title: Prognostic value of extracapsular tumor spread for locoregional control in premenopausal patients with node-positive breast cancer treated with classical cyclophosphamide, methotrexate, and fluorouracil: long-term observations from International Breast Cancer Study Group Trial VI.
abstract: OBJECTIVE
  We sought to determine retrospectively whether extracapsular spread (ECS) might identify a subgroup that could benefit from radiotherapy after mastectomy, especially patients with 1 to 3 positive lymph nodes (LN1-3+).
  
  
  METHODS
  We randomized 1,475 premenopausal women with node-positive breast cancer to three, six, or nine courses of "classical" CMF (cyclophosphamide, methotrexate, and fluorouracil). After a review of all pathology forms, 933 patients (63%) had information on the presence or absence of ECS. ECS was present in 49.5%. The median follow-up was 10 years.
  
  
  RESULTS
  In univariate analyses, ECS was associated with worse disease-free survival (DFS) and overall survival (OS). In multivariate analyses adjusting for tumor size, vessel invasion, surgery type, and age group, ECS remained significant (DFS: hazard ratio, 1.61; 95% CI, 1.34 to 1.93; P < .0001; OS: 1.67; 95% CI, 1.34 to 2.08; P < .0001). However, ECS was not significant when the number of positive nodes was added. The locoregional failure rate +/- distant failure (LRF +/- distant failure) within 10 years was estimated at 19% (+/- 2%) without ECS, versus 27% (+/- 2%) with ECS. The difference was statistically significant in univariate analyses, but not after adjusting for the number of positive nodes. No independent effect of ECS on DFS, OS, or LRF could be confirmed within the subgroup of 382 patients with LN1-3+ treated with mastectomy without radiotherapy.
  
  
  CONCLUSIONS
  Our results do not support an independent prognostic value of ECS, nor its use as an indication for irradiation in premenopausal patients with LN1-3+ treated with classical CMF. However, we could not examine whether extensive ECS is of prognostic importance.
authors.affiliation: Department of Radiation Oncology, and the Institute of Medical Oncology, Inselspital, Switzerland. guenther.gruber@ksa.ch
authors.forename: Günther
authors.initials: G
authors.lastname: Gruber
authors.forename: Marco
authors.initials: M
authors.lastname: Bonetti
authors.forename: M Laura
authors.initials: ML
authors.lastname: Nasi
authors.forename: Karen N
authors.initials: KN
authors.lastname: Price
authors.forename: Monica
authors.initials: M
authors.lastname: Castiglione-Gertsch
authors.forename: Carl-Magnus
authors.initials: CM
authors.lastname: Rudenstam
authors.forename: Stig B
authors.initials: SB
authors.lastname: Holmberg
authors.forename: Jurij
authors.initials: J
authors.lastname: Lindtner
authors.forename: Rastko
authors.initials: R
authors.lastname: Golouh
authors.forename: John
authors.initials: J
authors.lastname: Collins
authors.forename: Diana
authors.initials: D
authors.lastname: Crivellari
authors.forename: Antonino
authors.initials: A
authors.lastname: Carbone
authors.forename: Beat
authors.initials: B
authors.lastname: Thürlimann
authors.forename: Edda
authors.initials: E
authors.lastname: Simoncini
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fey
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.forename: Alan S
authors.initials: AS
authors.lastname: Coates
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000532:radiotherapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008408:Mastectomy; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D017698:Postmenopause; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate