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      DEGRO practical guidelines: radiotherapy of breast cancer I : Radiotherapy following breast conserving therapy for invasive breast cancer

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          Abstract

          Background and purpose

          The aim of the present paper is to update the practical guidelines for postoperative adjuvant radiotherapy of breast cancer published in 2007 by the breast cancer expert panel of the German Society for Radiooncology (Deutsche Gesellschaft für Radioonkologie, DEGRO). The present recommendations are based on a revision of the German interdisciplinary S-3 guidelines published in July 2012.

          Methods

          A comprehensive survey of the literature concerning radiotherapy following breast conserving therapy (BCT) was performed using the search terms “breast cancer”, “radiotherapy”, and “breast conserving therapy”. Data from lately published meta-analyses, recent randomized trials, and guidelines of international breast cancer societies, yielding new aspects compared to 2007, provided the basis for defining recommendations according to the criteria of evidence-based medicine. In addition to the more general statements of the DKG (Deutsche Krebsgesellschaft), this paper addresses indications, target definition, dosage, and technique of radiotherapy of the breast after conservative surgery for invasive breast cancer.

          Results

          Among numerous reports on the effect of radiotherapy during BCT published since the last recommendations, the recent EBCTCG report builds the largest meta-analysis so far available. In a 15 year follow-up on 10,801 patients, whole breast irradiation (WBI) halves the average annual rate of disease recurrence (RR 0.52, 0.48–0.56) and reduces the annual breast cancer death rate by about one sixth (RR 0.82, 0.75–0.90), with a similar proportional, but different absolute benefit in prognostic subgroups (EBCTCG 2011).

          Furthermore, there is growing evidence that risk-adapted dose augmentation strategies to the tumor bed as well as the implementation of high precision RT techniques (e.g., intraoperative radiotherapy) contribute substantially to a further reduction of local relapse rates. A main focus of ongoing research lies in partial breast irradiation strategies as well as WBI hypofractionation schedules. The potential of both in replacing normofractionated WBI has not yet been finally clarified.

          Conclusion

          After breast conserving surgery, no subgroup even in low risk patients has yet been identified for whom radiotherapy can be safely omitted without compromising local control and, hence, cancer-specific survival. In most patients, this translates into an overall survival benefit.

          Zusammenfassung

          Zielsetzung

          Aktualisierung der DEGRO-Leitlinien von 2007 zur Radiotherapie (RT) invasiver Mammakarzinome nach brusterhaltender Operation. Die hier präsentierten Empfehlungen basieren auf der interdisziplinären S3-Leitlinie der Deutschen Krebsgesellschaft, deren aktuelle Version 2012 publiziert wurde.

          Methodik

          Die DEGRO-Expertengruppe Mammakarzinom führte eine Literaturrecherche aktueller klinisch kontrollierter Studien, systematischer Reviews und Metaanalysen sowie Leitlinien internationaler Gesellschaften im Hinblick auf neue Aspekte gegenüber 2007 durch, wobei sie sich an den Kriterien evidenzbasierter Medizin orientierte. Suchbegriffe waren „breast cancer“, „radiotherapy“ und „breast conserving therapy“. Ergänzend zu den allgemeineren Statements der S3-Leitlinie zielt diese Arbeit auf Indikationsstellung, Zielvolumendefinition, Dosierung und Techniken einer Bestrahlung nach brusterhaltender Operation invasiver Mammakarzinome.

          Ergebnisse

          Von den zahlreichen Publikationen, die im Intervall seit den letzten DEGRO-Empfehlungen erschienen sind, stellt der rezente EBCTCG-Bericht aus dem Jahr 2011 die bislang zahlenmäßig größte Metaanalyse dar. In einer 15-Jahres-Nachbeobachtung an 10.801 Patienten konnte gezeigt werden, dass eine Ganzbrustbestrahlung die jährliche Rezidivrate halbiert (RR 0,52; 0,48–0,56) und die jährliche Rate der Brustkrebssterblichkeit um ein Sechstel reduziert (RR 0,82; 0,75–0,90), mit ähnlicher proportionaler, aber unterschiedlicher absoluter Ausprägung in prognostischen Untergruppen (EBCTCG 2011).

          Darüber hinaus besteht zunehmende Evidenz, dass risikoadaptierte Strategien einer Dosiserhöhung im Tumorbett sowie die Anwendung hochpräziser RT-Techniken (z. B. IORT) entscheidend zu einer weiteren Reduktion der Lokalrezidivraten beitragen. Ein Schwerpunkt der aktuellen Forschung liegt in der Evaluierung von Techniken der Partialbrustbestrahlung sowie im Einsatz hypofraktionierter Dosierungsschemata in der Ganzbrustbestrahlung. Das Potenzial beider Strategien, eine normofraktionierte Ganzbrustbestrahlung zu ersetzen, ist derzeit nicht abschließend geklärt.

          Schlussfolgerungen

          Nach brusterhaltender Operation invasiver Mammakarzinome konnte selbst bei Niedrigrisiko-Patientinnen bislang keine Subgruppe identifiziert werden, bei der auf eine nachfolgende Radiotherapie verzichtetet werden kann, ohne die lokale Tumorkontrolle und in weiterer Folge das krebsspezifische Überleben zu beeinträchtigen. Überdies resultiert bei den meisten Patientinnen durch die Bestrahlung ein Überlebensvorteil.

