Publications

Few trials of adjuvant breast radiotherapy have incorporated patient-reported breast symptoms and related areas of quality of life. We assessed these measures in a quality-of-life study that was part of the randomised START (Standardisation of Breast Radiotherapy) trials.

Deregulation of normal regenerative responses to physical, chemical and biological toxins in susceptible individuals leads to abnormal remodelling of extracellular matrix with pathological fibrosis. Processes deregulated after radiotherapy have much in common with processes associated with fibrotic diseases affecting the heart, skin, lungs, kidneys, gastro-intestinal tract and liver. Among the secreted factors driving fibrosis, transforming growth factor beta 1 (TGFβ1) produced by a wide range of inflammatory, mesenchymal and epithelial cells converts fibroblasts and other cell types into matrix-producing myofibroblasts. Even if required for the initiation of fibrosis, inflammation and the continued stimulus of TGFβ1 may not be needed to maintain it. After myofibroblast activation, collagen production can be perpetuated independently of TGFβ1 by autocrine induction of a cytokine called connective tissue growth factor. The role of inflammation, the origins and activation of myofibroblasts as biosynthetic cells and the downstream pathways of extracellular matrix synthesis in common fibrotic states are reviewed. Oxidative stress, hypoxia and microvascular damage are also considered, before examining the same processes in the context of radiotherapy. One of the main uncertainties is the relevance of very early events, including inflammatory responses in blood vessels, to fibrosis. Despite the power of animal models, including genetic systems, the potential contribution of research based on human tissue samples has never been greater. A closer interaction between scientists researching fibrosis and radiation oncologists holds enormous promise for therapeutic advances.

Despite the improvement in outcome for women with early breast cancer undergoing breast conservation surgery and radiotherapy, there are significant gaps in our understanding of local tumour relapse. In this Personal View, we propose two hypotheses: early-onset changes in breast-duct anatomy limit the degree of intraductal spread and explain much of the substantial age-related difference in risk of local tumour relapse; and wound-healing proteins stimulate the growth of cancer cells left behind after surgery. These mechanisms help to explain why generous surgical margins offer no greater protection against local tumour relapse than narrow margins after complete microscopic tumour excision.

Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration.

The international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size.

The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2.0 Gy over 5 weeks, but there is a long history of non-standard regimens delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2.0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy.