Cyfra 21-1, neuron specific enolase and prognosis of non-small cell lung cancer: prospective study in 621 patients.

BACKGROUND: CYFRA 21-1, a serum cytokeratin 19 fragment, and neuron specific enolase (NSE), the gamma-subunit of enolase, are putative markers of lung cancer. Their clinical applicability as prognostic factors in non-small cell lung cancer (NSCLC) would need an appraisal by simultaneous evaluation of other known survival determinants in a large population followed over a long period. AIM: To determine the prognostic value of different clinical and routine biological variables at presentation with particular attention paid to the above-mentioned markers.
METHODS: 621 histologically proven and previously untreated NSCLC patients have been prospectively studied (seven were lost to follow-up). Median follow-up was 4 years and 2 months. At presentation, 16 clinical and biological variables were recorded. Serum NSE and CYFRA 21-1 were assayed blind without any clinical information given.
RESULTS: The serum CYFRA 21-1 distribution differed significantly according to histology, disease stage and performance status, with the highest levels observed in squamous cell carcinomas, metastatic stage, positive mediastinal nodal status and poor performance status. However, the respective "receiver operating characteristic" curves showed that the CYFRA 21-1 serum level did not accurately predict tumour stage. Serum NSE distribution correlated neither with tumour stage nor with performance index and its sensitivity in the whole NSCLC was low. In the Cox proportional hazard model, the following variables were independent determinants of a poor outcome: performance status 2 or 3, hazard ratio (HR): 2.25; Nodal status N(2-3), HR: 1.84; Metastatic disease, HR: 1.73; NSE>12.5 ng/ml, HR: 1.52; CYFRA 21-1>3.6 ng/ml, HR: 1.41 and Tumour status T(3-4), HR: 1.31. When the survival analysis was restricted to the 274 patients affected by a metastatic stage, we observed that performance status, nodal status, NSE and CYFRA 21-1 remained prognostic determinants with similar hazard ratios.
CONCLUSION: The prognostic information given by a high serum CYFRA 21-1 level is independent from other well-known variables such as performance status and disease stage and is perennial throughout extended follow-up period. A high NSE level also prognosticates a poor outcome probably by reflecting tumour heterogeneity and underestimated neuroendocrine differentiation.