USANZ 2017 Conference Summary Part 1

Joseph Ischia: Hello, I’m Joseph Ischia and I’m talking urology. We’ve put together the conference highlights from the recent USANZ 2017 70th annual scientific meeting from the National Convention Center in Canberra. It was a wonderful program put together by the conveners Nathan Lawrentschuk and Shomik Sengupta. I managed to catch up with some of the keynote speakers and I asked them to take us through the key two to three points from their talks. In some cases, I was able to catch up with a local expert to give us an Australian or New Zealand perspective. The speakers were very generous with their time. In the interest of keeping the podcast short and snappy. I sometimes had to edit the interview. If you would like to hear the full version, please go to the website talkingurology.com.au. The meeting was run in conjunction with the 22nd Annual ANSUNZ meeting for urology nurses. The program was a great success with congratulations going to the conveners Kath Schubach and Carla D’Amico, so let’s put our international speakers to work.

The program kicked off with a bang with Laurie Klotz talking about his 20-year experience with active surveillance for prostate cancer. Let’s hear from Laurie about some of his take home points.

Dr Laurence Klotz: Well, I really made four points. One is that the approach to active surveillance has changed pretty substantially since we started this close to 20 years ago. We now have a much better idea of who are the bad actors, why some patients are failing. We took an inclusive approach initially including Gleason 6 and selected patients with higher-grade cancer, and we now have the benefit of long-term follow up on these patients. And our analysis has showed that while the PSA at baseline isn’t very predictive, the presence of any Gleason 4 pattern at diagnosis conferred almost four times greater risk of progression of metastatic disease over 15 years. So, we have stepped back a bit. We’re more cautious with the Gleason 7s, we do offer it to selected patients where there’s only a very small amount less than 5% or 10% Gleason 4 because a lot of those are artifactually upgraded. But, in a younger man with Gleason 3+4 nowadays, we really discourage him from having surveillance unless he falls in that very borderline category, which would also mean negative MRI. The next point is that interestingly, The Hopkins Group, which took a restrictive approach had the benefit of fewer progression to metastatic disease, has liberalized their approach. So, there’s kind of been a convergence from very inclusive on our part and very restrictive on theirs. Now, I think most people, including myself, believe that almost all patients with Gleason 6 should be managed conservatively, recognizing that there’s some borderline cases who are at risk for harboring higher grade cancer particularly in younger men in whom treatment may be warranted.

Joseph Ischia: How about the high-volume Gleason 6 in a young man?

Dr Laurence Klotz: So, again, the significance of high volume is not they need to be treated because the evidence is very clear that Gleason 6 is a non-metastasizing cancer. The problem with higher volume is there is an increased risk for harboring higher-grade cancer so you got to scrutinize them more carefully. They should clearly have an MRI. If it shows a target, they should have a targeted biopsy. In my view, if that doesn’t show higher-grade cancer, there may also be a role for one of the genetic biomarker tests in that group. But, if everything pans out, all they have is Gleason 6, nothing unusual; we manage those patients conservatively even if they are younger. Again, we have a deep conviction based on huge studies that you do not have to worry about metastatic disease with Gleason 6 cancer. The final point I can make is that a lot of the time these low-risk patients are middle aged guys who haven’t had a lot of medical attention, and as the urologist, you maybe actually their main access to the medical system. So, I think there’s a role for the urologist to act as the primary care physician with these guys, you know, get them to stop smoking, lose weight, be physically active. There’s probably a role for some interventions with statins perhaps with other micronutrients to try and reduce the risk of progression in this pace. I’m very pro-statin in the surveillance cohort.

Joseph: So, while Laurie is adding Simvastatin to the Canadian water supply, I managed to catch up with Maria Ribal. She is a urologist from Barcelona and a member of the panel that puts together the guidelines for muscle-invasive bladder cancer. Her talk covered the EAU guidelines and where we need to do better in muscle-invasive disease. Let’s hear from Maria about her highlights and who she would recommend be offered neoadjuvant chemotherapy.

