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Video: Four-year outcomes from a multiparametric MRI based active surveillance programme

Four‐year outcomes from a multiparametric magnetic resonance imaging (MRI)‐based active surveillance programme: PSA dynamics and serial MRI scans allow omission of protocol biopsies

 

Abstract

Objectives

To report outcomes from a multiparametric (mp) magnetic resonance imaging (MRI)‐based active surveillance programme that did not include performing protocol biopsies after the first confirmatory biopsy.

Patients and Methods

All patients diagnosed with Gleason 3 + 3 prostate cancer because of a raised PSA level who underwent mpMRI after diagnosis were included. Patients were recorded in a prospective clinical database and followed up with PSA monitoring and repeat MRI. In patients who remained on active surveillance after the first MRI (with or without confirmatory biopsy), we investigated PSA dynamics for association with subsequent progression. Comparison between first and second MRI scans was undertaken. Outcomes assessed were: progression to radical therapy at first MRI/confirmatory biopsy and progression to radical therapy in those who remained on active surveillance after first MRI.

Results

A total of 211 patients were included, with a median of 4.2 years of follow‐up. The rate of progression to radical therapy was significantly greater at all stages among patients with visible lesions than in those with initially negative MRI (47/125 (37.6%) vs 11/86 (12.8%); odds ratio 4.1 (95% CI 2.0–8.5), P < 0.001). Only 1/56 patients (1.8%) with negative initial MRI scans who underwent a confirmatory systematic biopsy had upgrading to Gleason 3 + 4 disease. PSA velocity was significantly associated with subsequent progression in patients with negative initial MRI (area under the curve 0.85 [95% CI 0.75–0.94]; P <0.001). Patients with high‐risk visible lesions on first MRI who remained on active surveillance had a high risk of subsequent progression 19/76 (25.0%) vs 9/84 (10.7%) for patients with no visible lesions, despite reassuring targeted and systematic confirmatory biopsies and regardless of PSA dynamics.

Conclusion

Men with low‐risk Gleason 3 + 3 prostate cancer on active surveillance can forgo protocol biopsies in favour of MRI and PSA monitoring with selective re‐biopsy.

 

 

PSMA at the cutting edge of prostate cancer treatment: Report from a PSMA Symposium convened at The University of Oxford


The potential of PSMA

While molecular imaging is not exactly a new technology (TIME Magazine named PET-CT as the medical invention of the year back in 2000), recent developments in radio-pharmacy have positioned the field at the forefront of innovations in cancer imaging and, tantalisingly, novel therapeutic approaches to cancer treatment.

Urologists have typically been forward thinking and innovative, and have been quick to acknowledge the value of molecular imaging as a tool to enhance the accuracy of the diagnostic process and improve patient outcomes. The recent development of radiotracers directed against prostate-specific-membrane-antigen (PSMA) has taken things to a new level; there is now a solid body of evidence for the performance of 68Ga-PSMA PET/CT in primary and secondary staging, with an ability to accurately detect small volume disease at far lower serum PSA levels – the use of 68Ga-PSMA PET/CT as a diagnostic adjunct is becoming increasingly mainstream in continental Europe and Australia.

Oxford PSMA Symposium 2018

It is in this context that, on 22 November 2018, the Nuffield Department of Surgical Sciences in Oxford hosted a symposium at the Old Road Campus Research Building focused on the utility of PSMA-related technologies. The symposium attracted an impressive array of attendees from across the UK, Europe and Australia.

The symposium was opened with comments by Professor Freddie Hamdy of Oxford, who welcomed all attendees and speakers, some of whom who had travelled more than 10,000 miles to attend the gathering.

Many uses for PSMA in specialist prostate cancer management

Liberal use of PSMA-PET down under

The first speaker, Professor Declan Murphy, from Melbourne’s Peter MacCallum Cancer Centre, shared comprehensive data and experience from Victoria in Australia, where access to 68Ga-PSMA PET/CT is seemingly unrestricted. Professor Murphy delivered a fascinating talk, expounding the gamut of PSMA PET applications in prostate cancer, from primary staging (promising data), to biochemical recurrence (there is definite evidence that PSMA PET accurately detects early recurrence and can guide salvage treatment options), right through to therapeutic uses of PSMA. In particular, he discussed the use of Lutetium-177 (177Lu)-PSMA-617 (LuPSMA) as a treatment in men with CRPC, presenting the findings of their recent Lancet Oncology study led by Michael Hoffman. Although still in the early stages, the data here look very exciting and hale a potential revolution in the way we manage high risk and advanced prostate cancer.

Declan Murphy expounds the translational utility of PSMA imaging and theranostics

How easy is it to set up a PSMA imaging service in the UK?

The next speaker was Professor Jamshed Bomanji from the Institute of Nuclear Medicine, University College London (UCL), who presented an eye-opening talk that focussed on the challenges of setting up a PSMA-PET service within an NHS Trust in England. The effort he and his team put into developing their service in the face of significant practical resistance has been frankly heroic. Pleasingly, these efforts have been worthwhile as the team from UCL have clearly demonstrated that PSMA PET/CT has had a significant impact on the management of men with biochemical recurrence with the team contributing to guidelines drawn up to standardise use, keeping similar standards of testing as https://www.blinkhealth.com/zoloft. It is very disappointing that NHS England saw fit to withdraw funding for the gallium tracer required for PSMA-PET scanning in August 2018. This does seem rather short-sighted given the clear evidence favouring the utility of PSMA-PET over other modalities such as FDG or Choline-PET, both of which are still funded. All in all, Professor Bomanji’s talk was a sobering examination of the challenges we face in our commitment to delivering cutting edge, world-class cancer services whilst at the same time considering the financial implications to the NHS of providing such high-end services.

Associate Professor Bart Cornelissen along with Dr Rebekka Hueting who runs PROx (PET Radiopharmacy Oxford) presented their intentions for 68Ga-PSMA-PET imaging in Oxford, and the University’s imminent plan to install a cyclotron on site that will allow PET imaging with locally generated radioisotopes to increase dose efficiency – the half-life of gallium means that any requirement to transport the dose reduces the number of scans that can be performed at destination. This is particularly important given some recent negative press coverage.

Surgery for men with metastases?

Prasanna Sooriakumaran (PS) of University College London Hospital (UCLH) Department of Urology discussed the TRoMbone Study, a UK feasibility RCT that he has set up aimed at testing radical prostatectomy in men with oligometastatic prostate cancer. This interesting study promises to tease out the possible benefits of radical prostatectomy to men with low-volume metastatic disease. There are examples in other cancers whereby aggressive management of the primary tumour confers survival benefits in patients with low-burden metastatic disease and it is not unreasonable to think this may be the case for prostate cancer. Recruitment to such trials of ‘oligometastatic’ disease is contingent upon definitions of ‘low-volume’ disease, and accurate detection of such disease. PSMA-PET imaging is positively helping with this paradigm with its far superior sensitivity to conventional cross-sectional staging. 

PSMA as a tool to improve surgery

Pim van Leeuwen of the Netherlands Cancer Institute delivered an engaging talk entitled “PSMA intra-operative enhancement of lymph node dissection”, accompanied by some excellent video demonstrations.  Next up were Boris Vojnovic and Alastair Lamb of Oxford who discussed fluorescence optics and intra-operative use of PSMA as part of the on-going ProMOTE study (Prostate Molecular Targeting to Enhance Surgery). We wish the investigators good luck as the study progresses and we eagerly look forward to seeing the data as they emerge.

Summary

In summary, the Oxford PSMA symposium 2018 brought together clinicians from around the globe who share a common enthusiasm for PSMA-related technologies that promise to revolutionise prostate cancer management in the near future. Common themes included the use of PSMA in staging, therapeutics and intra-operative guidance. The message from our overseas guests, both European and Antipodean, was that PSMA-based imaging is increasingly part of routine care in the management of prostate cancer and definite benefits are seen, particularly in regard to accurate staging and identification of very early recurrence. While we in the UK are a little behind the curve when it comes to adoption of this increasingly established technology, we are hopeful of increasing the use of this technology in the NHS in order to rationalise appropriate treatment, reduce futile expenditure and ensure gold-standard management of men with prostate cancer.


Conference dinner at Balliol College, Oxford, UK
From Left: Alastair Lamb (Oxford), Declan Murphy (Melbourne), Freddie Hamdy (Oxford), Boris Vojnovic (Oxford), Prasanna Sooriakumaran (UCLH), Richard Bryant (Oxford), Ben Lamb (Cambridge)

Aaron Leiblich, Clinical Lecturer, Nuffield Department of Surgical Sciences;
Alastair Lamb, Consultant Urologist, Churchill Hospital Cancer Centre; on behalf of the meeting faculty


Alastair Lamb is a Cancer Research UK Clinician Scientist, Senior Fellow in Robotic Surgery & Honorary Consultant Urologist at the Nuffield Department of Surgery, University of Oxford, and Oxford University Hospitals NHS Foundation Trust. Alastair is interested in delivering excellent and timely prostate cancer care, focussing on state-of-the-art diagnostics with multiparametric MRI and targeted transperineal biopsies, followed by robotic-radical prostatectomy (RARP) or active surveillance. He also has an interest in novel molecular imaging techniques such as 68Ga-PSMA PET/CT and their use in disease stratification and selection of patients for surgery. Alastair is a local investigator for the ProMOTE, PART and TRoMbone studies.

Twitter: @lambalastair

 

Article of the month: Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 study

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

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

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

 

Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG‐4) study

Walter Cazzaniga*†‡, Hans Garmo§¶, David Robinson**, Lars Holmberg, Anna Bill-Axelson and Pär Stattin
 
 
*Division of Experimental Oncology/Unit of Urology URI, IRCCS Ospedale San Raffaele, University Vita-Salute San Raffaele, Milan, Italy, Department of Surgical Sciences, Uppsala University, §Regional Cancer Centre Uppsala Örebro, Uppsala University Hospital, Uppsala, Sweden, Division of Cancer Studies, Cancer Epidemiology Group, King’s College London, London, UK, and **Department of Urology, Ryhov Hospital, Jönköping, Sweden
 

 

Read the full article

Abstract

Objectives

To investigate if results in terms of absolute risk in mature randomised trials are relevant for contemporary decision‐making. To do so, we compared the outcome for men in the radical prostatectomy (RP) arm of the Scandinavian Prostate Cancer Group Study number 4 (SPCG‐4) randomised trial with matched men treated in a contemporary era before and after compensation for the grade migration and grade inflation that have occurred since the 1980s.

Patients and Methods

A propensity score‐matched analysis of prostate cancer mortality and all‐cause mortality in the SPCG‐4 and matched men in the National Prostate Cancer Register (NPCR) of Sweden treated in 1998–2006 was conducted. Cumulative incidence of prostate cancer mortality and all‐cause mortality was calculated. Cox proportional hazards regression analyses were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for a matching on original Gleason Grade Groups (GGG) and second, matching with GGG increased one unit for men in the NPCR.

 
Figure 1: Cumulative incidence of prostate cancer mortality (PCM) and all‐cause mortality (ACM) in the SPCG‐4 and the NPCR of Sweden. FU, follow‐up after date of diagnosis or primary treatment. A and B based on original GGG. C and D based on upgraded GGG classification in the NPCR with an increase of one grade in GGG.

Results

Matched men in the NPCR treated in 2005–2006 had half the risk of prostate cancer mortality compared to men in the SPCG‐4 (HR 0.46, 95% CI 0.19–1.14). In analysis of men matched on an upgraded GGG in the NPCR, this difference was mitigated (HR 0.73, 95% CI 0.36–1.47).

Conclusion

Outcomes after RP for men in the SPCG‐4 cannot be directly applied to men in the current era, mainly due to grade inflation and grade migration. However, by compensating for changes in grading, similar outcomes after RP were seen in the SPCG‐4 and NPCR. In order to compare historical trials with current treatments, data on temporal changes in detection, diagnostics, and treatment have to be accounted for.

Read more Articles of the week

Editorial: Are historical studies relevant in the setting of grade migration?

While randomized controlled trials are the ‘gold standard’ for comparative effectiveness research, it is important that they be taken in context of their limitations. This is especially true in surgical trials for prostate cancer. For one, factors such as blinding and allocation concealment are often impossible in surgery, and surgeon skill may have a large impact [1]. What is more, it can take over a decade before interventions yield detectable differences in prostate cancer survival. Consequently, shifts in diagnosis and management may make historical clinical trial findings less useful for contemporary patients. For example, the landmark Scandinavian Prostate Cancer Group Study number 4 (SPCG‐4) showed a survival benefit for men treated with radical prostatectomy rather than observation during the 1989–1999 time period [2] but management in the study differed from contemporary practice as, in the 1990s, strict ‘active surveillance’ protocols did not exist.

