Standardisation Of Breast Radiotherapy Research Articles

Abstract P5-16-10: Post-mastectomy radiotherapy following immediate implant based reconstruction: A possible solution to a reconstructive challenge

Abstract Aims: The National Mastectomy and Breast Reconstruction Audit report (NMBRA, 2011)1 revealed that immediate implant-based breast reconstruction (IIBR) was the most common type of primary reconstruction performed in the UK (37%). The main reason given by clinicians for not offering immediate breast reconstruction was the need for adjuvant radiotherapy. Post-mastectomy radiotherapy (PMRT) decreases the rate of local recurrence as well as increase the long-term survival in patients who demonstrate intermediate to high-risk features2,3 but has been shown to increase the risk of implant complications in IIBR by up to 24% (Berry et al, 2010)4. Cordeiro et al (2004)5 showed the incidence of capsular contracture was 28% higher in the PMRT group compared with non-irradiated patients. Most patients in the UK receive hypofractionated PMRT of 40.05Gy in 15 fractions over 3 weeks based on the UK Standardisation of Breast Radiotherapy (START) trial6, which demonstrated that hypofractionated PMRT is as safe and effective as the conventional PMRT of 50Gy in 25 fractions over 5 weeks. The aim of this study was to determine whether the conventional PMRT of 50Gy in 25 fractions over 5 weeks (2Gy per fraction) was associated with a reduced risk of implant complications in patients undergoing mastectomy with IIBR compared with hypofractionated PMRT regiment of 40.05Gy in 15 fractions over 3 weeks (2.67Gy per fraction). Methods: A single centre retrospective review of data on patients who underwent IIBR followed by PMRT between September 2012 and May 2017 was conducted. Radiotherapy-related complications (surgical site infection, contracture, implant rupture or leakage, wound breakdown) were compared between the two groups of patients receiving conventional and hypofractionated PMRT. Results: Fifty-nine patients underwent IIBR followed by PMRT. Twenty-six patients received hypofractionated PMRT and thirty-three patients received conventional PMRT. Radiotherapy-related complications occurred in 62% of patients in the hypofractionated PMRT group compared with 45% in the conventional PMRT group (p = 0.30). The incidence of capsular contracture (31% in vs. 21%, p = 0.55) and wound breakdown (23% vs. 15%, p = 0.51) was higher in the hypofractionated PMRT group, but surgical site infection (SSI) was more common in the conventional group (4% vs. 6%, p = 1.00). Discussion: Possible confounding factors (BMI, smoking status, and adjuvant chemotherapy) were not analysed due to the small sample size and limitations of the retrospective nature of this study. However, our overall rate of SSI is low in comparison with national data from the NMBRA (2011), which states the SSI rate of 25% in patients who underwent breast reconstruction surgery. Conclusions: This study suggests that the rate of radiotherapy-related complications is lower in patients treated with conventional PMRT compared with hypofractionated PMRT, however the sample size is too small to demonstrate statistical significance. Further research is required to evaluate the effectiveness of conventional PMRT as an option to facilitate immediate implant-based reconstruction following mastectomy. Citation Format: Chaichanavichkij P, Arun KS, Conibear J, Ullah MZ. Post-mastectomy radiotherapy following immediate implant based reconstruction: A possible solution to a reconstructive challenge [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-16-10.

Women's Free-text Comments on their Quality of Life: An Exploratory Analysis from the UK Standardisation of Breast Radiotherapy (START) Trials for Early Breast Cancer

AimsExploratory analysis of patients' unsolicited written comments in the first 2 years of the Standardisation of Breast Radiotherapy (START) trial quality of life study highlighted a potential effect of non-treatment-related problems on the ratings and interpretation of patient self-reported questionnaires. At 5 years of follow-up all eligible subjects were invited to write comments to further explore these findings. Materials and methodsUsing inductive qualitative methods informed by the exploratory analysis, comments were allocated to relevant themes. Key patient-reported outcome measures (PROMs), clinical and demographic factors were collated for patients who did and did not comment at 5 years and comparisons between the groups explored. ResultsOf 2208 women completing baseline PROMs, 482 proffered comments from 0 to 24 months, forming nine distinct themes, including chronic conditions, life events and psychosocial concerns. At 5 years, 1041/1727 (60.3%) women contributed comments, of whom 500 randomly selected participants formed the sample for analysis. Findings revealed comorbidity, impaired physical functioning and psychosocial problems as key themes, with prevalent adverse effects from local and systemic treatments. Eight new themes emerged at 5 years, including ageing, concerns about future cancer and positive aspects of care. Women commenting were better educated, slightly older and more likely to have had chemotherapy compared with non-commenters. They had significantly worse PROM scores for global health and key quality of life domains relevant to the difficulties they revealed. ConclusionsDifficult personal circumstances and other health concerns affected many women's PROM ratings at 5 years of follow-up, in addition to ongoing cancer treatment effects. Greater attention to multiple sources of distress and adversity could facilitate personalised care and aid interpretation of PROMs.

Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials

Background and purposeAdjuvant lymphatic radiotherapy (LNRT) is recommended for selected axillary node positive women with early breast cancer. We investigated whether hypofractionated LNRT is safe combined with similarly-hypofractionated breast/chest wall radiotherapy (RT). Material and methodsThe Standardisation of Breast Radiotherapy (START) pilot, A and B trials randomised women with early breast cancer to schedules of 2.67–3.3 Gy versus 2.0 Gy fractions (control). RT adverse effects were assessed by patients using the EORTC QLQ-BR23 and protocol-specific questions, and by physicians. Rates of arm/shoulder effects were compared between schedules for patients given LNRT. Results864/5861 (14.7%) patients received LNRT (385 START-pilot, 318 START-A, 161 START-B). Prevalences of moderate/marked arm/shoulder effects were low up to 10 years. There were no significant differences between the hypofractionated and control groups for patient- and physician-assessed symptoms in START-A or START-B. In START-pilot, adverse effect rates were higher after 13 fractions of 3.3 Gy, consistent with effects reported in the breast/chest wall (significant for shoulder stiffness, HR 3.07, 95%CI 1.62–5.83, p = 0.001). ConclusionsThe START trial results suggest that appropriately-dosed hypofractionated LNRT is safe in the long-term, according to patient and physician-assessed arm and shoulder symptoms. These findings are consistent with those reported after the same schedules delivered to the breast/chest wall.

Patient reported outcomes following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials. Presented on behalf of the START Trial Management Group

Patient reported outcomes following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials. Presented on behalf of the START Trial Management Group

Prolongation of overall treatment time as a cause of treatment failure in early breast cancer: An analysis of the UK START (Standardisation of Breast Radiotherapy) trials of radiotherapy fractionation

BackgroundTests of tumour treatment time effect in patients prescribed post-operative radiotherapy for early breast cancer have focussed on time to start of radiotherapy rather than overall treatment time. The START randomised trials of radiotherapy fractionation provide an opportunity to directly estimate the effect of treatment acceleration. MethodsBetween 1986 and 2002, a total of 5861 women with early breast cancer were recruited into the UK START pilot (START-P), START-A and START-B randomised trials. START-P and START-A tested 13 fractions of 3.0–3.3Gy against 25 fractions of 2.0Gy with a fixed treatment duration of 5weeks for all schedules; START-B tested 15 fractions of 2.67Gy in 3weeks against 25 fractions of 2.0Gy over 5weeks. Estimates of the effect of length of treatment for local–regional relapse and for a measure of late normal tissue effects (change in photographic breast appearance, for patients following breast conserving surgery) were obtained from Cox proportional hazards regression analyses stratified according to trial. ResultsAt a median follow-up of 10years, 444/5831 (7.6%) patients with data available had a local–regional relapse, and 1135/3185 (35.6%) had mild or marked change in photographic breast appearance by 5years. Adjusting for prognostic factors, the estimate of the overall treatment time effect for local–regional relapse was 0.60Gy/day (95%CI 0.10 to 1.18Gy/day, p=0.02), and 0.14Gy/day (95%CI −0.09 to 0.34Gy/day, p=0.29) for change in photographic breast appearance. ConclusionsCombined analysis of the START trials generates the hypothesis that overall treatment time is a significant determinant of local cancer control after adjuvant whole breast radiotherapy, with approximately 0.6Gy per day ‘wasted’ in compensating for tumour cell proliferation.

Do Patient-reported Outcome Measures Agree with Clinical and Photographic Assessments of Normal Tissue Effects after Breast Radiotherapy? The Experience of the Standardisation of Breast Radiotherapy (START) Trials in Early Breast Cancer

AimsIn radiotherapy trials, normal tissue effects (NTE) are important end points and it is pertinent to ask whether patient-reported outcome measures (PROMs) could replace clinical and/or photographic assessments. Data from the Standardisation of Breast Radiotherapy (START) trials are examined. Materials and methodsNTEs in the treated breast were recorded by (i) annual clinical assessments, (ii) photographs at 2 and 5 years, (iii) PROMs at 6 months, 1, 2 and 5 years after radiotherapy. Hazard ratios for the radiotherapy schedules were compared. Measures of agreement of assessments at 2 and 5 years tested concordance. ResultsPROMs were available at 2 and/or 5 years for 1939 women, of whom 1870 had clinical and 1444 had photographic assessments. All methods were sensitive to the dose difference between schedules. Patients reported a higher prevalence for all NTE end points than clinicians or photographs (P < 0.001 for most NTEs). Concordance was generally poor; weighted kappa at 2 years ranged from 0.05 (telangiectasia) to 0.21 (shrinkage and oedema). The percentage agreement was lowest between PROMs and photographic assessments of change in breast appearance (38%). ConclusionsAll three methods produced similar conclusions for the comparison of trial schedules, despite low concordance between the methods on an individual patient basis. Careful consideration should be given to the different contributions of the measures of NTE in future radiotherapy trials.

The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials

5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens. From 1999 to 2002, women with completely excised invasive breast cancer (pT1-3a, pN0-1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast-conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START-A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41·6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. START-A enrolled 2236 women. Median follow-up was 9·3 years (IQR 8·0-10·0), after which 139 local-regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41·6 Gy and 50 Gy regimen groups (6·3%, 95% CI 4·7-8·5 vs 7·4%, 5·5-10·0; hazard ratio [HR] 0·91, 95% CI 0·59-1·38; p=0·65) or the 39 Gy (8·8%, 95% CI 6·7-11·4) and 50 Gy regimen groups (HR 1·18, 95% CI 0·79-1·76; p=0·41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41·6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9·9 years (IQR 7·5-10·1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4·3%, 95% CI 3·2-5·9) and the 50 Gy group (5·5%, 95% CI 4·2-7·2; HR 0·77, 95% CI 0·51-1·16; p=0·21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group. Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer. Cancer Research UK, UK Medical Research Council, UK Department of Health.

The role of radiotherapy-resistant stem cells in breast cancer recurrence.

Although the effectiveness of anti cancer therapies has improved dramatically, breast cancer (BC) remains the second leading cause for cancer-related death among women in the western world [1]. The observed improvement in the survival rate and remission for primary tumors are essentially related to the advances in early diagnosis with more sensitive imaging technology [2,3]. However, the death rate remains unacceptably high for BC patients due to hard-to-treat metastatic and recurrent tumors, necessitating new, effective approaches and anticancer agents. Accumulating evidence suggests that cancer stem cells (CSCs), which are present in many cancers including BC, mediate tumor metastasis and contribute to relapse due to their resistance to current conventional therapies [4,5]. These unique cells possess stem cell-like characteristics, such as the capacity of self-renewal, which makes the tumor capable of regenerating its entire bulk. CSCs are resistant to proapoptotic factors, rendering them a formidable adversary to anticancer agents. In part, this is related to their quiescence capacity, which holds them in a standby mode in their niche microenvironment, sheltering them from radiation and other anticancer agents, since these agents are effective only on highly proliferative cells [6,7]. In addition to their powerful DNA repair machinery, breast CSCs (BCSCs) express ALDH, which is suspected to play a part in their death-resistance phenotype by being involved with cell detoxification machinery [8,9]. Thus, BCSCs represent a major challenge in the battle against BC, and an opportunity to develop more effective target to treat metastatic lesions.

