Episode 8 – Dr Hendrik Van Poppel

I’m Joseph Ischia

And I’m Nathan Lawrentschuk.

And we’re Talking Urology where we go to the source and chat to the world opinion leaders about their landmark papers. Our goal is to empower doctors to develop a deeper understanding of the literature to ensure we apply the right evidence to the right patient.

We are all about “bringing the literature to life”.

Joseph:  Today we are talking about the landmark partial vs radical nephrectomy paper by Hein Van Poppel but we still have some great podcasts coming up:

• Montorsi’s landmark penile rehab paper following radical prostatectomy with tadalafil
• Neil Fleshner discussing his REDEEM study on dutasteride in men on AS for prostate cancer.
• Stephen Boorjian monitoring the SRM
• Maurizio Brausi on his paper of short term vs. long term maintenance BCG for NMIBC

Nathan:

• A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma’
• European Urology in 2011.

And now introducing Dr Hendrik Van Poppel

Hendrik: I am Dr Hendrik Van Poppel, I am a urological surgeon. I am confined actually to do oncological urology- so bladder, kidney, prostate and testicular cancer. I started doing my first partial nephrectomy around 1980 and I had my first paper published in the BGU at that time and in 1985 – 1986.

Joseph:

• Why was study done?
• PN provided equal cancer control with improved renal function
• Safe with a slightly higher complication rate
• Retrospective data about the improved survival (decreased CVS risk)
• But there were no prospective trials

Hendrik: The idea of designing the trial was actually, I was doing partial nephrectomies as I said in the very early stages, even on tumours of 12cm in my first publication; and I wanted to show that at least it was as good as a radical nephrectomy when it comes to the oncological outcome.

Nathan:

• Aim- to assess both morbidity and cancer control RN vs PN
• Primary endpoint- OS
• Secondary end points
  • Disease-specific survival (DSS),
  • Progression
  • Surgical side-effects
• Study was originally designed as a non-inferiority European multicenter study
  • Initially intended 310 patients
  • Trying to rule out a difference of 10% in 5-yr survival from 90% for RN to 80% for PN.
• Eligibility criteria
  • Solitary renal lesion ≤5 cm suspicious for RCC
  • Normal contralateral kidney
  • WHO PS of 0–2.

Joseph:

• Accrual began in 1992, and 300 patients were entered in 5.5 yr.
• Going ok but realized that 10% difference in survival was not realistic.
• In 1998- redesign: 3% in 5-yr survival from 90% on RN to 87% on PN (hazard ratio [HR]: 1.3)
• But now you need more patients! Now- 1300 patients and 368 deaths were now required

Nathan:

• Also, there was a shift going on out there- PN was becoming the new normal and accrual was dropping

Hendrik: That was one of the major problems. I was the most accruing centre, and while the enthusiasm of randomising patients was very high in the beginning everybody started doing partial nephrectomy because in the other literature it was said that the partial was probably better when it comes to kidney function to cardiovascular disease and so on. And everybody believed it and did not want their patients to be randomised for a radical because we were convinced that it was worse. So I continued to randomise the patients for the sake of the study, but many of the other centres stopped. Because it went so slowly in Europe, we went across the ocean and we asked our colleagues from SWOG and we asked people from University of Southern California we even asked the Canadians with Laurie Klotz to join, but this had an implication that instead of having a non inferiority study where we needed 350 patients, we wanted to have an equal results study on partial versus radical, and we needed 1300 patients to be randomised. It took about 11/2 years before we got this off the ground and finally when they should start randomising it faded out and essentially the EORTC closed the study prematurely.

Nathan:

• So it was opened to North Americans- SWOG and ECOG, American College of Surgeons Oncology Group, National Cancer Institute of Canada [NCIC])
• But- January 2003, the study was prematurely closed – poor accrual.
• In total, 541 patients were randomized
  • (EORTC: 527 patients; NCIC: 11 patients; USA (ECOG/SWOG): 3 patients).

Joseph: So American centres doing over 100 partial nephrectomies were not submitting patients to the trial and it all comes down to what Hein said- surgeons were just not prepared to submit patients with small renal tumours that might be randomized to RN.

Hendrik: Many centres, major ones such as Germany for example; were doing partial nephrectomies for years and then we needed to convince them that they needed to randomise the patients in the trial to finally show and evidence based basis that partial and radical were equal but they continued to do the partials and not randomising the patients.

Joseph:

• The primary analysis was based on intention-to-treat (ITT) principle- important- crossover between groups – discuss in a minute

• Tests for both non-inferiority and superiority were carried out.

Nathan:

• 541 patients from 45 institutions (17 countries) were randomized- around 270 in each arm.
• Exclusions
  • 4 patients- multifocality or other cancers
  • 136 patients- were pathologically ineligible
    • No renal adenocarcinoma
    • Tumour pT3+
    • Tumour >5 cm,
    • Positive surgical margins (3)

Joseph:

• Of the patients randomised to RN, 6% underwent NSS (in general as a result of the patient’s decision).
• Of the patients randomised to NSS, 15% underwent RN (in general as a result of pathologic disease characteristics).
• This is one of the problems with non-blinded studies- patients or surgeons will choose their treatment.
• Also, this unequal crossover has been one of the criticisms of the paper.
• We asked Hein if he was disappointed or concerned about the crossover:

Hendrik: No. This can be expected in a trial like this where you have patients in major centres. I remember that one surgeon randomised a patient for a radical and then another surgeon took the patient on and he saw a small tumour and then said I’m not going to do a radical for that tumour and he did a partial. Although, he had informed consent from the patient to have a radical. Sometimes also the partial seemed to be too difficult for the guy who was doing the case and he intraoperatively decided to do a radical nephrectomy. But I think there was no other major reasons why there was this high percentage of cross over.

Nathan:

• Another critique has been that there was a significantly higher rate of other chronic diseases in the nephron sparing group compared to the radical nephrectomy group being 13% versus 8%
• It was close to significance but didn’t achieve it
• We asked Hein if he thought that that this affected overall survival in favour of radical nephrectomy?

Hendrik: I do not believe that this really impacts on it. I don’t think that this is important. The difference is not statistically significant and I do not believe that it’s impacted in favour of radical nephrectomy.

Joseph:

• All performed by open operation
• Pleural damage rate of almost 10%- you rarely see this laparoscopically.
• There was a higher complication rate with NSS
  • Double the perioperative bleeding 30% c/w 15%
  • Urinary leak rate of 4% in NSS, 0 in RN.
• I asked Hein if he thought there would be any differences in the modern laparoscopic era:

Hendrik: I don’t think so.

Nathan:

• Lets get to the crux of the paper- the results
• Median follow-up 9.3 years
• Serum creatinine better in NSS arm 1.3 mg/dl c/w 1.5 in RN-wide ranges- not statistically different
• Of 541 patients- 117 deaths
  •  67 in the NSS group
  • 50 in the RN group.
• Only 12 (i.e. 2.2%) died of renal cancer- 8 in NSS, 4 in RN- small numbers-not significant.
• Cardiovascular disease- the leading cause of death (almost 40%)- i.e. it is significant cause of death to consider
  • 25 CV deaths in the NSS group
  • 20 in the RN group

Joseph:

• NB When you look back and remember that this was powered assuming a 90% 5 year survival in the RN group that is about right.
• The ITT analysis showed 10-yr OS rates:
  • 76% for NSS
  • 81% for RN.
  • With an estimated HR of 1.50
  • The statistical test for non-inferiority of OS is not significant ( p = 0.77),
  • While the unplanned test for superiority is significant (p=0.03
• But- just look at patients who had confirmed RCC on final pathology, after excluding clinically and pathologically eligible patients: i.e.
  • • No renal adenocarcinoma
    • pT3+
    • Tumour >5 cm,
    • Multifocality
    • Positive surgical margins
    • Then the test for superiority is no longer statistically significant (p = 0.07 and p = 0.17, respectively).
• Regarding the secondary end point, progression- small numbers
  •  12 patients in the NSS group
  • 9 patients in the RN group
  • Not statistically significant
• So knowing all this- what does Hein think is the role of partial nephrectomy:

Hendrik: The conclusion from all the open studies, the respective studies and also the prospective ones that have been showing the so called advantage of the partial over the radical, has only to do via selection of the patients that were brought to partial nephrectomy. There’s a very nice study and meta analysis done by Capitano where you look at the difference of the two curves of the partial and the radical nephrectomy patients. If you would believe that, partial is indeed better than radical, you should see this effect over time getting bigger and bigger. But if you look at the curves, at the start; they both drop immediately and then they go apart and then in the end, it’s like a banana they come together again. So, I believe that simply the patients in all the open studies were subjected to partial nephrectomy were better patients. And because they were better they had a better survival, and then you look for what reason – cardiovascular or whatever disease, so they live longer than the radical nephrectomy in the open series. But then the only randomised study, this does not show. Importantly, all the patients in the EORTC trial had normal contralateral kidney. So, probably we do not need to do this complex and sometimes morbid, difficult, oncologically unsafe partial nephrectomy for the T1b tumours when the contralateral kidney is normal because it has been shown that kidney function has a small drop but then recovers, and they remain stable. In the secondary analyses of the trial by Scosyrev, Messing, Richardson, Lester and myself you see that there is no deleterious effect over time. It exactly remains the same in the partial and in the radical nephrectomy. So, I do not believe that radical is worse and I continue to believe in the randomised trial and not in the others.

Nathan: So did the trial change Hein’s approach to surgery for the SRM?

Hendrik: I’ve done so many partial nephrectomies and I love to do the surgery, I love to do difficult partial nephrectomy even when it is not needed in the presence of normal contralateral kidney I still do partial nephrectomy. Why is that? Because in reference centre we are, you’ll get cases referred with solitary kidney with tumours and you can gain experience. I’ve gained enormous experience by doing maybe superfluous, not really necessary partial nephrectomies in very difficult situations. And now I feel happy to do partial nephrectomy on tumours of 15cm and then reconstruct the kidneys. So that’s probably the only advantage for the surgeon – doing this in elective cases is that he is going to get a quota and is going to get the experience to do this when it’s really needed in the imperative cases.

Nathan:

• Maybe that explains it- in retrospective studies- more likely to do RN in less healthy and older patients- more likely to have CVS disease rather than NSS preventing CVS disease
• NB- present study was not designed to test the hypothesis of reduced CV events with NSS.

Joseph:

• Limitations
  • Underpowered- failed to accrue- selection bias
  • Significant crossover
  • Maybe some issue with differences in morbidities between groups
  • Not powered to detect difference in CKD, CVS events
  • Central pathology in only 49% of patients
  • Serum creatinine rather than eGFR for assessment of renal impairment
  • These study- patients from 1990. Is it still applicable in modern cohort of patients with stage migration from increased incidental detection with modern imaging?

Nathan: We asked Hein- if he did the trial again what would he do differently?

Hendrik: Firstly, I would go to the T1b and the T1a tumours and not to the 5cm cut off. Secondly, I would not include only patients with normal contralateral kidneys. Nephron sparing surgery is important in CKD2 and CKD3 patients, in CKD4 it doesn’t matter. Even if you operate on a bad kidney, you take the kidney out or you do a partial; they do not so much worse they do badly already. It’s the 2 and 3, that’s the category where you need to do partial nephrectomies and not taking the kidney out.  So we would probably stratify must stronger and say, this is a group of patients with normal kidney function, these are patients with CKD – CKD1, CKD2; and those then should be the ones for partial or for radical.

Joseph: Do you think we need another trial as you suggested to answer this question or do we have enough information?

Hendrik: I am fed up with trials. I have done 3 major trials in my life. The first trial was comparing high-risk renal cell cancer patients with no post-operative treatment or adjuvant treatment with interleukins, interferons and five FU. It turned out to be a negative trial. The second trial was the Bolart trial. After radical prostatectomy and high-risk positive surgical margins T3a and b, to give immediate post operative radiotherapy or not give it. There is a biochemical progression free survival benefit. There is no overall survival benefit, so it’s actually a negative trial. And now we know today that early salvage is probably as good as immediate adjuvant. And to show that partial nephrectomy is as good as radical nephrectomy, everybody does it. The only evidence that says that actually it’s not needed, but everybody does it so it didn’t help. And another randomised trial is not going to change that. We are not going to do randomised trials for radiofrequency ablation; we do not do randomised trials for robot surgery. This is not the way in which surgery makes progress. Surgery makes progress because there’s experts that do a different thing in a different way that everybody accepts is good to do.

Nathan: So what is Hein’s take home message?

Hendrik: In the beginning I could not believe it because I designed the trial to show that partial was at least as good as probably better than radical which I couldn’t. In the beginning I didn’t believe it and I presented the trial the first time to the Academic Association of? Surgeons, and in the end I got the question – so what do you do now? I said, I continue to do partials. That’s very strange because the evidence points towards another politic. I will continue to say that all the advantages shown by open studies is a selection of patients. If you have normal contralateral kidneys and you have an easy tumour on the left side, why would we as urologists take the kidney out? You do a proper partial nephrectomy – no

complications, not too much pain, no open surgery. And the patient will do well. If you have a complicated tumour, that’s different. If it’s a complex tumour invasion of the pelvic calyceal system, maybe invasion of segmental veins; sometimes you can do it. Because in imperative cases you do the same.  But I think they are the normal urologists who is not doing high volumes of partial nephrectomies. He should just do a simple laparoscopic radical nephrectomy, which is not morbid at all, and the patient will not suffer chronic kidney disease. Unless at the beginning he was CKD2 or 3. So with a normal contralateral kidney, my advice would be – do the safe thing. Take the kidney out.

Joseph:

• There you have it. When you are sitting in your next MDM looking at a SRM in a kidney, quote the guidelines- do a partial.
• And if its too hard, and they have normal renal function and a normal contralateral kidney, quote the literature- do a radical. Simple.

Nathan:

• Thanks for listening
• Thank you to Hein Van Poppel for his comments
• And any feedback to talkingurology@gmail.com

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