Vol 28, No 3 (2023)
Research paper
Published online: 2023-07-03

open access

Page views 1102
Article views/downloads 357
Get Citation

Connect on Social Media

Connect on Social Media

Significance of neutrophil to lymphocyte ratio as a predictor of outcome in head and neck cancer treated with definitive chemoradiation

Joanna Kaźmierska12, Tomasz Bajon3, Tomasz Winiecki3, Dominika Borowczak3, Anna Bandurska-Luque3, Malgorzata Jankowska3, Małgorzata Żmijewska-Tomczak4
Rep Pract Oncol Radiother 2023;28(3):389-398.

Abstract

Background: The role of host immune system in carcinogenesis and response to treatment is increasingly studied, including predictive potential of circulating neutrophils and lymphocytes.

The objective of the study was to evaluate the prognostic value of pre- and post-treatment neutrophil-to-lymphocyte (NLR) for treatment outcome in patients diagnosed with squamous cell carcinoma of head and neck (HNSCC) treated with definitive chemoradiation.

Materials and methods: Electronic medical records of patients were evaluated and NLR was calculated. Cox regression was used to assess the impact of selected variables on overall survival (OS), disease specific survival (DSS), progression free survival (PFS) and distant failure free survival (DFFS). Logistic regression was used to estimate odds ratios of complete response with NLR.

Results: 317 patients' records were included in the study. Increases in both pre-and post-NLR were associated with decreased OS in univariable analysis [hazard ratio (HR): 2.26 (1.25–4.07), p = 0.0068 and HR: 1.57 (1.03–2.37), p = 0.035 respectively). Post-NLR remained significant for OS in multivariable analysis [HR: 1.93 (1.22–3.1), p = 0.005] as well as for unfavorable DSS [HR: 2.31 (1.22–4.4), p = 0.01]. Pre-treatment NLR and nodal status correlated with shorter DFFS in multivariable analysis [HR 4.1 (1.14–14), p = 0.03 and HR 5.3: (1.62–18), p = 0.0062, respectively].

Strong correlation of increased both pre- and post-NLR with probability of clinical tumor response (CR) was found [odds ratio (OR): 0.23 (0.08–0.6), p = 0.003, and OR: 0.39 (0.2–0.8), p = 0.01 respectively].

Conclusion: NLR evaluated before and post treatment was a strong predictor of unfavorable treatment outcome and can be used for risk evaluation and clinical decision about treatment and post-treatment surveillance.

research paper

Reports of Practical Oncology and Radiotherapy

2023, Volume 28, Number 3, pages: 389–398

DOI: 10.5603/RPOR.a2023.0042

Submitted: 15.04.2023

Accepted: 30.06.2023

© 2023 Greater Poland Cancer Centre.

Published by Via Medica.

All rights reserved.

e-ISSN 2083–4640

ISSN 1507–1367

Significance of neutrophil to lymphocyte ratio as a predictor of outcome in head and neck cancer treated with definitive chemoradiation

Joanna Kaźmierska12Tomasz Bajon1Tomasz Winiecki1Dominika Borowczak1Anna Bandurska-Luque1Malgorzata Jankowska1Małgorzata Żmijewska-Tomczak3
1Radiotherapy Department II, Greater Poland Cancer Center, Poland
2Electroradiology Department, University of Medical Sciences, Poznan, Poland
3Radiotherapy Department I, Greater Poland Cancer Center, Poznan, Poland

Address for correspondence: Joanna Kaźmierska, Greater Poland Cancer Centre, Radiotherapy and Oncology, Garbary 15, Poznań, 61–866 Poznan, Poland; e-mail: joanna.kazmierska@wco.pl

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially

Abstract
Background: The role of host immune system in carcinogenesis and response to treatment is increasingly studied, including predictive potential of circulating neutrophils and lymphocytes. The objective of the study was to evaluate the prognostic value of pre- and post-treatment neutrophil-to-lymphocyte (NLR) for treatment outcome in patients diagnosed with squamous cell carcinoma of head and neck (HNSCC) treated with definitive chemoradiation.
Materials and methods: Electronic medical records of patients were evaluated and NLR was calculated. Cox regression was used to assess the impact of selected variables on overall survival (OS), disease specific survival (DSS), progression free survival (PFS) and distant failure free survival (DFFS). Logistic regression was used to estimate odds ratios of complete response with NLR.
Results: 317 patients’ records were included in the study. Increases in both pre-and post-NLR were associated with decreased OS in univariable analysis [hazard ratio (HR): 2.26 (1.25–4.07), p = 0.0068 and HR: 1.57 (1.03–2.37), p = 0.035 respectively). Post-NLR remained significant for OS in multivariable analysis [HR: 1.93 (1.22–3.1), p = 0.005] as well as for unfavorable DSS [HR: 2.31 (1.22–4.4), p = 0.01]. Pre-treatment NLR and nodal status correlated with shorter DFFS in multivariable analysis [HR 4.1 (1.14–14), p = 0.03 and HR 5.3: (1.62–18), p = 0.0062, respectively]. Strong correlation of increased both pre- and post-NLR with probability of clinical tumor response (CR) was found [odds ratio (OR): 0.23 (0.08–0.6), p = 0.003, and OR: 0.39 (0.2–0.8), p = 0.01 respectively].
Conclusion: NLR evaluated before and post treatment was a strong predictor of unfavorable treatment outcome and can be used for risk evaluation and clinical decision about treatment and post-treatment surveillance.
Key words: neutrophil-to-lymphocyte ratio; head and neck cancer; prediction
Rep Pract Oncol Radiother 2023;28(3):389–398

Introduction

Head and neck cancer remains a global concern and its incidence is increasing. At the same time, gradual change in etiology is observed as exemplified by HPV driven oropharyngeal cancer [1]. Numerous studies demonstrated the key role of host immune system in carcinogenesis [2–6] and response to treatment of many solid tumors, including lung, head and neck, breast, osteosarcoma and prostate. [7–12] Chronic inflammation is considered to be a facilitator of tumorigenesis [13]; however, the role of the immune system and its components in host-tumor interactions is complex. For example, neutrophils, essential for innate immunity, are recruited from the bone marrow by the tumor and facilitate angiogenesis and distant metastasis [2]. Recruitment of neutrophils from bone marrow and radiotherapy both decrease the number of lymphocytes in circulating blood and their antitumor activity. This phenomenon translates to increased post-treatment neutrophil-to-lymphocyte ratio (post-NLR). On the other hand, neutrophils can also help in tumor elimination, depending on their phenotype. [14]

Assessment of neutrophil and lymphocytes circulating in blood, easily obtained from standard complete blood count (CBC) can be exploited for clinically useful evaluation of host immune response. The interaction and balance between neutrophils and lymphocytes in CBC expressed as a neutrophil-to-lymphocyte ratio (NLR) proved to be an important predictor of outcome in solid tumors. Meta-analysis based on data of 2232 patients by Hu at al. suggested that high pre-treatment NLR (pre-NLR) was associated with poor overall survival and progression free survival in patients with hypopharyngeal cancer [15]. In a meta-analysis including 5475 patients, Yu et al. confirmed previous findings that higher pre-NLR is associated with higher probability of tumor recurrence and increased mortality risk. However, optimal cut-off value to define high and low NLR is not yet established and varies across studies [16, 17] Moreover, further research is needed to explain how higher NLR translates into worse prognosis.

The objective of this study was to evaluate the prognostic value of pre- and post-treatment neutrophil-to-lymphocyte ratio (pre-NLR, post-NLR) for treatment outcomes: overall survival, disease specific survival, progression free survival, distant failure free survival and complete response in patients diagnosed with squamous cell carcinoma of head and neck (HNSCC) treated with definitive radiotherapy or chemoradiation

Materials and methods

Electronic medical records of consecutive patients diagnosed with newly diagnosed head and neck squamous cell carcinoma (HNSCC) were retrospectively collected and evaluated. 331 patients were initially included into the study according to the inclusion criteria: primary site of cancer: nasopharynx, oropharynx, hypopharynx, larynx or oral cavity, treatment with definitive chemoradiation or radiation, performance status Eastern Cooperative Oncology Group (ECOG 0–1), no surgery other than biopsy before definitive treatment, follow up time equal or longer than 2 years, known survival status and available CBC before and after treatment.

All patients were treated with curative intent at the Greater Poland Cancer Center between 1 January 2010 and 26 January 2021 with intensity-modulated radiation therapy (IMRT) to total dose of 70 Gy in 2 Gy daily fraction, with or without concomitant cisplatin in dose of 100 mg/m2 every three weeks, up to 3 courses or 40 mg/m2 weekly up to 6 courses. Patients with active infection before start of treatment, chronic inflammatory disease or steroid use were excluded from this study.

Included patients were followed up according to standard institutional procedure: evaluation by an ear, nose, and throat (ENT) surgeon and radiation oncologist in the first and third month after completion of the treatment and every 3 months for the first 2 years and afterwards every 6 months. First computed tomography (CT) scan for response assessment was performed 3 months after treatment or earlier if treatment failure was suspected.

14 patients were excluded due to missing survival data, leaving 317 patients available for analysis. Follow up and survival analysis was censored on 26 January 2023.

The primary objective of this study was to determine correlation of pre- and post-treatment neutrophil-to-lymphocyte ratio (pre-NLR, post-NLR), calculated as the ratio of absolute neutrophil count to absolute lymphocyte count obtained directly before start and at the end of radiotherapy with overall survival (OS) of included patients. Secondary outcomes were correlation of both NLR variables with disease specific survival (DSS), locoregional progression free survival (PFS) and distant failure free survival (DFFS).

Follow up time (FU) was defined as the time between the end of treatment and the last physical visit. Overall survival (OS) time was defined as the time between the end of treatment and date of death from any reason or date of censoring (26 January 2023), whichever came first. Disease specific survival (DSS) was defined as the time between the end of treatment and date of death from cancer. Progression free survival (PFS) was defined as the time between the end of treatment date and date of confirmed diagnosis of locoregional failure. Distant failure free survival (DFFS) was defined as the time between the end of treatment and date of confirmation of distant failure. Separate analysis was performed for a subgroup of patients with oropharyngeal cancer.

Variables assessed as important for outcomes were age, gender, active tobacco smoking, T and N stage [the 7th edition of the American Joint Committee on Cancer (AJCC7)], tumor primary site, chemoradiation vs. radiation, pre-NLR and post-NLR and p16 status for oropharyngeal cancer.

Ethical approval for this study was waived by the Ethics Committee of the Poznan University of Medical Sciences (KB-291/23) due to the retrospective nature of the study.

Statistical analysis

Both pre- and post-NLR were log-transformed and treated as continuous variables. Survival outcomes were analyzed using the Cox proportional hazards model and logistic regression was used for binary outcomes (CR). A two-tailed p value of < 0.05 was deemed statistically significant. Statistical analysis was performed using the R software.

Results

Patient and disease characteristics

317 patients were available for analysis. 231 patients were male. The most common primary sites were oropharynx (46%) and larynx (28%) (Tab. 1).

Table 1. Patient characteristics

Characteristic (n = 317)

Value (%)

Age (years)

Median

Range

60

2081

Gender

Male

Female

237 (74.7)

80 (25.2)

Smoking

Yes

No

242

75

Follow up (months)

Median FU

Range

27.8

0139

Primary site

Nasopharynx

Oropharynx

Hypopharynx

Oral cavity

Larynx

24 (7.6)

134 (42.3)

34 (10.7)

39 (12.3)

86 (27.1)

Tumor classification

T1

T2

T3

T4

13 (4.4)

87 (27.5)

91 (29.1)

123 (38.9)

Nodal classification

N0

N1

N2

N3

85 (26.8)

50 (15.8)

168 (53)

14 (4.4)

Stage AJCC v.7

I

II

III

IV

3 (0.9)

30(9.5)

68 (21.6)

216 (68.1)

HPV status

Positive

Negative

Unknown

30 (9.5)

44 (13.9)

243 (76.70)

Treatment

RT

RTCT

72(22.7)

245(77.3)

Treatment outcome

CR

PR, SD, PRO

Unknown

226 (71.3)

87 (24.4)

4 (1.3)

pre-NLR

Median

Range

post-NLR

Median

Range

Unknown

2.51

(0.3422.05)

6.91

(0.19147.78)

41

Median FU was 27.8 months (0–139.2). 199 patients died (62.8%) including 102 cancer related deaths (32.2%) and 17 (5.4%) deaths from unknown causes. 118 (37.2%) patients were still alive at the time of analysis. Median overall survival for the whole group was 34.2 months (0–135). 58 (18.3%) locoregional failures, diagnosed as progression of residual tumor or recurrence after complete response of primary and/or lymph nodes at least 6 months after completion of the treatment and 39 (12.3%) metastatic progressions of the disease were diagnosed. Complete response of the primary evaluated as residual tumor 3 months after treatment completion was observed in 226 patients, whereas partial response, stable disease or progression during treatment were diagnosed in 87 patients. Data for 4 patients was missing.

Overall survival

2-year overall survival reached 60.1% (190 patients) (Fig. 1). The median PFS was 28.6 months (range 0–185.9) and median DFFS 32.13 months (range 0–186).

Kazmierska-1.png
Figure 1. Kaplan-Meier plot of overall survival for the whole group

In univariate analysis both pre-NLR and post-NLR were significant for OS [hazard ratio (HR): 2.26 (1.25–4.07), p = 0.0068 and HR: 1.57 (1.03–2.37), p = 0.035 respectively) as well as site of primary tumor in larynx [HR: 2 (1.05–3.81), p = 0.03) and oral cavity [HR: 3.46 (1.74–6.87), p = 0.00034) and stage N2 [HR: 1.55 (1.1–2.18), p = 0.01) (Tab. 2).

Table 2. Univariable Cox regression analysis of overall survival. Asterisk marks p-values < 0.05

Variable

Reference

HR (95% CI)

p

T STAGE

T1

T2: 1.08 (0.462.55)

T3: 1.85 (0.794.29)

T4: 2.07 (0.914.73)

0.85

0.15

0.08

N STAGE

N0

N1: 0.78 (0.48 -1.3)

N2: 1.55 (1.12.18)

N3: 1.23 (0.582.61)

0.38

0.01*

0.59

Age

1 year

1.02 (11.03)

0.04*

Site

Nasopharynx

Oropharynx: 1.32 (0.692.48)

Hypopharynx: 1.74 (0.843.56)

Larynx: 2 (1.053.81)

Oral cavity: 3.46 (1.746.87)

0.39

0.13

0.03*

0.0004*

Treatment

RTCT vs. RT

0.77 (0.561.06)

0.11

Smoking

10 pack years

1 (0.991)

0.78

Stage AJCC7

AJCC stage I

AJCC7 II: HR 0.56 (0.132.49)

AJCC7 III: HR 0.66 (0.162.75)

AJCC7 IV: HR 0.95 (0.243.84)

0.45

0.56

0.94

log 10 pre-NLR

1 log NLR

2.26 (1.254.07)

0.0068*

log10 post-NLR

1 log NLR

1.57 (1.032.37)

0.035*

In multivariable analysis post-NLR was associated with OS [HR: 1.93 (1.22–3.1), p = 0.005) together with age [HR: 1.03 (1.01–1.1), p = 0.002], stage N2 [HR: 1.63 (1.11–2.4), p = 0.013) and oral cavity cancer as a primary site of the tumor [HR: 2.67 (1.29–5.5), p = 0.008) (Fig. 2).

Kazmierska-2.png
Figure 2. Multivariable Cox regression analysis of overall survival. Asterisk marks p-values < 0.05
Disease specific survival

All variables were also evaluated for correlation with disease specific survival (DSS). Higher pre- and post-NLR [HR: 3.1 (1.38–6.95), p = 0.006 and HR: 2.43 (1.36–4.36), p = 0.003 respectively] and N2 stage [HR: 3.07 (1.69–5.55), p = 0.0002) and oral cavity primary [HR: 3.19 (1.35–7.52), p = 0.008] were all associated with worse DSS in univariable analysis (Tab. S1 Supplementary File).

In multivariable analysis post-NLR remained significant [HR: 2.31 (1.22–4.4), p = 0.01) together with N2 stage [HR: 2.69 (1.44–5), p = 0.002] and primary site oral cavity [HR: 3.55 (1.42–8.9), p = 0.007] (Fig. S1 Supplementary File).

Treatment failure

Secondary endpoints in this study were time to locoregional failure (PFS) and time to distant failure (DFFS).

None of the tested variables was significant in univariable analysis of locoregional PFS, except primary site oral cavity [HR: 2.69 (1.03–7.04), p = 0.04) (Tab. S2 Supplementary File). Consequently, no multivariable analysis was conducted.

Distant failure

Higher pre-NLR [HR: 4.52 (1.22–16.8), p = 0.02] and N stage [HR: 5.42 (1.64–17.8), p = 0.005] were significantly associated with higher distant failure risk in univariable analysis (Tab. S3, Supplementary File). Both variables remained significant in multivariable analysis [HR: 4.1 (1.14–14), p = 0.03 and HR: 5.3 (1.62–18), p = 0.0062, respectively) (Fig. S2 Supplementary File).

Oropharyngeal cancer

Additionally, a subgroup of patients with oropharyngeal cancer was analyzed for OS and DSS. Univariable analysis revealed significant correlation of pre-NLR, N2 stage with OS [HR: 3.19 (1.21–8.44), p = 0.02 and [HR: 2.95 (1.26–6.88), p = 0.01, respectively] as well as smoking [HR: 1.03 (1–1.05), p = 0.002] (Tab. 3). p16 status was included in analysis in this group of patients and, as expected, was strongly correlated with OS [HR: 0.25 (0.09–0.71), p = 0.0087]. However, these results should be considered with caution due to the high number of missing data.

Table 3. Univariable Cox regression analysis of overall survival in oropharyngeal cancer subgroup. Asterisk marks p values < 0.05

Variable

Reference

HR (95% CI)

p

T STAGE

T1

T2: 0.5 (0.112.31)

T3: 1.4 (0.326)

T4: 1.45 (0.356)

0.37

0.64

0.61

N STAGE

N0

N1: 1.76 (0.654.76)

N2: 2.95 (1.266.88)

N3: 1.83 (0.457.36)

0.26

0.01*

0.39

Age

1 year

1.01 (0.981.04)

0.29

Tretament

RTCT vs RT

0.66 (0.361.18)

0.54

Smoking

10 pack years

1.03 (11.05)

0.002*

log 10 pre-NLR

1 log NLR

3.19 (1.218.44)

0.02*

log10 post-NLR

1 log NLR

1.06 (0.542.19)

0.79

p16

Positive vs. negative

0.25 (0.090.71)

0.0087*

Only pre-NLR and smoking remained significant in multivariable analysis [HR: 3.06 (1.11–8.4), p = 0.03, HR: 1.02 (1–1), p = 0.015) (Fig. S3 Supplementary File). p16 was not included in multivariable analysis due to a small number of observations.

