10.14639/0392-100X-N1437
Objective. To report outcome and predictive factors in patients with N3 (&gt; 6 cm) nonmetastatic locally advanced head and neck squamous cell carcinoma (LAHNSCC) treated with a conservative approach or with initial surgery. Methods. 104 patients were included: 69 treated with radiotherapy (RT)   chemotherapy (CT) and 35 with nodal surgery with or without primary tumour resection, which was completed in 30 patients by adjuvant RT   CT. Positron-emission tomography-computed tomography (PET-CT) guided surveillance after RT   CT was standard. Results. Two-year overall survival (OS) and locoregional control (LRC) were 39.4% and 37.5%, respectively. In univariate analysis, body mass index (BMI), performance status (PS), p16 status and haemoglobin value influenced OS and disease-free survival (DFS). In multivariate analysis, p16 positive status and BMI ≥ 25 remained independent prognostic factors for better OS (p = 0.023) and DFS (p = 0.002). Only under/normal weight remained an independent and adverse significant prognostic factor in multivariate analysis for regional control (RC). Patients treated with primary RT   CT had slightly better 2-year OS (43.5% versus 33.3%, p = 0.31). Conclusions. Patients with N3 LAHNSCC have poor prognosis, but long term LRC is achievable, especially in overweight patients and those with a good PS.
text/xml
1827-675X
1437
en
Ulrike Schick
https://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
prognostic factors
N3 (> 6 cm) squamous cell carcinoma of the head and neck: outcomes and predictive factors in 104 patients
Text.Serial.Journal
https://www.actaitalica.it/
41
Head and neck
2021-07-07
2021-02-01
2021-07-08
2021-07-08
221-229
1
Ulrike Schick
2021/07/07
10.14639/0392-100X-N1437
221
Oncology Department, University Hospital, Brest, France; INSERM, UMR 1101, LaTIM, University of Brest, Brest, France
1827-675X
prognostic factors
229
N3 (> 6 cm) squamous cell carcinoma of the head and neck: outcomes and predictive factors in 104 patients
https://www.actaitalica.it/article/download/1437/620
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:221-229; doi: 10.14639/0392-100X-N1437




Head and neck


N3 (> 6 cm) squamous cell carcinoma of the head and
neck: outcomes and predictive factors in 104 patients
Il carcinoma squamocellulare della testa e collo con N3 (> 6 cm): risultati e fattori
prognostici in 104 pazienti
Selima Sellami1, Jean Christophe Leclere1,2, François Lucia1,3, Yves Gobel2, Arnaud Uguen4, Jean Rousset5,
Dominique Gouders6, Olivier Pradier1,3, Rémi Marianowski2, Ronan Abgral7, Ulrike Schick1,3
1
  Oncology Department, University Hospital, Brest, France; 2 Head and Neck Surgery Unit, University Hospital, Brest, France;
3
 INSERM, UMR 1101, LaTIM, University of Brest, Brest, France; 4 Pathology Unit, University Hospital, Brest, France; 5 Department
of Radiology, University Hospital of Brest and Military Hospital, Brest, France; 6 Radiation Oncology Department, Hospital de
Cornouaille, Quimper, France; 7 Nuclear Medicine, University Hospital, Brest, France


SUMMARY
Objective. To report outcome and predictive factors in patients with N3 (> 6 cm) non-
metastatic locally advanced head and neck squamous cell carcinoma (LAHNSCC) treated
with a conservative approach or with initial surgery.
Methods. 104 patients were included: 69 treated with radiotherapy (RT) ± chemotherapy
(CT) and 35 with nodal surgery with or without primary tumour resection, which was com-
pleted in 30 patients by adjuvant RT ± CT. Positron-emission tomography-computed to-
mography (PET-CT) guided surveillance after RT ± CT was standard.
Results. Two-year overall survival (OS) and locoregional control (LRC) were 39.4% and
37.5%, respectively. In univariate analysis, body mass index (BMI), performance status             Received: January 31, 2021
(PS), p16 status and haemoglobin value influenced OS and disease-free survival (DFS). In           Accepted: February 18, 2021
multivariate analysis, p16 positive status and BMI ≥ 25 remained independent prognostic
factors for better OS (p = 0.023) and DFS (p = 0.002). Only under/normal weight remained           Correspondence
an independent and adverse significant prognostic factor in multivariate analysis for re-          Selima Sellami
gional control (RC). Patients treated with primary RT ± CT had slightly better 2-year OS           Radiation Oncology Unit, University Hospital
(43.5% versus 33.3%, p = 0.31).                                                                    2 avenue Foch, 29200 Brest, France
Conclusions. Patients with N3 LAHNSCC have poor prognosis, but long term LRC is                    Tel. + 33 (0) 298223398. Fax + 33 (0) 298223087
                                                                                                   E-mail: selimasellami@hotmail.com
achievable, especially in overweight patients and those with a good PS.
KEY WORDS: N3 (> 6 cm), head and neck cancer, surgery, radiotherapy, prognostic factors            Funding
                                                                                                   None.
RIASSUNTO
Obiettivo. Analizzare i risultati e fattori predittivi in pazienti con carcinoma a cellule squa-   Conflict of interest
mose della testa e del collo localmente avanzato non metastatico con N3 (> 6 cm) (LAHN-            The Authors declare no conflict of interest.
SCC N3) trattati con un approccio conservativo o con intervento chirurgico
Metodi. Sono stati inclusi 104 pazienti: 69 trattati con radioterapia (RT) ± chemioterapia           How to cite this article: Sellami S, Leclere
(CT) e 35 con chirurgia linfonodale con o senza resezione del tumore primario, di cui 30             JC, Lucia F, et al. N3 (> 6 cm) squamous cell
pazienti con RT ± CT adiuvante. La sorveglianza dopo RT ± CT è stata eseguita mediante               carcinoma of the head and neck: outcomes and
tomografia computerizzata a emissione di positroni (PET-TC)                                          predictive factors in 104 patients. Acta Otorhi-
Risultati. La sopravvivenza globale (OS) a 2 anni e il controllo locoregionale (LRC) erano           nolaryngol Ital 2021;41:221-229. https://doi.
rispettivamente del 39,4% e del 37,5%. Nell’analisi univariata, l’indice di massa corporea           org/10.14639/0392-100X-N1437
(BMI), il performance status (PS), lo stato di p16 e il valore dell’emoglobina hanno influen-
zato l’OS e la sopravvivenza libera da malattia (DFS). Nell’analisi multivariata, la positi-       © Società Italiana di Otorinolaringoiatria
                                                                                                   e Chirurgia Cervico-Facciale
vità di p16 e il BMI ≥ 25 sono rimasti fattori prognostici indipendenti per una migliore OS
(p = 0,023) e DFS (p = 0,002). Lo stato di malnutrizione o normale status nutrizionale sono
                                                                                                                  OPEN ACCESS
rimasti fattori prognostici significativi indipendenti e negativi nell’analisi multivariata per
il controllo regionale (RC). I pazienti trattati con RT ± CT primaria avevano una OS a 2           This is an open access article distributed in accordance with
anni leggermente migliore (43,5% contro 33,3%, p = 0,31).                                          the CC-BY-NC-ND (Creative Commons Attribution-Non-
                                                                                                   Commercial-NoDerivatives 4.0 International) license. The
Conclusioni. I pazienti con LAHNSCC N3 hanno una prognosi sfavorevole, ma è possibile otte-        article can be used by giving appropriate credit and mentio-
nere un LRC a lungo termine, specialmente nei pazienti in sovrappeso e in quelli con un buon PS.   ning the license, but only for non-commercial purposes and
                                                                                                   only in the original version. For further information: https://
PAROLE CHIAVE: N > 6 cm, tumore della testa e del collo, chirurgia, radioterapia, fattori          creativecommons.org/licenses/by-nc-nd/4.0/deed.en
prognostici


                                                                                                                                                           221
S. Sellami et al.




Introduction                                                   • Surgery
                                                                 Surgery consisted of a unilateral or bilateral neck dissec-
Two-thirds of patients diagnosed with head and neck
                                                                 tion with or without a resection of the primary tumour.
squamous cell carcinoma (HNSCC) present with locally
                                                               • Chemotherapy
advanced stage III-IV disease at diagnosis. Among these,
                                                                 Induction CT (ICT) was considered in patients with
patients with metastatic lymph nodes measuring > 6 cm
                                                                 good performance status (ECOG: 0-1). Standard ICT
have a poor prognosis with a 2-year disease-free surviv-
                                                                 consisted of 2-3 cycles of PF (cisplatin (CDDP) and
al (DFS) of approximately 30%, especially because of
                                                                 5-fluorouracil (5FU) 800 mg/m2 every 3 weeks) or from
a high rate of distant metastases 1. Although it is gen-
                                                                 2011 TPF (docetaxel 75 mg/m2, CDDP 75 mg/m2 and
erally appreciated that the prognosis of such patients is
                                                                 5FU, 750 mg/m2 every 3 weeks) in selective fit patients.
poor, aggressive treatment improves survival and should
                                                                 Regarding concomitant CT, CDDP delivered every three
be considered even in patients with high tumour burden.
                                                                 weeks (100 mg/m2) was the standard regimen from
However, the optimal treatment strategy for large neck
                                                                 2011. In case of contraindications to CDDP, weekly car-
disease remains a controversial issue 2. Chemoradiother-
                                                                 boplatin (area under curve 2) or cetuximab were substi-
apy (CRT) has now been established as one of the stand-
                                                                 tuted. Before 2011, patients received either a FP regimen
ard of care for unresectable locally-advanced HNSCC
                                                                 consisted of 5-FU and CDDP at a 3 week interval.
(LAHNSCC) in multiple randomised trials 3, but outcome
                                                               • Radiotherapy
of patients with N3 (> 6 cm) are poorly defined as these
                                                                 The standard biologically equivalent dose in 2 Grays
patients represent only 10% of patients with LAHNSCC
                                                                 (Gy) fractions to the primary tumour and involved nodes
and are routinely combined with patients with smaller
                                                                 was typically 70 Gy. Prophylactic dose to uninvolved
nodes (N1-2) in clinical trials.
                                                                 nodes was 56 Gy in 28 fractions, although dose regimens
In this study, we aimed to report outcomes of patients with
                                                                 could slightly vary at the clinician’s discretion. Postop-
N3 LAHNSCC treated with definitive radiotherapy (RT)
and with upfront surgery to find prognostic factors in this      erative delivered dose was 66 Gy in case of extracapsu-
population.                                                      lar extension or positive margins. Patients were irradi-
                                                                 ated using a three-dimensional (3D) conformal RT or,
                                                                 from 2014, Intensity Modulated Radiotherapy (IMRT).
Materials and methods
                                                               Response assessment and follow-up
Patient population                                             To assess therapeutic response, computed tomography (CT)
All patients with histologically N3 LAHNSCC according          was performed 3 months after treatment completion until
to the 7th American Joint Committee on Cancer (AJCC)           2008, when these imaging modalities were substituted with
and treated with curative intent between 2005 and 2016         18-flurodeoxyglucose (18FDG) positron emission tomogra-
were retrospectively identified at our two institutions. As    phy (PET)-CT. Tumour response was accordingly assessed
the TNM classification was updated in December 2016,           based on the Response Evaluation Criteria in Solid Tumors
surgical patients were restaged following the 8th version:     1.1 (RECIST) or the Positron Emission Tomography Re-
in case of extracapsular extension, patients were clas-        sponse Criteria in Solid Tumors (PERCIST) 4.
sified as pN3b, while the others were classified pN3a.         Salvage neck dissection was considered after RT only in
Patients with nasopharyngeal or salivary gland cancer          the case of incomplete nodal response alongside with com-
were not considered. The need for informed consent was         plete response (CR) at the primary site.
waived by the medical ethics of our institution because        Clinical follow-up consisted of physical examination eve-
of the retrospective nature of the study at the time it was    ry second month until 2 years after diagnosis, every four
designed.                                                      months during the third year, and every six months up to
                                                               5 years.
Treatment characteristics
Treatment decisions were made at the weekly multidisci-        Statistical analysis
plinary team meeting. Of note, p16 status was not routinely    Isolated neck failure was defined as recurrence in the neck
performed at the time patients were treated and was retro-     after completion of treatment (i.e., including neck dissec-
spectively analysed for oropharyngeal tumours for the pur-     tion if done) or as unresectable persistent neck disease after
pose of this study. As such, the fact that some tumours were   treatment, with primary and distant disease control.
human papillomavirus (HPV)-driven did not influence the        Chi-square and Fisher’s exact tests were used to compare
therapeutic management.                                        variables between groups. Survival curves were plotted



