Prognostic Role of Neutrophil-to-lymphocyte Ratio in Cancer

Study champions NLR as a reliable, cost-effective biomarker

By Jen Green, ND, FABNO

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Reference 

Templeton AJ, McNamara MG, Šeruga B, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014;106(6):dju124. Print 2014 Jun.

Study Design 

A systematic review and meta-analysis were conducted to examine the association between neutrophil-to-lymphocyte ratio (NLR) and overall survival (primary outcome), cancer-specific survival, progression-free survival, and disease-free survival (secondary outcomes). The meta-analysis included 100 studies with a total of 40,559 cancer patients.

Results 

A NLR of greater than 4 was associated with statistically poorer survival in all disease subgroups, sites, and stages. The hazard ratio (HR) for overall survival was 1.81 (95% CI:1.67-1.97; P<.001). HRs for NLR greater than 4 were 1.61 for cancer-specific survival, 1.63 for progression-free survival, and 2.27 for disease-free survival (all P<.001).

Weakness 

The main weakness of the meta-analysis is that the majority of studies included were retrospective.

Practice Implications 

Cancer is an inflammatory process, and systemic inflammation has been shown to predict cancer-related mortality.1,2 Oncology professionals have been looking for a low-cost, reliable marker of inflammation to evaluate patient prognosis. NLR is an inflammation-based score that has emerged as a good candidate. NLR is cost effective, readily available as part of routine testing, and predictive of mortality both preoperatively and postoperatively.3 NLR also provides valuable information about the status of the immune system.  
The neutrophil-to-lymphocyte ratio alerts us to the fact that the immune system is dysregulated from inflammation and that our cancer patients are at higher risk of mortality. 
Humans have an elegant immune system that relies on different types of white blood cells to protect us from harm. Two of these types of white blood cells are neutrophils and lymphocytes. Neutrophils protect us from bacterial infections and respond to inflammation. Lymphocytes (which include natural killer cells, T cells, and B cells) protect us from viruses and cancer.4 When we experience inflammation, the body is dealing with a perceived wound, so it drives up our surface immunity/neutrophils and drives down our anticancer immunity/lymphocytes. When we look at the NLR, it becomes clear how inflammation suppresses cancer immunity in some patients. 
 
Using results from a complete blood count with differential, it is easy to calculate the ratio of the absolute neutrophil count to lymphocyte counts. If the neutrophil number is 4 times greater than the lymphocytes (>4:1), then the patient has a poorer prognosis than if the ratio were less than 4:1. 
 
Different cutoffs for NLR have been found to be predictive of cancer survival depending on the tumor type. While 4 is a good cutoff for all tumors types combined, it may be appropriate to look for an NLR of less than 3 in breast cancer5 and less than 3 in prostate cancer.6 I calculate NLR by looking at the lymphocyte value, multiplying by 3 or 4, and seeing if the neutrophils are higher than this product. If so, this is a warning that inflammation is high and cancer immunity is compromised.
 
As naturopathic physicians, we are trained to support the immune system to prevent cancer. We now have some new information that inflammation can prevent adequate cancer immune surveillance. In fact, chemoprevention agents like aspirin and COX-2 inhibitors that we formerly thought just worked by controlling inflammation also appear to be working through the immune system.7 Even curcumin, a prominent anti-inflammatory agent, has been shown in animal models to shift T helper (Th)2 to Th1 immunity, upregulate T-cell cytotoxicity, and boost cancer immunity.8 It is likely that in order for natural immune agents to work, inflammation must be addressed at the same time.
 
NLR is a helpful red flag for clinicians. It alerts us to the fact that the immune system is dysregulated from inflammation and that our cancer patients are at higher risk of mortality. It calls us to treat inflammation more aggressively so that the immune system and vital force can restore balance. 

About the Author

Jen Green, ND, FABNO, was born in Toronto, received her arts & science degree from McMaster University, and graduated from the Canadian College of Naturopathic Medicine in 2000. Green founded the Naturopathic Department at Beaumont Hospitals in 2008 and served as the department head for 5 years. Green was co-investigator in a trial on Essiac in breast cancer and wrote a systematic review on the use of probiotics in children. Green's publications include chapters in the book My Breasts, My Choice, the review Identifying & Treating Metabolic Syndrome in Breast Cancer, as well as articles in the Journal of Complementary & Integrative Medicine and Townsend Letters.

References

  1. Pierce BL, Ballard-Barbash R, Bernstein L, et al. Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol.2009;27(21):3437-3444.
  2. McMillan DC, Elahi MM, Sattar N, Angerson WJ, Johnstone J, McArdle CS. Measurement of the systemic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer. Nutr Cancer. 2001;41(1-2):64-69. 
  3. Bugada D, Allegri M, Lavand'homme P, De Kock M, Fanelli G. Inflammation-based scores: a new method for patient-targeted strategies and improved perioperative outcome in cancer patients. Biomed Res Int. 2014;2014:142425. Epub 2014 Apr 27. 
  4. Schindler L, Kerrigan D, Kelly J, Hollen B. Understanding Cancer and Related Topics: Understanding the Immune System. Available at: http://www.scribd.com/doc/42572355/NCI-Immune-System-and-Cancer-PDF. Accessed November 5, 2014.
  5. Azab B, Bhatt VR, Phookan J, et al. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol. 2012;19(1):217-224. Epub 2011 Jun 3.
  6. Keizman D, Gottfried M, Ish-Shalom M, et al. Pretreatment neutrophil-to-lymphocyte ratio in metastatic castration-resistant prostate cancer patients treated with ketoconazole: association with outcome and predictive nomogram. Oncologist. 2012;17(12):1508-1514. 
  7. Marzbani E, Inatsuka C, Lu H, Disis ML. The invisible arm of immunity in common cancer chemoprevention agents. Cancer Prev Res (Phila). 2013;6(8):764-773. 
  8. Bhattacharyya S, Md Sakib Hossain D, Mohanty S, et al. Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts. Cell Mol Immunol. 2010;7(4):306-315.