Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Prognostic value of CA 19-9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy

Abstract

Purpose

CA 19-9 is the only established tumor marker in pancreatic cancer (PC); the prognostic role of other serum markers like CEA, CRP, LDH or bilirubin has not yet been defined.

Methods

We pooled pre-treatment data on CA 19-9, CEA, CRP, LDH and bilirubin levels from two German multicenter randomized phase II trials together with prospective patient data from one high-volume German Cancer Center. Marker levels were assessed locally before the start of palliative first-line therapy for advanced PC and serially during treatment (for CA 19-9 only). Clinical and biomarker data (overall 12 variables) were correlated with the efficacy endpoints time-to-progression (TTP) and overall survival (OS) by using uni- and multivariate Cox models.

Results

Data from 291 patients were included in this pooled analysis; 253 patients (87 %) received treatment within prospective clinical trials. Median TTP in the study cohort was 5.1 months and median OS 9.0 months. In univariate analysis, pre-treatment CA 19-9 (HR 1.55), LDH (HR 2.04) and CEA (HR 1.89) levels were significantly associated with TTP. Regarding OS, baseline CA 19-9 (HR 1.46), LDH (HR 2.07), CRP (HR 1.69) and bilirubin (HR 1.62) were significant prognostic factors. Within multivariate analyses, pre-treatment log [CA 19-9] (as continuous variable for TTP) and log [bilirubin] as well as log [CRP] (for OS) had an independent prognostic value. A CA 19-9 decline of ≥25 % during the first two chemotherapy cycles was predictive for TTP and OS, independent of the applied CA 19-9 assay.

Conclusion

Baseline CA 19-9 and CA 19-9 kinetics during first-line chemotherapy are prognostic in advanced PC. Besides that finding other serum markers like CRP, LDH and bilirubin can also provide prognostic information on TTP and OS.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. Boeck S, Stieber P, Holdenrieder S, Wilkowski R, Heinemann V (2006) Prognostic and therapeutic significance of carbohydrate antigen 19–9 as tumor marker in patients with pancreatic cancer. Oncology 70(4):255–264

  2. Boeck S, Hoehler T, Seipelt G, Mahlberg R, Wein A, Hochhaus A et al (2008) Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer. Ann Oncol 19(2):340–347

  3. Boeck S, Haas M, Laubender RP, Kullmann F, Klose C, Bruns CJ et al (2010) Application of a time-varying covariate model to the analysis of CA 19–9 as serum biomarker in patients with advanced pancreatic cancer. Clin Cancer Res 16(3):986–994

  4. Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JA (2001) Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 19(15):3447–3455

  5. Canna K, McArdle PA, McMillan DC, McNicol AM, Smith GW, McKee RF et al (2005) The relationship between tumour T-lymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer. Br J Cancer 92(4):651–654

  6. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825

  7. Duffy MJ, Sturgeon C, Lamerz R, Haglund C, Holubec VL, Klapdor R et al (2010) Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol 21(3):441–447

  8. Falconer JS, Fearon KC, Ross JA, Elton R, Wigmore SJ, Garden OJ et al (1995) Acute-phase protein response and survival duration of patients with pancreatic cancer. Cancer 75(8):2077–2082

  9. Heinemann V, Haas M, Boeck S (2012) Systemic treatment of advanced pancreatic cancer. Cancer Treat Rev 38(7):843–853

  10. Hess V, Glimelius B, Grawe P, Dietrich D, Bodoky G, Ruhstaller T et al (2008) CA 19–9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial. Lancet Oncol 9(2):132–138

  11. Humphris JL, Chang DK, Johns AL, Scarlett CJ, Pajic M, Jones MD et al (2012) The prognostic and predictive value of serum CA19.9 in pancreatic cancer. Ann Oncol 23(7):1713–1722

  12. Kullmann F, Hollerbach S, Dollinger MM, Harder J, Fuchs M, Messmann H et al (2009) Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study. Br J Cancer 100(7):1032–1036

  13. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93(4):387–391

  14. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical trials group. J Clin Oncol 25(15):1960–1966

  15. Moses AG, Maingay J, Sangster K, Fearon KC, Ross JA (2009) Pro-inflammatory cytokine release by peripheral blood mononuclear cells from patients with advanced pancreatic cancer: relationship to acute phase response and survival. Oncol Rep 21(4):1091–1095

  16. Pine JK, Fusai KG, Young R, Sharma D, Davidson BR, Menon KV et al (2009) Serum C-reactive protein concentration and the prognosis of ductal adenocarcinoma of the head of pancreas. Eur J Surg Oncol 35(6):605–610

  17. Reni M, Cereda S, Balzano G, Passoni P, Rognone A, Fugazza C et al (2009) Carbohydrate antigen 19–9 change during chemotherapy for advanced pancreatic adenocarcinoma. Cancer 115(12):2630–2639

  18. Stocken DD, Hassan AB, Altman DG, Billingham LJ, Bramhall SR, Johnson PJ et al (2008) Modelling prognostic factors in advanced pancreatic cancer. Br J Cancer 99(6):883–893

  19. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL et al (2009) Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 27(13):2231–2237

  20. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011) Pancreatic cancer. Lancet 378(9791):607–620

Download references

Acknowledgments

The authors would like to thank all patients and their families, nurses, study coordinators and investigators that actively participated in the Ro96 and the GEMOXCET study, thereby enabling this pooled analysis. This work is part of the doctoral thesis of Michael Haas.

Conflict of interest

All authors declare that they have no conflict of interest.

Author information

Correspondence to Stefan Boeck.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Haas, M., Heinemann, V., Kullmann, F. et al. Prognostic value of CA 19-9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy. J Cancer Res Clin Oncol 139, 681–689 (2013). https://doi.org/10.1007/s00432-012-1371-3

Download citation

Keywords

  • Gemcitabine
  • Pancreatic cancer
  • Prognostic factor