
==== Front
Braz J Otorhinolaryngol
Braz J Otorhinolaryngol
Brazilian Journal of Otorhinolaryngology
1808-8694
1808-8686
Elsevier

S1808-8694(24)00108-3
10.1016/j.bjorl.2024.101493
101493
Original Article
Walking one hour per day and the derived neutrophil-to-lymphocyte ratio are associated with outcome in palliative second-line immunotherapy for patients with recurrent and/or metastatic squamous cell carcinoma of head and neck
Caballero-Borrego Miguel mcaba@clinic.cat
abc⁎
Piedra Aida d
Gallego Óscar d
López-Pousa Antonio d
Castillo Paola e
Navarrete Pilar f
Prat Alba g
Grau Juan J. h
a Hospital Clinic of Barcelona, Otolaryngology Department, Barcelona, Spain
b Universitat de Barcelona, Facultat de Medicina i Ciències de la Salut, Departament de Cirurgia i Especialitats Mèdicoquirúrgiques, Barcelona, Spain
c Institut d'Investigacions Biomèdiques Agusti Pi Sunyer (IDIBAPS), Barcelona, Spain
d Hospital de la Santa Creu i Sant Pau, Medical Oncology Department, Barcelona, Spain
e Hospital Clinic of Barcelona, Pathology Department, Barcelona, Spain
f Universitat de Barcelona, Facultat de Medicina i Ciències de la Salut, Departament de Medicina, Barcelona, Spain
g Hospital de la Santa Creu i Sant Pau, Pathology Department, Barcelona, Spain
h Hospital Clinic of Barcelona, Medical Oncology Department, Barcelona, Spain
⁎ Corresponding author. mcaba@clinic.cat
10 8 2024
Nov-Dec 2024
10 8 2024
90 6 10149321 2 2024
3 8 2024
© 2024 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier España, S.L.U.
2024
Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Highlights

• Immune system status influences the effectiveness of immunotherapy.

• Exercising improves the immune system.

• The neutrophil-lymphocyte derived ratio is a measure of the immune system.

• Walking one hour a day improves survival in patients treated with immunotherapy.

• High neutrophil-lymphocyte derived ratio improves survival in these patients.

Objectives

To determine whether routinary walking activity and the derived neutrophil-to-lymphocyte ratio are associated with outcomes in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck.

Methods

This multicenter retrospective cohort study included 64 patients diagnosed with recurrent and/or metastatic squamous cell carcinoma of head and neck and treated with immunotherapy (Programmed Death-1 and Programmed Death-ligand-1 proteins inhibitors) at two tertiary centers. We compared a group that performed uninterrupted physical activity for 1 h per day and controls who performed no activity. The derived neutrophil-to-lymphocyte ratio was calculated as follows: [neutrophils / (leukocytes – neutrophils)]. Progression-free survival and overall survival were evaluated.

Results

We included 28 (44%) and 36 (56%) patients in the activity and non-activity groups, respectively. Patient characteristics, treatment details, and tumor Programmed Death-ligand-1 expression were not associated with either progression-free survival or overall survival. Physical activity was an independent beneficial factor for progression-free survival (p < 0.001) and overall survival (p < 0.001). By contrast, a derived neutrophil-to-lymphocyte ratio <3.5 was an independent beneficial factor for overall survival (p = 0.013), but not for progression-free survival (p = 0.328).

Conclusions

Walking one hour per day and having a high proportion of lymphocytes to neutrophiles (expressed as a low derived neutrophil-to-lymphocyte ratio) independently predict a better prognosis in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck treated with immunotherapy.

Level of evidence

III.

Keywords

Head and neck cancer
Physical activity
Immunotherapy
Derived neutrophil-to-lymphocyte ratio
Prognosis
Abbreviations

SCCHN Squamous Cell Carcinoma of the head and neck

R/M Regional or Metastatic

PD-L1 Programmed Death-Ligand-1

PD-1 Programmed Death-1

HR Hazard Ratio

CI Confidence Intervals

NLR Neutrophil/Lymphoid Ratio

dNLR Derived Neutrophil/Lymphoid Ratio

ECOG Eastern Cooperative Oncology Group

WA Walker

NW Non-Walker

TPS Tumor Positive Score

CPS Combined Positive Score

OS Overall Survival

PFS Progression-Free Survival
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pmcIntroduction

Primary tumors located in the oral cavity, hypopharynx, and larynx have an annual incidence of more than 700,000 cases worldwide and a mortality rate of about 50%.1 Squamous Cell Carcinoma of the Head and Neck (SCCHN) accounts for most cases, with surgery and/or chemoradiotherapy as the main treatment strategies. The curative rate for early-stage disease is high. On the contrary, despite advances in these treatments, approximately 40% of locally advanced SCCHN will not respond or recur after treatment. In addition, up to 50% will develop loco-regional recurrence and up to 20% will develop distant metastasis.2

Palliative treatments for patients with R/M SCCHN usually include radiotherapy, which is limited by normal tissue dose tolerance, and systemic therapy with platinum-based drugs, antifolates, taxanes, and cetuximab.3 Fortunately, the more recent study of cancer immunology has led to the development of new treatments that modulate the immune system and improve survival.4 Among these, immune checkpoint inhibitors block certain proteins, called “checkpoints”, created by T-cells and some cancer cells. These checkpoints help prevent immune responses from becoming too strong and can sometimes prevent T-cells from killing cancer cells. Examples include Programmed Death-Ligand-1 (PD-L1) on tumor cells and Programmed Death-1 (PD-1) on T cells. The development of immune checkpoint inhibitors (e.g., avelumab, nivolumab, tremelimumab, or pembrolizumab) that block PD-L1 binding to PD-1 enable T-cells to eliminate tumor cells, showing durable responses and survival improvements in patients with R/M SCCHN treated using platinum-based drugs.5, 6, 7 Some authors have also studied the effectiveness of immune checkpoint inhibitors in patients with R/M SCCHN who have low or negative PD-L1 expression.7

Many authors have demonstrated the importance of immune cell distribution in patients with cancer. Chronic inflammation in these patients results in an increased neutrophil count and a decreased lymphocyte count in the peripheral blood that are associated with poor clinical response.8 Kuss et al. demonstrated that patients with head and neck cancer have lower lymphocyte counts compared with healthy controls.9 Since lymphocytes are responsible for the immune response against cancer, their counts inversely correlate with cancer severity.10 Given these associations, several markers of cancer-related inflammation have been proposed, with the Neutrophil/Lymphoid Ratio (NLR)7, 11, 12 and the derived NLR (dNLR; Neutrophil/Leukocyte minus Lymphocyte ratio) becoming strong predictors of outcome.13 Higher NLR or dNLR values indicate lower lymphocyte counts and worse prognosis.10 Despite the low cost and ease of collection of these biomarkers in routine clinical practice, few articles have studied their value for head and neck cancer.14, 15

Finally, it has been suggested that regular physical activity after a cancer diagnosis may improve treatment outcomes.16 Some authors have even argued that regular physical activity could modify the distribution of immune cells in the tumor microenvironment and improve the antitumor response.17

This study aimed to evaluate the effect of routine physical activity (defined as walking for ≥1 h/day), the immune biomarker dNLR, and tumor cell PD-L1 expression on the outcomes of patients with R/M SCCHN treated with PD-1/PD-L1 inhibitors.

Methods

Patients

The design of this study was a multicenter cohort study of consecutive patients with R/M SCCHN undergoing treatment with PD-1/PD-L1 inhibitors (nivolumab, durvalumab, and avelumab) in two tertiary referral hospitals. Clinical data were collected prospectively, and histopathological evaluation of tumors were analyzed retrospectively. The inclusion criteria were as follows: biopsy-proven R/M SCCHN in the oral, pharyngeal, laryngeal, or rhinosinus region before treatment; not amenable to curative treatment; having received PD-1 or PD-L1 inhibitor therapy either in routine practice or within a clinical trial; having an Eastern Cooperative Oncology Group (ECOG) performance-status score ≤2; and having no physical or mental limitations to perform the minimum physical activity requirement.

Treatment protocol

All included patients were presented at a multidisciplinary board with participation of head and neck surgeons or dermatologists, radiation oncologists, and medical oncologists where treatment plan was discussed and decided together.

PD-L1 or PD1 inhibitors were used to the point of disease progression or unacceptable toxicity. Patients received either nivolumab (240 mg), durvalumab (10 mg/kg), or avelumab (10 mg/kg) every 2 weeks. This treatment, as a second-line palliative treatment for recurrent and metastatic disease, did not require PD-L1 assessment for initation and was conducted for research purposes.

All enrolled patients were advised to walk every day for 1 h from one week before to the end of treatment. Patients were divided into Walker (WA) and Non-Walker (NW) groups by whether they completed the activity.

This study was approved by the Institutional Review Board (HCB/2022/1152). All patients signed the informed consent form.

Data collection and assessments

We collected demographic and clinical data. This included the complete blood cell count at baseline, within 30 days before the first immunotherapy treatment to calculate the dNLR. The dNLR was then calculated as previously defined: [absolute neutrophil count/(white blood cells – absolute neutrophil count)].13

Biopsies of the primary tumor were analyzed to determine PD-L1 expression by immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections using PD-L1 22C3 pharmDx antibody on a Dako Autostainer Link 48. A sample was considered valid when a minimum number of 100 viable tumor cells were present. The PD-L1 expression level was then expressed as the Tumor Positive Score (TPS) and the Combined Positive Score (CPS). TPS evaluates the percentage of viable tumor cells showing partial or complete membrane staining at any intensity and is reported as a percentage. CPS evaluates the number of PD-L1 stained cells (e.g., tumor cells, lymphocytes, and macrophages) relative to all viable tumor cells on a scale from 0 to 100.

Clinical response was classified according to the immune-related modified Response Evaluation Criteria in Solid Tumors (iRecist) criteria based on radiological assessments at baseline and every 12 weeks thereafter, according to established guidelines.18 The Overall Survival (OS) was defined as the length of time that patients survived from the start of treatment. Progression-Free Survival (PFS) was defined as the length of time that patients survived with the disease, without progression or death, during and after treatment.

Statistical analysis

To achieve an 80% statistical power with a bilateral alpha error of 5%, the sample size was calculated. After analysis of type I and II error, at least 62 patients would be necessary, 31 patients in each arm, using Fleiss formula and assuming a 25% of survival after 1 year of follow-up in patients with less than 1 h of exercise and anticipating a 60% of survival after 12 months of follow-up in patients with more than 1 h of exercise. The study was designed to detect this difference if it occurred.

Patient characteristics were compared using the chi-squared or Fisher exact test, or for continuous variables, using analysis of variance. Receiver-Operating Characteristic (ROC) curve was used to determine cut-off point of dNLR that best differentiate survivance after 1 year of follow-up. Survival analyses were performed using the Kaplan-Meier method and the log-rank test. Multivariate Cox regression was performed to determine the factors independently associated with OS and PFS, with outcomes expressed as Hazard Ratios (HRs) with 95% Confidence Intervals (CIs). Statistical analyses were performed using IBM SPSS, Version 25.0 (IBM Corp., Armonk, NY, USA), and all p-values < 0.05 were considered statistically significant.

Results

Patients and treatment

This study included 64 consecutive patients treated with the PD-1/PD-L1 inhibitors nivolumab (n = 54), durvalumab (n = 9), and avelumab (n = 1). Their characteristics are shown in Table 1. Gender, age, ECOG status, primary tumor, HPV p16+ status (in oro/hypo-pharyngeal tumors), and previous treatments were not associated with either the OS or the PFS (Table 1).Table 1 Baseline patient characteristics and survival data.

Table 1	Total	Walkers	Non-walkers	PFS (median, 95% IC)	OS (median, 95% IC)	
n (%)	64 (100%)	28 (44%)	36 (56%)			
Gender				p = 0.748	p = 0.748	
 Male	47 (72%)	22 (79%)	25 (69%)	3 (1.7–4.3)	8 (4.2–11.8)	
 Female	17 (28%)	6 (21%)	11 (31%)	2 (0.9–3.1)	10 (3.8–16.1)	
AGE (median)	63 (49–85)	61 (49–78)	64 (54–85)			
Age coded				p = 0.936	p = 0.862	
 <65 years	41 (64%)	20 (56%)	21 (75%)	2 (1.2–2.8)	10 (6.2–13.8)	
 >65 years	23 (36%)	16 (44%)	7 (25%)	3 (2.1–3.9)	6 (3.2–8.8)	
ECOG				p = 0.546	p = 0.533	
 1	55 (86%)	25 (39%)	30 (47%)	3 (2.0–4.0)	9 (5.4–12.6)	
 2	9 (14%)	3 (5%)	6 (9%)	2 (0.2–3.9)	3 (0.8–5.9)	
Primary tumor				p = 0.875	p = 0.366	
 Rhinosinusal	4 (6%)	2 (7%)	2 (6%)	3 (0.9–5.1)	9 (3.2–14.8)	
 Oral Cavity/Oropharynx	31 (48%)	11 (39%)	20 (59%)	3 (0.7–5.3)	10 (6.6–13.3)	
 Hypopharynx	15 (23%)	10 (36%)	5 (29%)	2 (0.7–3.3)	3 (0.0–6.3)	
 Larynx	14 (22%)	5 (18%)	9 (6%)	2 (2.1–3.9)	9 (5.1–13.1)	
HPVp16 (oropharyngeal)				p = 0.125	p = 0.076	
 Positive	6 (9%)	4 (15%)	2 (5%)	5 (0.2–9.8)	6 (2.3–9.7)	
 Negative	31 (49%)	11 (39%)	20 (56%)	2 (1.0–3.0)	11 (6.6–15.4)	
 Non evaluated	27 (42%)	13 (46%)	14 (39%)	3 (1.4–4.6)	11 (2.2–19.8)	
Previous treatment				p = 0.476	p = 0.102	
 Chemoradiotherapy (Extreme)	33 (52%)	15 (24%)	18 (28%)	3 (1.7–4.3)	7 (2.9–11.1)	
31 (48%)	13 (20%)	18 (28%)	2 (0.5–3.9)	14 (4.9–23.1)	
PD-L1 expression						
 TPS > 50	3 (5%)	1 (2%)	2 (3%)	p = 0.987	p = 0.766	
 CPS > 1	14 (22%)	5 (8%)	9 (14%)	p = 0.985	p = 0.830	
CPS, Combined Positive Score; TPS, Total Positive Score; PFS, Progression Free Survival; OS, Overall Survival.

Physical activity

In total, 28 patients (44%) completed ≥1 -h/day of uninterrupted physical activity during the treatment period and were included in the WA group. The remaining 36 patients (56%) comprised the NW group. The main argument for not walking was discomfort in social contact due to either a tracheotomy or aesthetic alterations from previous surgeries.

At the first evaluation, 12 weeks after the start of treatment, 15 patients (23%) had obtained clinical benefit (Objective response or Stable disease) according to the iRecist criteria. The number of patients with clinical benefit was higher in the AW group (10 patients; 36%) than in the NW group (5 patients; 14%). The percentage of patients with a survival longer than 12 months only showed a trend, not statistically significant (p = 0.08), to be higher in the WA group (9 patients, 47%) than the NW group (5 patients, 16%).

The entire group had a mean follow-up of 8.6 months (range, 1–45) and a mean PFS of 5.3 months (range, 1–39). The median PFS was significantly longer in the WA group (9-months) than in the NW group (2-months; p < 0.001; Fig. 1). The median OS was also better in the WA group (25-months) than in the NW group (4-months; p < 0.001; Fig. 2).Fig. 1 Progression-free survival by whether patients completed a walking activity. We compared walking (≥1 h/ day; WA = 28) and non-walking (NW = 36) groups.

Fig. 1

Fig. 2 Overall survival by whether patients completed a walking activity. We compared walking (≥1 h/day; WA = 28) and non-walking (NW = 36) groups.

Fig. 2

Derived neutrophil/lymphoid ratio

The cut-off of dNLR to analyze survival was greater than 3.25 according to the results of the ROC curve (AUC = 72%, 95% IC 57%–86%; Sensitivity = 0.64; 1-Specificity 0.28; p = 0.014). The 28 patients with a baseline dNLR < 3.25 showed a significantly better OS than the 36 patients with a dNLR ≥ 3.25 (17 vs. 10-months; p = 0.012; Fig. 3). The PFS was not different according to baseline dNLR (9 vs. 5-months, p = 0.160). The dNLR expression after the first immunotherapy dose (dNLRpost) was only determined in 61 patients because 3 did not receive the second treatment cycle. The OS and PFS were not significantly different between patients in the low and high dNLRpost groups (14 vs. 13-months, p = 0.954; and 7 vs. 6-months, p = 0.604, respectively).Fig. 3 Overall survival according to the baseline dNLR. The dNLR was calculated as [absolute neutrophil count / (white blood cells – absolute neutrophil count)], with a cut-off point of <3.5 for a low ratio (high, ≥3.5). dNLR, Derived Neutrophil-to-Lymphocyte Ratio.

Fig. 3

Treatment with immunotherapy did not result in a significant change in dNLR scores when looking at all patients. The categories of the variables Age coded, Gender, Perfomance status (ECOG), Primary tumour and Physical activity were independently assessed and a significant decrease in dNLR after treatment was observed in Females, patients with Oral tumors and in patients in the NW group (Table 2).Table 2 Values of dNLR.

Table 2	Basal dNLR media (SD)	dNLR after treatment media (SD)	p	
All cases	5.4 (5.1)	3.5 (3.2)	0.250	
Gender				
 Male	4.5 (4.4)	3.7 (3.6)	0.146	
 Female	7.8 (6.0)	3.1 (1.7)	0.008	
Age coded				
 <65 years	5.5 (4.8)	3.6 (3.7)	0.275	
 >65 years	5.3 (5.5)	3.4 (2.1)	0.082	
ECOG				
 1	5.8 (5.3)	3.6 (3.3)	0.08	
 2	2.9 (1.5)	3.3 (2.3)	0.334	
Primary tumor				
 Rhinosinusal	2.3 (1.3)	2.2 (2.1)	0.444	
 Oral	6.7 (6.2)	3.3 (4.0)	0.008	
Cavity/Oropharynx				
 Hypopharynx	5.3 (4.6)	4.0 (1.9)	0.138	
 Larynx	5.6 (4.8)	3.6 (2.2)	0.100	
Physical activity				
 Walking group	3.7 (2.1)	3.8 (1.6)	0.394	
 No walking group	6.7 (6.2)	3.3 (4.0)	0.008	

PD-L1 tumor expression

PD-L1 expression was only evaluated in 52 patients due to either a lack of material or poor material preservation (12 cases). The TPS was ≥ 50% in 3 patients (WA group, 1; NW group, 2; p = 0.645) and the CPS was ≥ 1 in 34 patients (WA group, 13; NW group, 21; p = 0.443). A CPS ≥ 20 was observed in 4 patients from the WA group and 6 from the NW group (p = 0.613). No significant differences were observed in the PFS or OS by PD-L1 status.

Multivariate analysis

Patient characteristics, treatments, physical activity, baseline dNLR, and post-treatment (12-weeks) dNLR were introduced to a Cox proportional hazards regression model. Physical activity was independently associated with PFS, the WA group having a better PFS (HR = 2.451; 95% CI 1.234–4.868; p = 0.010). Both physical activity and baseline dNLR were independently associated with OS, the WA group having a better OS (p = 0.002) and the group with a low baseline dNLR having a better OS (p = 0.042) (Table 3).Table 3 Cox proportional hazards regression analysis results of overall survival.

Table 3Risk factor	Hazard ratio (HR) (95% CI for HR)	p-value	
Walking group	3.433 (1.568–7.517)	0.002	
Low baseline dNLR	2.190 (1.029–4.660)	0.0042	

Discussion

A healthy immune system has an important effect on the prognosis of cancer, especially in patients treated with immunotherapy. Many conditions can modify the immune system, including physical activity. Our study found that both routine physical activity (walking one hour per day) and the proportion of lymphocytes to neutrophils in the blood (i.e., dNLR) independently affect survival in patients with R/M SCCHN who receive PD-1/PD-L1 inhibitors.

Research has shown that even moderate levels of regular physical activity can increase the effectiveness of the immune system.19, 20, 21 This has been identified as an independent prognostic factor in both experimental animal models22, 23, 24 and in patients with cancer,19 including breast,25 hematologic,26 and colorectal cancers.27 The exercise also improved the response in patients treated with immunotherapy, consistent with Gustafson et al.’s research.28 Our study adds that walking for ≥1-h/day can also improve PFS and OS in patients with R/M SCCHN (rhinosinusal, oral, pharyngeal, and laryngeal tumors). However, our study could only show a trend in the percentage of patients who survived more than 12-months in the patients who did the physical activity; the lack of statistical significance in this variable could be due to the fact that survival in both groups was lower than expected and used for sample calculation, and we also had only 28 patients who did not the exercise. The biological mechanisms linking exercise to prognostic changes in cancer are poorly understood, with various hypotheses implicating changes in leukocyte populations, increased antioxidant defense mechanisms, alterations in inflammatory mediators, and changes in specific antitumor mechanisms.19, 25, 29

NLR and the dNLR have been popularized as biomarkers of systemic inflammatory response in patients with some types of cancer.11, 12, 13, 14, 30, 31, 32 In particular, elevated dNLR values have been associated with poor prognosis, as in our study, for several types of cancer,13 including melanoma,33 breast cancer,34 and more recently, laryngeal,14, 15, 35 oral,36, 37 and nasopharyngeal38 cancers, Researchers from our department have also demonstrated an association been high dNLR and a poor prognosis in patients with non-small cell lung cancer treated with PD-1/PD-L1 inhibitors,39 similar to our results. However, this relationship was not observed in patients undergoing chemotherapy,39 reflecting that our understanding of the relationship between dNLR and prognosis needs further clarification. Donnem et al. hypothesized that oncologic activity may be associated with decreased lymphocyte counts and increased neutrophil counts in patients with cancer.40 We believe that immunotherapy requires a more efficient lymphocyte function for an anticancer response (specifically CD8+)14 than chemotherapy.

Some authors have specifically studied the positive influence of physical activity on the NLR and, therefore, the dNLR.41, 42 Pedersen et al. explain this influence through an increase in part of the lymphocyte count, particularly the distribution of cytotoxic T lymphocytes, that improves the response to anti-PD-1/PD-L1 agents during treatment.43 Our study revealed no association between physical activity and a low dNLR. Furthermore, PD-L1 expression in the tumor did not affect either PFS or OS. Both findings probably reflect the low number of patients involved. Ito et al. reported a strong correlation between a TPS ≥ 40% and a CPS ≥ 20 for head and neck cancer treated with nivolumab.44 These investigators also noted that TPS may be used as a predictor of prognosis and efficacy, but they could not demonstrate the prognostic value of CPS, consistent with our results. However, the main limitation of this study was how we recorded physical activity. By failing to reflect personal differences in the practice of physical activity, we cannot draw definitive conclusions. A prospective controlled study will be necessary for such analysis, but it could have ethical implications. Despite the limitations, this study can inform future research in this area.

Conclusions

Walking for ≥1-h/day and having a high ratio of lymphocytes to neutrophiles (expressed as an elevated dNLR ratio) represent independent predictors of a better OS in patients with advanced SCCHN treated with immunotherapy. Despite the better results in patients who performed physical activity, studies with better control of variables and with larger numbers of patients are needed to establish a direct relationship between exercise and survival in cancer patients. The result on dNLR can serve as a potentially useful tool when selecting idoneal patients for immunotherapy treatment.

Authors’ contributions

Design: JJG. Acquisition of data: AP, PC and AP. Analysis: OG. Writing and drafting: MC and PN. Critical Revision: AL.

Meetings at which the manuscript was presented

This investigation was presented in the 74th Congress of the Spanish Society for Otorhinolaryngology and Head and Neck Surgery (SEORL-CCC) and in the XIX Spanish-Portuguese Congress, October 5–8, 2023.

Justification of the number of authors

The number of investigators is justified because this study has been conducted by investigators from two independent institutions (4-authors each) and covers both clinical and basic research.

Ethics approval and consent to participate

Ethics approval and consent to participate this study was approved by the Ethics Committee of Hospital Clínic of Barcelona (HCB/2022/1152).

Consent for publication

Not applicable (the manuscript does not contain data from any individual person).

Funding

The authors have no financial support or financial interests.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgments

We would like to thank Dr Robert Sykes and Michael Maudsley, scientific editors at the Language Services of the University of Barcelona, for help with the English.
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References

