Targeted Oncology

, Volume 10, Issue 4, pp 549–555 | Cite as

The Association of Serum Carcinoembryonic Antigen, Carbohydrate Antigen 19-9, Thymidine Kinase, and Tissue Polypeptide Specific Antigen with Outcomes of Patients with Metastatic Colorectal Cancer Treated with Bevacizumab: a Retrospective Study

  • Ondrej FialaEmail author
  • Jindrich Finek
  • Tomas Buchler
  • Vit Martin Matejka
  • Lubos Holubec
  • Jana Kulhankova
  • Zbynek Bortlicek
  • Vaclav Liska
  • Ondrej Topolcan
Original Research


The aim of our retrospective study was to analyze the association of selected tumor markers (TMs) including serum carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), thymidine kinase, and tissue polypeptide specific antigen with outcomes in patients with metastatic colorectal cancer (mCRC) treated with bevacizumab. There is an increasing body of evidence from retrospective/observational studies that some serum TMs may be predictive of effect of targeted therapies in mCRC. In our study, the cohort included 152 patients treated with bevacizumab-based therapy between years 2005 and 2014 at Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen. Serum samples for measurement of TMs were collected within 1 month before the initiation of bevacizumab-based treatment. In multivariate Cox analysis that included serum tumor markers and clinical baseline parameters, the number of metastatic sites (hazard ratio [HR] = 2.00, p = 0.001) and CEA levels (HR = 2.80, p < 0.001) were significantly associated with progression-free survival, whereas CA 19-9 levels (HR = 2.25, p = 0.008) were the only studied parameter associated with overall survival. Quantification of serum CEA and CA 19-9 is simple and readily available, and their candidate prognostic importance in the setting of antiangiogenesis therapy deserves to be studied in prospective trials.


Vascular Endothelial Growth Factor Bevacizumab Thymidine Kinase Serum Tumor Marker Tissue Polypeptide Antigen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to thank all patients voluntarily taking part in the observational, population-based registry CORECT. This study is supported by the Ministry of Health, Czech Republic—conceptual development of research organization Faculty Hospital in Pilsen—FNPl, 00669806 and by the project CZ.1.05/2.1.00/03.0076 from the European Regional Development Fund.

Conflict of Interest

JF has received honoraria from Astra Zeneca, Roche, and Novartis for consultations and lectures unrelated to this project. TB has received honoraria from Roche for consultations and lectures unrelated to this project. OF, VMM, LH, JK, ZB, VL, and OT declare that they have no actual or potential conflict of interest including any financial, personal, or other relationships with other people or organizations that could inappropriately influence this work.


  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefPubMedGoogle Scholar
  2. 2.
    Ferlay J, Parkin DM, Steliarova-Foucher E (2010) Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 46:765–81CrossRefPubMedGoogle Scholar
  3. 3.
    Yamashita K, Watanabe M (2009) Clinical significance of tumor markers and an emerging perspective on colorectal cancer. Cancer Sci 100:195–9CrossRefPubMedGoogle Scholar
  4. 4.
    Duffy MJ, Lamerz R, Haglund C, Nicolini A, Kalousová M, Holubec L et al (2014) Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update. Int J Cancer 134:2513–22PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Benchimol S, Fuks A, Jothy S, Beauchemin N, Shirota K, Stanners CP (1989) Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell 57:327–34CrossRefPubMedGoogle Scholar
  6. 6.
    Screaton RA, Penn LZ, Stanners CP (1997) Carcinoembryonic antigen, a human tumor marker, cooperates with Myc and Bcl-2 in cellular transformation. J Cell Biol 137:939–52PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Bramswig KH, Poettler M, Unseld M, Wrba F, Uhrin P, Zimmermann W et al (2013) Soluble carcinoembryonic antigen activates endothelial cells and tumor angiogenesis. Cancer Res 73:6584–96CrossRefPubMedGoogle Scholar
  8. 8.
    Ballehaninna UK, Chamberlain RS (2012) The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. J Gastrointest Oncol 3:105–19PubMedCentralPubMedGoogle Scholar
  9. 9.
    Zhou J, He E, Skog S (2013) The proliferation marker thymidine kinase 1 in clinical use. Mol Clin Oncol 1:18–28PubMedCentralPubMedGoogle Scholar
  10. 10.
    Rydlander L, Ziegler E, Bergman T, Schöberl E, Steiner G, Bergman AC et al (1996) Molecular characterization of a tissue-polypeptide-specific-antigen epitope and its relationship to human cytokeratin 18. Eur J Biochem 241:309–14CrossRefPubMedGoogle Scholar
  11. 11.
    Bodenmuller H (1995) The biochemistry of CYFRA 21-1 and other cytokeratin tests. Scand J Clin Lab Investig Suppl 221:60–6CrossRefGoogle Scholar
  12. 12.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al (2000) New guidelines to evaluate the response to treatment in solid tumours. European organization for research and treatment of cancer, national cancer institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 3:205–16CrossRefGoogle Scholar
  13. 13.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al (2004) Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 250:2335–42CrossRefGoogle Scholar
  14. 14.
    Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S (2005) Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival in patients with metastatic colorectal cancer. J Clin Oncol 23:3706–12CrossRefPubMedGoogle Scholar
  15. 15.
    Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–9CrossRefPubMedGoogle Scholar
  16. 16.
    Kozloff M, Yood MU, Berlin J, Flynn PJ, Kabbinavar FF, Purdie DM et al (2009) Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist 14:862–70CrossRefPubMedGoogle Scholar
  17. 17.
    Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M et al (2009) Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 20:1842–7CrossRefPubMedGoogle Scholar
  18. 18.
    Goede V, Coutelle O, Neuneier J, Reinacher-Schick A, Schnell R, Koslowsky TC et al (2010) Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br J Cancer 103:1407–14PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Lambrechts D, Lenz HJ, de Haas S, Carmeliet P, Scherer SJ (2013) Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol 31:1219–30CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang W, Azuma M, Lurje G, Gordon MA, Yang D, Pohl A et al (2010) Molecular predictors of combination targeted therapies (cetuximab, bevacizumab) in irinotecan-refractory colorectal cancer (BOND-2 study). Anticancer Res 30:4209–17PubMedGoogle Scholar
  21. 21.
    Huh JW, Oh BR, Kim HR, Kim YJ (2010) Preoperative carcinoembryonic antigen level as an independent prognostic factor in potentially curative colon cancer. J Surg Oncol 101:396–400PubMedGoogle Scholar
  22. 22.
    Sun LC, Chu KS, Cheng SC, Lu CY, Kuo CH, Hsieh JS et al (2009) Preoperative serum carcinoembryonic antigen, albumin and age are supplementary to UICC staging systems in predicting survival for colorectal cancer patients undergoing surgical treatment. BMC Cancer 9:288PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Park IJ, Choi GS, Lim KH, Kang BM, Jun SH (2009) Serum carcinoembryonic antigen monitoring after curative resection for colorectal cancer: clinical signifi- cance of the preoperative level. Ann Surg Oncol 16:3087–93CrossRefPubMedGoogle Scholar
