|Year : 2020 | Volume
| Issue : 3 | Page : 437-444
Exploring the prognostic significance of the pretreatment inflammatory markers in hypopharyngeal cancers: A retrospective analysis
Saket Mittal1, Arvind Krishnamurthy1, Sri Kamakshi Kothandaraman1, Manikandan Dhanushkodi2, Alexander John3
1 Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
2 Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
3 Department of Radiation Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
|Date of Submission||11-Apr-2020|
|Date of Decision||25-May-2020|
|Date of Acceptance||07-Jul-2020|
|Date of Web Publication||19-Sep-2020|
Department of Surgical Oncology, Cancer Institute (WIA), 38, Sardar Patel Rd., Adyar, Chennai - 600 036, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: There is increasing evidence pertaining to the prognostic significance of pretreatment inflammatory markers such as platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and the combination of platelet count and neutrophil-to-lymphocyte ratio (COP-NLR) in many solid tumors, including head and neck cancers. However, there are limited data related to these markers in hypopharyngeal cancers.
Objectives: We aimed to explore the association of the pretreatment inflammatory markers with survival outcomes in our cohort of hypopharyngeal cancers.
Materials and Methods: The electronic medical records for the consecutive patients with carcinoma of the hypopharynx, treated at our center between January 1, 2016, and December 31, 2016, were accessed. The association between the clinico-demographic-laboratory variables and pretreatment inflammatory markers was analyzed using the Chi-square test, and the survival analysis was performed using the Kaplan–Meier method.
Results: Seventy-nine eligible patients were included in the study. The median age of our cohort was 45 years; the male-to-female ratio was 2.9:1. There was a significant association of NLR with sex, hemoglobin, and the primary site; however, no such association was observed between PLR and these variables. Further, our study showed that higher values of NLR, PLR, and COP-NLR were predictive of poor outcomes, both in terms of the disease-free and overall survival.
Conclusion: The readily available pretreatment systemic inflammatory markers, such as NLR, PLR, and COP-NLR, can be used as prognostic tools in patients with squamous cell carcinoma of the hypopharynx. The role of these potential markers, especially PLR, appears interesting and warrants further evaluation in other subsites of the head and neck as well.
Keywords: Carcinoma hypopharynx, combination of platelet count and neutrophil to lymphocyte ratio, head and neck squamous cell carcinoma, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, prognosis, NLR, COP-NLR
|How to cite this article:|
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
|How to cite this URL:|
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 [serial online] 2020 [cited 2020 Oct 22];3:437-44. Available from: https://www.crstonline.com/text.asp?2020/3/3/437/295533
| Introduction|| |
Hypopharyngeal cancers are considered biologically more aggressive than malignancies arising from the other sub-sites of the head-and-neck region. Apart from the tumor node metastasis (TNM) staging, various other tumor-and patient-related factors have been studied in an attempt to better prognosticate the outcomes for patients with hypopharyngeal cancers. These factors include age, sex, habits, tumor grade, performance status, and comorbidities among others; however, several studies have shown their limited utility in prognostication. Human papillomavirus positivity and p16 immunoexpression are important prognostic factors in oropharyngeal cancers, but their prognostic value in hypopharyngeal cancers is limited and unclear.,
Several studies have suggested a strong relationship between inflammation and cancer.,,,,,,,,, Furthermore, studies have shown that the complex interplay between inflammation, immunity, and cancer can impact tumor initiation, progression, and treatment response., It has been suggested that the presence of neutrophils in the tumor microenvironment plays a pro-tumor role through the formation of neutrophil extracellular traps, the release of reactive oxygen species, secretion of pro-tumor cytokines and chemokines, and promotion of immunosuppression. The lymphocytes act as anti-tumor agents by inhibiting proliferation and inducing cytotoxic cell death.,, A recent meta-analysis has shown a favorable prognostic role of tumor-infiltrating lymphocytes in head neck cancers. A few studies have shown poor survival with pretreatment thrombocytosis across many cancer sites, including those in the head and neck.,,,,,
Based on the promising preclinical data, the prognostic value of the various inflammatory markers has been explored in different solid tumors. The inflammatory markers include the pretreatment platelet counts, neutrophils, monocytes, lymphocytes, platelet-to-lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), and the combination of platelet count and NLR (COP-NLR) among others. There is growing evidence regarding the prognostic significance of pretreatment PLR, NLR, and COP-NLR in several solid tumors, including head and neck cancers.,,,,, However, the use of these inflammation-based prognostic markers in hypopharyngeal cancers has not been well documented. Therefore, in this study, we have attempted to explore their prognostic significance in hypopharyngeal cancers.
| Materials and Methods|| |
General study details
We performed a retrospective analysis of the data from patients with carcinoma of the hypopharynx managed in the Department of Head and Neck Services of the Cancer Institute (WIA), the regional cancer center in Chennai, Tamil Nadu. The study was conducted in accordance with the principles of the International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki, and the guidelines laid down by the Indian Council of Medical Research and was approved by our Institutional Ethics Committee (IEC/2020/May 02, approved on 6th May 2020). The trial protocol is available as Supplementary Appendix 1. Informed consent was obtained from all the patients for the use of their anonymized data for research and publication purposes. As this was a retrospective analysis, the ethics committee waived the need for obtaining additional written informed consent from each patient. The study was not registered in a public clinical trials registry.
The electronic medical records of all the consecutive patients with carcinoma of the hypopharynx, who received treatment at our center between January 1, 2016, and December 31, 2016, were accessed and retrospectively analyzed. The said time period was chosen to ensure an adequate follow-up to capture the survival outcomes. The inclusion criteria were a histologically proven squamous cell carcinoma of the hypopharynx, availability of the pretreatment complete blood counts, treatment with potentially curative intent, and completion of the intended definitive treatment at our center. The exclusion criteria were active infection, documented chronic inflammation, and unavailability of follow-up details.
The primary aims of the study were to evaluate the clinico-demographic profile and the relationship to the inflammatory biomarkers in patients with hypopharyngeal cancers, and to study the association of the inflammatory biomarkers with the survival outcomes.
We recorded the demographic data; clinical stage; complete hemogram; platelet count; absolute neutrophil count (ANC); absolute lymphocyte count (ALC); NLR, defined as the ratio of ANC to ALC; PLR, defined as the ratio of platelet count to ALC; treatment received (primary, adjuvant, salvage); last follow-up date; and condition at that time. Disease-free survival (DFS) was defined as the time from treatment completion to recurrence, disease progression, or death. Overall survival (OS) was defined as the time from treatment completion to death.
The pretreatment NLR, PLR, and platelet count were divided into the low and high categories according to the values described by Nakahira etal., which are <3 and ≥3, <150 and ≥150, and <300 × 109/L and ≥300 × 109/L, respectively. In addition, the COP-NLR was calculated. A platelet count of ≥300 × 109/L and an NLR≥3 were assigned to COP-NLR 2. Patients with only one value raised and no value raised were assigned to COP-NLR 1 and COP-NLR 0, respectively.
As this was a retrospective analysis, a sample size was not calculated. We included all patients who fulfilled the inclusion and exclusion criteria during the study period.
The association of clinico-demographic-laboratory variables, namely the TNM stage, T group, N group, and tumor grade with the pretreatment NLR and PLR were analyzed using the Chi-square test. The median follow-up was calculated, including the surviving as well as the deceased patients. Survival analysis (univariate) was performed using the Kaplan–Meier method. For analysis of the OS, the time from treatment completion to the date of the last follow-up or date of death was considered. Prognostic factors in the treatment groups were analyzed using the Cox proportional univariate regression analysis., A P-value of less than 0.05 was considered significant. All the statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS version 20, IBM Corp., Armonk, NY, USA).
| Results|| |
A total of 93 patients with carcinoma of the hypopharynx received treatment at our center between January 1, 2016, and December 31, 2016. Of these, 79 fulfilled the eligibility criteria and were included in the analysis [Figure 1]. The median age of our cohort was 45 years (range, 29–69 years), 67% of the patients were men, and the male-to-female ratio was 2.9:1. A vast majority of the patients (86.3%) had stage III/IV disease, and 96.2% of the patients received upfront nonsurgical treatment (concurrent chemoradiation in 62% and radical radiation in 34.2%, as per the decision of a multi-disciplinary tumor board). The preferred regimen for chemoradiation was 66 Gy of external beam radiation along with cisplatin (100 mg/m2, once in 3 weeks). The cisplatin-ineligible patients were considered for carboplatin (area under the curve 2). The median follow-up of our cohort was 19 months (1.13–41.53 months).
The demographic variables of our cohort have been elaborated in [Table 1]. A significant association of pretreatment NLR was noted with sex (P = 0.001), hemoglobin (P = 0.005), and primary sub-site (P = 0.043). However, the pretreatment PLR was not found to be associated with the above variables.
The median DFS was 17.17 months (95% confidence interval [CI], 15.00–21.01 months), while the median OS was 19 months (95% CI, 16.94–22.53 months). On univariate analysis, the factors that were found to have a significant association with DFS and OS were pretreatment NLR (P = 0.025 and P = 0.037, respectively), pretreatment PLR (P = 0.001 and P = 0.004, respectively), pretreatment COP–NLR (P = 0.006 and P = 0.002, respectively), TNM stage (P = 0.037 and P = 0.047, respectively), and nodal stage (P = 0.045 and P = 0.043, respectively). Higher TNM stage, nodal stage, NLR, PLR, and COP–NLR were associated with poor DFS and OS [Figure 2], [Figure 3], [Figure 4]. There was a statistically significant association between the platelet count and OS (P = 0.025), but not with DFS (P = 0.088). Moreover, there was a significant difference in the DFS (P = 0.031) of patients who had received radiation and concurrent chemoradiation, but the difference in their OS was not significant (P = 0.98). The association of the clinico-demographic-laboratory variables with the survival outcomes is described in [Table 2]. A formal multivariate analysis of all the variables that showed significance on univariate analysis could not be performed as there were many interdependent variables. However, a multivariate analysis after adjustment for known prognostic variables showed PLR to be a significant predictor of both DFS and OS [Table 3].
|Figure 2: Kaplan–Meier estimate of the overall survival stratified by neutrophil to lymphocyte ratio|
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|Figure 3: Kaplan–Meier estimate of the overall survival stratified by platelet to lymphocyte ratio|
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|Figure 4: Kaplan–Meier estimate of the overall survival stratified by the combination of platelet count and neutrophil to lymphocyte ratio|
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|Table 2: Association of the clinico-demographic-laboratory variables with the survival outcomes|
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|Table 3: Multivariate analysis after adjustment for known prognostic variables showed platelet-to-lymphocyte ratio to be a significant predictor of both disease free as well as overall survival|
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| Discussion|| |
Analysis of the clinico-demographic-laboratory variables in our cohort revealed a significant association of the pretreatment NLR with sex, hemoglobin, and the primary site. However, no association of the pretreatment PLR was noted with these variables. There are several other studies that have evaluated the association between clinico-demographic-laboratory variables and the pretreatment NLR and PLR. However, they have shown mixed results, thus precluding any definitive conclusions.,,,,,,,,,,
The cutoff value for NLR that can consistently categorize the patients with head and neck cancers into different prognostic groups is still unclear. A meta-analysis of the prognostic significance of the pretreatment NLR values from 24 studies suggested that categorizing the patients into three groups based on the NLR values (<2, 2–6, and ≥6) could better predict the differences in their survival outcomes. In our cohort, the pretreatment NLR, PLR, platelet counts, and COP-NLR were categorized according to the values described by Nakahira etal.
The prognostic significance of pretreatment NLR and PLR has been explored in many clinical studies involving patients with head and neck cancers (including the hypopharynx as well as other sub-sites), but with contradictory results. Many studies have shown a significant association between the pretreatment NLR and survival outcomes in patients with head and neck cancers, where a higher NLR predicted a poor outcome.,,,,,,,, Similarly, a few other studies have shown a significant association between the pretreatment PLR and survival outcomes. A few meta-analyses have explored the prognostic role of NLR in head and neck cancers.,,, In addition, some studies have assessed the prognostic significance of the pretreatment NLR and PLR in exclusive cohorts of patients with hypopharyngeal cancers;,,,,, the salient findings of these studies have been summarized in [Table 4].
|Table 4: Association of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio with survival outcomes from studies focusing exclusively on hypopharyngeal cancers|
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Ishizuka et al. evaluated the prognostic significance of COP-NLR in gastric and colorectal cancers and observed COP-NLR to be a useful predictor of survival., Further, Nakayama et al. investigated the role of COP-NLR in hypopharyngeal cancers and concluded that COP-NLR could be a useful prognostic marker. Our results mirrored those of Nakayama etal.'s study, with a higher pretreatment COP-NLR predicting poor survival.
The limitations of our study are the modest size of our cohort and its retrospective design. It would have been interesting to know what the NLR, PLR, and COP-NLR were posttreatment, especially in patients who had poorer DFS and OS and to evaluate whether there was any correlation with outcomes. Unfortunately, these values were not consistently available for all patients across specific time points, and this could not be evaluated. However, our study was focused on a single sub-site (hypopharynx) and used the readily available pretreatment laboratory inflammatory markers to predict the outcomes, which add to its merits. Pretreatment NLR, PLR, and COP-NLR are easy to calculate and can be used even in a resource-constrained setting for aiding in prognostication. The positive correlation of PLR with outcomes in our cohort of patients with hypopharyngeal cancers appears exciting and needs to be explored further.
| Conclusion|| |
The study has shown that the readily available pretreatment laboratory inflammatory markers, namely the NLR, PLR, and COP-NLR, can be used as prognostic tools in patients with squamous cell carcinoma of the hypopharynx. The role of these markers, especially the PLR, appears interesting. However, our findings need to be validated in a larger cohort of patients. Moreover, similar studies can be performed in patients with other solid cancers, especially those in the other sub-sites of the head and neck.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| Supplementary Appendix 1|| |
| Retrospective Study of the role of inflammatory markers in Head and Neck Cancers|| |
Background and Rationale: Head and Neck cancers are a significant cause of morbidity and mortality globally and more so in the Indian Sub-continent. Apart from the Tumour Node Metastasis (TNM) staging, various other tumour and patient related factors have been studied, in an attempt to better prognosticate patients with head and neck cancers. These factors include age, gender, habits, grade, performance status, co-morbidities among others, however many studies have shown their limited utility in prognostication. Inflammation is considered to be one of the hallmarks of cancer. A few of the inflammatory markers are being explored as possible prognostic biomarkers across various solid cancers. The inflammatory markers include neutrophils, lymphocytes, monocytes and platelet counts studied either as individual values or as ratios to each other i.e. neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) among others. There is a growing body of evidence pertaining to the prognostic significance of NLR and PLR in head and neck cancers and we wish to further explore this association.
- To study the clinic-demographic profile and their relationship to the inflammatory biomarkers.
- To study the association of the inflammatory biomarkers with the survival outcomes
Study design: Retrospective study of patients treated in our institution for head and neck squamous cell carcinomas from 2014-2016. These will be further divided into sub-cohorts for comparative analysis.
For this study, the following data from the Electronic Medical Records will be collated:
- Clinical parameters including age, gender, site of primary tumour
- Laboratory Parameters including complete hemogram, platelet counts, absolute neutrophil counts, absolute lymphocyte counts
- Primary tumor characteristics include tumour diameter (mm), margins of resection tumour thickness, presence of bone invasion, presence of perineural invasion (PNI), presence of lymphovascular invasion (LVI) and degree of differentiation (well, moderate or poor)
- Neck nodes pathological characteristics include the presence of nodal metastasis (N0 versus N1-3), number of involved nodes (single versus multiple) and the presence of extracapsular nodal spread (ECS).
- Treatment details including Surgery and the administration of radiotherapy and/or chemotherapy
- Survival outcomes.
Statistical analysis: Disease free survival was defined as time from treatment completion till occurrence of first event defined as recurrence, disease progression or death. Overall survival was defined as time from treatment completion till death. Hazard ratios and interactions between age and prognostic variables will be calculated using Cox proportional hazard models and Kaplan-Meier curves generated for graphical analysis.
The generated data will be anonymous and no patient identifiers will ever be shared.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]