Highlighting Welsh Cancer Research

Combining drugs with radiotherapy

Prof John Staffurth - Cardiff University, Cardiff, UK

Radiotherapy is incredibly potent, incredibly effective and important for cancer care. About 50% of patients with cancer will get radiotherapy at some point in their treatment; it’s a fantastic curative treatment option. So about 40% of the patients who are cured of their cancer receive radiotherapy as part of it; over 100,000 patients each year in the UK receive radiotherapy as part of their treatment so obviously any way of improving radiotherapy is going to potentially benefit a vast number of patients.

It’s also potentially useful for virtually every different tumour site at some stage for some type of patients. As a curative primary treatment it can be used in brain, oesophageal, lung, pancreas tumours and these are the CR UK cancers of unmet need, as well as head and neck, rectal, prostate cancer, I can go on and go on. It’s incredibly important for cancer care to get radiotherapy better.

So radiotherapy is already often combined with systemic therapies and this is a slide from the BC2001 study looking at bladder cancer patients adding in chemotherapy in blue compared to radiotherapy alone in red. This is a trial done in the UK and it showed improvement in local control dramatically with the addition of chemotherapy to radiation. This was done, it’s very well tolerated. You get a slight increased risk of acute toxicities, no increased effect of late toxicities, improved tumour control, improved survival and better preservation of the bladder itself. You don’t need to have surgery to take the bladder out because it’s all completely eradicated so patients get a better quality of life. I could do this for oesophageal cancer, lung cancer, brain cancers, anal cancers, I could go on and on. But we want to make it better.

Now radiotherapy itself is getting better and this is a slide looking at technical radiotherapy. So one of the first ones is SABR, or stereotactic ablative body radiotherapy so this is very highly accurately targeted radiation with imaging before, during and immediately after radiotherapy so that we’re so accurate with the radiotherapy we’re giving we don’t treat anywhere near as much of the normal tissue as we used to do. This means we can treat patients we couldn’t treat before and we can treat in very high doses given in just two or three fractions, maybe three or four fractions, with a very, very low side effect profile. So we can now treat patients very, very accurately and this can be done on linear accelerators, in Cardiff, for example, we’ve had particularly an accelerator called a TrueBeam STx bought by the Welsh Assembly a couple of years ago and another one being commissioned at the moment.

You’ve already mentioned proton beam therapy, the same sort of concept really which is that if you give your radiation in a way that gives less dose to your normal structures patients get less side effects so you can treat more patients, you can treat them to maybe higher doses. As radiotherapy is starting to change we’re also thinking, well, what else can we do with radiation? This is going to be combining the novel drugs with radiotherapy because however good technical radiotherapy gets we’re not going to be able to cure all patients, we know that.

The development in molecular biology means we’re better starting to understand why patients aren’t being cured with radiation and the development of drugs targeting particular pathways that are wrong with these patients means that we’ve now got very accurate drugs which are going to be used for individual patients but they’re probably not going to cure patients on their own. But they may be able to be combined with radiation to get the optimal benefit.

So we’ve just done a review published in Nature Reviews Clinical Oncology , this is a CTRad initiative, which is a UK collaborative I’ll tell you about in a moment, looking at the potential areas that combining novel drugs with radiotherapy might benefit. Basically throughout the whole of the pathway of aberrant molecular pathways, which are the background to why cancers are formed and why they are resistant to treatments, you have the potential to add in novel targets, novel agents against these novel targets, to improve the outcome. The areas I’ve highlighted are hypoxia, so that’s poor blood supply because you know that’s incredibly important for the failure of radiotherapy and there has been work done for many, many years trying to modify the oxygen supply to blood vessels and there are new agents coming through, coming to clinical trials at the moment.

Then on the left hand side you’ve got DNA damage and repair pathways and this is very important because obviously radiation causes DNA damage and tumours have aberrant DNA repair mechanisms and maybe if you combine the right targeted agent with radiation you might be able to get improved outcome. And the one on the right I’m going to give you a little bit more about which is about immunotherapeutics and the potential for radiation to enhance the novel immune checkpoint inhibitors coming through at the moment.

One of the reasons why you combine radiation with immunotherapies and other systemic agents is because they have different spatial effects. So radiation is a local treatment and the drugs may be more of a systemic treatment. So you’ve got two different treatments working in two different anatomical parts of the patient and often the side effects don’t overlap – the radiation effects are different from the drug effects - so you can combine them together without getting too much serious long-term consequences.

Also we know that a lot of the new drugs specifically target the mechanisms of resistance. So with radiotherapy it can be poor local invasion of the cytotoxic T-cells into the cancer eradicating the cancer and radiotherapy might be able to help that. Also we know that a lot of the tumours that are resistant to radiation have a high mutagenic load because they’ve got a very aberrant genetic background and that these are the very cancer types that seem to respond best to immunotherapeutics.

So if you then look at the tumour scenario and you add in radiation and if you think about the setting of adding in a new immune checkpoint inhibitor, there’s a lot of the benefits of radiation particularly work in the immune setting. So you can improve the vasculature so that the immune cells can get into the tumour and try to eradicate them. You can open up the repertoire of the cancer antigens, so the peptides that are on the tumour cells, which are presently masked so the immune system can’t see the cancer and radiation actually unlocks new antigens allowing the host immune system to see the cancer and try to eradicate it.

We also know with radiation that if you give a low dose of radiation you get one effect and if you give a very high dose of radiation you get a different effect, often in the high dose area of very immunogenic cell death really giving a danger signal to the host, to the human, the patient, there’s a nasty going on here, come and kill it. And the radiation can actually stimulate the immune system to work collaboratively with the immune system.

So there’s a lot of modelling work and there has now been some mouse work, this is some mouse work published from Manchester, The Christie, in mice work showing that the sequencing of the drugs and radiation is very important. If you use an immune checkpoint inhibitor and you give it before radiation, then give the radiation, you get a fantastic benefit overcoming the resistance of radiation. But if you give the radiation first and then add the drug in afterwards you get no benefit. So you need to do a lot of laboratory work and that has generally been done and we’re now moving into the setting of wanting to do clinical trials.

The clinical trial work in radiation has been relatively poor over the last ten years or so but about seven years ago the National Cancer Research Institute set up CTRad, Clinical and Translational Radiotherapy Research Working Group, and this has reinvigorated radiotherapy research in the UK. This group has tried to bring a collaboration of researchers around the UK to develop drug radiotherapy combinations. They’ve done it by first of all setting up an early phase drug combination work-stream and that is currently co-chaired by Richard Adams, my colleague in Cardiff. We’ve set up an organisation called RADCOM which basically tries to pull the various preclinical researchers around the UK together to work collaboratively in developing all the preclinical work that needs to be done before you take these novel agents into clinical trials. We’ve got radiation oncologists such as myself but not actually myself onto the CR UK’s new agents committee to try to help get the optimal design for these complex trials of radiation and drugs and have published a group consensus including pharma, funding bodies, FDA, to try to talk and work out how you might encourage pharma companies to invest in drug radiotherapy combination trials because it’s quite complex for pharmaceutical companies to get their drugs to market in combination with radiation.

We had a series of science meetings, one done very recently, looking at drugs and immunotherapy agents and radiation. One of the things that this showed is that at the moment there’s only four centres in the UK that have really got the infrastructure at the moment to do early phase drug radiotherapy trials. Now this is partly because the early phase drug trial work is generally done by medical oncologists and I’m a radiation oncologist and so there isn’t necessarily that experience and collaboration in a lot of the centres of working with radiation oncologists and medical oncologists, partly because the setting of radiation of irradiating patients who have been curative, and we’re already on a very fine balance between curing patients without causing side effects yet if we give too much radiation we can cause critical additional side effects and so the balance of adding in a new drug can be very detrimental. So it’s only at the moment the bigger centres, The Marsden, Oxford, Christie and Glasgow, that are able to do these trials.

Saying that, The Marsden have got a series of seven trials they’re running, all with one of the immune checkpoint inhibitors, pembrolizumab. But the important thing here is they’re doing it in a variety of different tumour sites, so melanoma, bladder,  radiotherapy with mixed tumour sites, cervix cancer, head and neck cancer, lung cancer and mesothelioma. They’re doing it in both the radical setting and in the palliative setting, sometimes using brachytherapy, so implanted radiation, and lots of different schedules. So one of the centres that is able to do these trials is doing it in a broad spectrum of tumour sites and that’s the excitement of drug radiation combinations.

So what I want to try and do is put Cardiff on the map and try and get us to have the infrastructure to be able to work collaboratively with our colleagues around the UK. So what we’ve done over the last just six months, a very short time frame, is working with the established solid tumour early phase trial groups, this is with the medical oncologists running in Cardiff, and working with our established radiotherapy trials group which has got a history of leading and designing clinical trials and delivering clinical trials over the last 15-20, 30 years, certainly before I came here about twelve years ago. We’ve identified two test trials that we’re going to try and run, the first in the next six months and one early next year. Now, one of these is in oesophageal cancer, it’s a collaboration with Oxford looking at a hypoxia modifying agent with a colleague, Paul Shore [?]. The second is going to be with a PARP inhibitor, so looking at DNA damage inhibition in the radical setting in glioblastomas, so brain tumours, working with Glasgow. So we’re already working with the leading centres in the UK.

We’ve explored our initial delivery issues; we’ve got short term to allow us to do these two studies and we’re starting to identify potential follow-on trials which include not just academic trials but actually a first commercial trial coming in. That would be one of the first commercial trials in the UK in this setting. Then working with John and the larger bid back to CR UK hopefully looking at longer term funding that can come in if this initial trial test works OK.

Then we’ll try and design new trials. So there are three trials currently in development at the moment, two led by Richard Adams, one in anal cancer in the radical setting, one, again with Richard, in rectal cancer in the palliative setting and the first one has gone to funding and one much earlier on. Then we’re trying to do translational opportunities so we’re doing a lot of work engaging with the Cardiff University researchers, with the immunologists, trying to basically tell them, ‘We’ve got these trials running, we’re designing the trials, what translational research can we do to work with you to get more understanding from the trials that we’re doing?’

It’s not the only thing going on in Cardiff radiation, we are also aiming to be a recognised UK Centre of Excellence, as described there and I guess I’d better stop there. So I think it’s a very exciting time, a lot of developments in clinical radiotherapy, a lot of developments in the UK for radiotherapy research. Radiotherapy is technically complex, it needs a team approach. Doing drug radiotherapy combinations is increasingly complex, it also needs a team approach and fortunately here we have got the team. So this is the Avengers Assemble, trying to show that if we work together we can be a lot better. At the moment we’ve got in a really short time-frame we’ve got five or six clinical oncologists working at a national level designing trials already wanting to get into this area. We’ve got the Early Phase Trial Group which is currently in Velindre which has been delivery trials which are supporting this brilliantly in starting one or two early trials. Then the Radiotherapy Trials Group which we need to support, the high quality radiation will come through and hopefully there will be opportunities doing this with protons in the future, we’ll have to see about that.