title: Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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).
authors.affiliation: Research Department of Surgery, Division of Surgery and Interventional Science, University College London, London, UK. jayant.vaidya@ucl.ac.uk
authors.forename: Jayant S
authors.initials: JS
authors.lastname: Vaidya
authors.forename: David J
authors.initials: DJ
authors.lastname: Joseph
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Tobias
authors.forename: Max
authors.initials: M
authors.lastname: Bulsara
authors.forename: Frederik
authors.initials: F
authors.lastname: Wenz
authors.forename: Christobel
authors.initials: C
authors.lastname: Saunders
authors.forename: Michael
authors.initials: M
authors.lastname: Alvarado
authors.forename: Henrik L
authors.initials: HL
authors.lastname: Flyger
authors.forename: Samuele
authors.initials: S
authors.lastname: Massarut
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eiermann
authors.forename: Mohammed
authors.initials: M
authors.lastname: Keshtgar
authors.forename: John
authors.initials: J
authors.lastname: Dewar
authors.forename: Uta
authors.initials: U
authors.lastname: Kraus-Tiefenbacher
authors.forename: Marc
authors.initials: M
authors.lastname: Sütterlin
authors.forename: Laura
authors.initials: L
authors.lastname: Esserman
authors.forename: Helle M R
authors.initials: HM
authors.lastname: Holtveg
authors.forename: Mario
authors.initials: M
authors.lastname: Roncadin
authors.forename: Steffi
authors.initials: S
authors.lastname: Pigorsch
authors.forename: Marinos
authors.initials: M
authors.lastname: Metaxas
authors.forename: Mary
authors.initials: M
authors.lastname: Falzon
authors.forename: April
authors.initials: A
authors.lastname: Matthews
authors.forename: Tammy
authors.initials: T
authors.lastname: Corica
authors.forename: Norman R
authors.initials: NR
authors.lastname: Williams
authors.forename: Michael
authors.initials: M
authors.lastname: Baum
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery*; D018270:Carcinoma, Ductal, Breast / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007430:Intraoperative Care; D015412:Mastectomy, Segmental; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant