Dr Yaxley is a past Chairman of the Northern Section of the Urological Society of Australia and New Zealand.
In the area of prostate cancer, Dr Yaxley has performed over 2600 radical prostatectomy surgery procedures, including more than 700 operations with robotic surgery. He is the lead author of the world’s first randomised trial comparing robotically-assisted laparoscopic radical prostatectomy to the traditional open surgical technique.
TALKING UROLOGY podcast transcript
Talking Urology Landmark Paper – Series 2, Episode 1
I’m Joseph Ischia
I’m Nathan Lawrentschuk.
Joseph: And we’re Talking Urology where we discuss the landmark urological papers and chat to the authors to get some insights into their fantastic studies. This podcast is made possible by an educational grant from Ipsen and we really appreciate their ongoing support. Today, we are talking with John Yaxley, a urologist from Brisbane, who is the lead author on one of the most important papers to come out of Australia in recent years, entitled “Robot assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study”. This was published in The Lancet in July 2016 and, Nathan, it’s hard to recall a recent paper that has generated a more lively discussion.
Nathan: Since the first reported robot assisted laparoscopic prostatectomy by Binder and Kramer in 2001, there has been a rapid adoption of this technology, where the red dots on the global map representing hospitals with robots has spread across the globe like a killer virus outbreak in a B grade disaster movie. And like a B grade disaster movie, there seems to have been little regard for the facts… or the evidence in our case. Almost overnight, the robot has usurped the crown as the “Gold Standard” technique for separating a man from his prostate based on good marketing, excitement, and the love of all things shiny. But do the numbers stack up?
Joseph: I agree, Nathan. It seems more electrons have been wasted discussing the economics of the robot than have ever left the sun, but today we want to look closely at the hard facts of the only successful randomized trial of patient benefits and outcomes and try to ascertain once and for all, is the robot any better? To answer this question, you are going to need two of the greatest minds in prostate cancer management. Unfortunately, they couldn’t make it, so instead you are stuck with Nathan and me. But fortunately, we do have one of the leading lights and lead author, John Yaxley, to help us dig deep in to this paper.
John: It’s my pleasure to be here Joseph. I am John Yaxley and I’m one of the open surgeons. I perform the open surgery in the randomised trial of open vs robotic prostatectomy and I was the lead author in The Lancet paper
Nathan: John, thank you for joining us. This paper was essential. There is a lack of high-quality evidence for robot assisted laparoscopic prostatectomy. Before this study, the published literature comprised non-randomised longitudinal studies of robotically assisted and open prostatectomies alone or collated in meta-analyses. The study aimed to assess clinical and quality of life outcomes in radical retropubic prostatectomy compared with robot-assisted laparoscopic prostatectomy
Joseph: I want to go back to how this trial started because one of the great things about it is that nobody else has ever been able to achieve it. John gives us some insights in to how our sunburnt friends in Queensland were able to succeed where all others had failed.
John: Queensland started late, we didn’t have a robot and in 2009 the question was still asked, “is robotic surgery going to give you better outcomes than open surgery” and the best scientific evidence is a level 1 trial. So we had the opportunity to do a randomised trial because our hospital supported us to buy a robot specifically designed with the idea of doing a randomised trial. That’s why we bought the robot – to do the randomised trial. And so the reason to do the trial was to find the truth, where does a robot and open prostatectomy fit with respect to primary outcomes of continence, erections and a cure, i.e.: in positive margins or later in biochemical failure; and what are the potential benefits of a minimally invasive robotic surgery?
Nathan: That sounds like a reasonable deal and so a study was designed to enroll men aged 35-70 with newly diagnosed clinically localized prostate cancer who had chosen surgery as their primary treatment. They were randomly assigned to receive either robot-assisted laparoscopic prostatectomy or radical retropubic prostatectomy. One surgeon did all the robot cases and one surgeon did all the open cases.
Joseph: Wow, Nathan, let me stop you there and let’s jump right in to one of the biggest talking points in the debates and blogs around this paper: the one surgeon for each arm design and particularly the perceived difference in experience. Let’s get John’s take on it.