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          Most cited references73

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          Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.

          To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.
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            Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial.

            To investigate the long-term impact of a boost radiation dose of 16 Gy on local control, fibrosis, and overall survival for patients with stage I and II breast cancer who underwent breast-conserving therapy. A total of 5,318 patients with microscopically complete excision followed by whole-breast irradiation of 50 Gy were randomly assigned to receive either a boost dose of 16 Gy (2,661 patients) or no boost dose (2,657 patients), with a median follow-up of 10.8 years. The median age was 55 years. Local recurrence was reported as the first treatment failure in 278 patients with no boost versus 165 patients with boost; at 10 years, the cumulative incidence of local recurrence was 10.2% versus 6.2% for the no boost and the boost group, respectively (P < .0001). The hazard ratio of local recurrence was 0.59 (0.46 to 0.76) in favor of the boost, with no statistically significant interaction per age group. The absolute risk reduction at 10 years per age group was the largest in patients
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              Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial.

              After breast-conserving surgery, 90% of local recurrences occur within the index quadrant despite the presence of multicentric cancers elsewhere in the breast. Thus, restriction of radiation therapy to the tumour bed during surgery might be adequate for selected patients. We compared targeted intraoperative radiotherapy with the conventional policy of whole breast external beam radiotherapy. Having safely piloted the new technique of single-dose targeted intraoperative radiotherapy with Intrabeam, we launched the TARGIT-A trial on March 24, 2000. In this prospective, randomised, non-inferiority trial, women aged 45 years or older with invasive ductal breast carcinoma undergoing breast-conserving surgery were enrolled from 28 centres in nine countries. Patients were randomly assigned in a 1:1 ratio to receive targeted intraoperative radiotherapy or whole breast external beam radiotherapy, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy. Neither patients nor investigators or their teams were masked to treatment assignment. Postoperative discovery of predefined factors (eg, lobular carcinoma) could trigger addition of external beam radiotherapy to targeted intraoperative radiotherapy (in an expected 15% of patients). The primary outcome was local recurrence in the conserved breast. The predefined non-inferiority margin was an absolute difference of 2.5% in the primary endpoint. All randomised patients were included in the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00983684. 1113 patients were randomly allocated to targeted intraoperative radiotherapy and 1119 were allocated to external beam radiotherapy. Of 996 patients who received the allocated treatment in the targeted intraoperative radiotherapy group, 854 (86%) received targeted intraoperative radiotherapy only and 142 (14%) received targeted intraoperative radiotherapy plus external beam radiotherapy. 1025 (92%) patients in the external beam radiotherapy group received the allocated treatment. At 4 years, there were six local recurrences in the intraoperative radiotherapy group and five in the external beam radiotherapy group. The Kaplan-Meier estimate of local recurrence in the conserved breast at 4 years was 1.20% (95% CI 0.53-2.71) in the targeted intraoperative radiotherapy and 0.95% (0.39-2.31) in the external beam radiotherapy group (difference between groups 0.25%, -1.04 to 1.54; p=0.41). The frequency of any complications and major toxicity was similar in the two groups (for major toxicity, targeted intraoperative radiotherapy, 37 [3.3%] of 1113 vs external beam radiotherapy, 44 [3.9%] of 1119; p=0.44). Radiotherapy toxicity (Radiation Therapy Oncology Group grade 3) was lower in the targeted intraoperative radiotherapy group (six patients [0.5%]) than in the external beam radiotherapy group (23 patients [2.1%]; p=0.002). For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered as an alternative to external beam radiotherapy delivered over several weeks. University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research (BMBF). Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                F.Sedlmayer@salk.at
                Journal
                Strahlenther Onkol
                Strahlenther Onkol
                Strahlentherapie Und Onkologie
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0179-7158
                1439-099X
                5 September 2013
                5 September 2013
                2013
                : 189
                : 825-833
                Affiliations
                [ ]Department of Radiotherapy and Radiation Oncology, LKH Salzburg, Paracelsus Medical University Hospital, Muellner Haupstr. 48, Salzburg, Austria
                [ ]Klinik für Radioonkologie und Strahlentherapie, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
                [ ]University Hospital Duesseldorf, Duesseldorf, Germany
                [ ]University Hospital Schleswig-Holstein, Luebeck, Germany
                [ ]Klinikum Neukoelln, Berlin, Germany
                [ ]University Hospital Erlangen, Erlangen, Germany
                [ ]formerly St.-Vincentius-Kliniken, Karlsruhe, Germany
                [ ]St. Clara Hospital, Basel, Switzerland
                [ ]University Hospital Tübingen, Tübingen, Germany
                [ ]University Hospital Mannheim, Mannheim, Germany
                [ ]University Hospital Erlangen, Erlangen, Germany
                Article
                437
                10.1007/s00066-013-0437-8
                3825416
                24002382
                c9435742-3ddb-4a18-9f7e-1d9dd558a20a
                © ©The Authors (2013) This article is published with open access at Springerlink.com 2013
                History
                Categories
                Original Article
                Custom metadata
                © Springer Heidelberg Berlin 2013

                Oncology & Radiotherapy
                breast conserving therapy,whole breast irradiation,partial breast radiotherapy,boost radiotherapy,fractionation,brusterhaltende therapie,ganzbrustbestrahlung,partialbrustbestrahlung,boostbestrahlung,fraktionierung

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