Give early breast tumours fewer, larger doses of radiation, rather than more, smaller doses

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Published: 14 Nov 2013
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Prof John Yarnold - The Royal Marsden, London, UK

Prof John Yarnold talks to ecancertv at the UK's National Cancer Research Institute ( NCRI ) 2013 meeting about optimial radiotherapy for breast cancer.

Breast cancer is as sensitive to radiation fraction size as normal tissues, 10-year follow-up of clinical trials, including the UK START trials, has shown.

This means it makes sense to give early breast tumours fewer, larger doses of radiation, rather than more, smaller doses.

The result has been to switch from a standard five-week schedule of 25 fractions to a more convenient three-week schedule delivering 15 fractions of 2.7 Gy.

Current 15-fraction schedules are standard of care for local-regional radiotherapy in the UK, but 15- or 16-fraction regimens are unlikely to represent the lower limit.

It is now important to find out if there is wide variation between breast cancers in their sensitivity to different levels of radiation.

If there is a lot of variation between cancers, it highlights the need to identify tests to exploit this variation for the benefit of future patients.
By the end of this decade, research could bring about a regimen of local-regional radiotherapy with as few as five fractions for women with early breast cancer.

John Yarnold is Professor of Clinical Oncology at The Institute of Cancer Research, London, and Honorary Consultant at the Royal Marsden NHS Foundation Trust.

The ten year results of the START trial were published just a few weeks ago so I presented those to the audience and it confirms the hypothesis that had been under test that breast cancer is as sensitive to the size of the daily dose, or what we call the fraction, as the dose limiting normal tissues which means that continuing the historical practice of giving lots of small doses that we’re sparing the breast cancer as much as we’re sparing the healthy tissues. In other words, there’s no advantage to that practice. And that a fifteen day schedule of radiotherapy is as safe and non-inferior to a traditional 25 fraction, five week schedule so that has been standard of care in the UK and increasingly in other countries for several years now. Since then we are conducting a trial which is evaluating a one week course of radiotherapy against the three week standard, the so-called FAST-Forward trial. That’s been running for two years in the UK and it’s just recruited its 3000th patient. So that will finish accrual in about three months’ time with 4000 patients and we would hope then within five years to have a curative treatment of radiotherapy for breast cancer patients which would involve five days, one week, of therapy and that’s clearly a very good proposition.

At the same time we’re interested to know whether all breast cancers are equally sensitive to fraction size. We know they are on average so one of the translational priorities for the next ten years is to actually identify whether there’s a wide range of sensitivities that we can actually exploit and stratify patients to, whether that stratification might be generalizable to other cancers, for example. So that will be one avenue of future translational research. Another would be that the three week schedule performed in our trial, START trial B, slightly better than we expected it to be. Not only did it appear non-inferior but in fact local control was 1% better than in the 15 fraction arm in the 25 fraction arm. If that result were to be representative of breast cancer response to radiotherapy, we suggest that treatment time is much more important than we thought. In other words, the shortening from five weeks to three weeks, of itself, had a therapeutic effect. If one does fairly simple calculations it would mean that about 0.6Gy, or 25% of our daily dose, is in fact compensating for proliferation overnight and over weekends. That’s an interesting proposition and that is certainly known already for other cancers, head and neck cancer for example, where we treat over the weekends for that very reason but it’s never been considered in the context of breast cancer.

Are we looking at an approach of personalised treatment?

To the extent that breast cancer, we’ve demonstrated that it is, on average, sensitive to fraction size, then we stratify our cancer patients by breast cancer type and we then allocate them, if you like, a stratified schedule, the 15 fraction schedule which we didn’t do before. As I’ve just mentioned, if we can identify biomarkers that would actually measure an individual’s likely sensitivity to fraction size we would then start to stratify sub-populations of patients. That would be a long-term research aim and by long-term I mean a five to ten year programme. But that certainly would be certainly a realisable research objective and, we would hope, would be generalised beyond breast cancer to other tumour types.