Hopwood, P., Haviland, J.S., Sumo, G., Mills, J., Bliss, J.M., Yarnold, J.R. & START Trial Management Group,
(2010). Comparison of patient-reported breast, arm, and shoulder symptoms and body image after radiotherapy for early breast cancer: 5-year follow-up in the randomised Standardisation of Breast Radiotherapy (START) trials. Lancet oncol,
BACKGROUND: 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. METHODS: In START trial A, 2236 patients were randomly assigned to receive either 39 Gy or 41.6 Gy delivered in 13 fractions over 5 weeks or a global standard of 50 Gy in 25 fractions. In START trial B, 2215 women were randomly assigned to receive either 40 Gy in 15 fractions over 3 weeks or the same control regimen (50 Gy in 25 fractions) as in trial A. 2739 patients were eligible for the quality-of-life study of whom 2208 (81%) were accrued (1129 patients from trial A and 1079 from trial B). Participants completed the EORTC QLQ-C30 and BR23 questionnaires and protocol-specific radiotherapy items up to 5 years after radiotherapy. We compared results across regimens with generalised estimating equations and survival analyses. The START trials are registered, ISRCTN59368779. FINDINGS: At 5 years, up to 40% women reported moderate or marked changes to the breast after radiotherapy, and arm and shoulder pain affected up to a third of patients. Breast symptoms and body image concerns reduced over time. Rates of radiotherapy adverse effects were lower for the 39 Gy regimen in trial A and the 40 Gy regimen in trial B, compared with the 50 Gy control regimen; rates of radiotherapy adverse effects were similar between the 41.6 Gy and 50 Gy regimens in trial A. Adverse change in skin appearance was significantly lower for patients who received 39 Gy compared with those who received 50 Gy (HR 0.63, 95% CI 0.47-0.84) and for those who received 40 Gy compared with those who received 50 Gy (0.76, 0.60-0.97); no significant difference was observed between patients who received 41.6 Gy and those who received 50 Gy in trial A (0.83, 0.63-1.08). Patient self-ratings of breast symptoms discriminated a 10% difference in randomised dose intensity. Up to a third of women reported moderate or marked pain in the arm and shoulder over 5 years whilst more than 10% experienced moderate or marked arm and hand swelling, with no significant difference in arm/shoulder subscale scores between the regimens in trial A or trial B; many baseline arm and shoulder symptoms were associated with prior surgery. INTERPRETATION: A substantial proportion of women report moderate or marked breast, arm, and shoulder symptoms over 5 years of follow-up after radiotherapy, but with no detriment to body image. Nonetheless, most patients stand to gain from hypofractionated radiotherapy regimens with a potential for fewer adverse effects; this strengthens the evidence from the START trials for hypofractionated regimens for women requiring radiotherapy for early breast cancer. FUNDING: Cancer Research UK, UK Medical Research Council, UK Department of Health..
Yarnold, J. & Brotons, M.-.
(2010). Pathogenetic mechanisms in radiation fibrosis. Radiother oncol,
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..
Mannino, M. & Yarnold, J.
(2009). Effect of breast-duct anatomy and wound-healing responses on local tumour recurrence after primary surgery for early breast cancer. Lancet oncol,
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..
Ellis, P., Barrett-Lee, P., Johnson, L., Cameron, D., Wardley, A., O'Reilly, S., Verrill, M., Smith, I., Yarnold, J., Coleman, R., et al.
(2009). Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet,
BACKGROUND: 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. METHODS: In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2), cyclophosphamide 600 mg/m(2) at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m(2) at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m(2) at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. FINDINGS: All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0.95, 95% CI 0.85-1.08; p=0.44). 75.6% (95% CI 73.7-77.5) of patients in the experimental group and 74.3% (72.3-76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). INTERPRETATION: This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. FUNDING: Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche..
START Trialists' Group, , Bentzen, S.M., Agrawal, R.K., Aird, E.G., Barrett, J.M., Barrett-Lee, P.J., Bliss, J.M., Brown, J., Dewar, J.A., Dobbs, H.J., et al.
(2008). The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet oncol,
BACKGROUND: 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. METHODS: Between 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy versus 41.6 Gy or 39 Gy in 13 fractions of 3.2 Gy or 3.0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 749 women were assigned to the 50 Gy group, 750 to the 41.6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5.1 years (IQR 4.4-6.0) the rate of local-regional tumour relapse at 5 years was 3.6% (95% CI 2.2-5.1) after 50 Gy, 3.5% (95% CI 2.1-4.3) after 41.6 Gy, and 5.2% (95% CI 3.5-6.9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0.2% (95% CI -1.3% to 2.6%) after 41.6 Gy and 0.9% (95% CI -0.8% to 3.7%) after 39 Gy. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0.69 (95% CI 0.52-0.91, p=0.01). From a planned meta-analysis with the pilot trial, the adjusted estimates of alpha/beta value for tumour control was 4.6 Gy (95% CI 1.1-8.1) and for late change in breast appearance (photographic) was 3.4 Gy (95% CI 2.3-4.5). INTERPRETATION: The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41.6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions..
START Trialists' Group, , Bentzen, S.M., Agrawal, R.K., Aird, E.G., Barrett, J.M., Barrett-Lee, P.J., Bentzen, S.M., Bliss, J.M., Brown, J., Dewar, J.A., et al.
(2008). The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet,
BACKGROUND: 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. METHODS: Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy over 5 weeks or 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6.0 years (IQR 5.0-6.2) the rate of local-regional tumour relapse at 5 years was 2.2% (95% CI 1.3-3.1) in the 40 Gy group and 3.3% (95% CI 2.2 to 4.5) in the 50 Gy group, representing an absolute difference of -0.7% (95% CI -1.7% to 0.9%)--ie, the absolute difference in local-regional relapse could be up to 1.7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy. INTERPRETATION: A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions..