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Immunotherapy in urological malignancies: can you take your knowledge to the next level?

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bju13648-fig-0001In this month’s issue of the BJUI, we highlight the evolving era of immunotherapy in solid tumour therapy. As urological surgeons, we spend a large portion of our time working with anatomy, instruments, and robots – things we can see, touch, and control. Immunotherapy is a different conversation – cartoon pathways, process blockades, molecular expression levels, combination therapies, and treatment resistance. Curing a patient with a successful operation is a major draw to our field, but we know our limitations when faced with lethal variant prostate cancer, and high-grade/high-stage bladder and kidney cancers in particular. Systemic therapies have been around for decades and are part of our guidelines – so why all the excitement over immunotherapy?

Our highlighted articles are a review from Mataraza and Gotwals [1] and a comment from Elhage et al. [2]. I urge you to start with the review article [1] and give it a full line-by-line read. You may need to pull out pen and paper, and practice spelling and pronouncing a number of new compounds. They may sound as awkward as abiraterone did the first time you heard of it years ago but will eventually become familiar and attached to yet another catchy trade name from pharma. Here is a quick list/homework assignment: ipilimumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab. Another 20 or more are in development. Challenge yourself to write out their pathways, and you may re-learn a thing or two about familiar agents like sipuleucel-T, interferon α, and interleukin 2.

A major theme in both articles is the experience with immunotherapy in advanced melanoma. The enticing message is that a cohort of patients with metastatic melanoma treated with ipilimumab survived 3 years and the Kaplan–Meier curves plateau out to 10 years. This observation sparks different possible futures such as immune ‘memory’, durable response, and ultimately the word we like to use in surgery – cure.

The picture in urological cancers is not entirely as rosy as the melanoma Kaplan–Meier curve. Multiple trials are highlighted by our review with familiar themes of single agent trials, combination immunotherapies, and combined immunotherapy plus anti-angiogenesis agents. Many trials enrol heavily pre-treated populations with limited remaining options. Many endpoints still observe responses followed by resistance patterns. An important theme to follow is the coupling of biomarkers that link expression to treatment response (i.e. predictive vs prognostic), and the USA Food and Drug Administration (FDA) has approved such a biomarker for nivolumab response. However, even this story line is perplexing, as drug response is not always linked to the marker, and immune cell expression may be ‘inducible and dynamic’ [1].

Last step – re-read the review and comment articles and see if you can write down some key agenda items for future immunotherapy. How are checkpoint inhibitors different from vaccines? How do we generate a durable immune response? What is the ‘abscopal effect’? What are three major areas of research and development in immunotherapy?

If you can spend the time on these articles and ponder these challenging questions, you will move up to the next level of understanding and enjoy a greater appreciation of the next abstract you hear at a major meeting. In closing, I am reminded of the oft-repeated words from the hit television show Game of Thrones (based on the novels of George R.R. Martin) from the House Stark: ‘Winter is Coming’. In urological oncology, ‘Immunotherapy is Coming’, so be prepared!

 

John W. Davis

BJUI Associate Editor Urological Oncology

 

References

1 Mataraza JM, Gotwals P. Recent advances in immuno-oncology and its application to urological cancers. BJU Int 2016; 118: 506– 14

 

2 Elhage O, Galustian C , Dasgupta P. Immune checkpoint blockade – a treatment for urological cancers? BJU Int 2016; 118: 498–505

 

The optimal treatment of patients with localized prostate cancer: the debate rages on

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The widely anticipated results of the ProtecT study have now been published. Unfortunately, the results do little to advance our understanding as to whether surgery or radiation provides better outcomes.

 

In summary

The study followed oncologic and functional outcomes of 545 patients randomized to active monitoring (surveillance), 553 to radical prostatectomy, and 545 to radiotherapy. With a median follow-up of 10 years, the authors report no significant differences in prostate cancer specific (p=0.48) or overall survival (p=0.87) among the three treatment groups. They did demonstrate an increase in disease progression and metastasis among men managed with surveillance.

In an accompanying manuscript, the authors examined patient reported outcome measures out to 6 years following treatment. The authors report worse urinary continence and erectile function following surgery and worse voiding symptoms and bowel function following radiotherapy.

 

What do we take from this?

