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Editorial: Palliative care in patients with bladder cancer: an opportunity for value improvement?

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The concept of improving value in healthcare translates, in practical terms, to maximizing patient outcomes per dollar spent [1]. Palliative care has been shown to improve quality of life and possibly survival while reducing overall treatment costs amongst the seriously ill by as much as 33% per patient [2]. In this context, appropriate integration of palliative services within urological oncology care can serve as a mechanism for improving value in the field.

In this issue of BJUI, Hugar et al. [3] provide a valuable characterization of the current state of palliative care service utilization for patients with bladder cancer. Within a contemporary population of Medicare beneficiaries, the authors found receipt of palliative care services by only 4.1% of patients with advanced bladder cancer (defined as those with T4, N+, or M+ disease). Most interestingly, this value did not differ in a statistically significant manner from the rate of utilization amongst a broader cohort including all patients with muscle‐invasive (i.e. T2) bladder cancer collectively, nor did the rate of utilization vary by time.

These findings suggest that, generally, clinicians are not taking advantage of a high‐value service for patients with bladder cancer. Furthermore, the fact that utilization rates are not distinctly higher for those who meet criteria for early palliative care under American Society for Clinical Oncology guidelines (i.e. those with metastatic or locally advanced disease) indicates that barriers to adoption may be rooted in factors beyond simple recognition of advanced malignancy.  Considered in the context of this study showing no momentum towards increasing adoption, one must consider what clinical or policy interventions could alter current utilization trends. For more info follow grid-nigeria .

The authors appropriately identify that absence of physician buy‐in and a traditional lack of emphasis on cost‐conscious care are among the possible explanations for the low, flat utilization figures they observed. Indeed, fee‐for‐service reimbursement is generally oriented towards rewarding volume over quality and is known to encourage inefficiencies, high costs, service duplication, and a lack of care coordination. As such, a powerful corrective counterbalance to these forces could include restructuring reimbursement such that clinicians’ financial incentives become more closely aligned with patient outcomes and goals [4]. Palliative care is merely one of the high‐value services that stands to be more appropriately integrated into clinical practice under such reforms.

Value‐oriented alternative payment models, such as bundled payments, have been shown to improve coordination of care amongst providers [5]. And, in fact, there are already data suggesting that integration of palliative services into an improved care coordination environment yields improved outcomes. Check here at spiritofthesea  for more details. For example, a comprehensive care management plan known as the Aetna Compassionate Care Programme was shown to decrease lengths of inpatient hospitalization while resulting in overall end‐of‐life cost savings of 22% [6].

As the appropriate rate of palliative care utilization in muscle‐invasive bladder cancer remains open to debate, so too does the question of which interventions could assist in moving towards that level. In that sense, employing reimbursement incentives as a driver of more appropriate utilization of palliative care services should be viewed as but one of many potential approaches to improve the practice patterns illustrated in the present study. Future research will be necessary to better elucidate both the barriers to palliative care adoption as well as the most effective tactics to overcome them. The authors should be commended for providing the preliminary contextual data for these conversations, as urologists seek to integrate palliative services properly into high‐value care delivery for patients with advanced malignancy.

 

References

  1. Kaplan, RS, Porter, ME. How to solve the cost crisis in health care. Harv Bus Rev 2011; 89: 46– 52
  2. Brumley, R, Enguidanos, S, Jamison, P et al. Increased satisfaction with care and lower costs: results of a randomized trial of in‐home palliative care. J Am Geriatr Soc 2007; 55: 993– 1000
  3. Hugar, L, Lopa, S, Yabes, J et al. Palliative care use among patients with bladder cancer. BJU Int 2019; 123: 968– 75
  4. Miller, HD. From volume to value: better ways to pay for health care. Health Aff (Millwood) 2009;28: 1418– 28
  5. Bakker, DH, Struijs, JN, Baan, CB et al. Early results from adoption of bundled payment for diabetes care in the Netherlands show improvement in care coordination. Health Aff (Millwood)2012; 31: 426– 33
  6. Spettell, CM, Rawlins, WS, Krakauer, R et al. A comprehensive case management program to improve palliative care. J Palliat Med 2009; 12: 827– 32

 

Editorial: Prostatic Artery Embolization: Adding to the arsenal against the hapless prostate.

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Ever since Hugh Hampton Young introduced the cold punch method in 1909 for ‘punching out’ pieces of the prostate through a modified urethroscope, urologists have used a bewildering array of technology and methods to wage war against the hapless prostate. Methods in the current arsenal include ‘heat and kill’ (transurethral needle ablation, transurethral microwave therapy and Rezum treatment), ‘freeze and kill’ (cryotherapy), ‘slice’ (transurethral incision of prostate), ‘dice’ (transurethral resection of prostate [TURP]), ‘eviscerate and leave the prostate a shell of its former self’ (open prostatectomy and holmium laser enucleation of prostate), ‘suspend and open’ (Urolift), ‘poison’ (intraprostatic injections with Botox, alcohol and NX 1207), ‘vaporize’ (photoselective vaporization of the prostate [PVP]) and, if the prostate dares to turn cancerous, then we just cut it out with scalpels or robots. For the best Botox treatment baytown do follow us.  Prostatic artery embolization (PAE) adds to our already impressive armamentarium via a technique similar to strangulation by blocking arterial flow and essentially causing prostatic infarction. PAE also brings a member of another medical discipline to the frontline: the radiologist.

In this issue of BJUI, Müllhaupt et al. [1] report an in-hospital cost analysis of PAE compared to TURP, in their post hoc analysis of a randomized controlled trial. Treatment costs are an important component of healthcare but are a narrow and focused view of the overall management of BPH in an individual patient. The authors report that the in-hospital costs for PAE and TURP are similar and, therefore, cost should not be a consideration when deciding between PAE and TURP. Interestingly, the main procedural costs for TURP were anaesthesia, and the main cost factor for PAE was medical supplies. The urologist and radiologist physician charges were ~13% and ~15% of the procedural costs, respectively. So, if the costs of PAE and TURP are similar, how do you assess which to use?

The article by Müllhaupt et al. should be read in conjunction with other papers describing the efficacy, safety and outcomes of PAE compared to TURP, especially the original article by Abt et al. [2] from which this cost analysis is derived and the UK-ROPE study by Ray et al. [3].

Historically, prostatic infarction is known to be a possible result of cross-clamping the aorta for coronary or aortic surgery, hypotensive myocardial infarction or septic shock. PAE is an iatrogenic cause of prostatic infarction. In 1947, Wilbur G. Rogers [7], in ‘Infarct of the Prostate’, documented that ‘There is first swelling of the area involved, with degeneration and necrosis of the cells. This may be followed by absorption of the damaged area and fibrosis and cicatrization of the parts so that eventually the volume is much less than it was originally’. This is one of the early descriptions of how PAE potentially works.

Prostatic artery embolization as a technique is feasible and has been shown to be relatively safe and efficacious in certain specialized institutions, as shown by the UK-ROPE study [3] and by Abt et al. [2]. It should be noted that PAE can be a technically challenging procedure and, although bilateral embolization is the goal, only unilateral embolization is possible in 25% of cases [1]. Highly specialized training is required, and the technique continues to evolve to avoid embolization of extraprostatic branches [3]. PAE is more painful than TURP, with higher reported pain on a visual analogue scale and higher analgesic use [2], but is associated with a shorter length of hospital stay [1,2]. PAE is reported to be associated with an earlier return to normal activities but is less effective than TURP at 12 weeks with regard to changes in maximum rate of urinary flow, postvoid residual urine, prostate volume and desobstructive effectiveness according to pressure flow studies [2] and has a 20% reoperation rate after 12 months [3].

There are still some questions and issues surrounding PAE that may eventually be addressed with time and further studies. Embolizing an artery causes cell death and necrosis and eventual atrophy. This process is uncontrolled, however, and unpredictable in any individual patient. There is no way to know how much tissue or which part of the prostate is going to infarct and undergo necrosis with unilateral or bilateral embolization. If or when a potential abscess forms has not been defined or studied.

The longer-term effects of radiation dosage for PAE will not be known for many years. In the Abt et al. study cohort [2], the radiation dose (dose area product [DAP]) was 176.5 Gy/cm2. A standard anteroposterior and lateral chest X-ray exposes the patient to 0.3 Gy/cm2. An abdominal CT scan exposes the patient to ~32 Gy/cm2. PAE is thus roughly equivalent to ~5–10 standard abdominal/pelvic CT scans (more if using ultra-low dose scanners), 586 chest X-rays, 4.4 barium enemas or 8.8 voiding cysto-urethrograms. Markar et al. [4] reported that there was a significant increase in abdominal cancer within the radiation field in 14 150 patients undergoing endovascular aneurysm repair (EVAR), with 18% of patients who underwent EVAR succumbing to cancer. The mean radiation exposure (or DAP) in a review of 24 studies on EVAR [5] was 79.48 Gy/cm2, which is approximately half the radiation exposure of PAE.

Müllhaupt et al. [1] showed that PAE was associated with a quicker return to normal activities and a shorter length of stay than TURP, with similar in-hospital costs in Switzerland. Cost, however, must be considered alongside safety and efficacy data both in the short and long term. It is important to appreciate the specialized and technical expertise required to safely perform PAE and the importance of a urologist being part of the multidisciplinary management team as recommended in the National Institute for Health and Care Excellence (NICE) guidelines [6] (IPG611 April 2018). Radiation exposure will need close scrutiny and detailed reporting to document long-term effects, as demonstrated in the EVAR trials. Radiation dosage is cumulative over a lifetime and this must be considered when other interventional radiological procedures such as coronary angiograms and positron-emission tomography/CT are becoming more common. PAE should be compared with other emerging minimally invasive BPH procedures such as Urolift and Rezum in future studies, instead of just TURP to determine its role in BPH management and whether the radiation dose is justified. Longer-term studies are needed to assess the costs of managing any long-term
complications, re-operation rates and longer-term efficacy associated with PAE.

by Peter Chin
South Coast Urology, Wollongong, NSW, Australia

References

  1. Müllhaupt G, Hechelhammer L, Engeler D et al. In-Hospital cost analysis of prostatic artery embolization compared to transurethral resection of the prostate: post hoc analysis of a randomized controlled trial. BJU Int 2019;123: 1055-60
  2. Abt D, Hechelhammer L, Müllhaupt G et al. Comparison of prostatic artery embolization (PAE) versus transurethral resection of the prostate (TURP) for benign prostatic hyperplasia: randomized, open label, noninferiority trial. BMJ 2018; 361: k2338
  3. Ray AF, Powell J, Speakman MJ et al. Efficacy and safety of prostate artery embolization for benign prostatic hyperplasia: an observational study and propensity-matched comparison with transurethral resection of the prostate (the UK-ROPE study). BJU Int 2018; 122: 270–82
  4. Markar SR, Vidal-Diez A, Sounderajah V et al. A population-based cohort study examining the risk of abdominal cancer after endovascular abdominal aortic aneurysm repair. J Vasc Surg 2018; Article in Press. https://doi.org/10.1016/j.jvs.2018.09.058 [Epub ahead of print]
  5. Monastiriotis S, Comito M, Lapropoulos N. Radiation exposure in endovascular repair of abdominal and thoracic aortic aneurysms. J Vasc Surg 2015; 62: 753–61
  6. NICE Guidance. Prostate artery embolisation for lower urinary tract symptoms caused by benign prostatic hyperplasia. BJU Int 2018; 121: 825–34
  7. Rogers WG. Infarct of the prostate. J Urol 1947; 57: 484–7

 

Editorial: The bladder cancer conundrum: how do we treat the right tumour with the right treatment, at the right time?

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The bladder cancer conundrum is how to accurately determine the type of tumour, treatment and timing that is ideal for each patient? This is epitomised by the use of neoadjuvant chemotherapy (NAC) for muscle‐invasive bladder cancer (MIBC). MIBC is a deadly disease; if untreated, the 2‐year mortality rate is 85% [1] and even if treated the overall survival (OS) rate at 5 years is 50%. In this context, NAC is appealing because it may improve outcomes. In 2003, a landmark study by Grossman et al. [2] examined NAC prior to radical cystectomy (RC) for MIBC. The median survival (44 vs 77 months, P = 0.06) and pT0 rates, which equate to the best survival rates (30% vs 15%, P < 0.001), were improved with NAC. A meta‐analysis of 11 randomised control trials in >3000 patients reported an OS benefit of 5% at 5 years with platinum‐based NAC [3]. Whilst NAC improves outcomes, especially for those patients who achieve pT0, it is also important to examine outcomes for patients with persistent MIBC and to determine if NAC is helpful in those patients.

In this issue of the BJUI, Lane et al. [4] attempt to answer this question by examining outcomes for patients with persistent MIBC after RC alone or NAC followed by RC. Using Surveillance, Epidemiology, and End Results (SEER)‐Medicare data, the authors examined 1505 patients that underwent RC alone and 381 patients that received NAC and RC from 2004 to 2011. The authors report that after propensity weighted Kaplan–Meier analysis, the 5‐year OS rate was improved amongst patients that received NAC and RC as compared to patients that had RC alone if there was pT2–T4N0M0 disease on final pathology (43.5% vs 37.2%, P = 0.001). However, there was no difference in cancer‐specific survival (CSS) for NAC with RC compared to only RC (53.7% vs 58.4%, P = 0.76). After adjusting for confounders, the authors found similar results. The use of NAC and RC was found to have an OS benefit (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.67–0.94; P = 0.006) for pT2–4N0M0 patients but not a CSS benefit (HR 0.88, 95% CI 0.72–1.08; P = 0.23).

Since previous studies have established the value of NAC in patients that are down‐staged to pT0 disease, the authors also focused their subset analysis on patients not down‐staged and instead had persistent MIBC. On subset analysis, NAC and RC patients with pT2N0M0 disease had an OS but no CSS benefit. For pT3–T4N0M0 patients, there was no OS or CSS benefit. This may suggest that a subset of non‐responders, such as those with pT2 disease, may experience some benefit from NAC despite persistent disease. Lastly, it is worth noting that whilst NAC improves outcomes, is better tolerated before surgery than adjuvant therapy, and is supported by high‐quality evidence, utilisation remains suboptimal. In this study [4], 381 of 1886 patients (or only 20%) had NAC and only 55% of these received cisplatin‐based therapy. Utilisation patterns vary and updated studies may show different results though. Overall, the authors should be congratulated for a study that is relevant, thoughtful and directed at an important clinical topic.

In this study [4], one issue that is raised is the challenges of accurate preoperative staging. The authors in this paper analysed patients according to pathological stage to limit confounding, as determining the exact stage of patients prior to NAC and RC cannot be done exactly. In this study, pT2 patients had on OS benefit after NAC but pT3–4 patients did not benefit. Clinical staging relies on transurethral resection, imaging and examination under anaesthesia to establish the diagnosis. Without final staging, it is difficult to precisely parse out which patients are clinical T2 vs T3 disease before RC. Predicting which patients are non‐responders is particularly important because these patients may be exposed unnecessarily to the risks of chemotherapy and may have delays in surgery that can negatively impact their outcomes. Therefore, even if the optimal treatment is known, identifying which patients will benefit can be challenging.

Fortunately, there is an exciting future for MIBC on the horizon. First, traditionally bladder cancer staging relies on determining the depth of invasion. In the future, more refined categorisation may help better characterise tumour subtypes. Through innovative multiplatform analyses, an improved understanding of distinct subtypes in bladder cancer has emerged [5]. Consequently, better subtype recognition may herald more targeted, and effective, therapy. Next, it is essential to determine the right type of treatment. Now, NAC is the standard of care for MIBC. However, there are several exciting trials examining other effective options to be used alternatively or synergistically. For example, the use of immunotherapy in the preoperative space is being studied and may shift how we manage MIBC. Lastly, the question of timing is key. Now, the order of surgery and systemic therapy may be a new frontier and perhaps the most significant question we are trying to solve. The possibility of understanding new subtypes of tumours and having new treatment options may require new timing for specific therapies in certain patients. It is conceivable that certain subtypes would be best managed with systemic therapy immediately whilst others with upfront surgery.

Certainly, more work needs to be done. So, what can we do now? We can promote the overall well‐being of our patients. Urologists can be conduits to help patients live healthy lifestyles and engage in behaviours that will promote psychological stability and physical strength. Encouraging daily activity, increasing fruit and vegetable consumption and, if needed, weight loss are options. Smoking cessation represents an imperative opportunity where urologists can make a positive impact [6]. Prehabilitation programmes focused on preparation for surgery can be done during NAC or while waiting for surgery and incorporate these elements. In this way, waiting time is leveraged to make small but cumulative improvements – ‘a little bit at a time’ is possible.

For now, we will continue to study the bladder cancer conundrum: subtypes of tumours, various treatments, and the best timing for therapy. Regardless of these results, it is likely patients with bladder cancer will still need some combination of surgery, systematic therapy and supportive care while they heal. In the interim, promoting well‐being is one way to help patients live healthier lives whilst making them more resilient to undergo whatever treatments may emerge next.

by Matthew Mossanen and Adam S. Kibel

References

  1. Prout, GR, Marshall, VF. The prognosis with untreated bladder tumors. Cancer 1956; 9: 551– 8
  2. Grossman, HB, Natale, RB, Tangen, CM et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349: 859– 66
  3. Advanced Bladder Cancer Overview Collaboration. Neoadjuvant chemotherapy for invasive bladder cancer. Cochrane Database Syst Rev 2005; 2: CD005246.
  4. Lane, G, Risk, M, Fan, Y, Krishna, S, Konety, B. Persistent muscle‐invasive bladder cancer after neoadjuvant chemotherapy: an analysis of Surveillance, Epidemiology and End Results‐Medicare data. BJU Int 2019; 123: 818– 25
  5. Robertson, AG, Kim, J, Al‐Ahmadie, H et al. Comprehensive molecular characterization of muscle‐invasive bladder cancer. Cell 2018; 174: 1033
  6. Mossanen, M, Caldwell, J, Sonpavde, G, Lehmann, LS. Treating patients with bladder cancer: is there an ethical obligation to include smoking cessation counseling? J Clin Oncol 2018; 36: 3189– 91

Editorial: Conversion to negative surgical margin after intraoperative frozen section – (un)necessary effort and relevance in 2019?

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The assessment and impact of positive surgical margins (PSMs) at the time of radical prostatectomy (RP) have been discussed for many decades. The determination and reporting should be performed in a standardised fashion according to the International Society of Urological Pathology [1]. The SM is considered positive if tumour cells touch the inked surface of the RP specimen. However, reasons for difficulty in truly differentiating between negative SMs (NSMs) and PSMs include iatrogenic disruption of the prostatic capsule, penetration of ink into small cracks on the outside, or cases in which prostate cancer cells are very close to, but not definitely touching, the inked margins.

A systematic review by Yossepowitch et al. [2] found a contemporary PSM rate of 15% (range 6.5–32%), which increases with extracapsular extension. In addition, the likelihood of PSM is strongly influenced by surgeon experience, independent of the surgical technique. Although PSM is considered an adverse pathological outcome and associated with an increased risk of biochemical recurrence (BCR), the impact on long‐term survival and actual prognostic value remains debatable. The association with other endpoints, such as prostate‐cancer specific mortality and overall survival, is controversial and may be primarily influenced by other risk factors, such as preoperative PSA level, Gleason score, and pathological T‐stage [2].

The role of intraoperative frozen section analysis in order to reduce the PSM rate continues to evolve. In a study by von Bodman et al. [3], 92.3% of patients with a PSM on frozen‐section analysis could ultimately be converted to a NSM. Similar findings were reported by Schlomm et al. [4] in 5392 patients using the intraoperative neurovascular structure‐adjacent frozen section examination (NeuroSAFE) technique, PSMs were detected in 25%, leading to re‐resection and conversion to definitive NSMs in 86% of these patients. In the setting of increasing experience with intraoperative frozen section analysis, a false‐positive SM status was found in only 48 patients (3.3%).

The study by Pak et al. [5], published in this issue of the BJUI, reported that specimens with initial PSMs were converted to NSMs upon permanent specimen evaluation (NCSM) in 4.9% of 2013 men undergoing RP. In this subgroup, the 5‐year BCR‐free survival (BCRFS) rates did not differ from those observed in National Comprehensive Cancer Network (NCCN) low‐ and intermediate‐risk patients with an initially NSM. However, the benefit of conversion from an initial PSM to final NSM was not apparent in high‐risk patients, as the authors found a significantly lower rate of BCRFS amongst this NCSM group. In multivariate analysis, NCSM status was independently associated (hazard ratio 0.624, P = 0.033) with BCR but not distant metastasis. These findings corroborate the findings of the Schlomm et al. [4] study, in which the BCRFS rates of propensity score‐based matched patients with conversion to NSMs did not differ significantly from patients with primarily NSMs.

What is the current role of intraoperative frozen section analysis during RP? How important is it to achieve NSMs in contemporary practice? In whom and how should the assessment be performed? Although it is clearly desirable to completely remove the entire tumour at the time of surgery, and NSMs are a surrogate marker of adequate local excision, the devil is in the details. First, in this study [5], the authors only assessed SMs at the bladder neck and apex. Although the apex is one of the most frequent locations for PSMs, other and/or multiple sites of PSMs are possible and could have been missed. Alternatively, the NeuroSAFE method is able to assess the entire laterorectal circumference albeit with the trade‐off of more extensive pathological involvement and assessment. Second, intraoperative frozen section analysis, and manoeuvers for NCSM, may ultimately be necessary and beneficial in only a small number of patients currently undergoing RP. An increasing proportion of men harbour more aggressive, higher‐risk disease in whom PSMs may have no impact on oncological outcomes or treatment decisions. In these men, long‐term cancer outcomes are probably more related to risks of unsuspected metastatic disease rather than residual, microscopic cancer within the prostatic fossa. As suggested in this study [5], an initial PSM in high‐risk men, independent of ultimate NCSM, may be a surrogate for non‐localised disease and poorer outcomes; PSMs were found in 53% of men with pT3b. In low‐risk men, the issues are whether active surveillance is a more appropriate initial management strategy and that routine intraoperative frozen section analysis may not be worthwhile with a PSM rate of only 10%. How does this alter the decision for adjuvant therapy? Adjuvant radiotherapy is probably under‐utilised in men with PSMs after RP (~11%), and NCSM may spare men from unnecessary treatment, particularly with lower‐risk disease [6]. However, men with PSMs and additional adverse pathological features, such as extraprostatic extension or seminal vesicle invasion, should probably receive adjuvant therapy, primarily driven by T stage.

The incremental value and potential clinical benefit of intraoperative frozen section analysis to achieve NSMs remain to be determined. Although one would suspect that PSM leading to excision of additional tissue could lead to worse functional outcomes, the study from Mirmilstein et al. [7] is reassuring. Despite higher Gleason score and pT stage in those undergoing the NeuroSAFE approach, the PSM rate was lower in this group (9.2%) compared with those undergoing standard intraoperative nerve‐sparing while leading to greater bilateral nerve preservation, higher potency rates at 12 months, and pad‐free continence.

In the future, other methods may guide surgical decision‐making and may eventually alter PSM rate including preoperative MRI of the prostate to evaluate extracapsular extension, genomic risk scores, or real‐time, near‐infrared fluorescent surgical guidance with prostate‐specific membrane antigen ligands [8]. However, one should not forget that outcomes are not solely based on the SM status. Various pathological and clinical factors and patients’ comorbidities and preference should be taken into consideration in the surgical management and that evaluation of validated oncological and functional outcomes is critical.

by Annika Herlemann and Maxwell Meng

References

  1. Tan, PH, Cheng, L, Srigley, JR et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 5: surgical margins. Mod Pathol 2011; 24: 48– 57
  2. Yossepowitch, O, Briganti, A, Eastham, JA et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol 2014; 65: 303– 13
  3. Bodman, C, Brock, M, Roghmann, F et al. Intraoperative frozen section of the prostate decreases positive margin rate while ensuring nerve sparing procedure during radical prostatectomy. J Urol 2013; 190: 515– 20
  4. Schlomm, T, Tennstedt, P, Huxhold, C et al. Neurovascular structure‐adjacent frozen‐section examination (NeuroSAFE) increases nerve‐sparing frequency and reduces positive surgical margins in open and robot‐assisted laparoscopic radical prostatectomy: experience after 11,069 consecutive patients. Eur Urol 2012; 62: 333– 40
  5. Pak, S, Park, S, Kim, M, Go, H, Cho, YM, Ahn, H. The impact on oncological outcomes after radical prostatectomy for prostate cancer of converting soft tissue margins at the apex and bladder neck from tumour‐positive to ‐negative. BJU Int 2019; 123: 811– 7
  6. Ghabili, K, Nguyen, K, Hsiang, W et al. National trends in the management of patients with positive surgical margins at the time of radical prostatectomy. J Clin Oncol 2018; 36 (Suppl.): 111
  7. Mirmilstein, G, Rai, BP, Gbolahan, O et al. The neurovascular structure‐adjacent frozen‐section examination (NeuroSAFE) approach to nerve sparing in robot‐assisted laparoscopic radical prostatectomy in a British setting – a prospective observational comparative study. BJU Int 2018;121: 854– 62
  8. Neuman, BP, Eifler, JB, Castanares, M et al. Real‐time, near‐infrared fluorescence imaging with an optimized dye/light source/camera combination for surgical guidance of prostate cancer. Clin Cancer Res 2015; 21: 771– 80

 

Editorial: Urinary tract infection vaccines – the ‘burning’ issue

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The current ‘hot topic’ in UTI is antibiotic‐free prevention. At the forefront of this is the development of new immunomodulating vaccines, which utilise the most common strains of uropathogens, both surface antigen or inactivated whole bacterium, to induce a host immune response to prevent recurrent infections. Vaccines currently with established randomised control trials (RCTs) are Uro‐Vaxom® (OM Pharma, Myerlin, Switzerland), Urovac® (Solco Basel Ltd, Basel, Switzerland) and ExPEC4V (GlycoVaxyn AG, Schlieren, Switzerland), which have recently been reviewed by Aziminia et al. [1].

Vaccines classically work by inducing a systemic adaptive host immune response by pre‐sensitisation to the bacterial surface antigen. As most uropathogens share similar antigenic structures, a broad spectrum response is possible against other pathogens and not limited solely to the bacteria within the vaccine itself.

UroVaxom® is an oral tablet composed of bacterial extracts from 18 strains of Escherichia coli given daily for 90 days. Its use has been reported in the literature since 1990 and was found in the systematic review to reduce UTI recurrence rates the most (risk ratio [RR] 0.67, 95% CI 0.57–0.78).

Urovac® is composed of 10 inactivated uropathogen strains including six E. coli strains and one Proteus mirabilis, Morganella morganii, Enterococcus faecalis and Klebsiella pneumoniae. It is delivered as a weekly vaginal suppository for three doses, followed by three booster doses at 6, 10 and 14 weeks. Urovac® has also been shown to effectively reduce UTI recurrence rates (RR 0.75, 95% CI 0.63–0.89).

ExPEC4V is composed of O‐antigens of four E. coli serotypes delivered as a single i.m. injection. Whilst effective in initial trials, to date there is only one RCT, which reported no reduction in UTI recurrence rates (RR 0.82, 95% CI 0.62–1.10).

Overall, Aziminia et al. [1] concluded that a firm conclusion about the efficacy of UTI vaccines could not be reached. The studies thus have in general been limited by many factors, including the definition of what constitutes a UTI, the heterogeneity of participants, and variable definitions of trial endpoints, making comparisons difficult [1]. More targeted research is therefore needed.

UTI is a major problem and is one of the most common infections worldwide, affecting disproportionately more women than men. In the UK, 40–50% of women experience at least one episode of UTI in their lifetime, of which 20–30% proceed to develop recurrent UTIs (as defined by three or more episodes of UTI within a 12‐month period) [2,3]. Yet despite its prevalence, mainstream preventative options rely heavily upon long‐term antibiotic usage, either as low‐dose prophylaxis or recurrent rescue courses.

However, the problem is the concurrent and rapid rise in global bacterial multidrug resistance, such that the WHO has declared antibiotic resistance as one of the biggest risks to public health in our lifetimes and created a Global Action Plan to combat this issue. There is, therefore, an urgent need to find antibiotic‐free alternatives.

More recently, site‐targeted immune response has been shown to be effective in delivering a UTI vaccine. In particular, the genitourinary tract harbours both an innate and adaptive mucosal immune system. Within this there is mucosa‐associated lymphoid tissue (MALT) through which immunocytes transit. This is part of a larger mammalian lymphoid organ system. Stimulation at one MALT site induces an activation and dissemination of immunity to other MALT sites. In particular the activation of the sublingual mucosa has been linked with a broad spectrum immune response in the genitourinary tract [4].

Uromune® (Q‐Pharma, Alicante, Spain) is a new sublingual vaccine targeting this pathway. Composed of inactivated E. coli, Klebsiella pneumoniae, Proteus vulgaris and Enterococcus faecalis, it has been shown in two large retrospective Spanish studies to decrease UTI recurrence by up to 90% when compared to antibiotic prophylaxis [5]. A prospective UK observational study found after 3 months of daily administration, 78% of women developed no further UTIs in the 12‐month follow‐up period [6]. To date, there is no RCT available on the efficacy of Uromune®, although one international multicentre phase III RCT is currently underway, due to report in 2019/2020.

In general, whilst initial trials on UTI vaccines show potential, further research is needed to bring UTI vaccinations into mainstream treatment. In particular, future trials need to have robust definitions of the following (which previous studies have often lacked):

  • Definition of UTI – presence of symptoms and bacteriuria, as opposed to asymptomatic bacteriuria, which is often self‐limiting; and
  • Defined eligibility criteria – previous studies included hugely variable populations that included patients with neurogenic bladders, males and females, patients with indwelling catheters, and even immunosuppressed patients.

Furthermore, whilst comparison against placebo is important, comparison against antibiotic prophylaxis, the current ‘gold standard’, is also vital in providing evidence of efficacy.

Finally, the longevity of the vaccines’s effects also needs to be determined, in particular whether and when a booster dose is required in order to maintain the immune memory.

Overall though the future is exciting on tackling this ‘burning issue’ of UTI prevention.

 

References

  1. Aziminia, N, Hadjipavlou, M, Philippou, Y, Pandian, SS, Malde, S, Hammadeh, MY. Vaccines for the prevention of recurrent urinary tract infections: a systematic review. BJU Int 2019; 123: 753– 68
  2. Foxman, B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am 2014; 28: 1– 13
  3. Albert, X, Huertas, I, Pereiró, II, Sanfélix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in non‐pregnant women. Cochrane Database Syst Rev 2004; 3:CD001209
  4. Holmgren, J, Czerkinsky, C. Mucosal immunity and vaccines. Nat Med 2005; 11 ( Suppl.): S45– 53
  5. Yang, B, Foley, S, Toozs‐Hobson, P. Urinary tract infections: current and new preventative options. SM J Clin Med 2016; 2: 1018
  6. Yang, B, Foley, S. First experience in the UK of treating women with recurrent urinary tract infections with the bacterial vaccine Uromune®. BJU Int 2018; 121: 289– 92

 

Editorial: Expanding the feasibility of nephron‐sparing surgery: time for a paradigm shift?

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With the rapid implementation of ‘targeted’ therapies, kidney cancer has entered a new era where old paradigms are being challenged, and new ones can be explored. The idea of delivering ‘neoadjuvant’ systemic therapy to alter the surgical treatment of advanced RCC was suggested in this same journal ~10 years ago as a proof‐of‐concept study [1]. Since then, a plethora of small case series has investigated the safety and feasibility of different targeted agents in the preoperative setting to facilitate surgical resection of locally advanced disease, mostly with a ‘cytoreductive’ (rather than ‘curative’) intent.

In this issue of the BJU Int, Lebacle et al. [2] evaluated the role of neoadjuvant axitinib, an oral tyrosine kinase inhibitor currently recommended as a second‐line option for metastatic clear cell RCC, to downstage cT2 kidney cancer and allow a partial nephrectomy (PN). In this multicentre prospective study, 18 patients with RCC (median tumour size 7.6 cm and R.E.N.A.L. [Radius; Exophytic/Endophytic; Nearness; Anterior/Posterior; Location] score 11) were enrolled. A median tumour size reduction of 17% was obtained, and the primary outcome (‘clinical downstaging’ to cT1 to allow PN) was achieved in 12 patients (67%). Overall, 16 patients underwent PN, as this was successfully done also in four of six (67%) patients who were not ‘down‐staged’ by the drug. Notably, about half of the PNs were performed with a robotic approach. Whilst axitinib was well tolerated, five patients experienced a high‐grade complication after surgery, including one death. Interestingly, final pathology showed upstaging to pT3a disease in seven patients, and two positive margins. Moreover, about a third of patients had metastatic progression and two had recurrence at 2 years. Thus, while the authors noted axitinib to be effective in reducing tumour size and achieving a clinical downstaging in most patients, the significant presence of pT3a disease calls into question the overall efficacy (to truly pathologically downstage) or desirability (most of the tumours that were not downstaged still successfully underwent PN) of the study’s main stated aim.

The rapid adoption of robotic surgery and the increasing experience with PN techniques translated into expanding indications for minimally invasive nephron‐sparing surgery (NSS), to include also T1b and T2 renal masses [3], and the field is primed for a possible paradigm shift. Whether or not a PN is doable, regardless of the technique, remains in the hands of the surgeon, who makes that decision based on previous personal experience. This is also the case for the present study, where the primary outcome was simply represented by the number of patients who could get a PN (instead of a radical nephrectomy). As such, is such a subjective endpoint (feasibility of PN) clinically meaningful? While disagreement may occur over the risk of PN in complex and elective cases, the desirability of nephron preservation in imperative and most elective circumstances is supported by evidence that largely suggests that PN translates into better renal function. In addition, recent findings suggest that estimated GFR preservation might translate into better cancer‐specific survival [4]. Certainly, this type of endpoint (whether a PN is feasible) is prone to intrinsic bias and limitations.

Only a limited number of studies have specifically explored the role of neoadjuvant therapy to enable NSS with variable results [5] (Table 1) [2, 6, 7, 8, 9]. Overall, these studies suggest that even a modest tumour size reduction can facilitate kidney preservation in a significant number of cases. Amongst these studies, only one had assessed axitinib in this specific setting [9]. Differences in outcomes between that trial and the present one by Lebacle et al. [2] could be explained by differences in study populations and/or drug regimens. A more recent study by Karam et al. [10], showed that inter‐observer agreement regarding the feasibility of a PN is quite variable, which is not surprising. For this reason, those authors advocated the need for a ‘resectability score’.

In conclusion, utility of neoadjuvant therapy to modify tumour size and facilitate NSS is an active and exciting area of clinical investigation, fuelled by the rapidly changing landscape of systemic therapies for RCC. It is too early to call for a paradigm shift, but a few ongoing studies might provide some meaningful answers soon. Amongst these, the PADRES (Prior Axitinib as a Determinant of Outcome of REnal Surgery) is an ongoing North American multicentre phase II study of axitinib with the aim of recruiting 50 patients [5]. While waiting for more robust evidence, the use of neoadjuvant therapy to facilitate NSS should still be deemed as investigational.

