title: Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial.
abstract: BACKGROUND
  We previously confirmed the non-inferiority of accelerated partial breast irradiation (APBI) with interstitial brachytherapy in terms of local control and overall survival compared with whole-breast irradiation for patients with early-stage breast cancer who underwent breast-conserving surgery in a phase 3 randomised trial. Here, we present the 5-year late side-effects and cosmetic results of the trial.
  
  
  METHODS
  We did this randomised, controlled, phase 3 trial at 16 centres in seven European countries. Women aged 40 years or older with stage 0-IIA breast cancer who underwent breast-conserving surgery with microscopically clear resection margins of at least 2 mm were randomly assigned 1:1, via an online interface, to receive either whole-breast irradiation of 50 Gy with a tumour-bed boost of 10 Gy or APBI with interstitial brachytherapy. Randomisation was stratified by study centre, menopausal status, and tumour type (invasive carcinoma vs ductal carcinoma in situ), with a block size of ten, according to an automated dynamic algorithm. Patients and investigators were not masked to treatment allocation. The primary endpoint of our initial analysis was ipsilateral local recurrence; here, we report the secondary endpoints of late side-effects and cosmesis. We analysed physician-scored late toxicities and patient-scored and physician-scored cosmetic results from the date of breast-conserving surgery to the date of onset of event. Analysis was done according to treatment received (as-treated population). This trial is registered with ClinicalTrials.gov, number NCT00402519.
  
  
  RESULTS
  Between April 20, 2004, and July 30, 2009, we randomly assigned 1328 women to receive either whole-breast irradiation (n=673) or APBI with interstitial brachytherapy (n=655); 1184 patients comprised the as-treated population (551 in the whole-breast irradiation group and 633 in the APBI group). At a median follow-up of 6·6 years (IQR 5·8-7·6), no patients had any grade 4 toxities, and three (<1%) of 484 patients in the APBI group and seven (2%) of 393 in the whole-breast irradiation group had grade 3 late skin toxicity (p=0·16). No patients in the APBI group and two (<1%) in the whole-breast irradiation group developed grade 3 late subcutaneous tissue toxicity (p=0·10). The cumulative incidence of any late side-effect of grade 2 or worse at 5 years was 27·0% (95% CI 23·0-30·9) in the whole-breast irradiation group versus 23·3% (19·9-26·8) in the APBI group (p=0·12). The cumulative incidence of grade 2-3 late skin toxicity at 5 years was 10·7% (95% CI 8·0-13·4) in the whole-breast irradiation group versus 6·9% (4·8-9·0) in the APBI group (difference -3·8%, 95% CI -7·2 to 0·4; p=0·020). The cumulative risk of grade 2-3 late subcutaneous tissue side-effects at 5 years was 9·7% (95% CI 7·1-12·3) in the whole-breast irradiation group versus 12·0% (9·4-14·7) in the APBI group (difference 2·4%; 95% CI -1·4 to 6·1; p=0·28). The cumulative incidence of grade 2-3 breast pain was 11·9% (95% CI 9·0-14·7) after whole-breast irradiation versus 8·4% (6·1-10·6) after APBI (difference -3·5%; 95% CI -7·1 to 0·1; p=0·074). At 5 years' follow-up, according to the patients' view, 413 (91%) of 454 patients had excellent to good cosmetic results in the whole-breast irradiation group versus 498 (92%) of 541 patients in the APBI group (p=0·62); when judged by the physicians, 408 (90%) of 454 patients and 503 (93%) of 542 patients, respectively, had excellent to good cosmetic results (p=0·12). No treatment-related deaths occurred, but six (15%) of 41 patients (three in each group) died from breast cancer, and 35 (85%) deaths (21 in the whole-breast irradiation group and 14 in the APBI group) were unrelated.
  
  
  CONCLUSIONS
  5-year toxicity profiles and cosmetic results were similar in patients treated with breast-conserving surgery followed by either APBI with interstitial brachytherapy or conventional whole-breast irradiation, with significantly fewer grade 2-3 late skin side-effects after APBI with interstitial brachytherapy. These findings provide further clinical evidence for the routine use of interstitial multicatheter brachytherapy-based APBI in the treatment of patients with low-risk breast cancer who opt for breast conservation.
  