1 Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin. 71 2021 209 249 33538338
2 Denaro N. Merlano M.C. Russi E.G. Follow-up in head and neck cancer: do more does it mean do better? A systematic review and our proposal based on our experience Clin Exp Otorhinolaryngol. 9 2016 287 297 27337948
3 Adelstein D. Gillison M.L. Pfister D.G. Spencer S. Adkins D. Brizel D.M. NCCN guidelines® insights head and neck cancers, version 2.2017 featured updates to the NCCN guidelines JNCCN J Natl Compr Cancer Netw 15 2017 761 770
4 Poulose J.V. Kainickal C.T. Immune checkpoint inhibitors in head and neck squamous cell carcinoma: a systematic review of phase-3 clinical trials World J Clin Oncol. 13 2022 388 411 35662989
5 Cohen E.E.W. Soulières D. Le Tourneau C. Dinis J. Licitra L. Ahn M.J. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study Lancet 393 2019 156 167 30509740
6 Ferris R.L. Blumenschein G. Fayette J. Guigay J. Colevas A.D. Licitra L. Nivolumab for recurrent squamous-cell carcinoma of the head and neck N Engl J Med. 375 2016 1856 1867 27718784
7 Siu L.L. Even C. Mesía R. Remenar E. Daste A. Delord J.P. Safety and efficacy of durvalumab with or without tremelimumab in patients with PD-L1-low/negative recurrent or metastatic HNSCC: the phase 2 CONDOR randomized clinical trial JAMA Oncol. 5 2019 195 203 30383184
8 McMillan D.C. The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer Cancer Treat Rev. 39 2013 534 540 22995477
9 Kuss I. Hathaway B. Ferris R.L. Gooding W. Whiteside T.L. Imbalance in absolute counts of T lymphocyte subsets in patients with head and neck cancer and its relation to disease Adv Otorhinolaryngol. 62 2005 161 172 15608426
10 Zhang J. Huang S.-H. Li H. Li Y. Chen X.-L. Zhang W.-Q. Preoperative lymphocyte count is a favorable prognostic factor of disease-free survival in non-small-cell lung cancer Med Oncol. 30 2013 352 23275140
11 Templeton A.J. McNamara M.G. Šeruga B. Vera-Badillo F.E. Aneja P. Ocaña A. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis J Natl Cancer Inst. 106 2014 dju124
12 Zhang J. Zhang H.-Y. Li J. Shao X.-Y. Zhang C.-X. The elevated NLR, PLR and PLT may predict the prognosis of patients with colorectal cancer: a systematic review and meta-analysis Oncotarget 8 40 2017 68837 68846 28978160
13 Proctor M.J. McMillan D.C. Morrison D.S. Fletcher C.D. Horgan P.G. Clarke S.J. A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer Br J Cancer. 107 2012 695 699 22828611
14 Eskiizmir G. Uz U. Onur E. Ozyurt B. Karaca Cikrikci G. Sahin N. The evaluation of pretreatment neutrophil-lymphocyte ratio and derived neutrophil–lymphocyte ratio in patients with laryngeal neoplasms Braz J Otorhinolaryngol. 85 2019 578 587 29936214
15 Chang H. Gao J. Xu B.Q. Guo S.P. Lu R.B. Li G. Haemoglobin, neutrophil to lymphocyte ratio and platelet count improve prognosis prediction of the TNM staging system in nasopharyngeal carcinoma: development and validation in 3,237 patients from a single institution Clin Oncol (R Coll Radiol). 25 2013 639 646 23910226
16 Friedenreich C.M. Neilson H.K. Farris M.S. Courneya K.S. Physical activity and cancer outcomes: a precision medicine approach Clin Cancer Res Off J Am Assoc Cancer Res. 22 2016 4766 4775
17 Koelwyn G.J. Quail D.F. Zhang X. White R.M. Jones L.W. Exercise-dependent regulation of the tumour microenvironment Nat Rev Cancer. 17 2017 620 632 28943640
18 Wolchok J.D. Hoos A. O’Day S. Weber J.S. Hamid O. Lebbé C. Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria Clin Cancer Res. 15 2009 7412 7420 19934295
19 Walsh N.P. Gleeson M. Shephard R.J. Jeffrey M.G. Woods A. Bishop N.C. Position statement: immune function of exercise Exerc Immunol Rev. 17 2011 6 63 21446352
20 Scheffer D.L. Latini A. Exercise-induced immune system response: Anti-inflammatory status on peripheral and central organs Biochim Biophys Acta Mol Basis Dis. 1866 2020 165823
21 Wang J. Liu S. Li G. Xiao J. Exercise regulates the immune system Adv Exp Med Biol. 1228 2020 395 408 32342473
22 Hoffman-Goetz L. Physical activity and cancer prevention: animal-tumor models Med Sci Sports Exerc. 35 2003 1828 1833 14600546
23 Packer N. Hoffman-Goetz L. Exercise training reduces inflammatory mediators in the intestinal tract of healthy older adult mice Can J Aging. 31 2 2012 161 171 22647663
24 Rundqvist H. Veliça P. Barbieri L. Gameiro P.A. Bargiela D. Gojkovic M. Cytotoxic T-cells mediate exercise-induced reductions in tumor growth Elife 9 2020 e59996
25 Figueira A.C.C. Cortinhas A. Soares J.P. Leitão J.C. Ferreira R.P. Duarte J.A. Efficacy of exercise on breast cancer outcomes: a systematic review and meta-analysis of preclinical data Int J Sports Med. 39 2018 327 342 29564842
26 Sitlinger A. Brander D.M. Bartlett D.B. Impact of exercise on the immune system and outcomes in hematologic malignancies Blood Adv. 4 2020 1801 1811 32343800
27 Meyerhardt J.A. Heseltine D. Niedzwiecki D. Hollis D. Saltz L.B. Mayer R.J. Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803 J Clin Oncol. 24 2006 3535 3541 16822843
28 Gustafson M.P. Wheatley-Guy C.M. Rosenthal A.C. Gastineau D.A. Katsanis E. Johnson B.D. Exercise and the immune system: taking steps to improve responses to cancer immunotherapy J Immunother Cancer. 9 7 2021 e001872 10.1136/jitc-2020-001872
29 Pollán M. Casla-Barrio S. Alfaro J. Esteban C. Segui-Palmer M.A. Lucia A. Exercise and cancer: a position statement from the Spanish Society of Medical Oncology Clin Transl Oncol. 22 2020 1710 1729 32052383
30 Singh S. Singh J. Ganguly R. Chandra S. Samadi F.M. Suhail S. Diagnostic efficacy of neutrophil to lymphocyte ratio (NLR) in oral potentially malignant disorders and oral cancer Indian J Pathol Microbiol. 64 2021 243 249 33851615
31 Kawashita Y. Kitamura M. Soutome S. Ukai T. Umeda M. Saito T. Association of neutrophil-to-lymphocyte ratio with severe radiation-induced mucositis in pharyngeal or laryngeal cancer patients: a retrospective study BMC Cancer. 21 1 2021 1064 34583669
32 Werner J. Strobel K. Lehnick D. Rajan G.P. Overall neutrophil-to-lymphocyte ratio and SUV (max) of nodal metastases predict outcome in head and neck cancer before chemoradiation Front Oncol. 11 2021 679287
33 Ferrucci P.F. Ascierto P.A. Pigozzo J. Del Vecchio M. Maio M. Antonini Cappellini G.C. Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab Ann Oncol. 29 2018 524 28379318
34 Krenn-Pilko S. Langsenlehner U. Stojakovic T. Pichler M. Gerger A. Kapp K.S. The elevated preoperative derived neutrophil-to-lymphocyte ratio predicts poor clinical outcome in breast cancer patients Tumour Biol. 37 2016 361 368 26219894
35 Chen H. Song S. Zhang L. Dong W. Chen X. Zhou H. Preoperative platelet-lymphocyte ratio predicts recurrence of laryngeal squamous cell carcinoma Future Oncol. 16 2020 209 217 31984780
36 Grimm M. Rieth J. Hoefert S. Krimmel M. Rieth S. Teriete P. Standardized pretreatment inflammatory laboratory markers and calculated ratios in patients with oral squamous cell carcinoma Eur Arch Otorhinolaryngol. 273 2016 3371 3384 26926692
37 Jariod-Ferrer ÚM. Arbones-Mainar J.M. Gavin-Clavero M.A. Simón-Sanz M.V. Moral-Saez I. Cisneros-Gimeno A.I. Are comorbidities associated with overall survival in patients with oral squamous cell carcinoma? J oral Maxillofac Surg. 77 2019 1906 1914 30980811
38 Song S. Chen H. Dou X. Wang K. Yan J. Yu C. The prognostic value of before treatment neutrophil-to-lymphocyte ratio in nasopharyngeal carcinoma Eur Arch Otorhinolaryngol. 279 5 2022 2485 2492 34510259
39 Mezquita L. Auclin E. Ferrara R. Charrier M. Remon J. Planchard D. Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer JAMA Oncol. 4 2018 351 357 29327044
40 Donnem T. Al-Shibli K. Andersen S. Al-Saad S. Busund L.-T. Bremnes R.M. Combination of low vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 expression and high lymphocyte infiltration is a strong and independent favorable prognostic factor in patients with nonsmall cell lung cancer Cancer 116 2010 4318 4325 20549821
41 Howard R. Scheiner A. Kanetsky P.A. Egan K.M. Sociodemographic and lifestyle factors associated with the neutrophil-to-lymphocyte ratio Ann Epidemiol. 38 2019 11 21.e6 31481293
42 Walzik D. Joisten N. Zacher J. Zimmer P. Transferring clinically established immune inflammation markers into exercise physiology: focus on neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index Eur J Appl Physiol. 121 2021 1803 1814 33787989
43 Pedersen L. Idorn M. Olofsson G.H. Lauenborg B. Nookaew I. Hansen R.H. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution Cell Metab. 23 2016 554 562 26895752
44 Ito T. Okamoto I. Tokashiki K. Sato H. Okada T. Yamashita G. PD-L1 expression and survival rates using TPS and CPS for nivolumab-treated head-and-neck cancer Anticancer Res. 42 2022 1547 1554 35220251
