title: Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy.
abstract: OBJECTIVE
  The aim of this study was to determine the maximum tolerated dose (MTD) delivered within 6 weeks in patients with non-small-cell lung cancer (NSCLC). The impact of tumor volume and delivered dose on failure-free interval (FFI) and overall survival (OS) were also studied.
  
  
  METHODS
  A Phase I/II trial was performed including inoperable NSCLC patients. According to the relative mean lung dose (rMLD), five risk groups with different starting doses were defined: Group 1, rMLD 0.0 to 0.12; Group 2, rMLD 0.12 to 0.18; Group 3, rMLD 0.18 to 0.24; Group 4, rMLD 0.24 to 0.31; and Group 5, rMLD 0.31 to 0.40. Patients underwent irradiation with 2.25 Gy per fraction and a fixed overall treatment time of 6 weeks. The dose was escalated with 6.75 Gy after 6 months follow-up without dose-limiting toxicity. If more than 30 fractions were prescribed, twice-daily irradiation was performed with at least a 6-h interval.
  
  
  RESULTS
  A total of 88 patients were included. Tumor Stage I or II was found in 53%, IIIA in 31%, and IIIB in 17%. The MTD was not achieved in risk Group 1 (reached dose, 94.5 Gy). For risk Groups 2 and 3 the MTD was 81 Gy. The 74.3-Gy dose was determined to be safe for Group 4 and the 60.8-Gy dose for Group 5. In 2 patients (5%) an isolated nodal relapse occurred. Based on multivariable analysis, higher doses significantly increased the FFI (p = 0.02) for the total group. The OS was increased in the lower risk groups (p = 0.05) but not in the higher risk groups (p = 0.4).
  
  
  CONCLUSIONS
  Dose escalation is safe up to 94.5 Gy in 42 fractions in 6 weeks in patients with an MLD 13.6 Gy or less. Higher doses are associated with a better FFI and OS for smaller tumor volumes. Involved-field irradiation results in a low percentage of isolated nodal relapses.
authors.affiliation: Department of Radiation Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. j.belderbos@nki.nl
authors.forename: Jose S A
authors.initials: JS
authors.lastname: Belderbos
authors.forename: Wilma D
authors.initials: WD
authors.lastname: Heemsbergen
authors.forename: Katrien
authors.initials: K
authors.lastname: De Jaeger
authors.forename: Paul
authors.initials: P
authors.lastname: Baas
authors.forename: Joos V
authors.initials: JV
authors.lastname: Lebesque
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000532:radiotherapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000532:radiotherapy*; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011832:Radiation Injuries / Q000401:mortality; D011880:Radiotherapy Planning, Computer-Assisted / Q000379:methods; D020266:Radiotherapy, Conformal / Q000009:adverse effects / Q000379:methods*