|Year : 2020 | Volume
| Issue : 3 | Page : 564-565
Reevaluating how we define inflammation in head-and-neck cancers
University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA
|Date of Submission||02-Jul-2020|
|Date of Decision||08-Jul-2020|
|Date of Acceptance||26-Jul-2020|
|Date of Web Publication||19-Sep-2020|
University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland, 22 S. Greene Street, Baltimore, MD
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mehra R. Reevaluating how we define inflammation in head-and-neck cancers. Cancer Res Stat Treat 2020;3:564-5
Squamous cell cancers of the head and neck (SCCHNs) are epithelial malignancies that can arise from the oral cavity, oropharynx, hypopharynx, larynx, or nasopharynx. For many, the disease is curable, but at the expense of long-term morbidity. However, a subset of SCCHN, including those that arise in the hypopharynx, is associated with a poor prognosis and an aggressive disease course. These tumors are generally induced by carcinogens and often harbor mutations in the TP53 gene. The prognostic factors for SCCHN include clinical parameters such as the tumor–node–metastasis stage and performance status. However, these factors do not address the underlying biology of a malignancy that often drives a patient's disease course. As our scientific capabilities expand with the ability to perform molecular analyses and characterization of the tumor immune microenvironment, we seek to understand the underlying biology of an aggressive disease. However, this is often done at the time of recurrence, when the options are limited, and with utilization of significant resources.
Mittal etal. in their study have assessed the clinically available biomarkers that relate to the patients' inflammatory state with the goal of identifying those who have a worse prognosis in a cost-effective manner. This is a retrospective study on 79 patients with hypopharyngeal cancers who were treated at a single institution over the course of 1 year. The pretreatment systemic inflammatory biomarkers included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and a combination score (COP-NLR) from the standard laboratory assessments. The cutoff value to define high versus low scores had been reported by Nakahira etal. in a separate single-institution retrospective analysis. Statistical methods were employed to associate clinical and pathologic variables with the pretreatment inflammatory biomarkers in univariate and multivariate analyses. The majority of patients were men with advanced stage (III/IV) disease. In addition, 96% of the patients received nonsurgical treatment. Pretreatment NLR, PLR, and COP-NLR had a statistically significant association with disease-free survival (DFS) and overall survival (OS); in a multivariate analysis, PLR was found to be a significant prognostic factor for DFS (hazard ratio [HR], 2.899; P = 0.005) and OS (HR, 3.229; P = 0.004).
The authors accurately describe the limitations of their study, including the lack of consensus in the field regarding the optimal cutoff values for inflammatory biomarkers. In addition, as this was a single-institution retrospective analysis with a limited sample size, confounding factors include patient selection and individual variations with regard to care. Radiation alone was the definitive treatment for 34% of the patients, and concurrent treatment did impact the DFS. Moreover, cisplatin-ineligible patients received weekly carboplatin, which may also have impacted the outcomes. Finally, the cutoff values for the selected inflammatory markers were based on another retrospective single-institution analysis, without confirmation in a larger validation set. Thus, further analysis of the optimal cutoff values for NLR, PLR, and COP-NLR in a more heterogeneous group of patients reflective of various racial and ethnic groups is likely needed.
Despite these limitations, the results reported are intriguing and hypothesis generating. The authors provide a comprehensive list of similar analyses in the field. Many of these cited works were also retrospective analyses, but the trends support the impact of inflammatory markers on survival. In addition, elevated NLR has been a biomarker of interest to predict the survival upon treatment with programmed cell death protein 1 inhibitors in the metastatic setting. Diem etal. studied NLR and PLR levels among patients with metastatic non-small-cell lung cancer treated with nivolumab. In their series of 52 patients, elevated NLR was associated with survival (HR, 3.64). As I write this editorial during the coronavirus disease 2019 (COVID-19) pandemic, it is notable that NLR has also been evaluated as a marker for immune dysregulation and an increased inflammatory state among hospitalized patients with COVID-19, with an 8% higher risk of in-hospital mortality for each unit increase in NLR.
It appears that NLR, PLR, and COP-NLR are surrogates for a biological phenotype that is probably yet to be fully defined. In an analysis of cytokine profiles and NLR in patients with metastatic colorectal cancer, NLR was associated with a poor prognosis (HR, 1.73) and increased expression of interleukin 6 (IL-6), IL-8, IL-2Rα, hepatocyte growth factor, macrophage colony-stimulating factor, and vascular endothelial growth factor. Thus, it is possible that clinical assessment of inflammatory biomarkers is a simple measure of a prognostic cytokine signature. Mutations in the TP53 gene commonly occur in carcinogen-induced head and neck cancers, but to this point, they are nontargetable. In a breast cancer model, the loss of TP53 resulted in an increased secretion of the WNT ligands with increased production of IL-1β and a subsequent increase in systemic inflammation. Finally, it is known that chronic infection and inflammation result in T-cell exhaustion and an inhibitory immune environment. This has prompted the study and use of immune checkpoint inhibitors in clinical practice, and it is likely that a simple marker of increased inflammation is a surrogate for this complex process.
What should be the next steps in this field? Larger, prospective, and retrospective studies with clear definitions of inflammatory markers should be conducted with training and validation sets. Head and neck cancer is a global disease, and hence, a comprehensive study of inflammatory biomarkers should move beyond single-institution series to a more diverse patient population. This could be a useful clinical biomarker, but mechanistic studies are required in order to further understand how to improve the therapies for the poor prognostic subsets. Perhaps this could include targeting the TP53 or WNT pathways, or perhaps modulation of the immune microenvironment will be important. While biomarkers are used to guide prognostic decisions for patients, as clinicians, we also need to use biomarkers to select the optimal therapy. NLR, PLR, and COP-NLR are feasible to obtain in underresourced areas. Similarly, the treatments that are developed to address the poor prognosis associated with the heightened inflammatory state should be widely accessible.
In conclusion, the authors provide us with an interesting analysis that opens our minds to future areas of study in hypopharyngeal cancer, an aggressive disease. Although their initial work cannot immediately change the clinical practice, it is an important addition to the growing literature in this field.
| References|| |
Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015;517:576-82.
Mittal S, Krishnamurthy A, Kothandaraman SK, Dhanushkodi M, John A. Exploring the prognostic significance of the pretreatment inflammatory markers in hypopharyngeal cancers: A retrospective analysis. Cancer Res Stat Treat 2020;3:437-44. [Full text]
Nakahira M, Sugasawa M, Matsumura S, Kuba K, Ohba S, Hayashi T, et al
. Prognostic role of the combination of platelet count and neutrophil-lymphocyte ratio in patients with hypopharyngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 2016;273:3863-7.
McCusker MG, Mehra R, Molitoris JK, Taylor R, Cullen KJ, Goloubeva OG. Cisplatin every three weeks versus weekly cisplatin or carboplatin with definitive radiotherapy for squamous cell carcinoma of the head and neck is associated with improved overall survival in a representative national population. J Clin Oncol 2020;38;6536.
Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, et al
. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer 2017;111:176-81.
Liu Y, Du X, Chen J, Jin Y, Peng L, Wang HH, et al
. Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect 2020;81:e6-e12.
Chen ZY, Raghav K, Lieu CH, Jiang ZQ, Eng C, Vauthey JN, et al
. Cytokine profile and prognostic significance of high neutrophil-lymphocyte ratio in colorectal cancer. Br J Cancer 2015;112:1088-97.
Wellenstein MD, Coffelt SB, Duits DEM, van Miltenburg MH, Slagter M, de Rink I, et al
. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature 2019;572:538-42.
Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis 2015;6:e1792.