Purpose 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. Materials and Methods 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. Results 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. Conclusion 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.
Bibliographical noteFunding Information:
Supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 to the Alliance for Clinical Trials in Oncology and the following grants to the legacy Cancer and Leukemia Group B: CA04326; CA31983 (L.W.M.); CA33601, U10CA180882 (X.W. and L.G.); CA16450 (D.H., M.A.M., and R.A.K.); CA21060 (N.A. and L.J.K.); CA59518 (T.L.D.); CA47577 (D.H.H.); CA37347 (K.K.); CA77440 (G.A.P.); and CA47577 (R.T.V.). The following institutions participated in this study: University of Maryland Medical School, Baltimore, MD, Linda W. Martin, MD, supported by CA31983; Dana Farber Cancer Institute, Boston, MA, Harold J. Burstein, MD, PhD, supported by CA32291; Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH, Konstantin Dragnev, MD, supported by CA04326; Duke University Medical Center, Durham, NC, Jeffrey Crawford, MD, supported by CA47577; State University of New York Upstate Medical University, Syracuse, NY, Stephen L. Graziano, MD, supported by CA21060; University of Iowa, Iowa City, IA, Daniel A. Vaena, MD, supported by CA47642; University of Maryland Greenebaum Cancer Center, Baltimore, MD, Martin Edelman, MD, supported by CA31983; University of Minnesota, Minneapolis, MN, Bruce A. Peterson, MD, supported by CA16450; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO, Karl E. Freter, MD, supported by CA12046; University of North Carolina at Chapel Hill, Chapel Hill, NC, Thomas C. Shea, MD, supported by CA47559; and Washington University School of Medicine, St Louis, MO, Nancy Bartlett, MD, supported by CA77440.