SERUM BIOMARKERS FACILITATE THE RECOGNITION OF EARLY STAGE CANCER AND MAY GUIDE THE SELECTION OF SURGICAL CANDIDATES: a study of Carcinoembryonic Antigen (CEA) and Tissue Polypeptide Antigen (TPA) in operable patients with Non-Small Cell Lung Cancer (NSCLC).

Running title: CEA and TPA in the pre-operative evaluation of NSCLC

From the Cuneo Lung Cancer Study Group at the "S. Croce e Carle" Hospital, Cuneo I-12100, Italy

Authors:
1. Gianfranco Buccheri, M.D.
Divisione di Pneumologia , Ospedale "S. Croce e Carle" , Cuneo, I-12100, Italy, Tel. 0039.0171.441733, Fax. 0039.0171.441764, e-mail: buccheri@culcasg.org
2. Domenico Ferrigno, M.D.

Corresponding author: Gianfranco Buccheri, M.D.

Key words:
Lung neoplasm, non-small cell lung cancer, neoplasm staging, classification, carcinoembryonic antigen, tissue polypeptide antigen, tumor markers

Acknowledgments:
The authors thank Lorena Gribaudo and Anna Merlo, nurses of their outpatients' unit, for the invaluable help and support.

ABSTRACT
Study Objectives: Copious literature shows that in lung cancer many serum markers, especially the cytokeratin degradation products, correlate with the extent of disease. In 1995, we suggested that it should be possible to predict the resectability of non-small cell lung cancer (NSCLC) by measuring the plasmatic level of the tissue polypeptide antigen (TPA), a marker of the cytokeratin family. This study was designed: 1.) To confirm the earlier data in a new prospective evaluation; 2.) To comparatively assess another classic biomarker (i.e., the carcinoembryonic antigen, CEA); and 3.) To incorporate their results into the pre-surgical evaluation of NSCLC.

Design: Analysis of a single-institution database over a 5-year period (1994-1998).

Setting: Community-based Hospital and Second Referral Level Institution for a province of 500,000 people.

Patients: 124 consecutive patients (105 males), with pathologically documented lung cancer (50% with adenocarcinoma) accurately staged, clinically judged operable or potentially operable, and eventually operated upon.

Interventions: Anthropometric, clinical, laboratory data - including the CEA and TPA serum levels -, and the results of a complex staging work-up were prospectively recorded. Receiver-operating characteristic (ROC) curves and diagnostic formulas were used for data analysis.

Measurement and Results: The computed tomography (CT) of thorax, upper abdomen and brain was the most accurate pre-operative method to assess tumor resectability (ROC area: 0.76, 95% CI: 0.67-0.86, p=0.000; accuracy rate 77%, CI: 69-84%). TPA was also predictive for tumor resectability (ROC area: 0.62, 95% CI: 0.51-0.73, p=0.035, accuracy rate at a threshold level of 110 U/L: 65%, 95% CI: 56-73%). CEA was diagnostic only at the extreme values of its distribution (accuracy rate at a level up to 10 ng/ml: 69%, 95% CI: 60-77%). The probability of finding a resectable disease at the time of the operation increased from 78% (baseline CT-based probability) to 83%, when TPA was lower than 90 U/L, and to 85%, when CEA was below 10 ng/mL. The probability of discovering an advanced disease increased from 68% (baseline CT-based probability) to 89%, when also TPA resulted abnormal, and to 100%, when CEA was higher than 10 ng/mL. Conversely, the predictability of CT was diminished by contrasting biomarkers’ results, requiring further clinical investigations.

Conclusions: CT remains the gold standard for the pre-operative evaluation of NSCLC, although it may significantly underestimate the real tumor extension. The addition of the easy and inexpensive TPA test (with or without CEA) is capable to correct this underestimation, and helps to decide whether to completely rely on CT or order additional clinical investigations.