  
  BACKGROUND
  German Cancer Aid.
authors.affiliation: Center of Radiotherapy, National Institute of Oncology, Budapest, Hungary. Electronic address: polgar@oncol.hu.
authors.forename: Csaba
authors.initials: C
authors.lastname: Polgár
authors.affiliation: Department of Radiation Oncology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Ott
authors.affiliation: Department of Radiation Oncology, University Hospital Leipzig, Leipzig, Germany; Department of Radiation Oncology, University Hospital Rostock, Rostock, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Hildebrandt
authors.affiliation: Department of Radiation Oncology, University Hospital AKH Wien, Vienna, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kauer-Dorner
authors.affiliation: Department of Radiation Oncology, University Hospital Rostock, Rostock, Germany.
authors.forename: Hellen
authors.initials: H
authors.lastname: Knauerhase
authors.affiliation: Center of Radiotherapy, National Institute of Oncology, Budapest, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Major
authors.affiliation: Brachytherapy Department, Centrum Onkologii-Instytut im Marii Skłodowskiej, Warsaw, Poland; Podkarpacki Hospital Cancer Center Brzozów, Brzozów, Poland.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Lyczek
authors.affiliation: Department of Radiation Oncology, Valencian Institute of Oncology, Valencia, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Guinot
authors.affiliation: Department of Radiation Oncology, University Hospital Kiel, Kiel, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dunst
authors.affiliation: Department of Radiation Oncology, Catalan Institute of Oncology, Barcelona, Spain.
authors.forename: Cristina Gutierrez
authors.initials: CG
authors.lastname: Miguelez
authors.affiliation: Department of Radiation Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Slampa
authors.affiliation: Department of Radiation Oncology, Hospital Barmherzige Brüder, Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Allgäuer
authors.affiliation: Department of Radiation Oncology, University Hospital Bern, Inselspital, Switzerland.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lössl
authors.affiliation: Department of Radiation Oncology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Bülent
authors.initials: B
authors.lastname: Polat
authors.affiliation: Interdisciplinary Brachytherapy Unit, University of Lübeck/Universitätsklinikum Schleswig-Holstein Campus Lübeck, Lübeck, Germany.
authors.forename: György
authors.initials: G
authors.lastname: Kovács
authors.affiliation: Department of Radiation Oncology, Clemens Hospital, Münster, Germany.
authors.forename: Arnt-René
authors.initials: AR
authors.lastname: Fischedick
authors.affiliation: Department of Radiation Oncology, University Hospital Erlangen, Erlangen, Germany; Department of Radiation Oncology, University Hospital Rostock, Rostock, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fietkau
authors.affiliation: Department of Radiation Oncology, University Hospital AKH Wien, Vienna, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Resch
authors.affiliation: Brachytherapy Department, Centrum Onkologii-Instytut im Marii Skłodowskiej, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kulik
authors.affiliation: Department of Radiation Oncology, Valencian Institute of Oncology, Valencia, Spain.
authors.forename: Leo
authors.initials: L
authors.lastname: Arribas
authors.affiliation: Department of Radiation Oncology, University Hospital Kiel, Kiel, Germany; Department of Radiotherapy, Sana Hospital Offenbach, Offenbach, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Niehoff
authors.affiliation: Department of Radiation Oncology, Catalan Institute of Oncology, Barcelona, Spain.
authors.forename: Ferran
authors.initials: F
authors.lastname: Guedea
authors.affiliation: Department of Radiation Oncology, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Schlamann
authors.affiliation: Department of Radiation Oncology, University Hospital AKH Wien, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Pötter
authors.affiliation: Department of Medical Informatics, Biometry and Epidemiology, University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Gall
authors.affiliation: Department of Medical Informatics, Biometry and Epidemiology, University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uter
authors.affiliation: Department of Radiation Oncology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Vratislav
authors.initials: V
authors.lastname: Strnad
mesh_terms: D000368:Aged; D001918:Brachytherapy / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D018275:Carcinoma, Lobular / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D003131:Combined Modality Therapy; D003358:Cosmetics; D005218:Fat Necrosis / Q000175:diagnosis / Q000209:etiology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008408:Mastectomy / Q000009:adverse effects*; D015412:Mastectomy, Segmental / Q000009:adverse effects*; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011855:Radiodermatitis / Q000175:diagnosis / Q000209:etiology*; D011879:Radiotherapy Dosage; D013997:Time Factors
chemical_list: D003358:Cosmetics