The investigators and participating patients should be congratulated for successfully completing this study. Numerous authors have documented their failure to adequately accrue to randomized studies of surgery versus radiotherapy in localized prostate cancer (including MRC PR06 and SPIRIT). The failure of these trials, among others, prompted Dr. Wilt to ask “Can randomized treatment trials in early stage prostate cancer be completed?” These authors have unequivocally proven that the answer is “yes”.

However, there are many caveats in applying these results to our patients:

 

(1) Study power

The study was clearly underpowered to evaluate the primary outcome of prostate-cancer specific mortality.  Drs. Roobol and Bokhorst eloquently described important limitations of the ProtecT study. The authors designed the study assuming prostate cancer mortality of 15% at a median follow-up of 10 years. This was later adjusted downwards to 10% based on updated UK data. In the end, rates were closer to 1%. The conclusions of the primary analysis are based on a total of 17 (17!!) deaths.

 

(2) Study cohort – enriched with low risk disease

Among the randomized patients, the median PSA was 4.6 ng/mL, 76% had clinical stage T1c disease, and 77% had Gleason score 6 disease. These patients would almost certainly be considered most suitable for active surveillance, rather than active therapy, if seen in clinic today. Clinically meaningful decisions between surgery and radiotherapy are in the realm of treatment of intermediate and high-risk localized prostate cancer and these comprise a small group in this study.  Based on this baseline distribution, it will be unlikely that any significant differences will be found in future follow-up studies.

 

(3) Outcomes for active surveillance

Perhaps the most notable findings of this study involve the significantly higher rates of progression, metastasis and prostate cancer specific mortality for patients treated on the surveillance protocol as compared to those treated actively, though statistical significance was not reached for PCSM. The manuscript does not provide further details regarding the pathologic characteristics of these patients. Relevantly, what was the Gleason score for these patients? This is of particularly importance as many surveillance proponents are advocating an expanding role of AS.

 

(4) Treatments administered

RCTs typically require significant periods of accrual, follow-up and analysis. As a result, they may be out of date prior to completion. This is certainly true of the ProtecT study. This most prominently affects patients allocated to radiotherapy. In the study protocol, patients received 3D conformal radiotherapy at 74 Gy, not the IMRT which has now become widely used. Thus, proponents of radiotherapy will likely to discount any findings which do not favour radiotherapy.

In addition, the current day relevance of the surgical treatment provided is questionable. First, the vast majority of patients in the surgical arm underwent open RP. More concerning is the quality of surgery provided: 93 patients (24%) of the cohort had positive surgical margins. In contemporary series, the average rate is under 15% with centers of excellence approaching 5%. While PSM rates clearly affect oncologic outcomes, they likely are also a surrogate of surgical quality which may affect functional outcomes.

 

 (5) Comparison of active treatments

In the accompanying editorial, Dr. D’Amico comments on a “trend favouring radiation and ADT over surgery” and suggests that “one may consider radiation and ADT as a preferred option”. The basis for this conjecture is 5 deaths in the surgery group and 4 in the radiotherapy group, hardly a convincing sample. In contrast to these data, there was a higher number of patients with metastasis among those treated with radiotherapy (16 vs 13). These discordant results would certainly suggest that any preference for radiotherapy is premature. Indeed, with additional follow-up one would expect the patients with metastasis to die of prostate cancer, thus favouring those treated surgically.

On a methodological note, while the inclusion of active surveillance is a strength of the study, it poses analytic difficulties. The primary analysis assesses a null hypothesis assuming equality across all study interventions. Thus, as this was non-significant, pairwise testing of surgery and radiotherapy, and each with surveillance, is inappropriate and conclusions on these comparisons should not be drawn.

 

(6) Functional outcomes and treatment-related complications

Most clinicians are well aware that many complications other than erectile function and urinary incontinence may affect that life trajectory of patients following prostate cancer treatments. ProtecT offers the opportunity to examine the risks of secondary malignancy, repeat urologic and gastrointestinal interventions, surgeries and hospitalizations following treatment. However, these are not currently included in the published data.

Further, the PCOS studies have clearly shown that differences in patient reported urinary, sexual and bowel function change over time with convergence after long term follow-up (15 years). With ongoing maturity, it will be interesting to see if a similar pattern emerges in ProtecT.