Abstract S4-1: The UK START (Standardisation of Breast Radiotherapy) Trials: 10-year follow-up results

Abstract Background International standard adjuvant radiotherapy regimens following primary surgery for early breast cancer have historically delivered a high total dose (50Gy) in 25 small daily doses (fractions) over 5 weeks, however randomised trials, including START, indicate that a lower total dose delivered in fewer, larger fractions (Fr) is likely to be at least as safe and effective (START Trialists' Group, Lancet 2008 &amp; Lancet Oncol 2008). With patients remaining at risk of local relapse for many years, information on long-term outcomes is needed to provide confidence in clinical practice. Here, we report 10-year follow-up of the UK START Trials testing 13- and 15-Fr regimens in terms of local cancer control and late adverse effects. Methods Between 1999 and 2002, 4451 women with completely excised invasive breast cancer (T1-3, N0-1, M0) were randomised after primary surgery to comparisons of 50Gy in 25Fr over 5 weeks vs 41·6Gy or 39Gy in 13Fr over 5 weeks (START A), or 50Gy in 25Fr over 5 weeks vs 40Gy in 15Fr over 3 weeks (START B). Women were eligible if aged over 18 years and did not have an immediate surgical reconstruction. Protocol-specified principal endpoints were local-regional (LR) tumour relapse and late normal tissue effects. Analysis was by intention to treat. Findings Median follow-up in survivors is now 9.3 years in START A and 9.9 years in START B, with 139 LR relapses in START A and 95 in START B. In START A, the 10-year rate of LR relapse was 7.4% (95%CI 5.5–10.0) after 50Gy, 6.3% (95%CI 4.7–8.5) after 41·6Gy and 8.8% (95%CI 6.7–11.4) after 39Gy. In START B, the 10-year rate of LR relapse was 5.5% (95%CI 4.2–7.2) after 50Gy and 4.3% (95%CI 3.2–5.9) after 40Gy. Clinician assessments suggested lower 10-year rates of any moderate/marked late normal tissue effects after 39Gy (43.9%; 95%CI 39.3–48.7) and similar rates after 41.6Gy (49.5%; 95%CI 44.9–54.3) compared with 50Gy (50.4%; 95%CI 45.8–55.3) in START A and lower rates after 40Gy in START B (37.9%; 95%CI 34.5–41.5) compared with 50Gy (45.3%; 95%CI 41.7–49.0). From a planned meta-analysis of START A and the START pilot trial (Owen et al, Lancet Oncol 2006), the adjusted estimate of α/β value for tumour control was 3.5Gy (95% CI 1.2–5.7) and for late change in photographic breast appearance was 3.1Gy (95% CI 2.0–4.2). Interpretation Long-term follow-up confirms that breast cancer and the surrounding dose-limiting healthy tissues respond similarly to radiotherapy fraction size and thus that appropriately-dosed hypofractionated radiotherapy is safe and effective in treatment of patients with early breast cancer. 41·6Gy in 13Fr and 40Gy in 15Fr each appear comparable to 50Gy in 25Fr in terms of local-regional tumour control and late normal tissue effects. These results support the continued use of 40Gy in 15Fr as standard of care (UK NICE Guidance 2009) for women requiring adjuvant radiotherapy for early breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S4-1.

Quality of life after breast radiotherapy

1 Hopwood P, Haviland JS, Sumo G, Mills J, Bliss JM, Yarnold JR. 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 2010; 11: 231–40. 2 Carling M, Goodare H, Ironside A, Millington J, Rogers C. Radiotherapy hypofractionation in early breast cancer. Lancet 2008; 372: 204–05. 3 Bartelink H, Arriagada R. Hypofractionation in radiotherapy for breast cancer. Lancet 2008; 371: 1050–52. 4 Withers HR. Radiation biology and treatment options in radiation oncology. Cancer Res 1999; 59 (suppl): 1676–84. 5 Powell S, Cooke J, Parsons C. Radiation-induced brachial plexus injury: followup of two diff erent fractionation schedules. Radiother Oncol 1990; 18: 213–20. 6 Hanley B, Staley K. Yesterday’s women: the story of R.A.G.E. London: Macmillan Cancer Support, 2006. Correspondence Quality of life after breast radiotherapy

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

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. 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. 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. 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. Cancer Research UK, UK Medical Research Council, UK Department of Health.

Hitting the right spot

Philip Hunter explores how recent technological and conceptual developments are helping clinicians improve the efficacy and safety of radiotherapy against obstinate cancers.

Shorter fractionation schedules in breast cancer radiotherapy: Clinical and economic implications

An accumulating body of level I evidence from randomised trials of adjuvant radiotherapy in early breast cancer supports the safety and efficacy of giving a lower total dose in fewer larger fractions (hypofractionation) than the historical standard of 50 Gy in 25 fractions of 2.0 Gy over 5 weeks. 1 Bentzen S.M. Agrawal R.K. Aird E.G. et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet. 2008; 371: 1098-1107 Abstract Full Text Full Text PDF PubMed Scopus (861) Google Scholar , 2 Bentzen S.M. Agrawal R.K. Aird E.G. et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008; 9: 331-341 Abstract Full Text Full Text PDF PubMed Scopus (809) Google Scholar , 3 Owen J.R. Ashton A. Bliss J.M. et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol. 2006; 7: 467-471 Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar , 4 Whelan T. MacKenzie R. Julian J. et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst. 2002; 94: 1143-1150 Crossref PubMed Scopus (554) Google Scholar The published phase 3 trials relate to patients prescribed whole breast radiotherapy, but the principle is being extended to trials evaluating partial breast irradiation restricted to the tumour bed. 5 Orecchia R. Ciocca M. Lazzari R. et al. Intraoperative radiation therapy with electrons (ELIOT) in early-stage breast cancer. Breast. 2003; 12: 483-490 Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar , 6 Vaidya JS, Baum M, Tobias JS, Houghton J. Lancet. Targeted intraoperative radiotherapy; 1999. <http://www.thelancet.com/journals/lancet/misc/protocol/99PRT-47>. Google Scholar , 7 Strnad V, Polgar C. On behalf of the European Brachytherapy Breast Cancer GEC-ESTRO Working Group. GEC-ESTRO APBI Trial: interstitial brachytherapy alone versus external beam radiation therapy after breast conserving surgery for low risk invasive carcinoma and low risk duct carcinoma in-situ (DCIS) of the female breast; 2006. <http://www.apbi.uni-erlangen.de/outline/outline.html>. Google Scholar , 8 Wolmark N, Curran WJ. Trial protocol March 13, 2007. On behalf of NSABP and RTOG of the American College of Radiology (ACR). NSABP Protocol B-39. RTOG Protocol 0413. A randomized phase III study of conventional whole breast irradiation versus partial breast irradiation for women with stage 0, I, or II breast cancer. National surgical adjuvant breast and bowel project (NSABP); 2007. p. 1–132. Google Scholar , 9 OCOG. Ontario Clinical Oncology Group (OCOG), Canadian Institutes of Health Research (CIHR), Canadian Breast Cancer Research Alliance. RAPID: Randomized Trial of Accelerated Partial Breast Irradiation; 2008. <http://clinicaltrials.gov/ct2/show/NCT00282035>. Google Scholar , 10 Yarnold J, Coles C. Trial Protocol, version 4, 19.02.2008. On behalf of the IMPORT LOW Trial Management Group: Intesity Modulated and Partial Organ Radiotherapy. Randomised trial testing intensity modulated and partial organ radiotherapy following breast conservation surgery for early breast cancer. Sutton, Surrey, UK: The Institute of Cancer Research: Royal Cancer Hospital; 2008. p. 1–74. Google Scholar , 11 http://www.irmatrial.it/. Google Scholar Interest in hypofractionation is based not only on the practical advantages to patients and health services of fewer hospital visits, but also on two postulated clinical benefits. The first is that breast cancer is more sensitive to fraction size than formerly thought, so that fewer larger fractions maintain current levels of anti-tumour effect without increasing late adverse effects. The second is that shorter overall treatment times (accelerated hypofractionation) may be more effective in patients with rapidly proliferating tumours.

The effects of radiotherapy on normal tissues in early breast cancer: results of the UK standardisation of breast radiotherapy (START) trials.

The effects of radiotherapy on normal tissues in early breast cancer: results of the UK standardisation of breast radiotherapy (START) trials.

The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial

SummaryBackgroundThe 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.MethodsBetween 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.Findings749 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 α/β 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).InterpretationThe 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.

The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial

SummaryBackgroundThe 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.MethodsBetween 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.Findings1105 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.InterpretationA 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.

1100 POSTER Body image and breast symptoms in early breast cancer: first results of the UK standardisation of breast radiotherapy (START) trials

1100 POSTER Body image and breast symptoms in early breast cancer: first results of the UK standardisation of breast radiotherapy (START) trials

2037 POSTER The effect of hypofractionation and radiation dosimetry on the incidence of symptomatic rib fractures in women treated with radiotherapy for early breast cancer in the UK standardisation of breast radiotherapy (START) Trials

2037 POSTER The effect of hypofractionation and radiation dosimetry on the incidence of symptomatic rib fractures in women treated with radiotherapy for early breast cancer in the UK standardisation of breast radiotherapy (START) Trials

2026 ORAL Results of the UK standardisation of breast radiotherapy (START) trials testing hypofractionation for early breast cancer – on behalf of the START trials centres

To evaluate early and late reactions, local control, disease-free survival, cause-specific survival, and overall survival of elderly breast cancer patients treated with definitive once-a-week hypofractionated radiotherapy together with hormonal therapy.Between 1987 and 1999, 115 patients with a median age of 83 presenting with 124 non-metastatic breast carcinoma were treated with definitive once weekly hypofractionated radiotherapy associated with hormonal therapy. The main reasons for adopting this schedule were patient refusal of surgery, very old age, locally advanced case, and/or comorbid disease. Radiation was delivered as once-a-week, 6.5 Gy for a total breast dose of 32.5 Gy in five fractions, followed with 1–3 fractions of 6.5 Gy to the tumour site. The median follow-up was 41 months.Neoadjuvant hormonal therapy led to 56% reduction of the tumour volume. Late reactions occurred in 46 patients; they were mild to moderate in 87% of these patients. The Kaplan–Meier rate was 52% of patients, with 6% experiencing grade 3 reactions. The 5-year local progression-free rate was 78%. The corresponding cause-specific survival was 71%, and was influenced by T classification, nodal status, oestrogen receptors and the total dose. The first three factors retained an independent prognostic impact on multivariate analysis. The 5-year overall survival was 38%. It was affected by the T classification, lymph node involvement and the performance status (PS). Using a multivariate analysis, only T classification and PS were identified as independent factors regarding overall survival.Definitive hypofractionated radiotherapy allows a good local control, with acceptable toxicity. This schedule associated with hormonal therapy is a good alternative to surgery in non-operable old patients and in case of patient refusal to surgery and to standard fractionation.

The Institute of Cancer Research, Clinical Trials and Statistics Unit (ICR-CTSU)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by The Institute of Cancer Research, Clinical Trials and Statistics Unit (ICR-CTSU). Clinical trials include: The NCRI Adjuvant Breast Cancer (ABC) trial. ISRCTN31514446The UK randomized trial of hormone replacement therapy (HRT) in women with a history of early stage breast cancer. ISRCTN29941643NCRI Standardisation of Breast Radiotherapy (START) trial. ISRCTN59368779TACT: A randomized trial of standard anthracycline-based chemotherapy (fluorouracil, epirubicin and cyclophosphamide (FEC) or epirubicin and CMF (Epi-CMF)) versus FEC followed by sequential docetaxel in women with early breast cancer. ISRCTN 79718493SoFEA: Study of Faslodex with or without concomitant Arimidex versus Exemestane following progression on non-steroidal Aromatase inhibitors. ISRCTN: 44195747TACT2: Trial of accelerated adjuvant chemotherapy with Capecitabine in early breast cancer. ISRCTN68068041FAST trial: Prospective randomized clinical trial testing 5.7 Gy and 6.0 Gy fractions of whole breast radiotherapy in terms of late normal tissue responses and tumour control.IMPORT low trial.IMPORT high trial.Adjuvant chemotherapy in older women (ACTION).