New radiotherapy techniques target lung cancer with less toxicity

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Published: 10 Nov 2014
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Prof Robert Timmerman - The University of Texas Southwestern Medical Center, Dallas, USA

Prof Timmerman talks to ecancertv at NCRI 2014 about new radiotherapy techniques which target cancer more precisely, sparing the surrounding tissue from the "collateral" damage that was previously a significant issue.

The people organising the meeting asked me to talk about some newer forms of radiotherapy. Radiotherapy has always been a technology driven field and the technologies have improved really dramatically, especially with faster and more modern computers and they’re driving these machines that can highly focus radiation to specific spots in the body to try to target the cancer. Historically radiotherapy caused a lot of collateral damage, that is the field would often encompass a swathe of tissue throughout the body causing just as much normal tissue injury as it did targeting the cancer. These newer techniques are able to focus the radiation specifically at the tumours, even tumours that are moving, and target them without much normal tissue exposure. It’s only getting better with things like charged particles, protons, carbon, things like that, to the point where the collateral damage is really minimised.

So these technologies are expensive and so one has to make sure that they’re worth the added cost. Historically, radiation oncologists unfortunately didn’t do many clinical trials, they just basically had new technology, touted its benefits without confirming it in clinical trials. We’re not getting away with that anymore and so the expectation is that we’ll do clinical trials. One in particular, called stereotactic ablative radiotherapy, has been shown in early clinical testing to be quite significantly better at treating early lung cancer, that is stage 1 lung cancer, where it’s quite limited. This is a cancer that has been treated with surgery for decades, a very good treatment but at a significant cost to patients. It’s simply hard on the patient to have a big surgery like that and many people with lung cancer are already having frailties that make that operation difficult. So this is a completely non-invasive outpatient treatment typically done in one to three or five treatments, which is very different than the conventional radiotherapy which is six weeks or seven weeks of daily treatment. So in the early clinical testing of this stage 1 lung cancer it was shown that tumours could be eradicated that were aimed at with the therapy with a probability of over 90%. That, of course, rivals surgery.

Not a perfect therapy; sometimes when the tumours were very close to the centre of the chest where the airways branch off there was more toxicity but this was a dramatic difference than historical non-invasive treatments that had control rates in the 40-50% range. So that has been extensively now utilised throughout the world and I think that there’s pretty much buy-in that this is a very nice alternative, especially for the patients who can’t tolerate surgery and there are many of those.

But what I’m talking about at this conference, which is really exciting for us, is we decided to use this therapy at the other end of the spectrum, that is people with metastatic disease. These patients, of course, have dismal survival rates. Historical use of systemic therapies like chemotherapy have been able to maybe shrink some of the tumours some of the time but pretty much no chance of a cure and very short survival. For example, in patients who are first diagnosed with metastatic lung cancer the median survival is under six months so the tumour is unrelenting and often leads to a quick demise of the patient.

In the past surgery has been used to try to treat metastatic disease and surgery also, like the SABR treatment, is a local treatment but at a fairly high cost. So when patients had their metastatic disease resected they often ended up with long hospitalisations and difficulty in recovery. Some patients were cured, though, leading to an excitement about something we call oligometastatic disease, or few tumours, instead of the widespread metastatic disease that also exists.

This new treatment, though, might not be so costly for the patient and so we tested it in a group of patients with metastatic lung cancer. These were the worst of the worst, they had already had progression on conventional standard chemotherapy like platinum based treatment and we decided to treat every tumour that was visible on scanning with this SABR treatment. We treated 24 patients in this phase II pilot study, rather modest doses of the stereotactic ablative treatment, the SABR treatment, which therefore didn’t lead to much toxicity. Typically these patients have a median progression free survival of 2-3 months and in this pilot trial they had a median progression free survival of nearly 15 months. This is really a dramatic improvement. Some of the patients are out four and five years without progression. I’m not saying they’re cured but by adding this local therapy we did seem to extend their progression free survival by a lot. This was coupled with a drug called erlotinib which is a molecular targeted agent that had already been established in that role but it dramatically improved their results.

So this new sort of model of adding a local therapy to an already established systemic therapy may have legs and it does make some sense that the systemic treatments have always thought to be best against microscopic disease because they do struggle with tumour bulk. In many studies the first site of progression in patients treated with chemotherapy or targeted agents is often the sites that were already visible when they were enrolled to the treatment. So if you can add to that a little help, a little extra nudge, from a local therapy that’s not so costly, this actually makes a lot of sense and may be the extra effort that causes a cure, improves survival.

Is there potential to use this in other areas?

In the first step with lung cancer, which is a tough disease to treat, most people would have been sceptical that this was the right model to use but there are so many patients that it just made sense to us to at least try it in this dismal disease. So we’re moving on to diseases that might not have quite such a heterogeneity of tumour type and poor prognosis. So there are trials now being done in breast cancer, which has similar patterns of relapse, and importantly we’re looking at paediatric cancers to try to cure children who have metastatic cancer. So the first step is to confirm that indeed the local therapy can be added safely to the systemic treatment and then conduct the clinical trials, initially comparing it to historical results but later we’ll do more high level evidence of testing.

How is this type of radiotherapy different?

Conventional radiotherapy has used these very small daily doses and therefore adding them up over many days. So, like I say, the typical treatment course for conventional radiotherapy is a month or two of daily treatment. The reason that that was done was when more short courses were used historically, and I’m talking about almost a hundred years ago, there was severe toxicity, mostly related to the fact that the technology couldn’t differentiate the tumour from the normal tissues. So a treatment that can kill a tumour can obviously also kill normal tissue and therefore there was no therapeutic benefit; you hurt the patient just as much as you helped them. So these small daily doses were used to try to exploit slight differences between the normal tissue’s reaction to the radiation and the tumour’s reaction to the radiation. This was done for decades with this technique and it really limited the ability of radiotherapy to make an impact short of mopping up after surgery, or something like that.

This new treatment, though, utilises technologies that allow the dose to be highly localised, using very small fields, often hundreds of fields. Each field doesn’t cause much entry or exit damage but they’re precisely localised on the tumours, overlapping to where they can really push hard on the tumour itself. Tumours move and so accommodation has to be made for the motion of the tumour that historically was not done or in the past it was just that the field has expanded to deal with any motion. But this course adds to the toxicity and so these new techniques track the motion or account for it in a more sophisticated way.

Then, most importantly, giving the treatment in what’s called hypofractionated or oligo-fractionated fractions, where only 1-5 treatments are given rather than 30-40 treatments, dramatically increases the potency of the treatment at the site where the beams actually overlap. It would cause great harm to any tissue that is in the sites but hopefully it’s only the tumour and limited other tissue. In this way we’ve learned through the clinical trials that we’ve done how to deal with the tissue on the edge, that is the adjacent tissue to the tumour, and we’re learning a lot from surgeons who, by their very nature, surgeons cause tissue damage when they try to get to the tumour. But they’ve learned over the years how to poise the tissue to heal after such an insult. We’ve never done that before in our field but we’re learning how to approach the problem using radiotherapy as the knife and then still poise the patient to heal after this type of treatment.

I think it’s an elegant way of getting there where surgery is still a rather crude way of getting to the target and once we’re at the target it then becomes a very simple and bullying therapy to try to cause the tumour great harm.