 

In conclusion

The ProtecT study may raise more questions than it answers. Among a low risk group of patients, it has shown that active treatment of PSA-detected prostate cancer can reduce the progression to metastatic disease. Assessment of prostate cancer specific and overall mortality, as well as the comparative efficacy of surgery and radiotherapy, is not possible due to power limitations.

Will you be changing you patient counselling based on these results?

 

cw-head-shot-smallChristopher Wallis, MD
Resident,
Division of Urology,
Department of Surgery,
University of Toronto
Doctoral Student in Clinical Epidemiology and Health Care Research, Institute of Health Policy, Management & Evaluation
University of Toronto		 nam_drrobert_portrait-2010-small

 

 

 

 

 

 


Robert Nam, MD MSc FRCSC
Ajmera Family Chair in Urologic Oncology
Professor,
Division of Urology,
Department of Surgery
University of Toronto
Head, Genitourinary Cancer Site
Odette Cancer Centre
Sunnybrook Health Sciences Centre

 

 

 

 

Asia-Pacific Prostate Cancer Conference 2016 Highlights

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JSAfter briefly venturing to tropical Cairns in 2015, the Asia-Pacific Prostate Cancer Conference returned to its traditional home in Melbourne for its 17th edition in 2016 (#APCC16). The meeting has previously featured the who’s who of prostate cancer and this year was no different with an all-star multidisciplinary faculty consisting of 18 international members in addition to our local experts. The meeting was well attended by over the 750 delegates from all parts of the globe and remains one of the largest prostate cancer educational events worldwide.

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Conference president Professor Tony Costello opened the conference with the famous Whitmore aphorisms and outlined the impressive progress and discoveries we have made in the field over the last century. The first case of prostate cancer was described in 1853 in the London Hospital and was noted by the surgeon to be a “very rare disease” whereas now it is known to be the most commonly diagnosed malignancy amongst men. Pleasingly, research and emphasis on men’s health has grown with the disease highlighted by the newly completed, world-class Parkville Biomedical precinct in Melbourne, which includes “The Royal Men’s Hospital” (@APCR). Melbourne’s Lord Mayor (@LordMayorMelb) also dropped-by to reiterate his support for the meeting and the advancements made in men’s health.

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In what is becoming an annual tradition, honourary Melbournian and Australian, Dr Stacy Loeb (@LoebStacy) once again got the sessions off to a flying start by delivering the ‘prostate cancer year in review’ which was an excellent overview of the abstracts produced over the last 12 months. The male attendees in particular were excited by the recent paper suggesting that more than 21 ejaculations per month acted as a protective factor for the development of prostate cancer. Although confounding factors may have played a role in the association seen, these were easily over-looked and its results were accepted as gospel and promoted as a public health message. The abstract featured the following day on the home page of The Australian Financial Review (https://www.afr.com/lifestyle/health/mens-health/tell-your-partner-frequency-counts-even-against-cancer-20160831-gr5fs4) – who knew that the answer to the world economic problems was so simple!

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The meeting did however become more scientific as we heard from a range of international and local experts on the challenges of trying to find the balance of precision oncology in a time of tumour heterogeneity. It was clear that the future has arrived with recent advances in the field of genomics and biomarkers. These discoveries appear to be only the tip of the iceberg and further research holds the key in understanding tumour behavior in order to tailor treatment on a patient-to-patient level. Having witnessed a variety of experts from all parts of the globe present their finding there is little doubt that a major breakthrough is just around the corner. A special mention to Dr Niall Corcoran whose research was of such high quality that A/Prof Henry Woo (@DrHWoo) raised the white flag early in the Melbourne vs. Sydney inter-city rivalry.

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The named lectures of #APCC16 were highlights of the conference. Keeping with the theme of the first morning, Dr Martin Gleave delivered the 4th Patrick C Walsh lecture titled ‘Two Tales of Precision Oncology.” Prof Peter Wiklund gave the inaugural ERUS lecture on the role of surgery for high risk and metastatic prostate cancer.

It wouldn’t have been a prostate cancer conference without the age-old debate of surgery vs. radiotherapy being revisited. Over three days Dr Robert Nam presented a series of talks on Canadian long-term outcomes and meta-analysis showing favourable results for team surgery. He also predicted that the highly anticipated ProtecT randomised trial due in the NEJM would show no difference ensuring the debate prolongs into the future and vowed to “eat my shorts” if the trial demonstrated a result favouring either modality. Dr John Violet flew the flag strongly for radiation oncologists in presenting the promising outcomes for 177Lu-PSMA in the mCRPC setting. Similarly, Dr Andrew Kneebone presented a compelling case for stereotactic radiation for oligometastatic disease.

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Imaging of the prostate was a hot topic throughout the conference. The excitement around PSMA-PET was at a climax following The Victorian Comprehensive Cancer Centre’s (@VCCC) experience that was presented by Associate Professors Michael Hofman (@DrMHofman) and Nathan Lawrentschuk (@lawrentschuk). The proceeding panel discussion focused on how to best utilise the technology and the role it currently plays in the prostate cancer landscape.  Despite not being FDA approved, its role in evaluating recurrence appears to be entrenched with data to support its superiority over other modalities but it was also proposed that it might have a place in initial staging of high-risk cancer.  The advancement of PSMA over conventional imaging also raised the question of how we now interpret previous trials such as CHAARTED and STAMPEDE whose results are based on superseded technology.

The hype surrounding PSMA-PET only just eclipsed that of mpMRI in the imaging landscape. Professor Philip Stricker presented a nomogram, which integrated MRI in determining who to biopsy and Dr Rob Reiter reported a terrific novel study of using 3D modeling to compare MRI results to final histopathology to determine correlation but did caution us with performing targeted biopsies alone which risks missing clinically significant cancers. Dr Nam also chimed in with a pilot study of using MRI as a screening test.

Suspense was built until Friday for the highly anticipated session on open vs. robotic surgery featuring the first presentation of the Brisbane RCT. The results of the trial have been already widely debated in the urological community and a discussion similar to the recent BJUI blog (https://www.bjuinternational.com/bjui-blog/its-not-about-the-machine-stupid/) ensued. Regardless of individual opinions on the trial, there is no dispute about the volume of work required to conduct a surgical randomised trial and there was wide praise for the efforts of the Brisbane team. Prof Peter Wiklund and Dr Homi Zargar (@hzargar) also reported the Swedish and Victorian experience respectively. The overall consensus was that robotic surgery offers the benefit of minimally invasive surgery but it is the surgeon rather than the modality, which has the most significant impact on outcomes.

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There was a strong multi-disciplinary theme throughout the conference. The Nursing & Allied Health and Translational Science streams both had strong contingents attending. The quality of research presented and engagement amongst attendee was of the highest standard. This was exemplified by the session ‘MDT 2020’, which was a case-centred discussion by a panel of experts from a variety of professions and highlighted the value of a multidisciplinary approach in patient care.

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The social program of #APCC16 was not overshadowed by its academic counterpart. The conference dinner was held at The Glasshouse where the food was exquisite and entertainment was provided by three waiters come tenors. Their classical renditions were received by guests with napkin twirling and swinging wine glasses. The frivolities were thoroughly enjoyed by all.

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The final day of the conference was highlighted by the masterclasses. The 6th da Vinci© Prostatectomy Masterclass was convened by Drs Daniel Moon (@DrDanielMoon) and Geoff Coughlin and featured international faculty involvement by Dr John Davis (@jhdavis) and Professors Thalman and Wiklund. Considering the hype surrounding MRI it was no surprise that the 3rd Prostate MRI Imaging and Biopsy masterclass reached capacity many months ago. It should also be mentioned that the sponsored satellite meetings and breakfast sessions in the previous days which starred Dr Stacy Loeb, Dr Tia Higano (@thigano), Dr Jaspreet Sandhu, Prof Bertrand Tombal (@BertrandTOMBAL) and Genevieve Muir-Smith drew large numbers of attendees.