John: What you need in a trial if you are comparing technologies is you need competent surgeons that are well trained and get good outcomes. Royal Brisbane didn’t have a robot. To start a multi surgeon trial would have been to introduce bias against robotic surgery because it would have been a robotic training curve trial v’s an experience robotic surgeon and an experience open surgeon. And that brings into the point that we were able to get the most experience open surgeon at Royal Brisbane, which was myself, and compare him to the most experienced robotic surgeon in Queensland. And to make sure the surgeon in the trial who was robotic was experienced, we sent Geoff off to be trained overseas and without disrespecting a laparoscopic fellowship in the United Kingdom following that, Geoff went to do 2 years of training in a robotic centre and he worked with Vic Patel for 2 years. I don’t think you can question when a centre does 8100 radical prostatectomy’s a year so Geoff’s exposed as a fellowship trainee was up to 2000 cases that the actual volume and the number of cases you do under the supervision of one of the world’s best robotic surgeons – to come back from that you’ve got to be a well trained surgeon. And then after that Geoff then does 200 cases before we start the trial and Vic Patel set our centre up, Vic actually came to Brisbane and set the centre up and during the period of the trial Geoff Coglan did more robotic surgery in 3-4 years than any other surgeon in Australia, another 800 on top of the 200 before on top of 2 years of high volume fellowship as well as robotic partial assisted nephrectomies as well robotic pyeloplasties as well as robotic cystectomies. You have a well-trained robotic surgeon compared to a well-trained open surgeon, and that took away the bias against robotic surgery if we had multiple surgeons.
Joseph: OK, so Geoff sounded pretty experienced and can tell the difference between DaVinci’s two great works, the Mona Lisa and the Xi. The primary outcomes were urinary function and sexual function at 6 weeks, 12 weeks and 24 months and immediate oncologic outcome, particularly positive surgical margin rates. Study investigators involved in data analysis were blinded to each patient’s condition. In addition, a blinded central pathologist reviewed the biopsy and radical prostatectomy specimens. It sounds like everyone was blind, just like a traditional Australian Christmas.
Nathan: Secondary endpoints included intraoperative events, postoperative complications, pain scores, bleeding complications, ICU admissions and length of hospital stay. This paper reports the early outcomes of all of these endpoints at 6 weeks and 12 weeks. The study initially aimed to recruit 400 men but the trial was stopped early after 300 men. Let’s hear from John about how the trial was powered and run.
Joseph: One of the criticisms of the paper has been that it was underpowered to detect differences in these key outcomes. John:
John: we had a delta of .05, a confidence interval of 90% with a power to predict a moderate difference effect with a size sample of 400. That was providing we kept 70% of the patients in the trial. So the 75% trial recruitment which is once we had done over 300 patients we had already predetermined to have an independent data committee look at the outcomes, blinded to the type of surgery and then make a decision on whether to continue the trial not 400 or cease the trial early. And after the independent data committee assessment, the trial was ceased.
Joseph: So the trial was stopped due to futility with around 150 men in each arm. With regards to the primary outcomes at 6 weeks and 12 weeks post surgery, there was no significant difference in the Urinary function scores and the Sexual function scores. From an Oncological viewpoint, while there was fewer positive margins on the open group (15 men (ie 10%)), compared with the robot group (23 men (which makes 15%)), analyses showed that these rates did not differ significantly. Well there you go, the robot is no better, I’m done (make noise like getting up to leave or Mic drop).
Nathan: Hang about, Joseph. Let’s look at some of the secondary endpoints where there were definite and important differences in favour of the robot group. The duration of surgery was 30 mins shorter in the robot group compared to the open group. Furthermore, men in the robot arm were less likely to have an intraoperative event, had a third of the blood loss (400ml vs 1300mL), and less likely to get a post-op blood transfusion. There were also benefits in the robot arm for less early postoperative pain at 24 hours and 1-week timepoints, but not at 6 weeks or 12 weeks after surgery. The robot had a reduced length of hospital stay of 1.55 days compared with 3.27 days in the open arm, and the rate of unplanned ICU admission was 0 in the robot arm and two for open.
Joseph: Nathan, it reminds me of the great Monty Python sketch about the Romans: Sure, the robot has meant less operating time, less pain, less blood loss, less hospital stay, and less ICU admissions, but what has the robot done for us?? Google “what have the robots done for us” on YouTube and enjoy a reimagining of the classic sketch.
Nathan: Joseph, how you jest, but don’t forget that these are all short-term issues and in the end, what really matters is cancer control, potency, and continence which were all the same. So is that the death knell for the robot?
John: But if you look at the primary outcomes of other surgical procedures, so; if I was going to have my gallbladder removed the primary outcome of removing it – if your end point is (for gallbladder removal) cholecystectomy is total and safe removal of the gallbladder, well than a laparoscopic procedure and an open procedure are equal and are safe in removal of a gallbladder. But, I won’t have my gallbladder removed in an open case in 2017 because I know of the minimally invasive advantages of laparoscopic surgery. That will be similar in the long term with robot v’s open surgery. At the moment the outcome that patients want, particularly are cure, continence and erections. It’s pick your surgeon at the 3 month mark until we know the data with a 2 year publication
Joseph: Everyone knows that as time passes, urinary and sexual function can continue to improve so the key question is whether or not the data will change after two years of analysis. I asked John if he believes it will?
