Zealand but it is an important time to reflect on such issues as we move ever forward in the multimodality era.

In the USA the use of self-referral by urologists of men for adjuvant radiotherapy (RT) has come under scrutiny. Some urology groups have integrated intensity modulated RT (IMRT), a RT treatment carrying a high reimbursement rate, into their practice. This was highlighted in a recent New England Journal of Medicine article where the rate of IMRT use by urologists working at National Comprehensive Cancer Network centres remained stable at 8% but increased by 33% among matched self-referring urology groups [1]. This study has been criticised for bias but nonetheless captured political and academic attention. Certainly this situation has not arisen in our hemisphere but it remains important we think critically of what treatments we offer our patients and ensure patient’s best interests are maintained.

Clearly more research is required as to who should be receiving adjuvant RT and at what stage. In the latest issue of the BJUI USANZ supplement we highlight the Radiotherapy – Adjuvant vs Early Salvage (RAVES) trial for prostate cancer biochemical failure and high-risk disease [2]. There is no doubt this is an important trial because to date we have been unable to establish exactly which patients should receive adjuvant RT and when. Recruitment has been challenging as patients doing well after surgery often do not want additional treatment and a very small subset who are still recovering want to be enrolled but due to timing missing eligibility. Enthusiastic patients also may demand treatment rather than be randomised. Critics would also argue that the trial can never really answer the question because many men not requiring adjuvant RT will receive it [3]. Ongoing support of all parties should achieve accrual and in time, robust data. Excitingly imaging with MRI and other modalities will ensure further trials to assist in identifying disease in the salvage setting making choices easier based on more objective data [4].

Read the USANZ Supplement

Consumerism has driven robotic surgery [5] and is doing the same for RT but descriptions of treatment would be better placed to remain generic. The use of the term ‘radiosurgery’ has highlighted the shift away from the term ‘radical radiotherapy’. Of course the term ‘robot’ has become synonymous with radical prostatectomy but the ‘radical’ contribution remains and interestingly the term ‘robot’ has been trialled by radiotherapists: ‘image-guided robotic radiosurgery’ or its other more commonly used term Cyberknife^® (Accuracy Incorporated, Sunnyvale, CA, USA). Certainly this would be more accurately known as stereotactic body RT (SBRT). It is these terminology changes and continual shifts in treatment regimens that rankles many, with the old argument that RT treatment was done with inferior technology so results should be ignored receives disproportionate use at conferences. All groups need to acknowledge treatments have improved rather than disowning data from older treatment regimes. On the counter side one example from brachytherapy [6] concluded that despite the hype of improving dosimetry and reducing complications, the preoperative condition regarding erectile function and LUTS are the most important factors regarding postoperative outcome. This is almost certainly true for surgery as well. Comparison of side-effects appears unfair with grading of radiation toxicities more lenient than Clavien listed complications – an even playing field for comparison of complications is warranted.

Multimodality treatment for high-risk disease is becoming the standard of care. Urologists are beginning to embrace this regime of planned surgery with likely RT and ultimately systemic therapies. However, radiation oncologists often prefer to use radiation and hormonal manipulation and consider this ‘modified monotherapy’. Some men receive different modes of RT with concerns this leads to significantly more complications and in combination with androgen deprivation comes with all of the secondary effects of such therapy. An ideal study for such high-risk patients would randomise men to RT and androgen deprivation vs a graded multimodality treatment starting with surgery and then progressing to RT and systemic therapies when required (as some men will have T2 or T3a disease with clear margins that can be observed for a PSA rise necessitating treatment).

Complications do develop after any therapy and urologists are expertly placed to deal with them. Yet, there is a belief that RT and its long-term effects are real and these are often underplayed. This is contributed by a paucity of follow-up data beyond 5 years with primary RT. Major problems from surgery are generally able to be repatriated. However, the same may not be stated for RT complications: cystitis, stricture disease, permanent catheter drainage and chronic pain syndromes although uncommon, are not rare events and not easily remedied due to the altered tissues. Urologists are able to assist with these conditions but some feel that their efforts are unrecognised and that they share too much of the burden from somewhat surprised patients when situations are not able to be satisfactorily resolved. This reinforces the involvement by enthusiastic urologists with the patient selection and follow-up of brachytherapy and even other RT treatments being the cornerstone for ideal patient management and success.

Other areas worthy of engagement are with patients who develop a recurrence after RT treatment where the available data are sparse, making a decision even more difficult [3]. The perceived reluctance to refer RT failures to urologists in a timely fashion meaning many men are not offered salvage surgery or other options [7]. Occasionally urologists do the same with surgical failures but with multi-disciplinary teams, this is a rare event.

Communication remains a key to a multidisciplinary approach. Against the successes and strains, there are newer developments that will conspire to bring teams closer together, such as newer systemic therapies and the consideration of RT in men with oligometastatic disease. Also, based on Surveillance, Epidemiology and End Results (SEER) data, it appears that patients with limited metastatic disease may benefit from having treatment of the primary disease with a significant decrease in mortality (slightly more pronounced with surgery than radiation) [8]. This will ensure further debate on how far we stretch our primary treatment boundaries for the betterment of patients. Finally, use of fiducial markers and spacers will hopefully minimise morbidity and these are discussed in this supplement [9].

