title: Clinical relevance of thymidine kinase for the diagnosis, therapy monitoring and prognosis of non-operable lung cancer.
abstract: BACKGROUND
  Whether thymidine kinase (TK) is considered a new diagnostic biomarker in lung cancer depends on it being superior to or adding further information to already established tumor markers. Here, we investigated its relevance in diagnosis, therapy monitoring and prognosis of patients with diverse forms of lung cancer.
  
  
  METHODS
  Pretherapeutic TK concentrations were analyzed by radioimmunoassay in serum of 181 patients with advanced lung cancer (53 small cell lung cancer (SCLC), 128 non-small cell lung cancer (NSCLC)), 40 with benign lung diseases, 44 with benign non-lung-related diseases and 29 healthy controls. Diagnostic power of TK was compared with that of established lung cancer markers carcinoembryonic antigen (CEA), cytokeratin 19-fragments (CYFRA 21-1), neuron-specific enolase (NSE) and progastrin-releasing peptide (ProGRP). Furthermore, TK courses of 29 NSCLC patients during cytotoxic chemotherapy were recorded and prognostic relevance of pretherapeutic TK levels was tested in 128 NSCLC patients.
  
  
  RESULTS
  While healthy controls had low TK serum levels (median 2.5 U/l, 95th percentile 8.8 U/l), they were significantly higher in patients with lung cancer (median 4.2 U/l, p=0.014) and also in patients with benign lung diseases (median 5.7 U/l; p=0.002). Patients with lung cancer and benign lung diseases could not be separated by TK values. No noticeable difference of TK concentrations was further found in NSCLC (median 4.3 U/l) as compared with SCLC patients (median 3.7 U/l) neither in adeno cell carcinomas (median 5.4 U/l) and squamous cell carcinomas (median 3.0 U/l). In NSCLC, the best diagnostic capacity versus benign lung diseases was found for CYFRA 21-1 (AUC 88.2%), NSE (AUC 86.4%), and CEA (AUC 82.9%), while TK reached only an AUC of 45.7%. The best diagnostic profile in SCLC versus benign lung diseases was observed for NSE (AUC 93.9%) and ProGRP (AUC 85.4%), while TK did not have any diagnostic power (AUC 46.6%). Concerning therapy monitoring, TK was unable to discriminate between the various response groups, neither pretherapeutically, nor before therapy cycles 2 and 3. However, pretherapeutic TK levels showed high prognostic value for overall survival in NSCLC patients: While median survival in patients with TK levels >or=20 U/l was only 3.1 months, it was 9.0 months in patients with TK levels <20 U/l. In multivariate analyses, TK remained an independent prognostic marker, along with the clinical variables stage and performance score.
  
  
  CONCLUSIONS
  Although the performance of serum TK for diagnosis and therapy monitoring of advanced lung cancer was poor, it has a promising prognostic relevance which will have to be further validated.
authors.affiliation: Institute of Clinical Chemistry, University Hospital Munich-Grosshadern, Munich, Germany. Stefan.Holdenrieder@med.uni-muenchen.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Holdenrieder
authors.forename: Joachim
authors.initials: J
authors.lastname: Von Pawel
authors.forename: Thomas
authors.initials: T
authors.lastname: Duell
authors.forename: Knut
authors.initials: K
authors.lastname: Feldmann
authors.forename: Hannelore
authors.initials: H
authors.lastname: Raith
authors.forename: Annette
authors.initials: A
authors.lastname: Schollen
authors.forename: Dorothea
authors.initials: D
authors.lastname: Nagel
authors.forename: Petra
authors.initials: P
authors.lastname: Stieber
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000201:enzymology / Q000628:therapy; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D053539:Keratin-19 / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000201:enzymology* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011379:Prognosis; D011863:Radioimmunoassay; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D053539:Keratin-19; D010751:Phosphopyruvate Hydratase