ESTRO 2010, 12-16 September, Barcelona, Spain

Professor Harry Bartelink – Netherlands Cancer Institute, Netherlands

Breast conserving therapy

What’s happened at ESTRO in the breast area? What has really got you excited?

The first thing, that I was already involved with for a long time, was introducing a breast conserving therapy and I’m very fortunate that I could lead a couple of trials in breast conserving therapy, first to show that the results with mastectomy for breast conservancy were similar in terms of survival. Then secondly we showed that with a higher radiation dose, with giving a boost, that you reduce local recurrence in breast cancer by a factor of 2 so that’s important. Then what we learned is that young patients with breast cancer do worse. We tried to explain and we looked to our database that has considered more than 5,000 patients who were randomised in the first boost trial for what the explanation is on why do the young patients do worse and also what are the consequences.

So we looked into detail, we looked at histology, we looked at clinical features – tumour size, lepto metastases and we could not very well explain that. But nowadays, with the most recent analysis that I’ve presented here, we think there are two factors. One, the young patients have more high grade tumours and second is that probably they have more DCIS, so microscopic disease around the tumour bed. So we compared, for example, the MRI; if you have MRI say for this tumour size, then we looked at the pathology also around that tumour site using MRI. We found much more microscopic tumour sites and amount of tumour cells and tumour cell density. So we think that poor outcomes in young patients are probably explained to more tumour elsewhere in the breast or the breast is pre-malignant.

So why isn’t the radiation tackling those microscopic deposits?

What we do and what I could show yesterday in this meeting is that yes, this group of patients with high grade and microscopic depth of carcinoma site around, that if you give a boost that you do much better. So we developed a mamogram and each individual doctor can see for his patients what will happen if you give adjuvant chemotherapy or tamoxifen or boosters and you have disease, you can really predict that this patient has, for example a 20% higher chance of local recurrence and then what you can add and what should do better.

So the next step is what we are basing now in Amsterdam, is to characterise more the gene profiles, what is the difference between the old and young patients, and soon, within one or two years, we really hope to show which patients are worse off with breast conserving therapy based upon the gene profile.

Presumably you looked at triple negative and that sort of thing? There was nothing there at all?

No, no. We know, for example, that triple negative do worse but of course they have high grade so that’s similar. And luminal A do better, that we have seen and demonstrated. Also we showed that the gene profile, if you have an activated gene profile you do worse. But still that’s not enough for young patients with high chance, so that we’re working on.

Next step?

The next step, what we are busy now with radiotherapy and certainly in Amsterdam, is that we do much better at image guided radiotherapy. We have developed an imaging device that you can see during radiotherapy, how patients are treated, we come to a much more precise focus in radiotherapy. Then we decided instead of waiting after surgery to treat the patients, now we do it beforehand and the advantage now is with the scans that we make on the linear accelerator, we see the tumour fairly well located so we can focus on the tumour itself and then deliver a higher radiation dose. Thereafter we do surgery because nowadays all these partial breast stories, the surgery removes it. In 95%, I would say, the tumour is at the centre of the specimen so you don’t know where the effects are minimal and where it is extensive and where the tumour was because it’s gene, so now we know much better. Apart from that we’ve got fresh tumour material, we see the changes in gene profile and proteomics so we can predict which patients are sensitive for radiotherapy or not, or for the drugs that fit the profile.

And you’re doing this with a cohort?

Yes, this is a joint trial that I set up, you mentioned that I was a Professor in Paris together in Amsterdam, so I have a link with Institute Gustave Roussy, Amsterdam and Karolinska in Stockholm; the three of us are now doing this trial.

And now you have a Dutchman running Gustave Roussy.

So that will stimulate further co-operation. We see the Dutch mafia is extending throughout.

Harry, thank you very much indeed.

Can I tell you some of my work?

Yes, go for it.

I would like to tell you one of my worries I have now at the present time. You know at the ASCO, the CLCB study has published and shown that giving hormone adjuvant treatment instead of radiotherapy has produced extremely good results. We have the STAR trial, probably you have discussed it before, but what all these trials are suggesting is that you can do different things than radiotherapy, or different approaches, in a very easily replicable way to deliver long-term hormonal treatment, you can get the same results. But I would warn the community that they should not jump on T3 cells, we should be extremely careful because you should look at the selection criteria of the trial and I think what is more important is that we, as the radiation community, should investigate much more in depth which patients need radiotherapy and which patients don’t need radiotherapy. And immediately replacing with hormone therapy, like HER mutation inhibitors, that’s the wrong way to go, I think, because you know very well the side effects if you take them for five years you’ve got problems with your breast, you’ve got some muscular problems, you’ve got a high chance of bone fracture etc instead of the simple treatment of radiotherapy for three weeks.

I mentioned before about image guided radiotherapy, that’s a completely different radiotherapy to the past because nowadays we are much better at sparing the heart, sparing the normal tissues and so the side effects that we know from previous trials with conventional radiotherapy do not necessarily exist anymore in the future.

So I think for old patients instead of five years of treatment with drugs with side effects compared to the three weeks of treatment, it’s a much easier treatment and the old patients are much better and we are sure that the dose is delivered.

And are there plans to do that in Europe?

Yes. I can refer, for example, to a simple trial in Denmark, where they’re trying now to extend it after five years to continue but mostly older patients stop at five years because they are fed up with the side effects.

All because five years was the tamoxifen time and doctors just do five years, because that’s what they always did.

Yes, but it’s mostly the patients that suffer.

I share your concern, particularly about length of follow up with some of these trials and the selection criteria are clearly very confused, as I see them, in the TARGET paper. I also, however, am a little bit concerned with the image-guided radiosurgery technologies which are in evidence at this meeting. I’m not seeing too many randomised trials comparing the knives with the conventional radiation, does this bother you or is this just because I don’t understand the physics?

Well, let’s say, for example, lung trial of lung patients, we’re now doing a trial in Holland to do the stereotactic irradiation first then surgery. So these are small tumours in the lung and, despite the fact that  we’ve shown in our institute that with this group of patients, T1, T2 tumours, small tumours, we give them only three sessions, so three times a very high radiation dose and then we have seen local control in 90-95% of the patients. That’s in a phase II study but now this is developing in a phase III study where we compare, let’s say, surgery so a tumorectomy versus radiotherapy. So that’s coming on, but if you look at the phase II data of the lung trial it’s absolutely convincing because there’s no morbidity, you don’t have to go to the operation theatre, it’s not possible.

And all these knives are the same?

Absolutely not. It really needs very dedicated, very sophisticated radiotherapy and you have to take care of the movement, you have to calculate precisely, you have to emit it precisely. So it’s not an easy job.

So will we know in two years’ time at ESTRO 31, for instance?

It will take three to four years.

Longer than that?

Yes.

Harry, I can rely on you to do evidence based clinical trials for ever. Thank you very much.