We would like to congratulate all attendees and their teams on the abstracts presented throughout the conference. The BJUI once again proudly supported the meeting with all accepted abstracts published in a special supplements issue and BJUI Associate Editors Declan Murphy (@declanmurphy), John Davis, and Nathan Lawrentschuk being prominent figures throughout the conference. A special mention to the poster prize winners from this year:

  • Clinical Urology: Jonathan Kam – Do multi-parametric MRI guided biopsies add value to the standard systematic prostate needle biopsy? – early experience in an Australian regional centre
  • Nursing & Allied Health: Thea Richardson – An Androgen Deprivation Therapy Clinic: An integrative approach to treatment
  • Translational Science: Natalie Kurganovs – Identifying the origins and drivers of castration resistant prostate cancer

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On behalf of all the delegates, we thank the entire international and local faculty who shared their knowledge over the conference and devote their time to improving men’s health. Furthermore, meetings such as this would not occur without the unheralded behind the scenes work. We extend our thanks to president Prof Costello, the convenors of the streams (A/Prof Declan Murphy, Dr Niall Corcoran, A/Prof Chris Hovens, Ms Helen Crowe (@helenrcrowe) & Mr Dave Gray (@DavidGrayAust)) and the APCC committee. We also graciously thank our sponsors without whom none of this would be possible and are vital to further advancements in men’s health.

Last but not least, given the rich history of social media seen at this conference, it would be remiss not to acknowledge another #SoMe landmark. Melbourne has previously been responsible in welcoming urology SoMe royalty, Dr Stacy Loeb, to the twitter world and this year the twitterati were introduced to Dr Peter Carroll (@pcarroll_). He managed to send out 4 tweets and eclipse 100 followers before the end of the conference.

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#APCC17 will return to Melbourne on 30th of August 2017 – we hope to see you there!

Dr Niranjan Sathianathen (@NiranjanJS) is a researcher at Peter MacCallum Cancer Centre, Melbourne.

 

Randomised Controlled Trials in Robotic Surgery

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

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

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

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

A few additional reflections are perhaps appropriate at this time:

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

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

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

Prokar Dasgupta @prokarurol
Editor-in-Chief, BJUI 

@declangmurphy
Associate Editor BJUI

References

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

4

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

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

5

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

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

 

The impact factor may be flawed but important

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It has been a nice summer for the BJUI. Our impact factor has gone up to 4.387, the highest ever in the history of the Journal and we made the Altmetrics Top 50 for the first time ever with a score of 1166, Nature being the numero uno. I wanted to thank our editorial team, readers, authors and reviewers for their dedication and commitment, which made this possible.

bju13563-fig-0001

 

The question is how did we do this? For a journal without official society guidelines, it was not easy. So we had to focus on original articles rather than reviews and guidelines. There were three essential steps:

  1. Publishing the highest quality, citable papers irrespective of geographical location [1] – for example, this month we have highlighted the importance of personalised medicine in BPH from Taiwan [2], whereby the authors show that an endothelial nitric oxide synthase (eNOS) genetic polymorphism has a negative impact on response to α-blockers.
  2. Reducing the number of papers published while selecting clinically relevant, large prospective studies and trials – an example of this is the LAParoscopic Prostatectomy Robot Open (LAPPRO) study from Sweden [3], showing that even in very-low-risk prostate cancer, upgrading after radical prostatectomy occurs in over a third of patients and that the functional outcomes are not as good as expected.
  3. Amplifying our content through social media – this means that we believe in interaction with a wider audience, immediacy of response, and are not afraid of the occasional controversy and debate. An example is the comment on clostridium histolyticum collagenase followed by a brief editorial on what may increasingly be seen as an important treatment option for Peyronie’s disease [4].

Many consider the impact factor of a journal as a ‘gaming’ exercise, flawed by its very nature. I was very pleased to receive a WhatsApp from one of my colleagues saying how pleased he was that at the BJUI we have always played ‘with a straight bat’. An important consideration is that Universities often count original papers in the best journals for measuring academic output, which in turn drives income from various sources. In the UK this is given the term ‘returnable’ when considered within a system called the Research Excellence Framework. I am really pleased that the BJUI is now ‘returnable’ with its new impact factor and is seen as a serious player within a highly demanding system. I am aware that this also true for other international institutions, which is in keeping with our global presence as a journal without boundaries.

Prokar Dasgupta @prokarurol
Editor-in-Chief, BJUI 

References

1 Dasgupta P. Quality has no boundaries. BJU Int 2014; 113: 1

 

2 Lee Y-C, Juan Y-S, Liu C-C et al. The association of endothelial nitric oxide synthase (eNOS) G894T gene polymorphism with responsiveness to a selective a 1-blocker in men with benign prostatic hyperplasia related lower urinary tract symptoms. BJU Int 2016; 118: 313–19

 

3 Carlsson S, Jaderling F, Wallerstedt A et al. Oncological and functional outcomes 1 year after radical prostatectomy for very low risk prostate cancer. Results from the prospective LAPPRO trial. BJU Int 2016; 118: 205–12

 

4 Poullis C, Shabbir M, Eardley I, Mulhall J, Minhas S. Clostridium histolyticum collagenase – Is this revolutionary medical treatment for Peyronie’s disease? BJU Int 2016; 118: 186–92

 

It’s not about the machine, stupid

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Robotic surgery trial exposes limitations of randomised study design

 

Here it is, the highly anticipated randomised controlled trial of open versus robotic radical prostatectomy published today in The Lancet. Congratulations to the team at Royal Brisbane Hospital for completing this landmark study.

DM1

The early headlines around the world include everything from this one in the Australian Financial Review:

DM2b      –   to this from The Telegraph in London

DM3bAs ever, there will be intense and polarising discussion around this. One might expect that a randomised controlled trial, a true rarity in surgical practice, might settle the debate here; however, it is already clear that there will be anything BUT agreement on the findings of this study. Why is this so? Well let’s look first at what was reported today.

 

Study design and findings:

This is a prospective randomised trial of patients undergoing radical prostatectomy for localised prostate cancer. Patients were randomised to undergo either open radical prostatectomy (ORP, n=163) or robotic-assisted radical prostatectomy (RARP, n=163). All ORPs were done by one surgeon, Dr John Yaxley (JY), and all RARPs were done by Dr Geoff Coughlin (GC). The hypothesis was that patients undergoing RARP would have better functional outcomes at 12 weeks, as measured by validated patient-reported quality of life measures. Other endpoints included positive surgical margins and complications, as well as time to return to work.

So what did they find? In summary, the authors report no difference in urinary and sexual function at 12 weeks. There was also no statistical difference in positive surgical margins. RARP patients had a shorter hospital stay (1.5 vs 3.2days, p<0.0001) and less blood loss (443 vs 1338ml, P<0.001), and less pain post-operatively, yet, these benefits of minimally-invasive surgery did not translate into an earlier return to work. The average time to return to work in both arms was 6 weeks.

The authors therefore conclude by encouraging patients “to choose an experienced surgeon they trust and with whom they have a rapport, rather than choose a specific surgical approach”. Fair enough.

In summary therefore, this is a randomised controlled trial of ORP vs RARP showing no difference in the primary outcome. One might reasonably expect that we might start moth-balling these expensive machines and start picking up our old open surgery instruments. But that won’t happen, and my prediction is that this study will be severely criticized for elements of its design that explain why they failed to meet their primary endpoint.

 

Reasons why this study failed:

1.      Was this a realistic hypothesis? No it was not. For those of us who work full-time in prostate cancer, the notion that there would be a difference in sexual and urinary function at 12 weeks following ORP or RARP is fanciful. It is almost like it was set up to fail. There was no pilot study data to encourage such a hypothesis, and it remains a mystery to me why the authors thought this study might ever meet this endpoint. I hate to say “I told you so”, but this hypothesis could never have been proved with this study design.

2.      There is a gulf in surgical experience between the two arms. The lack of equipoise between the intervention arms is startling, and of itself, fully explains the failure of this study to meet its endpoints. I should state here that both surgeons in this study, JY (“Yax”) and GC (“Cogs”), are good mates of mine, and I hold them in the highest respect for undertaking this study. However, as I have discussed with them in detail, the study design which they signed up to here does not control for the massive difference in radical prostatectomy experience that exists between them.  Let’s look at this in more detail:

  1.        ORP arm: JY was more than 15 years post-Fellowship at the start of this study, and had completed over 1500 ORP before performing the first case in the trial.
  2.       RARP arm: GC was just two years post-Fellowship and had completed only 200 RARP at the start of the study.

