In order to investigate the possibility of detecting occult tumor cells of small cell lung cancer (SCLC), we used the methylation-specific PCR assay to detect methylation of retinoic acid receptor-β (RARβ) in peripheral mononuclear cells (PMNC). The methylation-specific PCR assay can detect one tumor cell per 103 normal cells. Seventy-two patients participated in this study. They received an initial full-dose of combination chemotherapy for SCLC between October 1995 and June 2000. The patients were classified according to the clinical stage of their tumors as limited disease (LD) in 31 patients and extensive disease (ED) in 41. PMNC were obtained before each patient underwent chemotherapy. We detected RARβ methylation in PMNC from 42 of the 72 SCLC patients (58.3%). Nineteen of 31 patients with LD-SCLC (61.3%) and 23 of 41 patients with ED-SCLC (56.1%) were positive for RARβ methylation. The overall survival for patients who were positive and negative for RARβ methylation was not significantly different in both the LD- and ED-SCLC groups (log-rank test, p=0.13 and p=0.38, respectively); however, 2-year survival was significantly greater in the RARβ methylation-positive LD-SCLC patients (χ2 test, p=0.044). In conclusion, occult tumor cells can be detected in the peripheral blood of patients with SCLC using methylation of RARβ, and long-term survival appears to be better in LD-SCLC patients with occult tumor cells in their blood.

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