Prognostic significance of pre-treatment neutrophil-to-lymphocyte ratio (nlr) in patients with oropharyngeal cancer treated with radiotherapy

ABSTRACT BACKGROUND This study aimed to evaluate the prognostic value of pre-treatment NLR in patients with oropharyngeal cancer. METHODS Patients who completed definitive radiotherapy (RT)

for oropharyngeal cancer and had blood counts taken pre-RT from 2002 to 2013 were included. NLR was calculated as total neutrophil/lymphocytes. Survival rates were estimated using the

Kaplan–Meier method. Univariable and multivariable analyses were conducted with linear and Cox regression methods. NLR was analysed posteriori and dichotomised on the discovered median.

RESULTS Eight hundred and forty-eight patients were analysed. The median pre-RT NLR was 3. Patients with NLR of <3 had improved overall survival (OS) than those with NLR ≥ 3 (5-year OS 85

vs 74%, _p_ < 0.0001). OS differences remained significant when stratified according to HPV status (HPV-positive _p_ = 0.011; HPV-negative _p_ = 0.003). Freedom from any recurrence

(FFR), locoregional control (LRC) and freedom of distant recurrence (FDR) were better in those with NLR < 3. The negative impact of elevated pre-RT NLR on OS (HR = 1.64, _p_ = 0.001), FFR

(HR = 1.6, _p_ = 0.006) and LRC (HR = 1.8, _p_ = 0.005) remained significant on multivariable analysis. CONCLUSIONS Pre-RT NLR is an independent prognostic factor in patients with

oropharyngeal cancer regardless of HPV status. Patients with lower NLR had more favourable OS and disease control. SIMILAR CONTENT BEING VIEWED BY OTHERS PROGNOSTIC VALUE OF

NEUTROPHIL-TO-LYMPHOCYTE RATIO CHANGE IN PATIENTS WITH LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER TREATED WITH THORACIC RADIOTHERAPY Article Open access 25 May 2024 COMBINED PRETREATMENT

NEUTROPHIL-LYMPHOCYTE RATIO AND PLATELET-LYMPHOCYTE RATIO PREDICTS SURVIVAL AND PROGNOSIS IN PATIENTS WITH NON-METASTATIC NASOPHARYNGEAL CARCINOMA: A RETROSPECTIVE STUDY Article Open access

30 April 2024 NOMOGRAMS BASED ON THE LYMPHOCYTE–ALBUMIN–NEUTROPHIL RATIO (LANR) FOR PREDICTING THE PROGNOSIS OF NASOPHARYNGEAL CARCINOMA PATIENTS AFTER DEFINITIVE RADIOTHERAPY Article Open

access 05 March 2024 BACKGROUND The incidence of oropharyngeal cancer is on the rise in the developed countries.1 As human papillomavirus (HPV) is an infectious agent, there is renewed

interest to investigate the extent of host’s inflammatory reaction to the persistent HPV infection contributing to neoplastic transformation, cancer treatment response and patient’s

prognosis. While inflammation can be protective against malignancy in the initial phase, activating the innate immune system and recruiting primitive immune cells such as neutrophils to the

site is attributed to promote tumorigenesis and cancer progression.2 It is postulated that chronic inflammation promotes quick turnover of cells, thereby accumulating and propagating

mutations contributing to malignant transformation. In addition, the inflammatory cascade leads to capillary leakiness potentially promoting tumour angiogenesis and metastatic potential.

Neutrophil-to-lymphocyte ratio (NLR) is a simple biomarker of systemic inflammation and has been demonstrated to be a prognostic marker in several solid cancers, including prostate,3 renal,4

gastric,5 brain6 and hypopharyngeal7 cancers. Here we evaluated the effect of pre-treatment NLR on outcomes in patients with oropharyngeal cancer in the contemporary era. METHODS This

retrospective study was approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center. This study was performed in accordance with the Declaration of

Helsinki. All patients, above the age of 18 years, who completed curative-intent radiotherapy for squamous cell carcinoma of the oropharynx and had blood counts taken within 2 weeks before

radiotherapy from 2002 to 2013 were included in this study. All patients received curative-intent radiation dose. Patients with distant metastatic disease (M1) at diagnosis, had no blood

counts taken within 2 weeks of commencing radiotherapy or had a haematologic disorder affecting lymphocyte and/or neutrophil counts were excluded. Patient, tumour and treatment

characteristics, clinical outcomes and pre-radiotherapy total neutrophil and lymphocyte counts (TNC and TLC, respectively) were recorded. HPV status was collected, whenever available, and is

deemed positive if either p16 immunohistochemistry or HPV in situ hybridisation was positive. The disease was staged according to the American Joint Committee on Cancer (AJCC) staging

system (Seventh edition). NLR was calculated as TNC divided by TLC. NLR was analysed posteriori and dichotomised on the discovered median (rounded to nearest whole number). STATISTICAL

ANALYSIS Overall survival (OS) was calculated with the Kaplan–Meier method from the date of completion of radiotherapy to date of death. Freedom from locoregional failure was measured from

the date of completion of radiotherapy to the date of first locoregional failure. Freedom from distant metastasis was calculated from the date of completion of radiotherapy to the date of

first distant disease. Freedom from recurrence was calculated from the date of completion of radiotherapy to the date of any first recurrence. For all survival calculations, patients without

events were censored at last follow-up time. The impact of NLR on survival and disease control rates was estimated using the Kaplan–Meier method and compared with log-rank tests. Potential

prognostic factors for OS and freedom from recurrence were evaluated with univariable and multivariable analyses and were conducted with linear and Cox proportional hazard regression models.

Variables that achieved a _p_ value of ≤0.1 in univariable analyses were included in the multivariable analysis. A two-tailed _p_ value of <0.05 was deemed statistically significant.

Statistical analyses were performed using JMP v14.0 (SAS Institute Inc.). RESULTS PATIENT CHARACTERISTICS From 2002 to 2013, 1124 patients with localised oropharyngeal cancer received

definitive radiotherapy. Of these, 276 patients were excluded from this analysis: 273 patients did not have a blood count within 2 weeks of commencing radiotherapy, 2 had chronic lymphocytic

leukaemia, and 1 had a spurious high neutrophil count. Therefore, a total of 848 patients were eligible for analysis. Table 1 summarises the patient, disease and treatment characteristics.

The median age of the cohort was 57 years (range: 29–87 years). The majority (87%) were males and approximately half the cohort were never smokers or previous smokers with <10 pack year

history. Base of tongue and tonsil were the predominant sites accounting for 98% of the cohort primary site. Six hundred and three (71%) patients had HPV/p16-positive squamous cell

carcinoma. The median radiation dose fractionation delivered was 70 Gy in 33 fractions. Almost half the cohort received induction chemotherapy and 88% had concurrent chemotherapy.

PRE-TREATMENT NLR AND OUTCOMES The median pre-treatment NLR was 2.52 (range: 0.05–23.9). The median follow-up time was 59 months (range: 6–153 months). At last follow-up, 183 (22%) patients

had died. Overall, 141 (17%) patients developed disease recurrence: 70 with distant disease (including 11 with local and/or regional disease, 37 with local disease, 29 with regional disease,

and 5 with local and regional disease. Patients with NLR < 3 had a 5-year OS of 85% compared to 74% (_p_ < 0.0001) for those with NLR ≥ 3. Freedom from recurrence, locoregional

failure and distant metastasis were better in those with NLR < 3 (5-year freedom from recurrence 86 vs 77%, _p_ = 0.0009; 5-year freedom from locoregional failure 92 vs 85%, _p_ = 0.003;

5-year freedom from distant metastasis 91 vs 86%, _p_ = 0.038; Fig. 1). To verify that our results were not influenced by outliers, we re-analysed the data with just the patients whose NLR

was in the 5–95% values (range: 0.95–7.97). This demonstrated that the improved outcomes in those with NLR < 3, as shown in the overall cohort analysis, remained significant.

STRATIFICATION BY HPV STATUS HPV status was available for 674 patients—603 HPV positive and 71 HPV negative. When stratified according to HPV status, those with NLR < 3 continued to have

a significantly better OS than those with NLR ≥ 3 (HPV positive: 5-year OS 85 vs 78%, _p_ = 0.011; HPV negative: 5-year OS 88 vs 61%, _p_ = 0.003; Fig. 2). Similar effect is observed for

freedom from recurrence (HPV positive: 5-year 86 vs 80%, _p_ = 0.036; HPV negative: 5-year 84 vs 69%, _p_ = 0.051). On logistic regression analysis, there was association between NLR and T

stage (_p_ = 0.0003) and N stage (_p_ = 0.002) but no significant association with HPV status (_p_ = 0.75) nor smoking status (_p_ = 0.88). Figure 3 shows the impact of combined T stage and

NLR on OS. UNIVARIABLE AND MULTIVARIABLE ANALYSES Univariable analyses of variable of interest are shown in Table 2. On multivariable analyses, NLR remained as an independent prognostic

factor for OS and freedom from recurrence with NLR ≥ 3 having a risk ratio of 1.64 (95% confidence interval (CI) 1.22–2.19, _p_ = 0.001) and 1.62 (95% CI 1.15–2.26, _p_ = 0.006),

respectively. In addition to NLR, patient’s smoking status, age and T stage were also associated with OS outcome. Radiation dose (higher dose) and NLR < 3 were associated with improved

freedom from recurrence. To determine whether the effect of NLR is relatively linear as an overall continuous degree of inflammation, NLR was analysed as a continuous variable. On

univariable analysis, lower NLR was associated with better freedom from recurrence (_p_ = 0.003, HR = 1.04, 95% CI = 1.01–1.06) and locoregional failure (_p_ = 0.007, HR = 1.05, 95% CI = 

1.01–1.07). However, NLR as a continuous variable had no significant correlation with OS (_p_ = 0.37) and freedom from distant metastasis (_p_ = 0.92). DISCUSSION Our study which consisted

of a large cohort of patients with squamous cell carcinoma of the oropharynx demonstrated that the pre-radiotherapy NLR has significant impact on OS and disease control. Patients with NLR of

<3 before radiotherapy had an improved 5-year survival of 85% compared to 74% in those with NLR of 3. The impact of NLR on clinical outcomes was independent of HPV status. NLR is a

simple inflammatory marker that has been proven to be a prognostic marker in multiple malignancies.3,4,5,6,8 A large meta-analysis reporting on a 100 studies with >40,000 patients

demonstrated that patients with solid tumours and a higher NLR (>4) had worse OS and disease outcomes, regardless of cancer stage or subsites.8 In head and neck cancer, NLR has been

extensively investigated as a prognostic marker although variable cut-off values and timepoints were used.7,9,10,11,12,13,14,15 The majority of studies have included a heterogeneous group of

patients with tumours from differing head and neck subsites.7,11,13,14,15,16 More recently, in a smaller study than ours, So et al.12 reported on a cohort of 104 patients with

HPV-associated oropharyngeal cancer and showed that patients with high NLR had worse 5-year disease-free survival. In patients with HPV-negative disease, Lin et al.17 reported that an

elevated NLR at 3 months after completion of radiotherapy was associated with worse survival. Our study results are consistent with previous literature and provide a validation for the use

of pre-treatment NLR as a prognostic marker in a contemporary cohort of patients with oropharyngeal cancer. The relationship between inflammation and cancer has become an increasingly

interesting but intricate area of research. Although inflammation has been identified as one of the hallmarks of cancer,18 the complex relationship between inflammation and the tumour

microenvironment, promoting angiogenesis and malignant transformation and subsequently cancer progression, remain poorly understood. While HPV is now identified as a cause of oropharyngeal

cancer, our study has shown that NLR remained as an effective prognostic biomarker regardless of viral status. One might assume that the persistent HPV infection releases pro-inflammatory

cytokines resulting in chronic inflammation and subsequently carcinogenesis. However, it appears that the inflammatory tumour microenvironment may differ between HPV-positive and

HPV-negative tumours, as patients with HPV-positive oropharyngeal cancer have improved outcomes compared to those with HPV-negative cancer. For example, it has been noted that patients with

HPV-positive oropharyngeal cancer tend to have radiologically cystic or necrotic neck nodes19,20 compared to those with HPV-negative disease. Necrosis is proinflammatory and can recruit

immune cells to the area with the intent of clearing the necrotic debris.18 Although the intent of inflammatory infiltrate is to remove debris and promote healing, interleukin-1α released by

necrotic cells for cell proliferation can inadvertently expedite neoplastic transformation and progression.21 Our study comes with caveats of a single institution retrospective cohort

study. Second, relative to those with HPV-positive disease, the number of patients with HPV-negative oropharyngeal cancer in this cohort is only 71 (8.4%), thereby limiting the statistical

power and further analysis to determine the impact of NLR on disease-specific outcomes due to the small number of events. Third, although we reported the number of patients who received

induction and concurrent chemotherapy, we did not detail the chemotherapeutic agents. The vast majority who received induction chemotherapy received taxane–platinum-based regimens, while our

concurrent patients received single agent platin or cetuximab. Nevertheless, our results are consistent with the previous studies in head and neck and other cancers indicating that NLR, as

a marker of systemic inflammation, is prognostic for clinical outcomes. In this large cohort of patients with oropharyngeal cancer, we highlighted that pre-radiotherapy NLR is an independent

prognostic factor in patients with oropharyngeal cancer regardless of HPV status. Patients with lower NLR had more favourable clinical outcomes in terms of survival and disease control. NLR

could be explored prospectively as a potential cost-effective biomarker for further pre-treatment risk stratification of patients with oropharyngeal cancer for treatment

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INFORMATION AUTHORS AND AFFILIATIONS * Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Sweet Ping Ng, Houda Bahig, Amit Jethanandani, 

Baher Elgohari, G. Brandon Gunn, Jack Phan, David I. Rosenthal, Steven J. Frank, Clifton D. Fuller & Adam S. Garden * Department of Radiation Oncology, Peter MacCallum Cancer Centre,