The whole world knows that surgeon experience is the single most important determinant of outcomes following radical prostatectomy, and much data exists to support this fact. In the accompanying editorial, Lord Darzi reminds us that the learning curve for functional and oncological outcomes following RARP extends up to 700 cases. Yes 700 cases of RARP!! And GC had done 200 radical prostatectomies prior to operating on the first patient in this study. Meanwhile his vastly more experienced colleague JY, had done over 1500 cases. The authors believe that they controlled for surgeon heterogeneity based on the entry numbers detailed above, and state that it is “unlikely that a learning curve contributed substantially to the results”. This is bunkum. It just doesn’t stack up, and none of us who perform this type of surgery would accept that there is not a clinically meaningful difference in the experience of a surgeon who has performed 200 radical prostatectomies, compared with one who has performed 1500. Therein lies the fundamental weakness of this study, and the reason why it will be severely criticized. It would be the equivalent of comparing 66Gy with 78Gy of radiotherapy, or 160mg enzalutamide with 40mg – the study design is simply not comparing like with like, and the issue of surgeon heterogeneity as a confounder here is not accounted for.

3.      Trainee input is not controlled for – most surprisingly, the authors previously admitted that “various components of the operations are performed by trainee surgeons”. One would expect that with such concerns about surgeon heterogeneity, there should have been tighter control on this aspect of the interventions. It would have been reasonable within an RCT to reduce the heterogeneity as much as possible by sticking to the senior surgeons for all cases.

Having said all that, John and Geoff are to be congratulated for the excellent outcomes they have delivered to their patients in both arms of this study. These are excellent outcomes, highly credible, and represent, in my view, the best outcomes to be reported for patients undergoing RP in this country. We are all too familiar with completely unbelievable outcomes being reported for patients undergoing surgery/radiotherapy/HIFU etc around the world, and we have a responsibility to make sure patients have realistic expectations. John and Geoff have shown themselves to be at the top of the table reporting these credible outcomes today.

 

“It’s about the surgeon, stupid”

To paraphrase that classic phrase of the Clinton Presidential campaign of 1992, this study clearly demonstrates that outcomes following radical prostatectomy are about the surgeon, and not about the robot. Yet one of the co-authors, a psychologist, comments that, “at 12 weeks, these two surgical approaches yielded similar outcomes for prostate cancer patients”. Herein lies one of the classic failings of this study design, and also a failure of the investigators to fully understand the issue of surgeon heterogeneity in this study. It is not about the surgical approach, it is about the surgeon experience.

If the authors had designed a study that adequately controlled for surgeon experience, then it may have been possible for the surgical approach to be assessed with some equipoise. It is not impossible to do so, but is certainly challenging. For example a multi-centre study with multiple surgeons in each arm would have helped balance out the gulf in surgical experience in this two-surgeon study. Or at the very least, the authors should have ensured that they were comparing apples with apples by having a surgeon with in excess of 1500 RARP experience in that arm. Another approach would have been to get a surgeon with huge experience of both procedures (eg Dr Smith at Vanderbilt who has performed >3000 RARP and >3000 ORP), and to randomise patients to be operated on only by a single surgeon with such vast experience. That would have truly allowed the magnitude of the surgical approach effect to be measured, without the bias inherent in this study design.

 

Robotic surgery bridges the experience gap:

Having outlined these issues with surgeon heterogeneity and lack of equipoise, there is another angle which my colleague Dr Daniel Moon has identified in his comments in the Australian media today and which should be considered.

Although this is a negative study which failed to meet its primary endpoints, it does demonstrate that a much less experienced surgeon can actually deliver equivalent functional and oncological outcomes to a much more experienced surgeon, by adopting a robotic approach. Furthermore, his patients get the benefits of a minimally-invasive approach as detailed in the paper. This therefore demonstrates that patients can be spared the inferior outcomes that may be delivered by less experienced surgeons while on their learning curve, and the robotic approach may therefore reduce the learning curve effect.

On that note, a point to consider would be what would JY’s outcomes have been in this study if he had 13 years and 1300 cases less experience to what he had entering this study? Would the 200 case experience-Yax have been able to match the 1500 case experience-Yax?? Surely not.

And finally, just as a footnote for readers around the world about what is actually happening on the ground following this study. During the course of this study, the ORP surgeon JY transitioned to RARP, and this is what he now offers almost exclusively to his patients. Why is that? It is because he delivers better outcomes by bringing a robotic approach to the vast surgical experience that he also brings to his practice, and which is of course the most important determinant of better outcomes.