Just like any long-term relationship, the balance will shift at times and there has to be give and take on both sides. Many of the points in this editorial could be switched the other way with urologists at fault, so we must always be careful to be global, and not focal in our approaches. With everyone working together we have improved outcomes and survival of many with many urological malignancies. Overall, there is still harmony but room for even greater communication and collaboration as we strive towards better outcomes in future decades.

Nathan Lawrentschuk
University of Melbourne, Department of Surgery and Ludwig Institute for Cancer Research, Austin Hospital and Peter MacCallum Cancer Centre, Department of Surgical Oncology, Melbourne, VIC, Australia

Read the USANZ Supplement

References

Mitchell JM. Urologists’ use of intensity-modulated radiation therapy for prostate cancer. N Engl J Med 2013; 369: 1629–1637
Pearse M, Fraser-Browne C, Davis ID et al. A Phase III trial to investigate the timing of radiotherapy for prostate cancer with high-risk features: background and rationale of the Radiotherapy – adjuvant versus Early Salvage (RAVES) trial. BJU Int 2014; 113: 7–12
Chen RC. Making individualized decisions in the midst of uncertainties: the case of prostate cancer and biochemical recurrence. Eur Urol 2013; 64: 916–919
Thompson J, Lawrentschuk N, Frydenberg M, Thompson L, Stricker P. The role of magnetic resonance imaging in the diagnosis and management of prostate cancer. BJU Int 2013; 112 (Suppl. 2): 6–20
Alkhateeb S, Lawrentschuk N. Consumerism and its impact on robotic-assisted radical prostatectomy. BJU Int 2011; 108:1874–1878
Meyer A, Wassermann J, Warszawski-Baumann A et al. Segmental dosimetry, toxicity and long-term outcome in patients with prostate cancer treated with permanent seed implants. BJU Int 2013; 111: 897–904
de Castro Abreu AL, Bahn D, Leslie S et al. Salvage focal and salvage total cryoablation for locally recurrent prostate cancer after primary radiation therapy. BJU Int 2013; 112: 298–307
Cheng J. Would you really do a radical prostatectomy on a man with known metastatic prostate cancer? BJU Int BLOG posted 09 December 2013. Available at: https://www.bjuinternational.com/bjui-blog/would-you-really-do-a-radical-prostatectomy-on-a-man-with-known-metastatic-prostate-cancer/. Accessed January 2014
Ng M, Brown E, Williams A, Chao M, Lawrentschuk N, Chee R. Fiducial markers and spacers in prostate radiotherapy: current applications. BJU Int 2014; 113: 13–20

Text and the city

March 3, 2014/1 Comment/by Tet Yap

From the spectacular rise of bitcoin to the passing of Mandela and Thatcher, the horrors of Boston and Nairobi to the resignation of the Pope, the breakthroughs in human stem cell cloning [1] to the promise of medical three-dimensional printing [2] – our personal and professional lives are influenced by global and technological events in a way that seemed unimaginable just a few decades ago.

The clinical and scientific research community has never been more international as it is now. Publications of researchers from China and India in prestigious Science Citation Index (SCI – maintained by Thomson Reuters) journals has increased steadily, with Chinese papers accounting for 9.5% of all published in 2011 from a negligible figure a decade ago, second only to America [3].

At the BJUI, we are proud to be able to facilitate and receive the best high-quality research from any part of the world. Recent efforts in developing our print, online and social media channels have allowed us to disseminate this work to a greater worldwide audience than ever before. We are affiliated with the Urological Associations in Britain, Ireland, the Caribbean, India, Hong Kong and Australia and New Zealand. The ‘I’ in BJUI is something we work hard to foster.

In celebration of the global reach of the BJUI, all our 2014 covers will showcase the city or country of origin of our key feature within the issue. We wanted to reflect the sense of community that runs through the competitive, yet closely linked international network of research teams that are published within the BJUI. We hope that you will appreciate the stunning visual impact that complements the topical diversity, superlative quality and intellectual rigour of each new issue of the BJUI in 2014.

The article of the month in this issue features the androgen receptor and prostate cancer – a reflection of a life time of translational research from David Neal’s group at Cambridge [4]. Our Editor-in-Chief was inspired by the Zacchary Cope lecture at The Royal Society of Medicine, London and convinced David to send his paper to the BJUI. Furthermore during the annual meeting of the BAUS section of Academic Urology this January in Cambridge, it became obvious that punting was just as iconic as the awe inspiring university buildings in this beautiful city.

Tet Yap
Royal College of Surgeons of England, London, UK
Director of Glass Magazine

References

Tachibana M, Amato P, Sparman M et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 2013; 153: 1228–1238
Fischer S. The body printed. IEEE Pulse 2013; 4: 27–31
Lamb AD, Massie CE, Neal DE. The transcriptional programme of the androgen receptor (AR) in prostate cancer. BJU Int 2014; 113: 361–369

Editorial – Prostate cancer surgery vs radiation: has the fat lady sung?