In addition to shifts in management, men diagnosed with prostate cancer today differ from those diagnosed in previous decades. This was shown by Dalela et al. [3] who compared registry‐based data from the USA with data on patients enrolled in the Prostate Cancer Intervention Versus Observation (PIVOT) trial, and found significant differences between the two cohorts.

In a similar vein, Cazzaniga et al. [4] designed an elegant study to assess the generalizability of the SPCG‐4 to contemporary cohorts of men with prostate cancer. They focused on histological grading and compared the natural history of men in the SPCG‐4 study to men in similar grade categories diagnosed approximately one decade later in Sweden.

The contemporary cohort was made up of men with localized prostate cancer drawn from the Swedish National Prostate Cancer Register (NPCR). Men in the NPCR diagnosed in 2005–2006 had lower prostate cancer‐specific and all‐cause mortality compared to men with similar grade cancer in the SPCG‐4 (hazard ratios 0.46, 95% CI 0.19–1.14, and 0.66, 95% CI 0.46–0.95, respectively). While some of the observed differences in survival may have been attributable to improved treatments, Cazzaniga et al. hypothesized that grade migration was to blame.

As expected, the authors found a shift in Gleason grading, with a decrease in Gleason Grade Group (GGG) 1 disease, corresponding to a historical score of Gleason 3 + 3 = 6, and a concurrent increase in GGG2 and GGG3 disease, corresponding to historical scores of 3 + 4 = 7 and 4 + 3 = 7, respectively. Importantly, these differences in prostate cancer‐specific and all‐cause mortality were mitigated after compensating for grade migration by increasing GGG by one for the NPCR group; in other words, men in the SPCG‐4 treated in the 1990s had similar prostate cancer‐specific and all‐cause mortality to men in a later period with a one‐unit higher GGG.

Grade migration has been a gradual process, which was hastened by the major 2005 International Society of Urological Pathology revision that recategorized some Gleason patterns from 3 to 4. Changes in 2014 further refined these, and the concept of grade groups was introduced by Epstein two years later. Older cases of Gleason score 6 cancer include histological patterns, such as cribriform and poorly formed glands, which today would be considered Gleason pattern 4.

Grade migration was also demonstrated by Danneman et al. [5] who analysed the Gleason scoring of prostate biopsies from the NPCR in Sweden for the period 1998–2011. There was an increasing incidence of low‐risk cancer (cT1 20% in 1998 to 51% in 2011) and a concurrent decrease in high‐risk cancers (cT3 29% to 16%), reflecting earlier detection. With earlier diagnosis from screening, one would expect a shift towards lower grades at diagnosis, but they found the opposite. Among low‐risk tumours (stage cT1 and PSA 4–10 ng/mL) the proportion of Gleason score 7–10 increased from 16% to 40%. Among high‐risk tumours (stage cT3 and PSA 20–50 ng/mL) the proportion of Gleason 7–10 increased from 65% to 94%.

Gleason score reclassification was also addressed by Albertsen et al. [6], who had prostate biopsy slides for the period 1990 to 1992 re‐reviewed by an experienced pathologist in 2002–2004. They found an upward shift in Gleason grading, with 55% of the samples upgraded, 14% downgraded, and 31% unchanged. Comparing matched cohorts of historical vs contemporary patients with prostate cancer, one might erroneously infer better survival. This illusory change in prognosis is known as the ‘Will Rogers phenomenon’.

While randomized trials such as the SPCG‐4 represent one of the highest levels of clinical evidence, it is important to keep in mind that these trials have limitations. Given the interval changes in grading criteria for prostatic adenocarcinoma, predicting clinical outcomes based on historical cohorts is rarely as simple as it may seem. While the fundamental conclusions of the SPGC‐4 remain valid, the finding that Gleason grade did not modify the effect of prostatectomy on survival is now less certain. Physicians should therefore use caution when inferring prognosis based on those results.

Cazzaniga et al. should be congratulated for this important work which will help physicians better counsel patients making decisions based on trials like the SPCG‐4.

References

  1. Trinh QD, Cole AP, Dasgupta P. Weighing the evidence from surgical trials. BJU Int 2017; 119: 659–60
  2. Bill‐Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708–17
  3. Dalela D, Karabon P, Sammon J et al. Generalizability of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) results to contemporary North American men with prostate cancer. Eur Urol 2017; 71: 511–4
  4. Cazzaniga W, Garmo H, Robinson D, Holmberg L, Bill‐Axelson A, Stattin P. Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG‐4) study. BJU Int 2019; 123: 421–8
  5. Danneman D, Drevin L, Robinson D, Stattin P, Egevad LJ. Gleason inflation 1998–2011: a registry study of 97,168 men. BJU Int 2015; 115: 248–55
  6. Albertsen PC, Hanley JA, Barrows GH et al. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005; 97: 1248–53C

 

March 2019 – About the cover

 

The Article of the Month for March (Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG-4) study) is from work carried out at Uppsala University in Sweden.

Uppsala University was founded in the 15th century in Sweden’s fourth biggest city, Uppsala. It was the first university in the nordic region and today has over 40 000 students.

March’s cover picture shows Uppsala Cathedral, which was built in 1270. It is open daily and offers tours in English.

 

Article of the week: Does the robot have a role in radical cystectomy?

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

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

If you only have time to read one article this week, we recommend this one.

Does the robot have a role in radical cystectomy?

Read the full article

Abstract

Between 2014 and 2015, 3742 radical cystectomies (RCs) were performed in the UK. The majority of these were open RCs (ORCs), and only 25% were performed with robot assistance. These data contrast starkly with the picture in radical prostatectomy (RP), for which most operations are robot assisted (79.4% of the 7673 in 2016). Given that most pelvic surgeons have access to robotic facilities (as shown by the RP trends) and urologists are typically early adopters, one must question why many surgeons have yet to be convinced by robot‐assisted RC (RARC). This question is particularly perplexing given that RC is a more morbid operation than RP and most patients with bladder cancer are considerably less fit than the average man with prostate cancer, and therefore, reductions in morbidity are especially rewarding in this cohort.

Read more Articles of the week

Editorial: Evidence trumps consensus

We read with great interest the article by Khetrapal et al. [1]. Certain advantages of robotic cystectomy have been shown in retrospective studies and confirmed in the RAZOR trial [2]. Robotic cystectomy has been associated with lower blood loss, lower transfusion rates and a shorter length of stay; however, two randomized trials have shown no difference in complication rates, which was the original reason robotic cystectomy was attempted [2,3]. Khetrapal et al. seem to believe that this was because diversions were performed extracorporeally, and intracorporeal diversion would allow urologists to uncover the true benefit of robotic cystectomy. When the RAZOR trial was being designed (in 2009), intracorporeal diversion was early in development. Even today its use in the USA is restricted to a few centres and the Pasadena consensus statement (2015) acknowledges that only 3% of all diversions were performed intracorporeally [4]. While more commonly performed in Europe, intracorporeal diversions still form the minority of all urinary diversions. To date there are no reliable prospective data to convince us that intracorporeal diversion is superior, and the low quality of available evidence has been acknowledged in the Pasadena statement [4]. The iROC trial is a step in the right direction and we await its results with interest [5].

We agree with the authors that cost analysis is essential in evaluating the exact role of robotic cystectomy. It is also worth factoring in the indirect costs of the two procedures, given that most patients undergoing robotic cystectomy will have a shorter hospital stay and fewer blood transfusions, although robotic cystectomies may take longer to perform. We anticipate that as newer robotic systems are introduced the direct surgical costs may be reduced.

There is no universally accepted learning curve for performing a cystectomy based on prospective studies. Ten cystectomies in the preceding year before enrolment in the RAZOR trial was the lowest number of cystectomies permitted for the surgeon to be eligible to participate [2]. All surgeons were fellowship-trained with high-volume bladder cancer practices, and the majority had performed significantly more than 10 cystectomies. The high quality of surgical surrogates for both approaches that we reported, namely, lymph node yield, positive margins and complication rates, are testament to this. We believe that the authors’ statement that novice surgeons may have operated on trial patients is simply inaccurate. It is largely self-serving to fit the results of the RAZOR trial into their own narrative about their beliefs in the advantages of robotic surgery. The iROC trial requires surgeons to have carried out 30 or more intracorporeal diversions in their entire career, with accredited surgeons being required to perform more than 10 cystectomies per year for the last 2 years as primary surgeon, which does not seem remarkably different from the RAZOR trial criteria for surgeon participation [5].While it is clear that large volumes are associated with better outcomes, the magic number is unclear. The Pasadena Consensus Statement cites the National Institute for Health and Care Excellence (NICE) guidelines in the UK, which mandate a minimum of five cystectomies per year per surgeon as adequate surgical volume [4].