References

  1. Shuch, B, Riggs, SB, LaRochelle, JC et al. Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm. BJU Int 2008; 102: 692– 6
  2. Lebacle, C, Bensalah, K, Bernhard, JC et al. Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study. BJU Int 2019; 123: 804– 10
  3. Bertolo, R, Autorino, R, Simone, G et al. Outcomes of robot‐assisted partial nephrectomy for clinical T2 renal tumors: a multicenter analysis (ROSULA Collaborative Group). Eur Urol 2018; 74:226– 32
  4. Antonelli, A, Minervini, A, Sandri, M et al. Below safety limits, every unit of glomerular filtration rate counts: assessing the relationship between renal function and cancer‐specific mortality in renal cell carcinoma. Eur Urol 2018; 74: 661– 7
  5. Bindayi, A, Hamilton, ZA, McDonald, ML et al. Neoadjuvant therapy for localized and locally advanced renal cell carcinoma. Urol Oncol 2018; 36: 31– 7
  6. Silberstein, JL, Millard, F, Mehrazin, R et al. Feasibility and efficacy of neoadjuvant sunitinib before nephron‐sparing surgery. BJU Int 2010; 106: 1270– 6
  7. Rini, BI, Plimack, ER, Takagi, T et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J Urol 2015; 194: 297– 303
  8. Lane, BR, Derweesh, IH, Kim, HL et al. Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma. Urol Oncol 2015; 33: 112.e15–21.
  9. Karam, JA, Devine, CE, Urbauer, DL et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. Eur Urol 2014; 66: 874– 80
  10. Karam, JA, Devine, CE, Fellman, BM et al. Variability of inter‐observer agreement on feasibility of partial nephrectomy before and after neoadjuvant axitinib for locally advanced renal cell carcinoma (RCC): independent analysis from a phase II trial. BJU Int 2016; 117: 629– 35

 

Editorial: Oxidative stress and lower urinary tract symptoms: cause or consequence?

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Oxidative stress has been defined as ‘an imbalance between oxidants and anti-oxidants in favour of the oxidants, leading to a disruption of redox signalling and control and/or molecular damage’ [1]. Reactive oxygen and nitrogen species (ROS/RNS) produced under oxidative stress are known to damage all cellular biomolecules (lipids, sugars, proteins and polynucleotides). ROS/RNS is often used as a generic term but it has been emphasized that all ROS/RNS molecules are not the same [2] and the term encompasses a diverse range of species, including, for example, superoxide, hydrogen peroxide, nitric oxide and peroxynitrite. The biological impacts of ROS/RNS depend critically on the particular molecule(s) involved, and on the microenvironment and physiological or pathological context in which it is being generated [2]. It should be emphasized that ROS are not only harmful agents that cause oxidative damage in pathologies but they also have important roles as regulatory agents in a range of biological phenomena. They are normally generated as by-products of oxygen metabolism; however, environmental stressors (ultraviolet radiation, ionizing radiations, pollutants, heavy metal and xenobiotics) contribute to greatly increase ROS/RNS production.

It is difficult to measure ROS/RNS, therefore, biomarkers are often used as a surrogate; however, many of the biomarkers are insufficiently validated and it is often difficult to draw general conclusions on their significance [3]. 8-OHdG, one of the major products of DNA oxidation, is one of the most commonly used biomarkers of oxidative stress. Advanced glycation end-products (AGEs) are a group of heterogeneous molecules that arise from the non-enzymatic reaction of reducing sugars with amino groups of lipids, DNA and especially long-lived proteins. This process occurs during normal metabolism but is even more pronounced under oxidative stress conditions. AGEs may be harmful and include modified proteins and/or lipids with damaging potential. Using 8-OHdG, AGEs and other biomarkers, several attempts have been made to link oxidative stress, either as a cause or contributor, or both, to a variety of diseases, including LUTS. As pointed out by Ghezzi et al. [4] ‘Today it is a challenge to find a disease for which a role of oxidative stress has not been postulated.’

Matsumoto et al. [5] investigated the possible relationship between some markers of oxidative stress and LUTS in a population of community-living subjects participating in a health promotion project. As markers of oxidative stress, they used 8-OHdG (urine) and AGEs (skin autofluorescence), while structured questionnaires were used to assess LUTS. In their study, despite univariate analyses revealing several significant associations, multivariate analyses showed that the only statistically significant finding was that AGEs were associated with moderate to severe nocturia. This association is thought-provoking but, without functional studies, difficult to evaluate. LUTS are multifactorial and reflect a number of different comorbidities/pathophysiologies. It cannot be excluded that this may contribute to the lack of associations between oxidative stress markers and symptoms.

The finding of an association (or lack of it) between biomarkers of oxidative stress and LUTS does not reveal whether oxidative stress causes or contributes to LUTS. If ROS/RNS were causative/contributing factors to LUTS, it would be predicted that a positive response to antioxidant therapy and a decrease in ROS/RNS levels would not only support an involvement but would also be a promising treatment approach. In a prospective cohort study in the USA of 1670 men aged 65–100 years, Holton et al. [6] examined whether dietary antioxidants were associated with a reduced likelihood of LUTS progression or an increased likelihood of LUTS. They found that there were no significant associations between multiple dietary antioxidants and LUTS progression or remission over 7 years. Many other attempts to validate and exploit chronic antioxidant therapies have provided disappointing results, and still there is no antioxidant with sufficient efficacy to be approved by health authorities [4]. The question of whether antioxidant therapy may be harmful has not yet been answered. If the cause of LUTS is an increase of ROS/RNS in the bladder, it is questionable whether normalization of indicators of oxidative stress is safe, considering that the normal function of ROS/RNS in the rest of the body may be affected.

The clinical relevance of oxidative stress as a pathophysiological factor in lower urinary tract dysfunction or as a treatment target for various lower urinary tract disorders is still unclear. In addition, it has not been established that antioxidant therapy has any beneficial effect on LUTS.

by Karl-Erik Andersson

References

  1. Sies H. Oxidative stress: a concept in redox biology and medicine. Redox Biol 2015; 4: 180–3
  2. Murphy MP, Holmgren A, Larsson NG et al. Unraveling the biological roles of reactive oxygen species. Cell Metab 2011; 13: 361–6
  3. Frijhoff J, Winyard PG, Zarkovic N et al. Clinical relevance of biomarkers of oxidative stress. Antioxid Redox Signal 2015; 23: 1144–70
  4. Ghezzi P, Jaquet V, Marcucci F, Schmidt HHHW. The oxidative stress theory of disease: levels of evidence and epistemological aspects. Br J Pharmacol 2017; 174: 1784–96
  5. Matsumoto T, Hatakeyama S, Imai A et al. Relationship between oxidative stress and lower urinary tract symptoms: results from a community health survey in Japan. BJU Int 2019; 123 877-84
  6. Holton KF, Marshall LM, Shannon J et al. Osteoporotic fractures in men study group. Dietary antioxidants and longitudinal changes in lower urinary tract symptoms in elderly men: the Osteoporotic Fractures in Men study. Eur Urol Focus 2016; 2: 310–8

 

Editorial: Bladder function and fetal treatment of myelomeningocele

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In utero myelomeningocele repair and urological outcome: the first 100 cases of a prospective analysis. Is there an improvement in bladder function? Comments on bladder function and fetal treatment of myelomeningocele [1].