Maria Ribal: I would say the first highlight I will stress about bladder cancer is that we have not changed mortality in the last three years. So, it’s time to do the things in a different way. So, I would say the first is that we need to treat perhaps patients earlier; we need to identify the non-muscle-invasive disease at high risk of progression, and probably offer radical therapy in this moment of the disease. And once we have the muscle-invasive disease already established, there are some key points that we should keep in mind. First, is that it’s hard to believe that we can treat it only with surgery. Probably the most rational possibility is to treat it in a multimodality form using chemotherapy and surgery. So, neoadjuvant chemotherapy has demonstrated an impact in overall survival, so it’s an advantage and we need to use it.

Joseph: On that point, we have lots of MDTs in Australia where if they’ve got an obstructed kidney, they often resolve need to go straight to surgery. What’s your thoughts on that Maria?

Maria: Yes, this is a tricky, tricky situation. It’s true that it’s hard to believe that you can do in a safety way neoadjuvant chemotherapy with an obstructive kidney, but if the patient is fit for chemotherapy you can use a nephrostomy. You can take care of your encounter treating antibiotics, and then it’s safe to perform neoadjuvant chemotherapy in these patients.

Joseph: So, I asked Maria, what patients should be offered a neobladder.

Maria: Those patients that are fit for being submitted to neobladder, that they are young enough, that they are fair enough, should be offered neobladder. One thing that we should avoid is not offering neobladder because we don’t know how to do it. So, if a patient deserves a neobladder, we should refer the patient to that one hospital that is able to do it. So, I think that this is a key message in this sense.

Joseph: And who would she recommend be offered adjuvant chemotherapy.

Maria: It has been demonstrated recently that those patients that take most advantage of using adjuvant chemotherapy are those with locally advanced disease and zero disease. So, if we have not used neoadjuvant chemotherapy, we can use adjuvant chemotherapy.

Joseph: And are you excited by these new checkpoint inhibitors that are coming for bladder cancer?

Maria: I would say the word is exactly excited because I think that this is the first change in therapy in bladder cancer in the last 15 years. So, we have been on chemo and those ends our MVAC, cis-gem, and this is the first change we have already in muscle-invasive bladder cancer. So, now we know that patients that are progressing, chemotherapy could be treated with PD-L1 inhibitors, but probably we will move this therapy to the adjuvant setting, for example, we can see them in the neoadjuvant setting as well and perhaps we will see them in the non-muscle-invasive disease at high risk of progression. So, I think there’s a lot of opportunities for this therapy in the future.

Joseph: So, please listen to the full version to hear Maria’s views on radiation for bladder cancer and why we need to invest more funds and time into research. For a local perspective, I managed to call on Shomik Sengupta who had these thoughts.

Dr. Shomik Sengupta: Well, it was interesting to hear that what they’re experiencing in Europe is fairly similar to our experience here in that outcomes from bladder cancer haven’t really improved over time. She was talking about muscle invasive disease where surgery forms a mainstay of treatment. But the tips and tricks that she gave us are things that we’re aware of and we just need to do better. We need to select our patients well, we need to give them systemic therapy because multi-modal treatment improves outcome, and chemotherapy is probably best delivered in the neoadjuvant setting and they are recommending enrolling every patient for neoadjuvant treatment and I think there is some sense to that.

Joseph: Even in the obstructed kidney?

Shomik: Well, you want unobstructed. I mean sometimes that’s a nephrostomy, sometimes that’s a stent placement. I think that is a different group of patients but perhaps they are the ones that might potentially benefit the most. And then you’ve got to do the surgery based on the surgical technical points out to make sure that the clearance is adequate, avoid positive margins, take lymph nodes. So, those were all the important messages. On the other hand, you’re trying to balance the quality of life effects so trying to do a competent reconstruction were possible, trying to do nerve sparing or vaginal sparing surgery to enable sexual function. So, I think there are lots of things that we can work on to incrementally improve bladder cancer outcomes and Maria’s talks given us some pointers to try and do that.

Joseph: Thank you Shomik. Next, I managed to catch up with Stephen Boorjian from The Mayo Clinic in the US. Stephen gave a great talk on the role of lymph node dissection at the time of radical prostatectomy for high-risk prostate cancer. Let’s hear his key points on the why, when and how far.