222
                                                                                             Management of N3 (> 6 cm) head and neck cancer




based on the Kaplan-Meier method, and compared using            Table I. Patients and tumour characteristics.
the log-rank test. Impact of clinical variables (gender, age,    Characteristics                       Radiotherapy                  Surgery
body mass index (BMI), performance status (PS), smok-                                                       group                     group
ing habit, haemoglobin value (Hb), primary site, T stage,                                                  n = 69       %       n = 35        %
presence of extracapsular extension according to the 8th         Age: years and (range)                    62.1 (46.9-85.9)      63 (40.4-81.3)
AJCC version for patients treated with surgery, p16 status       Sex
and primary treatment modality (RT versus surgery) on              Male                                      65        94.2        32        91.4
overall survival (OS), regional control (RC), locoregional         Female                                     4         5.8         3         8.6
control (LRC) and DFS was analysed by univariate (UVA)           PS
and multivariate analysis (MVA). Statistical significance          0-1                                       41        59.4        17        48.6
was defined as a p value of < 0.05. A subgroup analysis on         2                                         28        40.6        18        51.4
patients with oropharyngeal tumours was also performed.          Smoking
                                                                   Nonsmoker                                 3         4.4         0         0.0
Results                                                            Ex-smoker                                 21        30.4        11        31.4
                                                                    Current smoker                           45        65.2        24        68.6
Patient and tumour characteristics                               BMI before treatment
One hundred and four patients with N3 (> 6 cm) LAHN-                < 18.5                                   7         10.1        2         5.7
SCC were indentified and included in the analysis. The ma-          18.5 -< 25                               26        37.7        15        42.9
jority of patients were male (93.3%) and had oropharyn-             25 -< 30                                 22        31.9         5        14.3
geal (38.5%) or hypopharyngeal (40.4%) cancer. Median               ≥ 30                                      6         8.7         2         5.7
age was 61.7 years (range, 40.4-85.9). There were no sig-           NA                                        8        11.6        11        31.4
nificant differences in baseline characteristics between pa-     Hb before CRT
tients treated with definitive radio(chemo)therapy and those        ≥ 13.5 (M) or 12.5 (F)                   20        28.9        7          20
treated with initial surgery, except for tumour size which          < 13.5 or 12.5                           32        46.4        9         25.7
was larger in patients who underwent RT (p =< 0.001;                NA                                       17        24.7        19        54.3
Tab. I). Median maximal lymph node diameter was 6.7 cm           Primary tumour site
(range 6-15).                                                       CUP                                       6        8.7         7          20
                                                                    Oral cavity                               5        7.2         3         8.6
Treatment characteristics                                           Oropharynx                                28       40.6        11        31.4
Two main groups of patients were identified: group 1 in-            Hypopharynx                               24       34.8        10        28.6
cluded patients who were not suitable for surgery (poor             Larynx                                     1        1.4         1         2.9
performance status, nodes or primary tumour unresectable)
                                                                    2 Sites                                    5        7.2         3         8.6
and were treated with concomitant CRT (n = 28, 40.6%),
                                                                 T stage
RT alone (n = 11, 15.9%), ICT followed by CRT (n = 23,
                                                                    T1-T2                                     11        15.9       16        45.7
33.4%), or ICT followed by RT alone (n = 7, 10.1%). Pa-
                                                                    T3-T4                                     52        75.4       12        34.3
tients in group 2 were treated by surgery, including surgery
                                                                    Tx (CUP)                                   6         8.7        7         20
alone (n = 5, 14.3%) because of adjuvant treatment refusal
                                                                 pN3 stage for group 2 (n = 35)
(n = 1), dramatically rapid tumour progression (n = 1),
postoperative complications (n = 2) or both (n = 1), sur-           pN3a                                       -         -         4       11.4
gery followed by CRT (n = 15, 42.9%) or RT alone (n = 11,           pN3b                                       -         -         31      88.6
31.4%), and surgery preceded by ICT and followed by              p16 status for OPC (n = 40)                       n = 29             n = 11
post-operative CRT (n = 4, 11.4%; Tab. II).                         Positive                                  8         27.6        2      18.2
                                                                    Negative                                  16        55.2        9      81.8
Treatment response                                                  NA                                         5        17.2        0        0
At the first evaluation 3 months after treatment comple-        PS: performance status; BMI: body-mass index; Hb: haemoglobin;
                                                                CRT: chemoradiotherapy; M: male; F: female; NA: not available; CUP: cancer of unknown
tion, all but 2 patients could be analysed for therapeutic      primary origin; OPC: oropharynx; HPC: hypopharynx; HPV: human papillomavirus.
response. Among these, 43 had a PET and 59 had a CT
to assess therapeutic response. Thirty-two patients (46.4%)
and 26 (34.8%) patients in group 1 and 14 (38.9%) and 14
(38.9%) patients in group 2 achieved a CR in the primary



                                                                                                                                               223
S. Sellami et al.




and nodal sites, respectively. Among the 40 patients who         Table II. Treatment characteristics.
achieved a nodal CR, 7 relapsed regionally during follow-         Treatment                                  Radiotherapy        Surgery group
up. Thirty-eight patients (36.5%) (25 in group 1 and 13 in                                                      group
group 2) achieved a CR at the primary site and the neck                                                    n = 69        %       n = 35       %
[including 8 carcinoma of unknown primary (CUP)], 21              Induction chemotherapy
(20.2%) achieved CR at the primary site only (including           Yes                                         30       43.5        4         11.4
5 CUP) and 35 (33.7%) did not achieve CR at either the               FP                                        5       16.7        3         75.0
primary site or in the neck.                                         TPF                                      24       80.0        1         25.0
Among the 21 patients who did achieve CR at the primary              Carboplatin-cetuximab                     1        3.3        0          0
site but not in the neck, 5 were diagnosed with metastatic        None                                        39       56.5        31        88.6
disease and therefore did not proceed to neck dissection,         Concomitant chemotherapy
8 patients were not eligible to neck dissection as the mass       Yes                                         51       73.9        19        54.3
was deemed unresectable, and 8 had a neck dissection                 CDDP                                     26       37.7        10        28.6
which showed proliferating cancer cells.
                                                                     Cetuximab                                15       21.7         3         8.6
                                                                     FP                                        8       11.6         5        14.3
Overall survival and disease-free survival
                                                                     Carboplatin                               2        2.9         1         2.9
Median follow-up of surviving patients was 49.0 months
                                                                  None                                        18       26.1        16        45.7
(range, 23.2-133.9). At last follow-up, 69 (66.3%) patients
had died of HNSCC, 5 following treatment complications            Radiotherapy
(4.8%), 10 (9.6%) of an unrelated cause (including 5 for          Yes/dose (Gy)/Fr                            66      95.7         30      85.7
other cancers), 4 (3.8%) were alive with disease and 16              30/10 + 25/10                             2        3.0         0        0
(15.4%) were alive and free of disease.                              60-66/30-33                               0         0         18      60.0
The 2- and 5-year OS rates were 39.4% and 20.0%, respec-             70/35                                    62      93.9         10      33.3
tively, while the median OS was 16.0 months (95% CI,                 Early stopping*                          2         3.1        2        6.7
10.4-21.6). The 2- and 5-year DFS rates were 29.0% and            None                                        0          0         5       14.3
18.3% respectively, and the median DFS was 6.2 months             Planned but not made*                       3        4.3          -        -
(95% CI, 4.2-8.1).                                                Radiation technique (n = 96)                   n = 66               n = 30
Patients treated with primary RT ± CT had slightly better         VMAT                                        8       12.1         0         0
OS than those treated with primary surgery with a 5-year          IMRT                                        26      39.4         11      31.4
OS of 23.2% (95% CI 12.4-34.0) vs 13.0% (IC95%, 0.8-              3D                                          32      48.5         19      54.3
26.8) and a median survival of 18.2 months (IC95 9.7-26.7)       FP : 5-fluorouracil (800mg/m2 days 2-5) + cisplatin (80 mg/m2 day 1); TPF: docetaxel
vs 14.9 months (95% CI, 9.0-20.9), but this difference was       (75 mg/m2 day 1), cisplatin (75 mg/m2 day 1) and 5FU (750 mg/m2 days 2-5); CDDP:
                                                                 cisplatin; Cet: cetuximab; Gy: Grays; Fr: fractions; VMAT: volumetric modulated arc
not statistically significant (p = 0.308).                       therapy; IMRT: intensity modulated radiotherapy; 3D: three dimensional radiotherapy
                                                                 *
                                                                   : due to worsening of the general state and/or obvious progression.
Locoregional and distant control
At last follow up, 74 of all patients (71.2%) exhibited treat-
ment failure: 61 patients (58.7%) experienced neck failure,      89.7 months (95% CI, 0.0-182.9) versus 9.9 months (95%
56 (53.8%) primary site failure and 37 (35.6%) distant           CI, 7.8-12.0) in favour of patients with p16 positive oro-
metastasis. Only 4 patients (3.8%) had isolated neck fail-       pharyngeal cancer. On MVA, p16 positive status remained
ure (Tab. III). In summary, 82.4%, 75.7% and 50.0% of            independently correlated with better OS (p = 0.023; Fig. 1;
all cases of failures involved regional relapse, local relapse   Tab. IV).
and distant metastasis, respectively. The 2- and 5-year LRC      Regarding DFS, the same prognostic factors for better sur-
rates were 37.5% (95% CI, 27.7-47.3) and 29.8% (95% CI,          vival were found, while only overweight/obesity remained
19.2-40.4), respectively.                                        an independent prognostic factor in MVA (p = 0.002).
Neither RC nor LRC were influenced by the therapeutic            The UVA for RC showed that BMI ≥ 25, PS 0-1 and hae-
modality (p = 0.963 and 0.857 respectively).                     moglobin values were statistically significant, while being
                                                                 overweight (p = 0.001) and having a good general state
Prognostics factors                                              (p = 0.009) remained independent prognostic factors in
On UVA, BMI ≥ 25, PS 0-1, positive p16 status and Hb             MVA, with a 5-years RC of 59.5% (95% CI, 42.7-76.3) for
values ≥ 13.5 for men and ≥ 12.5 for women were found            overweight/obese patients vs 28.6% (95% CI, 15.0-42.2)
to significantly influence OS, with a median survival of         for normal/underweight patients (Fig. 2).



224
                                                                                                      Management of N3 (> 6 cm) head and neck cancer




Table III. Status at last follow up.
 Status at last follow-up                                                    Radiotherapy group              Surgery                     All
                                                                                                              group
 Progression / Site of failure                                                   49 (71.0%)                25 (71.4%)                74 (71.7%)
   Isolated primary                                                                   1                         0                         1
   Isolated nodal                                                                     3*                        1                         4
   Primary and nodal                                                                 20#                        6                        26
   Primary and nodal (without distant reassessment)                                   3                         3                         6
   Primary nodal and distant                                                         13 *                       4                        17
   Primary and distant                                                                3*                        3                         6
   Nodal and distant                                                                  4                         4                         8
   Isolated distant                                                                   2                        4*                         6
 Without failure                                                                  20 (29%)                 10 (28.6%)                30 (28.3%)
   Remission                                                                         12                         4                        16
   After completion of initial treatment                                             10                         4                        14
   After salvage ND                                                                   2                         0                         2
   Death due to treatment’s complications                                             2                         3                         5
   Death – other reasons                                                              6                         3                         9
*
  : one still alive with disease; #: one died of pulmonary cancer
ND: neck dissection.




Figure 1. Kaplan-Meier curve for overall survival based on p16 expression.   Figure 2. Kaplan-Meier curve for regional control based on body mass index.


LRC was significantly better in overweight/obese patients,                   by the administration of ICT (p =0.339 and p = 0.837,
in patients with PS 0-1, in those having haemoglobin values                  respectively).
≥ 13.5-12.5g/dl and in case of p16 positive status, but only                 In the subgroup analysis, among patients diagnosed with
BMI ≥ 25 remained an independent prognostic factor (55.0%                    oropharyngeal cancer, we found a significant difference
vs 15.3% at 5-year (p = 0.002); supplementary Tab. I).                       for patients with p16 positive tumours in terms of OS for
We also studied prognostic factors in patients treated                       group 1 (62.5% vs 6.3% at 5 years, p = 0.011) whereas this
with definitive RT. Age ≥ 62 years, BMI ≥ 25, PS 0-1,                        survival advantage was not found for patients treated with
haemoglobin value and p16 positive status conferred                          primary surgery (p = 0.363).
significantly better OS. On MVA, age, PS and p16 status
remained independent prognostic factors for survival.
Regarding LRC, only BMI ≥ 25 remained an independ-
                                                                             Discussion
ent factor on MVA. Neither OS nor LRC was influenced                         We found a relatively poor 5-year OS of 20% in this large



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S. Sellami et al.




Table IV. Uni- and multivariate analysis for overall survival.
 Variables                                                              Univariate analysis                          Multivariate analysis
                                                                 HR             95% IC              p         HR          95% IC              p
 Patients parameters
    Sex (male versus female)                                     0.70         (0.26-1.92)         0.494
    Age (> 62 vs ≤ 62)                                           1.36         (0.88-2.11)         0.162
    BMI (< 25 vs ≥ 25)                                           2.45         (1.43-4.18)         0.001       1.36      (0.30-6.15)          0.686
    PS (≥ 2 vs 0-1)                                              3.82         (2.36-6.18)        < 0.001      2.48      (0.85-7.25)          0.095
    Smoking (active vs none or past)                             1.33         (0.84-2.12)         0.226
    Hb (< 13.5 or 12.5)                                          2.21         (1.23-3.98)         0.008       0.79      (0.22 2.78)          0.714
 Tumour parameters
    Site (others vs oropharynx)                                  0.97         (0.62-1.52)         0.911
    T stage (T3-4 vs T1-2)                                       1.22         (0.77-1.92)         0.397
    N stage (pN3b vs pN3a)                                       1.95         (0.46-8.31)         0.366
    p16 status (+ vs -)                                          0.26         (0.09-0.70)         0.008       0.17      (0.04-0.78)          0.023
 Treatment
 Surgery vs radiotherapy                                         1.22         (0.78-1.92)         0.383
Hb: haemoglobin; BMI: body-mass index; PS: performance status.



cohort of patients treated for HNSCC with N3 (> 6 cm).                            The majority of failures were locoregional in our cohort,
This is consistent with previous series reporting on out-                         and the rate of distant metastasis (35.6%) was the same
comes after CRT 2,5,6 and surgery 7. Primary surgery does                         to that found in other series 1,2,5,10-12. Indeed, these patients
not seem to influence outcomes compared to RT ± CT. As                            are at high risk of having clinically occult micrometastat-
such, radiation-based conservative treatment with PET-                            ic disease on presentation and this raises the question on
guided surveillance does seem appropriate even in very                            the benefit of ICT to reduce the rate of distant metastasis.
advanced regional disease.                                                        We did not find any benefit of ICT and this is in line with
This is in agreement with a retrospective series of 69 pa-                        recent randomised trials which failed to show a survival
tients with N3 (> 6 cm) treated with definitive RT ± CT                           benefit of ICT in combination with CRT 13-15. The recent
(n = 42) or surgery (n = 27), without any significant differ-                     phase III trial of the French GORTEC group which tested
ence in 3–year OS (48% vs 41%, respectively) 2.                                   the benefit of induction TPF chemotherapy followed by RT
Because nodes > 6 cm were deemed to be unlikely eradi-                            associated with cetuximab over CRT specifically in N2b-
cated by non-surgical means alone, neck dissection after RT                       N3 patients suggests that the rate of distant metastases is
was historically recommended in patients with N2-N3 dis-                          decreased by the use of ICT, but without improvement in
ease. More recently, the integration of PET-CT has improved                       OS (p = 0.48) 16.
the accuracy of response assessment in the setting of residual                    Many other therapeutic strategies are currently being tested
nodal disease thanks to its high negative predictive value 8.                     with the aim to improve outcomes in patients with LAHN-
On the basis of data from the recent British phase III PET-                       SCC, such as RT dose escalation, gemcitabine-based
NECK trial, the strategy of systematic planned neck dissec-                       chemoradiation 17, altered fractionation with hypoxic cells
tion after RT is no longer justified in patients who achieve                      radiosensitiser (NCT01880359) and, more recently, immu-
a CR on PET-CT at 3 months following RT completion 9.                             notherapy in combination with RT. Indeed, immune check-
However, N3 (> 6 cm) patients represented only 17 of the                          point inhibitors have become a standard in the treatment of
564 patients included in this trial, making it difficult to draw                  recurrent or metastatic HNSCC and are now being tested
any conclusion on this subgroup of patients.                                      prospectively in the locally-advanced setting. Through im-
In our study, the rate of isolated neck failure (3.8%) was                        munogenic cancer cell death and effect on the tumour mi-
low. These results suggest the high negative predictive                           croenvironment and vasculature, RT may enhance the ef-
value of PET still seems to be maintained with nodes > 6                          fect of immune checkpoints inhibitors 18.
cm and that planned neck dissection is unnecessary even in                        The role of PS is widely known to predict response to treat-
patients with large nodes > 6 cm if they achieve metabolic                        ment and survival 19. More surprising is the positive im-
CR. This is in agreement with other studies 8,10.                                 pact of BMI ≥ 25 kg/m2 on outcomes. Historically, studies



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have demonstrated that patients with low BMI have worse         mours were treated with initial surgery, and p16 positive
outcome 20, an expected finding given the poor nutritional      tumours were also more represented in the RT group, and
status of underweight patients. However, those studies did      this may have influenced outcomes.
not address whether overweight patients have better sur-
vival rates than normal weight patients. We found that be-      Conclusions
ing overweight (BMI ≥ 25) at diagnosis conferred a signifi-
cantly better prognosis with a 5-years LRC of 55% versus        Patients with N3 (> 6 cm) LAHNSCC have poor prognosis,
15% in favour of overweight patients.                           but long term LRC is achievable, especially in those with a
This observation has already been reported in a study of        good performance status and BMI ≥ 25, and long term sur-
578 patients with HNSCC, showing that higher BMI was            vival is possible for patients with HPV-related oropharyn-
associated with drastically better survival (p < 0.001) with    geal cancer.
5-year OS rates ranging from 33.8% in underweight to
74.8% and 76.0% in overweight and obese patients, respec-       References
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Supplementary Table I. Uni- and multivariate analysis for regional and locoregional control.
 Regional control                                                  Univariate analysis                               Multivariate analysis
                                                                 HR          95% IC              p           HR           95% IC              p
 Patient parameters
    Sex (male vs female)                                         0.66      (0.20-2.09)          0.477
    Age (> 62 vs ≤ 62)                                           1.15      (0.69-1.92)          0.585
    BMI (< 25 vs ≥ 25)                                           2.59      (1.39-4.81)          0.003       3.93        (1.69-9.12)          0.001
    PS (≥ 2 vs 0-1)                                              3.62      (2.11-6.23)         < 0.001      2.60        (1.27-5.33)          0.009
    Smoking (active vs none or past)                             1.18      (0.68-2.06)          0.549
    Hb (< 13.5 or 12.5)                                          2.05      (1.03-4.05)          0.039       1.39        (0.66-2.90)          0.384
 Tumour parameters
    Site (others vs oropharynx)                                  0.90      (0.54-1.51)         0.701
    T stage (T3-4 vs T1-2)                                       1.48      (0.86-2.55)         0.161
    N stage (pN3b vs pN3a)                                       0.94      (0.21-4.11)         0.931
    p16 status (pos vs neg)                                      0.37      (0.12-1.12)         0.079
 Treatment
   Surgery vs radiotherapy                                       0.96      (0.55-1.67)         0.894
 Locoregional control                                                   Univariate analysis                          Multivariate analysis
                                                                 HR          95% IC              p           HR           95% IC              p
 Patient parameters
    Sex (male vs female)                                         0.57      (0.18-1.83)          0.348
    Age (> 62 vs ≤ 62)                                           1.17      (0.72-1.90)          0.525
    BMI (< 25 vs ≥ 25)                                           2.67      (1.47-4.85)          0.001       6.87       (2.01-23.45)          0.002
    PS (≥ 2 vs 0-1)                                              3.35      (2.01-5.58)         < 0.001      1.80        (0.55-5.84)          0.328
    Smoking (active vs none or past)                             1.20      (0.72-2.02)          0.486
    Hb (< 13.5 or 12.5)                                          1.91      (0.12-3.57)          0.042       0.84        (0.19-3.81)          0.826
 Tumour parameters
    Site (others vs oropharynx)                                  0.92      (0.57-1.50)         0.741
    T stage (T3-4 vs T1-2)                                       1.50      (0.90-1.51)         0.118
    N stage (pN3b vs pN3a)                                       1.01      (0.23-4.40)         0.992
    p16 status (pos vs neg)                                      0.30      (0.10-0.89)         0.03         0.41        (0.07-2.53)          0.337
 Treatment
    Surgery vs radiotherapy                                      1.05      (0.62-1.76)         0.857
Hb: haemoglobin; BMI: body-mass index; PS: performance status.




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