title: Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.
abstract: BACKGROUND
  Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results.
  
  
  METHODS
  Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033.
  
  
  RESULTS
  Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8-14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001).
  
  
  CONCLUSIONS
  A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years.
  
  
  BACKGROUND
  Fonds Cancer, Belgium.
authors.affiliation: Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands. Electronic address: h.bartelink@nki.nl.
authors.forename: Harry
authors.initials: H
authors.lastname: Bartelink
authors.affiliation: Department of Radiation Oncology, Centre Georges-Francois Leclerc, Dijon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Maingon
authors.affiliation: Department of Radiation Oncology, Institute Verbeeten, Tilburg, Netherlands; Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Poortmans
authors.affiliation: Department of Radiation Oncology, KU Leuven, University Hospitals Leuven, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Weltens
authors.affiliation: Department of Radiation Oncology, Institut Curie, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fourquet
authors.affiliation: Department of Radiation Oncology, Maastro Clinic, Maastricht, Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jager
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Dominic
authors.initials: D
authors.lastname: Schinagl
authors.affiliation: Department of Radiation Oncology, Institute Verbeeten, Tilburg, Netherlands.
authors.forename: Bing
authors.initials: B
authors.lastname: Oei
authors.affiliation: Department of Radiation Oncology, Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Carla
authors.initials: C
authors.lastname: Rodenhuis
authors.affiliation: Clinique de Genolier, Genolier, Switzerland.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Horiot
authors.affiliation: Department of Radiation Oncology, Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Struikmans
authors.affiliation: Department of Radiation Oncology, KU Leuven, University Hospitals Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Van Limbergen
authors.affiliation: Department of Radiation Oncology, Institut Curie, Paris, France.
authors.forename: Youlia
authors.initials: Y
authors.lastname: Kirova
authors.affiliation: Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Paula
authors.initials: P
authors.lastname: Elkhuizen
authors.affiliation: Department of Radiation Oncology, Universitaetsklinikum Köln, Köln, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Bongartz
authors.affiliation: Division of Radiation Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
authors.forename: Raymond
authors.initials: R
authors.lastname: Miralbell
authors.affiliation: Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: David
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Institut Régional du Cancer Montpellier, Montpellier, France.
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Dubois
authors.affiliation: Department of Radiotherapy, Clinique et Maternité Sainte Elisabeth, Namur, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Remouchamps
authors.affiliation: Clinique La Source, Lausanne, Switzerland.
authors.forename: René-Olivier
authors.initials: RO
authors.lastname: Mirimanoff
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Collette
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Collette
mesh_terms: D000328:Adult; D000367:Age Factors; D001315:Australia; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery*; D005060:Europe; D005260:Female; D005355:Fibrosis; D006801:Humans; D057194:Intention to Treat Analysis; D007557:Israel; D053208:Kaplan-Meier Estimate; D008408:Mastectomy; D015412:Mastectomy, Segmental / Q000009:adverse effects / Q000401:mortality; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D018579:Patient Selection; D016016:Proportional Hazards Models; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant; D012086:Reoperation; D016879:Salvage Therapy; D013997:Time Factors; D016896:Treatment Outcome