Molecular Diagnostics

Prognostic significance of pre- and post-operative tumour markers for patients with gastric cancer

Abstract

Background

In clinical practice, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are the most common markers measured before and after surgery for gastric cancer (GC). However, which pre- or post-operative combined tumour markers (CEA and CA19-9) have more prognostic value remains unclear.

Methods

Consecutive patients undergoing a resection for GC at the Fujian Medical University Union Hospital were included as a discovery database between January 2011 and December 2014. The prognostic impact of pre- and post-operative tumour markers was evaluated using Kaplan–Meier log-rank survival analysis and multivariable Cox regression analysis. The results were then externally validated.

Results

A total of 735 and 400 patients were identified in the discovery cohort and in the validation cohort, respectively. Overall survival rates decreased in a stepwise manner in association with the number of pre- and post-operative positive tumour markers (both P < 0.001). Multivariable analysis revealed that the number of pre-operative positive tumour markers was an independent prognostic factor (P < 0.05). For patients with abnormal pre-operative tumour markers, normalisation of tumour markers after surgery is an independent prognostic protective factor (hazard ratio (HR) = 0.618; 95% confidence interval (CI) = 0.414–0.921), and patients with both positive post-operative tumour markers had double the risk of overall death (HR = 2.338; 95% CI = 1.071–5.101). Similar results were observed in the internal validation and external validation cohorts.

Conclusion

Pre-operative tumour markers have a better discriminatory ability for post-operative survival in GC patients than post-operative tumour markers, and the normalisation of tumour markers after surgery was associated with better survival.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Kaplan–Meier analysis of OS of the patients who underwent curative surgery for GC.
Fig. 2: Time-dependent ROC curves for tumour makers.

References

  1. 1.

    Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 136, E359–E386 (2015).

    CAS  Article  Google Scholar 

  2. 2.

    Amin, M. B., Edge, S. B., Greene, F. L., Byrd, D. R., Brookland, R. K., Washington, M. K. et al. AJCC Cancer Staging Manual 8th edn (Springer, New York, 2010).

  3. 3.

    Ferrone, C. R., Finkelstein, D. M., Thayer, S. P., Muzikansky, A., Fernandez-delCastillo, C. & Warshaw, A. L. Perioperative CA19-9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma. J. Clin. Oncol. 24, 2897–2902 (2006).

    CAS  Article  Google Scholar 

  4. 4.

    Marrelli, D., Pinto, E., De Stefano, A., de Manzoni, G., Farnetani, M., Garosi, L. et al. Preoperative positivity of serum tumor markers is a strong predictor of hematogenous recurrence of gastric cancer. J. Surg. Oncol. 78, 253–258 (2001).

    CAS  Article  Google Scholar 

  5. 5.

    Wang, W., Seeruttun, S. R., Fang, C., Chen, J., Li, Y., Liu, Z. et al. Prognostic significance of carcinoembryonic antigen staining in cancer tissues of gastric cancer patients. Ann. Surg. Oncol. 23, 1244–1251 (2016).

    CAS  Article  Google Scholar 

  6. 6.

    Choi, A. R., Park, J. C., Kim, J. H., Shin, S. K., Lee, S. K., Lee, Y. C. et al. High level of preoperative carbohydrate antigen 19-9 is a poor survival predictor in gastric cancer. World J. Gastroenterol. 19, 5302–5308 (2013).

    Article  Google Scholar 

  7. 7.

    Lin, J. X., Wang, W., Lin, J. P., Xie, J. W., Wang, J. B., Lu, J. et al. Preoperative tumor markers independently predict survival in stage III gastric cancer patients: should we include tumor markers in AJCC staging? Ann. Surg. Oncol. 25, 2703–2712 (2018).

    Article  Google Scholar 

  8. 8.

    Nakane, Y., Okamura, S., Akehira, K., Boku, T., Okusa, T., Tanaka, K. et al. Correlation of preoperative carcinoembryonic antigen levels and prognosis of gastric cancer patients. Cancer 73, 2703–2708 (1994).

    CAS  Article  Google Scholar 

  9. 9.

    Suenaga, Y., Kanda, M., Ito, S., Mochizuki, Y., Teramoto, H., Ishigure, K. et al. Prognostic significance of perioperative tumor marker levels in stage II/III gastric cancer. World J. Gastrointest. Oncol. 11, 17–27 (2019).

    Article  Google Scholar 

  10. 10.

    Uda, H., Kanda, M., Tanaka, C., Kobayashi, D., Inaoka, K., Tanaka, Y. et al. Perioperative serum carcinoembryonic antigen levels predict recurrence and survival of patients with pathological T2–4 gastric cancer treated with curative gastrectomy. Dig. Surg. 35, 55–63 (2018).

    CAS  Article  Google Scholar 

  11. 11.

    Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 14, 113–123 (2011).

    Article  Google Scholar 

  12. 12.

    Bang, Y. J., Kim, Y. W., Yang, H. K., Chung, H. C., Park, Y. K., Lee, K. H. et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 379, 315–321 (2012).

    CAS  Article  Google Scholar 

  13. 13.

    Sasako, M., Sakuramoto, S., Katai, H., Kinoshita, T., Furukawa, H., Yamaguchi, T. et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J. Clin. Oncol. 29, 4387–4393 (2011).

    CAS  Article  Google Scholar 

  14. 14.

    Nam, D. H., Lee, Y. K., Park, J. C., Lee, H., Shin, S. K., Lee, S. K. et al. Prognostic value of early postoperative tumor marker response in gastric cancer. Ann. Surg. Oncol. 20, 3905–3911 (2013).

    Article  Google Scholar 

  15. 15.

    Sturgeon, C. M., Duffy, M. J., Hofmann, B. R., Lamerz, R., Fritsche, H. A., Gaarenstroom, K. et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in liver, bladder, cervical, and gastric cancers. Clin. Chem. 56, e1–e48 (2010).

    CAS  Article  Google Scholar 

  16. 16.

    Kochi, M., Fujii, M., Kanamori, N., Kaiga, T., Kawakami, T., Aizaki, K. et al. Evaluation of serum CEA and CA19-9 levels as prognostic factors in patients with gastric cancer. Gastric Cancer 3, 177–186 (2000).

    Article  Google Scholar 

  17. 17.

    Lin, J. X., Lin, J. P., Xie, J. W., Wang, J. B., Lu, J., Chen, Q. Y. et al. Prognostic importance of the preoperative modified systemic inflammation score for patients with gastric cancer. Gastric Cancer 22, 403–412 (2019).

    CAS  Article  Google Scholar 

  18. 18.

    Wang, S. C., Chou, J. F., Strong, V. E., Brennan, M. F., Capanu, M. & Coit, D. G. Pretreatment neutrophil to lymphocyte ratio independently predicts disease-specific survival in resectable gastroesophageal junction and gastric adenocarcinoma. Ann. Surg. 263, 292–297 (2016).

    Article  Google Scholar 

  19. 19.

    Suzuki, Y., Okabayashi, K., Hasegawa, H., Tsuruta, M., Shigeta, K., Kondo, T. et al. Comparison of preoperative inflammation-based prognostic scores in patients with colorectal cancer. Ann. Surg. 267, 527–531 (2018).

    Article  Google Scholar 

  20. 20.

    Aziz, M. H., Sideras, K., Aziz, N. A., Mauff, K., Haen, R., Roos, D. et al. The systemic-immune-inflammation index independently predicts survival and recurrence in resectable pancreatic cancer and its prognostic value depends on bilirubin levels: a retrospective multicenter cohort study. Ann. Surg. 270, 139–146 (2019).

    Article  Google Scholar 

  21. 21.

    Dilege, E., Mihmanli, M., Demir, U., Ozer, K., Bostanci, O., Kaya, C. et al. Prognostic value of preoperative CEA and CA 19-9 levels in resectable gastric cancer. Hepatogastroenterology 57, 674–677 (2010).

    PubMed  Google Scholar 

  22. 22.

    Tachibana, M., Takemoto, Y., Nakashima, Y., Kinugasa, S., Kotoh, T., Dhar, D. K. et al. Serum carcinoembryonic antigen as a prognostic factor in resectable gastric cancer. J. Am. Coll. Surg. 187, 64–68 (1998).

    CAS  Article  Google Scholar 

  23. 23.