Operating time in RAZOR was defined as the time from patient entry to the time the patient exited the operating theatre [2]. In most instances, the time for positioning and anaesthesia (preparation and induction) before making any incision and the time after closure for extubation and leaving the room is generally ~60–80 min. The Pasadena Consensus statement recommends that experienced surgeons should aim to complete robotic cystectomies within 5–6 h, depending on the type of diversion, basing their recommendation on three available studies [4]. Of those papers, Hayn et al. (overall mean operating time 386 min and mean operating time after 50th case 339 min) and Richards et al. (mean operating time 449 min after 40th case of learning curve) defined operating time in their papers as incision to closure time [6,7]. The paper by Collins et al. does not define operating time; however, the mean operating time for cystectomy with intracorporeal diversion for both surgeons in that study was 438 min, and 87.5% of the cases selected in this study had ≤pT2 disease, suggesting a significant selection bias [8]. This institution is a part of the International Robotic Cystectomy Consortium (IRCC) which defines operating time as incision to closure time, leading us to believe that this was the probably the definition they used [8]. A recent study from the IRCC reported a mean operating time (incision to closure) of 364 min in 2134 patients [9]. All these data suggest that operating times in RAZOR were extremely competitive if not actually faster, once again attesting to the proficiency of the participating surgeons. Khetrapal et al. would have reached a different conclusion about the RAZOR trial results had they accurately interpreted the scientific data from the above-mentioned studies.

The RAZOR trial provided level 1 evidence proving the oncological efficacy of robotic cystectomy and confirming advantages such as reduced blood loss and length of stay [2]. We agree that the true place for robotic cystectomy will be determined once a cost–benefit analysis can be performed, and after we obtain high-level prospective data about intracorporeal diversions. To this end, we look forward to the successful completion of the iROC trial and await its publication. Until such time, we suggest more reliance on high-level evidence than on consensus statements and narratives.

by Vivek Venkatramani and Dipen J. Parekh on behalf of RAZOR trial investigators

References

  1. Khetrapal P, Kelly J, Catto J, Vasdev N. Does the robot have a role in radical cystectomy? BJU Int 2019; 123(3): 380-2.
  2. ParekhDJ, Reis IM, Castle EP et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an openlabel, randomised, phase 3, non-inferiority trial. Lancet 2018; 391: 2525–36
  3. Bochner BH, Dalbagni G, Sjoberg DD et al. Comparing open radical cystectomy and robot-assisted laparoscopic radical cystectomy: a randomized clinical trial. Eur Urol 2015; 67: 1042–50
  4. Wilson TG, Guru K, Rosen RC et al. Best practices in robot-assisted radical cystectomy and urinary reconstruction: recommendations of the Pasadena Consensus Panel. Eur Urol 2015; 67: 363–75
  5. Catto JWF, Khetrapal P, Ambler G et al. Robot-assisted radical cystectomy with intracorporeal urinary diversion versus open radical cystectomy (iROC): protocol for a randomised controlled trial with internal feasibility study. BMJ Open 2018; 8: e020500
  6. Hayn MH, Hussain A, Mansour AM et al. The learning curve of robot- assisted radical cystectomy: results from the international robotic cystectomy consortium. Eur Urol 2010; 58(2): 197–202
  7. Richards KA, Kader K, Pettus JA et al. Does initial learning curve compromise outcomes for robot-assisted radical cystectomy? A critical evaluation of the first 60 cases while establishing a robotics program. J Endourol 2011; 25(9): 1553–8
  8. Collins JW, Tyritzis S, Nyberg T et al. Robot-assisted radical cystectomy (RARC) with intracorporeal neobladder – what is the effect of the learning curve on outcomes? BJU Int 2014; 113(1): 100-7
  9. Hussein AA, May PR, Ahmed YE et al. Development of a patient and institutional-based model for estimation of operative times for robot-assisted radical cystectomy: results from the international robotic cystectomy consortium. BJU Int 2017; 120(5): 695–701

Video: Does the robot have a role in radical cystectomy?

