title: Hypofractionated and accelerated radiotherapy with cytoprotection (HypoARC): a short, safe, and effective postoperative regimen for high-risk breast cancer patients.
abstract: OBJECTIVE
  Although the role of radiotherapy (RT) after mastectomy in reducing the local relapse rate is well established, its impact on overall survival is strongly questioned. Up to 70% of patients will not benefit from additional RT, and a "wait and see" policy is often adopted. Establishment of short, still safe, and effective RT regimens would render adjunctive radiotherapy more appealing. We evaluated the toxicity and efficacy of a Hypofractionated and intensively Accelerated RT regimen supported with amifostine Cytoprotection (HypoARC) in a cohort of 72 high-risk breast cancer patients treated with modified mastectomy or conservative surgery and FEC (5-fluorouracil/epirubicin/cyclophosphamide) chemotherapy.
  
  
  METHODS
  A high dose of amifostine, 1,000 mg, was given as a 5-min i.v. infusion before each of the 12 consecutive fractions of RT (4 x 3.5 Gy/fraction and 8 x 4 Gy/fraction, 1 fraction/day, 5 fractions/week). The breast or chest wall, as well as supraclavicular and axillary area, was included in the RT fields. The follow-up of patients ranged from 18 to 42 months (median, 28 months). Alkaline phosphatase (AF) expression was assessed immunohistochemically in normal and cancerous breast tissues.
  
  
  RESULTS
  Ninety-two percent of patients successfully completed the regimen, the only side effects being mild nausea and asthenia. In 7% of patients, amifostine was interrupted because of a rash/fever reaction. A dramatic reduction in acute skin toxicity was noted (p < 0.0001). Acute pneumonitis, as well as late toxicity in breast, chest wall, axillary, and lung tissue, was lower with the HypoARC regimen, although not significantly, than with the standard fractionation regimen used to treat two matched control cohorts. Both HypoARC and standard RT significantly reduce the local relapse rate (p < 0.0001), although the local relapse-free and overall survival times were marginally better for the HypoARC group of patients (p > 0.09). AF showed a mixed nuclear/cytoplasmic pattern of expression in the epithelial, endothelial, and stromal component of the normal breast and benign lesions, whereas an impressive loss of AF expression was noted in in situ and invasive breast cancer and tumoral stroma.
  
  
  CONCLUSIONS
  The HypoARC regimen is convenient for both patients and radiotherapy departments. The regimen is well tolerated and shows a significantly better profile in terms of early toxicity; a reduced rate of late sequel may be expected. The local relapse rate is as low as that expected from conventional RT. The absence of AF expression in cancer cells and tumoral stroma is probably a major reason for the selective protection of normal breast tissue by amifostine.
authors.affiliation: Department of Radiotherapy/Oncology, Demokritus University of Thrace, Alexandroupolis, Greece. targ@her.forthnet.gr
authors.forename: Michael I
authors.initials: MI
authors.lastname: Koukourakis
authors.forename: Alexandra
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: Charalambos
authors.initials: C
authors.lastname: Kouroussis
authors.forename: Stelios
authors.initials: S
authors.lastname: Kakolyris
authors.forename: Efthimios
authors.initials: E
authors.lastname: Sivridis
authors.forename: Chryssi
authors.initials: C
authors.lastname: Frangiadaki
authors.forename: George
authors.initials: G
authors.lastname: Retalis
authors.forename: Vassilis
authors.initials: V
authors.lastname: Georgoulias
mesh_terms: D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D004999:Amifostine / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000532:radiotherapy* / Q000601:surgery; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage; D019583:Dose Fractionation, Radiation; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D008408:Mastectomy; D015411:Mastectomy, Modified Radical; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D017564:Radiation Pneumonitis / Q000209:etiology; D011837:Radiation-Protective Agents / Q000009:adverse effects / Q000627:therapeutic use; D011853:Radiobiology; D011855:Radiodermatitis / Q000209:etiology; D018714:Radiotherapy, Adjuvant; D016019:Survival Analysis; D014839:Vomiting / Q000139:chemically induced
chemical_list: D011837:Radiation-Protective Agents; D015251:Epirubicin; D003520:Cyclophosphamide; D000469:Alkaline Phosphatase; D004999:Amifostine; D005472:Fluorouracil