Dr. Stephen Boorjian: Thanks very much. It’s been an honor to be here. The topic of lymph nodes and prostate cancer remains quite controversial. The, I think, most important take home points that I want to leave people with about the issue of lymph nodes and prostate cancer are who to do a lymph node dissection on, how many lymph nodes we should be taking at the time of dissection, and what’s the benefit of taking out the lymph nodes. In terms of who to do a lymph node dissection on, I think that decision has to be risk stratified. There are a number of different ways of doing that stratification. A very straightforward one is the EAU intermediate-and high-risk patient population. I think if we want to go one more level of sophistication there’s a Briganti nomogram, It’s in European Urology that can be used to assess patient’s risk of lymph node metastasis. I think once the decision is made to do a lymph node dissection though I think critically importantly is that it’s an extended pelvic lymph node dissection. A good take home message is that there is limited value to a limited pelvic lymph node dissection for patients and in terms of what’s the benefit of a lymph node dissection, lymph node dissection to identify the presence of positive lymph nodes is helpful for risk stratification, it’s helpful for patient counselling, it’s helpful to identify candidates for adjuvant therapy such as hormones or radiation therapy, and there may in fact be an oncologic benefit to the complete surgical resection even of lymph node metastatic prostate cancer.

Joseph: Do you have a number on that Briganti nomogram where you draw the line?

Stephen: So, the authors of that paper used a 5% threshold for the presence of lymph node metastatic disease and they found that if you use that threshold, you would reduce the number of lymph node dissections by almost two-thirds and you’d miss only 1.5% or so of positive nodes.

Joseph: And I know in your talk you did talk about the long-term biochemical recurrence free survival after removing a positive lymph node, what was that number?

Stephen: So, in patients who’ve received no further therapies up to a quarter of patients with a positive lymph node may be continually free of disease long term.

Joseph: Well, Steven’s talks certainly generated some heated discussion during question time. So, let’s hear from Morgan Pokorny from Brisbane who has a special interest in imaging techniques for prostate cancer and what does he think of the role of lymph node dissection.

Dr Morgan Pokorny: In summary, I think the jury’s out around the world on whether there’s any oncological or curative benefit to lymph node dissection. But he did make the point that in their units and in their experience, it provides important prognostic information and guides adjuvant therapy in the early setting. So, we’ve thought about this here in Australia and locally in Brisbane and we’ve analyzed a few figures over the last year and it’s quite interesting. If you look at Medicare data, more than 50% of men in Australia who are having a prostate removed, have lymph node dissection at the same time and I think the figures roughly 55% and when we’ve gone back and looked at our own histology in Brisbane of all the lymph node dissections done through our units about 4% were positive. So, it means that over 90% of men are having a procedure that does them no good and potentially does harm. Of course, as your oncologist, we’re always concerned about under staging patients or perhaps not having provided the full chance of cure. So, this makes the discussion quite difficult and that’s what Stephen covered yesterday.

Joseph: Morgan went on to discuss the Brisbane experience regarding the lymph node false negative rate of 22% for PSMA scanning in preoperative staging and he highlights what this means for Australian men and the pelvic lymph node dissection.

Morgan: So, what this means is that if you operate on men with a negative scan and don’t do a lymph node dissection you miss 20% of those men you actually had positive lymph nodes and then John Yaxley has gone and looked at some other data and found that if patients have just one positive lymph node the chance of long-term cure is about 10%. So, if you take those two figures together, roughly 2% of men with a negative PSMA scan might benefit from a pelvic lymph node dissection. So, that’s our spin on the whole situation and I think we’re very fortunate in Australia we’ve been early adopters of PSMA and high-resolution MRI. So, I think that’s helped us finesse our approach a bit more.

Joseph: So, Morgan, is there anything on the horizon that might be better than PSMA?

Morgan: Well, Stephen alluded in his talk to lymphotropic nanoparticle MRI which was pioneered by Jelle Barentsz and colleagues and published in Nijmegen in 2003 with fantastic sensitivities and specificities of 93% to 96%. Their technology unfortunately disappeared from the market for over 10 years but Jelle has recently bought the license and the manufacturing rights and we’re very privileged to be able to be starting a trial later this year in conjunction with Jelle’s team in Holland and Phil Stricker’s team in Sydney to do a multi-center prospective trial looking at PSMA and Combidex or nanoparticle MRI staging for men prior to prostate surgery with planned pelvic lymph node dissection.

Joseph: And isn’t that just the same old story in medicine just when we get used to the accuracy, the benefits and the limitations of any one imaging modality, they invent something better. Next I caught up with John Davis from the MD Anderson Cancer Center in Texas. John gave the BJUI lecture on the topic of prostate cancer genetics. Let’s hear from John.

