title: Accelerated hyperfractionated radiotherapy within trimodality therapy concepts for stage IIIA/B non-small cell lung cancer: Markedly higher rate of pathologic complete remissions than with conventional fractionation.
abstract: BACKGROUND
  Radiation dose escalation within definitive radiochemotherapy (RTx/CTx) was not successful for stage III non-small cell lung cancer (NSCLC) using conventional fractionation (CF). Accelerated-hyperfractionation (AHF) counteracts tumour cell repopulation. In this observational study, the effects of neoadjuvant RTx/CTx using AHF or CF were studied by histopathology and using the survival end-point.
  
  
  METHODS
  Data from all consecutive lung cancer patients treated with neoadjuvant RTx/CTx and thoracotomy between 08/2000 and 06/2012 were analysed. Patients received induction chemotherapy (cisplatin-doublets) followed by concurrent RTx/CTx using AHF (45 Gy/1.5 Gy bid) or CF-RTx (46 Gy/2 Gy qd). For estimating the AHF versus CF treatment effects, multivariate analysis (MA), propensity score weighting (PS), and instrumental variable analysis (IV) were used.
  
  
  RESULTS
  239 patients were treated, median age 58 (34-78)years, stage II/IIIA/B: 19/88/132, squamous cell/adenocarcinomas/other: 98/107/34; AHF/CF-RTx 112/127 patients. No significant differences between both groups, in tumour related factors (age, gender, Charlson comorbiditiy score, lactate dehydrogenase (LDH), haemoglobin, stage, histopathology and grading), existed. Crude rates of pathologic complete responses (pCR) in AHF and CF groups were 37% and 24% respectively. The dose fractionation effect on pCR was significant (p ⩽ 0.006, PS and IV analyses). There was a significant dependence of pCR on biologically effective dose. pCR also depended on treatment time (MA, p = 0.04; PS, p = 0.0004). Median treatment time was 22 d or 31 d using AHF or CF (p<0.0001), respectively. Adenocarcinomas had lower pCR rates in comparison to other histologies. Five-year survival of patients with pCR was 65%, independent of the fractionation.
  
  
  CONCLUSIONS
  This large monoinstitutional analysis demonstrates an increased effect of AHF on pCR of lung cancer which modifies overall survival.
authors.affiliation: Department of Radiotherapy, West German Tumour Centre, University of Duisburg-Essen, Essen, Germany. Electronic address: christoph.poettgen@uk-essen.de.
authors.forename: C
authors.initials: C
authors.lastname: Pöttgen
authors.affiliation: Department of Internal Medicine (Cancer Research), West German Tumour Centre, University of Duisburg-Essen, Essen, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Eberhardt
authors.affiliation: Department of Radiotherapy, West German Tumour Centre, University of Duisburg-Essen, Essen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Graupner
authors.affiliation: Institute of Pathology and Neuropathology, West German Tumour Centre, University of Duisburg-Essen, Essen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Theegarten
authors.affiliation: Department of Internal Medicine (Cancer Research), West German Tumour Centre, University of Duisburg-Essen, Essen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Gauler
authors.affiliation: Department of Interventional Pulmonology, Ruhrlandklinik, West German Tumour Centre, Essen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Freitag
authors.affiliation: Department of Radiotherapy, West German Tumour Centre, University of Duisburg-Essen, Essen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Abu Jawad
authors.affiliation: Institute of Pathology and Neuropathology, West German Tumour Centre, University of Duisburg-Essen, Essen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wohlschlaeger
authors.affiliation: Department of Thoracic Surgery, Ruhrlandklinik, West German Tumour Centre, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Welter
authors.affiliation: Department of Thoracic Surgery, Ruhrlandklinik, West German Tumour Centre, Essen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Stamatis
authors.affiliation: Department of Radiotherapy, West German Tumour Centre, University of Duisburg-Essen, Essen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Stuschke
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality / Q000628:therapy*; D059186:Chemoradiotherapy, Adjuvant / Q000379:methods* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods; D008175:Lung Neoplasms / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D057216:Propensity Score; D016896:Treatment Outcome
chemical_list: D005047:Etoposide; D002945:Cisplatin