Elucidating the Role of Chest Wall Irradiation in ‘Intermediate-risk’ Breast Cancer: the MRC/EORTC SUPREMO Trial

Abstract

IntroductionThe role of post-mastectomy radiotherapy has long been controversial. Three landmark Danish and Canadian trials established that comprehensive locoregional irradiation reduced breast cancer mortality in addition to reducing locoregional recurrence in high-risk pre-menopausal and post-menopausal patients receiving adjuvant systemic therapy [1Overgaard M. Hansen P.S. Overgaard J. et al.Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial.N Engl J Med. 1997; 337: 949-955Crossref PubMed Scopus (2186) Google Scholar, 2Ragaz J. Jackson S.M. Le N. et al.Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer.N Engl J Med. 1997; 337: 956-962Crossref PubMed Scopus (1474) Google Scholar, 3Overgaard M. Jensen M.B. Overgaard J. et al.Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCCG 82c randomised trial.Lancet. 1999; 353: 1641-1648Abstract Full Text Full Text PDF PubMed Scopus (1372) Google Scholar]. Whelan et al.[4Whelan T.J. Julian J. Wright J. Jadad A.R. Levine M.L. Does loco-regional radiation therapy improve survival in breast cancer? A meta-analysis.J Clin Oncol. 2000; 18: 1220-1229Crossref PubMed Scopus (443) Google Scholar] supported this in a systematic review of post-mastectomy radiotherapy in patients also receiving adjuvant systemic therapy. The Early Breast Cancer Trialists Collaborative Group (EBCTCG), in its overview of all trials concerning locoregional treatment, confirmed that, indeed, postoperative locoregional radiotherapy improves locoregional control, and therewith long-term survival [5Clarke M. Collins R. Darby S. et al.Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 366: 2087-2106Abstract Full Text Full Text PDF PubMed Scopus (3951) Google Scholar]. They stated that: ‘For every 4 local recurrences prevented, in the long run one life is saved’ [5Clarke M. Collins R. Darby S. et al.Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 366: 2087-2106Abstract Full Text Full Text PDF PubMed Scopus (3951) Google Scholar]. On the basis of this evidence, post-mastectomy radiotherapy was adopted widely as a standard of care for women with high-risk breast cancer, defined as: four or more pathologically involved axillary nodes (N2) and/or tumours larger than 5 cm (T3) [6Recht A. Bartelink H. Fourquet A. et al.Postmastectomy radiotherapy: questions for the twenty-first century.J Clin Oncol. 1998; 16: 2886-2889PubMed Google Scholar], i.e. with a 10-year risk of locoregional recurrence of 20% or more.For patients with an intermediate risk of locoregional recurrence, i.e. one to three positive nodes (N1) or T2 with additional risk factors (grade 3 histology and/or lymphovascular invasion) the effect of postoperative locoregional radiotherapy remains uncertain. Subset analyses of updates of the above-mentioned Danish and Canadian trials suggest that the long-term survival benefit also exists in this category of patients [7Ragaz J. Olivotto I.A. Spinelli J.J. et al.Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial.J Natl Cancer Inst. 2005; 97: 116-126Crossref PubMed Scopus (833) Google Scholar, 8Danish Breast Cancer Cooperative Group Nielsen H.M. Overgaard M. Grau C. Jensen A.R. Overgaard J. Study of failure pattern among high-risk breast cancer patients with or without postmastectomy radiotherapy in addition to adjuvant systemic therapy: long-term results from the Danish Breast Cancer Cooperative Group DBCCG 82 b and c randomized studies.J Clin Oncol. 2006; 24: 2268-2275Crossref PubMed Scopus (275) Google Scholar, 9Nielsen H.M. Overgaard M. Grau C. Jensen A.R. Overgaard J. Loco-regional recurrence after mastectomy in high-risk breast cancer risk and prognosis. An analysis of patients from the DBCCG 82 b&c randomization trials.Radiother Oncol. 2006; 79: 147-155Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar]. In the most recent EBCTCG analysis, a survival benefit was shown not only for the high-risk subset, but also for this intermediate-risk subgroup [10EBCTCG Highlights from the early breast cancer triallists' collaborative group (EBCTCG) 2005–2006 worldwide overview.Breast Cancer Res Treat. 2006; 100 ([abstract 40]): S19Google Scholar]. However, this analysis has not yet been published as a full paper. Because all trials that led to the EBCTCG overview applied locoregional radiotherapy, it is unclear whether the effect was due to the prevention of local recurrences per se, or of adjuvant regional irradiation, i.e. of the internal mammary chain (IMC), axillary apex and/or medial supraclavicular (MS) lymph nodes. The question as to whether adjuvant regional (IMC/MS) lymph node irradiation has an effect on long-term outcome is being addressed by the European Organization for Research and Treatment of Cancer (EORTC) trial 22922/10925 that was closed for accrual in 2002 with 4000 patients enrolled [11Poortmans P.M. Venselaar J.L. Struikmans H. et al.The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC phase III randomized trial 22922/10925 in stage I–III breast cancer(1).Int J Radiat Oncol Biol Phys. 2001; 49: 1399-1408Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar]. This trial has as yet too few events for a final analysis.Despite the positive results of individual trials and overviews we have to be cautious about adopting locoregional radiotherapy as a standard treatment. Apart from the potential benefits, there is also evidence of adverse effects. The 2005 EBCTCG overview showed a clear excess in the ‘non breast cancer’ death rate, believed to be caused by cardiac toxicity of radiotherapy [5Clarke M. Collins R. Darby S. et al.Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 366: 2087-2106Abstract Full Text Full Text PDF PubMed Scopus (3951) Google Scholar]. This late cardiac toxicity was probably partially due to the regional irradiation, in particular irradiation of the IMC lymph nodes and partially to excess cardiac volume included in the tangential fields in older trials [12Rutqvist L.E. Lax I. Fornander T. Johansson H. Cardiovascular mortality in a randomised trial of adjuvant radiation therapy versus surgery alone in primary breast cancer.Int J Radiat Oncol Biol Phys. 1992; 22: 887-896Abstract Full Text PDF PubMed Scopus (369) Google Scholar]. The Danish Breast Cancer Cooperative Group (DBCCG) investigated this issue in their above-mentioned trials and found no difference in ischaemic heart disease or cardiac mortality at 12 years between the irradiated and non-irradiated patients [13Hojris I. Andersen J. Overgaard M. Overgaard J. Late treatment-related morbidity in breast cancer patients randomized to postmastectomy radiotherapy and systemic treatment versus systemic treatment alone.Acta Oncol. 2000; 39: 355-372Crossref PubMed Scopus (115) Google Scholar]. They postulated that the radiation techniques used in their trials diminished the radiation dose to the heart to an acceptable level. Yet we are not sure whether these reassuring results will hold with longer follow-up. Furthermore, currently used systemic treatments, such as anthracyclines and, more recently, trastuzumab, have shown cardiac toxicities and may enhance late radiation toxicity. In addition, current chemotherapy schemes have been shown to improve locoregional control and hence may diminish the necessity of radiation in subsets of patients.Thus, despite the increasing evidence that post-mastectomy radiotherapy may be beneficial in patients at intermediate risk of local recurrence, the following questions remain: Is the benefit due to the prevention of local recurrences (and hence local chest wall irradiation only) or of adjuvant regional treatment? Is the expected improvement still counterbalanced by late (cardiac) toxicity, particularly in view of the interaction with potentially cardiotoxic systemic treatments currently used? Is, with current standards of systemic adjuvant treatment, the improvement in locoregional control still of the same order of magnitude? Answering these questions for the ‘intermediate-risk’ group of patients (with a 10-year risk of locoregional recurrence of 15% or less) is the aim of the MRC SUPREMO/EORTC 22051/10052 (BIG 2-04) trial, which is open to accrual in the UK, continental Europe and internationally.The SUPREMO TrialThe aim of the SUPREMO trial is to determine the effect on overall survival of chest wall irradiation after mastectomy and axillary surgery in women with operable breast cancer at ‘intermediate-risk’ of locoregional recurrence.Eligible patients with pT1, pNI, MO or pT2, pNI, MO or pT2, NO (with grade 3 histology and/or lymphovascular invasion) will have undergone a simple mastectomy (with minimum 1 mm clear margin). For node-positive patients, an axillary clearance with a minimum of 10 nodes is required. For node-negative patients, the nodal procedures can also include sentinel node biopsy or an axillary node sample. Patients who have undergone