John: I don’t know. I keep an open mind the reality is that no one knows. And we are blinded to collection of data, we don’t collect the data, we are independent of that. But what the trial has shown with level 1 evidence is – there is less intraoperative bleeding, there’s less risk of perioperative complications due to blood loss, less admission to ICU because of cardiovascular instability, earlier discharge from hospital and less pain for at least 1-week post operatively. So there is positive level 1 outcomes in favour of robotic surgery in the trial.
Joseph: Since we first recorded this with John, the 2 year results paper has come out in Lancet Oncology in July 2018 and for those of you who don’t want to know the ending to the Sixth Sense or this paper, turn off now, because Bruce Willis was dead from the start and there is no difference in urinary or sexual function between the robot and open at 6, 12, or 24 months. Sorry to all the Halley Joel Osmand fans out there.
Nathan: This publication was too soon to pick up on bladder neck contracture rates and they are not reported in the 24-month update. One thing even the most skeptical roboticists have noticed is that their bladder neck contractures have almost completely disappeared.
John – I agree. I don’t know in our trial bladder neck contracture will be a major issue, I know personally as a surgeon who has done a lot of robotic prostatectomies; I can’t think of a bladder neck contracture and so the robotic bladder neck contracture rate is low across the board. As far as bladder neck contracture in my open cohort, it’s not something that’s prevalent and I think that relates to technique and I put 12 sutures in my anastomoses, so I put a suture in every o’clock – so there’s 12 hours in a clock at open. And bladder neck contracture is a technique. If you have urinary leak and you get perianastomotic fibrosis, in my opinion you’ll have an increased instance of getting a bladder neck contracture. In the trial the catheter was removed at the same time – I think 7. something days – and there was no difference in cystogram leak rates. So I think when you’re paying attention to technique and it’s all about attention to technique; you will decrease you bladder neck contracture at open surgery. But, even so there will be in my opinion a higher probability of bladder neck contracture with an open operation than a robot. But I don’t expect to find it to be a major issue in this trial, there is one that I know of early on but again, we will wait too the data to see what the 2 year figures show. And the 2 year figures will be a min 2 years, it will be more than 5 year follow up in some men.
Joseph: 12 sutures!! I don’t know anyone doing that. Maybe we won’t see a difference in bladder neck contracture rate after all.
Nathan: So do we need another trial or a bigger trial to answer the question?
John: From a research point of view, the more trials you get the better. The ultimate trial would be a multi centre, multi surgeon trial providing the surgeons that are included in the study reach a standard of competence. And to me it’s not numbers that make competence its outcomes. So you need to make sure the surgeons in your trial are all competent, but it would be hard to recruit. We were lucky. Once technology is disseminated and once the impression to the surgeons and the community is that – the newer technology is better than the old technology – it will be very hard to recruit. Where as, we had a technology starting for the first time and we did the randomised study at the start of introduction of the technology into our community, and so I suppose the message for future randomised trials is – start your randomised trial early in the introduction of a new technology providing your surgeon is trained in that technology before it’s disseminated that the opinion, which is probably the lowest level scientific evidence is personal opinion. Once personal opinion is that one technology is better, then your randomisation process is harder to achieve.
Joseph: Some sage advice on doing research early. I think we are getting better at doing surgical research and maybe this trial gives us hope that it can be done well. So what is John’s take home message after all of that?
John: I think the take away message from the trial is just the outcomes of the trial. The outcome with respect to our primary objective, which was continence, erectile dysfunction and margin status is equivalent providing you’ve got a well-trained surgeon. So I think the most important thing in the long term is to pick a surgeon that you know is well trained, has got good surgical techniques rather than numbers and someone you trust to have rapport with. In the long term with respect to whether one is better, we just have to wait and keep an open mind until the 2 year data comes out as to whether even in that scenario a well trained surgeon will get better outcomes in the long term, where as it hasn’t been shown in the short term
Nathan: Final question…a cheeky one…does John still do open radical prostatectomies?!
John: No, I’ve converted to robotic surgery because of the fact that I get the same outcomes with my robotic surgery with the advantages of minimally invasive surgery and a throw advantage of my back is a lot less painful at the end of a days operating.
Joseph: Good point on the surgeon comfort aspect, which has been lost in all the noise but unfortunately beyond the scope of this trial. A really excellent paper. We really enjoyed picking John’s brains. We’ve been Talking Urology today with John Yaxley. We still have some great podcasts coming up:
- Montorsi’s landmark penile rehab paper following radical prostatectomy with Tadalafil
- And Nick James talking STAMPEDE.
Nathan: Thanks for listening. We hope you enjoyed the show. You can contact us with questions, corrections, or updates at email@example.com.
Joseph: Written by Joseph Ischia and Mark Quinlan. Produced by Joseph Ischia and Cara Webb with the generous support of Ipsen, purveyors of fine LHRH agonists.