Increased CYFRA 21-1, CEA and NSE are Prognostic of Poor Outcome for Locally Advanced Squamous Cell Carcinoma in Lung: A Nomogram and Recursive Partitioning Risk Stratification Analysis

Abstract

Objectives: This study aimed to: (1) assess the prognostic significance of serum tumor markers in locally advanced squamous cell carcinoma in lung (LA-SCCL); (2) generate a nomogram to predict the overall survival (OS) and (3) identify a prognostic stratification to assist the therapeutic decision-making.

Methods: LA-SCCL patients receiving definitive radiotherapy and baseline tumor marker measurement were eligible for this retrospective study. Cox proportional hazards regression was used to determine independent factors associated with various survival indexes and a nomogram was created to estimate the 5-year OS probability for individual patient. The identified prognostic factors were recruited into a recursive partitioning analysis (RPA) for OS to stratify patients with distinct outcome.

Results: A total of 224 patients were eligible for analysis. Increased cytokeratin-19 fragment (CYFRA 21-1) was independently associated with inferior OS, progression free survival (PFS) and a borderline decreased local-regional progression free survival (LRPFS). Elevated carcino-embryonic antigen (CEA) served as an unfavorable determinant for OS and increased neuron-specific enolase (NSE) was predictive of poor distant metastasis free survival (DMFS). A nomogram integrating KPS, TNM stage, CEA and CYFRA 21-1 was created, resulting in a c-index of 0.62. RPA identified 4 prognostic classifications, with median OS of 27.6, 19.9, 17.3 and 10.9 months for low, intermediate, high and very-high risk groups, respectively.

Conclusions: Baseline tumor marker panel including CYFRA 21-1, CEA and NSE can be prognostic of outcome for LA-SCCL receiving definitive radiotherapy. The RPA identified four prognostic subgroups, which could assist personalized therapy and clinical trial design in LA-SCCL.

Figure 1

Diagram of patient selection and study design. LA-NSCLC: locally advanced non-small cell lung cancer; SCC: squamous cell carcinoma; PFS: progression free survival.

Figure 2

Kaplan–Meier estimates of (A) overall survival, (B) local-regional progression free survival, (C) distant metastasis free survival and (D) progression free survival between patients with low- and high-level of baseline cytokeratin-19 fragment (CYFRA 21-1).

Figure 3

(A) Nomogram predicting 1-year, 3-year and 5-year overall survival for locally advanced squamous cell carcinoma. In the nomogram, each variable value is assigned a score, and the final sum of the scores is projected to the corresponding probability of survival; (B) Calibration plots for nomogram-predicted 1-y, 3-y and 5-y overall survival (x-axis) as compared to Kaplan–Meier OS estimates (y-axis) for internal validation. A plot along the 45-degree line would indicate a perfectly accurate nomogram prediction model.

Figure 4

(A) Prognostic stratification (low-, intermediate-, high- and very high-risk groups) of locally advanced squamous cell carcinoma determined by Recursive partitioning analysis (RPA); (B) overall survival curves and survival data for four classes stratified by RPA.