Melbourne, VIC, Australia Sweet Ping Ng * Department of Radiation Oncology, Centre Hospitalier de l’Universite de Montreal, Montreal, QC, Canada Houda Bahig * Department of Head and Neck

Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Erich M. Sturgis * Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson

Cancer Center, Houston, TX, USA Faye M. Johnson & Renata Ferrarotto Authors * Sweet Ping Ng View author publications You can also search for this author inPubMed Google Scholar * Houda

Bahig View author publications You can also search for this author inPubMed Google Scholar * Amit Jethanandani View author publications You can also search for this author inPubMed Google

Scholar * Erich M. Sturgis View author publications You can also search for this author inPubMed Google Scholar * Faye M. Johnson View author publications You can also search for this author

inPubMed Google Scholar * Baher Elgohari View author publications You can also search for this author inPubMed Google Scholar * G. Brandon Gunn View author publications You can also search

for this author inPubMed Google Scholar * Renata Ferrarotto View author publications You can also search for this author inPubMed Google Scholar * Jack Phan View author publications You can

also search for this author inPubMed Google Scholar * David I. Rosenthal View author publications You can also search for this author inPubMed Google Scholar * Steven J. Frank View author

publications You can also search for this author inPubMed Google Scholar * Clifton D. Fuller View author publications You can also search for this author inPubMed Google Scholar * Adam S.

Garden View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS S.P.N.: conceptualisation, data curation, formal analysis, investigation,

methodology, project administration, visualisation, writing—original draft, and writing—review and editing. H.B.: data curation, investigation, visualisation, and writing—review and editing.

A.J.: data curation and writing—review and editing. E.M.S., F.M.J., G.B.G., R.F., J.P., D.I.R., S.J.F. and C.D.F.: resources, methodology, and writing—review and editing. B.E.: methodology

and writing—review and editing. A.S.G.: supervision, project administration, resources, writing—original draft, and writing—review and editing. CORRESPONDING AUTHORS Correspondence to Sweet

Ping Ng or Adam S. Garden. ETHICS DECLARATIONS ETHICS APPROVAL AND CONSENT TO PARTICIPATE This study was approved by the Institutional Review Board of The University of Texas MD Anderson

Cancer Center. Informed consent was waived. This study was performed in accordance with the Declaration of Helsinki. CONSENT TO PUBLISH Not applicable. DATA AVAILABILITY Data will be

available on request. COMPETING INTERESTS The authors declare no competing interests. FUNDING INFORMATION S.P.N. is funded by the Australian Postgraduate Award, the Royal Australian and New

Zealand College of Radiologists (RANZCR) Research Grant and the Radiological Society of North America (RSNA) Fellow Grant. C.D.F. was supported by Andrew Sabin Family Fellowship. C.D.F.

received funding support from the National Institutes of Health (NIH)/National Institute for Dental and Craniofacial Research (NIDCR) (1R01DE025248-01/R56DE025248-01). C.D.F. was previously

funded via the National Science Foundation (NSF), Division of Mathematical Sciences, Joint NIH/NSF Initiative on Quantitative Approaches to Biomedical Big Data (QuBBD) Grant (NSF

DMS-1557679) and is currently supported by the NIH National Cancer Institute (NCI)/Big Data to Knowledge (BD2K) Program (1R01CA214825-01), the NIH/NCI Head and Neck Specialized Programs of

Research Excellence (SPORE) Developmental Research Program Career Development Award (P50CA097007-10); the NCI Paul Calabresi Clinical Oncology Program Award (K12 CA088084-06); a General

Electric Healthcare/MD Anderson Center for Advanced Biomedical Imaging In-Kind Award; an Elekta AB/MD Anderson Department of Radiation Oncology Seed Grant; the Center for Radiation Oncology

Research (CROR) at MD Anderson Cancer Center Seed Grant and the MD Anderson Institutional Research Grant (IRG) Program. C.D.F. has received speaker travel funding from Elekta AB. This study

was supported in part by the NIH/NCI Cancer Center Support (Core) Grant CA016672 to The University of Texas MD Anderson Cancer Center (P30 CA016672). F.M.J. has received research funding

from PIQUR Therapeutics and Trovagene. E.M.S. has a research award from Roche Diagnostics supporting HPV testing of oral rinse and mucosal swab samples on the clinical trial for HPV-related

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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Ng, S.P., 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_ 124, 628–633 (2021). https://doi.org/10.1038/s41416-020-01106-x Download citation * Received: 06 February 2020 * Revised:

07 September 2020 * Accepted: 11 September 2020 * Published: 14 October 2020 * Issue Date: 02 February 2021 * DOI: https://doi.org/10.1038/s41416-020-01106-x SHARE THIS ARTICLE Anyone you

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