Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular Diagnostics

Systemic inflammation scores correlate with survival prognosis in patients with newly diagnosed brain metastases

Abstract

Background

Systemic inflammation measured by the neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and CRP/albumin ratio (CRP/Alb) was shown to impact the survival prognosis in patients with extracranial solid cancer.

Methods

One thousand two hundred and fifty patients with newly diagnosed brain metastases (BM) were identified from the Vienna Brain Metastasis Registry.

Results

PLR and CRP/Alb were higher in patients with progressive extracranial disease and lower in patients with no evidence of extracranial disease. Lower NLR (cut-off = 5.07; 9.3 vs. 5.0 months), LLR (cut-off = 5.76; 10.0 vs. 5.3 months), PLR (cut-off = 335; 8.0 vs. 3.8 months), MLR (cut-off = 0.53; 6.0 vs. 3.5 months) and CRP/Alb (cut-off = 2.93; 8.5 vs. 3.7 months; padj < 0.05) were associated with longer overall survival (OS). In multivariate analysis with graded prognostic assessment (hazard ratio (HR) 1.45; 95% confidence interval (CI): 1.32–1.59; padj = 1.62e − 13), NLR (HR 1.55; 95% CI: 1.38–1.75; padj = 1.92e − 11), LLR (HR 1.57; 95% CI: 1.39–1.77; padj = 1.96e − 11), PLR (HR 1.60; 95% CI: 1.39–1.85; padj = 2.87955e − 9), MLR (HR 1.41; 95% CI: 1.14–1.75; padj = 0.027) and CRP/Alb (HR 1.83; 95% CI: 1.54–2.18; padj = 2.73e − 10) remained independent factors associated with OS at BM diagnosis.

Conclusions

Systemic inflammation, measured by NLR, LLR, PLR, MLR and CRP/Alb, was associated with OS in patients with BM. Further exploration of immune modulating therapies is warranted in the setting of BM.

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: Levels of systemic inflammation scores according to the status of the extracranial disease.
Fig. 2: Levels of platelet-to-lymphocyte ratio according to prior chemotherapy before diagnosis of BM.
Fig. 3: Overall survival from diagnosis of BM according to markers of systemic inflammation.

References

  1. 1.

    Achrol, A. S., Rennert, R. C., Anders, C., Soffietti, R., Ahluwalia, M. S., Nayak, L. et al. Brain metastases. Nat. Rev. Dis. Prim. 5, https://doi.org/10.1038/s41572-018-0055-y (2019).

  2. 2.

    Moravan, M. J., Fecci, P. E., Anders, C. K., Clarke, J. M., Salama, A. K. S., Adamson, J. D. et al. Current multidisciplinary management of brain metastases. Cancer https://doi.org/10.1002/cncr.32714 (2020).

    Article  PubMed  Google Scholar 

  3. 3.

    Long, G. V., Atkinson, V., Lo, S., Sandhu, S., Guminski, A. D., Brown, M. P. et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 19, 672–681 (2018).

    CAS  Article  Google Scholar 

  4. 4.

    Tawbi, H. A., Forsyth, P. A., Algazi, A., Hamid, O., Hodi, F. S., Moschos, S. J. et al. Combined Nivolumab and Ipilimumab in melanoma metastatic to the brain. N. Engl. J. Med. 379, 722–730 (2018).

    CAS  Article  Google Scholar 

  5. 5.

    Galea, I., Bechmann, I. & Perry, V. H. What is immune privilege (not)? Trends Immunol. 28, 12–18 (2007).

    CAS  Article  Google Scholar 

  6. 6.

    Berghoff, A. S., Fuchs, E., Ricken, G., Mlecnik, B., Bindea, G., Spanberger, T. et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology 5, e1057388 (2016).

    Article  Google Scholar 

  7. 7.

    Diakos, C. I., Charles, K. A., McMillan, D. C. & Clarke, S. J. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 15, e493–e503 (2014).

    Article  Google Scholar 

  8. 8.

    Käsmann, L., Bolm, L., Schild, S. E., Janssen, S. & Rades, D. Neutrophil-to-lymphocyte ratio predicts outcome in limited disease small-cell lung cancer. Lung 195, 217–224 (2017).

    Article  Google Scholar 

  9. 9.

    Fukuda, H., Takagi, T., Kondo, T., Shimizu, S. & Tanabe, K. Predictive value of inflammation-based prognostic scores in patients with metastatic renal cell carcinoma treated with cytoreductive nephrectomy. Oncotarget 9, 14296–14305 (2018).

    Article  Google Scholar 

  10. 10.

    Riedl, J. M., Posch, F., Moik, F., Bezan, A., Szkandera, J., Smolle, M. A. et al. Inflammatory biomarkers in metastatic colorectal cancer: prognostic and predictive role beyond the first line setting. Oncotarget 8, 96048–96061 (2017).

    Article  Google Scholar 

  11. 11.

    Bumma, N., Jeyakumar, G., Kim, S., Galasso, C., Thakur, M. K., Gadgeel, S. M. et al. Neutrophil lymphocyte ratio (NLR) as a predictive biomarker for PD-1/PD-L1 directed therapy in metastatic non-small cell lung cancer (NSCLC). J. Clin. Oncol. 35, e20633–e20633 (2017).

    Article  Google Scholar 

  12. 12.

    He, X., Li, J.-P., Liu, X.-H., Zhang, J.-P., Zeng, Q.-Y., Chen, H. et al. Prognostic value of C-reactive protein/albumin ratio in predicting overall survival of Chinese cervical cancer patients overall survival: comparison among various inflammation based factors. J. Cancer 9, 1877–1884 (2018).

    Article  Google Scholar 

  13. 13.

    Heppt, M. V., Heinzerling, L., Kähler, K. C., Forschner, A., Kirchberger, M. C., Loquai, C. et al. Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition. Eur. J. Cancer 82, 56–65 (2017).

    CAS  Article  Google Scholar 

  14. 14.

    Ishihara, H., Tachibana, H., Takagi, T., Kondo, T., Fukuda, H., Yoshida, K. et al. Predictive impact of peripheral blood markers and C-reactive protein in nivolumab therapy for metastatic renal cell carcinoma. Target Oncol. 14, 453–463 (2019).

    Article  Google Scholar 

  15. 15.

    Shoji, F., Takeoka, H., Kozuma, Y., Toyokawa, G., Yamazaki, K., Ichiki, M. et al. Pretreatment prognostic nutritional index as a novel biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors. Lung Cancer 136, 45–51 (2019).

    Article  Google Scholar 

  16. 16.

    Sperduto, P. W., Chao, S. T., Sneed, P. K., Luo, X., Suh, J., Roberge, D. et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int. J. Radiat. Oncol. Biol. Phys. 77, 655–661 (2010).

    Article  Google Scholar 

  17. 17.

    Charlson, M. E., Pompei, P., Ales, K. L. & MacKenzie, C. R. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J. Chronic Dis. 40, 373–383 (1987).

    CAS  Article  Google Scholar 

  18. 18.

    CRAN. Package maxstat. https://cran.r-project.org/web/packages/maxstat/index.html (2020).

  19. 19.

    Chen, Y., Huang, J., He, X., Gao, Y., Mahara, G., Lin, Z. et al. A novel approach to determine two optimal cut-points of a continuous predictor with a U-shaped relationship to hazard ratio in survival data: Simulation and application. BMC Med. Res. Methodol. 19, 96 (2019).

    Article  Google Scholar 

  20. 20.

    Therneau, T. M. Survival analysis [R package survival version 3.1-8]. https://cran.r-project.org/web/packages/survival/index.html (2020).

  21. 21.

    CRAN. Package survminer. https://cran.r-project.org/web/packages/survminer/index.html (2020).

  22. 22.

    Ohsugi, Y. Recent advances in immunopathophysiology of interleukin-6: an innovative therapeutic drug, tocilizumab (recombinant humanized anti-human interleukin-6 receptor antibody), unveils the mysterious etiology of immune-mediated inflammatory diseases. Biol. Pharm. Bull. 30, 2001–2006 (2007).

    CAS  Article  Google Scholar 

  23. 23.

    McMillan, D. C. The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat. Rev. 39, 534–540 (2013).

    Article  Google Scholar 

  24. 24.

    Klinger, M. H. F. & Jelkmann, W. Role of blood platelets in infection and inflammation adaptation of thrombopoiesis. J. Inter. Cytokine Res. 22, 913–922 (2002).

    CAS  Article  Google Scholar 

  25. 25.

    Palumbo, J. S., Talmage, K. E., Massari, J. V., La Jeunesse, C. M., Flick, M. J., Kombrinck, K. W. et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 105, 178–185 (2005).

    CAS  Article  Google Scholar 

  26. 26.

    Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    CAS  Article  Google Scholar 

  27. 27.

    Chua, W., Charles, K. A., Baracos, V. E. & Clarke, S. J. Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br. J. Cancer 104, 1288–1295 (2011).

    CAS  Article  Google Scholar 

  28. 28.

