ISH 2016

Radiotherapy in Hogkin lymphoma: reducing risk in later life

Dr Graham Collins - Oxford University Hospitals NHS Foundation Trust, Oxford, UK

Radiotherapy is a very powerful treatment modality in Hodgkin lymphoma and, in fact, fifty years ago it cured people with early stage disease. The issue that we know about with radiotherapy is that years later there’s a much higher risk of developing cancer in previously irradiated sites. Again, Hodgkin’s is a curable disease so we need to be thinking about what our treatments are doing to people in twenty, thirty, forty years’ time - is it giving more people cancer, heart disease etc? So one major aim of Hodgkin’s treatment is to maintain the good cure rates while reducing the late effects of chemotherapy. One way we might be able to do that is to use PET scanning and in people who have a very early PET negative scan, the prognosis of these patients is very good, so can we omit radiotherapy from those patients meaning that they have a much less chance of these late effects? There have been randomised controlled trials looking at this and trials are really designed to answer questions but one thing sometimes they do is they just make the questions more interesting and I think that’s what these trials have done. So the debate now is what these trials have shown is that whenever you omit radiotherapy, whenever you leave radiotherapy out, the chance of relapse, even in PET negative patients, is slightly higher, by about 4-5%. So that’s a clear message from these trials but the majority of patients are still cured who don’t have radiotherapy.

So where we’re moving to now, and what the debate will focus on, is personalising the treatment approach so one standard doesn’t necessarily fit all. So if you have a young woman who has disease in the high neck and high mediastinum, actually the risk of secondary cancers from radiotherapy in that region is relatively low so my practice would be to offer radiotherapy in that situation. Whereas, if you have low mediastinal disease and bilateral axillary disease the risk of radiotherapy causing breast cancer later is really quite high, 30% at thirty years, that’s a substantial risk. Yet again it involves a discussion with the patient but patients often say to me they would be happy to accept a 4% increase in relapse risk knowing that their risk of breast cancer later in life is substantially lower. So I think these trials are helping us to personalise the treatment approach for each patient.

Why should we use this treatment?

I’m arguing that we should be using PET to drop radiotherapy in certain patients and, again, it’s all focussed on the late effects. If we can drop radiotherapy that is a good thing for patients later in life, it reduces the risk of breast cancer, heart disease. I’ve talked about using it in early stage patients, I actually think the evidence for doing this in late stage, advanced stage, disease is even stronger. So if you’re treated with a BEACOPP based approach, which most people in the UK aren’t but certainly worldwide many countries use this, then actually leaving out radiotherapy in PET negative patients the results are excellent. So I think that’s not very controversial. Even in patients who are treated with ABVD, which is more of a UK, North America style approach, a recent UK study didn’t use radiotherapy at all in patients who were PET negative early on and again the three year progression free survival was 85%. So in advanced stage disease actually there’s increasing evidence that if you get PET negative early that means you’re responding really well, omitting radiotherapy, yes, it might slightly increase the relapse rate but actually the cure rates are still very high and you’re saving patients from those late toxic effects.

However, I’m sure what my opponent will point out, and he’s quite right, is that whenever radiotherapy is omitted the relapse rate is slightly higher. So there is a cost to reducing late effects and that is a slightly higher relapse rate early on and that’s really where the debate focusses.

What about relapse rates?

Any trial that has looked at this the relapse rate is slightly higher and whenever people have done a meta-analysis, so looked at lots of trials and combined them all, of course this was in the pre-PET era so it doesn’t quite reflect what our debate will be focussed on, but whenever people have done meta-analyses then often those meta-analyses show a worse overall survival if you omit radiotherapy. So what we don’t want to do is throw the baby out with the bath water. I certainly don’t think we should be saying PET negative means definitely no radiotherapy in all situations. It is an extremely effective treatment modality so I’ll be interested to see how the debate goes. I think with most of these debates it won’t be completely polar, I’m sure there will be some common ground but watch this space.

How accessible is PET imaging?

We’re extremely fortunate in the UK actually, most centres have pretty good access to a PET scan. Sometimes patients have to travel and that’s still an issue but, on the whole, the access is there and it is funded. So that’s not the case for every country around the world by any means but in the UK we are quite fortunate.

Will immunotherapy affect PET scans?

Immunotherapy and PET scanning is a really hot topic. The immunotherapies, the PD-1s, are very good at inducing remissions in Hodgkin’s, they’re not very good at inducing complete remissions, in other words, the PETs often remain positive. The question in my mind, though, is what that means because a PET scan, what’s positive on a PET isn’t always lymphoma or cancer, it could be inflammation. If you’ve got an agent that’s stimulating the immune system, which is what PD-1s are supposed to do, then actually you might get false positives on a PET scan. So PET may not be the best modality to assess response to immunotherapy agents. We just don’t know what a positive PET scan means with immunotherapy so it does throw the whole use of PET into question when using that class of drugs. I don’t want to minimise the utility of PET, it’s a very valuable treatment modality in Hodgkin’s but it does depend on the treatment that you’re using.