Dr John Davis: For many years we’ve talked about getting more genetic testing into prostate cancer to try to risk stratify patients and there are two basic decision points where that might be helpful. One of course is a patient who might be a candidate for active surveillance versus intervention. And even the folks who go through surgery, you might then want to risk stratify who should be observed versus do postoperative radiation. I learned along this journey, you know, some terminology that’s helpful. There are commercially available biomarkers in the U.S., some in Europe, and they’re mostly what we call prognostic markers meaning they can help risk refine the odds of an event happening. Now, my colleagues in medical oncology look at this differently and they mainly emphasize predictive markers where a biomarker’s efficacy is linked to the drug working or not working. But in prostate cancer, we can still get some information out of prognostic markers; one for example is Prolaris that looks at cell cycle progression genes. If they’re extremely aggressive looking or extremely non-aggressive looking, that may help break the tie between surveillance radiation.

Another one called oncotype looks at the risk of having unfavorable prostatectomy, you know, high grade T3 stage. So, I sometimes use that in young patients where you know any degree of unfavorable pathology you know in a 50 year old would be not a good candidate for surveillance for example.

In the postop setting what is interesting is there is a third marker called Decipher that really hones in on the risk of metastatic progression and they’ve also been able to retrospectively link that to postoperative radiation. So, in simple terms if they’ve got a favorable Decipher profile, you probably put them on observation even if they have a positive margin or T3 stage. But if they have an aggressive Decipher, that’s about 20% of the high-risk population, then they clearly have a better durable response to radiation if it was given adjuvants. And for us, that’s a valuable question because as a default most of our patients don’t want adjuvant radiation unless you can give them a really strong argument that they need it, so this can help us with that.

Joseph: These tests sound really useful, but they don’t seem to have really taken off, why is that?

John: Now in the biopsy world, it’s understandable because if you’ve got high-quality MRI and fusion-related biopsies you may prefer to use that to differentiate who needs surveillance versus treatment. In the U.S., high quality MRI is not universally available. It’s really in high-volume centers whereas if they run a genetic profile it’s the same profile regardless of where it comes from because these go to referee labs. Again, clinical utility is a bit of an eye of the beholder. If you have a patient whose mind is made up, maybe you don’t need any more information. But I’m sure we all experience patients who are indecisive and they want as much information as they can get their hands on.

Joseph: So there you have it those $400 dollar MRI as we’ve been complaining about have been saving us from the $4000 dollar prostate genetic tests. Next, we’ll hear from Laurence Levine from Rush University in Chicago. In his 10-minute, talk he covered everything you need to know about the treatment options for Peyronie’s disease. Here are the highlights.

Dr. Laurence Levine: Well Joe, there are a variety of treatments that have been used historically for Peyronie’s disease but at this time, I don’t think we have any reliable non-surgical treatment. Having said that though, I think there’s some things we can offer patients with hopes that if they are in the acute phase that we can prevent progression because up to 50% of patients in the first year will get worse if we do nothing at all. So, what oral therapy makes sense? There really aren’t any that clearly work but the sensible ones based upon some basic science are Pentoxifylline 400 mg t.i.d., L-Arginine 1000 mg b.i.d., and maybe the PDE5 inhibitors being taken daily might enhance not only the fibrosis but may have a benefit in terms of vascular supply. That’s it as far as oral therapy.

There is injection therapy and there are several that are now being used worldwide. The only one which is approved by the FDA in the U.S. and I think approved here is Xiaflex or Xiapex as you call it.

Joseph: We do call it Xiaflex here.

Laurence: This makes great scientific sense because they’re using an enzyme to break down the scar tissue. But I think we’re going to need more evidence to show whether this is really the most effective approach and maybe even more importantly patient selection, who are the best patients for it. In my mind, men who have rather severe curve are probably not going to get enough benefit but they may get enough so that we can do a simpler operation. It’s costly and there is risk in terms of certainly hematoma and even a risk of tissue disruption, corporal rupture.