Sadly, “Yax” and “Cogs”, the two surgeons who operated in this study, have been prevented from speaking to the media or to being quoted in or commenting on this blog, but we are looking forward to hearing from them when they present this data at the Asia-Pacific Prostate Cancer Conference in Melbourne in a few weeks.

 

Declan G Murphy
Associate Editor BJUI; Urologist & Director of Genitourinary Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

Twitter: @declangmurphy

 

 

 

Article of the Week: Impact of Re-TUR on BCG-Treated T1 HG/G3 Bladder Cancer

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

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

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Francesca Pisano and Paolo Gontero, discussing their paper.

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

The impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with T1 high-grade/Grade 3 bladder cancer treated with bacille Calmette–Guerin

Paolo Gontero1, Richard Sylvester2, Francesca Pisano1, Steven Joniau3, Marco Oderda1, Vincenzo Serretta4,Stephane Larre5, Savino Di Stasi6, Bas Van Rhijn7, Alfred J.Witjes8, Anne J. Grotenhuis8, Renzo Colombo9, Alberto Briganti9, Marek Babjuk10, Viktor Soukup10, Per-Uno Malmstrom11, Jacques Irani12, Nuria Malats13, Jack Baniel14, RoyMano14, Tommaso Cai15, Eugene K. Cha16, Peter Ardelt17, John Vakarakis18, Riccardo Bartoletti19, Guido Dalbagni20, Shahrokh F. Shariat16, Evanguelos Xylinas16, Robert J.Karnes21 and Joan Palou22

 

1Urology Clinic, Citta della Salute e della Scienza di Torino, University of Studies of Turin, Turin ,4Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, 6Policlinico Tor Vergata-University of Rome, Rome, 9Dipartimento di Urologia, Universita Vita-Salute. Ospedale S. Raffaele, Milan, 15Department of Urology, SantaChiara Hospital, Trento, 19Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy, 2Formerly Department of Biostatistics, EORTC Headquarters, Brussels, 3Oncologic and Reconstructive Urology, Department of Urology, University Hospitals Leuven, Leuven, Belgium, 5Department of Surgical Science, John Radcliffe Hospital, University of Oxford, Oxford, UK, 7Department of Urology, Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, 8Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 10Department of Urology, Motol Hospital, University of Praha, Praha, Czech Republic, 11Department of Urology, Academic Hospital, Uppsala University, Uppsala, Sweden, 12Department of Urology, Centre Hospitalier Universitaire La Miletrie, University of Poitiers, Poitiers, France, 13Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, 22Department of Urology, Fundacio Puigvert, University of Barcelona, Barcelona, Spain, 14Department of Urology, Rabin Medical Centre, Tel Aviv, Israel, 16Department of Urology, Weill Medical College of Cornell University in New York City, 20Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, 21Department of Urology, Mayo Clinic, Rochester, MN, USA, 17Facharzt fur Urologie, Abteilung fur Urologie. Chirurgische Universitats klinik, Freiburg, Germany, and 18Department of Urology, Sismanoglio Hospital, University of Athens, Athens, Greece

 

Read the full article

Objectives

To determine if a re-transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1-high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS).

Patients and methods

In a large retrospective multicentre cohort of 2451 patients with T1-HG/G3 initially treated with bacille Calmette–Guérin, 935 (38%) had a re-TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in four groups: group 1 (no muscle, no re-TUR), group 2 (no muscle, re-TUR), group 3 (muscle, no re-TUR) and group 4 (muscle, re-TUR). Clinical outcomes were compared across the four groups.

JUlAOTW4Results

Results

Re-TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary TUR specimen. Adjusting for the most important prognostic factors, re-TUR in the absence of muscle had a borderline significant effect on time to recurrence [hazard ratio (HR) 0.67, P = 0.08], progression (HR 0.46, P = 0.06), CSS (HR 0.31, P = 0.07) and OS (HR 0.48, P = 0.05). Re-TUR in the presence of muscle in the primary TUR specimen did not improve the outcome for any of the endpoints.

Conclusions

Our retrospective analysis suggests that re-TUR may not be necessary in patients with T1-HG/G3, if muscle is present in the specimen of the primary TUR.

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