Episode 2 – A/Prof Shahrokh Shariat

I’m Joseph Ischia

I’m Nathan Lawrentschuk

And we’re talking Urology where we discuss the key points of the landmark papers that guide your practice everyday. 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 looking at the landmark paper by Shahrokh Shariat which was published in the Journal of Urology in 2006 titled Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. We were lucky enough to chat to Shahrokh about this paper which of his 714 papers, this is his second most cited.

Shahrokh: I’m Shahrokh Shariat and I’m now currently Professor and Chairman at the University of Vienna. I also hold two other positions in the US of Cornell and UTS in Dallas. Two places where I trained before and I have a good relationship with my friends there and still have labs ongoing and research ongoing.

Joseph: Let’s begin by looking at why is this paper important? Up until this paper, there had only been single centre papers describing outcomes after radical cystecotmy, and this was the first to bring together multiple centres and paved the way for an international collaboration which was the Bladder Cancer Research Consortium and a centralised database.

Nathan: It really set the benchmark for survival outcomes in the pre-neoadjuvant chemotherapy era that we now accept as the standard following radical cystectomy and LN dissection for bladder cancer.

Joseph: The purpose of the study was to report the characteristics and disease outcomes of a large multi-institutional cohort of patients treated with radical cystectomy and bilateral lymphadenectomy for bladder TCC in 888 patients during a 20 year period from 1984 – 2003. A database was developed to collect retrospective and prospective data on consecutive patients with bladder TCC who were treated with radical cystectomy and pelvic lymphadenectomy at three academic centres in Texas (University of Texas, Baylor, John Hopkins) during a 20-year period (1984–2003).

Nathan: Shahrokh was instrumental in putting this database together. It was a monumental task and we asked him why he did it.

Shahrokh: The question was, can we answer some of these critical questions that are still open in bladder cancer. Not only prognostic factors but what can we learn about the disease, how can we modify the disease. The first stage of getting this work to come together and this group to come together and focus on the main issues that matter to the individual patient. Integrating research in our clinical management was to collect the data of what we already knew, and that is retrospective approach to it, so we built a bladder cancer research consortium.

Joseph:  It must have been phenomonally difficult to get up and running

Shahrokh: It’s like everything in life. You’re trying to convince a lot of people that are busy in their life, specifically the senior guys; to invest some time but actually at the end of the day it was easier than what I thought. All these people are auto selected, they selected themselves, they believe in what you believe, they believe in changing the status quo in this disease, their passionate about the disease and the patients they’re taking care of and they’re seeing the limits of what we are doing now.

Nathan:  So let’s take a look at the paper.

Joseph: It included 888 consecutive patients with urothelial cancer who underwent radical cystectomy and pelvic lymphadenectomy with curative intent to treat bladder cancer

Nathan: It is important to note that this is largely a pre-neoadjuvant era with Neoadjuvant and adjuvant chemotherapy administered to 5% and 26% of patients, respectively, and only in those with evidence of advanced disease by clinical or pathological staging.

Joseph:  Indeed, outcomes were measured by time to clinical recurrence, i.e. DFS, OS, and BCS survival. The study population comprised 19% female and 81% male patients, and the median age was 66.2 years. I used to think it was all just smoking related , but it is clear that men are still more likely to get bladder cancer and I asked Shahrokh why he thought this was the case.

Shahrokh: That is a great question. Men and female are dramatically different. (A man of great insight). From the point of view of genetics, there is something we have not fully understood. We know that females that smoke are more likely to get bladder cancer than men that smoke, females that present with a cancer present at higher stages and even stage for stage have a worse prognosis than men. However, there’s alway whatever you do, in the smoking cohort and in a non smoking cohort, you still have a high proportion of men getting the cancer. What is the risk underlying that? It’s probably more multifactorial, it’s certainly some Epigenetic factors at play, a major response to different stress factors that effect the bladder, but as well what I think is not only the exposure to carcinogens, but it’s also probably something inherent of your genetic material. Men and female are dramatically different in their genetic material. To give you an example, the difference between man and female and between two females or two males is 15 fold in the genetic material.  It is almost we have the same number of genetic material in common with a female of the human race as with a chimpanzee. So if you think about it, we are close so that explains a lot for the women.

Joseph:  Closer to chimpanzees? It does explain orthopaedic surgeons.

Nathan: Patients were followed for a median 39 months (0.4–183.4) and local or distant disease recurrence developed in 35% of patients, and 28% died of bladder cancer.

Joseph: In the analysis 25% of patients had extra-vesical tumour extension with negative LNs and 24% had LN metastasis. I wonder if these numbers would be less in modern series after neoadjuvant chemotherapy.

Shahrokh: I’m absolutely convinced about the value of neoadjuvant chemotherapy with properly selected patients. That is the whole question, which patient should get neoadjuvant chemotherapy and then with the new immunotherapies that’s going to change again and the side effect profile might make it more attractive to using it more commonly. But certainly what we have seen in series that we have published actually later on in patients that had definitive chemo for positive nodes or neoadjuvant, we see a change in the number of lymph nodes positive and we certainly see a down staging. Those patients are the responders. The problem is that everybody is a responder and selecting the right patient for the right drug and the right time is all about personalised medicine.

Nathan: Radical cystectomy with bilateral lymphadenectomy provided durable local control and long-term survival with 5-year recurrence-free survival rates of 58% and a BCS rate of 66%.

Joseph:  We often see that word, “durable” in the final line of a retrospective studies. I asked Shahrokh if this was a throw away line that he often used? What would be a non-durable result?

Shahrokh: The interpretation of what durable local control so in this disease if you don’t treat it you have 90-100% that die within 2 years. So we have already changed the natural outcome of this disease with surgery.  That is already a big leap for work but I probably done surgery. So 58-60%, and probably today it depends on the case mix you have of the patient at disease stage at presentation, you get a good control especially. It’s certainly not sufficient. The patients, when you talk about durable local control is, these patients mostly recur systemically. So that is the role of the preoperative chemotherapy, be it adjuvant or neoadjuvant, so we need to do more. The micrometastatic disease that we need to control is really what we find short in this disease. And that’s what we see here.

Nathan:  Logically, the rate of LN involvement increased with advancing pathological stage. Pre-operative multivariate analysis showed that clinical tumour stage and neoadjuvant systemic chemotherapy were associated with cancer recurrence

Joseph:  Wait on- neoadjuvant chemo did worse??

Shahrokh: In most of these patients in the older series, the patients that were selected for neoadjuvant or for adjuvant were the worst patients. There’s a lot of things you can capture with disease stage, grade and lymph vascular invasion and lymph node metastasis, but still in a multi varied analysis you trying to adjust for the covariant, you’re still not capturing the whole disease and you’re not capturing the bowel disease. So a multi varied analysis does not adjust for these negatively selected patients. The proper way of doing it, if you want to do it statistically correct is maybe by propensity matching, and even then you are not achieving it fully. And that’s a flaw of all these retrospective data sets.

Nathan:  More advanced age, clinical tumour stage, and preoperative carcinoma in situ were associated with BCS mortality.

Joseph:  Why are old people more likely to do worse apart from the obvious age variable which should be accounted for in multivariate analysis. Shahrokh had some real gems on this point.

Shahrokh: We know that older patients are more likely to have complications, we know that in preoperative mortality.  But this was cancer specific mortality. At any single data base you look at with muscle invasive disease, older patients do worse.

Joseph: Then why put older people through it if its not going to be effective? Why bother?

Shahrokh: The reality is, still a huge proportion of these patients benefit from it. And if you look at the old ratio of how many of these older patients did worse, it’s a very small change. Statistically significant but it’s not something that clinically would be significant for the individual patients. The variability between patients who’s bigger than the variability of age affected. Also from gender affected, and that has to do with, probably also in this case series the older patients have a worse immune system, heavy smoker, exposed to more cardiovascular disease and that also effects the primary disease in a certain manner. They also cannot get optimal therapy, if you’re older your GFR, your toxicity probably prevents you getting the appropriate treatment. What we also see in population based data sets, all the patients get sub optimal, not only therapy they get chemoradiation often but even if they get cystectomy, they get less lymph nodes taken and so. So, that is not correct.  They may be not getting the same therapy they should get based on their age, and we are not giving them not the same chance as a younger patient.

Joseph:  So its more an issue of fitness and failure to get through all treatment options that leads to worse outcomes- fantastic reasoning.

Nathan:  Post-operative multivariate analysis showed that pathological tumour stage, LN metastasis, lymphovascular invasion, adjuvant radiotherapy, and adjuvant chemotherapy were associated with cancer recurrence

Joseph:  LVI is not something we usually talk about in the MDM’s I’m involved with, due you think lymphovascular invasion should really push you over to absolutely needing neoadjuvant chemo from your TURBT specimen?

Shahrokh: Well, let’s look at it. If you have a T1 with lymphovascular you certainly have to have a cystectomy. But if you have a T2 with lymphovascular invasion, that’s a high risk of micrometastasis, this is a patient that is ideally for neoadjuvant chemo, hydronephrosis and variant histology. (he’s talking about the big three: micropapillary, sarcomatoid, plasmacytoid) If you have those three or you have a T3 on a bimanual exam or MRI. So it’s one of many criteria for your neoadjuvant selection, because these patients are more likely than not T3’s and positive lymph nodes at the end of the day. So I think these are strong predictive factors. The problem is you have to get your pathologist to report on the lymphovascular invasion

Nathan:  Higher pathological tumour stage, more advanced age, LN metastasis, lympho-vascular invasion, and adjuvant radiotherapy were associated with disease-specific survival. Patients with metastasis to regional LNs were at significantly higher risk for bladder cancer recurrence and death than patients with extra-vesical tumour extension (pT3N0).

