title: Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis.
abstract: Chemotherapy (CT) combined with radiotherapy is the standard treatment of 'limited-stage' small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and CT.
  
  
  
  We carried out a meta-analysis of individual patient data in randomized trials comparing earlier versus later radiotherapy, or shorter versus longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival.
  
  
  
  Twelve trials with 2668 patients were eligible. Data from nine trials comprising 2305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, 'earlier or shorter' versus 'later or longer' thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of 'earlier or shorter' radiotherapy among trials with a similar proportion of patients who were compliant with CT (defined as having received 100% or more of the planned CT cycles) in both arms (HR 0.79, 95% CI 0.69-0.91), and in favour of 'later or longer' radiotherapy among trials with different rates of CT compliance (HR 1.19, 1.05-1.34, interaction test, P < 0.0001). The absolute gain between 'earlier or shorter' versus 'later or longer' thoracic radiotherapy in 5-year overall survival for similar and for different CT compliance trials was 7.7% (95% CI 2.6-12.8%) and -2.2% (-5.8% to 1.4%), respectively. However, 'earlier or shorter' thoracic radiotherapy was associated with a higher incidence of severe acute oesophagitis than 'later or longer' radiotherapy.
  
  
  
  'Earlier or shorter' delivery of thoracic radiotherapy with planned CT significantly improves 5-year overall survival at the expense of more acute toxicity, especially oesophagitis.
authors.affiliation: Department of Radiation Oncology (MAASTRO Clinic), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands Department of Oncology, Experimental Radiation Oncology, KU Leuven, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: De Ruysscher
authors.affiliation: Department of Biostatistics and Epidemiology and "Ligue Nationale Contre le Cancer" meta-analysis platform, Gustave Roussy, Villejuif, France CESP, INSERM U1018, Université Paris-Sud, Université Paris-Saclay, Villejuif.
authors.forename: B
authors.initials: B
authors.lastname: Lueza
authors.affiliation: Department of Oncology and radiation therapy, Gustave Roussy, Villejuif Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: C
authors.initials: C
authors.lastname: Le Péchoux
authors.affiliation: UT Southwestern University School of Medicine, Dallas, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Johnson
authors.affiliation: EORTC Data Center, Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: O'Brien
authors.affiliation: British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Murray
authors.affiliation: University College London Hospitals, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Spiro
authors.affiliation: Alliance Data and Statistical Center, Duke University, Durham, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Osaka Prefectural Habikino Hospital, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takada
authors.affiliation: Hôpital St Antoine, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Lebeau
authors.affiliation: Wake Forest University School of Medicine, Winston-Salem, USA.
authors.forename: W
authors.initials: W
authors.lastname: Blackstock
authors.affiliation: Second Department of Medical Oncology, Metropolitan Hospital N. Faliro, Athens, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Skarlos
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Baas
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: H
authors.initials: H
authors.lastname: Choy
authors.affiliation: NHS Lothian and University of Edinburgh, Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK.
authors.forename: A
authors.initials: A
authors.lastname: Price
authors.affiliation: NCIC Clinical Trials Group and Queen's University, Kingston, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Gustave Roussy, Villejuif, France Karolinska Institutet, Stockholm, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Arriagada
authors.affiliation: Department of Biostatistics and Epidemiology and "Ligue Nationale Contre le Cancer" meta-analysis platform, Gustave Roussy, Villejuif, France CESP, INSERM U1018, Université Paris-Sud, Université Paris-Saclay, Villejuif jean-pierre.pignon@gustaveroussy.fr.
authors.forename: J-P
authors.initials: JP
authors.lastname: Pignon
mesh_terms: D002945:Cisplatin / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004358:Drug Therapy; D005260:Female; D006801:Humans; D008297:Male; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D002945:Cisplatin
keywords: chemotherapy compliance; individual participant data meta-analysis; radiotherapy timing; randomized clinical trials; small-cell lung cancer; thoracic radiotherapy