10.14639/0392-100X-N2358
Objectives. To evaluate the prognostic value of pre-treatment prognostic-nutritional index (PNI) in patients with HPV-negative head and neck squamous cell carcinoma (HNSCC). Methods. A multi-institutional retrospective series of HPV-negative, Stages II-IVB, HNSCCs treated with upfront surgery was evaluated. Correlation of pre-operative blood markers and PNI with 5-year overall (OS) and relapse-free (RFS) survival was tested using linear and restricted cubic spline models, as appropriate. The independent prognostic effect of patient-related features was assessed with multivariable models. Results. The analysis was conducted on 542 patients. PNI ≥ 49.6 (HR = 0.52; 95% CI, 0.37-0.74) and Neutrophil-to-Lymphocyte Ratio (NLR) &gt; 4.2 (HR = 1.58; 95% CI, 1.06-2.35) confirmed to be independent prognosticators of OS, whereas only PNI ≥ 49.6 (HR = 0.44; 95% CI, 0.29-0.66) was independently associated with RFS. Among pre-operative blood parameters, only higher values of albuninaemia and lymphocyte count (&gt; 1.08 x 103/microL), and undetectable basophile count (= 0 103/microL) were independently associated with better OS and RFS. Conclusions. PNI represents a reliable prognostic tool providing an independent measure of pre-operative immuno-metabolic performance. Its validity is supported by the independent prognostic role of albuminaemia and lymphocyte count, from which it is derived.
text/xml
1827-675X
2358
en
Paolo Boscolo-Rizzo
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
prognostic nutritional
The prognostic-nutritional index in HPV-negative head and neck squamous cell carcinoma treated with upfront surgery: a multi-institutional series
Text.Serial.Journal
https://www.actaitalica.it/
43
Head and neck
2023-05-16
2022-10-24
2023-05-19
2023-05-19
170-182
1
Paolo Boscolo-Rizzo
2023/05/16
10.14639/0392-100X-N2358
170
Department of Medical, Surgical and Health Sciences, Section of Otolaryngology, University of Trieste, Trieste, Italy
1827-675X
prognostic nutritional
en
182
The prognostic-nutritional index in HPV-negative head and neck squamous cell carcinoma treated with upfront surgery: a multi-institutional series
https://www.actaitalica.it/article/download/2358/986
43
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:170-182; doi: 10.14639/0392-100X-N2358




Head and neck


The prognostic-nutritional index in HPV-negative head
and neck squamous cell carcinoma treated
with upfront surgery: a multi-institutional series
Il prognostic-nutritional index nel carcinoma squamoso testa-collo HPV-negativo
trattato chirurgicamente: studio multi-istituzionale
Michele Tomasoni1, Cesare Piazza1, Alberto Deganello1, Paolo Bossi2, Giancarlo Tirelli3, Piero Nicolai4,
Maria Cristina Da Mosto5, Gabriele Molteni6, Vittorio Giacomarra7, Pietro Canzi8, Stefano Pelucchi9, Jerry Polesel10,
Daniele Borsetto11, Paolo Boscolo-Rizzo3
1
  Unit of Otorhinolaryngology-Head and Neck Surgery, ASST Spedali Civili di Brescia, Department of Medical and Surgical
Specialties, Radiological Sciences, and Public Health, University of Brescia, School of Medicine, Brescia, Italy; 2 Unit of Medical
Oncology, ASST Spedali Civili di Brescia, Department of Medical and Surgical Specialties, Radiological Sciences, and Public
Health, University of Brescia, School of Medicine, Brescia, Italy; 3 Department of Medical, Surgical and Health Sciences, Section of
Otolaryngology, University of Trieste, Trieste, Italy; 4 Section of Otolaryngology, Department of Neurosciences, University of Padua,
Padua, Italy; 5 Section of Otolaryngology, Department of Neurosciences, University of Padua, Treviso, Italy; 6 Section of Ear Nose
and Throat (ENT), Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy; 7 Unit
of Otolaryngology, Azienda Ospedaliera “S. Maria degli Angeli”, Pordenone, Italy; 8 Department of Otorhinolaryngology, University
of Pavia, IRCCS Policlinico “San Matteo” Foundation, Pavia, Italy; 9 ENT Department, University Hospital of Ferrara, Ferrara, Italy;
10
   Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy; 11 Department of ENT,
Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom


SUMMARY
Objectives. To evaluate the prognostic value of pre-treatment prognostic-nutritional index
(PNI) in patients with HPV-negative head and neck squamous cell carcinoma (HNSCC).
Methods. A multi-institutional retrospective series of HPV-negative, Stages II-IVB, HN-
                                                                                                  Received: October 24, 2022
SCCs treated with upfront surgery was evaluated. Correlation of pre-operative blood mark-
                                                                                                  Accepted: January 8, 2023
ers and PNI with 5-year overall (OS) and relapse-free (RFS) survival was tested using linear
and restricted cubic spline models, as appropriate. The independent prognostic effect of
                                                                                                  Correspondence
patient-related features was assessed with multivariable models.                                  Michele Tomasoni
Results. The analysis was conducted on 542 patients. PNI ≥ 49.6 (HR = 0.52; 95% CI, 0.37-0.74)    Department of Otorhinolaryngology-Head and
and Neutrophil-to-Lymphocyte Ratio (NLR) > 4.2 (HR = 1.58; 95% CI, 1.06-2.35) confirmed to        Neck Surgery, Spedali Civili, University of Brescia,
be independent prognosticators of OS, whereas only PNI ≥ 49.6 (HR = 0.44; 95% CI, 0.29-0.66)      piazzale Spedali Civili 1, 25123 Brescia, Italy
was independently associated with RFS. Among pre-operative blood parameters, only higher          E-mail: tomasoni.michele@gmail.com
values of albuninaemia and lymphocyte count (> 1.08 x 103/microL), and undetectable basophile
count (= 0 103/microL) were independently associated with better OS and RFS.                        How to cite this article: Tomasoni M, Piazza
Conclusions. PNI represents a reliable prognostic tool providing an independent measure             C, Deganello A, et al. The prognostic-nutritional
of pre-operative immuno-metabolic performance. Its validity is supported by the independ-           index in HPV-negative head and neck squa-
ent prognostic role of albuminaemia and lymphocyte count, from which it is derived.                 mous cell carcinoma treated with upfront sur-
                                                                                                    gery: a multi-institutional series. Acta Otorhi-
KEY WORDS: carcinoma, squamous cell of head and neck, lymphocytopenia,                              nolaryngol Ital 2023;43:170-182. https://doi.
hypoalbuminaemia, basophils, index, prognostic nutritional                                          org/10.14639/0392-100X-N2358

                                                                                                  © Società Italiana di Otorinolaringoiatria
RIASSUNTO                                                                                         e Chirurgia Cervico-Facciale
Obiettivi. Valutare il valore prognostico dell’indice prognostico-nutrizionale (PNI) pre-
trattamento nei pazienti con carcinoma a cellule squamose testa-collo (HNSCC) HPV-                               OPEN ACCESS
negativi.                                                                                         This is an open access article distributed in accordance with
Metodi. È stata valutata una serie retrospettiva multi-istituzionale di HNSCC HPV-negativi,       the CC-BY-NC-ND (Creative Commons Attribution-Non-
di stadio II-IVB, trattati con chirurgia upfront. La correlazione dei marcatori ematici pre-      Commercial-NoDerivatives 4.0 International) license. The
                                                                                                  article can be used by giving appropriate credit and mentio-
operatori e del PNI con la sopravvivenza globale (OS) e libera da recidiva (RFS) a 5 anni
                                                                                                  ning the license, but only for non-commercial purposes and
è stata testata utilizzando modelli linear and restricted cubic spline. L’effetto prognostico     only in the original version. For further information: https://
indipendente delle variabili correlate al paziente è stato valutato con modelli multivariabili.   creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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                                                                                               Prognostic-nutritional index in head and neck cancer




Risultati. L’analisi è stata condotta su 542 pazienti. PNI ≥ 49,6 (HR = 0,52; 95%CI, 0,37-0,74) e Neutrophile-to-Lymphocyte Ratio (NLR)
> 4,2 (HR = 1,58; 95%CI, 1,06-2,35) si sono confermati fattori prognostici indipendenti di OS, mentre solo PNI ≥ 49,6 (HR = 0,44; 95% CI,
0,29-0,66) era associato in modo indipendente a RFS. Tra i parametri ematici pre-operatori, solo valori più elevati di albuminemia e conta dei
linfociti (> 1,08 103/microL), e una conta dei basofili indosabile (= 0 103/microL) erano indipendentemente associati a una migliore OS e RFS.
Conclusioni. Il PNI rappresenta uno strumento prognostico affidabile che fornisce una misura indipendente della performance immuno-
metabolica pre-operatoria. La sua validità è supportata dal ruolo prognostico indipendente dell’albuminemia e della conta linfocitaria, da
cui deriva.
PAROLE CHIAVE: carcinoma squamocellulare testa-collo, linfocitopenia, ipoalbuminemia, basofili, indice prognostico nutrizionale



Introduction                                                             most studied, validated and applied. However, despite the
                                                                         robust results obtained in head and neck cancer and other
Although the negative prognostic role of malnutrition and
                                                                         malignancies such as in non-small cell lung cancer 10, and
consequent impairment of the immune-metabolic profile in                 the integration of data of both metabolic (albuminaemia)
cancer patients has been widely demonstrated 1, there is still           and immune (lymphocyte count) status, the application of
a great disparity in the assessment and understanding of tu-             PNI in HNSCC is still limited.
mour- and patient-related characteristics in the pre-treatment           The aim of this study was therefore to evaluate the prog-
setting. In fact, while the detailed analysis of clinical, radio-        nostic value of PNI and other blood indexes in HPV-nega-
logical, and pathological features is nowadays considered                tive HNSCC patients.
mandatory, a thorough evaluation of the immune-metabolic
performance status is still frequently neglected.
Head and neck squamous cell carcinoma (HNSCC) repre-                     Materials and methods
sents the 6th most common cancer worldwide 2, with 5-year                Participants and data
overall survival (OS) ranging from 25% to 60% accord-                    A multicentric retrospective analysis of 1001 consecu-
ing to different subsites 3. With the exception of the human             tive patients affected by primary HNSCC treated by up-
papillomavirus (HPV) status which, however, only applies                 front surgery (with or without adjuvant chemoradiotherapy
to oropharyngeal cancers, risk stratification in HNSCC is,               [CRT]) from March 2004 to June 2018 was conducted at 8
so far, based exclusively on tumour-related parameters (e.g.             Italian centres (Brescia, Ferrara, Padova, Pavia, Pordenone,
site, stage, and grading) 4. The integration of host-related             Treviso, Trieste, and Verona) 11. Inclusion criteria were: a)
risk factors into the currently available prognostic models              diagnosis of Stages II-IVB primary HNSCC originating
may provide a more accurate and tailored risk stratification             from the oral cavity, oropharynx, larynx, and hypopharynx;
assessment with potential utility in both the prognostica-               b) upfront surgery performed as primary treatment with cu-
tion of non-oropharyngeal cancers and in the heterogene-                 rative intent; c) availability of comprehensive pre-operative
ous subgroup of HPV-negative oropharyngeal cancers 5.                    blood tests within two months prior to surgery. Exclusion
Screening of performance status in treatment-naïve patients              criteria were: a) histologically proven p16+ and/or HPV-
should consider two crucial aspects, immune and metabol-                 DNA-positive tumour; b) presence of distant metastasis at
ic, and can be accomplished through routine pre-treatment                diagnosis; c) any previous treatment for HNSCC; d) clini-
blood tests. Evaluation of immune performance, through                   cal history of previous or synchronous cancer (at any site).
quantitative analysis of peripheral leukocyte subpopulations,            Finally, 542 patients were eligible for the present analysis.
is based on the concept of cancer as a systemic disease, in              Medical records were retrieved to collect baseline demo-
which tumour-associated immune response and inflamma-                    graphics, clinical, tumour-, and treatment-related charac-
tion play a pivotal role in cancer development, progression,             teristics. Information regarding smoking habit and alcohol
and distant spread 6,7. Relative to metabolic performance,               consumption were retrieved as well. Pre-operative routine
malnutrition is a common condition at cancer diagnosis with              blood tests included: red blood cell count (RBC, 103/mi-
a complex multifactorial origin, resulting in cachexia, im-              croL); white blood cell count (WBC, 103/microL); platelet
pairment of vital functions and reduced survival 1,8.                    count (103/microL); haemoglobin (Hb, g/L); haematocrit
Based on the above evidence, in the attempt to further sim-              (Hct, %); mean corpuscle volume (MCV, fL); neutrophil,
plify and favour the inclusion of patient-related features in            lymphocyte, monocyte, basophil, and eosinophil counts
the therapeutic algorithm, many prognostic indices combin-               (103/microL); and albumin (g/dL). For all patients, NLR
ing multiple blood parameters have been proposed. Among                  and PNI were calculated as follows NLR = (Neutrophils
these, the “neutrophil-to-lymphocyte ratio” (NLR) 6 and the              [103/microL])/Lymphocytes [103/microL]) and PNI = 10 x
“prognostic-nutritional index” (PNI) 9 represent two of the              Albumin (g/dL) + 0.005 x Lymphocytes/microL.



