Prognostic Role of Neutrophil-to-lymphocyte Ratio in Cancer

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.

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.

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).

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

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.  

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.