European Multidisciplinary Conference in Thoracic Oncology (EMCTO 2011) 24—26th February 2011, Lugano

FDG-PET scans to avoid unnecessary radiation in NSCLC treatment

Professor Dirk de Ruysscher – University Hospital Maastricht, Netherlands

Professor Dirk de Ruysscher, we’re very fortunate to have you here on ecancer.tv to talk about one of the emerging topics in non-small cell lung cancer and that is you’re talking about intra-tumour heterogeneity. Now one would imagine that was a disadvantage but I gather it could be an advantage?

Indeed. We know for many years that when you look at the tumour, the primary tumour in itself, that the tumour is heterogeneous. So that means when you look in histological slides you have some areas where you have a lot of cancer cells, other areas where you have less cancer cells; areas where you have good oxygenation and vascularisation and other areas where it isn’t the case. Now if you think about that, it’s logical to imagine that those areas within the tumour which actually differ from the tumour may need another radiation dose or another drug dose in order to be eradicated. So actually what we did, we could, by just taking one FDG-PET scan before the treatment, identify which regions within the same tumour are more or less susceptible for radiotherapy or for chemoradiation.

Are you saying that PET gives you that ability to say which tumour can benefit from the higher dose?

We can, on the basis of the FDG-PET scan with a probability of something like 80%, indeed identify which areas within the tumour are less susceptible for the current treatments and hence they should be treated with a higher dose to only those little parts of the tumour which need those higher doses and the normal dose to the other parts. As a net result we can increase the probability of tumour control and eradication of the cancer cells without increasing the toxicity to the normal tissues.

Now you’re talking about intensifying the dose of radiotherapy, this may or may not be accompanied by chemotherapy, you wouldn’t change the chemotherapy?

Of course not. This is very complementary because basically what we show, we can identify which areas are more or less susceptible. So basically we can identify which areas need a higher dose, be it with radiation or something else, and which areas don’t need it. So it’s a kind of redistribution to give more to the ones who need it and less to the ones who don’t need it.

And how effectively can you intensify to those regions and also how effectively can you avoid dose to organs at risk?

Well, for that purpose we are running now a phase II randomised clinical trial in the first instance, together with the NKI in Amsterdam and within a couple of months it will be a European trial because we can really do that from a technical point of view. And that is because we don’t increase the dose to each part of the tumour but we increase the dose to the parts that really need it. Hence you can really avoid increasing the toxicity which is not trivial. Now the other part of your question was about FDG-PET scan, we are doing in the phase II trial also translation research in order to improve the ability of PET by looking at other PET traces than FDG and also looking at other means like diffusion and perfusion CT scans of the tumour.

How much of a margin of cancer destructiveness can you get, to literally hope to cure the disease and not do much collateral damage?

To give you an idea, in the normal circumstances we give something like 70 Gray in 35 fractions to those huge centrally located tumours, most of those patients have stage 3 disease. Now we can even more than double the biological effect, so double the dose to those areas, in the same magnitude as we give now with stereotactic body radiation. So, from a theoretical point of view, we could increase the local tumour control something like from 50-60% to something like 90%. That is the statistics that the phase II randomised clinical trial is based on.

Now this is very optimistic for, the future of radiotherapy for patients with non-small cell lung cancer. How much do you predict this could improve the outcome in patients in terms of length of life and quality of life?

First of all, the aim is to increase the cure rate further on of course, because this is still a major problem. If everything goes right we could improve the net five year survival by something like 15-20%. So long term, without increasing the toxicity because the aim and also the calculations are that way done that we never increase the dose to the normal tissues. At the same time, this concept of intra-tumour heterogeneity is also applicable to drugs because we, and other people, have also made drugs which are coupled together with positron emission scans, together with the Free University of Amsterdam we have done that. We can also see that some parts of the tumour have a higher uptake of drugs compared to other parts. You can imagine that you can only irradiate or give a high dose to those parts of the tumour where the drug isn’t reached and other parts of the tumour where you don’t see a drug uptake you give radiation and to parts of the tumour where you do see the drug you can decrease the radiation dose. So intra-tumour heterogeneity is also a possibility for increasing the efficacy of drugs as well.

Now how do you do all this? You’re potentially getting a double whammy to improve the targeting, not only in terms of where the tumour will respond anyway, but also where it hasn’t benefitted from the drugs. How much do you think that can do for the patient in the long term?

Again, from a radiation therapy point of view together with the drug therapy view, we should be able to reach something like 85-90% of the tumours to be locally controlled first of all. Second, the same concepts can be applicable to distant metastases as well. But, of course, this is on a long run.

How easy is it to do FDG-PET scanning and, indeed, labelling of the drugs to see where the drugs are going? How easy is all of that?

Well, like always, if you do the research and development it’s quite difficult but at the point we are looking now with FDG-PET scans and the technique to increase radiation dose, this is feasible in any centre which has experience with intensity modulated radiation therapy, first of all. Second, the labelling of drugs, at this point it is possible that one centralised centre makes the drugs and export centres export the drug to other centres in the country or abroad. So, yes, I think that these types of trials, and if it would work, would be broadly applicable throughout Europe, yes.

Clearly a very important emerging modality for treatment, but what should busy cancer clinicians make of your ideas right now?

At this moment it’s not for routine practice but I hope that within, let’s say, three to four years we will see that this concept will gain acceptance and will be applicable in clinical practice on a large scale. And what I should also stress is that the concept of looking at intra-tumour heterogeneity both with radiation and with labelled drugs will also decrease the cost because you do a further individualisation, you only use one pre-treatment FDG-PET scan and you can increase the dose to those parts that need it of radiation within the tumour just by application of the normal IMRT technique, so without increasing the cost because it doesn’t increase the number of fractions of radiation. From the point of view of the drug you can really see whether the drug is taken up in the tumour or not. So that means you can decrease the cost in the very long run and this is also not trivial in these times, I think.

And which groups of patients are likely to benefit the most from this?

The patients where we have the most problems now, that is to say patients with tumours of a diameter of 4cm or more or the patients with stage 3 disease.

So all in all, the bottom line you’d like doctors to take home from this is what?

The bottom line is that a tumour is not one bag of cancer cells, it’s very heterogeneous, both from the sensitivity for radiation, chemotherapy and targeted agents. And by investigating this we will improve the outcomes, so the survival, without increasing the toxicity and even by decreasing the costs.

And you can improve the level of optimism that both patients and doctors can have about their disease?

Basically it’s further individualisation, not only on the basis of the patient’s characteristics, on the characteristics of the tumour cells but also within the tumour, within the so-called society of the cancer we can look at some subgroups with different sensitivities to all the different modalities we have.

Dirk, thank you very much for talking with ecancer.tv here in Lugano.

Thank you very much.