February 26, 2014/by Tony Costello

The current article by Sun et al. [1] representing a number of institutions involved in prostate cancer treatment provision is thought-provoking and hypothesis-generating. The authors contention when mining Surveillance, Epidemiology and End Results data for 67 000 men who had localized prostate cancer between 1988 and 2005 is that those with a life expectancy >10 years had less likelihood of prostate cancer death when treated with surgery rather than by radiotherapy or being left to observation. The Scandinavians have already shown, in the randomized study by Hugosson et al. [2], that if you have your prostate cancer removed you have less likelihood of symptomatic local recurrence, lower likelihood of metastasis and progression, and a 29% reduced likelihood of prostate cancer death. The current study asks the question ‘Is radiation therapy less likely to provide a long-term cure for prostate cancer than surgery?’ and gives an answer in the affirmative.

The current paper, in its way, neatly encapsulates the contemporary angst generated in the community when prostate cancer screening, diagnosis and therapy are discussed. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) trial [3] allegedly shows no benefit from treatment over observation and contends perhaps that we surgeons and radiation oncologists are harm-workers, not life-savers. The PLCO has a 52% PSA contamination in its control arm [3]. That flawed trial compared screening with de facto screening and produced, in my view, a null hypothesis. How do we explain the paradox of a 44% reduction in prostate cancer-specific mortality between 1993 and 2009? How do we explain the disconnect between these trials and the facts? What do we do with the data not yet considered by the expert panels showing that early PSA testing at age <50 years is highly predictive of subsequent lethal prostate cancer? [4]

Clinicians are rapidly moving to an era of judicious risk assessment. This can only be done after biopsy is performed. We now frequently enrol patients with apparently indolent prostate cancer into surveillance protocols [5]. So the question should be ‘If the disease found on biopsy is moderate to high risk, and potentially lethal for that man, should we remove his prostate surgically or radiate it with intensity-modulated radiation therapy, brachytherapy, proton therapy, +/- hormone therapy?’.

As a surgeon I have an inherent dislike of combining hormone therapy in primary treatment. At least 50% of men in high-risk prostate cancer cohorts who receive radiation therapy also receive hormone therapy as adjuvant or neoadjuvant treatment [6]. Hormone therapy has a myriad of side effects. Even if the playing field was level between surgery and radiation therapy, the avoidance of hormone therapy as a first-line treatment gives surgery a seductive advantage.

The authors of the current report show a significant survival advantage in the cohort for surgery over radiation therapy and observation. There will never be a randomized trial between the two potentially curative treatment methods surgery and radiation. The scourge of commercial interest with spurious claims of superiority of one form of therapy over another, proton beam vs intensity-modulated radiation therapy, robotics vs high-intensity focused ultrasonography, means that we risk having our decisions regarding appropriate therapy formed by multibillion dollar technology companies with powerful marketing capacity. The current paper confirms what is self-evident: untreated localized prostate cancer can be lethal. Surgery and radiation therapy lower the morbidity and mortality from prostate cancer. Which is the better method of curative therapy is moot, but we do know that cure is very much predicated on the expertise and location of the practitioner.

We know mostly when and who to treat and what treatments work well. In my view, the prostate cancer testing debate resonates with the contemporary discussion about childhood immunization for infectious diseases. Some parents now, who clearly cannot remember the devastating epidemics of polio and other childhood illnesses, refuse to immunize their children. Prostate cancer practitioners who did not live in the quite recent era where the initial presentation of prostate cancer was bone metastasis +/− crush fracture to the vertebra and sometimes paraplegia, may be unknowingly steering us backwards.

At the recent 2013 AUA meeting, Adams et al. [7] reported on the fate of men not screened for prostate cancer, i.e. those men who presented with a PSA >100 ng/mL. There was a 3-year survival rate of 9.7%, a 19.7% cord compression rate and a 64% hospitalization rate. Those who do not learn the lessons of history are condemned to repeat them.

Anthony J. Costello
Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia

Read the full article

References

Sun M, Sammon JD, Becker A et al. Radical prostatectomy vs radiotherapy vs observation among older patients with clinically localized prostate cancer: a comparative effectiveness evaluation. BJU Int 2014; 113: 200–208
Hugosson J, Carlsson S, Aus G et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010; 11: 725–732
Andriole GL, Crawford ED, Grubb RL 3rd et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012; 104: 125–132
Vickers AJ, Ulmert D, Sjoberg DD et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40–55 and long term risk of metastasis: case-control study. BMJ 2013; 346: f2023
Evans SM, Millar JL, Davis ID et al. Patterns of care for men diagnosed with prostate cancer in Victoria from 2008 to 2011. Med J Aust 2013; 198: 540–545
Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. Cancer 2010; 116: 5226–5234
Adams W, Elliott CS, Reese JH. The fate of men presenting with PSA over 100 ng/mL: what happens when we do not screen for prostate cancer? AUA 2013. Abstract 2696