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

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.

Prognosis of Patients With Stages I and II Non-Small Cell Lung Cancer With Nodal Micrometastases

“…Several studies have shown that the presence of OM detected immunohistochemically in regional LNs obtained during pulmonary resection is associated with worse survival rates in patients with stage I NSCLC [4,[11][12][13][14] and in a heterogeneous group of stages I and II patients [10]. In this study, we found that OM detected preoperatively in mediastinal LNs obtained during TEMLA were an independent negative prognostic factor for 5-year overall and disease-free survival.…”

“…Relapse at distant sites is thought to result from the presence of occult micrometastases (OM) undetected by standard diagnostic methods at the time of the preoperative workup. The prevalence of OM in the mediastinal lymph nodes (LNs) is higher in patients with recurrence after surgical treatment [3], and the presence of OM is associated with reduced survival after complete resection [4]. The current data about the clinical significance of the mediastinal LN OM are based on the postoperative detection in LNs resected during a complete operation.…”

Improving post-resection risk stratification in non-small cell lung cancer: ‘wit, whither wander you?’

“…Although systematic nodal examination was mandated, only 31% of patients in the CALGB study had all the mandated lymph node stations examined. Indeed, 26% of resections had 2 or more missing nodal stations (11). The thoroughness of hilar and intrapulmonary lymph node examination was not reported in either study.…”

“…The report of the mature results of CALGB 9761 (Alliance) is the most recent effort in this direction (11).…”

Perspectives on the effect of nodal downstaging and its implication of the role of surgery in stage IIIA (N2) non-small cell lung cancer

“…In a review of more than 6,500 patients undergoing (7). The sensitivity of these techniques improve using immunohistochemistry antibodies to cytokeratins, or other molecular detector with reverse transcriptase polymerase chain reaction (RT-PCR) methodology but this has not been proven to definitively impact survival or recurrence rates (8,9).…”