title: Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis.
abstract: OBJECTIVE
  We aimed to report the final toxicity results on a radiation-dose escalation trial designed to test a hypothesis that very high doses of radiation could be safely administered to patients with non-small-cell lung cancer (NSCLC) by quantifying the dose-volume toxicity relationship of the lung.
  
  
  METHODS
  A total of 109 patients with unresectable or medically inoperable NSCLC were enrolled and treated with radiation-dose escalation (on the basis of predicted normal-lung toxicity) either alone or with neoadjuvant chemotherapy by use of 3D conformal techniques. Eighty-four patients (77%) received more than 69 Gy, the trial was stopped after the dose reached 103 Gy. Estimated median follow-up was 110 months.
  
  
  RESULTS
  There were 17 (14.6%) Grade 2 to 3 pneumonitis and 15 (13.8%) Grade 2 to 3 fibrosis and no Grade 4 to 5 lung toxicity. Multivariate analyses showed them to be (1) not associated with the dose prescribed to the tumor, and (2) significantly (p<0.001) associated with lung-dosimetric parameters such as the mean lung dose (MLD), volume of lung that received at least 20 Gy (V20), and the normal-tissue complication probability (NTCP) of the lung. If cutoffs are 30% for V20, 20 Gy for MLD, and 10% for NTCP, these factors have positive predictive values of 50% to 71% and negative predictive value of 85% to 89%.
  
  
  CONCLUSIONS
  With long-term follow-up for toxicity, we have demonstrated that much higher doses of radiation than are traditionally administered can be safely delivered to a majority of patients with NSCLC. Quantitative lung dose-volume toxicity-based dose escalation can form the basis for individualized high-dose radiation treatment to maximize the therapeutic ratio in these patients.
authors.affiliation: Department of Radiation Oncology, University of Michigan, and Radiation Oncology, Veterans Administration Medical Center, Ann Arbor, MI 48109, USA. Fengkong@med.umich.edu
authors.forename: Feng-Ming
authors.initials: FM
authors.lastname: Kong
authors.forename: James A
authors.initials: JA
authors.lastname: Hayman
authors.forename: Kent A
authors.initials: KA
authors.lastname: Griffith
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Kalemkerian
authors.forename: Douglas
authors.initials: D
authors.lastname: Arenberg
authors.forename: Susan
authors.initials: S
authors.lastname: Lyons
authors.forename: Andrew
authors.initials: A
authors.lastname: Turrisi
authors.forename: Allen
authors.initials: A
authors.lastname: Lichter
authors.forename: Benedick
authors.initials: B
authors.lastname: Fraass
authors.forename: Avraham
authors.initials: A
authors.lastname: Eisbruch
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Randall K
authors.initials: RK
authors.lastname: Ten Haken
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy*; D017024:Chemotherapy, Adjuvant; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000532:radiotherapy* / Q000601:surgery; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D015999:Multivariate Analysis; D017564:Radiation Pneumonitis / Q000209:etiology* / Q000473:pathology; D020266:Radiotherapy, Conformal / Q000009:adverse effects*