Prenatal care with maternal screening for neural tube defects and high‐resolution maternal fetal sonography has led to the early diagnosis of fetal myelomeningocele [2]. Revolutionary fetal surgery to correct myelomeningocele in utero has reduced the need for cerebrospinal fluid shunting and improved motor outcomes in these babies, based on 30‐month follow‐up data [3]. Sponsored by the National Institute of Health, the prospective randomized ‘Management of Myelomeningocele Study’ (MOMS) trial documented the outcomes of 158 patients assessed after either fetal repair prior to 26 weeks’ gestation or standard postnatal repair of the myelomeningocele defect. The trial was stopped early when evaluation showed that the primary outcome, rate of shunt placement, in the postnatal repair group (82%) was approximately double that in the prenatal surgery group (40%). Prenatal surgery also resulted in improvement in outcomes for mental development, motor function and ambulation, also evaluated at 30 months postnatally. However, prenatal surgery was associated with an increased risk of preterm delivery and uterine dehiscence at the time of delivery.

Bladder function was also evaluated at 30 months in the MOMS trial, comparing the need for clean intermittent catheterization (CIC) in 115 patients with adequate urological follow‐up, consisting of clinical outcomes in respect to continence, sonographic appearance of the kidneys and bladder and urodynamic evaluation [4]. Prenatal surgery did not significantly reduce the need for CIC measured at 30 months of age, but was associated with less bladder trabeculation and open bladder neck. Longer follow‐up was recommended and is in progress to document further bladder outcomes.

Macedo et al. [1] report similar short‐term bladder outcomes in 100 patients undergoing in utero myelomeningocele repair. Their report documented bladder characteristics in these patients at a mean postnatal age of ~6 months. In their unique cohort, antenatal diagnosis of fetal myelomeningocele was made at ~21 weeks’ gestation, in utero surgery was performed at ~25.5 weeks’ gestation and preterm birth occurred at ~33 weeks’ gestation, parameters consistent with the patients in the MOMs trial. Short‐term evaluation showed that ~53% of the patients had high‐risk bladders with poor compliance, ~27% were incontinent with weak sphincteric activity and only ~15% had normal urodynamic profiles. CIC was initiated in ~ 57% of the Macedo et al. cohort, again similar to the MOMs trial. The long‐term outcomes after potty training and during childhood and adolescence will be especially interesting in this valuable cohort.

Some of the pitfalls that will need to be accounted for include the validation and standardization of urodynamic testing [5]. Even at the same institution with clinicians who have undergone similar training, consistent interpretation of urodynamic studies can be variable, potentially affecting therapeutic options [6].

The goal of patients, parents and providers is to avoid the urological sequelae of myelomeningocele. To date, the reality is that the majority of these children, whether or not they have undergone in utero fetal repair or postnatal surgery, will require the assistance of CIC for urological health to protect the kidneys from excess pressure, to facilitate bladder emptying and urinary continence and prevent UTI.

 

References

  1. Macedo, A, Ottoni, SL, Garrone, G et al. In utero myelomeningocele repair and urological outcome: the first 100 cases of a prospective analysis. Is there an improvement in bladder function? BJU Int 2019; 123: 676– 81
  2. Meller, C, Aiello, H, Otano, L. Sonographic detection of open spina bifida in the first trimester: review of the literature. Childs Nerv Syst 2017; 33: 1101– 6
  3. Adzick, NS, Thom, EA, Spong, CY et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011; 364: 993– 1004
  4. Brock, JW, Carr, MC, Adzick, NS et al. Bladder Function After Fetal Surgery for Myelomeningocele. Pediatrics 2015; 136: e906– 13
  5. Bauer, SB, Nijman, RJ, Drzewiecki, BA, Sillen, U, Hoebeke, P, International Children’s Continence Society Standardization Subcommittee. International Children’s Continence Society standardization report on urodynamic studies of the lower urinary tract in children. Neurourol Urodyn 2015; 34: 640– 7
  6. Dudley, AG, Casella, DP, Lauderdale, CJ et al. Interrater reliability in pediatric urodynamic tracings: a pilot study. J Urol 2017; 197: 865– 70

 

Editorial: A novel robotic procedure for bladder outlet obstruction

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We have become used to talking about robotic surgery in urology when we really mean robot‐assisted surgery. The novel aquablation procedure (AquaBeam®) for bladder outlet obstruction (BOO) described by Plante et al. [1] is executed by a robotically controlled waterjet system, conducting a pre‐planned image‐guided resection once the radiological parameters have been entered into the system. This is performed under real‐time ultrasonography guidance. It will deliver a standardized way of carrying out the surgery and will, to a large extent, take away the surgical learning curve whilst introducing a new imaging learning curve.

The present study [1] is an analysis of pre‐planned and exploratory subsets of patients from the WATER study [2], and confirms data from earlier studies [3,4]. The study suggests that, compared with TURP, aquablation is particularly effective in improving both LUTS and bother in the medium‐sized to larger prostate (50–80 mL) and in potentially more challenging prostates such as those with large middle lobes or middle lobe obstruction (judged at pre‐procedure cystoscopy).

It is suggested that the ability to map the resection plane surgically may enable the preservation of key anatomical landmarks and preserve normal sexual function. In this study, anejaculation occurred in only 2% of patients with larger prostates (>50 mL) in the aquablation group compared with 41% of comparable patients undergoing TURP (P < 0.001). The rate of anejaculation however appeared relatively higher in the overall aquablation group, at 10%, compared with 36% in the overall TURP group (P < 0.001). A prostate volume between 30 and 80 mL was an inclusion criterion for the WATER study. This procedure therefore appears to give the best possible rate of anejaculation in a resective surgical intervention in patients with a larger prostate and may have less advantage in patients with a smaller prostate.

Interestingly, the relative overall symptom relief advantage of aquablation over TURP was also not proven in men with smaller prostates; TURP may be equally effective at removing obstructing tissue in smaller as compared to larger prostates. It is not yet clear whether aquablation would not be recommended for prostates below a certain size. In the more recent WATER II study in 101 men with a mean prostate volume of 107 mL, aquablation was also shown to be feasible and safe in men with large prostates (80–150 mL) [5].

There will always be a possible downside to novel treatments and this may relate to poor radiological data entry which may, in turn, lead to sphincter damage, although this has not been an issue in the carefully controlled studies to date. There are also reports of troublesome postoperative bleeding in some cases, although haemostasis can be effectively achieved via a catheter balloon tamponade and traction device or by electrocautery [5,6].

Unlike most other surgical treatments for BOO, the resection times for aquablation are almost independent of prostate volume, although the overall operating time is similar to that of TURP, with the majority of the time being spent in the set up and image planning.

The principal study (WATER) [2] on which this sub‐analysis by Plante et al. is based is an example of a high‐quality randomized controlled trial but still represents data on only 116 patients undergoing aquablation and 65 undergoing TURP; therefore, more randomized controlled trial data and long‐term effectiveness studies are clearly needed. Formal urodynamic studies and trials in patients with even larger prostates would also be appropriate. In addition, there are still few published data on the cost‐effectiveness of aquablation, although it is likely to be in the range of higher‐cost laser ablation therapies.

With better radiology and machine learning or artificial intelligence, this technique may lead to truly standardized BOO surgery with more complete resection and may thereby reduce outcome variability.

References

  1. Plante, M, Gilling, P, Barber, N et al. Symptom relief and anejaculation after aquablation or transurethral resection of the prostate: subgroup analysis from a blinded randomized trial. BJU Int 2019; 123: 651– 60
  2. Gilling, P, Barber, N, Bidair, M et al. WATER: a double‐blind, randomized, controlled trial of Aquablation® vs transurethral resection of the prostate in benign prostatic hyperplasia. J Urol 2018; 199: 1252– 61
  3. Gilling, P, Reuther, R, Kahokehr, A et al. Aquablation ‐ image‐guided robot‐assisted waterjet ablation of the prostate: initial clinical experience. BJU Int 2016; 117: 923– 9
  4. Gilling, P, Anderson, P, Tan, A. Aquablation of the prostate for symptomatic benign prostatic hyperplasia: 1‐year results. J Urol 2017; 197: 1565– 72
  5. Desai, M, Bidair, M, Bhojani, N et al. WATER II (80‐150 mL) procedural outcomes. BJU Int 2019;123: 106– 12
  6. Aljuri, N, Gilling, P, Roehrborn, C. How I do it: balloon tamponade of prostatic fossa following Aquablation. Can J Urol 2017; 24: 8937– 40

 

Editorial: Can systematic biopsy be safely avoided at the time of MRI/ultrasonography fusion biopsy?

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In clinical practice, the need for maximising prostate cancer detection is often balanced against the theoretical risks of infection, bleeding, and pain associated with taking additional cores. In this novel study, Sathianathen et al. [1] provide a tool for measuring the oncological benefit of including concurrent systematic biopsy (SB) at the time of MRI‐guided targeted biopsy (TB). There were several key findings: (i) Amongst patients undergoing MRI‐guided biopsy (all biopsy settings), 11.6% were found to have significant cancers detected by SB alone; (ii) Amongst patients who had clinically significant cancers detected by SB alone, 52.2% were sampled within sextants outside the targeted regions of interest; (iii) According to the proposed nomogram, patients with prior negative biopsies, fewer MRI lesions, and lower Prostate Imaging‐Reporting and Data System (PI‐RADS) scores were at the lowest risk of missing significant cancer when SB was omitted.

Based on the present study, biopsy setting appears to be a key factor for deciding whether to omit SB. In the subset of patients undergoing primary biopsy, the authors found that 18.5% of cancers were detected by SB alone. These results are consistent with those of the MRI‐FIRST trial, which showed 14% of cancers were detected by SB only, 20% by TB only, and 66% by combining both techniques [2]. MRI‐FIRST concluded that in the primary biopsy setting, there was no difference between SB and TB in detection of clinically significant prostate cancer, although combining both techniques provided the highest detection rate.

Prior negative biopsy cohorts are generally at lower risk of harbouring significant cancer, as many cancers have already been ‘selected out’ by initial biopsies. In this setting, TB plays an important role in sampling tumour foci in difficult‐to‐reach regions of the prostate (e.g., anterior and apical) [3]. According to the authors’ nomogram, prior negative biopsy patients were least likely to benefit from concurrent SB. While the authors suggest a paradigm of selectively omitting SB, some authors have proposed omitting both TB and SB altogether in select patients. A previously reported multi‐institutional nomogram can be used to predict benign pathology after MRI‐guided biopsy, which can help reduce the number of unnecessary biopsies after MRI in the prior negative biopsy setting [4]. This clinical tool was further externally validated and optimised by Bjurlin et al. [5].

The ‘active surveillance (AS)’ setting typically refers to a confirmatory MRI‐guided biopsy in men with Grade Group 1 prostate cancer prior to enrollment in AS. Recently, the presence of cribriform morphology in Grade Group 2 patients was confirmed to be a key poor prognostic feature that would exclude patients from AS [6]. The present study, however, did not account for different Gleason pattern 4 morphologies in their analysis, as ‘significant cancer’ was defined by Grade Group alone. Studies by independent groups have found that TB combined with SB was more accurate than either modality alone for detecting cribriform at the time of MRI‐guided biopsy [7, 8]. Therefore, concurrent SB is required to properly sample cribriform cancers in patients who are considering AS.

In this study, Sathianathen et al. [1] provide clinicians with a clinical tool for quantifying the added oncological value of concurrent SB. However, concurrent SB is probably prudent for most patients, particularly for those considering AS or focal therapy for which accurate determination of whole gland grade, cancer volume, and cribriform status are essential. As reducing the number of cores has not yet been shown to reduce biopsy‐related complications, are we willing to suboptimise cancer sampling without proven compensation?

by Matthew Truong

References

  1. Sathianathen, NJ, Warlick, CA, Weight, CJ et al. A clinical prediction tool to determine the need for concurrent systematic sampling at the time of magnetic resonance imaging‐guided biopsy. BJU 2019; 123: 612– 7
  3. Salami, SS, Ben‐Levi, E, Yaskiv, O et al. In patients with a previous negative prostate biopsy and a suspicious lesion on magnetic resonance imaging, is a 12‐core biopsy still necessary in addition to a targeted biopsy? BJU Int 2015; 115: 562– 70
  4. Truong, M, Wang, B, Gordetsky, JB et al. Multi‐institutional nomogram predicting benign prostate pathology on magnetic resonance/ultrasound fusion biopsy in men with a prior negative 12‐core systematic biopsy. Cancer 2018; 124: 278– 85
  5. Bjurlin, MA, Renson, A, Rais‐Bahrami, S et al. Predicting benign prostate pathology on magnetic resonance imaging/ultrasound fusion biopsy in men with a prior negative 12‐core systematic biopsy: external validation of a prognostic nomogram. Eur Urol Focus 2018. [Epub ahead of print] https://doi.org/10.1016/j.euf.2018.05.005
  6. Kweldam, CF, Kümmerlin, IP, Nieboer, D et al. Presence of invasive cribriform or intraductal growth at biopsy outperforms percentage grade 4 in predicting outcome of Gleason score 3+4=7 prostate cancer. Mod Pathol 2017; 30: 1126– 32
  7. Truong, M, Feng, C, Hollenberg, G et al. A comprehensive analysis of cribriform morphology on magnetic resonance imaging/ultrasound fusion biopsy correlated with radical prostatectomy specimens. J Urol 2018; 199: 106– 13
  8. Prendeville, S, Gertner, M, Maganti, M et al. Role of magnetic resonance imaging targeted biopsy in detection of prostate cancer harboring adverse pathological features of intraductal carcinoma and invasive cribriform carcinoma. J Urol 2018; 200: 104– 13

 

 

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