title: Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.
abstract: BACKGROUND
  Evidence from retrospective studies suggests that disease progression after first-line chemotherapy for metastatic non-small-cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential effect of aggressive local consolidative therapy for patients with oligometastatic NSCLC is unknown. We aimed to assess the effect of local consolidative therapy on progression-free survival.
  
  
  METHODS
  In this multicentre, randomised, controlled, phase 2 study, eligible patients from three hospitals had histological confirmation of stage IV NSCLC, three or fewer metastatic disease lesions after first-line systemic therapy, an Eastern Cooperative Oncology Group performance status score of 2 or less, had received standard first-line systemic therapy, and had no disease progression before randomisation. First-line therapy was four or more cycles of platinum doublet therapy or 3 or more months of EGFR or ALK inhibitors for patients with EGFR mutations or ALK rearrangements, respectively. Patients were randomly assigned (1:1) to either local consolidative therapy ([chemo]radiotherapy or resection of all lesions) with or without subsequent maintenance treatment or to maintenance treatment alone, which could be observation only. Maintenance treatment was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic treatment. Randomisation was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, CNS metastases, intrathoracic nodal status, and EGFR and ALK status. The primary endpoint was progression-free survival analysed in all patients who were treated and had at least one post-baseline imaging assessment. The study is ongoing but not recruiting participants. This study is registered with ClinicalTrials.gov, number NCT01725165.
  
  
  RESULTS
  Between Nov 28, 2012, and Jan 19, 2016, 74 patients were enrolled either during or at the completion of first-line systemic therapy. The study was terminated early after randomisation of 49 patients (25 in the local consolidative therapy group and 24 in the maintenance treatment group) as part of the annual analyses done by the Data Safety Monitoring Committee of all randomised trials at MD Anderson Cancer Center, and before a planned interim analysis of 44 events. At a median follow-up time for all randomised patients of 12·39 months (IQR 5·52-20·30), the median progression-free survival in the local consolidative therapy group was 11·9 months (90% CI 5·7-20·9) versus 3·9 months (2·3-6·6) in the maintenance treatment group (hazard ratio 0·35 [90% CI 0·18-0·66], log-rank p=0·0054). Adverse events were similar between groups, with no grade 4 adverse events or deaths due to treatment. Grade 3 adverse events in the maintenance therapy group were fatigue (n=1) and anaemia (n=1) and in the local consolidative therapy group were oesophagitis (n=2), anaemia (n=1), pneumothorax (n=1), and abdominal pain (n=1, unlikely related).
  
  
  CONCLUSIONS
  Local consolidative therapy with or without maintenance therapy for patients with three or fewer metastases from NSCLC that did not progress after initial systemic therapy improved progression-free survival compared with maintenance therapy alone. These findings suggest that aggressive local therapy should be further explored in phase 3 trials as a standard treatment option in this clinical scenario.
  
  
  BACKGROUND
  MD Anderson Lung Cancer Priority Fund, MD Anderson Cancer Center Moon Shot Initiative, and Cancer Center Support (Core), National Cancer Institute, National Institutes of Health.
authors: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: dgomez@mdanderson.org.
authors: Daniel R
authors: DR
authors: Gomez
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: George R
authors: GR
authors: Blumenschein
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: J Jack
authors: JJ
authors: Lee
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Mike
authors: M
authors: Hernandez
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Rong
authors: R
authors: Ye
authors: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA.
authors: D Ross
authors: DR
authors: Camidge
authors: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA.
authors: Robert C
authors: RC
authors: Doebele
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Ferdinandos
authors: F
authors: Skoulidis
authors: Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, USA.
authors: Laurie E
authors: LE
authors: Gaspar
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Don L
authors: DL
authors: Gibbons
authors: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jose A
authors: JA
authors: Karam
authors: Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, USA.
authors: Brian D
authors: BD
authors: Kavanagh
authors: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Chad
authors: C
authors: Tang
authors: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Ritsuko
authors: R
authors: Komaki
authors: Department of Medical Oncology, London Health Sciences Center, London, ON, Canada.
authors: Alexander V
authors: AV
authors: Louie
authors: Department of Radiation Oncology, London Health Sciences Center, London, ON, Canada.
authors: David A
authors: DA
authors: Palma
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Anne S
authors: AS
authors: Tsao
authors: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Boris
authors: B
authors: Sepesi
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: William N
authors: WN
authors: William
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jianjun
authors: J
authors: Zhang
authors: Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Qiuling
authors: Q
authors: Shi
authors: Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Xin Shelley
authors: XS
authors: Wang
authors: Department of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Stephen G
authors: SG
authors: Swisher
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: John V
authors: JV
authors: Heymach
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis