title: Detection of Occult Micrometastases in Patients With Clinical Stage I Non-Small-Cell Lung Cancer: A Prospective Analysis of Mature Results of CALGB 9761 (Alliance).
abstract: Outcomes after resection of stage I non-small-cell lung cancer (NSCLC) are variable, potentially due to undetected occult micrometastases (OM). Cancer and Leukemia Group B 9761 was a prospectively designed study aimed at determining the prognostic significance of OM.
  
  
  
  Between 1997 and 2002, 502 patients with suspected clinical stage I (T1-2N0M0) NSCLC were prospectively enrolled at 11 institutions. Primary tumor and lymph nodes (LNs) were collected and sent to a central site for molecular analysis. Both were assayed for OM using immunohistochemistry (IHC) for cytokeratin (AE1/AE3) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for carcinoembryonic antigen.
  
  
  
  Four hundred eighty-nine of the 502 enrolled patients underwent complete surgical staging. Three hundred four patients (61%) had pathologic stage I NSCLC (T1, 58%; T2, 42%) and were included in the final analysis. Fifty-six percent had adenocarcinomas, 34% had squamous cell carcinomas, and 10% had another histology. LNs from 298 patients were analyzed by IHC; 41 (14%) were IHC-positive (42% in N1 position, 58% in N2 position). Neither overall survival (OS) nor disease-free survival was associated with IHC positivity; however, patients who had IHC-positive N2 LNs had statistically significantly worse survival rates (hazard ratio, 2.04, P = .017). LNs from 256 patients were analyzed by RT-PCR; 176 (69%) were PCR-positive (52% in N1 position, 48% in N2 position). Neither OS nor disease-free survival was associated with PCR positivity.
  
  
  
  NSCLC tumor markers can be detected in histologically negative LNs by AE1/AE3 IHC and carcinoembryonic antigen RT-PCR. In this prospective, multi-institutional trial, the presence of OM by IHC staining in N2 LNs of patients with NSCLC correlated with decreased OS. The clinical significance of this warrants further investigation.
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO. LM6YB@virginia.edu.
authors.forename: Linda W
authors.initials: LW
authors.lastname: Martin
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Jonathan
authors.initials: J
authors.lastname: D'Cunha
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Debra
authors.initials: D
authors.lastname: Herzan
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Lin
authors.initials: L
authors.lastname: Gu
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Naif
authors.initials: N
authors.lastname: Abraham
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Demmy
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Detterbeck
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Shawn S
authors.initials: SS
authors.lastname: Groth
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: David H
authors.initials: DH
authors.lastname: Harpole
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Krasna
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Kemp
authors.initials: K
authors.lastname: Kernstine
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Kohman
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: G Alexander
authors.initials: GA
authors.lastname: Patterson
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sugarbaker
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Robin T
authors.initials: RT
authors.lastname: Vollmer
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Maddaus
authors.affiliation: Linda W. Martin, University of Maryland Medical School, Baltimore, MD; Jonathan D'Cunha, University of Pittsburgh Medical Center, Pittsburgh, PA; Xiaofei Wang, Lin Gu, and David H. Harpole, Duke University; Robin T. Vollmer, Durham VA Medical Center, Durham, NC; Debra Herzan, Michael A. Maddaus, and Robert A. Kratzke, University of Minnesota, Minneapolis, MN; Naif Abraham and Leslie J. Kohman, State University of New York Upstate Medical University, Syracuse; Todd L. Demmy, Roswell Park Cancer Institute, Buffalo, NY; Frank C. Detterbeck, Yale University, New Haven, CT; Shawn S. Groth and David J. Sugarbaker, Baylor College of Medicine, Houston; Kemp Kernstine, University of Texas Southwestern Medical Center, Dallas, TX; Mark J. Krasna, Jersey Shore University Medical Center, Neptune, NJ; and G. Alexander Patterson, Washington University School of Medicine, St Louis, MO.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kratzke
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction