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Editorial: The robot to the rescue!

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Fortunately injuries to the urinary tract remain rare in obstetric and gynaecological surgery. Their potential for causing serious morbidity, not to mention the substantial medico-legal implications ensure that it remains a highly researched and evocative area [1].

Iatrogenic urinary tract injuries can be broadly divided into two groups; acute complications, such as bladder and ureteric lacerations or ligation and more chronic complications, such as vesicovaginal or ureterovaginal fistulae and ureteric strictures. Historically, iatrogenic trauma to the urinary tract most commonly followed open, abdominal hysterectomy with the most frequent complication being direct bladder injury. Gross bladder injuries are generally both detected and treated intraoperatively. In contrast, the management of more complex ureteric injuries and their long-term sequelae, such as fistula, pose greater surgical challenges. The complexity of these injuries is often further compounded by delay in diagnosis. It is generally accepted that, if possible, immediate repair provides the optimal treatment. However, when diagnosis is delayed, there is little consensus on the best management approach, although the current tendency is towards early repair [2].

The multicentre, retrospective study of robotic repair of 49 iatrogenic genitourinary injuries by Gellhaus et al. [3] should therefore serve to reassure gynaecologists with respect to the incidence of this feared complication. This paper, mainly looking at ureteric re-implants and fistula repairs, constitutes the largest cohort of robotic reconstructions to date. A zero conversion rate to open surgery suggests excellent case selection by the robotic surgeons. Four cases had undergone previous failed open or endoscopic management and this is clearly a challenging cohort. Yet, with the absence of total numbers of urology referrals received for such injuries, it is important to remember that it may not be a panacea for all.

There has been a considerable shift in the management of urological trauma from open to laparoscopic techniques. While the repair of basic injuries has been proven to be effective, less data is available to support the management of more complex injuries, such as ureteric transections or fistulae [4]. Numerous techniques for repairing ureteric injuries and fistulae have been described; nonetheless, the surgery remains technically challenging even for experienced laparoscopic surgeons and is generally limited to high-volume centres [5].

In comparison, this article [3] provides strong evidence for the effectiveness of robot-assisted (RA) repairs, even for complex injuries. The enviable 95.9% success rate from 47 operations is complemented by short recovery times and low complication rates. These results are especially impressive in view of the mean 23.5-month delay time to repair. But the authors do not report the reasons for these delays. Immediate robotic repair of RA injuries is clearly feasible especially in larger units. Whether immediate RA repair should be performed for other iatrogenic injuries needs further discussion. Is it realistic to convert to the robot in the case of laparoscopic trauma or should RA repairs remain a planned return to theatre?

The demand for RA reconstructive surgery and experienced robotic pelvic surgeons is likely to rise in the near future. As the authors note, the continued expansion of minimally invasive procedures is likely to lead to a shift in the patterns of complications from more straightforward bladder injuries to complex ureteric injuries. As mentioned previously these types of injury are more likely to be initially undetected.

Whilst rates of surgical complications involving the urinary tract remain low, obstetrical and gynaecological procedures account for 75% of these injuries. This article provides robust evidence for the key role that RA surgery can play in the management of these complex and feared injuries. When faced with such situations, Gellhaus et al. [3] have shown that it is increasingly likely that the robot saves the day.

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Nicholas Raison and Ben Challacombe

Department of Urology, Guy’s and St Thomas’ Hospital,London, UK

References

1 Preston JM. Iatrogenic ureteric injury: common medicolegal pitfalls. BJUInt 2000; 86: 313–7

2 El-Tabey NA, Ali-el-Dein B, Shaaban AA et al. Urological trauma aftergynecological and obstetric surgeries. Scand J Urol Nephrol 2006; 40:225–31

3 Gellhaus PT, Bhandari A, Monn MF et al. Robotic management ofgenito-urinary injuries from obstetrical and gynecological operations: amulti-institutional report of outcomes. BJU Int 2015; 115: 430–6

4 De Cicco C, Ussia A, Koninckx PR. Laparoscopic ureteral repairin gynaecological surgery. Curr Opin Obstet Gynecol 2011; 23:296–300

5 Rassweiler J, Pini G, Gözen AS, Klein J, Teber D. Role of laparoscopy inreconstructive surgery. Curr Opin Urol 2010; 20: 471–82

 

Editorial: On the Mark? Is AP a surrogate for BMD in hypogonadal men?

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The current issue of the BJUI contains a paper by Dubaja et al. [1] that may be of interest to physicians who have patients with hypogonadism. The authors speak to an unappreciated aspect of low testosterone; namely, the loss of bone in men and the possible recovery with treatment. Their retrospective study looked at 140 men with hypogonadism treated with exogenous testosterone replacement or clomiphene citrate testosterone enhancement. These men were also assessed for bone mineral density (BMD) markers at 6, 12 and 24 months after initial treatment. Importantly, dual-energy X-ray absorptiometry (DEXA) was performed a second time after 2 treatment years for a subset of these men. DEXA showed that there was a gain in BMD and a loss of serum alkaline phosphatase (AP) for all the men over time. The loss of AP was rapid but stabilized at 6 months. Testosterone and free testosterone increased as expected but there were no changes in vitamin D, calcium, parathyroid hormone or sex hormone-binding globulin. There was a correlation between AP and testosterone. The authors recognized poor bone density at baseline in those men with testosterone levels

Bone mineral density is the best way to predict osteoporosis and fragility fractures [2]. Women loose BMD after menopause and that is accompanied by many changes, including gains in AP [3]. The decline in serum oestrogens is a factor for women, and oestrogen replacement therapy historically has been used to prevent that loss. Not all men undergo a similar loss, i.e. andropause is not recognized in the same way as menopause. Even though osteoporosis is less common in men, the associated comorbidity may be more significant.

There is an age-related decline in testosterone and an acute loss for some men such that they approach their physicians with symptoms. The underlying cause of bone loss in men and women may be the same: serum oestrogen loss. Men who lose testosterone are also losing oestrogen because testosterone is the precursor via aromatase. Repros Therapeutics is developing a way to treat men with secondary hypogonadism. An ongoing 1-year DEXA study recruited eligible men. Key inclusion factors were age < 60 years and body mass index > 25 kg/m2. Remarkably 24% of men failed the screening test because of osteopenia, despite the fact that few of them were old or underweight.

The present paper by Dubaja et al. suggests that a readily available serum test may be able to monitor men on testosterone therapies for gain in BMD. Given the relatively low incidence of osteoporosis, screening every man by DEXA is not cost-efficient. The 1 year or more needed to find BMD loss by DEXA also wastes time and resources. Quantitative CT is more costly and is accompanied by high radiation exposure. The use of AP, as suggested in the present study, may represent a reasonable alternative.

The paper is not without its weaknesses. There was no indication of whether these men had primary or secondary hypogonadism. Transdermal testosterone should raise testosterone and oestrogen in both groups of men whereas clomiphene citrate works through changes in LH and FSH and requires an intact hypothalamic-pituitary-gonadal axis (useful in men with secondary hypogonadism only). Indeed, the two kinds of treatment will have the opposite effect on LH and FSH [4]. The authors recognized the importance of Leydig cells in producing testosterone, yet the effects of a transdermal testosterone would be to shut down testosterone production. We commend their suggestion that other factors that contribute to both bone and Leydig cell function, insulin-like 3 [5] and osteocalcin [6] should be studied in relation to AP. The loss of subjects throughout the 2 years was troubling, but it is known that men on transdermal treatments discontinue with disturbing frequency despite satisfaction [7]. If those who stayed in the present study were those with the best outcomes in terms of testosterone and BMD, potential bias may exist. If men can be encouraged to continue therapy through positive effects on BMD being detected as early as 6 months, AP monitoring may improve patient compliance. Only DEXA can give that assurance now. The authors noted the need for a larger prospective trial. Nevertheless, their paper provides a rationale for monitoring men on testosterone therapies that can be implemented with minimal cost or the need for new diagnostics.

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Martin C. Michel
Department of Pharmacology, Johannes Gutenberg University, Mainz, German
References
1 Dabaja A, Bryson C, Schlegel P, Paduch D. The effect of hypogonadism and testosterone-enhancing therapy on alkalinephosphatase and bone mineral density. BJU Int 2015; 115: 3
2 NIH Consensus Development Panel. Osteoporosis prevention, diagnosis and therapy. JAMA 2001; 285: 785–95
3 Biver E.Use of bone turnover markers in clinical practice. Curr O pin Endocrinol Dia betes Obes 2012; 19: 468–73
4 Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. JSexMed2013; 10: 1628–35
5 Ivell R, Anand-Ivell R. Biology of insulin-like factor-3 in human reproduction. Hum Reprod Update 2009; 15: 463–76
6 Karsenty G. Bone endocrine regulation of energy metabolism and male reproduction. CRBiol2011; 334: 720–4
7 Kovac J, Rajanahally S, Smith R, Coward R, Lamb D, Lipshultz L. Patient satisfaction with testosterone replacement therapies: the reasons behind the choices. JSexMed2014; 11: 553–62

 

Editorial: Enzalutamide withdrawal syndrome: is there a rationale?

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Enzalutamide is a second generation non-steroidal antiandrogen (AA), which significantly improved overall  survival (OS) and progression-free survival (PFS) after docetaxel (AFFIRM study), and OS and radiographic PFS before chemotherapy (PREVAIL study) in patients with metastatic castration-resistant prostate cancer (mCRPC) [1].

Being a potent androgen receptor (AR) antagonist, an enzalutamide withdrawal syndrome (EWS) appeared unlikely [2,3]. In contrast with this position, and considering the well-known AR structural alterations in CRPC, very recent preclinical and clinical data support the possibility of the existence of an EWS after the discontinuation of this drug, in a castration-resistant setting.

