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Prostate Cancer: Transfer of Clinical Results into Real Life - Noel Clarke and Nicolas Mottet at PC Debate, Baveno, April 2016
Professor Noel Clarke, Urologist, The Christie Clinic, Manchester, UK,
Professor Nicolas Mottet, Department of Urology, University Jean Monnet, St Etienne, France
Prostate Cancer Debates, Baveno, April 2016
The results of clinical trials can only be translated to real world patients if they have been represented in the studies. Some well-known trials however exclude patients with common comorbidities such as cardiovascular disease or hepatotoxicity with the consequence that the results can’t be extrapolated to the patient in real life and the final outcome might be different. This and other topics like toxicity and timing of treatment in patients with advanced prostate cancer or the impact of translational approaches are discussed by Professor Clarke, Manchester, UK, and Professor Mottet, St. Etienne, France at the Prostate Cancer Debates.
Noel Clarke: My name is Noel Clarke and I am a urologist and Professor of Urology in Manchester in the UK. We are here in Baveno in Italy, discussing elements of prostate cancer treatment. I am joined by –
Nicolas Mottet: Nicolas Mottet. I am Professor of Urology in France, currently chairman of the Prostate Cancer Guidelines at EAU. I am also in Bavena, discussing prostate cancer disease.
Mismatch of clinical studies and clinical practice
Noel Clarke: Nicolas, what we have been talking about for the last sessions has been about bringing the data that we have from the laboratory, from clinical trials and so on, into everyday clinical practice. We have had quite a number of circumstances where it has been apparent that the information from clinically trials, say, does not necessarily match the characteristics of the particular patient who is in front of us. Do you agree with that?
Mottet: That is absolutely true. It was clear, for example, regarding early chemotherapy that the effectiveness of chemotherapy in castration-resistant patients is proven, and the TAX 327 trial showed that.
If we turn to real life, it was very surprising to see that, in the same team involved in the trial, the side effects of patients treated outside of the trial by exactly the same team, managing the patients in the same way, was higher. This clearly suggests that the data we have from clinical trials has to be considered with some caution when we go into real life, because it includes patients who might be different, suggesting that the final outcome might be a little different. The real world, and the trials, do not match 100 per cent of the time.
Clarke: You put up a very interesting table in your talk, which looked at the exclusions for patients in trials. What was very clear, from looking at some of the very commonly published and very well-known trials – the ASCENT trial, the 302 trial, the PREVAIL and AFFIRM trials and so on – is that there were a great many exclusions including cardiovascular disease, any kind of hepatotoxicity, various elements of comorbidity. You then went on to show us the comorbidity associated with patients of the type we treat, and they are very different – in the trial profiles, the patients are much better and much fitter and, as a consequence, the results that come out of trials are not necessarily extrapolatable to our patients. We have to tailor these treatments and so on according to the patient who sitting in front of us, which is a really critical factor.
Mottet: I agree. The results we obtain in clinical trials are the best that we might have. In real life, we might expect to have slightly lower results based on comorbidity. We must also remember that all these trials that we are discussing were mainly based for drug registration, meaning that the industry behind them are very careful not to have too many side effects. That is absolutely correct, if you realise that. That is the difference.
Clarke: It is therefore incumbent upon us to get the sort of registration data which follows up – that is to say, cancer patient registration data as opposed to registration trial data, which flows out from information gleaned from clinical trials.
An example of that was in the 301 study, where there was an extended access programme which followed on thereafter, which was quite reassuring. Cora Sternberg was the author on that particular study, which showed that the side effect profile was reasonably close to the side effect profile seen with the trial-based patients. However, I wonder whether that would be the same with some of the docetaxel-based studies, where the toxicity is a little higher and the stringency for inclusion is a little more careful, and so on.
Mottet: We have data on that. Arnould Templeton’s paper, for example, clearly showed, it was at a time when Arnould worked with Ian Tannock, a famous medical oncologist who knows docetaxel very well. They clearly showed that the side effects were improved when the patient treated in the same team, were treated in the same place, but outside the trial, suggesting that the inclusion criteria to deliver docetaxel were wider. You must realise that, you must know that, and the best you might get are the results that you have in the clinical trial. You might expect less results and slightly increased toxicity when you go into real life. That is real life.
