title: Is intermediate radiation dose escalation with concurrent chemotherapy for stage III non-small-cell lung cancer beneficial? A multi-institutional propensity score matched analysis.
abstract: OBJECTIVE
  The clinical benefits and risks of dose escalation (DE) for stage III non-small-cell lung cancer (NSCLC) remain uncertain despite the results from Radiation Therapy Oncology Group (RTOG) protocol 0617. There is significant heterogeneity of practice, with many clinicians prescribing intermediate dose levels between the 0617 study arms of 60 and 74 Gy. This study investigated whether this strategy is associated with any survival benefits/risks by analyzing a large multi-institutional database.
  
  
  METHODS
  An individual patient database of stage III NSCLC patients treated with radical intent concurrent chemoradiation therapy was created (13 institutions, n=1274 patients). Patients were divided into 2 groups based on tumor Biological Effective Dose at 10 Gy (BED 10): those receiving standard dose (SD; n=552), consisting of 72Gy ≤ BED 10 ≤ 76.8 Gy (eg 60-64 Gy/30-32 fractions [fr]), and those receiving intermediate dose (ID; n=497), consisting of 76.8Gy < BED 10 < 100.8 Gy (eg >64 Gy/32 fr and <74 Gy/37 fr), with lower-dose patients (n=225) excluded from consideration. Patients were then matched using propensity scores, leading to 2 matched groups of 196 patients. Outcomes were compared using various statistics including interquartile range (IQR), Kaplan-Meier curves, and adjusted Cox regression analysis.
  
  
  RESULTS
  Matched groups were found to be balanced except for N stage (more N3 disease in SD), median treatment year (SD in 2003; ID in 2007), platinum and taxane chemotherapy (SD in 28%; ID in 39%), and median follow-up (SD were 89 months; ID were 40 months). Median dose fractionation was 60 Gy/30 fr in SD (BED 10 IQR: 72.0-75.5 Gy) and 66 Gy/33 fr (BED 10 IQR: 78.6-79.2 Gy) in ID. Survival curves for SD and ID matched cohorts were statistically similar (P=.27); however, a nonstatistically significant trend toward better survival for ID was observed after 15 months (median survival SD: 19.3 months; ID: 21.0 months). There was an increase in grades III to V lung toxicity associated with ID (13.0% vs 4.9%, respectively).
  
  
  CONCLUSIONS
  No significant overall survival benefits were found with intermediate DE; however, more grade III or greater lung toxicity was observed. The separation of survival curves after 15 months of follow-up suggests that a small overall survival improvement associated with intermediate DE cannot be excluded.
authors.affiliation: London Health Sciences Centre, London, Ontario, Canada. Electronic address: george.rodrigues@lhsc.on.ca.
authors.forename: George
authors.initials: G
authors.lastname: Rodrigues
authors.affiliation: MAASTRO Clinic, Maastricht, The Netherlands.
authors.forename: Cary
authors.initials: C
authors.lastname: Oberije
authors.affiliation: VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Suresh
authors.initials: S
authors.lastname: Senan
authors.affiliation: Hyogo Cancer Center, Akashi, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tsujino
authors.affiliation: MAASTRO Clinic, Maastricht, The Netherlands.
authors.forename: Terry
authors.initials: T
authors.lastname: Wiersma
authors.affiliation: Universidad de Navarra, Pamplona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Moreno-Jimenez
authors.affiliation: National Cancer Center, Goyang-si, Gy eonggi, Korea.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Kim
authors.affiliation: University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Marks
authors.affiliation: University of Washington, Seattle, Washington.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Rengan
authors.affiliation: Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Luigi
authors.initials: L
authors.lastname: De Petris
authors.affiliation: Campus Bio-Medico University, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ramella
authors.affiliation: Ghent University, Ghent, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: DeRuyck
authors.affiliation: Universidad Pompeu Fabra, Barcelona, Spain.
authors.forename: Núria Rodriguez
authors.initials: NR
authors.lastname: De Dios
authors.affiliation: London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Warner
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Bradley
authors.affiliation: London Health Sciences Centre, London, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Palma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy / Q000009:adverse effects* / Q000379:methods; D002945:Cisplatin / Q000008:administration & dosage; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D057216:Propensity Score; D011879:Radiotherapy Dosage; D012062:Relative Biological Effectiveness
chemical_list: D002945:Cisplatin