breast reconstruction are eligible for inclusion. Exclusion criteria include patients who have undergone neoadjuvant systemic therapy, have bilateral breast cancer or are known BRCA1 or BRCA2 mutation carriers or have positive internal mammary nodes on sentinel node procedure.Eligible patients will be randomised between no chest wall irradiation (standard) and chest wall irradiation (experimental arm). The primary end point is overall survival. Secondary end points are chest wall recurrence, disease-free survival, distant metastasis-free survival, acute and late morbidity, quality of life and cost-effectiveness. In total, 3700 patients will be required to detect a significant difference at the 5% level when 5-year survival rates are 75 and 79%. The hypothesised survival rates correspond to a hazard ratio of 1.22 and for 80% power with this hazard ratio, the necessary number of events (deaths) is 794. Follow-up visits will be made for at least 10 years, including mammography of the opposite breast at least every second year from the date of mastectomy.All aspects of the trial (surgery, pathology, radiotherapy and systemic therapy) will be subject to quality assurance. The radiotherapy quality assurance programme will be co-ordinated by the team responsible for the START trial radiotherapy quality assurance at Mount Vernon Hospital. A joint protocol of radiotherapy quality assurance has been established in collaboration with the EORTC and the Australian and New Zealand Breast Trials Group and Transtasman Radiation Oncology Group.SubstudiesIn order to acquire as much information as possible about the pros and cons of postoperative irradiation in this cohort of patients, a number of substudies were initiated. A biological substudy (TRANS-SUPREMO), a cardiac substudy, a quality of life study and a cost-effectiveness analysis are being undertaken.The TRANS-SUPREMO biological substudy is an important translational research component of the trial. In TRANS-SUPREMO, tumour-containing fixed tissue blocks will be requested on all patients to establish a tissue micro-array to be held on behalf of the trial management group at the Cancer Research UK centre in Edinburgh. The micro-array material will be made available to research groups on a project basis when long-term follow-up is available from the trial. The aim is to use the arrays to identify a molecular signature of risk of local relapse and radioresistance. In addition, plasma/serum will be stored for future studies of prognostic and predictive biochemical markers.Due to concerns of long-term cardiac effects of adjuvant breast cancer treatment, the SUPREMO study has a cardiac substudy. In this substudy (confined to the UK) the role of B type natriuretic peptide (BNP) will be investigated as an early marker of cardiac damage from radiotherapy and/or anthracycline-containing chemotherapy. Blood for BNP will be obtained at baseline and during treatment and follow-up. A baseline echocardiogram will be undertaken in all patients. The results of the BNP analysis will be returned to investigators. If there is any significant rise in BNP during the trial, the patient will be recalled for assessment and referred if necessary to a cardiologist. Advice on the management of individual patients is available from a panel of three trial cardiologists. To assess whether BNP has a similar threshold for detecting left ventricular dysfunction (LVD) in this clinical setting to that observed in other studies, the first 100 patients will undergo echocardiography and electrocardiography at each time point.The quality of life substudy (confined to the UK) will be carried out on a sample of 800 patients. The quality of life measures used will be EORTC core quality of life instruments EORTC QLQ C-30 and BR-23, Body Image Scale and Hospital Anxiety and Depression Scale.Although breast reconstruction is not a specific quality of life outcome, descriptive data will be obtained from patients who have had a reconstruction operation. The most important aspect of reconstruction is body image and this will be captured by the Body Image Scale. The first assessment will be made in the clinic before randomisation and follow-up postal questionnaires will be carried out at 1, 2, 5 and 10 years from randomisation.The health economics substudy will be coupled to the quality of life study. The cost-effectiveness of chest wall irradiation will be assessed by calculating the incremental cost per year gained and the incremental cost per additional quality-adjusted life-year. The EQ5D (EUROQOL, http://www.euroquol.org/) will be used to quality-adjust survival. The EQ5D comprises five simple questions (mobility, self-care, ability to undertake usual activities, pain/discomfort, and anxiety/depression). It will be given to patients together with the quality of life questionnaires at the same time points.DiscussionAs mentioned, the EBCTCG overview of breast cancer radiotherapy trials [5Clarke M. Collins R. Darby S. et al.Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 366: 2087-2106Abstract Full Text Full Text PDF PubMed Scopus (3951) Google Scholar] has shown a clear benefit of post-mastectomy radiotherapy for locoregional control leading to a long-term overall survival benefit, although the latter is partly counterbalanced by an ‘other than breast cancer’ survival disadvantage. These results have led to the wide acceptance of postoperative radiation as standard treatment for high-risk patients (≥T3 and/or ≥pN2).More controversy exists about its use for patients at intermediate risk for locoregional recurrence (pN1 or T2 with additional risk factors grade 3 and/or angio-invasion). The long-term analyses of the Danish and British Columbia trials [1Overgaard M. Hansen P.S. Overgaard J. et al.Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial.N Engl J Med. 1997; 337: 949-955Crossref PubMed Scopus (2186) Google Scholar, 2Ragaz J. Jackson S.M. Le N. et al.Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer.N Engl J Med. 1997; 337: 956-962Crossref PubMed Scopus (1474) Google Scholar, 3Overgaard M. Jensen M.B. Overgaard J. et al.Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCCG 82c randomised trial.Lancet. 1999; 353: 1641-1648Abstract Full Text Full Text PDF PubMed Scopus (1372) Google Scholar] as well as the most recent analysis of the EBCTCG overview [10EBCTCG Highlights from the early breast cancer triallists' collaborative group (EBCTCG) 2005–2006 worldwide overview.Breast Cancer Res Treat. 2006; 100 ([abstract 40]): S19Google Scholar] suggest that locoregional irradiation is of survival benefit in this category of patients too, and should be adopted as standard treatment. On the other hand, there are a number of arguments against this point of view. First, the overview radiotherapy data were obviously derived from older radiotherapy trials with possibly more extensive disease stages and different standard treatments than nowadays. Therefore, the advantage might be less pronounced in contemporary practice. Analyses of the effects of post-mastectomy radiotherapy on overall survival [14Van de Steene J. Vinh-Hung V. Cutuli B. Storme G. Adjuvant radiotherapy for breast cancer: effects of longer follow-up.Radiother Oncol. 2004; 72: 35-43Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar] do show a differential in the reduction in the mortality ratio, with a greater reduction for trials of patient groups with a better overall survival, e.g. around 70–80% at 10 years, which is the anticipated survival for SUPREMO candidates. Second, the surgery of the Danish post-mastectomy trials was criticised as less adequate (with a median of only seven nodes removed). This might explain the higher than usual locoregional recurrence rates (>30% at 10 years) in the no radiotherapy arm of the Danish pre-menopausal study [1Overgaard M. Hansen P.S. Overgaard J. et al.Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial.N Engl J Med. 1997; 337: 949-955Crossref PubMed Scopus (2186) Google Scholar]. More recently, Overgaard and colleagues [15Overgaard M. Nielsen H.M. Overgaard J. Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus? A subgroup analysis of the DBCCG 82 b&c randomized trials.Radiother Oncol. 2007; 82: 247-253Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar] have published an unplanned subset analysis of 1152 patients with eight or more nodes removed from the DBCCG 82b&c trials. They showed a significantly improved 15-year survival benefit in the one to three node-positive group (57% vs 48%, P=0.03). The authors and an accompanying editorial [16Poortmans P. A bright future for radiotherapy in breast cancer.Radiother Oncol. 2007; 82: 243-246Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar] recommended that on the basis of these data post mastectomy radiotherapy should become the standard of care for the one to three node-positive group. We would contend [17Kunkler I. van Tienhoven G. Dixon M. et al.Postmastectomy radiotherapy should not be the standard for care patients with 1–3 positive nodes.Radiother Oncol. 2007; 84: 103-104Abstract Full Text Full Text PDF Scopus (2) Google Scholar] that the persistently high locoregional recurrence rate of 27% at 15 years in the systemic therapy alone arm of this subset analysis [15Overgaard M. Nielsen H.M. Overgaard J. Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus? A subgroup analysis of the DBCCG 82 b&c randomized trials.Radiother Oncol. 2007; 82: 247-253Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar] continues to invalidate the generalisability of the findings of the Danish trials to routine clinical practice. Third, according to current standards, the adjuvant systemic therapy in all these trials is considered suboptimal. The efficacy of systemic therapy has improved from cyclophosphamide, methotrexate and 5-fluorouracil (CMF)-based regimens used in most trials in the overview to contemporary anthracycline-based regimens. The recent NEAT trial showed an improvement from adding epirubicin to CMF [18Poole C.J. Earl H.M. Hiller L. et al.Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer.N Engl J Med. 2006; 355: 1851-1862Crossref PubMed Scopus (168) Google Scholar]. The MA5 trial showed CEF to be better than CMF [19Levine M.N. Pritchard K.I. Bramwell V.H. et al.National Cancer Institute of Canada Clinical Trials GroupRandomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5.J Clin Oncol. 2005; 23: 5166-5170Crossref PubMed Scopus (173) Google Scholar]. Anthracycline-based chemotherapy is now generally seen as superior to CMF. Interestingly, in the post-mastectomy radiotherapy meta-analysis of Whelan et al.[4Whelan T.J. Julian J. Wright J. Jadad A.R. Levine M.L. Does loco-regional radiation therapy improve survival in breast cancer? A meta-analysis.J Clin Oncol. 2000; 18: 1220-1229Crossref PubMed Scopus (443) Google Scholar], the relative reduction in breast cancer mortality from locoregional irradiation was less in the five trials in which patients received anthracycline-containing chemotherapy (odds ratio 1.0; 95% confidence interval 0.73–1.38) than in the 13 trials in which they did not (odds ratio 0.79; 95% confidence interval 0.70–0.89). However, the difference did not reach statistical significance.Thus, the risks of chest wall recurrence after mastectomy and appropriate anthracycline-containing chemotherapy may be smaller and the absolute benefits of radiotherapy in local control and survival more modest than suggested by older trials. The main disadvantage, being the late cardiac toxicity shown in the EBCTCG overview [5Clarke M. Collins R. Darby S. et al.Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 366: 2087-2106Abstract Full Text Full Text PDF PubMed Scopus (3951) Google Scholar, 10EBCTCG Highlights from the early breast cancer triallists' collaborative group (EBCTCG) 2005–2006 worldwide overview.Breast Cancer Res Treat. 2006; 100 ([abstract 40]): S19Google Scholar], may also be relatively more important. The concern about cardiac toxicity is enhanced by the fact that anthracyclines are known to be cardiotoxic too. The same applies to trastuzumab, which showed efficacy in an important subset of patients [21Piccart-Gebhart M.J. Procter M. Leyland-Jones B. et al.Trastuzumab after adjuvant chemotherapy in HER-2 positive breast cancer.N Engl J Med. 2005; 353: 1650-1672Crossref PubMed Scopus (4160) Google Scholar]. Because anthracyclines may be seen as potential radio-enhancing agents, there may be a mutual enhancement of cardiotoxicity. Whether more modern radiotherapy planning techniques have diminished the cardiotoxicity of locoregional irradiation remains unproven. Whether IMC irradiation is necessary to obtain improvement in local control and survival is subject to other trials [11Poortmans P.M. Venselaar J.L. Struikmans H. et al.The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC phase III randomized trial 22922/10925 in stage I–III breast cancer(1).Int J Radiat Oncol Biol Phys. 2001; 49: 1399-1408Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 20Kaija H. Maunu P. Tangential breast irradiation with or without internal mammary chain irradiation: results of a randomized trial.Radiother Oncol. 