Timing prostate cancer treatment
Clarke: Sticking with that toxicity theme, a question which was asked commonly at the meeting here in Bavena was, what about the timing of treatment in patients who have progressive disease? Should they be treated straight away, or is there a window which allows the patient a little time, and allows the clinician some time to think about which particular treatment starts first, and when it starts? We had some views expressed, to the effect that it is possible to wait in some patients but, equally, a contrary view that you need to get on with treatment. My own view is that there are some patients in whom we can wait. Is that how you would see it?
Mottet: That is correct. Probably, the first point is that there is no need to rush, or that you have to take the pill immediately. The second point is that we have drugs that are proven to be effective. The earlier, meaning the less symptomatic, the less pain, the better the final outcome – but that is patient selection, and it is a lead-time bias, which has nothing to do with drug efficacy. However, once we know that, we have to balance the benefit with the induced side effects: if the side effects are very minimal and the drug is very well tolerated, why should we wait? Except if there is a strong request from the patient himself, to wait a little bit - waiting a little while is absolutely fine, provided we don’t lose time, but there is no rationale for waiting but, at the same time, there is no rationale to rush.
Clarke: Is there a group of patients that might be seen in your practice, where you might look at them and say, ‘Here are the characteristics I am looking for, so I will wait.’? Is there anything specific?
Mottet: If a patient is totally symptomatic, probably with a low volume without any impending spinal cord compression, or bone pain, perhaps with not such a high PSA, even if the MC or PC PSA doesn’t matter very much – probably there is the possibility to wait a little bit. However, then the discussion will start, ‘Now, probably in the situation you are in, you should have second line treatment’ – let’s say, Abi or Enza It is really there only for Abi or Enza, not for chemotherapy, because of pain.
Then, it will be very unusual for a patient to say, ‘Okay, I get the point. I understand the toxicity I might have from these drugs which is, to be absolutely honest, clearly limited, so why should I wait? If the patient wants to wait, that is fine, but I would never say ‘No, you have to take the pill immediately.’ The question is that it has been proved that ‘If I give you this drug now, your survival will improve. It might also be true in one, two or three months from now, so it is up to you, if you want to wait one to three months’ but, to be honest, that never happens to me in practice.
Clarke: My own view is that it is important to have a dialogue with the patient and look at their individual characteristics – what their social circumstances are, and what they want, and what the nature of their disease is, as best we can estimate it. With low volume, slowly progressive PSA, minimal symptoms, it is perfectly reasonable to wait, in my view. By contrasts, patients with a rapid PSA-doubling time, heavy disease load and symptomatic, clearly need to get on with treatment. In the middle of all of that, there are some who will go and there are some who might wait.
Mottet: You might wait, but there is no absolute reason to wait. You might wait, if the patient would prefer to wait.
Clarke: It is the art rather than the science of medicine, I would guess.
Mottet: Yes, exactly.
Translational prostate cancer research
Clarke: One final point that we discussed is that we had a very clear and comprehensive overview of translational research from Professor Chris Evans, with some of the leading edge technologies being applied, with high-level research teams, molecular medicine and so on. I wondered about how to get that into the clinic as quickly as we could, because it takes a long time to do a clinical trial and it takes a great deal of money. How do we do that?
Mottet: That is true, but it has to be acknowledged that it is not because it works in animals, or in tumour models, but that it finally translates into an improvement in the big animals, like man. We might face totally unexpected side effects, and we might face totally different outcomes. The benefit seen in vitro or in animal models might be totally different in humans. I would really caution – and Chris Evans repeatedly said this – don’t get the message that the drug, from an intuitive perspective rationale we believe might be of interest - don’t take the message that, when you are back home, you will use it immediately: it has to be shown that it changes the final outcome, without adding any significant side effect, otherwise we might face real trouble.
Clarke: Yes. We have this issue that we have to manage patients’ expectations, because they will read about these developments in the popular press, the lay press. They might not have an understanding of the science that is required to transpose that model from the lab into the human. That takes time and it takes clinical leadership, I guess.
Mottet: Exactly. That is exactly the added value of the doctor, which is to explain that.
Clarke: We have been discussing a number of interesting topics and wide-ranging issues around prostate cancer, both the hormone-naive and the metastatic castrate-resistant setting. We probably have as many questions as answers, but it is always good to air those in a big forum such as we have had here in Baveno. Thank you very much.
Mottet: Thank you.