In univariable analysis of variables significant for DSS and PFS, only pre-NLR was significantly correlated with increased risk of unfavourable outcome [HR: 7.4 (1.8–29.2), p = 0.004 and HR: 10.1 (1.8–56.6), p = 0.008 respectively]. None of the evaluated variables proved to be significant for DFFS in univariable analysis.

Complete response

In the analyzed dataset, complete radiological and clinical tumor response (CR) was confirmed in 226 patients, while partial response (PR), stable disease (SD) or progression were diagnosed in 87 patients. Strong negative correlation of pre- and post-NLR with probability of CR was found [odds ratio (OR): 0.23 (0.08–0.6), p = 0.003, and OR: 0.39 (0.2–0.8), p = 0.01, respectively) for the whole group. For the oropharyngeal cancer subgroup only pre-NLR was significantly correlated with CR [OR: 0.18 (0.04–0.8), p = 0.03).

Discussion

Results of research on the key role of the immune system in carcinogenesis and cancer treatment caused an increased interest in studying components of this system, including neutrophils and lymphocytes circulating in the blood [2, 3, 18]. Numerous studies investigated impact of NLR on outcome in non-small cell lung cancer [7, 8], but there is also growing evidence of negative impact of increased NLR on survival in other solid tumors [19, 20], including squamous cell carcinoma of head and neck [21–28]. A clear advantage of studying NLR and other components of CBC is their availability from routinely collected blood samples, low cost of analysis and lack of additional burden for patients. Results have a potential for clinical application and risk assessment. However, in the light of the latest basic research of the complex role of the immune system, translation of these results into clinical practice might not be straightforward.

Balance between neutrophils circulating in blood and maturating in bone marrow is related to chronic inflammation, which is cited as one of the hallmarks of cancer [29]. Circulating neutrophils have a complex influence on carcinogenesis. They facilitate proliferation of tumor cells by decreasing the impact of the host immune system and induce angiogenesis. [30] Neutrophils can promote the spread of cancer cells outside blood vessels, as well as support formation of metastases by inhibiting natural killer function (NK) [2, 30, 31]. Ongoing and further studies focus on identification of neutrophils subpopulations, like for example polymorphonuclear myeloid - derived suppressor cells (PMN-MDSC), and insight in their role in carcinogenesis and resistance for cancer therapies [32].

The complex and still not fully studied interplay of the immune system with host and cancer reflects the role of tumor associated neutrophils (TANs), which increase anti-tumor immune response by interacting with CD8+ lymphocytes. Also, TANs induced by radiotherapy increase production of reactive oxygen species (ROS), leading to increased rate of apoptosis of tumor cells. On the other hand, different phenotypes of TANs were recently discovered, which might exhibit different impacts on tumorigenesis. Their role is dynamic and their impact on the course of disease still needs to be studied. [18, 30] Moreover, immune system components localized in the tumor microenvironment (TME) play a very important role in increasing the benefit of radiotherapy, including potential abscopal effect [33].

Lymphocytes are another important component of the immune system involved in response to cancer. It is acknowledged that “hot tumors” infiltrated by tumor-infiltrating lymphocytes (TILs) have a more favorable prognosis than “cold tumors” [5, 34]. Lymphocytes are also very sensitive to irradiation and chronic decrease in lymphocyte population is often seen after radiotherapy and chemoradiation.

In this study, the impact of changes of pre- and post-treatment NLR was retrospectively evaluated in a group of patients treated for head and neck cancer with curative intent. The study demonstrated that NLR is a strong predictor of overall survival and cancer related death, supporting previous research [21, 22, 24]. In univariable analysis the increase of NLR at both time points was significant for cancer related death, with post-NLR remaining significant when adjusted for other factors in multivariable analysis. Pretreatment NLR also showed significant impact on the risk of distant metastases, which is in line with previous studies [27, 35]. The involvement of regional lymph nodes was a significant factor together with increased NLR in both OS and DFFS analyses, providing evidence for the suggested complex role of the immune system in pro- and anticancer response.

Results of research of impact of NLR on locoregional failure are conflicting. Concurrent with Bojaxiu, this study did not confirm decrease of time to locoregional failure in patients with higher pre- and post-NLR for the whole group of patients [22]. However, meta-analyses conducted by Yang and Yu [35, 36] suggests shorter time to locoregional failure for those with higher NLR. The reason could be the ethnicity of included patients, as according to Yang higher NLR has a negative impact on time to failure in Asian population with higher rate of nasopharyngeal cancer, whereas such impact was not observed in included studies with non-Asian patients [36].