Joseph:  Makes sense- the further it has spread, the worse you do.

Nathan: Patients with extra-vesical tumour extension (pT3N0) were at significantly higher risk than patients with organ-confined disease (pT2 N0 or less).

Joseph:  I think we are getting good at this.

Joseph: There are some obvious limitations with this study such as its retrospective nature.

Nathan: Also, because the study period spanned >20 years, the data may not have represented current practice patterns at the time of publication. For example, neoadjuvant chemotherapy was relatively underused in the patient series compared to existing recommendations and certain surgical techniques, indications for surgery, and follow-up protocols had changed with time.

Joseph: One of the key biases of these studies are that these data are representative of the quality of cystectomy performed by specialist trained in urological oncology at high-volume academic institutions.

Joseph: One of the final statements in the paper is that the data were representative of the quality of cystectomy performed by specialist’s trained in urological oncology at high volume academic institutions. This is a really important issue these days. What is high volume either by surgeon or institution that you nominate?

Shahrokh: This is a very difficult question because it’s not only a factor of the volume, it’s also of the training you’ve received. Did you do a fellowship, did you have the right mind set to have the proper support systems? So it’s not only the number of cases you do but also the team, including the medical oncologist, nursing and anaesthetists are all involved in it. What we know is, the number of cases you do will effect the preoperative complications, your intraoperative and postoperative mortality, your 60, 90, 120 days mortality, but not only that; also your cancer specific outcomes will be effected by your experience. Do we know how many cases you need to do….?

Joseph: Come on Shahrokh, I live in Australia and we’ve had 5 prime ministers in the last 6 years; I know politician speak when I hear it. Give us a number!

Shahrokh: I can only tell you what in certain countries they have looked at. Certain countries you don’t get reimbursed if you don’t do 10 – 20 cases a year. And you would be surprised, most urologists do less than 1 or 2. So, is 10-20 the right number? I think it’s too low actually.

Joseph: How many do you do Shahrokh?

Shahrokh: Well now when I took over the institution we had 21 a year and now we’re at 70 per year and all these 70 are done by myself. And the number is rising. This is a repercussion of centralisation because the health care system realised the cost of care increases because the complications are higher, so they want to keep that low so they’re doing the centralisation. On the other hand, patients and the local doctors realise that they will get better care if they come to a centre that is focused on that disease from every single cycle and with an appropriate approach. How much is appropriate? I don’t know but certainly more than 10 I would say.

Nathan:  Almost 1 per month. I think that is a good number as a minimum.

Nathan:  We see a lot of these large databases from large centres data mining for their results but are they still necessary? Shahrokh thinks so.

Shahrokh: Yes, I think they are still essential. I think whatever you do and whatever discipline, you need to see how well you do and you compare the benchmarks to other centres, see who are doing well and who are doing bad, learning from both directions. So I think data bases and continuously assessing what you’re doing and what your results are is important. But this should not only be done by big volume centres, it should be done by every single one of us and I think it has not only an effect on patient care but also on cost which is rising in every western country, so I think we have a continuous necessity of collecting data, quality checking the data and improving upon what you’re doing as a benchmark.

Joseph: I offered Shahrokh my magic 8 ball that would answer any question he had without the need for a long expensive trial. What would he ask it?

Shahrokh: How can I prevent the disease is the major issue. If you can prevent it, and if you can not prevent it, how can I detect it early without shifting the disease and making it a manageable disease. Everything else you ask asking is just limited, small steps. The question – which patient is neoadjuvant, which patient is this or that, robotic or open – these are not questions that are truly changing the natural history significantly to make a difference. Prevention is the key, and we already know the answer to it. I don’t need to ask a magic 8 ball. I know that ceasing smoking will have a major impact on changing this disease not only in it’s diagnosis but also in it’s prognosis. At any time you intervene, so the answer – we know it already but in Australia you have already done a tremendous effort in changing that.

Nathan:  That sounds about right. You are not allowed to smoke anywhere in Australia these days.

Joseph:  We can’t afford to. Did you know it costs $22 for a pack of smokes these days?

Joseph:  So what are the take home messages?

Nathan:  When you do a cystectomy, 25% will have extravesical tumor extension with negative lymph nodes and 23% will have lymph node metastasis. The risk of spread increases with advancing pathological stage. The risk of cancer recurrence and death increases with more advanced age, clinical tumor stage, LN mets, and lymphovascular invasion. Cystectomy and pelvic lymph node dissection provides durable local control and disease specific survival in patients with localized invasive transitional cell carcinoma.

Joseph: Thanks, Nathan and thanks to Shahrokh. Another great author and another great paper. I hope you found this interesting and if you have any questions, comments or feedback, all positive feedback can be sent to talkingurology@gmail.com, and all negative feedback directed to the parking inspectors around the Austin hospital in Heidelberg.

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