    Kao, S. C. H., Pavlakis, N., Harvie, R., Vardy, J. L., Boyer, M. J., Van Zandwijk, N. et al. High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin. Cancer Res. 16, 5805–5813 (2010).

    CAS  Article  Google Scholar 

  29. 29.

    Berghoff, A. S., Wolpert, F., Holland-Letz, T., Koller, R., Widhalm, G., Gatterbauer, B. et al. Combining standard clinical blood values for improving survival prediction in patients with newly diagnosed brain metastases—development and validation of the LabBM score. Neuro Oncol. 19, now290 (2017).

    Article  Google Scholar 

  30. 30.

    Berghoff, A. S. & Preusser, M. New developments in brain metastases. Ther. Adv. Neurol. Disord. 11, 175628641878550 (2018).

    Article  Google Scholar 

  31. 31.

    Capone, M., Giannarelli, D., Mallardo, D., Madonna, G., Festino, L., Grimaldi, A. M. et al. Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. J. Immunother. Cancer 6, 74 (2018).

    Article  Google Scholar 

  32. 32.

    Bilen, M. A., Martini, D. J., Liu, Y., Lewis, C., Collins, H. H., Shabto, J. M. et al. The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced-stage cancer treated with immunotherapy. Cancer 125, 127–134 (2019).

    Article  Google Scholar 

  33. 33.

    Tawbi, H. A.-H., Forsyth, P. A. J., Algazi, A. P., Hamid, O., Hodi, F. S., Moschos, S. J. et al. Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: results of the phase II study CheckMate 204. J. Clin. Oncol. 35, 9507–9507 (2017).

    Article  Google Scholar 

  34. 34.

    Caponnetto, S., Draghi, A., Borch, T. H., Nuti, M., Cortesi, E., Svane, I. M. et al. Cancer immunotherapy in patients with brain metastases. Cancer Immunol. Immunother. 67, 703–711 (2018).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We sincerely thank Felix Haupolter for his help in data acquisition. This study was performed within the Ph.D. thesis of Angelika M. Starzer with the title “Immune monitoring in cancer patients” in the N790 doctoral programme at the Medical University of Vienna, Austria. The content of this manuscript was partly presented at the Brain Metastasis Research Symposium in Vienna, Austria, in June 2019 and at the annual conference of the European Society for Medical Oncology (ESMO) in Barcelona, Spain, in September 2019 and nominated as best poster in the CNS session.

Author information

Affiliations

Authors

Contributions

Writing of manuscript draft: A.M.S., A.S.B. Statistical analysis: A.M.S., M.J.M., G.H., A.S.B. Data collection: A.M.S., A.S., A.S., C.D., G.W., B.G., K.D., M.P., A.S.B. Critical revision of important intellectual interdisciplinary content and correction of manuscript: A.M.S., A.S., M.J.M., A.S., C.D., G.W., B.G., K.D., G.H., M.P., A.S.B.

Corresponding author

Correspondence to Anna S. Berghoff.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of the Medical University of Vienna (Vote EK 078/2004). Due to the retrospective design of the study the ethics board waived the informed consent of individual patients. This study was performed in accordance with the Declaration of Helsinki.

Data availability

The data supporting the results in this manuscript is saved at a server of the Medical University of Vienna.

Competing interests

A.M.S. has received travel support from PharmaMar. A.S.B. has research support from Daiichi Sankyo and Roche, honoraria for lectures, consultation or advisory board participation from Roche, Bristol-Meyers Squibb, Merck, Daiichi Sankyo as well as travel support from Roche, Amgen, Daiichi Sankyo and AbbVie. M.P. has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen. The following for-profit companies have supported clinical trials and contracted research conducted by M.P. with payments made to his institution: Böhringer-Ingelheim, Bristol-Myers Squibb, Roche, Daiichi Sankyo, Merck Sharp & Dome, Novocure, GlaxoSmithKline, AbbVie. G.H. has received research support from Bristol-Meyers Squibb and Merck. All other authors report no conflicts of interest concerning this specific publication.

Funding information

The study costs were supported by a grant from the Margaretha Hehberger-Stiftung assigned to A.S.B. (Project 18085; title: Impact of local and systemic treatments on the inflammatory microenvironment composition in brain metastases). The funding source supported this study by partly financing a Ph.D. student.

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

Starzer, A.M., Steindl, A., Mair, M.J. et al. Systemic inflammation scores correlate with survival prognosis in patients with newly diagnosed brain metastases. Br J Cancer (2021). https://doi.org/10.1038/s41416-020-01254-0

Download citation

Search

Quick links