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M. Tomasoni et al.




For all enrolled patients a follow-up with clinical-endo-            the Monte-Carlo method: the above-described procedure was
scopic examination every 1-3 months for the first year,              replicated 1000 times and the results were averaged (random
every 3-4 months during the second year, and every 4-6               population numbers set at 1000). When significant (p < 0.05),
months after that was available. Chest CT-scan was done              the single cut-offs were applied in the entire cohort to catego-
annually. Additional clinical or imaging diagnostic proce-           rise patients into one of the two prognostic classes for each
dures were performed according to clinical presentation              variable under investigation.
and local protocols.                                                 Univariate analysis using Cox proportional hazards model
                                                                     was performed for variables of main interest, and results
Statistical analysis                                                 expressed in terms of HR and 95% CI. Schoenfeld residu-
Variables included in the analysis were expressed in terms           als were checked to assess the proportional hazard assump-
of median, interquartile range (IQR), range of values and            tion. Survival curves with relative 95% CI and number of
percentages. Differences in pre-operative parameters ac-             patients at risk by time were plotted using the Kaplan-Mei-
cording to age, gender, site of tumour origin, pT and pN             er method and compared with the log-rank test 13.
status, tumour grade and stage were tested with Wilcoxon-            The most relevant patient-, tumour- and treatment-related
Mann-Whitney and Kruskall-Wallis tests, as appropriate.              factors commonly considered in clinical practice and vo-
Outcomes of interest were: OS, defined as the time from sur-         luptuary habits that could influence blood parameters were
gery to death from any cause; relapse-free survival (RFS),           employed to draft a multivariable analysis using Cox pro-
defined as the time from surgery to first relapse of disease         portional-hazard model to assess how pre-operative blood
(at any site). Linear assumption of continuous variables for         markers affect survival outcomes. The role of NLR and
each outcome was first assessed through plot inspection of           PNI as independent prognosticators was assessed as well.
Martingale residuals. Further investigation of the linear re-        Statistical analysis was performed using R (version 4.1.2,
lationship between continuous variables and the outcome of           R Foundation for Statistical Computing, Vienna, Austria);
interest was tested by modelling their effect with restricted        p values < 0.05 (two-tailed) were considered statistically
cubic splines (RCS) and testing the non-linear component by          significant.
Chunk tests and plots inspection. If a non-linear effect was
shown, the variable was modelled with an RCS.
                                                                     Results
Blood parameters and indices derived (PNI and NLR) were
plotted as continuous variables against 5-year probability           Demographics and clinical presentation
of OS and RFS; in case of non-linear relationships, the plot         Five-hundred-forty-two patients were included [median
was developed from an RCS model. Similarly, blood pa-                (IQR) age, 67 (60-75) years; 392 (72.3%) men] (Tab. I).
rameters, PNI and NLR were plotted against hazard ratio              Patients were affected by SCC of the oral cavity, larynx,
(HR) for each outcome of reference (OS and RFS), with                oropharynx and hypopharynx in 49.8%, 33.2%, 8.9% and
median value set as reference (HR = 1), and relative 95%             8.1% of cases, respectively. Association between pre-
confidence interval (CI). In case of non-linear relation-            operative parameters according to age, gender, site of tu-
ships, the plot was developed from an RCS model, as well.            mour origin, pT and pN status, tumour grade and stage are
Pre-operative blood-tests with non-linear effect, PNI, and NLR       available in the Supplementary Material (Figs. S1-S13). A
were categorised into two prognostic classes as determined by        significant and progressive reduction in RBC and increase
the cut-off found with the X-tile software, based on the Ka-         in WBC, particularly neutrophil count, was observed with
plan Meier method (3.6.1 - Yale University, New Haven, CT,           higher tumour grade. Significantly higher WBC and neu-
USA) 12. The minimum percent of the total patient cohort for         trophil counts were found in patients with hypopharyngeal
each prognostic class was set at 10%. The patient dataset was        cancer. Patients affected by pT4 HNSCC showed lower al-
randomly split into two halves. The software performed a log-        buminaemia and higher neutrophil counts.
rank test for survival analysis in the first half to set the ideal
cut-off according to the lowest p value; once found, the second      Survival analysis
half was divided accordingly. Next, the same procedure was           At the time of analysis, 219 patients (40.6%) were dead,
performed to find the ideal cut-off in the second and applied in     and 172 (31.7%) experienced disease relapse (17.0%,
the first half. Finally, the software performed a survival analy-    13.8%, and 13.7% local, regional and distant relapse, re-
sis of the entire dataset based on these optimal cut-offs. To        spectively). The median survival of patients alive at the end
overcome the problem of multiple cut-points selection (sec-          of the study was 66 months (Q1-Q3: 48-91). Five-year OS
ondary to the random split of the dataset into two halves), the      and RFS were 60.7% (95% CI, 56.5-65.2%) and 67.3%
X-tile software performed the cross-validation according to          (95% CI, 63.2-71.5%), respectively.



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                                                                  Prognostic-nutritional index in head and neck cancer




Table I. Characteristics of the cohort of patients under study.
 Variable                                                           Median                    IQR (Q1-Q3)
 Age at diagnosis – yr                                                 67                      15 (60-75)
 Time between pre-operative lab tests and surgery – days               20                      18 (10-28)
 Red blood cell (RBC) – 10^3/microL                                  4.54                   0.73 (4.16-4.89)
 White blood cell (WBC) – 10^3/microL                                7.62                   2.88 (6.35-9.23)
 Platelets – 10^3/microL                                             227.5                 93.7 (184.0-277.7)
 Haemoglobin (Hb) – g/L                                              14.0                       2 (13-15)
 Haematocrit (Hct) – %                                               42.2                   5.3 (39.5-44.8)
 Mean corpuscle volume (MCV) – fL                                    93.2                    8.2 (89.0-97.2)
 Neutrophiles – 10^3/microL                                           4.84                  2.57 (3.71-6.28)
 Lymphocytes – 10^3/microL                                            1.80                  0.81 (1.40-2.21)
 Monocytes – 10^3/microL                                              0.60                  0.31 (0.48-0.79)
 Basophils – 10^3/microL                                              0.03                  0.05 (0.01-0.06)
 Eosinophils – 10^3/microL                                            0.15                  0.15 (0.09-0.24)
 Albumin – g/dL                                                       4.01                  0.49 (3.76-4.25)
 Neutrophil to lymphocyte ratio (NLR)                                 2.59                  1.72 (2.00-3.72)
 Prognostic-nutritional index (PNI)                                   49.6                   7.6 (45.9-53.5)
 Variable                                                             N.                           %
 Gender
     Male                                                             392                        72.3%
    Female                                                            150                        27.7%
 Smoking habit
    Never                                                             119                        23.9%
    Former                                                            111                        22.3%
    Current                                                           267                        53.7%
    Missing                                                           (45)
 Regular alcohol consumption (≥ 1 AU/day)
    Never                                                             262                        58.9%
    Former                                                             46                        10.3%
    Current                                                           137                        30.8%
    Missing                                                           (97)
 Site of origin
    Oral cavity                                                       270                        49.8%
    Oropharynx                                                         48                         8.9%
    Hypopharynx                                                        44                         8.1%
    Larynx                                                            180                        33.2%
 cT classification
    cT1                                                               38                         7.0%
    cT2                                                               177                        32.7%
    cT3                                                               141                        26.0%
    cT4                                                               186                        34.3%
 cN classification
    cN0                                                               300                        55.6%
    cN1                                                                78                        14.4%
    cN2a                                                               17                         3.1%
    cN2b                                                               97                        18.0%
    cN2c                                                               47                         8.7%
                                                                                                         continues   u



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M. Tomasoni et al.




Table I. Characteristics of the cohort of patients under study (follows).
 Variable                                                                                       Median               IQR (Q1-Q3)
    cN3                                                                                            1                    0.2%
    Missing                                                                                       (2)
 Clinical staging
    Stage I                                                                                       16                   3.0%
    Stage II                                                                                      130                  24.0%
    Stage III                                                                                     121                  22.3%
    Stage IV                                                                                      275                  50.7%
 Grading
    Low-grade                                                                                      44                  8.6%
    Intermediate grade                                                                            309                  60.2%
    High-grade                                                                                    160                  31.2%
    Missing                                                                                       (29)
 pT classification
    pT1                                                                                           18                   3.3%
    pT2                                                                                           186                  34.6%
    pT3                                                                                           142                  26.4%
    pT4                                                                                           192                  35.7%
    Missing                                                                                        (4)
 pN classification
    pN0                                                                                           280                  54.6%
    pN1                                                                                            56                  10.9%
    pN2a                                                                                           14                   2.7%
    pN2b                                                                                           57                  11.1%
    pN2c                                                                                           28                   5.5%
    pN3a                                                                                            2                   0.4%
    pN3b                                                                                           76                  14.8%
    Missing                                                                                       (29)
 Definitive staging
    Stage II                                                                                      133                  24.5%
    Stage III                                                                                     116                  21.4%
    Stage IVa                                                                                     215                  39.7%
   Stage IVb                                                                                      78                   14.4%
 Adjuvant (chemo)radiotherapy
   Not performed                                                                                  239                  44.7%
   Performed                                                                                      296                  55.3%
   Missing                                                                                         (7)



Correlation between pre-operative blood markers and OS                      The linear assumption was not observed for Hb, Hct,
Among pre-operative blood markers, a linear relationship                    platelet, lymphocyte, eosinophil, and basophil counts.
with a significant influence on OS was found for RBC                        Hb ≤ 12.9 g/L (HR = 2.34, p < 0.001), Hct ≤ 38.8%
(HR = 0.52, p < 0.001), MCV (HR = 1.02, p = 0.006),                         (HR = 2.22, p < 0.001), platelet count ≤ 168 103/microL
monocyte count (HR = 1.65, p = 0.042) and albumin                           (HR = 1.74, p < 0.001), lymphocyte count ≤ 1.08 103/mi-
(HR = 0.43, p < 0.001, Fig. 1). Although linear, the rela-                  croL (HR = 2.13, p < 0.001, Fig. 1), basophil count > 0
tionship of pre-operative WBC (p = 0.288) and neutrophil                    103/microL (HR = 1.72, p = 0.004), and eosinophil count
count (p = 0.165) values with OS was not significant.                       ≤ 0.07 (HR = 1.82, p < 0.001) were significant predictors of



174
                                                                                                          Prognostic-nutritional index in head and neck cancer




Figure 1. Non-linear and linear correlation of lymphocyte count and albuminaemia, respectively, in terms of both 5-year OS and RFS (first row). The correspond-
ing HR plots are reported in the second row.


worse OS. Plots are reported in the Supplementary Mate-                           nostic influence on RFS once adjusted for the most relevant
rial (Figs. S14-S17).                                                             patient-, tumour- and treatment-related covariates (Tab. III).
At multivariable analysis (Tab. II), once adjusted for patient-,
tumour-, and treatment-related factors, among pre-operative                       Neutrophil-to-lymphocyte ratio and prognostic-nutritional
blood markers, Hb ≤ 12.9 g/L (HR = 1.51, p = 0.041), lym-                         index
phocyte count ≤ 1.08 103/microL (HR = 1.85, p = 0.014),                           Both NLR and PNI showed a linear effect, with a signifi-
basophil count > 0 103/microL (HR = 1.47, p = 0.014) and                          cant association at univariate analysis with all the outcomes
albuminaemia (HR = 0.57, p = 0.006 – continuous) main-                            under investigation (Tab. IV).
tained an independent prognostic influence on OS.                                 Once adjusted for patient-, tumour- and treatment-related
                                                                                  factors, NLR was an independent prognostic factor for OS
Correlation between pre-operative blood markers and RFS                           (HR = 1.10, p < 0.001), but not for RFS. PNI, however,
A linear relationship with RFS was found for all pre-oper-                        confirmed its positive prognostic role as a continuous vari-
ative blood markers, except for lymphocyte and basophil                           able at multivariable analysis for both OS and RFS (Fig. 2).
counts. The linear correlation with RFS was significant for                       For clinical application purposes, the optimal prognostic
RBC (HR = 0.58, p < 0.001), Hb (HR = 0.84, p < 0.001), Hct                        cut-offs for NLR and PNI were investigated to categorise
(HR = 0.94, p = 0.001), MCV (HR = 1.02, p = 0.018), and                           each index into 2 prognostic classes. The ideal cut-off of
albumin (HR = 0.46, p< 0.001, Fig.1), but not for platelet                        NLR widely varied according to outcome under investi-
(p = 0.689), WBC (p = 0.228), neutrophil (p = 0.109), mono-                       gation. Once adjusted, the prognostic stratification based
cyte (p = 0.092) and eosinophil counts (p = 0.819). Lym-                          on NLR was independently associated only with OS
phocyte count ≤ 1.08 × 103/microL (HR = 1.94, p = 0.002,                          (NLR > 4.2, HR = 1.58, p = 0.024).
Fig. 1) and basophil count > 0 103/microL (HR = 2.05,                             The optimal cut-off for PNI was homogeneous according
p = 0.001) were significantly associated with a higher risk                       to the survival outcomes, and consistent with a PNI median
of disease relapse. Plots are reported in the Supplementary                       value of 49.6. This prognostic stratification was significant-
Material (Figs. S18-S21). Lymphocyte count ≤ 1.08 × 103/                          ly associated with any survival outcome at both uni- and
microL (HR = 2.05, p = 0.011), basophil count > 0 × 103/mi-                       multi-variable analysis. PNI ≥ 49.6 (HR = 0.52, p < 0.001)
croL (HR = 1.80, p = 0.035) and albuminaemia (HR = 0.51,                          and PNI > 49.6 (HR = 0.44, p < 0.001) were independent
p = 0.006 – continuous) maintained an independent prog-                           predictors of better OS and RFS, respectively.



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M. Tomasoni et al.




Table II. Univariate and multivariable analysis of pre-operative blood tests and the most relevant patient-, tumour- and treatment-related variables according to
OS. Optimal cut-off for pre-operative blood tests was found with the X-tile analysis.
 Overall survival (OS)                                                            Univariate analysis                         Multivariable analysis
 Variable                                                 Classes                  HR (95% CI)                  P-value                aHR (95% CI)                 P-value
 Age at diagnosis – 10 yr increase                  Linear                       1.39 (1.24-1.57)               < 0.001              1.37 (1.17-1.60)               < 0.001
 Gender                                             Female                          Reference                    0.736                  Reference                    0.853
                                                    Male                         1.05 (0.78-1.14)                                    0.96 (0.64-1.45)
 Smoking habit                                      Never smoker                    Reference                    0.597                  Reference                       0.330
                                                    Smoker                       1.09 (0.78-1.53)                                    1.35 (0.88-2.08)
 Regular alcohol consumption                        Never                           Reference                    0.689                  Reference                       0.865
                                                    Present or current           1.06 (0.79-1.43)                                    0.97 (0.69-1.37)
 Tumour origin                                      Hypopharynx                     Reference                                           Reference                       0.088
                                                    Larynx                       0.65 (0.40-1.04)                0.074
                                                    Oropharynx                   0.59 (0.32-1.10)                0.098
                                                    Oral cavity                  0.72 (0.46-1.14)               0.1650               1.41 (0.97-1.37)
 Tumour grade                                       G1-2                            Reference                   < 0.001                 Reference                       0.449
                                                    G3                           1.61 (1.21-2.13)                                    1.15 (0.80-1.66)
 pT classification                                  pT1-2                           Reference                                           Reference
                                                    pT3                          1.23 (0.85-1.76)                0.273               1.08 (0.67-1.75)                   0.740
                                                    pT4                          2.11 (1.552.89)                < 0.001              1.76 (1.16-2.66)                   0.008
 pN classification                                  pN0                             Reference                                           Reference
                                                    pN+ENE-                      1.57 (1.10-2.23)                0.012               2.34 (1.48-3.69)               < 0.001
                                                    pN+ENE+                      3.63 (2.64-5.01)               < 0.001              4.87 (3.02-7.86)               < 0.001
 Adjuvant RT                                        Not performed                   Reference                    0.007                  Reference                    0.005
                                                    Performed                    1.47 (1.11-1.93)                                    0.52 (0.33-0.82)
 RBC - 10^3/microL                                  Linear                       0.52 (0.42-0.64)               < 0.001
 Haemoglobin (Hb) – g/L                             > 12.9                          Reference                   < 0.001                 Reference                       0.041
                                                    ≤ 12.9                       2.34 (1.77-3.10)                                    1.51 (1.02-2.23)
 Haematocrit (Hct) - %                              > 38.8                          Reference                   < 0.001
                                                    ≤ 38.8                       2.22 (1.67-2.94)
 Mean corpuscle volume (MCV) – fL                   Linear                       1.02 (1.01-1.04)                0.006               1.02 (0.99-1.04)                   0.120
 Platelet count – 10^3/microL                       > 168                           Reference                   < 0.001                 Reference                       0.216
                                                    ≤ 168                        1.74 (1.27-2.40)                                    1.31 (0.85-2.01)
 WBC – 10^3/microL                                  Linear                       1.03 (0.98-1.08)                0.288
 Neutrophil count – 10^3/microL                     Linear                       1.04 (0.98-1.10)                0.165               1.05 (0.97-1.14)                   0.229
 Lymphocyte count – 10^3/microL                     > 1.08                          Reference                   < 0.001                 Reference                       0.014
                                                    ≤ 1.08                       2.13 (1.47-3.09)                                    1.85 (1.13-3.01)
 Monocyte count – 10^3/microL                       Linear                       1.65 (1.02-2.69)                0.042               1.27 (0.68-2.35)                   0.453
 Basophil count – 10^3/microL                        =0                             Reference                    0.004                  Reference                       0.014
                                                    >0                           1.72 (1.19-2.49)                                    1.47 (0.92-2.34)
 Eosinophil count – 10^3/microL                     > 0.07                          Reference                   < 0.001                 Reference                       0.265
                                                    ≤ 0.07                       1.82 (1.36-2.44)                                    1.25 (0.85-1.85)
 Albumin – g/dL                                     Linear                       0.43 (0.33-0.55)               < 0.001              0.57 (0.38-0.85)                   0.006
ENE, extranodal extension; G1, low-grade; G2, intermediate grade; G3, high grade; RBC, red blood cell count; RT, radiotherapy; WBC, white blood cell count; yr-years.


Discussion                                                                                   the most studied and widely applied. The prognostic role of
Many prognostic indices have been formulated to predict sur-                                 NLR in HNSCC has been extensively investigated and con-
vival outcomes in cancer patients. NLR and PNI are among                                     firmed, as evident from the most recent inherent meta-analyses



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Table III. Univariate and multivariable analysis of pre-operative blood tests and most relevant patient-, tumour- and treatment-related variables according to RFS.
Optimal cut-off for pre-operative blood tests was found with the X-tile analysis.
 Recurrence-free survival (RFS)                                                          Univariate analysis                    Multivariable analysis
 Variable                                                              Classes                HR (95% CI)            P-value             aHR (95% CI)                   P-value
 Age at diagnosis – 10 yr increase                              Linear                      1.22 (1.07-1.39)          0.003            1.22 (1.02-1.44)                 0.025
 Gender                                                         Female                         Reference              0.715               Reference                     0.128
                                                                Male                        0.94 (0.68-1.31)                           0.70 (0.45-1.11)
 Smoking habit                                                  Never smoker                   Reference              0.989               Reference                     0.961
                                                                Smoker                      1.00 (0.69-1.45)                           1.01 (0.63-1.61)
 Regular alcohol consumption                                    Never                          Reference              0.475                                             0.168
                                                                Present or current          0.89 (0.62-1.24)                           0.97 (0.64-1.48)
 Tumour origin                                                  Hypopharynx                    Reference                                  Reference                     0.886
                                                                Larynx                      0.58 (0.34-0.99)          0.048
                                                                Oropharynx                  0.65 (0.39-1.08)          0.434
                                                                Oral cavity                 0.77 (0.41-1.47)          0.097             0.97 (0.64-1.48)
 Tumour grade                                                   G1-2                           Reference              0.001                Reference                    0.470
                                                                G3                          1.68 (1.23-2.30)                            1.16 (0.77-1.75)
 pT classification                                              pT1-2                          Reference                                   Reference
                                                                pT3                         1.27 (0.84-1.94)         0.257              1.30 (0.74-2.27)                 0.357
                                                                pT4                         2.27 (1.59-3.25)        < 0.001             2.24 (1.39-3.63)                < 0.001
 pN classification                                              pN0                            Reference                                   Reference
                                                                pN+ENE-                     2.11 (1.41-3.18)        < 0.001             2.82 (1.68-4.73)                < 0.001
                                                                pN+ENE+                     5.01 (3.46-7.26)        < 0.001            6.96 (4.09-11.85)                < 0.001
 Adjuvant RT                                                    Not performed                  Reference            < 0.001                Reference                     0.024
                                                                Performed                   1.98 (1.40-2.69)                           0.55 (0.33-0.92)
 RBC – 10^3/microL                                              Linear                      0.58 (0.45-0.74)        < 0.001
 Haemoglobin (Hb) – g/L                                         Linear                      0.84 (0.77-0.93)        < 0.001            1.03 (0.89-1.19)                 0.727
 Haematocrit (Hct) – %                                          Linear                      0.94 (0.92-0.98)         0.001
 Mean Corpuscle Volume (MCV) – fL                               Linear                      1.02 (1.00-1.04)         0.018             1.02 (0.99-1.04)                 0.221
 Platelet count – 10^3/microL (10 units increase)               Linear                      1.00 (0.97-1.02)         0.689             1.00 (0.97-1.02)                 0.857
 WBC – 10^3/microL                                              Linear                      1.03 (0.98-1.09)         0.228
 Neutrophil count – 10^3/microL                                 Linear                      1.05 (0.99-1.12)         0.109             1.05 (0.96-1.16)                 0.272
 Lymphocyte count – 10^3/microL                                 >1.08                          Reference             0.002                Reference                     0.011
                                                                ≤1.08                       1.94 (1.27-2.96)                           2.05 (1.18-3.55)
 Monocyte count – 10^3/microL                                   Linear                      1.60 (0.92-2.76)          0.092            1.37 (0.66-2.84)                 0.403
 Basophil count – 10^3/microL                                    =0                            Reference              0.001               Reference                     0.035
                                                                >0                          2.05 (1.32-3.18)                           1.80 (1.04-3.12)
 Eosinophil count – 10^3/microL                                 Linear                      1.11 (0.44-2.82)         0.819             1.26 (0.39-4.03)                 0.698
 Albumin – g/dL                                                 Linear                      0.46 (0.34-0.62)        < 0.001            0.51 (0.32-0.82)                 0.006
ENE, extranodal extension; G1, low-grade; G2, intermediate grade; G3, high grade; RBC, red blood cell count; RT, radiotherapy, WBC, white blood cell count; yr-years.


published 6,14,15. However, an inconsistent prognostic cut-off of                            by a recent meta-analysis 17 that confirmed the correlation
the NLR value (1.92 to 5 for OS) emerges when analysing the                                  between PNI and poor survival outcomes in HNSCC. Of
results of the included studies, making the clinical applicabil-                             the studies included in the meta-analysis, most were on na-
ity of this index sometimes unpractical.                                                     sopharyngeal cancer 18-24 or HNSCC treated with non-sur-
The prognostic value of PNI in solid tumours has been ex-                                    gical protocols 25-27. Four 28-31 reported the prognostic value
tensively demonstrated, and the application of PNI in HN-                                    of PNI in surgical patients, but only on specific subsites
SCC encouraged 16 based on the solid evidence summarised                                     (oral cavity 28, hypopharynx 29,30, larynx 31).



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M. Tomasoni et al.




Table IV. Uni- and multi-variable analysis showing 5-year OS, RFS and the relative HR of NLR and PNI both as continuous and categorized variables.
                                                                                    Cox Proportional-Hazard model                        Log-rank test
 Variable                                                                              HR                P-value          Adjusted HR             P-value        5-year estimate
                                                                                    (95% CI)                               (95% CI)*                             overall survival
 Neutrophil- Continuous variable                                               1.10 (1.05-1.14)         < 0.001         1.10 (1.04-1.16)         < 0.001
 Lymphocyte Categorization according                             P-value
 Ratio (NLR) to X-tile analysis                                                    Reference
             Favourable prognosis                    ≤ 4.2        0.002                                                     Reference                                 62.7%
                                                                                                                                                                   (58.1-67.7%)
                  Poor prognosis                     > 4.2                     1.61 (1.17-2.21)           0.003         1.58 (1.06-2.35)           0.024              51.1%
                                                                                                                                                                   (41.7-62.7%)
 Prognostic- Continuous form                                                   0.93 (0.91-0.95)         < 0.001         0.94 (0.91-0.97)         < 0.001
 Nutritional Categorization according                            P-value
 Index (PNI) to X-tile analysis
             Poor prognosis           < 49.6                     < 0.001           Reference                                Reference                                 49.9%
                                                                                                                                                                   (44.0-56.7%)
                  Favourable prognosis              ≥ 49.6                     0.44 (0.34-0.58)         < 0.001         0.52 (0.37-0.74)         < 0.001              71.3%
                                                                                                                                                                   (65.8-77.2%)
                                                                              Relapse-free survival
 Neutrophil- Continuous form                                                   1.07 (1.02-1.12)           0.003         1.05 (0.98-1.12)           0.171
 Lymphocyte Categorization according                             P-value
 Ratio (NLR) to X-tile analysis
             Favourable prognosis                    ≤ 3.3        0.058            Reference                                Reference                                 70.5%
                                                                                                                                                                   (65.7-75.6%)
                  Poor prognosis                     > 3.3                     1.47 (1.08-2.00)           0.013         1.19 (0.81-1.73)           0.381              60.8%
                                                                                                                                                                   (53.9-68.7%)
 Prognostic       Continuous form                                              0.93 (0.91-0.96)         < 0.001         0.94 (0.91-0.97)         < 0.001
 Nutritional      Categorization according                       P-value
 Index (PNI)      to X-tile analysis
                  Poor prognosis           ≤ 49.6                 0.016            Reference                                Reference                                 56.0%
                                                                                                                                                                   (50.1-62.6%)
                  Favourable prognosis              > 49.6                     0.43 (0.31-0.59)         < 0.001         0.44 (0.29-0.66)         < 0.001              78.3%
                                                                                                                                                                   (73.3-83.6%)
* Adjusted HRs to most relevant patient (age, gender, smoking habit, regular alcohol consumption), tumour (site of origin, grade of differentiation, pT, pN), and treatment-related (ad-
juvant RT) prognostic factors.




For the first time, we herein investigated the prognostic role                                 The positive prognostic influence of albuminaemia in HN-
of PNI, NLR and other pre-operative immuno-metabolic                                           SCC patients undergoing surgery has been extensively stud-
parameters on a large series of patients affected by HPV-                                      ied and demonstrated 32. Our results confirm the independent
negative, Stages II-IV, HNSCC treated with curative intent                                     linear prognostic effect of albumin on any outcome, with a
by upfront surgery.                                                                            dramatic reduction in mortality and disease recurrence for
                                                                                               each increase of 1 g/dl. Of note, lower albuminaemia was
Prognostic-nutritional index                                                                   significantly associated with higher pT, pN and overall stag-
PNI showed the following advantages: 1) it was found to                                        ing, likely due to altered oral intake in patients with advanced
be independently associated with both OS and RFS, as a                                         and more symptomatic HNSCC, although its prognostic role
continuous linear variable and when categorised (with the                                      was independent of these covariates.
same cut-off, corresponding to the median value, for both                                      Although previously reported 33,34, in this study we fur-
outcomes); 2) it is calculated from two independent prog-                                      ther investigated the protective role of lymphocyte count,
nostic parameters (lymphocyte count and albuminaemia)                                          clearly depicting its non-linear correlation with OS and
which convey crucial information from immune and meta-                                         RFS, identifying an independent cut-off (1.08 103/microL),
bolic performances, respectively.                                                              which was uniform for both outcomes and consistent with



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Figure 2. Linear models showing the correlation between pre-operative PNI and NLR and 5-year OS and RFS with relative HR plots. Kaplan-Meier survival curves
(with relative 95% CI and table of patients at risk) show OS and RFS according to the prognostic classes found for PNI and NLR with the X-tile analysis.


the generally adopted definition of lymphocytopenia (< 1.0                      lymphocytes. In addition, it is worth mentioning that lym-
103/microL). Below this threshold of “immunocompe-                              phocyte count was not associated with tumour grade, pT, or
tence”, a progressive increase in the risks of mortality and                    pN stage, thus configuring as a host-related factor. These
recurrence was reported, which was greater at lower lym-                        findings support the need for routine pre-operative screen-
phocyte counts. In contrast, no significant outcome changes                     ing for lymphocytopenia in patients with HNSCC, regard-
were observed (especially for OS) for > 1.08 103/microL,                        less of tumour characteristics. Furthermore, as recently
suggesting a plateau in the protective effect of circulating                    demonstrated in other smoking-related cancers 35,36, PNI is



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M. Tomasoni et al.




strongly correlated with tumour-infiltrating lymphocytes, a       In addition, pre-operative basophil count > 0 103/microL was
well-established prognostic marker even in HNSCC 7. This          an independent negative prognostic factor in terms of both
result suggests that PNI, and hence circulating lympho-           survival and recurrence risk. Few studies have investigated
cytes and albuminaemia, might reflect the host-tumour en-         the prognostic role of basophil count in solid tumours, none
vironment and the ability to effectively counteract tumour        in HNSCC, however always with mixed results 42,43. Further
growth and spread.                                                studies on the biological mechanism underlying the role of
                                                                  basophils in cancer immune evasion are strongly warranted.
Neutrophil-to-lymphocyte ratio
NLR has shown two major limitations: 1) its prognostic cut-       The immune-nutrition in modern head and neck
offs varied widely for each outcome with a questionable reli-     cancer surgery
ability in the daily practice since it appears to be inconsist-   Over the past 2 decades, a new consciousness has devel-
ent not only among survival outcomes of interest, but also        oped around the importance of the immuno-metabolic
among studies, as seen in the published meta-analyses 14,15;      characteristics of the cancer patient. Although the prognos-
2) it is calculated as the ratio of neutrophil to lymphocyte      tic importance of intervening on metabolic deficits, such
count, implying that increased neutrophil count and de-           as hypoalbuminaemia, has long been known, the concept
creased lymphocyte count play a synergistic role in defining      of immune-nutrition has only recently emerged. Immune-
the increased risk of mortality and/or disease recurrence.        nutrition is defined as an intervention aimed at modulating
However, in contrast to previous reports 33,34, we did not find   the immune system and inflammatory response through the
a significant association between neutrophil counts and any       administration of specific nutrients 8. Studies to date on the
survival outcome. Furthermore, higher neutrophil count            role of immuno-nutrition in patients undergoing surgery for
appeared to be related to hypopharyngeal, high-grade and          HNSCC are generally small or of low quality, as shown by
high-stage tumours, which are well-known tumour-related           the recent meta-analysis by Howes et al. 44. However, tar-
risk factors. These findings suggest that higher values of        geted nutritional interventions have been shown to decrease
pre-operative circulating neutrophils may be a consequence        the risk of complications and length of stay, especially in
of advanced, aggressive, pro-inflammatory tumours.                the setting of salvage surgery after exclusive (C)RT, and
Considering the strong prognostic role of lymphocyte              to reduce the risk of toxicity with improved tolerance and
count, the NLR as a prognostic tool for survival seems to         quality of life in patients undergoing adjuvant treatments 8.
depend solely on its denominator.                                 To understand which patients may benefit the most from
                                                                  interventions of immune-metabolic correction, many prog-
Other prognostic blood parameters                                 nostic indexes have been developed. In this view, PNI
Higher Hb was an independent predictor of better OS, con-         represents a reliable prognostic tool that provides an in-
firming previous experiences in HNSCC treatment 37,38.            dependent measure of pre-operative immuno-metabolic
Although a lower risk of disease recurrence was observed          performance in patients affected by HNSCC. Its validity
with increasing Hb, this correlation was not confirmed as         is supported by the independent prognostic role of albu-
independent.                                                      minaemia and lymphocyte count, from which it is derived.
Better OS was documented for platelet counts > 168 103/
microL, although not confirmed as independent. This result        Study strengths and limitations
is in contrast to what reported by a recent meta-analysis 39,     The present study provides a prognostic analysis of the two
in which increased mortality was demonstrated for higher          most relevant and widely studied indexes in head and neck
platelet counts. It is worth mentioning that most studies cat-    oncology, supported by a similar evaluation of each rou-
egorised platelet count into two prognostic classes. In this      tinely available blood parameter in the pre-operative set-
regard, Rachidi et al. 40 stratified patients according to mul-   ting. In addition, the analyses were conducted on a large
tiple cut-offs, showing the worst survival in patients with       multicentre cohort of highly selected patients with strict
low (< 150) and high (> 315) platelet counts, although only       inclusion criteria, followed regularly after treatment as rec-
the latter was an independent factor.                             ommended by the American Cancer Society.
A negative linear effect of MCV on OS and RFS was found,          On the other hand, the main limitation of the current study
although non-independent. The negative prognostic role of         is its retrospective design. Also, given the long observation
macrocytosis is confirmed by previous reports 41, and may         period, HNSCCs were staged according to the Seventh Edi-
be seen as an indicator of poor nutritional status associ-        tion of the American Joint Commission on Cancer TNM
ated with alcohol abuse, which is common in patients with         Staging System. However, due to the exclusion of HPV-
HNSCC.                                                            positive HNSCCs, the differences between the Seventh and



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Eighth Editions are quite limited. In addition, data on the                        view and meta-analysis. Head Neck 2018;40:2546-2557. https://doi.
                                                                                   org/10.1002/hed.25324
waiting time between the onset of the first symptoms and
                                                                              7
                                                                                   Borsetto D, Tomasoni M, Payne K, et al. Prognostic significance of
treatment were not available, a variable that could have in-                       CD4+ and CD8+ tumor-infiltrating lymphocytes in head and neck
fluenced the tumour stage and nutritional status of patients                       squamous cell carcinoma: a meta-analysis. Cancers 2021;13:781.
at the time of surgery. Finally, because we did not collect                        https://doi.org/10.3390/cancers13040781
data on comorbidities, we could not determine the potential                   8
                                                                                   Adiamah A, Lewis S. Is there a survival advantage of oral immunonu-
                                                                                   trition in head and neck cancer? Am J Clin Nutr 2020;112:1427-1428.
role of these variables on blood parameter values in our                           https://doi.org/10.1093/ajcn/nqaa306
cohort of patients.                                                           9
                                                                                   Onodera T, Goseki N, Kosaki G. Prognostic nutritional index in gas-
                                                                                   trointestinal surgery of malnourished cancer patients. Nihon Geka
Conflict of interest statement                                                     Gakkai Zasshi 1984;85:1001-1005.
The authors declare no conflict of interest.
                                                                              10
                                                                                   Hu Y, Shen J, Liu R, et al. Prognostic value of pre-treatment prognos-
                                                                                   tic nutritional index in non-small cell lung cancer: a systematic review
                                                                                   and meta-analysis. Int J Biol Markers 2018;33:372-378. https://doi.
Funding                                                                            org/10.1177/1724600818799876
This research did not receive any specific grant from fund-                   11
                                                                                   Borsetto D, Sethi M, Polesel J, et al. The risk of recurrence in surgi-
ing agencies in the public, commercial, or not-for-profit                          cally treated head and neck squamous cell carcinomas: a conditional
                                                                                   probability approach. Acta Oncol 2021;60:942-947. https://doi.org/1
sectors.                                                                           0.1080/0284186X.2021.1925343
                                                                              12
                                                                                   Camp RL, Dolled-Filhart M, Rimm DL. X-Tile: a new bio-infor-
Author contributions                                                               matics tool for biomarker assessment and outcome-based cut-point
MT, DB, PBR: study design and concept; MT, MCDM,                                   optimization. Clin Cancer Res 2004;10:7252-7259. https://doi.
                                                                                   org/10.1158/1078-0432.CCR-04-0713
GM, VG, PC, SP, PBR: data collection; MT, JP, PBR: data                       13
                                                                                   Kalbfleisch JD, Prentice RL. The statistical analysis of failure time
analysis; MT, CP, DB, PBR: writing and editing; CP, AD,                            data. Second edition. New York, NY: Wiley-Interscience; 2002.
PB, PN, PBR: critical revision.                                               14
                                                                                   Cho JK, Kim MW, Choi IS, et al. Optimal cutoff of pre-treatment neu-
                                                                                   trophil-to-lymphocyte ratio in head and neck cancer patients: a meta-
Ethical consideration                                                              analysis and validation study. BMC Cancer 2018;18:969. https://doi.
                                                                                   org/10.1186/s12885-018-4876-6
In accordance with Italian regulations, the consent to par-                   15
                                                                                   Yang L, Huang Y, Zhou L, et al. High pre-treatment neutrophil-to-
ticipate was obtained from all alive patients while it was                         lymphocyte ratio as a predictor of poor survival prognosis in head and
waived for those who were already dead. This study was                             neck squamous cell carcinoma: systematic review and meta-analysis.
performed in line with the principles of the Declaration of                        Head Neck 2019;41:1525-1535. https://doi.org/10.1002/hed.25583
                                                                              16
                                                                                   Bossi P. Prognostic Nutritional Index: an easy nutritional screening for
Helsinki. Approval was granted by the Ethics Committee of                          patients with head and neck cancer? ESMO Open 2018;3:e000449.
Treviso and Belluno provinces (Date March 23th 2020/No.                            https://doi.org/10.1136/esmoopen-2018-000449
773/CE Marca).                                                                17
                                                                                   Luan CW, Tsai YT, Yang HY, et al. Pre-treatment prognostic nutri-
                                                                                   tional index as a prognostic marker in head and neck cancer: a sys-
                                                                                   tematic review and meta-analysis. Sci Rep 2021;11:17117. https://
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     hed.24159                                                                      CD010954.pub2




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