The 2013 George Edelstyn Lecture: The long and the short of radiotherapy fractionation in early breast cancer


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John Yarnold1
1The Institute of Cancer Research, London, UK

Abstract

The responses of different normal tissues to daily dose (fraction size) >2.0 Gy vary; late-reacting normal tissues being much more sensitive to fraction size than early-reacting normal tissues. Cancers vary too, most types being insensitive to fraction size. All tissues, normal and malignant are sensitive to total dose. The implication for radiotherapy dose prescriptions is that therapeutic ratio is, on average, optimised by aiming to deliver the highest total dose in the smallest (≤2.0 Gy) fractions. Over the last 5 years, level 1 evidence confirms that breast cancer is an exception in being as sensitive to fraction size as the dose-limiting late-reacting normal tissues, a conclusion based on 10-year follow up of >8,000 patients entered in randomised clinical trials, including the UK START trials. The result has been to switch from a standard 5-week schedule of 25 fractions to a more convenient 3-week schedule delivering 15 fractions of 2.7 Gy. Subgroup analyses based on patient age, breast size, tumour grade, receptor status, node status, surgery, lymphatic radiotherapy and systemic therapies are only fully represented in overviews involving tens of thousands of patients, but those conducted on current data sets are reassuring and suggest that the trial results are generalisable. In patients with left-sided cancer, there is no lower radiation dose threshold for major cardiac events, so the priority is to protect the heart whatever fractionation is used. The brachial plexus is also a critical normal tissue, but whatever estimate of fractionation sensitivity is assumed, 40 Gy in 15 fractions delivers a dose intensity lower than 50 Gy in 25 fractions. 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 for whole or partial breast external beam radiotherapy. Based on the UK FAST trial testing two 5-fraction schedules of whole breast radiotherapy delivered in 5 weeks, the current UK FAST Forward trial compares two 5-fraction regimens delivered in 1 week with a control regimen of 40 Gy in 15 fractions. Hypofractionation trials provide an evidence base for the current evaluation of synchronous boost techniques using intensity modulated radiotherapy, approaches that are under evaluation in current UK randomised intensity modulated and partial organ radiotherapy (IMPORT) trials. Over the next five years, the priority is to identify tumour biomarkers predicting fractionation sensitivity that allow patient stratification to larger or smaller fractions. Meanwhile, a 5-fraction regimen of local-regional radiotherapy for women with early breast cancer is a realisable research outcome by the end of this decade.

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