Does the robot have a role in radical cystectomy

Read the full article

Abstract

Between 2014 and 2015, 3742 radical cystectomies (RCs) were performed in the UK. The majority of these were open RCs (ORCs), and only 25% were performed with robot assistance. These data contrast starkly with the picture in radical prostatectomy (RP), for which most operations are robot assisted (79.4% of the 7673 in 2016). Given that most pelvic surgeons have access to robotic facilities (as shown by the RP trends) and urologists are typically early adopters, one must question why many surgeons have yet to be convinced by robot‐assisted RC (RARC). This question is particularly perplexing given that RC is a more morbid operation than RP and most patients with bladder cancer are considerably less fit than the average man with prostate cancer, and therefore, reductions in morbidity are especially rewarding in this cohort.

 

Article of the week: Prognostic evaluation of perinephric fat, renal sinus fat, and renal vein invasion for patients with pathological stage T3a clear‐cell RCC

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

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

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

Prognostic evaluation of perinephric fat, renal sinus fat, and renal vein invasion for patients with pathological stage T3a clear‐cell renal cell carcinoma

Paras H. Shah*, Timothy D. Lyon*, Christine M. Lohse, John C. Cheville,
Bradley C. Leibovich*, Stephen A. Boorjian* and R. Houston Thompson*
 
*Department of Urology, Department of Health Sciences Research, and
Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
 

 

Read the full article

Abstract

Objective

To investigate the prognostic significance of various patterns of extrarenal extension that comprise pathological stage T3a clear‐cell renal cell carcinoma (ccRCC) amongst patients undergoing nephrectomy for non‐metastatic disease.

Patients and Methods

A retrospective review of 563 patients who underwent radical nephrectomy for pathologically confirmed T3aN0/NxM0 ccRCC between 1970 and 2011 was performed. All pathological slides were re‐reviewed by one urological pathologist. Associations of patterns of extrarenal extension (perinephric fat [PF], renal sinus fat [SF], and renal vein [RV], in isolation or in any combination) with disease progression, cancer‐specific mortality (CSM), and all‐cause mortality were evaluated on multivariable analyses.

Fig. 1. Progression-free survival stratified by type of extrarenal extension

Results

Overall, PF invasion, renal SF invasion, and RV tumour thrombus were present in 144 (26%), 51 (9%), and 163 (29%) patients, respectively, with multiple patterns of extrarenal extension identified in 205 (36%) patients. There were no significant differences in survival outcomes for isolated involvement of PF, renal SF, or RV. However, patients with multiple patterns of extrarenal extension were at significantly increased risk of disease progression (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.04–1.65; P = 0.020), CSM (HR 1.64, 95% CI 1.27–2.12; P < 0.001), and all‐cause mortality (HR 1.32, 95% CI 1.08–1.61; P = 0.008).

Conclusions

The presence of multiple patterns of extrarenal extension is associated with a higher risk of disease progression and cancer‐related death after radical nephrectomy compared to isolated involvement of the PF, renal SF, or RV, which carry similar prognostic weight. If validated, these findings may help refine risk stratification of non‐metastatic T3a RCC by distinguishing patients with multiple vs one pattern of extrarenal extension.

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Editorial: Does knowing the risk of relapse in localized renal cell carcinoma matter?

Shah et al. [1] report a retrospective analysis from the Mayo Clinic investigating the prognostic significance of different patterns of pathological T3a clear‐cell RCC in patients who underwent radical nephrectomy for localized disease. There was no difference in disease progression, cancer‐specific mortality or all‐cause mortality when comparing isolated perinephric fat invasion vs isolated renal sinus fat invasion vs isolated renal vein invasion. Multiple sites of extra‐renal extension compared with one site, however, was independently associated with an increased risk of disease progression (hazard ratio [HR] 1.31, P = 0.02), death from RCC (HR 1.64, P < 0.001) and all‐cause mortality (HR 1.32, P = 0.008) when adjusting for multiple key variables including age, tumour size, grade, presence of coagulative tumour necrosis and sarcomatoid differentiation. The authors incorporated multiple sites of extra‐renal extension vs one site into three RCC prognostic models: SSIGN score, UISS and MSKCC nomogram. After controlling for these three predictive tools independently, multiple sites of extra‐renal disease predicted progression, death from RCC and all‐cause death. These data suggest that risk stratification for pT3aN0MO clear‐cell RCC is improved by differentiating multiple vs one site of extra‐renal extension.

Does an improved ability to predict recurrence and mortality increase the likelihood of cure in high‐risk localized RCC patients in 2018? Unfortunately, the answer is no. Ideally, prognostic models would identify patients at sufficient risk to consider adjuvant therapy, which would increase cure rates by eradicating micro‐metastatic disease with an acceptable toxicity. Regrettably, in RCC management there are no well‐established post‐surgical therapies that improve cure rates. The deficiency of established adjuvant therapies is not attributable to a lack of investigative trials. In the era before vascular endothelial growth factor receptor (VEGFR) targeting, adjuvant vaccines, immunotherapies and other systemic therapies failed to demonstrate improved recurrence‐free (RFS) or overall survival (OS) [2]. The efficacy of VEGFR‐targeted therapies in the metastatic setting re‐energized the hope for adjuvant therapy in patients with high‐risk localized RCC after surgical resection in the past two decades. The results to date have been disappointing. To date, three trials (ASSURE, PROTECT and S‐TRAC) have been completed, comparing oral VEGFR tyrosine kinase inhibitors with placebo in high‐risk localized clear‐cell RCC, with disease‐free survival (DFS) as the primary endpoint [3,4,5]. ASSURE and PROTECT showed no difference in RFS or OS [3,4,5]. S‐TRACT demonstrated an improvement in DFS but not in OS [4]. A pooled analysis of these three trials also failed to demonstrate improved DFS or OS with adjuvant VEGFR‐targeted therapy [6]. Significant side effects with discontinuation of adjuvant therapy occurred in 28–45% of patients as a result of drug‐related toxicity [6]. Trials investigating immune checkpoint inhibitors have yet to be published and, with the established efficacy of these drugs in the metastatic setting, hope still remains for adjuvant therapy in resected high‐risk localized RCC.

If the current literature does not support adjuvant therapy for resected high‐risk RCC, does knowing the risk of relapse alter surveillance? National Comprehensive Cancer Network guidelines for resected stage III RCC recommend chest and abdominal imaging within 3–6 months, along with subsequent chest and abdominal imaging every 3–6 months for 3 years, and then annually up to 5 years. Although the ideal schedule for surveillance imaging is unknown, further characterizing of the risk of relapse in high‐risk localized RCC would not be likely to affect this schedule significantly.

Although knowing the risk of relapse in high‐risk localized RCC does not help management in 2018, there is still a value to enhancing our prognostic tools. For one, our prognostic tools help clinicians counsel patients appropriately about their risk of recurrence. In addition, enhanced prognostic tools will assist in selecting appropriate patients with high‐risk localized RCC for future clinical trials of adjuvant therapy and also help us understand the results when comparing cohorts within and between trials.

References

  1. Shah PH, Lyon TD, Lohse CM. Prognostic evaluation of perinephric fat, renal sinus fat, and renal vein invasion for patients with pathologic stage T3a clear cell renal cell carcinoma. BJU Int 2019; 123: 270–6
  2. Scherr AJO, Lima JPSN, Sasse EC et al. Adjuvant therapy for locally advanced renal cell cancer: a systematic review with meta‐analysis. BMC Cancer 2011; 11: 115–21
  3. Haas N, Manola J, Uzzo R et al. Adjuvant sunitinib or sorafenib for high‐risk, non‐metastatic renal‐cell carcinoma (ECOG‐ACRIN E2805): a double‐blind, placebo‐controlled, randomised, phase 3 trial. Lancet 2016; 387: 2008–16
  4. Ravaud A, Motzer RJ, Pandha HS et al. Adjuvant sunitinib in high‐ risk renal‐cell carcinoma after nephrectomy. N Engl J Med 2016; 375: 2246–54
  5. Motzer RJ, Haas NB, Donskov F et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol 2017; 35: 3916–23
  6. Sun M, Marconi L, Eisen T et al. Adjuvant vascular endothelial growth factore‐targeted therapy in renal cell carcinoma. Eur Urol 2018; 74: 611–20

 

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