Finally, there is traction therapy I’m a big advocate of traction. We know that if we put braces on the teeth of a child those teeth are going to move with the chronic forces being applied to the teeth. So, similarly if we can get enough time to apply a device to the surface of the penis, we’re going to alter, I think, that tissue and potentially see benefit in terms of reduced curvature, length restoration, and maybe even girth enhancement as well.
Finally, I think the stable patient with Peyronie’s disease, with the disease not progressing any further, are surgical candidates. Surgery remains the gold standard for me and a lot of that again depends upon patient selection. Men with good-quality erections and mild to moderate curvature, less than 60 degrees, I think we can correct them with plication operations. On the other hand, if they have more severe deformity but have excellent quality erections, we can do various grafting procedures with I think a high degree of success. Finally, for those men who don’t have good erections and don’t respond to PDE5 inhibitors, then I think we need to consider placement of a penile prostheses. That can be combined with straightening maneuvers, of course, to get them both straight and functionally erect in the postoperative period.

Joseph: So, watch out for penises with braces, probably nothing they haven’t seen here in Canberra. Another hangover from when Canberra was the porn capital of Australia. Moving on, another highlight was hearing from Curtis Nickel, a specialist in chronic pain from Ontario Canada. He gave a very entertaining talk where he outlined how he was going to win a Nobel prize for finding the smoking gun that was the organism causing chronic pelvic pain. Unfortunately, he admitted that he has not found that single organism, but I am happy for my patients to go over the Canada and see him anyway. And he shattered another one of my medical school axioms and that is that the urine is sterile, so let’s have a listen to Curtis as he tells us about the urinary microbiome.

Dr. Curtis Nickel: Well, we make our clinical decisions in infectious disease in Urology based on technology that’s over 100 years old. We’re still taking urine samples, plating in an agar, and putting it in 24 hours in an incubator and then making a decision. We now know that we grow less than 1% of potential uropathogens by this technique. We don’t culture biofilm bacteria and we miss 99.9% of possible microorganisms that are in the environment that might be related to infectious disease. So, for years, my search for the putative organism, the smoking gun, of interstitial cystitis and chronic prostatitis was using this outdated technology and wasn’t able to find the organism. Now, with very high-tech, non-culture techniques, we can identify microorganisms. The one I used is an IBIS technique that works on the mass spec of molecular weight of the nucleus, which is unique for every microorganism. We are able to identify 98% of the microbiome in the urinary system, in the vagina and in the bowel, and what we found is what we learned in medical school that the urinary system, the bladder, the kidneys, were a sterile organ is not true. In fact, the bladder particularly the prostate are veritable microbial jungles. We’ve identified over 60 species in the bladder and 90 species in the prostate a bacteria that are present there in normal asymptomatic patients. We’re right now looking at the microbiome of the vagina, the bowel, and how it interrelates, and we’re learning that this very important microbiome that we all have communicates with the rest of our body through the neuroendocrine system. So, that bacteria in the bowel can affect what’s going on in the bladder. This is groundbreaking, and we come to the realization that we as a human have more microorganisms in our body than we do mammalian eukaryotic cells. We have more species of microorganisms than we have different eukaryotic cells. So, in fact, we’re nothing but a carrier for our microbiome which affects everything – our mood; our general health; our bowel function; and yes our bladder function; and pelvic, bladder, prostate pain.

Joseph: Are there any major differences between normal controls and those with interstitial cystitis or painful bladder syndrome in people that you found so far?

Curtis: So, that was our hypothesis. It was to find the microorganism that caused these diseases. So, we’ve just completed a four-year program, very expensive, on more than a thousand patients and age-matched controls, and what we did is we did find differences in the prevalence of certain bacteria and fungi between patients and controls; however, it wasn’t the smoking gun. These did not look like a putative organism that actually caused the mechanism. So, what we believe is it’s more a dysbiosis or a change in the microbial ecology or diversity that’s happening. That it may in fact not be one bacteria, but it’s the relationship or the diversity of the microbiome you have in your bladder and prostate compared to somebody who does not have symptoms. That’s where we’re going in the future.

Joseph: So, Curtis, if I get this right, in the future, we have to worry about the relationship between the bacteria in our bowel and our bladder? How do we resolve this conflict if we don’t want them to communicate?

Remember, you can hear the full versions of their talks at talkingurology.com.au and please tune in to podcast two where we will hear from Kevin McVary, Chris Chapple and James Eastham as well as more from our local experts.