European Multidisciplinary Conference in Thoracic Oncology (EMCTO) 2013

Using chemo-radiotherapy without increasing toxicity

Dr Dirk De Ruysscher - Leuven University, Belgium

Dirk, you’re addressing a very key issue here at the meeting in Lugarno because it’s all a question of using chemoradiotherapy, which is what you’re talking about here, but without increasing toxicity. What are the issues there that you’ve been looking at?

The problem is, in fact, that the so-called standard treatment for patients with irresectable stage 3 non-small cell lung cancer is concurrent chemoradiation. The problem is, first of all, that only about 40% of the patients can get the concurrent chemoradiation because of the toxicity issues, because we are dealing with old and frail patients because of the smoking and the age, of course. The second problem is that the patients who can get concurrent chemoradiation will have a bad prognosis because still in these cases only about one fourth of the patients will be alive after five years. So it’s too toxic for the majority and, let’s face it, the outcome is still below what you want to achieve in the population.

But there are solutions which is why you are working on it; it may be a difficult problem but you’re working on it. Can you tell me about the study you’ve been doing?

The solution is being studied, of course, so there’s no real solution at this moment unfortunately. First of all we should address the problem of local control and also the issue of distant metastases because both problems are still remaining very high in those patients. And it should be without increasing toxicity, even with decreasing toxicity. The first issue could be that we just escalate the radiation dose in order to achieve a better local control.

And you’ve been looking into this?

Yes, indeed. We have looked into that and actually the background is also important to know that classically you can add dose, so 2Gy a day, five times a week to the actual dose. There’s a very important American study of the RTOG which is not published yet but presented and they showed that just adding dose doesn’t solve the problem because you have even higher mortality in the high dose arms and the problem is that the cancer cells don’t wait until they are getting killed, the cancer cells will repopulate; that means that they will switch over to a higher rate. So that means that is not the real issue. What we should do is intensify the dose on the basis of individualised treatments and then what we do is actually we give a higher dose to parts of the tumour which show lower susceptibility for radiation and we remove a little bit of the dose from those parts who don’t need it.

So how have you been doing this highly individualised kind of therapy; what has been your approach?

The approach is first of all for the tumour that we look into the details of the molecular imaging, in this case based on FDG-PET scans and on the basis of FDG-PET scans we know which part of the tumour bear more or less susceptible areas for radiation or for chemoradiation. Second, we develop also models to know which parts of the lungs, the so-called normal tissues, are more or less susceptible for radiation damage. If you combine both in physical models or objective models then you can really deliver safe, very high doses which are biologically really 30-40% higher than what we deliver now without, and that’s very important, increasing the toxicity. I will address this in my talk in more details.

There are, of course, targeted therapies, new therapies coming along and being implemented already. How do they blend in with this spatially orientated approach based on investigation?

This is very important because the target agents, of course they have a lot of possibilities however until now we have not seen any trial where the combination of targeted agents together with chemoradiation improves survival or local control. On the other hand, it’s also true that by knowing the molecular targets or pathways much better than we do now, in combination with radiation which diminishes the dose to the normal tissues, we will probably be able to combine radiation with targeted agents aiming to eradicate more cancer cells and without increasing toxicity again. Because you can imagine, if you have left, let’s say, a small number of cancer cells because you have reached a lot of cell kill with irradiation you do not need a lot of extra cell kill with a little bit of targeted agents, which may be very specific for cancer cells.

To what extent have you been successful in spotting these hot spots where there are more cancer tumours and giving them more chemoradiation then?

At this moment we are doing a randomised trial. At this moment we have the analysis but only toxicity analysis of the first eighty patients included in the trial, which is an international European trial which is open in the Netherlands, in Belgium, in Sweden, in the UK and in Denmark. At this moment the toxicity is as expected so certainly not higher. But, of course, the trial is running and we hope that we can have data, let’s say within two or three years.

Give me some ballpark figures then, because currently with irresectable non-small cell lung cancer you might get, say, 25% five year survival. What do you think this could go up to by limiting the toxicity and individualising where you give that dose?

What it will come out is still a matter of debate, of course.

What are you shooting for?

15%, 10-15% absolute percentages. Then, of course, let’s face it, it will not only be the radiation that will do the job it will also be the combination of radiation with more specific drugs, not only targeted agents but maybe also immunotherapy. But that’s a longer shot, of course.

Of course you’re dealing with older patients, you’re dealing with frail patients. Another battle you need to win is one of confidence that this can be achieved and that it’s really worth doing. What would you say to cancer doctors at this point?

Don’t be too pessimistic. That is actually the point and also when a patient is quite old or frail you should also remember that by giving induction chemotherapy without concurrent radiation and then afterwards high dose accelerated radiation, what we have also published last year in the JCO, that by giving the radiation accelerated, so in a shorter overall treatment time, you can indeed increase your five year survival in a tolerable way. What is also important to remember, patients who get this treatment and who are cured are later on really good so really they can do their job again, they can enjoy living again and so on. So it’s a very hard treatment, unfortunately, but afterwards if you look three months afterwards, or something like that, the majority of the patients are very good. We have even shown that 10-20% of those patients have more exercise capacity after the treatment than before the treatment and there are different possibilities how to explain this. I think very importantly a lot of patients stop smoking and do some physical exercise and so on but anyway the net result is not to be too pessimistic.

And what do your patients make of this?

Most of my patients take the treatment of course, yes. But I’m very open with my patients.

Are they happy with the results?

No because if you’re a patient and I’m telling to a patient all the possible side effects, I’m very open on that, nobody would be very glad. But on the other hand if of course you succeed to cure them then indeed you can really show…

And at that time?

Yes, of course, at that time that not only they are cured but they are very good and they have very good performance status, they can do everything that they want. Yes, certainly.

And your summary, your final message for doctors coming out of this meeting here in Lugano?

First of all, don’t be too pessimistic. Second, also select your patients very well, so be realistic what you can achieve. Sometimes, it’s true, it’s only palliation but it’s also something that you should keep in mind. Third is that please, there are so many trials which address important questions and where the accrual is too slow compared to the number of lung cancer patients that are there in the community. So please join those international efforts so that we can proceed much faster than now.

And the balancing act between treating to prevent local disease or to give local control and preventing distant spread, how do you reach that?

I think both are very linked to each other. At a certain moment you have the tumour and then you have the metastasis and when you can’t eradicate the local tumour then of course there will be metastasis afterwards and this will be a new node, a new niche. There are some pre-clinical experiments showing that there is a recirculation of stem cells from the primary tumour to other sites in the body as well. So that’s pre-clinical, that’s not really shown in humans but there are still nice papers about that. So that means that actually you should not address only the local treatment or the distant treatment, it should be really a joint effort like it should be clear that it’s not only a local disease – local disease in lung cancer means also some distant metastases, maybe you can’t see it. On the other side you have some patients with a few distant metastases who can be cured also with systemic disease plus local treatment so it’s a continuum. Of course it doesn’t make life that easy but it’s more reality, I think.

Dirk, thank you for your very encouraging comments here.

Thank you.