Skip to main content

Baseline and Postoperative C-reactive Protein Levels Predict Long-Term Survival After Lung Metastasectomy

Abstract

Background

Blood level of C-reactive protein (CRP) at diagnosis is a well-know prognostic bio-marker in different primary tumors, but its role has not been investigated in resectable lung metastases. The aim of our study is to assess the predictive value of baseline (CRP0) and 3rd postoperative day (CRP3) levels on long-term survival of patients undergoing lung metastasectomy.

Methods

A total of 846 consecutive patients underwent the first pulmonary resection for lung metastases between January 2003 and December 2015, including 611 (72%) single surgical procedures, 235 (28%) multiple metastasectomies, 501 (59%) epithelial primary tumors, 276 (33%) sarcomas, 66 (8%) melanomas, 286 (33.8%) with 0 risk factors (CRP0 ≤ 2 and CRP3 ≤ 84 mg/L) and 560 (66.2%) with ≥ 1 risk factor (CRP0 > 2 and/or CRP3 > 84 mg/L).

Results

Cumulative 5-year survival was 57% in patients with low CRP (0 risk factors) versus 43% in high CRP (≥ 1 risk factor, p < 0.0002), 62% versus 50% respectively for epithelial tumors (p < 0.0140), and 51% versus 34% for sarcomas (p < 0.0111). Multivariable Cox analysis confirmed a mortality hazard ratio of 2.5 at 1-year and 1.5 at 5-years in patients with high CRP.

Conclusions

Baseline and postoperative CRP levels predict survival of patients with resectable lung metastases. These data provide a rationale for prospective clinical trials testing the efficacy of anti-inflammatory or immune-modulating agents as “adjuvant” therapy after lung metastasectomy, in patients with elevated pre- and/or postoperative CRP levels.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Treasure T, Milošević M, Fiorentino F, Macbeth F. Pulmonary metastasectomy: what is the practice and where is the evidence for effectiveness? Thorax. 2014;69(10):946–9.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Embun R, Fiorentino F, Treasure T, et al. Pulmonary metastasectomy in colorectal cancer: a prospective study of demography and clinical characteristics of 543 patients in the Spanish colorectal metastasectomy registry (GECMP-CCR). BMJ Open. 2013;3:e002787.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Martini N, Huvos AG, Miké V, Marcove RC, Beattie EJ Jr. Multiple pulmonary resections in the treatment of osteogenic sarcoma. Ann Thorac Surg. 1971;12(3):271–80.

    Article  CAS  PubMed  Google Scholar 

  4. Beattie EJ, Harvey JC, Marcove R, Martini N. Results of multiple pulmonary resections for metastatic osteogenic sarcoma after two decades. J Surg Oncol. 1991;46(3):154–55.

  5. Pastorino U, Gasparini M, Tavecchio L, Azzarelli A, Mapelli S, Zucchi V, Morandi F, Bellani FF, Valente M, Ravasi G. The contribution of salvage surgery to the management of childhood osteosarcoma. J Clin Oncol. 1991;9(8):1357–62.

    Article  CAS  PubMed  Google Scholar 

  6. McCormack PM, Martini N. The changing role of surgery for pulmonary metastases. Ann Thorac Surg 1979;28:139–45.

    Article  CAS  PubMed  Google Scholar 

  7. Pastorino U, Buyse M, Friedel G, Ginsberg RJ, Girard P, Goldstraw P, Johnston M, McCormack P, Pass H, Putnam JB Jr., International Registry of Lung Metastases. Long-term results of lung metastasectomy: prognostic analyses based on 5,206 cases. J Thorac Cardiovasc Surg. 1997;113(1):37–49.

  8. Holdenrieder S, Pagliaro L, Morgenstern D, Dayyani F. Clinically meaningful use of blood tumor markers in oncology. Biomed Res Int. 2016;2016:9795269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073–81.

    Article  CAS  PubMed  Google Scholar 

  10. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how is the link? Biochem Pharmacol. 2006;72(11):1605–21.

    Article  CAS  PubMed  Google Scholar 

  12. Shrotriya S, Walsh D, Bennani-Baiti N, Thomas S, Lorton C. C-reactive protein is an important biomarker for prognosis tumor recurrence and treatment response in adult solid tumors: a systematic review. PLoS ONE. 2015;10:e0143080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shiels MS, Katki HA, Hildesheim A, Pfeiffer RM, Engels EA, Williams M, Kemp TJ, Caporaso NE, Pinto LA, Chaturvedi AK. Circulating inflammation markers, risk of lung cancer, and utility for risk stratification. J Natl Cancer Inst. 2015;107(10):djv199.

    Article  Google Scholar 

  14. Leuzzi G, Galeone C, Gisabella M, Duranti L, Taverna F, Suatoni P, Morelli D, Pastorino U. Baseline C-reactive protein level predicts survival of early-stage lung cancer: evidence from a systematic review and meta-analysis. Tumori. 2016;102(5):441–9.

    Article  PubMed  Google Scholar 

  15. Pastorino U, Morelli D, Leuzzi G, Gisabella M, Suatoni P, Taverna F, Bertocchi E, Boeri M, Sozzi G, Cantarutti A, Corrao G. Baseline and postoperative C-reactive protein levels predict mortality in operable lung cancer. Eur J Cancer. 2017;79:90–7.

    Article  CAS  PubMed  Google Scholar 

  16. Li C, Xu Q, Chen L, Luo C, Ying J, Liu J. C-reactive protein (CRP) as a prognostic factor for colorectal cancer after surgical resection of pulmonary metastases. Bull Cancer. 2017;104(3):232–36.

    Article  PubMed  Google Scholar 

  17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Statist Assn. 1958;53(282):457–81.

    Article  Google Scholar 

  18. Mina LA, Sledge GW Jr. Rethinking the metastatic cascade as a therapeutic target. Nat Rev Clin Oncol. 2011;8(6):325–32.

    Article  CAS  PubMed  Google Scholar 

  19. Køstner AH, Kersten C, Löwenmark T, Ydsten KA, Peltonen R, Isoniemi H, Haglund C, Gunnarsson U, Isaksson B. The prognostic role of systemic inflammation in patients undergoing resection of colorectal liver metastases: C-reactive protein (CRP) is a strong negative prognostic biomarker. J Surg Oncol. 2016;114(7):895–99.

    Article  CAS  PubMed  Google Scholar 

  20. Wu Y, Potempa LA, El Kebir D, Filep JG. C-reactive protein and inflammation: conformational changes affect function. Biol Chem. 2015;396(11):1181e97.

  21. Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem. 2004;279(47):48487e90.

  22. Marnell LL, Mold C, Du Clos TW. C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol. 2005;117:104e11.

  23. Kishiki T, Masaki T, Mastuoka H, Abe N, Mori T, Sugiyama M. New prognostic scoring system for incurable stage IV colorectal cancer. Asian Pac J Cancer Prev. 2016;17(2):597–601.

    Article  PubMed  Google Scholar 

  24. Thomsen M, Kersten C, Sorbye H, Skovlund E, Glimelius B, Pfeiffer P, Johansen JS, Kure EH, Ikdahl T, Tveit KM, Christoffersen T, Guren TK. Interleukin-6 and C-reactive protein as prognostic biomarkers in metastatic colorectal cancer. Oncotarget. 2016;7(46):75013–22.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Haruki K, Shiba H, Horiuchi T, Sakamoto T, Gocho T, Fujiwara Y, Furukawa K, Misawa T, Yanaga K. Impact of the C-reactive protein to albumin ratio on long-term outcomes after hepatic resection for colorectal liver metastases. Am J Surg. 2017;214(4):752–6.

    Article  PubMed  Google Scholar 

  26. Morhij R, Mahendra A, Jane M, McMillan DC. The modified Glasgow prognostic score in patients undergoing surgery for bone and soft tissue sarcoma. J Plast Reconstr Aesthet Surg. 2017;70(5):618–24.

    Article  PubMed  Google Scholar 

  27. Iwamoto H, Izumi K, Shimura Y, Natsagdorj A, Maolake A, Takezawa Y, Nohara T, Shigehara K, Kadono Y, Mizokami A. Metastasectomy improves survival in patients with metastatic urothelial carcinoma. Anticancer Res. 2016;36(10):5557–61.

    Article  CAS  PubMed  Google Scholar 

  28. Akamine T, Takada K, Toyokawa G, Kinoshita F, Matsubara T, Kozuma Y, et al. Association of preoperative serum CRP with PD-L1 expression in 508 patients with non-small cell lung cancer: a comprehensive analysis of systemic inflammatory markers. Surg Oncol. 2018;27(1):88–94.

    Article  PubMed  Google Scholar 

  29. Kruger S, Legenstein ML, Rösgen V, Haas M, Modest DP, Westphalen CB, et al. Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer. Oncoimmunology. 2017;6(5):e1310358.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chang PH, Pan YP, Fan CW, Tseng WK, Huang JS, Wu TH, et al. Pretreatment serum interleukin-1β, interleukin-6, and tumor necrosis factor-α levels predict the progression of colorectal cancer. Cancer Med. 2016;5(3):426–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919–29.

    Article  CAS  Google Scholar 

  32. Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ; CANTOS Trial Group. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10105):1833–42.

  33. Rothwell PM, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012;379:1602–12.

    Article  CAS  PubMed  Google Scholar 

  34. Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol. 2011;29:2635–44.

    Article  CAS  PubMed  Google Scholar 

  35. Powe DG, et al. β-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget. 2010;1:628–38.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Liu JF, Jamieson GG, Wu TC, Zhu GJ, Drew PA. A preliminary study on the postoperative survival of patients given aspirin after resection for squamous cell carcinoma of the esophagus or adenocarcinoma of the cardia. Ann Surg Oncol. 2009;16:1397–402.

    Article  PubMed  Google Scholar 

  37. Forget P, Machiels JP, Coulie PG, Berliere M, Poncelet AJ, Tombal B, et al. Neutrophil:lymphocyte ratio and intraoperative use of ketorolac or diclofenac are prognostic factors in different cohorts of patients undergoing breast, lung, and kidney cancer surgery. Ann Surg Oncol. 2013;20(Suppl. 3):650–60.

    Article  Google Scholar 

  38. Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer. 2001;84(7):886–91.

  39. Murphy RA, Mourtzakis M, Chu QS, Baracos VE, Reiman T, Mazurak VC. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer. 2011;117(16):3774–80.

    Article  CAS  PubMed  Google Scholar 

  40. Perentes JY, Krueger T, Lovis A, Ris HB, Gonzalez M. Thoracoscopic resection of pulmonary metastasis: current practice and results. Crit Rev Oncol Hematol. 2015;95(1):105–13.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Ugo Pastorino MD or Alessandro Gronchi MD.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. 1

Kaplan–Meier survival curves by number of metastasectomy (A. single, B. multiple), according to C-reactive protein measured at baseline (CRP0) and 3 days after surgery (CRP3). Low CRP: CRP0 ≤ 2 and CRP3 ≤ 84-high CRP: CRP0 > 2 or CRP3 > 84 (TIFF 974 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pastorino, U., Morelli, D., Leuzzi, G. et al. Baseline and Postoperative C-reactive Protein Levels Predict Long-Term Survival After Lung Metastasectomy. Ann Surg Oncol 26, 869–875 (2019). https://doi.org/10.1245/s10434-018-07116-7

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-018-07116-7