Prognostic potential of neutrophil-to-lymphocyte ratio and lymphocyte nadir in stage III non-small-cell lung cancer
Abstract
Aim: Studies have shown increased pretreatment neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios to be predictive of survival in various cancers. Our aim was to evaluate the prognostic role of such inflammatory markers in non-small-cell lung cancer (NSCLC). Methods: One hundred and sixty-three patients with stage III NSCLC who received definitive treatment were included. Survival analysis was performed using Kaplan–Meier method. Hazard ratios for overall and recurrence-free survival were estimated using Cox proportional hazards model. Results: Both neutrophil-to-lymphocyte >Q75 (4.5) and lymphocyte nadir values <Q25 (0.25) and their unified values were associated with 90% increased overall mortality risk (p = 0.040) and a nonsignificant 50% decreased recurrence-free survival risk. Conclusion: Our exploratory analysis showed markers of systemic inflammation predicted survival outcomes in advanced NSCLC. Future prospective data analyses are needed to confirm this potential.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Epidemiology of lung cancer. Semin. Intervent. Radiol. 30(2), 93–98 (2013).
- 2 Non-small cell lung cancer survival rates by stage. www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates.
- 3 PROCLAIM: randomized Phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 34(9), 953–962 (2016).
- 4 The use of systemic treatment in the maintenance of patients with non-small cell lung cancer: a systematic review. J. Thorac. Oncol. 11(7), 989–1002 (2016).
- 5 . Cancer-related inflammation. Nature 454(7203), 436–444 (2008).
- 6 . Early neutrophil-to-lymphocyte ratio reduction as a surrogate marker of prognosis in never smokers with advanced lung adenocarcinoma receiving gefitinib or standard chemotherapy as first-line therapy. J. Cancer Res. Clin. Oncol. 138(12), 2009–2016 (2012).
- 7 . The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin. Cancer Res. 10(15), 4895–4900 (2004).
- 8 SEER Cancer Statistics Review, 1975–2009. http://seer.cancer.gov/csr/1975_2009_pops1909.
- 9 . Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146(5), 1029–1039 (1995).
- 10 . A systematic review and meta-analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours. Surg. Oncol. 23(1), 31–39 (2014). • This meta-analysis supports that elevated neutrophil-to-lymphocyte ratio (NLR) correlates with poor prognosis across various solid tumors, including non-small-cell lung cancer (NSCLC).
- 11 . Preoperative platelet lymphocyte ratio (PLR) is superior to neutrophil lymphocyte ratio (NLR) as a predictive factor in patients with esophageal squamous cell carcinoma. World J. Surg. Oncol. 12, 58 (2014).
- 12 . The platelet-to-lymphocyte ratio versus neutrophil-to-lymphocyte ratio: which is better as a prognostic factor in gastric cancer? Ann. Surg. Oncol. 22(13), 4363–4370 (2015).
- 13 Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int. J. Radiat. Oncol. Biol. Phys. 89(5), 1084–1091 (2014).
- 14 . Inflammation and cancer: back to Virchow? Lancet 357(9255), 539–545 (2001).
- 15 . Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011).
- 16 . Immunity, inflammation, and cancer. Cell 140(6), 883–899 (2010). •• Provides a comprehensive overview of the influence of inflammation and immunity on tumor development and as targets for cancer therapy.
- 17 . Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer. Head Neck 36(12), 1747–1753 (2014).
- 18 . Post-chemotherapy T-cell recovery is a marker of improved survival in patients with advanced thoracic malignancies. Br. J. Cancer 107(7), 1107–1115 (2012).
- 19 Preoperative lymphocyte count is an independent prognostic factor in node-negative non-small cell lung cancer. Lung Cancer 75(2), 223–227 (2012).
- 20 . Neutrophil-lymphocyte ratio predicts pathologic tumor response and survival after preoperative chemoradiation for rectal cancer. BMC Surg. 14(1), 94 (2014).
- 21 Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. Br. J. Cancer 109(2), 416–421 (2013).
- 22 . Inflammation and cancer. Nature 420(6917), 860–867 (2002).
- 23 Polarization of tumor-associated neutrophil phenotype by TGF-β:“N1” versus “N2” TAN. Cancer Cell 16(3), 183–194 (2009).
- 24 . CXCR2-mediated tumor-associated neutrophil recruitment is regulated by IFN-β. Int. J. Cancer 134(6), 1346–1358 (2014).
- 25 Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123(8), 3446–3458 (2013).
- 26 Prognostic factors for survival in advanced non-small-cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1,052 patients. The European Lung Cancer Working Party. J. Clin. Oncol. 13(5), 1221–1230 (1995).
- 27 Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00–03. Eur. J. Cancer 45(11), 1950–1958 (2009).
- 28 . Pretreatment neutrophil to lymphocyte ratio is associated with response to therapy and prognosis of advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy. Cancer Immunol. Immunother. 62(3), 471–479 (2013). • Finds that elevated pretreatment NLR may be a potential biomarker of worse response to first-line platinum-based chemotherapy, in terms of shorter progression-free and overall survival, for patients with advanced-stage NSCLC. This is an important supporting study that confirms the importance of measuring these values when determining treatment response and outcome in NSCLC.
- 29 . Elevated preoperative inflammatory markers based on neutrophil-to-lymphocyte ratio and C-reactive protein predict poor survival in resected non-small cell lung cancer. Anticancer Res. 32(8), 3535–3538 (2012).
- 30 Neutrophil to lymphocyte ratio associated with prognosis of lung cancer. Clin. Transl. Oncol.
doi:10.1007/s12094-016-1593-y (2016) (Epub ahead of print). - 31 . Prognostic factors for survival in patients with inoperable lung cancer. J. Natl Cancer Inst. 65(1), 25–32 (1980).
- 32 . Treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Cancer Invest. 31(3), 183–188 (2013).
- 33 . Lymphocyte depletion by radiation therapy alone is associated with poor survival in non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 96(2), E478 (2016). •• The absolute lymphocyte count at 2 weeks into radiation therapy was found to be a strong predictor of both progression and survival, which supports the importance of understanding the impact of cancer therapy on the immune system and inflammatory response.
- 34 Preoperative lymphocyte count is a favorable prognostic factor of disease-free survival in non-small-cell lung cancer. Med. Oncol. 30(1), 1–7 (2013).
- 35 . Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J. Immunol. 139(10), 3199–3206 (1987).
- 36 . A comparison of the acute effects of radiation therapy, including or excluding the thymus, on the lymphocyte subpopulations of cancer patients. J. Clin. Invest. 56(1), 88–97 (1975).
- 37 Treatment design and rationale for a randomized trial of cisplatin and etoposide plus thoracic radiotherapy followed by nivolumab or placebo for locally advanced non-small-cell lung cancer (RTOG 3505). Clin. Lung Cancer
doi:10.1016/j.cllc.2016.10.009 (2016) (Epub ahead of print). - 38 . The platelet contribution to cancer progression. J. Thromb. Haemost. 9(2), 237–249 (2011). •• Describes the role of platelets in cancer growth, progression and dissemination, and how antiplatelet therapies present a promising area of targeted cancer therapy.
- 39 Interaction of cancer cells with platelets mediated by Necl-5/poliovirus receptor enhances cancer cell metastasis to the lungs. Oncogene 27(3), 264–273 (2008).
- 40 The effect of peripheral blood values on prognosis of patients with locally advanced gastric cancer before treatment. Med. Oncol. 27(4), 1060–1065 (2010).
- 41 Pretreatment neutrophil/lymphocyte ratio is superior to platelet/lymphocyte ratio as a predictor of long-term mortality in breast cancer patients. Med. Oncol. 30(1), 1–11 (2013).
- 42 . Preoperative platelet lymphocyte ratio as an independent prognostic marker in ovarian cancer. Clin. Transl. Oncol. 13(7), 499–503 (2011).
- 43 . Platelet to lymphocyte ratio as a prognostic factor for epithelial ovarian cancer. J. Gynecol. Oncol. 23(4), 265–273 (2012).
- 44 Initial neutrophil lymphocyte ratio is superior to platelet lymphocyte ratio as an adverse prognostic and predictive factor in metastatic colorectal cancer. Med. Oncol. 30(1), 1–6 (2013).
- 45 Clinical significance of preoperative neutrophil-lymphocyte versus platelet-lymphocyte ratio in patients with operable colorectal cancer. Biomarkers 17(3), 216–222 (2012).
- 46 Pretreatment platelet-to-lymphocyte ratio (PLR) as a predictor of response to first-line platinum-based chemotherapy and prognosis for patients with non-small cell lung cancer. J. Thorac. Dis. 5(6), 783–789 (2013).
- 47 Neutrophil–lymphocyte and platelet–lymphocyte ratios as prognostic factors after stereotactic radiation therapy for early-stage non–small-cell lung cancer. J. Thorac. Oncol. 10(2), 280–285 (2015). • Shows the broad applicability of the pretreatment NLR and platelet-to-lymphocyte ratios in NSCLC patients treated with stereotactic radiation, as opposed to conventional radiotherapy.
- 48 . Prognostic impact of thrombocytosis in resectable non-small cell lung cancer. Interact. Cardiovasc. Thorac. Surg. 7(4), 613–615 (2008).
- 49 . Prognostic performance of inflammation-based prognostic indices in primary operable non-small cell lung cancer. Br. J. Cancer 110(8), 1930–1935 (2014).
- 50 . Revisions in the international system for staging lung cancer. Chest 111(6), 1710–1717 (1997).
- 51 The IASLC lung cancer staging project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J. Thorac. Oncol. 2(8), 694–705 (2007).
- 52 Nodal stage of surgically resected non-small cell lung cancer and its effect on recurrence patterns and overall survival. Int. J. Radiat. Oncol. Biol. Phys. 91(4), 765–773 (2015). • Nodal stage was found to be directly associated with overall survival and distant recurrence in patients who underwent R0 resection for stage I–IIIA NSCLC, which supports the importance of N-stage in a prognostic model for surgically resected NSCLC.