1995; 36: 172-176Abstract Full Text PDF PubMed Scopus (73) Google Scholar].The SUPREMO trial should answer the question: At the present time, with state-of-the-art surgery and adjuvant systemic treatment, does a reduction in local recurrence through post-mastectomy chest wall radiotherapy improve overall survival with minimal or no cardiac toxicity in patients at intermediate risk of local recurrence (N1 or T2 with additional risk factors)? The SUPREMO trial has minimum requirements as well as quality assurance for the main treatment modalities, surgery, adjuvant systemic treatment and radiotherapy. The cardiac toxicity is supposed to be less than with locoregional radiation because the IMC nodes are not routinely irradiated. Nevertheless, cardiac toxicity is an important end point in view of the above arguments and will be addressed in the cardiac substudy. The TRANS-SUPREMO biological substudy provides a great opportunity to prospectively study potential prognostic factors for local control as well as predictive factors of radiosensitivity. The latter may in the future lead us to tailor-made medicine, predicting who will or will not benefit from postoperative radiotherapy.We believe that the SUPREMO trial poses an important question, which the international community of breast trialists is well placed to answer. We strongly encourage investigators to enter patients into the trial so that we can base future practice on surer foundations. IntroductionThe role of post-mastectomy radiotherapy has long been controversial. Three landmark Danish and Canadian trials established that comprehensive locoregional irradiation reduced breast cancer mortality in addition to reducing locoregional recurrence in high-risk pre-menopausal and post-menopausal patients receiving adjuvant systemic therapy [1Overgaard M. Hansen P.S. Overgaard J. et al.Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial.N Engl J Med. 1997; 337: 949-955Crossref PubMed Scopus (2186) Google Scholar, 2Ragaz J. Jackson S.M. Le N. et al.Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer.N Engl J Med. 1997; 337: 956-962Crossref PubMed Scopus (1474) Google Scholar, 3Overgaard M. Jensen M.B. Overgaard J. et al.Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCCG 82c randomised trial.Lancet. 1999; 353: 1641-1648Abstract Full Text Full Text PDF PubMed Scopus (1372) Google Scholar]. Whelan et al.[4Whelan T.J. Julian J. Wright J. Jadad A.R. Levine M.L. Does loco-regional radiation therapy improve survival in breast cancer? A meta-analysis.J Clin Oncol. 2000; 18: 1220-1229Crossref PubMed Scopus (443) Google Scholar] supported this in a systematic review of post-mastectomy radiotherapy in patients also receiving adjuvant systemic therapy. The Early Breast Cancer Trialists Collaborative Group (EBCTCG), in its overview of all trials concerning locoregional treatment, confirmed that, indeed, postoperative locoregional radiotherapy improves locoregional control, and therewith long-term survival [5Clarke M. Collins R. Darby S. et al.Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 366: 2087-2106Abstract Full Text Full Text PDF PubMed Scopus (3951) Google Scholar]. They stated that: ‘For every 4 local recurrences prevented, in the long run one life is saved’ [5Clarke M. Collins R. Darby S. et al.Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 366: 2087-2106Abstract Full Text Full Text PDF PubMed Scopus (3951) Google Scholar]. On the basis of this evidence, post-mastectomy radiotherapy was adopted widely as a standard of care for women with high-risk breast cancer, defined as: four or more pathologically involved axillary nodes (N2) and/or tumours larger than 5 cm (T3) [6Recht A. Bartelink H. Fourquet A. et al.Postmastectomy radiotherapy: questions for the twenty-first century.J Clin Oncol. 1998; 16: 2886-2889PubMed Google Scholar], i.e. with a 10-year risk of locoregional recurrence of 20% or more.For patients with an intermediate risk of locoregional recurrence, i.e. one to three positive nodes (N1) or T2 with additional risk factors (grade 3 histology and/or lymphovascular invasion) the effect of postoperative locoregional radiotherapy remains uncertain. Subset analyses of updates of the above-mentioned Danish and Canadian trials suggest that the long-term survival benefit also exists in this category of patients [7Ragaz J. Olivotto I.A. Spinelli J.J. et al.Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial.J Natl Cancer Inst. 2005; 97: 116-126Crossref PubMed Scopus (833) Google Scholar, 8Danish Breast Cancer Cooperative Group Nielsen H.M. Overgaard M. Grau C. Jensen A.R. Overgaard J. Study of failure pattern among high-risk breast cancer patients with or without postmastectomy radiotherapy i