United Kingdom Experience: Clinical Trial Evolution, Techniques, Data, and Toxicity

As a general rule, cancers respond to the total dose more than to the size of daily fractions used to deliver it. This contrasts with the response of late-reacting, dose-limiting healthy tissues, which are sensitive both to the total dose and to the fraction size. The general rule has been challenged by randomized clinical trials conducted since the mid-1980s, including several United Kingdom (UK) studies offering high level evidence that breast cancer is, against earlier assumptions, equally sensitive to fraction size as the dose-limiting healthy tissues. On this basis, 40.0 Gy in 15 fractions over 3 weeks has been standard in the UK for local-regional breast/postmastectomy radiotherapy since 2009. A number of residual concerns have been resolved by 10-year follow-up of almost 6000 patients. Even assuming very low α/β values for organs at risk, the current standard schedule of 40 Gy in 15 fractions is gentler than the historical 50 Gy in 2.0 Gy fractions. Where the heart is concerned, the priority is protection regardless of fractionation regimen. Large-breasted women benefit from hypofractionation by virtue of less severe acute skin reactions and fewer consequential late effects, in the inframammary fold. The limit of whole breast hypofractionation is currently under test in the UK FAST-Forward trial evaluating a 5-fraction regimen delivered in 1 week.