Prostate cancer current treatment practices

Professor Noel Clarke
Prof Eleni Efstathiou
Dr Alberto Bossi
Dr Peter Iversen

NC: Welcome to Warsaw to the Prostate Cancer Current Treatment Practices meeting. We’re here to discuss the management of advanced prostate cancer and new drugs which are available for castrate resistant metastatic prostate cancer. I’m joined by some distinguished experts in the field: Peter Iversen, urologist from Copenhagen, Alberto Bossi from the Institut Gustave Roussy in Paris and Eleni Efstathiou from MD Anderson and Athens University, welcome. We’re going to cover some of the topics which we as urological oncologists deal with in advanced prostate cancer almost on a day to day basis. I’m going to start with you, Peter, if you would just give me a brief overview of the current standard of care for patients with metastatic castrate resistant disease.

PI: Well, ten years ago apart from palliative measures we didn’t really have very much to offer patients with metastatic disease once they progressed despite castration based therapy. But then in 2004 something happened, two large randomised trials proved docetaxel chemotherapy to be effective in patients with metastatic castration resistant disease and actually being able to prolong survival with 2.5 to 3 months. Then only three or four years ago something more happened, new drugs were developed and several of them in randomised trials have been proven able to prolong life in these patients. So it’s very, very exciting times that we are living in but we are now facing a lot of problems in how to sequence these drugs and how to possibly combine them and how to find the best suitable patients for each individual treatment modality.

NC: Thank you. Alberto, if I could ask you, clearly there are exciting new developments and clearly the perspectives for treatment have changed but necessarily the new therapies which are available are not suitable for all patients and there are certain types of patients who might benefit better from chemotherapy, let’s say, or hormone therapies. Could you give us a typical patient profile of somebody presenting to your department in Gustave Roussy – what kind of age they are, what kind of disease problems they have and how you might come to a decision about treatment?

AB: Well they are, of course, patients which have been through the classical treatment for prostate cancer. From their diagnosis they had prostate removed by surgery or irradiated by external beam or brachytherapy. Once they progressed they may have old age with several comorbidities, so a global situation that has to be evaluated carefully before proposing new treatments. I think that, as has already been mentioned, the different weapons we have today for these kinds of patients should be clearly evaluated as compared to the quality of life of the present patient and to the life expectancy they have and the comorbidities they have. We, as radiation oncologists, we are not very much for the moment accustomed to correctly evaluated comorbidities of our patients and I guess this should be done in a much more extensive way before treating those patients with new drugs and treatments.

NC: So if I might come to you, Eleni, how would you develop on Alberto’s statements that the patients are different, they need evaluation and they need to be directed down certain treatment pathways? How would you do that in your practice?

EE: Well I would just start by pointing out what Peter said earlier: we developed all these new reagents on a background of having nothing essentially. So we performed all these trials without being driven by certain markers or looking for them and hence we are now faced with what one would like to call a problem but essentially it’s a very positive problem – having too many reagents and little knowledge on how to apply them, as you’re saying. For the time being we can only be pragmatic and follow some recommendations that are out there based on how these trials were designed and actually at looking at the patient holistically based on whether the patient is in good performance status as opposed to being very frail, whether the patient has received in the past chemotherapy or not and essentially whether the patient has a load of disease that includes visceral metastases or not. So the question that comes up pragmatically, apart from something I did not bring up which is if you have access to this specific drug, and that varies from country to country and is probably the biggest issue we are faced with, however, the question that comes up right now is if a patient walks in the door who is in a good condition with regard to comorbidities unrelated to prostate cancer, has not received chemotherapy in the past, is asymptomatic or oligosymptomatic, you would definitely be more driven to give one of these new hormonal reagents. However, if you are under the impression as a physician that the patient has a very rapid progression of this disease you would consider, has some symptoms, providing first line chemotherapeutic reagents. Having said that, I think that six months from now we may be sitting here and having a different discussion. But I think we have to be pragmatic and follow what are the recommendations as formed by the trials that have been performed.

NC: So pragmatism is one of the key drivers of what we do and it’s interesting that you didn’t mention age in any of that. So, Alberto, if I could come back to you, what consideration do you give to the older patient coming in, bearing in mind that many of our patients presenting do so at a relatively old age, older age, should I say?

AB: Indeed, indeed. I’ve started thinking that age is not so much important as I was accustomed to think when I was defeated in tennis by an 82 year old guy and looking at the identity card I would never have guessed that and then… So this is just to tell you that, indeed, I think that what is the biology of our patients should be much more important than just the age. Patients themselves are really asking not to look at their age themselves because it’s quite common, I think, and my colleagues too, to have patients coming in and for them it would be very, very difficult to understand that you are not proposing them the update medicine you can propose them just because based on their age. So I think that from a cultural point of view this is something that we should probably start evaluating in a totally different way.

NC: So this is interesting – we have options which are available to patients, age is not necessarily a barrier and we have to rethink how we are addressing and approaching these patients. Peter, you mentioned in your opening comments that in 2004 cytotoxic chemotherapy came along and now we have hormone therapy and you have a particular international expertise in hormone therapy. There is some discussion about who the patient should be treated by, should this be by urologists or radiotherapists or medical oncologists or should it be by a combination of all three? Do you have a view on that?

PI: Well first of all I would say that some kind of collaboration is probably beneficial for the patient and for us. There’s a lot of controversy about this, however, and even within a relatively small country like my own there is not a consensus about who is going to administer these new drugs. First of all I’m talking about abiraterone and enzalutamide. It seems that medical oncologists are very keen and very interested in administering these treatments. I personally, with my background in endocrine therapy, find it very natural that at least in the pre-chemo setting urologists keep on going with their endocrine therapy.

NC: And the bringing in of other intellectual expertise and breadth of intellect through medical oncology is an important aspect and improves, in my view, the field. But there are certain considerations so, Alberto, coming to you again, in your home country of Italy I understand that urologists have been banned from prescribing a drug like abiraterone, that this has to be prescribed by a medical oncologist. Do you have a view on that?

AB: Well, from one side I would start saying that there is this, in my opinion, false impression that all these new drugs that are coming into the market are much more easy to handle and so everybody would feel at ease in prescribing them. I think that we are still in a stage in which there is some work to do and I think that medical oncologists should be involved in a much more full way because knowing in deep what the side effects of these drugs are, what the real indications for the correct population of patients is still something that I would not leave to a radiotherapist, who indeed has less experience in that. But to come back to your first question, I think that a multidisciplinary, really multidisciplinary, approach should be, especially for those patients, the approach that we should elect as the best one.

NC: So, just addressing this issue of different approaches, I’m going to come to you Eleni. Because one of the things which we are uncertain about is the timing, the initiation of treatment and which therapy we use as the first step, as the second step and potentially as the third step. Could you give us a view on the timing to start?

EE: At the danger of starting to sound boring, unfortunately we don’t have clear guidelines with regard to which treatment to initiate. We can only move forward based on the information that we have from the clinical trials. Just a little comment on what was previously said, I said that if any time is the best this is the time for a multidisciplinary approach. Knowledge is everything; all of us should be trained in using the different reagents. However, when it comes to the time when you’re going to be prescribing the patient either a chemotherapeutic reagent or earlier in the disease a hormonal reagent, you have to follow some guidelines. Some guidelines that are not black and white right now but you can move forward in a castrate resistant phase, looking at a patient who has an asymptomatic disease or oligosymptomatic, by prescribing a hormonal reagent obviously. And it can be debated whether you would include a patient with or without visceral metastatic disease, as we discussed extensively earlier during the day. Now, the problem that I would like to point out is mainly, and it’s becoming more and more important, I think we would all agree, the timing of the shift to a chemotherapeutic reagent. We should all be vigilant and alert and not forget about that point in time when the disease starts to progress rapidly. We should probably initiate chemotherapy and not lose the window of opportunity. I’m not giving you a straight answer but I think I’m shifting a little bit the question further on because it’s clear that hormonal agents in the earlier disease setting have their place now.

NC: But I’m not sure there’s a straight answer to the question, but if I might ask you specifically in what circumstance would you use chemotherapy in preference to hormone therapy in castrate resistant disease as a first line step?

EE: The only case where I would actually do that right now would be if a patient walked in the clinic highly symptomatic with a high load of disease obvious to me. But I think that pain and high performance status level, of two, would be my driver, my main driver.

NC: And Peter, do you have a view on that?

PI: So probably I would look at the PSA doubling time. If I see a very rapid PSA doubling time, say less than three months, I would probably consider referring that patient for chemotherapy instead of letting him on some endocrine therapy.

NC: Now, one of the things which is bedevilling us and which we’ve really not solved is the measurement of endpoints. Now, you mentioned PSA doubling time as something which you would use particularly in this circumstance as an indicator of a specific type of treatment. What other clinical indicators might you look for to help guide your treatment and how might you assess how well your treatment was working?

PI: If I’m trying to decide whether a particular patient would benefit from abiraterone, for instance, I would probably look at his response to his primary androgen deprivation therapy. If that’s very short there is some evidence to suggest that he will probably respond less well to abiraterone so that’s one thing I would probably look at. Also, of course, the patients have to be eligible, he should not have severe cardiac failure, he should not have liver disease. There are a number of things that he should fulfil before being eligible for the treatment. But in terms of tumour characteristics I would look at response to first line androgen deprivation therapy, I would look at his PSA doubling time, I would look at his symptoms, as Eleni said, and that would probably be what I would do.

NC: OK, thank you Peter. Alberto, one of the more difficult ways of assessing progress is assessing progression in bone. We have the bone scan, we have axial MR, we have experimental methodology with PET and so on. Could you give us a view as to where we are in relation to assessing disease in bone?