    Toyoda, H., Kumada, T., Tada, T., Niinomi, T., Ito, T., Kaneoka, Y. et al. Prognostic significance of a combination of pre- and post-treatment tumor markers for hepatocellular carcinoma curatively treated with hepatectomy. J. Hepatol. 57, 1251–1257 (2012).

    CAS  Article  Google Scholar 

  24. 24.

    Safi, F., Schlosser, W., Falkenreck, S. & Beger, H. G. Prognostic value of CA 19-9 serum course in pancreatic cancer. Hepatogastroenterology 45, 253–259 (1998).

    CAS  PubMed  Google Scholar 

  25. 25.

    Schlieman, M. G., Ho, H. S. & Bold, R. J. Utility of tumor markers in determining resectability of pancreatic cancer. Arch. Surg. 138, 951–955 (2003). 955-956.

    Article  Google Scholar 

  26. 26.

    Park, I. J., Choi, G. S., Lim, K. H., Kang, B. M. & Jun, S. H. Serum carcinoembryonic antigen monitoring after curative resection for colorectal cancer: clinical significance of the preoperative level. Ann. Surg. Oncol. 16, 3087–3093 (2009).

    Article  Google Scholar 

  27. 27.

    Toyoda, H., Kumada, T., Tada, T., Niinomi, T., Ito, T., Kaneoka, Y. et al. Prognostic significance of a combination of pre- and post-treatment tumor markers for hepatocellular carcinoma curatively treated with hepatectomy. J. Hepatol. 57, 1251–1257 (2012).

    CAS  Article  Google Scholar 

  28. 28.

    Steyerberg, E. W. & Harrell, F. J. Prediction models need appropriate internal, internal-external, and external validation. J. Clin. Epidemiol. 69, 245–247 (2016).

    Article  Google Scholar 

  29. 29.

    Kato, S., Okamura, R., Baumgartner, J. M., Patel, H., Leichman, L., Kelly, K. et al. Analysis of circulating tumor DNA and clinical correlates in patients with esophageal, gastroesophageal junction, and gastric adenocarcinoma. Clin. Cancer. Res. 24, 6248–6256 (2018).

    CAS  Article  Google Scholar 

  30. 30.

    Wang, Y., Zhao, C., Chang, L., Jia, R., Liu, R., Zhang, Y. et al. Circulating tumor DNA analyses predict progressive disease and indicate trastuzumab-resistant mechanism in advanced gastric cancer. EBioMedicine 43, 261–269 (2019).

    CAS  Article  Google Scholar 

  31. 31.

    National Health and Family Planning Commission of the people’s Republic of China. Guidelines for standardized diagnosis and treatment of gastric cancer (Trial). Chin. J. Front. Med. Sci. (Electron. Version) 5, 29–36 (2013).

    Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

Conception and design: J.-P.L., J.-X.L., Y.-B.M., C.-H.Z., P.L., C.-M.H. Provision of study materials or patients: All authors. Collection and assembly of data: All authors. Data analysis and interpretation: J.-P.L., J.-X.L., Y.-B.M., J.-W.X., S.Y., J.-B.W., J.L., Q.-Y.C., X.-F.M., L.-L.C., M.L., R.-H.T. Manuscript writing: J.-P.L., J.-X.L., Y.-B.M., C.-H.Z., P.L., C.-M.H. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors.

Corresponding authors

Correspondence to Chao-Hui Zheng or Ping Li or Chang-Ming Huang.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the institutional review board of Fujian Medical University Union Hospital. The requirement of informed consent from the patients was waived because of the retrospective design of this study, and patients’ information was protected. All procedures performed in the study involving human participants were in accordance with the Declaration of Helsinki.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding

This study was supported by scientific and technological innovation joint capital projects of Fujian Province, China (2017Y9011; 2017Y9004). Minimally invasive medical centre of Fujian Province (No. [2017]171). This project was supported by the Science Foundation of the Fujian Province, China (Grant No. 2018J01307).

Additional information

Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lin, J., Lin, J., Ma, Y. et al. Prognostic significance of pre- and post-operative tumour markers for patients with gastric cancer. Br J Cancer 123, 418–425 (2020). https://doi.org/10.1038/s41416-020-0901-z

Download citation

Further reading