  24. 24.
    Peng Y, Wang L, Gu J (2013) Elevated preoperative carcinoembryonic antigen (CEA) and Ki67 is predictor of decreased survival in IIA stage colon cancer. World J Surg 37:208–13CrossRefPubMedGoogle Scholar
  25. 25.
    Harrison LE, Guillem JG, Paty P, Cohen AM (1997) Preoperative carcinoembryonic antigen predicts outcomes in node-negative colon cancer patients: a multivariate analysis of 572 patients. J Am Coll Surg 185:55–9CrossRefPubMedGoogle Scholar
  26. 26.
    Yuste AL, Aparicio J, Segura A, López-Tendero P, Gironés R, Pérez-Fidalgo JA et al (2003) Analysis of clinical prognostic factors for survival and time to progression in patients with metastatic colorectal cancer treated with 5-fluorouracil-based chemotherapy. Clin Colorectal Cancer 2:231–4CrossRefPubMedGoogle Scholar
  27. 27.
    Wang WS, Lin JK, Chiou TJ, Liu JH, Fan FS, Yen CC et al (2002) CA19-9 as the most significant prognostic indicator of metastatic colorectal cancer. Hepatogastroenterology 49:160–4PubMedGoogle Scholar
  28. 28.
    Aggarwal C, Meropol NJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD et al (2013) Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer. Ann Oncol 4:420–8CrossRefGoogle Scholar
  29. 29.
    Prager GW, Braemswig KH, Martel A, Unseld M, Heinze G, Brodowicz T et al (2014) Baseline carcinoembryonic antigen (CEA) serum levels predict bevacizumab-based treatment response in metastatic colorectal cancer. Cancer Sci 105:996–1001PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Formica V, Massara MC, Portarena I, Fiaschetti V, Grenga I, Del Vecchio Blanco G et al (2009) Role of CA19.9 in predicting bevacizumab efficacy for metastatic colorectal cancer patients. Cancer Biomark 5:167–75PubMedGoogle Scholar
  31. 31.
    Narita Y, Taniguchi H, Komori A, Nitta S, Yamaguchi K, Kondo C et al (2014) CA19-9 level as a prognostic and predictive factor of bevacizumab efficacy in metastatic colorectal cancer patients undergoing oxaliplatin-based chemotherapy. Cancer Chemother Pharmacol 73:409–16CrossRefPubMedGoogle Scholar
  32. 32.
    Brockenbrough JS, Morihara JK, Hawes SE, Stern JE, Rasey JS, Wiens LW et al (2009) Thymidine kinase 1 and thymidine phosphorylase expression in non-small-cell lung carcinoma in relation to angiogenesis and proliferation. J Histochem Cytochem 57:1087–97PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Svobodova S, Topolcan O, Holubec L, Treska V, Sutnar A, Rupert K et al (2007) Prognostic importance of thymidine kinase in colorectal and breast cancer. Anticancer Res 27:1907–9PubMedGoogle Scholar
  34. 34.
    Treska V, Topolcan O, Stanislav K, Liska V, Holubec L (2009) Preoperative tumor markers as prognostic factors of colorectal liver metastases. Hepatogastroenterology 56:317–20PubMedGoogle Scholar
  35. 35.
    Glimelius B, Hoffman K, Einarsson R, Pählman L, Graf W (1996) Monitoring palliative chemotherapy in advanced gastrointestinal cancer using serial tissue polypeptide specific antigen (TPS) measurements. Acta Oncol 35:141–8CrossRefPubMedGoogle Scholar
  36. 36.
    Kornek G, Schenk T, Raderer M, Djavarnmad M, Scheithauer W (1995) Tissue polypeptide-specific antigen (TPS) in monitoring palliative treatment response of patients with gastrointestinal tumours. Br J Cancer 71:182–5PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Berglund A, Molin D, Larsson A, Einarsson R, Glimelius B (2002) Tumour markers as early predictors of response to chemotherapy in advanced colorectal carcinoma. Ann Oncol 13:1430–7CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Ondrej Fiala
    • 1
    • 2
    Email author
  • Jindrich Finek
    • 1
  • Tomas Buchler
    • 3
  • Vit Martin Matejka
    • 1
  • Lubos Holubec
    • 1
    • 2
  • Jana Kulhankova
    • 1
  • Zbynek Bortlicek
    • 4
  • Vaclav Liska
    • 2
    • 5
  • Ondrej Topolcan
    • 6
  1. 1.Department of Oncology and Radiotherapy, Medical School and Teaching Hospital in PilsenCharles University in PraguePilsenCzech Republic
  2. 2.Biomedical Center, Faculty of Medicine in PilsenCharles University in PraguePilsenCzech Republic
  3. 3.Department of Oncology and First Faculty of MedicineCharles University and Thomayer HospitalPragueCzech Republic
  4. 4.Institute of Biostatistics and Analyses, Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  5. 5.Department of Surgery, Medical School and Teaching Hospital in PilsenCharles University in PraguePilsenCzech Republic
  6. 6.Department of Nuclear Medicine, Medical School and Teaching Hospital in PilsenCharles University in PraguePilsenCzech Republic

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