In patients with mCRPC progressing on androgen-deprivation therapy (ADT), the AAWS, due to the interruption of first generation AAs (flutamide, bicalutamide, nilutamide, cyproterone acetate and megestrol acetate), often pursues as a further hormonal manipulation, although no level one studies supported its efficacy. AAWS leads to a PSA reduction in 15–30% of patients, with concomitant symptomatic relief and radiographic responses in some cases, without impacting on survival [1]. The molecular mechanisms of the AAWS are still unclear. One of the possible mechanisms responsible for the AAWS is the mutation of the AR. In vitro models showed that bicalutamide may switch from antagonist to agonist in LNCaP-cxD cell lines, due to an additional AR mutation in codon 741 during bicalutamide treatment [4]. Similarly, preclinical in vitro and in vivo studies demonstrated that initially enzalutamide exerts its AR antagonist activity, but during the treatment enzalutamide potently induces an AR mutation, leading to the mutant ARF876L, which confers agonism to enzalutamide, and resistance to enzalutamide therapy [1]. In the clinical setting, the first evidence of possible EWS has begun to appear. Phillips [5] observed EWS in one patient, 40 days after enzalutamide discontinuation. Rodriguez-Vida et al. [1] showed EWS in three of 30 (10%) patients with mCRPC after the drug cessation, although none of the 17 factors examined were statistically significant predictors of PSA decline after enzalutamide interruption. Considering the clinical characteristics of the three patients showing EWS, interestingly all of them were aged <70 years, had Gleason score ≥7, had bone and/or lymph node metastases without visceral sites of disease, and had had previous treatments with bicalutamide and docetaxel. In all three patients, EWS seems to have no correlation with: prostate cancer staging at diagnosis (M0 vs M1), PSA value before enzalutamide, PSA decline on enzalutamide treatment, LHRH analogues and enzalutamide therapy duration. Similarly to bicalutamide WS, in all three patients no symptomatic improvement was recorded during EWS.
Focusing on patient 1, interestingly he displayed initially a PSA response during enzalutamide and later a further PSA decline plus radiological response after enzalutamide interruption (i.e. EWS), showing a sensitivity either to initial enzalutamide antagonism and to subsequent agonism, and exhibiting an EWS not preceded by a bicalutamide WS. This supports previous data concerning different AR mutations for the two different AAs, without subsequent clinical correlations between the two different AAWSs. A LHRH analogue duration treatment (5 months) shorter than a subsequent enzalutamide duration therapy (21.4 months) suggests different tumoral cells sensitivity to different ADTs, in different stages (hormone naïve and castration-resistant prostate cancer), likely related to several AR structural alterations collected along the disease. Intriguingly, patient 3 discontinued enzalutamide after only 1.2 months, maybe due to primary resistance [6]; nevertheless, he showed a PSA
response after enzalutamide interruption, suggesting that EWS, characterised by the switch from enzalutamide antagonism to agonism, could occur even in prostate cancer patients primary resistant to this drug. Limitations of the two first clinical reports related to EWS include a restricted sample size, a reduced number of EWS events and a short duration of follow-up after enzalutamide discontinuation. Furthermore, preclinical studies on EWS and published data concerning AAWS described more frequently early stage mCRPC, while the two papers considered heavily pretreated patients with mCRPC, in whom EWS incidence could be reduced due to several previous treatments, which probably produced various AR alterations.

In conclusion, the preclinical models have demonstrated one possible plausible mechanism responsible for EWS and enzalutamide resistance. First clinical reports suggest the possibility of EWS in a minority of patients after enzalutamide discontinuation in mCRPC. Further studies are needed to confirm and detail the EWS, before translating these data into clinical practice.

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Alessandra Mosca
Medical Oncology, ‘Maggiore della Carità’ University Hospital, Novara, Italy

References

1 Rodriguez-Vida A, Bianchini D, Van Hemelrijck M et al. Is there an antiandrogen withdrawal syndrome with enzalutamide? BJU Int 2015; 115: 373–80

2 von Klot CA, Kramer MW, Böker A et al. Is there an anti-androgen withdrawal syndrome for Enzalutamide? World J Urol 2014; 32: 1171–6

3 von Klot CA, Kuczyk MA, Merseburger AS. No androgen withdrawal syndrome for enzalutamide: a report of disease dynamics in the postchemotherapy setting. Eur Urol 2014; 65: 258–9

4 Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 2003; 63: 149–53

5 Phillips R. An enzalutamide antiandrogen withdrawal syndrome. Nat Rev Urol 2014; 11: 366

6 Efstathiou E, Titus M, Wen S et al. Molecular characterization of Enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur Urol 2015; 67: 53–60

 

Editorial: Malignant medication? Testosterone and cancer

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Testosterone therapy (TTh) in men with hypogonadism is becoming more commonplace among urologists, endocrinologists and even primary practitioners. While the definition of hypogonadism remains a moving target, the literature reflects very clear benefits of TTh in appropriately selected patients. As with any drug, the adverse effect profile helps to dictate the risk:benefit ratio and, over the past several years, numerous, primarily retrospective, analyses have provided mixed insights into the impact of TTh on cardiovascular disease and cancer, specifically prostate cancer.

Eisenberg et al. [1] take a step back from the focus on prostate cancer and evaluate the impact of TTh on general cancer incidence in a cohort of men treated in a single, large-volume andrology practice over 20 years. The authors found no difference in either overall cancer incidence or in the prostate cancer incidence in men on TTh in comparison with men not on TTh. This finding is significant as it supports the hypothesis that testosterone does not harmfully affect either hormonally responsive (prostate cancer) or non-hormonally responsive malignancies. Interestingly, the authors also observe a lower rate of all cancers in men on testosterone therapy. While not statistically significant, this finding is consistent with that of at least one other study focused on prostate cancer, in which men with high-risk prostate cancer receiving exogenous testosterone had a lower recurrence rate than a matched control group [2]. If borne out in future studies, a protective relationship between TTh and cancer would indeed reflect a novel benefit of treatment.

Nevertheless, at this time the jury remains out on a definitive assessment of the effects of TTh on both cancer as well as cardiovascular disease, and will probably continue to do so until controlled, prospective studies are completed. Numerous, mostly retrospective studies have examined the effects of endogenous testosterone and of the administration of exogenous testosterone, primarily on prostate cancer. While the details of these studies are beyond the scope of the present editorial, their findings have varied with regard to whether testosterone does or does not have effects on cancer incidence, biopsy findings, grade, recurrence rates and margin status, preventing a clear perspective on the effects of testosterone on cancer. Similarly, studies evaluating the impact of TTh on cardiovascular disease have also widely varied in their conclusions [3, 4]. Several recent large retrospective studies have found a detrimental relationship between TTh and cardiovascular disease in specific male populations, but have come under withering criticism from the community, with significant doubts cast regarding the veracity of their findings [5, 6].

The growing popularity of TTh has subjected it to a level of scrutiny applied to few other medications, resulting in a slew of peer-reviewed publications of varying quality and conclusions. In the effort to safeguard patients, investigators have hurriedly carried out retrospective data evaluation, which, by design, limits compensation for confounding factors and unfortunately results in an overall murky understanding of long-term adverse events related to TTh. Nevertheless, the clinical benefits of TTh are clear, and many patients are satisfied with the results of treatment. While physicians should remain the stewards of patient care, informed consent and a patient’s acceptance of both the known as well as the unknown risks of testosterone treatment should continue to be an integral part of the initiation and continuation of TTh, until additional high-quality data from clinical trials become available in the coming years.

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Alexander W. Pastuszak
Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

 

References

 

1 Eisenberg ML, Li S, Betts P et al. Testosterone therapy and cancer risk. BJU Int 2015; 115: 317–21

 

2 Pastuszak AW, Pearlman AM, Lai WS et al. Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol 2013; 190: 639–44

 

3 Basaria S, Coviello AD, Travison TG et al. Adverse events associated with testosterone administration. NEnglJMed2010; 363: 109–22

 

4 Shores MM, Smith NL, Forsberg CW et al. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012; 97: 2050–8

 

5 Vigen R, O’Donnell CI, Baron AE et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310: 1829–36

 

6 Finkle WD, Greenland S, Ridgeway GK et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE 2014; 9: e85805

 

Editorial: How active should active surveillance be?

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 Many investigators, including those from Johns Hopkins University (JHU) and the Prostate cancer Research International: Active Surveillance project (PRIAS), have provided meaningful data to strongly support the increasing use of active surveillance (AS) across the world. There are a multitude of strategies to minimise excessive rates of prostate cancer over detection and overtreatment. After the diagnosis of prostate cancer, the single best is AS for appropriately selected men.

 For decades, the concept of not treating a prostate cancer in otherwise healthy men, even if low-grade and low-volume was typically considered nihilistic and heretical, particularly in the USA. Thankfully, data have largely made this line of thinking anachronistic. The era of sensibly applied AS is upon us, and single-institution series with intermediate-term follow-up are excellent, with exceedingly low rates of metastasis or cancer-related death. However, we await longer-term (>10 years) outcomes from the contemporary PSA screening era.

 The ‘success’ of AS is largely dependent on the entry criteria, follow-up strategies, and indications for curative intervention. Highly restrictive inclusion criteria, rigorous biopsy based follow-up and strict definitions of reclassification triggering treatment have produced superb outcomes. Critics appropriately argue these criteria exclude a significant proportion of men with a low rate of requiring treatment or having metastases, if allowed on AS. Conversely, other programmes with looser entry criteria, more lax follow-up, and relaxed indications for intervention will be more inclusive and have lower rates of immediate or delayed intervention but must be counterbalanced against the expected higher rate of metastases or death.

 The current study [1] evaluates two different AS follow-up strategies from JHU and PRIAS. In general, JHU uses annual biopsies with progression defined as a new PSA density >0.15 ng/mL/mL or increasing tumour volume or grade beyond a certain threshold, while PRIAS recommends less frequent biopsies (years 1, 4, and 7) while relying on serological (PSA doubling time, PSADT) alongside histological indicators for defining progression and recommending treatment.

 Not surprisingly, different strategies lead to varying expected outcomes. Among the JHU patients, 38% were reclassified at a median of 2.1 years. Nearly two-thirds of the reclassified would have been identified at the PRIAS year 1 or triennial biopsies with 16% identified between PRIAS biopsies at a median delay of 1.9 years. The unanswerable but incredibly important question is whether this delay is essentially a non-issue, perhaps a favourable attribute (more AS time without compromising cure rates), or clinically disastrous (patients no longer curable).

 PRIAS relies heavily on PSA kinetics, which can be a double-edged sword. Among men in the JHU programme with >5 years follow-up, 11% would have delayed reclassification compared with PRIAS at a median time of 4.7 years. Additionally, 12% would have undergone intervention due to PRIAS-defined PSADT but not progressed based on the JHU protocol. It is convenient and perhaps intuitive that PSA kinetics should predict progression and meaningful clinical events for men on AS; however, the data from multiple studies have simply not supported this concept [2, 3].

 The JHU programme has restrictive entry rules compared with most other programmes, a rigorous biopsy based follow-up protocol, and strict criteria to treat, which is exactly why no metastasis or death have been reported among 769 men, some with up to 15 years follow-up[4]. Guidelines are needed but should not be overly prescriptive or rigid. For example, a surveillance biopsy showing a single core of Gleason 6 encompassing 60% of the total core or three cores of Gleason 6 with total cancer length of 3 mm would lead to a recommendation of treatment according to published JHU criteria. Many of us would not be phased with these biopsy reports and comfortably recommend ongoing AS.

 Data from AS series are very encouraging but it is highly likely we can do even better. For example, 10-year cancer-specific survival is 97% in the Sunnybrook AS experience and all five cancer-related deaths occurred in patients that would not meet most contemporary AS entry criteria [5, 6]. I am hopeful and confident that emerging data incorporating MRI imaging, serum biomarkers (e.g. prostate health index), or tissue-based biomarkers (e.g. Prolaris, Oncotype Dx) will provide us with a more comprehensive understanding of these men’s cancer such that tailored, evidence-based recommendations can be even more accurate.

 There is much yet to be learned about AS and this study [1] adds to our knowledge. Surveillance for prostate cancer is definitely active, but it is also dynamic and evolving.

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Scott Eggener
Associate Professor of Surgery, University of Chicago, Chicago, IL, USA

 

References

 

1 Kates M, Tosoian JJ, Trock BJ, Feng Z, Carter HB, Partin AW. Indications for intervention during active surveillance of prostate cancer:
a comparison of the Johns Hopkins and Prostate Cancer Research International Active Surveillance (PRIAS) protocols. BJU Int 2015; 115: 216–22

 

2 Whitson JM, Porten SP, Hilton JF et al. The relationship between prostate specific antigen change and biopsy progression in patients on active surveillance for prostate cancer. J Urol 2011; 185: 1656–60

 

3 Fall K, Garmo H, Andrén O et al. Prostate-specific antigen levels as a predictor of lethal prostate cancer. JNatlCancerInst2007; 99: 526–32

 

4 Tosoian JJ, Trock BJ, Landis P et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol 2011; 29: 2185–90

 

5 Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 2010; 28: 126–31

 

6 Krakowsky Y, Loblaw A, Klotz L. Prostate cancer death of men treated with initial active surveillance: clinical and biochemical characteristics. J Urol 2010; 184: 131–5

 

Editorial: Conventional laparoscopic surgery – more pain, no gain!

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Advances in surgical technology have revolutionized the way surgery is performed today. Conventional laparoscopic surgery dominated the surgical paradigm for several decades, until robot-assisted surgery created the next giant leap. In the pressent article, Elhage et al. [1] compare and correlate physical stress and surgical performances among three modes of a standardized surgical step. Their study shows the obvious physical strain and technical limitations faced while performing conventional laparoscopic surgery, subsequently leading to compromised surgical outcomes. The physical impact of conventional laparoscopic surgery has been well documented through surgeon feedback as well as ergonomic assessment [2, 3]. Various studies have reported that higher physical stress, associated with ergonomic limitations, is experienced when performing conventional laparoscopy compared to the comfort and ease of robot-assisted surgery, as highlighted in the present study. Increased workload has also been associated with performance errors, with a steep learning curve needed to achieve surgical excellence during conventional laparoscopy [4].

Currently, the use of robot-assisted surgery is on the rise, as an alternative to both open and conventional laparoscopic surgery across the developed world, despite its obvious economic limitations. Better ergonomics during robot-assisted surgery will increase the comfort of the surgeon, but the future of surgery may easily be linked to the improvements experienced by all of us in the automobile industry. Developments, from manual gear-clutch control to automatic speed control and the luxury of adaptive cruise control today, make us safe drivers with minimal physical stress. The concept of adaptive cruise control, which adjusts the speed of a vehicle in relation to its surroundings, sounds similar to the leap from manual camera control during conventional laparoscopy to console-based control during camera navigation in robot-assisted surgery. With advances in the speed and size of computers, pneumatic-based joint mechanics and mindfulness meditation on the horizon, it will not be long before surgeons will sit back and watch the marvel of the machine. Surgeons just need to learn to hold on to their seats!

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Syed J. Raza*, Khurshid A. Guru† and Robert P. Huben†
*Fellow, †Endowed Professor of Urologic Oncology, Department of Urology and A.T.L.A.S (Applied Technology Laboratory for Advanced Surgery) Program, Roswell Park Cancer Institute, Buffalo, NY, USA

 

References

 

1 Elhage O, Challacombe B, Shortland A, Dasgupta P. An assessment of the physical impact of complex surgical tasks on surgeon errors and discomfort: a comparison among robot-assisted, laparoscopic and open approaches. BJU Int 2015; 115: 274–281

2 Plerhoples TA, Hernandez-Boussard T, Wren SM. The aching surgeon: a survey of physical discomfort and symptoms following open, laparoscopic and robotic surgery.

J Robotic Surg 2012; 6: 65–723 Hubert N, Gilles M, Desbrosses K, Meyer JP, Felblinger J, Hubert J. Ergonomic assessment of the surgeon’s physical workload during standard and robotic assisted laparoscopic procedures. Int J Med Robot 2013; 9:142–147

4 Yurko YY, Scerbo MW, Prabhu AS, Acker CE, Stefanidis D. Higher mental workload is associated with poorer laparoscopic performance as measured by the NASA-TLX tool. Simul Healthc 2010; 5: 267–271

 

Editorial: Opening the flood gates – HLE is superior to PVP for the treatment of CUR

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With the expansion in laser technology for treating symptomatic BPH, there are now two main techniques available to the budding urologist. Yet the management of chronic urinary retention (CUR) remains a significant challenge. In this issue of BJUI Jaeger et al. [1]present a retrospective study comparing holmium laser enucleation of the prostate (HoLEP) and photoselective vaporization of the prostate (PVP; using XPS 180 watt and HPS 120 watt systems) in the treatment of CUR.

Both HoLEP and PVP are now well-established treatment methods. Although PVP has seen a greater level of acceptance because of its shorter learning period, its use remains limited by prostate size and concerns about long-term durability. In contrast the favourable and enduring outcomes reported for HoLEP have meant that it is gaining recognition as the new ‘gold standard’ surgical treatment for BPH. Whilst PVP ablates the tissue laterally from the prostatic urethra, HoLEP involves an anatomical enucleation of all the prostatic adenoma before morcellation.

Over the past decade, there has been a shift towards medical management of BPH. Despite the resultant increase in numbers of men developing CUR, best practice for this challenging and clinically important group remains highly debated. The term CUR is used to describe a constellation of presentations, and current imprecise, even arbitrary, definitions make the interpretation of existing studies difficult. Historically, CUR has been almost universally excluded from trials because of the anticipation of poor outcomes and high complication rates, while the presence of detrusor hypotonia, particularly with low-pressure retention, has led to concerns of treatment failure following surgery. This dilemma for urologists has been aggravated by conflicting evidence in the published literature [2].

Jaeger et al. [1] assessed all patients with CUR who were treated in their institution either with HoLEP (72 patients) or PVP (31 patients). CUR was defined as a persistent post-void residual urine volume (PVR) >300 mL or urinary retention refractory to multiple voiding trials. While preoperative urodynamic studies were not routinely performed, those patients found to have low bladder contractility or acontractility were not excluded.

Both HoLEP and PVP produced similarly effective outcomes in terms of symptom score improvement, PVR reduction and Qmax increase in voiding patients. Complication rates were also similar in the two groups (15 and 26% for HoLEP and PVP, respectively, P = 0.27), but, importantly, HoLEP was shown to offer substantially better rates of spontaneous voiding than PVP, 99 vs 74% of patients, in spite of a lower median bladder contractility index in the HoLEP group (73 vs 90, P = 0.012).

Both PVP and HoLEP have previously been studied in isolation in treating patients with CUR. Whilst Woo et al. [3] demonstrated significant reductions in PVR after PVP (GreenLight HPS 120-W), the presence of detrusor under-activity was not established. Outcomes after PVP in patients with urodynamically proven detrusor hypotonia have been shown to be significantly worse than in patients with normal detrusor funtion [4].

The effectiveness of HoLEP has been shown in treating CUR secondary to BPH in a large study of 169 patients with symptom score improvements of 159% and spontaneous voiding in 98.25% [5]. Furthermore, even in patients with proven impaired bladder contractility, HoLEP led to spontaneous voiding in 95% [6] at least in the short term.

The findings from the present study further support the use of HoLEP specifically in CUR. Jaeger et al. are the first to compare the two technologies head on, albeit in a non-randomised study, in the treatment of CUR. Whilst both treatments showed reasonable efficacy despite low or absent bladder contractility in a number of patients, a significant advantage was seen with HoLEP, with the total removal of any obstructing tissue. These results were unaffected by the presence of preoperative impaired bladder on urodynamic studies. This study suggests that HoLEP is superior to PVP in the treatment of CUR, probably because of the larger prostatic channel that enucleation produces. Measurement of postoperative PSA readings would have been a useful addition to illustrate this. Nevertheless, the findings add to the growing body of evidence to support the use of HoLEP in treating CUR, irrespective of preoperative bladder function.

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Nicholas Raison and Ben Challacombe

Urology Department, Guy’s and St Thomas’ NHS Trust, Guy’s Hospital, Great Maze Pond, London, UK

References

1 Jaeger CD, Mitchell CR, Mynderse LA, Krambeck AE. Holmium laser enucleation and photoselective vaporization of the prostate for patients with benign prostatic hyperplasia and chronic urinary retention. BJU Int 2015; 115: 295–9

2 Ghalayini IF, Al-Ghazo MA, Pickard RS. A prospective randomized trial comparing transurethral prostatic resection and clean intermittent self-catheterization in men with chronic urinary retention. BJU Int 2005; 96: 93–7

3 Woo H, Reich O, Bachmann A et al. Outcome of GreenLight HPS 120-W laser therapy in specific patient populations: those in retention, on anticoagulants, and with large prostates (≥ 80 ml). Eur Urol Suppl 2008; 7: 378–83

4 Monoski MA, Gonzalez RR, Sandhu JS, Reddy B, Te AE. Urodynamic predictors of outcomes with photoselective laser vaporization prostatectomy in patients with benign prostatic hyperplasia and preoperative retention. Urology 2006; 68: 312–7

5 Elzayat EA, Habib EI, Elhilali MM. Holmium laser enucleation of prostate for patients in urinary retention. Urology 2005; 66: 789–93

6 Mitchell CR, Mynderse LA, Lightner DJ, Husmann DA, Krambeck AE. Efficacy of holmium laser enucleation of the prostate in patients with non-neurogenic impaired bladder contractility: results of a prospective trial. Urology 2014; 83: 428–32

Editorial: Geography – an increasingly important variable in prostate cancer clinical trials

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Enzalutamide is approved in the post-docetaxel phase for men with metastatic castrate-resistant prostate cancer (mCRPC) in North America (NA) and the European Union (EU). Merseburger et al. [1] now take a first look at comparing the efficacy and safety of enzalutamide in EU and NA patients treated in the AFFIRM trial. AFFIRM was a phase III double-blind, placebo-controlled multinational trial evaluating whether enzalutamide prolongs overall survival (OS) in men with mCRPC after docetaxel chemotherapy. This post hocexploratory analysis found a consistent OS benefit in both NA- and EU-treated patients. The safety profile was comparable in both regions.

Interestingly, the median OS appeared longer in the EU as compared with the NA cohort (‘not yet reached’ vs 17.4 months). With the placebo group in the EU the median survival was 16.2 vs 12.3 months in the NA cohort (3.9 months different). Direct statistical comparisons between regions were not performed but a median survival difference of 3.9 months is not inconsequential. Notably, drugs have been approved with lesser difference in OS.

The populations in AFFIRM have some baseline differences that may be of importance; the median time from diagnosis to randomisation was 68.9 months in the EU cohort vs 78.0 months in the NA cohort. Thus, it was possible that the NA cohort was ‘further along’ in the natural history of the disease despite apparently being well-balanced according to most baseline variables. The NA cohort was slightly more likely to have higher Gleason scores (50.6%) vs the EU cohort (44.0%), suggesting perhaps a slight difference in disease aggressiveness. It is also interesting that cardiac disease was present in 23.3% of the NA cohort vs only 7.2% of the EU cohort. Is it possible that cardiovascular diseases also contributed to a relative increase in mortality in the NA cohort? With regard to the post-protocol therapies, the use of abiraterone was more common in the EU cohort (30.5% of patients in the placebo group subsequently received abiraterone in the EU cohort vs 19.7% in the NA cohort). However, utilisation of cabazitaxel was more common in NA than in the EU (20.5% vs 9.9%). Some combination of pre-treatment and post-protocol variables in AFFIRM is probably the explanation for geographic variations in OS. Protocol treatments were well defined but these variables were not controlled.

These results in AFFIRM should also be considered in the context of geographic differences in medical care that may alter results and/or interpretation of phase III trials. Some of these differences have been previously documented in other phase III mCRPC trials. For instance, the recent phase III trials with orteronel reported no OS differences in the overall study [2]. However, in certain geographic regions (with less access to the newer life-prolonging drugs), the orteronel trials were clearly positive for the OS endpoint. In the TROPIC trial, cabazitaxel was associated with higher febrile neutropenia rates in some EU countries as compared with the USA. This was primarily due to geographic differences in prophylactic administration of granulocyte colony-stimulating factor (G-CSF) [3]. For the ALSYMPCA trial, striking geographic differences were noted in the timing (pre- or post-docetaxel) of radium-223 utilisation [4].

Understanding prognosis and treatment outcomes is increasingly critical in the design and interpretation of phase III clinical trials and particularly amongst trials that are designed to support regulatory approvals. Region or country where treatment takes place is an important variable to consider, especially if approved pre- and post-protocol treatments are not the same. This issue is even more important if the course of the disease is long (as in prostate cancer) and there are different treatments available from country to country.

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Oliver Sartor, Sumanta Kumar Pal*, Terhi Hermanson† and Charles L. Bennett‡,

Tulane Medical School, New Orleans, LA, *City of Hope Comprehensive Cancer Center, Duarte, CA, USA; † Helsinki University Central University, Helsinki, Finland; and ‡ College of Pharmacy, Medical University of South Carolina Cancer Center, Charleston, SC, USA

References

1 Merseburger AS, Scher HI, Bellmunt J et al. Enzalutamide in European and North American men participating in the AFFIRM trial. BJU Int 2015; 115: 41–9

2 Fizazi K, Jones R, Oudard S et al. Regional differences observed in the phase 3 trial (ELM-PC 5) with orteronel (TAK-700) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel. ASCO Meeting Abstracts. J Clin Oncol 2014; 32 (Suppl.): 5s (abstr 5042). Available at: https://meetinglibrary.asco.org/content/126314-144. Accessed November 2014

3 Ozguroglu M, Oudard S, Sartor AO et al. Effect of G-CSF prophylaxis on the occurrence of neutropenia in men receiving cabazitaxel plus prednisone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in the TROPIC study. ASCO Meeting Abstracts. J Clin Oncol 2011; 29 (Suppl.): abstr 144. Available at: https://meetinglibrary .asco.org/content/72386-104. Accessed November 2014

4 Parker C, Nilsson S, Heinrich D et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–23

 

Editorial: The Prostate – The gateway to men’s health

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We have been told for many years that the management of men with LUTS due to BPH was, for most, about treating the impact of those symptoms on their quality of life. However, evidence has been accumulating over recent years to suggest that BPH may be associated with the various components of the metabolic syndrome – a combination of central obesity, impairment of glucose tolerance, dyslipidaemia and hypertension. Hammarsten et al. [1] examined the link between BPH and 22 individual aspects of the metabolic syndrome and found that BPH was linked to 21 of these factors, including increased body mass index (BMI) and waist circumference, hypertension, type 2 diabetes, dyslipidaemia and atherosclerosis, lending support to the hypothesised association with metabolic syndrome as a whole.

In this issue of BJUI, Gacci et al. [2] report the results of a meta-analysis of eight studies examining this link between BPH and metabolic syndrome, including >5000 patients, of which over a quarter had metabolic syndrome. They report a higher prostate volume (and transitional zone volume) in men with metabolic syndrome than in those without, particularly in older and obese patients and those with low high-density lipoprotein (HDL)-cholesterol levels. Interestingly however, no difference was seen between the groups in terms of LUTS, as measured by total IPSS or the storage/voiding sub-scores, although other studies have reported this in the past [1]. They conclude that modification of lifestyle and cardiovascular risk factors, by weight loss, increased exercise, dietary improvements etc., may have a role to play in improving LUTS. In addition, further exploration of the role of medication, such as statins, in the management of LUTS due to BPH is recommended. These conclusions are supported in the literature by observational studies, showing for instance a decrease in the severity of LUTS with increasing exercise, an increased risk of LUTS with obesity, and a delay in the onset of LUTS for patients taking long-term statins of up to 7 years [3, 4].

BPH is not the only urological condition that appears to have links with metabolic syndrome [1]. It is well established that erectile dysfunction has strong associations with type 2 diabetes mellitus, cardiovascular disease, obesity and sedentary lifestyle. Less well known links are also seen with prostate cancer, renal calculi, hypogonadism and overactive bladder [5]. We are familiar with carrying out cardiovascular risk assessment, screening for diabetes and giving lifestyle advice to men with erectile dysfunction. Given the evidence suggesting that erectile dysfunction and BPH are closely associated, with many men suffering from both conditions [6], it would suggest that perhaps we should be doing the same for men presenting with symptomatic BPH.

An awareness and understanding of the connection between BPH and metabolic syndrome should encourage all physicians to assess patients with LUTS/BPH for underlying cardiovascular risk. It suggests that as a minimum, a number of baseline investigations should be carried out: blood pressure measurement, a fasting lipid profile (and formal cardiovascular risk profile using established algorithms, such as QRISK®), assessment for diabetes using fasting glucose or glycated haemoglobin (HbA1c), measurement of weight and BMI, or ideally the measurement of abdominal circumference (as central obesity is a far more sensitive marker of risk than BMI). Identification of features of the metabolic syndrome allows for tailored lifestyle intervention, in terms of increasing exercise, dietary changes, weight loss, smoking cessation advice and alcohol moderation. Medical management of hypertension, diabetes, dyslipidaemia and cardiovascular disease may be required according to national guidelines.

Huge numbers of men die prematurely from cardiovascular disease and complications of type 2 diabetes, and men are renowned for poor engagement with primary preventive strategies to decrease this risk. Men presenting to their GP or Urologist with symptoms from BPH are therefore presenting us with an opportunity to intervene and potentially save lives in the process – the prostate can be considered a gateway to wider aspects of men’s health, far beyond the quality-of-life impact of LUTS.

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Jonathan Rees

Backwell & Nailsea Medical Group, North Somerset, UK

References

1 Hammarsten J, Peeker R. Urological aspects of the metabolic syndrome. Nat Rev Urol 2011; 8: 483–94

2 Gacci M, Corona G, Vignozzi L et al. Metabolic syndrome and benign prostatic enlargement: a systematic review and meta-analysis. BJU Int 2015; 115: 24–31

3 Parsons JK, Messer K, White M et al. Obesity increases and physical activity decreases lower urinary tract symptom risk in older men: the Osteoporotic Fractures in Men Study. Eur Urol 2011; 60: 1173–80

4 St Sauver J, Jacobsen SJ, Jacobson DJ et al. Statin use and decreased risk of benign prostatic enlargement and lower urinary tract symptoms. BJU Int 2011; 107: 443–50

5 Rees J, Kirby M. Metabolic syndrome and common urological conditions: looking beyond the obvious. Trends in Urology and Men’s Health 2014; 5: 9–14

6 Rosen R, Altwein J, Boyle P et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol 2003; 44: 637–49

 

Editorial: Cognitive training and assessment in robotic surgery – is it effective?

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A formal and standardised process of credentialing and certification is required that should not merely be based on the number of completed cases but should be done via demonstration of proficiency and safety in robotic procedural skills. Therefore, validated assessment tools for technical and non-technical skills are required. In addition to effective technical skills, non-technical skills are vital for safe operative practice. These skill-sets can be divided into three categories; social (communication, leadership and teamwork), cognitive (decision making, planning and situation awareness) and personal resource factors (ability to cope with stress and fatigue) [1] (Fig. 1). Robotic surgeons are not exempt in requiring these skills, as situation awareness for example may become of even more significance with the surgeon placed at a distance from the patient. Most of these skills can, just like technical skills, be trained and assessed.

Various assessment tools have been developed, e.g. the Non-Technical Skills for Surgeons (NOTSS) rating system [1] that provides useful insight into individual non-technical skill performance. The Observational Teamwork Assessment for Surgery (OTAS) rating scale has additionally been developed and is suited better for operative team assessment [2]. Decision-making (cognitive skill) is considered as one of the advanced sets of skills and it consolidates exponentially with increasing clinical experience [3]. A structured method for this sub-set of skills training and assessment does not exist.

The present paper by Guru et al. [4] discusses an interesting objective method to evaluate robot-assisted surgical proficiency of surgeons at different levels. The paper discusses the use of utilising cognitive assessment tools to define skill levels. This incorporates cognitive engagement, mental workload, and mental state. The authors have concluded from the results that cognitive assessment offers a more effective method of differentiation of ability between beginners, competent and proficient, and expert surgeons than previously used objective methods, e.g. machine-based metrics.

Despite positive results, we think that further investigation is required before using cognitive tools for assessment reliably. Numbers were limited to 10 participants in the conducted study, with only two participants classified into the beginner cohort. This provides a limited cross-section of the demographic and further expansion of the remaining competent and proficient and expert cohorts used would be desirable. Furthermore, whilst cognitive assessment has the potential as a useful assessment tool, utility within training of surgeons is not discussed at present. Currently cognitive assessment shows at what stage a performer is within his development of acquiring technical skills; however, it does not offer the opportunity for identification as to how to improve the current level of skills. A tool with integration of constructive feedback is lacking. However, via identification of the stage of learning within steps of an individual procedure could provide this feedback. Via demonstration of steps that are showing a higher cognitive input, areas requiring further training are highlighted. Cognitive assessment may via this approach provide not only a useful assessment tool but may be used within training additionally.

The present paper [4] does highlight the current paucity and standardisation of assessment tools within robotics. Few tools have been developed specifically for addressing technical aspects of robotic surgery. The Global Evaluative Assessment of Robotic Skills (GEARS) offers one validated assessment method [5]. Additionally, several metrics recorded in the many robotic simulators available offer validated methods of assessment [6]. These two methods offer reliable methods of both assessing and training technical skills for robotic procedures.

It is now evident that validated methods for assessment exist; however, currently technical and non-technical skills assessments occur as separate entities. A true assessment of individual capability for robotic performance would be achieved via the integration of these assessment tools. Therefore, any assessment procedure should be conducted within a fully immersive environment and using both technical and non-technical assessment tools. Furthermore, standardisation of the assessment process is required before use for purposes of selection and certification.

Cognitive assessment requires further criteria for differentiation of skill levels. However, it does add an adjunct to the current technical and non-technical skill assessment tools. Integration and standardisation of several assessment methods is required to ensure a complete assessment process.

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Oliver Brunckhorst and Kamran Ahmed

MRC Centre for Transplantation, King’s College London, King’s Health Partners, Department of Urology, Guy’s Hospital, London, UK

References

1 Yule S, Flin R, Paterson-Brown S, Maran N, Rowley D. Development of a rating system for surgeons’ non-technical skills. Med Educ 2006; 40: 1098–104

2 Undre S, Healey AN, Darzi A, Vincent CA. Observational assessment of surgical teamwork: a feasibility study. World J Surg 2006; 30: 1774–83

3 Flin R, Youngson G, Yule S. How do surgeons make intraoperative decisions? Qual Saf Health Care 2007; 16: 235–9

4 Guru KA, Esfahani ET, Raza SJ et al. Cognitive skills assessment during robot-assisted surgery: separating the wheat from the chaff. BJU Int 2015; 115: 166–74

5 Goh AC, Goldfarb DW, Sander JC, Miles BJ, Dunkin BJ. Global evaluative assessment of robotic skills: validation of a clinical assessmenttool to measure robotic surgical skills. J Urol 2012; 187: 247–52

6 Abboudi H, Khan MS, Aboumarzouk O et al. Current status of validation for robotic surgery simulators – a systematic review. BJU Int 2013; 111: 194–205

 

 

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