AB: As you said, the classical way of assessing the presence and eventual progression of metastasis, bone metastasis, is bone scan. We know that it has some limits and the limitation of it is linked to the fact that this risk can be positive only when PSA is very high or when PSA doubling time or the kinetics of PSA is very high. So if we want to fine tune our treatment for those patients risk can be a little bit out of… So you mentioned, for example, axial MRI; we are using this consistently in those patients and indeed what I think, my point of view, is this is a method that can reliably give you an idea of the evolution of the situation of your patient. So in our experience it’s extremely useful to have a baseline exam that you will have to compare during the clinical history of your patient. The same is also true for PET, choline-PET, which is probably a little bit too much extensively used in those patients, especially when you don’t have a baseline exam to which you want to compare the further exams in the clinical history of your patient.

NC: And as a radiotherapist when would you step in with local radiotherapy to a metastasis in conjunction with newer therapies?

AB: Well, I would say that clinicians should not forget radiotherapy because it’s a very cheap way of palliation for bone metastases, can be very effective in a very few fractions, even one fraction. So for patients which are particularly affected please do not forget that radiotherapists are there to help patients in each, probably, stage of the disease. We see more and more patients that, due to all these new drugs coming in, are probably sent to radiotherapy at a little later stage. This sometimes is clinically, in my opinion, not completely correct.

NC: Eleni, Alberto mentioned palliation and we know that this not a curable scenario, these patients will not be completely cured of their disease. So when we’re looking at endpoints in clinical trials there’s something of a fixation on survival. Do you think that’s appropriate and what’s your view about the quality of life endpoint in this arena?

EE: I think that for the time being overall survival has been appropriate, given that we didn’t have enough weapons in our favour. However, moving forward and since we haven’t figured out yet how to perform marker driven trials, we will have to enhance the design of our trials and probably include some other parameters as co-primary endpoints, hopefully well-designed, well thought out. With regard to the quality of life parameters, they are important to be integrated in all those trials. We have not done a good job because we don’t power for those secondary endpoints and we probably, because here we are all sitting, three different disciplines working on prostate cancer, we probably need to involve epidemiologists more. We saw some being involved in these more novel trials with very good results. We need to take that endpoint as seriously probably the quality of life as others, would be my hope and actually what I would advocate moving forward.

NC: Thank you. Which brings us, really, to our last series of questions which is relating to the endpoints and the interpretation of the information that we have from clinical trials to current clinical practice. Because we know that although the studies have been well planned, well undertaken, they don’t always fit our patient profiles, do they Peter? So how are we going to take the studies in advanced prostate cancer with hormone therapy and apply them to our individual patients? Because we know that the trials are in younger patients, often fitter and so on, and our patients in everyday practice are going to be older, less fit and frail and so on. What’s the practical scenario that we have to follow?

PI: Of course I think that we should include all the available evidence to the extent it’s possible but always we have to combine with our own experience and also patients’ expectations and preferences, all that has to be boiled together into how you deal with the individual patient. That’s part of our job and it’s sometimes very, very difficult but it’s necessary.

NC: And Alberto, how are you going to apply that to your Parisian patients coming in? Will you give the drug to everybody or will you select?

AB: Indeed this is hopefully medicine is not just apply rules and recipes but part of our work is also being able to evaluate on an individualised basis what sort of patients we have in front of us. It’s true that in my experience in Paris we are seeing more and more patients coming in with consultation with already a big amount of data from the internet and very well informed about their story. So it becomes more and more difficult and hopefully, I think, to just give an advice which is only based on the internet and on Dr Google. So what they are asking us is really something more, indeed something which is really more difficult but then it takes time but I think it’s up to our profession to devote time and energy in these situations.

NC: So, Eleni, are we practising art or science or both?

EE: I would like to point out that all of us sitting here and in the room earlier today are very privileged. We work in academic centres, we have access to all these tools that a physician in his daily practice may not in his office, especially a urologist. So we need to get together and come up with some advice in using these reagents outside, as you said, the clinical trialsmanship or the access to MRIs. I think we should incorporate these new agents in daily clinical practice and guidelines. For instance, performing imaging in a metastatic patient, I think we would all agree, would be every six months, for instance. This should be incorporated in the use of these new drugs. And exclude patients from treatment either because they don’t want to be part of it, and that’s an option. We need to have some trials, we need to design them, similar to the PISCES trial for renal cancer cell, a choice of patients – we don’t have that. It’s what you brought up with the internet access. Then we also need to look at what is a very red no for giving each and every of these reagents. Just guide physicians out there that you can’t use it in this specific setting, cannot. That’s the only thing that we can do right now with the knowledge that we have. We can’t preclude patients, with the exception of a few contradictions, for these drugs.

NC: Thank you. I’d like to thank our guests for providing the overview. As you can see we have implemented the science of medicine and there is more to the application of that science illustrating that medicine is also an art and we need to continue to evolve and implement the treatments as appropriate for our patients. We’ve had some major advances in recent years, and particularly in the last couple of years, which have taken on our understanding of the disease considerably. We now have new tools available to us, it’s our privilege and our duty to implement those for the better of our patients in the future. Thank you.