However, in this study both pre- and post-treatment NLR were significant for locoregional failure in a subgroup of patients diagnosed with oropharyngeal cancer. These findings are in line with results of Ng and Gorphe studies [27, 37] and support the hypothesis that the immune system plays a key role in the etiology of p16 positive cancer [38]. P16 was not included in multivariable analysis in this study due to the relatively low number of patients with a known p16 status. Assessment of the p16 status became a standard in our center in 2018. Active smoking was a significant predictor of OS only for oropharyngeal cancer, which was also reported by Ng [27]. Active tobacco use has been shown to influence tumor immune microenvironment via suppression of IFN pathways, and decreasing the number of cytotoxic T lymphocytes in patients with head and neck cancer [39].

A novel finding of this study is the negative correlation of probability of complete response with increased pre-NLR level, which in this context likely reflects the different characteristics of tumor microenvironment (TIM). Infiltration of tumor by lymphocytes (“hot tumors”) was previously shown to correlate with better prognosis in comparison with “cold” tumors [34], where depletion and inhibition of lymphocyte population by the excess of neutrophils recruited from bone marrow protect tumors from infiltration by NK and T lymphocytes. These findings were also confirmed for oropharyngeal cancer, as well as for osteosarcoma and prostate [11, 12].

The NLR ratio could be potentially used in the clinic as an additional factor in planning treatment strategy for individual patients, including closer surveillance after treatment for high-risk patients. Many studies made an attempt to stratify the patients according to NLR ratio, generating risk groups or nomograms. Indeed, such an approach makes this parameter easier for use in daily practice; however, there is no consensus in available literature regarding valid threshold separating risk groups. Value varies from 3 to 5 and above, depending on the study [16, 17, 23]. Thus, in this study we did not make an attempt to find a threshold value but used the hazard ratio to assess individual patient’s risk.

The study has several limitations. First, the dataset was collected retrospectively. However, all of the included patients were treated according to the same therapeutic and supportive care procedures, making this group of patients uniquely homogenous and decreasing the probability of selection bias. The study also failed to demonstrate significant correlation of NLR with outcome in multivariable analysis if adjusted for p16 status due to a high number of missing observations.

An interesting novel finding is the negative impact of high pre- and post-NLR on complete response, both in the entire group and in patients diagnosed with oropharyngeal cancer. These findings support the concept of the role of the immune system and neutrophil subpopulations in the natural history of cancer and treatment response.

Conclusions

Neutrophil-to-Lymphocyte Ratio evaluated before and post chemoradiation of head and neck cancer was a strong predictor of unfavorable treatment outcome for the whole group of patients and, if confirmed in prospective studies, could be used for risk evaluation and clinical decision about treatment as well as for selection of high-risk patients for closer post-treatment surveillance. Further studies are necessary to translate the complex role of immune system components in pro- and anti-tumor activity and exploit it for individualization of the treatment.

Conflict of interests

None declared.

Funding

None declared.

References

  1. Gormley M, Creaney G, Schache A, et al. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J. 2022; 233(9): 780–786, doi: 10.1038/s41415-022-5166-x, indexed in Pubmed: 36369568.
  2. Ocana A, Nieto-Jiménez C, Pandiella A, et al. Neutrophils in cancer: prognostic role and therapeutic strategies. Mol Cancer. 2017; 16(1): 137, doi: 10.1186/s12943-017-0707-7, indexed in Pubmed: 28810877.
  3. Jaillon S, Ponzetta A, Di Mitri D, et al. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer. 2020; 20(9): 485–503, doi: 10.1038/s41568-020-0281-y, indexed in Pubmed: 32694624.
  4. Perri F, Ionna F, Longo F, et al. Immune Response Against Head and Neck Cancer: Biological Mechanisms and Implication on Therapy. Transl Oncol. 2020; 13(2): 262–274, doi: 10.1016/j.tranon.2019.11.008, indexed in Pubmed: 31869751.
  5. Ren X, Guo S, Guan X, et al. Immunological Classification of Tumor Types and Advances in Precision Combination Immunotherapy. Front Immunol. 2022; 13: 790113, doi: 10.3389/fimmu.2022.790113, indexed in Pubmed: 35296094.
  6. Cedervall J, Zhang Y, Olsson AK. Tumor-Induced NETosis as a Risk Factor for Metastasis and Organ Failure. Cancer Res. 2016; 76(15): 4311–4315, doi: 10.1158/0008-5472.CAN-15-3051, indexed in Pubmed: 27402078.
  7. Scilla KA, Bentzen SM, Lam VK, et al. Neutrophil-Lymphocyte Ratio Is a Prognostic Marker in Patients with Locally Advanced (Stage IIIA and IIIB) Non-Small Cell Lung Cancer Treated with Combined Modality Therapy. Oncologist. 2017; 22(6): 737–742, doi: 10.1634/theoncologist.2016-0443, indexed in Pubmed: 28533476.
  8. Kanzaki H, Hamamoto Y, Nagasaki K, et al. Impact of neutrophil-to-lymphocyte ratio throughout the course of chemoradiotherapy on overall survival and distant failure in unresectable stage III non-small cell lung cancer. Jpn J Radiol. 2021; 39(9): 914–922, doi: 10.1007/s11604-021-01129-1, indexed in Pubmed: 33999381.
  9. von Au A, Shencoru S, Uhlmann L, et al. Predictive value of neutrophil-to-lymphocyte-ratio in neoadjuvant-treated patients with breast cancer. Arch Gynecol Obstet. 2023; 307(4): 1105–1113, doi: 10.1007/s00404-022-06726-7, indexed in Pubmed: 35980458.
  10. Kim JY, Jung EJ, Kim JM, et al. Dynamic changes of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio predicts breast cancer prognosis. BMC Cancer. 2020; 20(1): 1206, doi: 10.1186/s12885-020-07700-9, indexed in Pubmed: 33287745.
  11. Tang H, Liu D, Lu J, et al. Significance of the neutrophil-to-lymphocyte ratio in predicting the response to neoadjuvant chemotherapy in extremity osteosarcoma: a multicentre retrospective study. BMC Cancer. 2022; 22(1): 33, doi: 10.1186/s12885-021-09130-7, indexed in Pubmed: 34983443.
  12. Lorente D, Mateo J, Templeton AJ, et al. Baseline neutrophil-lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use. Ann Oncol. 2015; 26(4): 750–755, doi: 10.1093/annonc/mdu587, indexed in Pubmed: 25538172.
  13. Greten FR, Grivennikov SI. Inflammation and Cancer: Triggers, Mechanisms, and Consequences. Immunity. 2019; 51(1): 27–41, doi: 10.1016/j.immuni.2019.06.025, indexed in Pubmed: 31315034.
  14. Oberg HH, Wesch D, Kalyan S, et al. Regulatory Interactions Between Neutrophils, Tumor Cells and T Cells. Front Immunol. 2019; 10: 1690, doi: 10.3389/fimmu.2019.01690, indexed in Pubmed: 31379875.
  15. Hu X, Tian T, Zhang X, et al. Neutrophil-to-lymphocyte and hypopharyngeal cancer prognosis: System review and meta-analysis. Head Neck. 2023; 45(2): 492–502, doi: 10.1002/hed.27246, indexed in Pubmed: 36367335.
  16. Ma SJ, Yu H, Khan M, et al. Evaluation of Optimal Threshold of Neutrophil-Lymphocyte Ratio and Its Association With Survival Outcomes Among Patients With Head and Neck Cancer. JAMA Netw Open. 2022; 5(4): e227567, doi: 10.1001/jamanetworkopen.2022.7567, indexed in Pubmed: 35426920.
  17. Cho JK, Kim MW, Choi IS, et al. Optimal cutoff of pretreatment neutrophil-to-lymphocyte ratio in head and neck cancer patients: a meta-analysis and validation study. BMC Cancer. 2018; 18(1): 969, doi: 10.1186/s12885-018-4876-6, indexed in Pubmed: 30309318.
  18. Shaul ME, Fridlender ZG. Tumour-associated neutrophils in patients with cancer. Nat Rev Clin Oncol. 2019; 16(10): 601–620, doi: 10.1038/s41571-019-0222-4, indexed in Pubmed: 31160735.
  19. 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, doi: 10.1093/jnci/dju124, indexed in Pubmed: 24875653.
  20. Zucker A, Winter A, Lumley D, et al. Prognostic role of baseline neutrophil-to-lymphocyte ratio in metastatic solid tumors. Mol Clin Oncol. 2020; 13(4): 25, doi: 10.3892/mco.2020.2095, indexed in Pubmed: 32774855.
  21. Mattavelli D, Lombardi D, Missale F, et al. Prognostic Nomograms in Oral Squamous Cell Carcinoma: The Negative Impact of Low Neutrophil to Lymphocyte Ratio. Front Oncol. 2019; 9: 339, doi: 10.3389/fonc.2019.00339, indexed in Pubmed: 31114760.
  22. Bojaxhiu B, Templeton AJ, Elicin O, et al. Relation of baseline neutrophil-to-lymphocyte ratio to survival and toxicity in head and neck cancer patients treated with (chemo-) radiation. Radiat Oncol. 2018; 13(1): 216, doi: 10.1186/s13014-018-1159-y, indexed in Pubmed: 30400969.
  23. Panje C, Riesterer O, Glanzmann C, et al. Neutrophil-lymphocyte ratio complements volumetric staging as prognostic factor in patients treated with definitive radiotherapy for oropharyngeal cancer. BMC Cancer. 2017; 17(1): 643, doi: 10.1186/s12885-017-3590-0, indexed in Pubmed: 28893236.
  24. Staniewska E, Tomasik B, Tarnawski R, et al. The prognostic value of red cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in radiotherapy for oropharyngeal cancer. Rep Pract Oncol Radiother. 2021; 26(6): 1010–1018, doi: 10.5603/RPOR.a2021.0126, indexed in Pubmed: 34992875.
  25. Schernberg A, Blanchard P, Chargari C, et al. Leukocytosis, prognosis biomarker in locally advanced head and neck cancer patients after chemoradiotherapy. Clin Transl Radiat Oncol. 2018; 12: 8–15, doi: 10.1016/j.ctro.2018.07.002, indexed in Pubmed: 30073209.
  26. Lin CH, Chou WC, Wu YY, et al. Prognostic significance of dynamic changes in lymphocyte-to-monocyte ratio in patients with head and neck cancer treated with radiotherapy: results from a large cohort study. Radiother Oncol. 2021; 154: 76–86, doi: 10.1016/j.radonc.2020.09.012, indexed in Pubmed: 32941957.
  27. Ng SP, Bahig H, Jethanandani A, et al. Prognostic significance of pre-treatment neutrophil-to-lymphocyte ratio (NLR) in patients with oropharyngeal cancer treated with radiotherapy. Br J Cancer. 2021; 124(3): 628–633, doi: 10.1038/s41416-020-01106-x, indexed in Pubmed: 33051590.
  28. Lin AJ, Gang M, Rao YJ, et al. Association of Posttreatment Lymphopenia and Elevated Neutrophil-to-Lymphocyte Ratio With Poor Clinical Outcomes in Patients With Human Papillomavirus-Negative Oropharyngeal Cancers. JAMA Otolaryngol Head Neck Surg. 2019; 145(5): 413–421, doi: 10.1001/jamaoto.2019.0034, indexed in Pubmed: 30920592.
  29. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5): 646–674, doi: 10.1016/j.cell.2011.02.013, indexed in Pubmed: 21376230.
  30. Hedrick CC, Malanchi I. Neutrophils in cancer: heterogeneous and multifaceted. Nat Rev Immunol. 2022; 22(3): 173–187, doi: 10.1038/s41577-021-00571-6, indexed in Pubmed: 34230649.
  31. Kalafati L, Mitroulis I, Verginis P, et al. Neutrophils as Orchestrators in Tumor Development and Metastasis Formation. Front Oncol. 2020; 10: 581457, doi: 10.3389/fonc.2020.581457, indexed in Pubmed: 33363012.
  32. Raskov H, Orhan A, Gaggar S, et al. Neutrophils and polymorphonuclear myeloid-derived suppressor cells: an emerging battleground in cancer therapy. Oncogenesis. 2022; 11(1): 22, doi: 10.1038/s41389-022-00398-3, indexed in Pubmed: 35504900.
  33. Kuang G, Wang Z, Luo C, et al. Mechanism of exosomes in the tumor microenvironment in the abscopal effect (Review). Int J Oncol. 2023; 62(1), doi: 10.3892/ijo.2022.5450, indexed in Pubmed: 36367187.
  34. Ribbat-Idel J, Perner S, Kuppler P, et al. Immunologic “Cold” Squamous Cell Carcinomas of the Head and Neck Are Associated With an Unfavorable Prognosis. Front Med (Lausanne). 2021; 8: 622330, doi: 10.3389/fmed.2021.622330, indexed in Pubmed: 33585526.
  35. Yu Y, Wang H, Yan A, et al. Pretreatment neutrophil to lymphocyte ratio in determining the prognosis of head and neck cancer: a meta-analysis. BMC Cancer. 2018; 18(1): 383, doi: 10.1186/s12885-018-4230-z, indexed in Pubmed: 29618336.
  36. Yang L, Huang Yu, Zhou L, et al. High pretreatment neutrophil-to-lymphocyte ratio as a predictor of poor survival prognosis in head and neck squamous cell carcinoma: Systematic review and meta-analysis. Head Neck. 2019; 41(5): 1525–1535, doi: 10.1002/hed.25583, indexed in Pubmed: 30597654.
  37. Gorphe P, Chekkoury Idrissi Y, Tao Y, et al. Anemia and neutrophil-to-lymphocyte ratio are prognostic in p16-positive oropharyngeal carcinoma treated with concurrent chemoradiation. Papillomavirus Res. 2018; 5: 32–37, doi: 10.1016/j.pvr.2017.12.002, indexed in Pubmed: 29253748.
  38. Welters MJP, Ma W, Santegoets SJ, et al. Intratumoral HPV16-Specific T Cells Constitute a Type I-Oriented Tumor Microenvironment to Improve Survival in HPV16-Driven Oropharyngeal Cancer. Clin Cancer Res. 2018; 24(3): 634–647, doi: 10.1158/1078-0432.CCR-17-2140, indexed in Pubmed: 29018052.
  39. de la Iglesia JV, Slebos RJC, Martin-Gomez L, et al. Effects of Tobacco Smoking on the Tumor Immune Microenvironment in Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2020; 26(6): 1474–1485, doi: 10.1158/1078-0432.CCR-19-1769, indexed in Pubmed: 31848186.



Reports of Practical Oncology and Radiotherapy