10.14639/0392-100X-N2223
Nasopharyngeal carcinoma (NPC) is the most interesting and intriguing malignant tumour located in the nasopharynx, because it is a “peculiar” malignancy, “different” from almost all the other head and neck tumours according to several points of view. Given that radiotherapy (RT) is the treatment of choice for NPC, chemotherapy (CT) has been added to standard RT to improve outcome in high-risk patients, either as an adjuvant, neoadjuvant or concurrent treatment modality with radiation. Surgery plays an important role in rescuing recurrent or persistent disease after primary (CT)RT. This second part of the review provides a critical analysis of various treatment described in the literature, both for primary cancer and for regional and distant metastases. The prognostic factors and the final results of the various treatments will also be analysed.
text/xml
1827-675X
2223
en
Giulio Cantù
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
prognosis
Nasopharyngeal carcinoma. A “different” head and neck tumour. Part B: treatment, prognostic factors, and outcomes
Text.Serial.Journal
https://www.actaitalica.it/
43
Reviews
2023-05-16
2022-07-13
2023-05-19
2023-05-19
155-169
1
Giulio Cantù
2023/05/16
10.14639/0392-100X-N2223
155
Former Director of Otorhinolaryngology and Cranio-Maxillo-Facial Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
1827-675X
prognosis
en
169
Nasopharyngeal carcinoma. A “different” head and neck tumour. Part B: treatment, prognostic factors, and outcomes
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ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43:155-169; doi: 10.14639/0392-100X-N2223




Review


Nasopharyngeal carcinoma.
A “different” head and neck tumour.
Part B: treatment, prognostic factors, and outcomes
Carcinoma rinofaringeo. Un tumore della testa e collo “diverso”.
Parte B: trattamento, fattori prognostici e risultati a distanza
Giulio Cantù
Former Director of Otorhinolaryngology and Cranio-Maxillo-Facial Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy


SUMMARY
Nasopharyngeal carcinoma (NPC) is the most interesting and intriguing malignant tumour
located in the nasopharynx, because it is a “peculiar” malignancy, “different” from almost
all the other head and neck tumours according to several points of view. Given that radio-
therapy (RT) is the treatment of choice for NPC, chemotherapy (CT) has been added to
standard RT to improve outcome in high-risk patients, either as an adjuvant, neoadjuvant
or concurrent treatment modality with radiation. Surgery plays an important role in rescu-
ing recurrent or persistent disease after primary (CT)RT. This second part of the review
provides a critical analysis of various treatment described in the literature, both for primary
cancer and for regional and distant metastases. The prognostic factors and the final results
of the various treatments will also be analysed.
KEY WORDS: nasopharyngeal carcinoma, intensity-modulated radiotherapy, endoscopic
surgery, prognostic factors, prognosis

RIASSUNTO
Il carcinoma rinofaringeo è il più interessante fra i tumori maligni che insorgono nel ri-
nofaringe, perché è un tumore “peculiare”, “diverso” da quasi tutti gli altri tumori della
testa e collo secondo molti punti di vista. La radioterapia è il trattamento di scelta ma
                                                                                                    Received: July 13, 2022
la chemioterapia è stata aggiunta con l’intento di migliorare la prognosi dei pazienti a            Accepted: January 8, 2023
rischio, sia in modalità adiuvante, neo-adiuvante o concomitante. La chirurgia gioca un
ruolo importante nel recupero delle recidive o delle persistenze di malattia. Questa seconda        Correspondence
parte della review presenta un’analisi critica dei vari trattamenti descritti in letteratura, sia   Giulio Cantù
per il tumore primitivo che per le metastasi regionali e a distanza. Saranno analizzati anche       via Milano 36, 20846 Macherio (MB), Italy
i fattori prognostici e i risultati a distanza dei vari trattamenti.                                E-mail: gcantu43@gmail.com
PAROLE CHIAVE: carcinoma rinofaringeo, radioterapia, chirurgia endoscopica, fattori
prognostici, prognosi                                                                                 How to cite this article: Cantù G. Naso-
                                                                                                      pharyngeal carcinoma. A “different” head
                                                                                                      and neck tumour. Part B: treatment, prog-
                                                                                                      nostic factors, and outcomes. Acta Otorhi-
                                                                                                      nolaryngol Ital 2023;43:155-169. https://doi.
Treatment                                                                                             org/10.14639/0392-100X-N2223
Primary local-regional disease
                                                                                                    © Società Italiana di Otorinolaringoiatria
Both surgery and chemo-radiotherapy (CT-RT) play an important role in the pri-                      e Chirurgia Cervico-Facciale
mary treatment of cancers of almost any location in the head and neck. Surgery
is preferred to RT in some sites and vice versa in others. For some sites, both                                    OPEN ACCESS
surgeons and chemo-radiotherapists claim the right to the primogeniture. On the                     This is an open access article distributed in accordance with
                                                                                                    the CC-BY-NC-ND (Creative Commons Attribution-Non-
contrary, there is no discussion about the primary treatment of nasopharyngeal                      Commercial-NoDerivatives 4.0 International) license. The
carcinoma (NPC). Apart from the indication for surgery for few rare histologic                      article can be used by giving appropriate credit and mentio-
                                                                                                    ning the license, but only for non-commercial purposes and
forms as minor salivary glands tumours, RT is the backbone of treatment for                         only in the original version. For further information: https://
NPC. Due to its radiosensitive behaviour and deep-seated anatomic location,                         creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                            155
G. Cantù




RT has been established as the primary treatment since the        tastases in regions III and IV of the neck, the thyroid gland is
1950s 1,2. In 1992, Lee et al. 3 analysed as many as 5,037        inevitably irradiated due to its proximity to the lymph nodes
cases treated with RT in the period 1976-1985, and wrote:         in the neck” 7.
“Because of its peculiar predilection for southern Chinese,       Particle therapy (protons and carbon ions) is gaining popu-
large series consisting of more than 1,000 patients were          larity, mainly when it is added as a boost for locally ad-
all reported from Oriental centres. Prospective randomised        vanced disease 8. The newest form of proton beam therapy
studies have rarely been conducted in the East because of         is intensity-modulated proton radiation therapy (IMPT),
resource limitations, and in the West because of insufficient     also known as “pencil beam proton therapy”. It is a sophis-
number of patients. Almost all the claims on improvement of       ticated mode of proton therapy that is analogous to IMRT
treatment results were based on comparison with historical        and an active area of investigation in cancer care. Li et al.
data”. Although the treatment in those years was made with        stated : “It has been found to significantly reduce the com-
conventional two-dimensional (2D-RT) or three-dimension-          plication probability of key surrounding normal tissues,
al RT (3D-RT), Lee et al. underlined that “wide field cover-      including parotid glands, inner ears, larynx, oral cavity,
age, high tumour dose, and technical accuracy were empha-         and esophagus, thereby being considered to be a promis-
sized in our radiation therapy for NPC” 3.                        ing irradiation modality pursuing a better QOL for patients
Nowadays, intensity-modulated RT (IMRT) has become                with NPC” 9. In a review on the IMPT, Moreno et al. wrote:
the gold standard in the management of NPC, providing en-         “Several dosimetric studies have demonstrated the superi-
hanced outcomes and less severe toxicities compared with          ority of IMPT over IMRT to improve dose sparing of near-
previous RT techniques. In a recent study, the authors found      by organs such as the larynx, salivary glands, and esopha-
10 publications meeting the criteria for their meta-analysis      gus. Evidence of the clinical translation of these dosimetric
and including 13,304 patients, of whom 5,212 received IM-         advantages has been demonstrated with documented tox-
RT and 8,092 were treated with 2D-RT 4. Compared with             icity reductions (such as decreased feeding tube depend-
2D-RT treatment, the IMRT group was associated with a             ency) after IMPT for patients with head and neck cancer
better 5-year overall survival (OS), local-regional free sur-     (HNC)” 10. However, in the literature there are few clinical
vival (LRFS), progression-free survival (PFS), and distant        studies and small series on the use of IMPT in the treatment
metastasis-free survival (DMFS). Additionally, the incidence      of NPC. Taheri-Kadkhoda 11 et al. presented 8 cases, and
of late toxicities such as xerostomia, trismus and temporal       Lewis et al. 12 treated with IMPT 10 patients. Both studies
lobe neuropathy for NPC patients in IMRT group was signif-        concluded that “The practicality of IMPT in NPC deserves
icantly lower than in 2D-RT group. However, the side effects      further exploration when this technique becomes available
are not negligible even in patients treated with IMRT, mainly     on wider clinical scale” 11, and “We observed dosimetric
in those with advanced tumours treated with high radiation        advantages conferred by IMPT compared to IMRT. Further
dose. In a series of 80 patients with T4 NPC treated with CT-     study is needed to determine if these translate into reduced
IMRT (70.4 Gy), Kong et al. 5 reported 6 cases of radiation-      toxicity and/or improved disease control” 12. One problem
induced temporal lobe necrosis, 16 cases of hearing loss and      with the systematic use of the IMPT in some countries is
2 cases of cranial nerve palsy. Huang et al. 6 conducted an       the availability of operational proton centres and its high
observational, cross-sectional study of quality of life (QOL)     cost (about 3.2-4.8 times that of IMRT). For example, Li
and late toxicities in 242 patients with NPC with survival of     et al. 9 made a theoretical analysis of the cost-effectiveness
> 5 years after treatment with IMRT (n = 100) or non-IMRT         of IMPT in China. China, despite having the largest global
(n = 142). They found that the IMRT group had both statisti-      amount of NPC cases (about 44,600 cases, that is 80% of
cally and clinically better outcomes in global QOL, cogni-        the newly diagnosed NPC cases worldwide), has only one
tive functioning, social functioning and fatigue than the 2D-     operational proton centre, although the government has au-
RT group. However, they reported that 34.0% of survivors          thorised 16 new ones. The authors concluded that: “IMPT
suffered from symptomatic xerostomia and 22.0% from dys-          has potential to be cost-effective for average Chinese NPC
phagia after IMRT. In a recent study, Weng et al. found that      patients and should be validated clinically”.
the late incidence of hypothyroidism in their patients treated    Since the 1970s, CT has been added to standard RT in some
with IMRT was 38%, higher than that previously reported in        centres to improve outcomes in high-risk patients, either
the era of 2D-RT (14%). The authors speculated that “In the       as adjuvant (AC) 13, neoadjuvant (induction chemotherapy,
pursuit of better local control rates, increasing the dose of     ICT) 14, or concurrent treatment with radiation (CRT) 15. AC
radiotherapy to the target area in clinical practice has led to   was tested also in childhood with contradictory results, ei-
increased radiotherapy complications. Although IMRT can           ther with improvement 16 or worsening 17 of the cure rate. A
delineate the thyroid gland in patients with lymph node me-       randomised clinical trial demonstrated that CRT was asso-



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ciated with a considerable survival benefit for patients with    tried to determine whether IC with paclitaxel, cisplatin, and
stage II NPC 18. In a meta-analysis performed in 2002 to         capecitabine (TPC) improves survival vs. PF prior to CRT
evaluate the impact of integrating CT with RT, Huncharek         for patients with stage IVA to IVB NPC 25. The authors
et al. 19 identified six randomised controlled trials (RCTs)     found that combined ICT regimen with 2 cycles of TPC
enrolling more than 1,500 patients and comparing CRT vs          for patients with stage IVA and IVB NPC improved fail-
RT alone. Pooling all six studies, the meta-analysis demon-      ure-free survival (FFS) compared with 2 cycles of PF, with
strated that concurrent CRT increased disease-free/pro-          no increase in the toxicity profile.
gression-free survival by 37% at 2 years, 40% at 3 years,        Another controversial issue is the ideal number of ICT cy-
and 34% at 4 years after treatment.                              cles. In another network meta-analysis, Li et al. 26 found
Nowadays, the standard treatment for stage I disease is RT       10 propensity score-matching studies investigating ICT +
alone 20. A systematic review and meta-analysis found 11         CRT, which included 1,431 participants. In almost all of
comparative studies (2,138 patients) on the treatment of pa-     these studies, patients underwent 2-3 cycles of ICT given
tients with stage II NPC and concluded that CRT was better       every 3 weeks. In none of the reported studies was the dura-
than 2D-RT alone with significant benefit in LRFS, while         tion of treatment with ICT specified and any lengthening of
IMRT alone was superior to CRT, with equivalent survival         the intervals between one cycle and another due to toxicity.
outcomes and fewer grade 3-4 acute toxicities 21. Stage III      However, the authors concluded that “The results showed
and IV without distant metastasis are treated by CRT with        that therapeutic strategies based on ICT + CRT may be rec-
cisplatin 20.                                                    ommended as the most effective treatment to improve OS
Because distant metastases are a major cause of treatment        and DMFS, but not LRFS”.
failure and death, intensification of systemic treatment has     It should be noted that some studies demonstrated that
been tested in several studies. A phase III RCT demonstrat-      another advantage of ICT is the possibility to reduce the
ed that AC with cisplatin and fluorouracil after CRT was         IMRT target volume without reducing the rates of local
difficult to complete for heavy adverse events and did not       control and survival in loco-regionally advanced NPC; the
significantly improve failure-free survival in loco-regional-    doses received by normal tissues can be decreased, and
ly advanced NPC 22.                                              QoL scores may improve 27.
A recent phase III trial compared ICT with gemcitabine           Hence, it is established that ICT improves prognosis of
and cisplatin plus CRT with CRT alone, and concluded             patients with advanced NPC; but, how can this treatment
that ICT and CRT significantly improved LRFS and OS,             interfere with the initiation of CT-RT? Two recent studies,
as compared with CRT alone, among patients with loco-            made by the same team on patients treated in the same Chi-
regionally advanced NPC 23.                                      nese Medical University Cancer Hospital, are paradigmatic
However, as many ICT regimens have been proposed over            of the pros and cons of a ICT that is too prolonged 28,29.
the years, Liu et al. 24 have recently performed a network       In the first study, the authors analysed 498 patients with
meta-analysis on this topic. The fundamental criterion for       locoregionally advanced NPC (LANPC) treated with 2-3
the inclusion of studies was that they were RCTs. In the         cycles of ICT plus CRT. All patients underwent naso-
initial database search, they identified as many as 1,789        pharyngeal and neck MRI at initial diagnosis and after two
records, and thereafter excluded 37 duplicates and 976 ir-       cycles of ICT. Two independent clinicians reviewed the
relevant articles. After reviewing the titles and abstracts of   images for evaluation of tumour response; 340 (68.3%)
the remaining 776 studies, 35 were screened in full-text.        patients were judged to have had a complete (CR) or par-
They excluded 3 phase II RCTs, 1 phase III RCT with pae-         tial (PR) response to treatment, and 158 (31.7%) patients
diatric patients, and 24 articles failing to meet their inclu-   had stable disease (SD) or progressive disease (PD). The
sion criteria. The remaining RCTs, involving 2,496 patients      5-year OS, LRFS, DMFS and PFS rates for SD/PD vs CR/
treated with different regimens of ICT, were enrolled in the     PR were 60.6% vs 84.0% (p < 0.001), 85.1% vs 94.3%
meta-analysis. The different regimens were: gemcitabine          (p < 0.001), 67.7% vs 85.0% (p < 0.001) and 49.7% vs
plus cisplatin (GP), paclitaxel plus carboplatin and gem-        76.4% (p < 0.001). Tumour response was an independent
citabine (GCP), mitomycin, epirubicin, cisplatin, fluoro-        prognostic factor 28. The second study included 648 patients
uracil plus leucovorin (MEPFL), cisplatin plus fluorouracil      with LANPC treated with ICT followed by CRT and ex-
(PF), capecitabine plus cisplatin (PX), and docetaxel plus       plored the prognostic significance of wait time for radical
cisplatin and fluorouracil (TPF). The analysis revealed that     RT. Authors stated: “Compared with those receiving two
the combined IC regimen of GP gained not only the most           cycles of ICT, patients with three cycles tended to have a
favourable OS benefit, but also longer DMFS and man-             wait time exceed 75 days (p < 0.001)”, and: “Moreover, we
ageable adverse events (AEs). An even more recent RCT            found older patients (≥ 50 years) were generally more as-



                                                                                                                             157
G. Cantù




sociated with prolonged wait time”. A worse 5-year DMFS          As stated above, post-attinic toxicity remains high, despite
rate (76.5% vs 83.9%, p = 0.023) was found in patients           the notable improvements after the introduction of IMRT.
with a prolonged wait time (≥ 75 days) than those with an        In order to avoid these problems, in 2019 Liu et al. 33 pre-
acceptable wait time (≤ 75 days) 29. To support this concept,    sented their initial experience with endoscopic nasophar-
He et al. demonstrated that two and three cycles of ICT are      yngectomy (ENPG) alone in stage I NPC, aiming to assess
associated with similar survival, while four cycles reduce       the efficiency and cost-effectiveness of such treatment as an
survival and increase treatment-related toxicity in endemic      alternative for IMRT in T1N0M0 NPC. The indication cri-
regions 30.                                                      teria for ENPG were: a maximum diameter of the primary
A recent network meta-analysis (20 trials and 5,144 pa-          tumour ≤ 1.5 cm, distance of the tumour margin to the in-
tients) tried to establish the best timing of the systemic       ternal carotid artery ≥ 0.5 cm, an axial diameter at MRI no
treatment 31. The authors identified seven treatments: RT        more than 0.4 cm for retropharyngeal lymph nodes (RLNs)
alone, which was used as the reference category; ICT fol-        and 0.6 cm for cervical lymph nodes (CLNs). Such small
lowed by RT (ICT-RT); RT followed by AC (RT-AC); ICT             tumours are rare; however, they stated: “With the popular-
followed by RT followed by AC (IC-RT-AC); CRT; ICT               ity of health education and the development of early cancer
followed by CRT (ICT-CRT); and CRT followed by AC                screening in NPC, an increasing number of NPC patients
(CRT-AC). The conclusion was that the addition of AC to          with early stage cancer were screened and diagnosed” 33. In
CRT achieved the highest survival benefit and consistent         the study by Liu et al, 10 newly diagnosed stage I NPC pa-
improvement for OS, PFS and distant control (DC). The            tients voluntarily received ENPG alone from June 2007 to
addition of ICT to CRT achieved the highest effect on DC.        September 2017 33. Simultaneously, the data of 329 stage I
Regarding toxicities, this network meta-analysis confirmed       NPC patients treated with IMRT were collected and used as
that the treatments with AC (CRT-AC and RT-AC) were the          a reference cohort. The survival outcomes, QOL and medical
most toxic regimens for mucositis/hearing loss and neutro-       costs between two groups were compared. After a median
penia/weight loss, which underlines the potential toxicity       follow-up of 59 months, no death, locoregional recurrence,
of AC, either alone or administered with CRT.                    or distant metastasis was observed in patients treated with
Given the jumble of results, the ESMO-EURACAN Clini-             ENPG. In addition, compared with IMRT, ENPG was asso-
cal Practice Guidelines stated: “As a prerequisite, ICT          ciated with decreased total medical costs and improved QOL
added to CRT should not hinder the subsequent delivery of        scores including dry mouth and sticky saliva. Correctly, the
full-dose CRT, and the time between the end of ICT and the       authors concluded that: “ENPG alone was associated with
start of RT should be kept as short as possible” 8.              promising long-term survival outcomes, low medical costs,
The NCCN guidelines conclude that the addition of CT to          and satisfactory QOL and might therefore be an alternative
CRT is indicated in patients with loco-regionally advanced       strategy for treating newly diagnosed localized stage I NPC
NPC, but it is not clear whether before or after CRT 20.         patients who refuse radiotherapy. However, the application
Given the aforementioned high frequency of neck lymph            of ENPG should be prudent, and prospective clinical trials
nodes (LN) metastases, radiation oncologists traditionally       are needed to further verify the results” 33.
treated all neck levels comprehensively with definitive-in-      In order to avoid or reduce post-attinic toxicity, a recent
tent or prophylactic RT. In 2009, Tang et al. 32 compared        study proposed a different strategy: ENPG combined with
the outcomes of patients with N0 disease who received se-        low-dose radiotherapy (LDRT) in T1-2 NPC. Zhang et al. 34
lective neck RT with the outcomes of those who received          recruited 37 newly diagnosed T1-2 NPC patients who vol-
comprehensive treatment of all neck levels to provide a          untarily accepted ENPG+LDRT. Meanwhile, the data of
reference for the volume to be irradiated. According to the      132 T1-2 NPC patients treated with IMRT were collected
criteria for involved LNs detected by MRI, the incidence         and used as a control group. In the ENPG+LDRT group, the
of metastases was 85.1% (786 of 924 patients). In patients       average RT dose was 58.6 + 0.9 Gy, which was significant-
who had N0 disease, the risks of regional recurrence and         ly lower than in the IMRT group (70.7 + 1.9 Gy, p < 0.001).
distant metastasis did not significantly differ between pa-      There were no significant differences in age, gender, body
tients with inferior border of the neck irradiation field ei-    mass index (BMI), smoking history, Karnofsky perfor-
ther at the cricoid cartilage or below the cricoid cartilage.    mance status score, T and N categories, clinical stage, or
The authors concluded that, as observed by using MRI,            chemotherapy between the two groups. The authors found
LN metastases spread in an orderly fashion from higher to        similar survival outcomes, including 5-year OS, DMFS,
lower neck levels, and that their results did not support pro-   and LRFS, between patients treated by ENPG+LDRT and
phylactic irradiation of Level IV and supraclavicular LNs        those receiving IMRT. Moreover, ENPG+LDRT exhibited
in N0 patients.                                                  better QOL and less late RT related sequelae. These authors



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concluded that well-designed large randomised clinical tri-         timisation of RT techniques and the addition of ICT and/
als are needed to confirm their findings.                           or AC to concomitant CT in high-risk patients. Although
                                                                    the most frequent relapses are distant metastases, a good
Personalised medicine and targeted therapy                          proportion of patients have recurrence of disease only at a
                                                                    local-regional level. Kong et al., in their series of 370 cases
In a recent review, Bashraheel et al. 35 wrote: “Until recently,    of NPC, found that “18 patients (4.9%) developed clini-
patients who have the same type and stage of cancer all re-         cal or radiographic local-regional recurrences; 78% (14/18)
ceive the same treatment. It has been established, however,         of the patients were locally advanced (staged T3 or T4).
that individuals with the same disease respond differently to       In the 18 patients who developed a local-regional recur-
the same therapy. Further, each tumour undergoes genetic            rences, 7 patients had isolated regional recurrences, other 7
changes that cause cancer to grow and metastasize. The              patients had isolated local recurrences, and 4 patients had
changes that occur in one person’s cancer may not occur in          both local and regional recurrences” 37. In another study of
others with the same cancer type. These differences also lead       81 T4 NPC analysed by Kong et al., 12 patients (14.8%)
to different responses to treatment. Precision medicine, also       experienced local-regional failure 5. In a series of 1,039
known as personalized medicine, is a strategy that allows the       patients with NPC receiving IMRT Liu et al. 38 found that
selection of a treatment based on the patient’s genetic make-       75/1039 patients developed recurrences, and 88% (66/75)
up”. Next generation sequencing (NGS) describes a DNA               were considered as having in-field failures. Among these,
sequencing technology which has revolutionised genomic              62.7% (40/66) had local recurrence alone, 32.0% (22/66)
research. Using NGS, an entire human genome can be se-              had regional recurrence alone, and 5.3% (4/66) had both
quenced in a single day. Many molecular targeted therapies          local and regional recurrence. Multivariable analysis re-
approved by the Food and Drug Administration (FDA) have             vealed that pre-treatment gross tumour volume (≥ 68.8 mL
demonstrated remarkable clinical success in the treatment of        vs ˂ 68.8 mL) and histopathological types (NKDC vs
a myriad of cancer types including breast, leukaemia, colo-         NKUC) were the most significant independent factors for
rectal, lung, and ovarian cancers. With regards specifically to     in-field local recurrence. The pre-treatment volume of the
the NPC, Kang et al. 36 wrote: “Targeted therapy involves the       involved lymph nodes (≥ 19.9 mL vs < 19.9 mL) and cer-
design of specific drugs that bind specifically to oncogenic        vical nodal necrosis (CNN) (presence vs absence) were
targets within tumour cells to inhibit the development of tu-       closely associated with in-field regional recurrence.
mours. The genetic and epigenetic alterations of NPC have           However, the fact is that for the same stage of T and N, his-
been unveiled by the constant genome-wide studies, which            topathological type, and macroscopic characteristics of the
involve cytogenic, allelotyping, comparative genomic hy-            tumour, there are still a non-negligible number of patients
bridization (CGH), and array-based CGH analysis”. I made            suffering from relapse and metastasis. Thus, in addition
a search on PubMed using the key words “nasopharyngeal              to the aforementioned features of the primary tumour and
carcinoma” and “targeted therapy”, and I found as many as           lymph node metastases, some authors tried to discover the
1,555 articles. Despite this huge number of studies, Kang           possible intrinsic causes of the radioresistance of NPCs. El-
underlined that “at present, clinical trials on targeted ther-      evated expression of 3-phosphoinositide-dependent protein
apy for NPC are not abundant, which are mainly targeting            kinase 1 (PDK1) was observed in various human cancers
the epidermal growth factor receptor (EGFR) and vascular            such as breast, colorectal, oesophageal, and hepatocellular
endothelial growth factor receptor (VEGFR)” 36. Moreover,           carcinoma, and overexpression of PDK1 was associated
they stated: “most of the clinical trials of targeted therapy       with poor prognosis of these tumours 39. Zhang et al. ex-
against NPC are clinical phase I or II trials, which show that      amined the expression of PDK1 and the role and potential
different targeted drugs can delay the process of NPC to dif-       mechanism of PDK1 in radiation in NPC. They demon-
ferent degrees and prolong the life of patients” 36. In addi-       strated that depletion of PDK1 enhanced radiosensitivity in
tion, there are some problems when studying clinical trials         NPC cells both in vitro and in vivo, and a specific inhibitor
in targeted therapy of NPC. They wrote: “The quantity of            of PDK1 also had radio-sensitising effects on radioresistant
patients is small, which may cause the inaccuracy of the re-        NPC cells 39.
sults. Almost all the targets that occurred in clinical trials of   The NCCN guidelines divide cases with local-regional re-
NPC are VEGFR or EGFR. More phase III clinical trials are           lapses into resectable and unresectable; for the former the
needed after the drug has passed phase I and phase II clinical      therapeutic indication is surgery ± post-operative reirradia-
trials” 36.                                                         tion or systemic therapy/RT, and for the latter, the therapeu-
There has been a great improvement in the effectiveness             tic indication is reirradiation ± systemic therapy. Recurrenc-
of the first NPC treatment over the years due to the op-            es in an untrated neck, should undergo radical, modified,



                                                                                                                                 159
G. Cantù




or selective neck dissection 20. The ESMO-EURACAN              morbidity. The only disadvantage is the development of
Clinical Practice Guidelines for diagnosis, treatment and      mild trismus, which responded to conservative treatment”.
follow-up of NPC specify that the main therapeutic options     In reality, things probably did not go so well, because in
for small local recurrences include nasopharyngectomy,         many subsequent (and often repetitive) articles, the authors
brachytherapy, radiosurgery, stereotactic RT (SRT), IMRT       modified their technique. First of all, to avoid a possible
or a combination of surgery and RT, with or without con-       palatal fistula, the incision over the soft tissue on the hard
current CT 8.                                                  palate was changed from the midline incision originally de-
                                                               scribed to a curved incision along the lingual border of the
The role of surgery                                            teeth on the upper alveolus. Second, and more importantly,
As mentioned above, the mainstay of treatment for NPC is       Chang et al., from the same staff as Wei, wrote that when
(CT)RT. Beyond the recent studies on the primary surgical      they began to operate on patients with extensive local re-
treatment of T1-T2 NPC 33,34, surgical resection of NPC has    lapses, exposing the internal carotid artery into the para-
traditionally been reserved for histological forms that are    pharyngeal space, “3 patients developed torrential bleeding
not very radiosensitive (adenoid cystic carcinoma, adeno-      and died from internal carotid artery blowout 6 weeks after
carcinoma, etc). On the contrary, surgical treatment plays     discharge from the hospital while they were receiving post-
an important role in rescuing recurrent or persistent NPC      operative adjuvant radiotherapy” 44. For this reason, they
after primary (CT)RT. Surgical salvage can be divided into     began to use free flaps to cover the exposed bone at the
salvage for locally recurrent cancer and salvage for nodal     clivus and the exposed internal carotid artery. From 1990
recurrence; only in exceptional cases can resection of dis-    to 2012, they performed as many as 338 nasopharyngecto-
tant metastases be indicated.                                  mies using the maxillary swing approach for persistent or
The deep position of the nasopharynx makes its surgical        recurrent NPC after previous chemoradiation 44. The maxil-
approach very difficult, because one must bypass unin-         lary swing was the most widely used approach for open re-
volved structures to reach a narrow operative field. Various   section of NPC recurrences, with hundreds of cases treated,
surgical approaches have been proposed in the past: trans-     mainly in Asian countries.
palatal, trans-maxillary, midline mandibulotomy, midfacial     In 1990’s, some surgeons started to perform endoscopic
degloving, and trans-pterygoid. Some other approaches          resection of sinonasal malignancies. Endoscopic naso-
have great historical value, but are very complex and dif-     pharyngectomy (ENPG) was a natural extension of ap-
ficult. Median labiomandibular glossotomy was proposed         plication of endoscopic sinus surgery. To my knowledge,
by Trotter in 1920 for tumours of the base of the tongue       the first reported case of ENPG was made by Yoshizaki et
and in the 1980s it was used to expose the nasopharynx and     al. in 2005 45. Since then, several small series of patients
the clivus 40. The infratemporal fossa approach developed      treated with ENPG for local recurrence of NPC have been
by Fisch is even more complex. It requires a mastoidec-        published. In 2020 Yang et al, performed a meta-analysis
tomy and subtotal petrosectomy with a complete conduc-         on recurrent NPC patients treated with ENPG and found a
tive hearing loss 41. The facial translocation approach in-    total of 761 articles 46.
volves elective osteotomies with temporary removal of a        Obviously, the role of surgery compared with reirradiation
large portion of the craniofacial skeleton (anterior wall of   in the primary treatment of patients with resectable, locally
the maxillary sinus, inferior and lateral walls of the orbit   recurrent NPC who have previously received radiotherapy
and zygomatic arch) 42. After resection of the tumour, these   was (and is) a matter of debate. In order to demonstrate
bones are replaced and fixed. However, as these bones are      which treatment of local relapses (rNPC) after (CT)RT
not vascularised, often previously irradiated, and subse-      achieves the best results, Liu et al. 47 reported the results
quently re-irradiated, the likelihood of possible osteora-     of a multicentre, open-label, randomised, controlled, phase
dionecrosis is very high. In 1991, Wei et al. 43 presented     III trial that was done in three hospitals in southern Chi-
their “maxillary swing approach”. They wrote: “The max-        na. Between Sept 30, 2011, and Jan 16, 2017, 200 eligible
illa, severed from its bony connections, is swung laterally    patients were randomly assigned to receive either ENPG
to provide exposure of the nasopharynx. Tumours in the         (n = 100) or IMRT (n = 100). The authors concluded that
nasopharynx and the paranaso-pharyngeal space can be ad-       “Endoscopic surgery significantly improved overall surviv-
equately resected and tubings for after loading brachyther-    al compared with IMRT in patients with resectable locally
apy can be positioned accurately during surgery. The blood     recurrent NPC. These results suggest that ENPG could be
supply of the maxilla is from the attached cheek flap and      considered as the standard treatment option for this patient
masseter muscle”. Wei et al. presented 3 cases and wrote:      population, although long-term follow-up is needed to fur-
“The wounds in all of them healed primarily with minimal       ther determine the efficacy and toxicity of this strategy” 47.



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The attempts to use the Da Vinci robot for endoscopic re-         in the soft tissues not inside the lymph nodes” 54. Moreover,
section of local NPC recurrences cannot be forgotten. To          Wei et al. found that metastatic cancers can spread to all five
my knowledge, the first cadaveric experiment on robotic           levels of lymph nodes in the neck in patients with extensive
nasopharyngectomy was described by Ozer and Waltonen              nodal metastasis. Hence, they proposed to adopt classical
in 2008 48. In 2015, Tsang et al. published a series of 12        radical neck dissection (RND) to salvage nodal failures in
cases of robotic-assisted ENPG; with a 2-year follow-up,          NPC in order to eradicate tumours in soft tissue that ex-
the cure rate was 86% 49. However, they pointed out two           tended beyond the capsule of the lymph nodes. Wei’s con-
disadvantages of robotic ENPG; first, the Da Vinci surgical       clusions were so authoritative that for several years no one
robot is not designed for use in the head and neck region         questioned them. A small attempt to propose less extensive
and still needs to be adapted for use in the nasopharynx,         interventions was made by Yen et al. 55. These authors pre-
and second, in order for the robotic arms to reach the naso-      sented 31 patients who underwent a RND, modified radical
pharynx via a transoral route, the soft palate needed to be       (MRND), or level I-sparing RND. It is not known which
split for access.                                                 patients were selected for a more limited intervention. In
More recently, some preclinical anatomic studies have been        2011, Zhang et al. 53 analysed a very large series of patients
published on the use of flexible robotic surgical systems us-     (355 cases) who were diagnosed with neck residue or recur-
ing human cadavers. Using a highly articulated endoscope          rence of NPC, after radical definitive radiotherapy with or
with flexible instrumentation, a complete nasopharyn-             without chemotherapy, and tried to assess the outcomes and
gectomy can be performed without palatal incisions 50. In         identify prognostic factors. The group with recurrent nodal
2016, Tsang et al. published the long-term results of 31 pa-      disease consisted of 285 patients (80.3%), while the group
tients treated with robotic-assisted nasopharyngectomy for        with residual nodal disease included 70 patients (19.7%).
recurrent nasopharyngeal carcinoma. The median follow-            All patients were pathologically confirmed as having neck
up period for all patients was 38 months. Five-year local         metastasis by FNA and underwent RND. The multivariable
control rate, OS, and DFS were 85.1%, 55.7%, and 69.1%,           analysis revealed that stage, EBV encoded RNA (EBERs),
respectively 51.                                                  lymph node status (residue or recurrence), invasion of the
Given the modern treatments of NPC (IMRT ± CT), isolat-           soft tissues or organ outside the lymph node, and complete-
ed nodal failure is uncommon. Li et al. 53 found that only        ness of the surgical excision had a significant correlation
6% of patients had isolated nodal failures. Some studies an-      with survival. In the residue group, 42/70 patients had only
alysed the recurrence-related characteristics with respect to     a single positive pathological lymph node after neck dis-
the original treatment, and classified failures as ‘in-field’,    section. These 42 patients had an increased chance of sur-
‘marginal’ or ‘out-field’. Li et al. 52 found that “6/10 of the   vival. The authors concluded that their study demonstrated
nodal failures were in-field, of which five occurred in level     that patients with a persistent single lymph node after neck
II; whereas four had out-field failures, all of which were in     therapy can be treated with selective lymph node dissec-
the protected parotid gland area”. These authors concluded        tion. In 2016 Wang et al. 56 analysed 153 patients with NPC
that “Comprehensive assessment of nodules in or around            who had previously undergone RT (with or without CT)
the parotid gland is therefore a key aspect of treatment          and had neck residue or recurrence without evidence of lo-
planning and follow-up”.                                          cal disease and distant metastases. All patients underwent
Zhang et al. wrote: “Salvage surgery has an important role        some variants of ND. Seventeen patients received bilateral
in the treatment of recurrent nodal disease, although some        simultaneous ND and therefore, in total, 170 neck dissec-
centres advocate re-irradiation with external beam or boost       tions were performed. The surgical procedures were: 106
radiotherapy, with reported cure rates of 14-28%. This,           modified radical neck dissection (MRND) (including selec-
however, is associated with treatment-related morbidity,          tive neck dissection [SND] in 28, local excision in 9, and
secondary to cumulative radiation-induced injury” 53.             parotidectomy in 3), 48 patients received RND, and 16 pa-
The type of neck dissection (ND) to be performed in case          tients received extended radical neck dissection (ERND).
of persistent or recurrent nodal disease is controversial. A      The authors concluded that MRND is suitable for most
historical study by Wei et al. in 1992 (in the pre-IMRT era)      cases, even if some have ECS.
showed that “70% of the nodal recurrences had extra-cap-
sular spread (ECS). The lymph nodes also had propensity           Distant metastases
to spread along the spinal accessory chain in the posterior       As mentioned in part A of this review, distant metastases at
triangle. Tumour tissue in close proximity of the spinal ac-      presentation are rare (about 5%) 8. In contrast, distant post-
cessory nerve was found in 27.5% of the specimens and             treatment metastases are quite frequent and represent the
35% of the specimens had isolated clusters of tumour cells        first cause of death in patients with NPC. The rates reported



                                                                                                                               161
G. Cantù




by various authors are different. In a series of 352 patients      (12.0%) had distant metastases. Of course, being Ameri-
analysed by Khor et al. in 1978, 99 developed distant me-          can patients, the histological composition of the series was
tastases (28.1%) 57. Similar rates were found in other stud-       different from that of endemic areas. In fact they explain
ies of the past century. However, even in the most recent          that “a total of 909 of 2,758 tumours (33.0%) were KSCC
series presented in 2018 by Ai et al., distant metastases          (keratinizing squamous cell carcinoma), 820 tumours
appeared in 128/579 NPC patients (22.1%) after chemo-              (29.7%) were DNKSCC (differentiated non-keratinizing
IMRT, and 5-year DMFS was 78.8% 58.                                squamous cell carcinoma), 515 tumours (18.7%) were
The treatment with cisplatin and gemcitabine is the first-         UNKSCC (undifferentiated non-keratinizing squamous
line choice and improves OS 8,20. Because poly-CT is more          cell carcinoma) and 514 tumours (18.6%) did not belong
active than mono-therapy, other regimens include cispl-            to any specified groups (other group)”. Regarding the site
atin or carboplatin plus a taxane, cisplatin/fluorouracil (5-      of metastases, 325 of 332 patients (97.9%) had metastases
FU), gemcitabine/carboplatin, or carboplatin/cetuximab 20.         in five organs [bone, brain, liver, lung, and distant lymph
However, the estimated PFS and OS with second-line ther-           nodes (DL)]. Bone was the most common metastatic organ,
apy are around 5 and 12 months, respectively 8. In a recent        followed, in order, by the liver, lung, DL and brain. There
phase III randomised clinical trial, capecitabine mainte-          were some differences in the metastatic patterns among
nance therapy significantly improved PFS for patients with         different histological types: UNKSCC was the most com-
newly-diagnosed metastatic NPC who achieved disease                mon histological type with bone, brain, liver, and DL me-
control after capecitabine-containing induction chemother-         tastases, while KSCC was the most common histological
apy. Capecitabine exhibited manageable toxic effects 59.           type with lung metastases. Some patients had only one me-
A particular category of patients are those who present with       tastasis, and others had multiple metastases that occurred
local-regional tumour and oligo-metastatic disease (OMD).          simultaneously or sequentially. The incidence of dual-site
The NCCN guidelines state that patients with OMD disease           metastasis was higher than that of single metastasis in all
can be treated with RT or surgery after systemic CT 20. Two        types. Liver metastasis (lmNPC) was associated with a dra-
recent studies analysed the results of locoregional radiation      matically worse prognosis regardless of the number of met-
therapy (LRRT) in metastatic NPC (mNPC). The authors               astatic sites. Despite best palliative chemotherapy (PCT),
of the first article carried out a retrospective study in a con-   the 3-year survival of patients with lmNPC did not exceed
secutive cohort of 168 patients with histologically-proven         22% 62. Faced with such a poor prognosis, the question of
NPC with distant metastasis at initial diagnosis 60. Among         whether definitive radiation therapy (DRT) of the head and
these patients, 106 and 62 cases were diagnosed with OMD           neck should be added to PCT in patients with lmNPC re-
and with polymetastatic disease (PMD), respectively. OMD           mains. Some previous retrospective studies reported con-
was defined as no more than five metastatic lesions and            tradicting results regarding DRT treatment of patients with
no more than two metastatic organs based on pathologi-             lmNPC. In a recent study, Yang et al. 63 analysed 2,213
cal examination and/or multiple radiologic imaging, while          untreated metastatic patients with pathological confirmed
PMD referred to those had more than 5 tumour lesions and/          NPC. Among them there were 610 patients with lmNPC
or more than 2 metastatic organs. All patients underwent           (27.5%). The presence of liver metastatic lesions had been
platinum-based chemotherapy as a first-line treatment for          confirmed by two different imaging scans and/or biopsy
a minimum of four cycles with or without definitive RT at          pathological examination. All patients were treated with
nasopharynx and neck. The analysis showed that median              PCT with or without DRT and liver local therapy (LLT).
OS was significantly longer for patients who received CT           The various treatments in the liver were radiofrequency
plus LRRT (69.5 months) than for those who received CT             ablation (16 patients), surgical resection (21 patients),
alone (17.8 months, p < 0.001) 60. The second study evalu-         and trans-arterial embolisation (18 patients). Overall, 395
ated the efficiency of local RT to metastatic lesions in 109       (64.8%) patients received PCT alone, 160 (26.2%) received
patients with mNPC after treatment of the nasopharynx and          PCT +DRT, and 55 (9.0%) received PCT+DRT+LLT. The
neck, and demonstrated that 2- and 5-year OS were 65.8%            authors concluded “Our study demonstrated that DRT can
and 35.7% for patients who received local radiotherapy             be recommended for all patients with lmNPC after PCT
(n = 61) and 45.3% and 26.2% for patients who did not              because DRT might be beneficial regardless of the tumour
receive radiotherapy to metastatic lesions (n = 48) 61.            response after PCT. For patients who achieved complete
Qu et al. 62 conducted a thorough retrospective analysis of        response/partial response (CR/PR) after PCT and received
NPC patients using the Surveillance, Epidemiology, and             DRT, LLT is not recommended because it might have fewer
End Results (SEER) database from 2010 to 2016. In total,           benefits, along with increased cost and side effects. For
2,758 patients were included in their study, of whom 332           patients with progressive disease/stable disease (PD/SD)



162
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after PCT, DRT +LLT is recommended because it might                              environment (TME), has shown promising synergy. Given
improve PFS and OS. LLT may be most suitable for pa-                             the encouraging results of ICI monotherapy and preclini-
tients with liver metastasis only and ≤ 3 metastatic sites” 63.                  cal evidence of the synergy between chemotherapy and
Regarding immunotherapy Xu et al. stated that “The gener-                        ICIs, clinical exploration of the combination of ICIs with
al immune landscape of nasopharyngeal carcinoma (NPC)                            chemotherapy is required to promote the management of
renders immunotherapy suitable for patients with NPC” 64.                        R/M NPC. Recently, two randomised trials have demon-
“In recent years, immunotherapy has prompted a revolu-                           strated that the addition of camrelizumab or toripalimab to
tion in the clinical management of many cancers. Immune                          gemcitabine and cisplatin might be a new standard of care
checkpoint inhibitors (ICIs) based on programmed death-1/                        for patients with recurrent or metastatic nasopharyngeal
programmed death ligand-1 (PD-1/PD-L1) blockade have                             carcinoma in the first-line setting. However, it should be
made a breakthrough and were approved for the treatment                          stressed, as the study authors themselves do, that “longer
of recurrence and/or metastatic NPC (R/M NPC) in 2021                            follow-up is needed to confirm this conclusion”.
in China” 64. The incorporation of ICIs into the treatment                       Those who wish to investigate thoroughly this item may
                                                                                 read the paramount paper by Xu et al. 64. Table I summa-
paradigms of NPC has become a clinical hot spot and many
                                                                                 rises treatment indications.
prospective clinical studies have been performed and are
ongoing. Some have been given rather fanciful acronyms
(POLARIS-02, CAPTAIN-1st, RATIONALE 309, JUPI-                                   Prognostic factors and outcomes
TER-02, etc.).The most studied ICIs are: camrelizumab,                           Progressive improvement of treatment results for NPC has
toripalimab, spartalizumab, pembrolizumab, etc. The com-                         been reported both from endemic and non-endemic areas.
bination of ICIs and chemotherapy, which can eliminate or                        The average 5-year survival steadily increased from around
modulate immune suppressive cells in the tumour micro-                           35% for patients treated between 1940-60 to 55-60%
                                                                                 for those treated between 1970-90. A recent study of pa-
                                                                                 tients without distant metastases treated during 1996-2000
Table I. Treatment.                                                              showed that 5-year disease-specific survival (DSS) was
 Chemo-radiotherapy                                                              81% and OS 75% 65. On the contrary, the 5- and 10-year
Radiotherapy (RT) is the treatment backbone for the NPC.                         actuarial survivals were 33% and 19%, respectively, in a
Nowadays, IMRT has become the gold standard in the management of NPC.            series of patients with NPC treated between 1958 and
Protons and carbon ions are gaining popularity, mainly when they are added       1983 by Haghbin et al. 66. In the series of Vikram et al.
as a boost for locally advanced disease.                                         the observed 5-year survival rate was also 35% for patients
The newest form of proton beam therapy is intensity-modulated proton ra-         treated between 1970 and 1976, and increased to 72%
diation therapy.
                                                                                 for those treated between 1977 and 1980. They remarked
Since the 1970s, chemotherapy (CT) has been added to standard RT (CRT)
to improve outcomes in high-risk patients (adjuvant, neoadjuvant, or concur-     that “The two patient populations were similar except that
rently with radiation).                                                          the dose of irradiation to the primary site was 6,000 rad
Nowadays, the standard treatment for stage I disease is RT alone.                during 1970-1976 and 7,000 rad during 1977-1980” 67. A
The treatment of patients with stage II NPC is controversial (RT alone or        retrospective analysis was performed by Yeh et al. on 326
CRT).                                                                            consecutive NPC patients treated between 2004 and 2015.
Stage III and IV without distant metastasis are treated by CRT with cisplatin    The 5-year OS and DFS rates of these patients were 77.9%
with the possible addition of ICT and/or AC.                                     and 70.5%, respectively 68. Another analysis of a very large
Waiting time for RT should be as short as reasonably achievable.                 series of 2,070 NPC treated by RT alone in Hong Kong
Surgery                                                                          between 1996 and 2000 showed that the 5-year progres-
Surgical treatment plays an important role in rescuing recurrent or persistent   sion-free, overall, and cancer-specific survival rates were
disease after primary (CT)RT.                                                    63%, 75%, and 80%, respectively; the OS decreased from
Surgical salvage can be divided into salvage for locally recurrent cancer and    90% for stage I to 58% for stage IVA-B 69. After the al-
salvage for nodal recurrence; only in exceptional cases can resection of dis-    most routine use of the association of CT-RT in the various
tant metastases be indicated.
                                                                                 combinations, the results improved further. In the series of
The deep position of the nasopharynx makes its surgical approach very dif-
ficult. Various surgical approaches have been proposed in the past: trans-       488 patients with stage II-IVa NPC reported by Yang et al,
palatal, trans-maxillary, midline mandibulotomy, midfacial degloving, trans-     the 5-year LRFS, DMFS, OS, and PFS rates were 87.7%,
pterygoid, infratemporal fossa, and maxillary swing.                             81.7%, 81.2%, and 69.3%, respectively 70.
A surgical endoscopic resection with or without low-dose post-operative RT       Many studies have analysed the various prognostic fac-
in T1-T2 NPC has recently been experimented.                                     tors that affect the ultimate cure rate of patients with NPC.



                                                                                                                                             163
G. Cantù




By doing a search on PubMed, using the keywords “naso-             DNA were independent predictive factors of OS and PFS.
pharyngeal carcinoma” and “prognostic factors”, you can            The authors developed a nomogram, integrating TNM
find 5,394 articles. Over the past decade, nomograms have          stage, post-ICT plasma EBV DNA, age, and treatment regi-
become very popular for predicting the chances of cure for         mens (IMRT alone or CRT) and achieved a satisfying value
patients with NPC; using the keywords “nasopharyngeal              in a validation cohort for predicting OS and PFS. Yang et al.
carcinoma” and “nomogram”, you can find 147 studies on             concluded “It is possible to guide clinicians to conduct per-
PubMed.                                                            sonalized therapy in clinical practice, including early treat-
It is often difficult to compare the results of the various        ment modification for high-risk patients, which implies that
studies because some have taken into consideration the en-         they should receive therapeutic intensification” 70. Howev-
tire series of NPCs treated in a single centre or all those        er, the authors correctly admit that a nomogram based on
present in the SEER or National Cancer Database (NCDB),            plasma EBV DNA is limited by the large interlaboratory
while others have considered only some specific catego-            variability. In this regard, the ESMO-EURACAN Clini-
ries (for example, stage II 71 or only patients after IC 28).      cal Practice Guidelines 8 also stated “Plasma EBV DNA
However, the most accepted prognostic factors that worsen          is a promising marker for the diagnosis of recurrence and
prognosis are male sex, older age, advanced T-N catego-            should be evaluated at least every year”. But, in the same
ries, and the presence of distant metastases 72-75. Regarding      guidelines there are the following statements “Due to the
sex, OuYang et al. 74 demonstrated that females showed sig-        variability in assessments between laboratories, EBV DNA
nificant advantage over males in both early and advanced           measurement needs further harmonization” … “However,
stage groups. However, this advantage persisted at premen-         more research is needed to refine the role of plasma EBV
opausal age, declined during menopause, and totally dis-           DNA in the management of NPC and to identify additional
appeared at postmenopausal age. According to the authors           molecular markers which could lead to advances in person-
probably, “Intrinsic biologic traits appear to be the exact        alised medicine in NPC” 8.
explanation according to the declining magnitude of sex            It is now a certain concept that systemic immunity and inflam-
effect with age” 74.                                               mation play a crucial role in the processes of tumour elimi-
Other important prognostic factors are histological type and       nation, regression, and metastasis 80-82. Lin et al. performed a
ethnicity, which are strictly dependent on each other. As          comparative analysis of 12 pre-treatment immune-related in-
mentioned earlier, the proportion K-NPC/NK-NPC among               dices in a double-centre retrospective cohort of patients with
all NPC is very different between endemic and non-endem-           NPC 82. The most significant were: absolute neutrophil count
ic areas. Since many studies have shown that K-NPC has a           (ANC), absolute lymphocyte count (ALC), platelet count
worse prognosis than NK-NPC, the different healing rates           (PLT), levels of albumin (ALB), C-reactive protein (CRP),
between one race and another are explained 76-79. Moreover,        haemoglobin, and lactate dehydrogenase (LDH), neutrophil-
comprehensive national data base analyses evaluating epi-          to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio
demiological factors associated with outcomes of NPC in            (MON), and platelet-to-lymphocyte ratio (PLR). In a meta-
the USA found that Asian patients had a survival advantage         analysis on the prognostic significance of haematological
relative to Caucasian patients even after adjusting for dis-       markers for patients with NPC, Yang et al. 83 analysed 23
ease histology 76,77. In the study by Stepan et al., stratifying   studies encompassing 23,417 patients. The results of this me-
by race and disease histology, Asian patients with K-NPC           ta-analysis suggested “that inflammatory cells (such as neu-
and DNK-NPC had significantly improved survival rela-              trophils, monocytes, lymphocyte and platelets) and proteins
tive to Caucasian patients after controlling for covariates.       (such as ALB, CRP and HDL-C) have the capacity to predict
In contrast, there was no significant relationship between         survival in cancer, including NPC. As widely available and
race and OS for those with UNK-NPC 76. These authors               inexpensive biomarkers, haematological parameters may fa-
concluded that their results suggest “interesting interac-         cilitate prognosis prediction in patients with solid tumors” 83.
tions between race and histological types of NPC that may          Among these immune-related indices, one of the most widely
reflect distinct biology” 76.                                      verified on large series has been the NLR 73,83,84. Zengh et al.
Another prognostic factor worsening the prognosis report-          wrote “Recently, immune-inflammation indexes including the
ed in various studies is EBV-DNA level, both pre-treatment         systemic inflammatory response index (SIRI) based on three
(≥ 4,000 copies/ml) and post-IC (positive) 70. Yang et al.         types of white cells (peripheral neutrophils, monocytes and
analysed 488 patients with stage II-IVa NPC, all of whom           lymphocytes) and the systemic immune-inflammation index
were treated with ICT. Among these, 124 patients received          (SII) based on three types of white cells (peripheral neutro-
ICT followed by IMRT alone, and 364 patients received              phils, platelet and lymphocytes) were investigated in various
ICT followed by CRT. Pre-treatment and post-ICT EBV                cancers. These inflammation indexes are also considered to be



164
                                                                                                     Nasopharyngeal carcinoma. Part B




independent prognostic factors for cancers, and their prognos-      In contrast, other studies demonstrated that cervical biopsy
tic value is higher than that of only white blood cells” 85. The    was not related to a higher risk of death, distant metastasis,
SIRI is defined as neutrophil count × monocyte/lymphocyte           or nodal relapse 92.
count. The SII is defined as neutrophils × platelets/lympho-        Two prestigious guidelines also report a different attitude
cytes. Jin et al. 86 retrospectively analysed 287 children and      towards lymph node biopsy. The Clinical Practice, pub-
adolescents with locoregionally advanced NPC. They found            lished in 2010 by the EHNS-ESMO-ESTRO (European
that elevated SIRI (≥ 1.53) and EBV DNA (≥ 4000 copy/ml)            Head and Neck Society-European Society for Medical
were significantly associated with inferior OS, and concluded       Oncology-European Society for Radiotherapy & Oncol-
that the combination of SIRI with EBV DNA provided a more           ogy), state that “This procedure is not recommended since
detailed understanding of patient risks, and enhanced risk dis-     it may reduce cure probability and have an impact on late
crimination. Chen et al. also agreed that “the pre-treatment        treatment sequelae” 93. Regarding the diagnostic work-up,
SIRI value is a novel systemic inflammatory marker for pa-          the NCCN guidelines are more permissive, allowing both
tients with NPC, and its value is significantly more than that of   biopsy of the primary and FNA of the neck 20.
conventional systemic inflammatory markers” 87.                     An association between prolonged waiting time to start the
A controversial prognostic factor is pre-treatment lymph            best therapy and worsening of prognosis has been demon-
node biopsy. Two older studies demonstrated that pre-irra-          strated for many cancers. Obviously, NPC does not escape
diation lymph-node biopsy consistently resulted in poorer           this rule. Chen et al. found that a prolonged waiting time
survival 88,89. Dickson 88 presented a racially balanced North      (> 4 weeks) between diagnosis and primary radical radio-
American series of 209 patients with NPC. When the nodes            therapy (WRT) is a disadvantage for NPC patients 94. These
were mobile, 5-year absolute (NED) survival was 46.9%               data were subsequently confirmed by other studies 29. The
in the non-biopsied group and 25% when nodes were ex-               conclusion of these studies was that WRT of NPC should
cised prior to primary irradiation therapy. Cai et al. 90 found     be as short as reasonably achievable.
that for patients with fixed and partially fixed neck nodes,        Finally, among the variety of prognostic factors that sig-
the interval between the first biopsy and radiotherapy and          nificantly influence OS in NPC there is one that has rarely
the type of biopsy done on the lymph node did not influ-            been considered in most studies, namely the “hospital” and
ence prognosis. On the contrary, for patients with movable          “physician” factor. Eskander et al. 95 analysed 17 studies
neck nodes, the interval between the first biopsy and radio-        examining a volume-outcome relationship in the treatment
therapy influenced the final outcome. Moreover, patients            of patients with head and neck cancer with meta-analysis
who received radiotherapy within 14 days after biopsy had           for long-term survival results, and found that high-volume
a 5-year survival of 61%, which is better than that of the          hospitals have better OS than low-volume hospitals. As for
patients who started their treatment beyond the 15th day            NPC specifically, a study from an endemic country (Tai-
(47.5%). These authors also showed that “For patients with          wan) demonstrated that patients with NPC treated by high-
movable lymph nodes, partial excision of the node gave              volume physicians (case load ≥ 35 patients per year) had
a poorer five year survival (22%) than that of patients on          better survival rates (p = 0.001) after adjusting for comor-
whom complete excision was done (50%). Therefore, com-              bidities, hospital, and treatment modality 96. These data have
plete excision of the node is advised for patients with mov-        also been confirmed in a non-endemic country (USA) 97,98.
able neck node metastasis” 89.                                      Both of these studies queried the NCDB for patients with
It should be pointed out that these series referred to patients     NPC. In the study by Goshtasbi et al. 97 a total of 8,260
treated in the pre IMRT era. However, the analysis of more          patients were included. The 1,114 unique facilities were
recent series also demonstrated that diagnostic excision of         categorised into 854 low-volume (treating 1-8 patients per
lymph nodes may worsen prognosis 63,90. Qu et al. found             year), 200 intermediate-volume (treating 9-23 patients),
that biopsy without complete removal of the lymph node              and 60 high-volume (treating 24-187 patients) facilities.
increased the likelihood of distant metastasis 63. Lv et al.        Kaplan-Meier log-rank analysis demonstrated significantly
analysed 2,910 patients with NPC from the SEER; 416 pa-             improved OS with high-volume facilities (p < 0.001). The
tients underwent pre-treatment lymph node biopsy. After             study by Yoshida et al. 98 included 3,941patients with stage
control for patient, tumour, and demographic characteris-           II-IVB NPC treated at 804 facilities, including 1025 pa-
tics, biopsy was not associated with impaired OS or DSS             tients (26.0%) treated at high volume facilities. The latter
but, in the subgroup analysis, the unfavourable effect of           had a significantly improved OS on multivariable analysis.
biopsy was observed for patients with differentiated non-           Interestingly, among patients treated at high volume facili-
keratinising squamous cell carcinoma (but not for other             ties, those treated at academic centres had better 5-year OS.
histologic types) 91.                                               These data support the concept of centralisation of tumours



                                                                                                                                165
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Table II. Prognostic factors and outcomes.                                           3
                                                                                          Lee AW, Foo W, Law SC, et al. Nasopharyngeal carcinoma: present-
 Progressive improvement of treatment results for NPC has been reported                   ing symptoms and duration before diagnosis. Hong Kong Med J
 both from endemic and non-endemic areas, mainly after IMRT became the                    1997;3:355-361.
 gold standard of treatment. After the almost routine use of the association of      4
                                                                                          Du T, Xiao J, Qiu Z, et al. Wu K. The effectiveness of intensity-modu-
 CT-RT in the various combinations, the results improved further.                         lated radiation therapy versus 2D-RT for the treatment of nasopharyn-
                                                                                          geal carcinoma: a systematic review and meta-analysis. PLoS One
 The most accepted prognostic factors that worsen the prognosis are male                  2019;14:E0219611. https://doi.org/10.1371/journal.pone.0219611
 sex, older age, advanced T-N stage, and presence of distant metastases. The
 impact of histologic grade on prognosis is controversial, although a number
                                                                                     5
                                                                                          Kong FF, Ying H, Du CR, et al. Effectiveness and toxicities of inten-
 of studies have shown that K-NPC has a worse prognosis than NK-NPC.                      sity-modulated radiation therapy for patients with T4 nasopharyngeal
                                                                                          carcinoma. PLoS One 2014;9:E91362. https://doi.org/10.1371/jour-
 Asian patients have a survival advantage relative to Caucasian patients even             nal.pone.0091362
 after adjusting for disease histology.                                              6
                                                                                          Huang TL, Chien CY, Tsai WL, et al. Long-term late toxicities and
 Another prognostic factor worsening the prognosis reported in various stud-              quality of life for survivors of nasopharyngeal carcinoma treated with
 ies is the EBV-DNA level, both pre-treatment (≥ 4,000 copies/ml) and post-               intensity-modulated radiotherapy versus non-intensity-modulated ra-
 IC (positive).                                                                           diotherapy. Head Neck 2016;38 (Suppl 1):E1026-E1032. https://doi.
 Systemic immunity and inflammation play a crucial role in the processes of tu-           org/10.1002/hed.24150
 mour elimination, regression and metastasis. The most significant immune-re-        7
                                                                                          Weng JJ, Wei JZ, Li M, et al. Prognostic value of hypothyroidism
 lated indices are: absolute neutrophil count, absolute lymphocyte count, plate-          in patients undergoing intensity-modulated radiation therapy for na-
 let count, levels of albumin, C-reactive protein, neutrophil-to-lymphocyte ratio,        sopharyngeal carcinoma. Head Neck 2022;44:1114-1123. https://doi.
 lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio.                           org/10.1002/hed.27006
 Pre-treatment lymph node biopsy is a controversial prognostic factor, al-           8
                                                                                          Bossi P, Chan AT, Licitra L, et al. Nasopharyngeal carcinoma: ESMO-
 though some studies demonstrated that pre-irradiation lymph-node biopsy                  EURACAN Clinical Practice Guidelines for diagnosis, treatment and
 consistently resulted in poorer survival.                                                follow-up. Ann Oncol 2021;32:452-465. https://doi.org/10.1016/j.
                                                                                          annonc.2020.12.007
 An association between prolonged waiting time to start the best therapy
 and a worsening of prognosis has been demonstrated for many cancers,
                                                                                     9
                                                                                          Li G, Xia YF, Huang YX, et al. Intensity-modulated proton radiation
 including NPC.                                                                           therapy as a radical treatment modality for nasopharyngeal carcinoma
                                                                                          in China: cost-effectiveness analysis. Head Neck 2022;44:431-442.
 Many studies have demonstrated that patients with NPC treated at high vol-               https://doi.org/10.1002/hed.26941
 ume facilities have significantly improved OS on multivariable analysis.            10
                                                                                          Moreno AC, Frank SJ, Garden AS, et al. Intensity modulated
 Therefore, given the complex and sophisticated treatments of the patients                proton therapy (IMPT) – the future of IMRT for head and neck
 with NPC, centralisation of these patients in high-volume centres is                     cancer. Oral Oncol 2019;88:66-74. https://doi.org/10.1016/j.
 appropriate.                                                                             oraloncology.2018.11.015
                                                                                     11
                                                                                          Taheri-Kadkhoda Z, Björk-Eriksson T, et al. Intensity-modulated ra-
                                                                                          diotherapy of nasopharyngeal carcinoma: a comparative treatment
                                                                                          planning study of photons and protons. Radiat Oncol 2008;3:4. htt-
that require complex treatments at centres that are able to                               ps://doi.org/10.1186/1748-717X-3-4
meet minimum volume thresholds to improve patient out-                               12
                                                                                          Lewis GD, Holliday EB, Kocak-Uzel E, et al. Intensity-modulated
comes. Table II summarises what has been described about                                  proton therapy for nasopharyngeal carcinoma: Decreased radiation
                                                                                          dose to normal structures and encouraging clinical outcomes. Head
prognostic factors and outcomes.                                                          Neck 2016;38 (Suppl 1):E1886-E1895. https://doi.org/10.1002/
                                                                                          hed.24341
Conflict of interest statement                                                       13
                                                                                          Rossi A, Molinari R, Boracchi P, et al. Adjuvant chemotherapy with
The author declares no conflict of interest.                                              vincristine, cyclophosphamide, and doxorubicin after radiotherapy
                                                                                          in local-regional nasopharyngeal cancer: results of a 4-year multi-
                                                                                          center randomized study. J Clin Oncol 1988;6:1401-1410. https://doi.
Funding                                                                                   org/10.1200/JCO.1988.6.9.1401
This research did not receive any specific grant from funding                        14
                                                                                          Palazzi M, Guzzo M, Bossi P, et al. Regionally advanced nasopharyn-
                                                                                          geal carcinoma: long-term outcome after sequential chemotherapy
agencies in the public, commercial, or not-for-profit sectors.                            and radiotherapy. Tumori 2004;90:60-65.
                                                                                     15
                                                                                          Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus
Ethical consideration                                                                     radiotherapy in patients with advanced nasopharyngeal cancer: phase
Not applicable.                                                                           III randomized Intergroup study 0099. J Clin Oncol 1998;16:1310-
                                                                                          1317. https://doi.org/10.1200/JCO.1998.16.4.1310
                                                                                     16
                                                                                          Kim TH, McLaren J, Alvarado CS, et al. Adjuvant chemo-
References                                                                                therapy for advanced nasopharyngeal carcinoma in childhood.
                                                                                          Cancer         1989;63:1922-1926.         https://doi.org/10.1002/1097-
1
    Sun XS, Li XY, Chen QY, et al. Future of radiotherapy in naso-                        0142(19890515)63:10<1922::aid-cncr2820631009>3.0.co;2-r
    pharyngeal carcinoma. Br J Radiol 2019;92:20190209. https://doi.                 17
                                                                                          Roper HP, Essex-Cater A, Marsden HB, et al. Nasopharyngeal carci-
    org/10.1259/bjr.20190209                                                              noma in children. Pediatr Hematol Oncol 1986;3:143-152. 1 https://
2
    Cellai E, Chiavacci A, Olmi P, et al. Carcinoma of the nasopharynx:                   doi.org/0.3109/08880018609031210
    results of radiation therapy. Acta Radiol Oncol 1982;21:87-95. https://          18
                                                                                          Chen QY, Wen YF, Guo L, et al. Concurrent chemoradiotherapy vs
    doi.org/10.3109/02841868209133989                                                     radiotherapy alone in stage II nasopharyngeal carcinoma: phase III




166
                                                                                                                           Nasopharyngeal carcinoma. Part B




     randomized trial. J Natl Cancer Inst 2011;103:1761-1770. https://doi.           pharyngeal carcinoma. Cancer Commun (Lond). 2019;39:75. https://
     org/10.1093/jnci/djr432                                                         doi.org//10.1186/s40880-019-0415-3
19
     Huncharek M, Kupelnick B. Combined chemoradiation versus                   34
                                                                                     Zhang B, Li Y, Weng J, et al. Efficacy and safety of endo-
     radiation therapy alone in locally advanced nasopharyngeal car-                 scopic nasopharyngectomy combined with low-dose radio-
     cinoma: results of a meta-analysis of 1,528 patients from six ran-              therapy for primary T1-2 nasopharyngeal carcinoma. Technol
     domized trials. Am J Clin Oncol 2002;25:219-223. https://doi.                   Cancer Res Treat 2021;20:15330338211011975. https://doi.
     org/10.1097/00000421-200206000-00002                                            org/10.1177/15330338211011975
20
     National Comprehensive Cancer Network. Head and neck cancers               35
                                                                                     Bashraheel SS, Domling A, Goda SK. Update on targeted cancer
     (Version 3.2021). http://www.nccn.org/professionals/physician_gls/              therapies, single or in combination, and their fine tuning for preci-
     pdf/bone.pdf                                                                    sion medicine. Biomed Pharmacother 2020;125:110009. https://doi.
21
     Xu C, Zhang LH, Chen YP, et al. Chemoradiotherapy versus radio-                 org/10.1016/j.biopha.2020.110009
     therapy alone in stage ii nasopharyngeal carcinoma: a systemic review      36
                                                                                     Kang Y, He W, Ren C, et al. Advances in targeted therapy mainly based
     and meta-analysis of 2138 patients. J Cancer 2017;8:287-297. https://           on signal pathways for nasopharyngeal carcinoma. Signal Transduct
     doi.org/10.7150/jca.17317                                                       Target Ther 2020;5:245. https://doi.org/10.1038/s41392-020-00340-2
22
     Chen L, Hu CS, Chen XZ, et al. Concurrent chemoradiotherapy plus           37
                                                                                     Kong F, Ying H, Du C, et al. Patterns of local-regional failure after pri-
     adjuvant chemotherapy versus concurrent chemoradiotherapy alone                 mary intensity modulated radiotherapy for nasopharyngeal carcino-
     in patients with locoregionally advanced nasopharyngeal carcinoma:              ma. Radiat Oncol 2014;9:60. https://doi.org/0.1186/1748-717X-9-60
     a phase 3 multicentre randomised controlled trial. Lancet Oncol
     2012;13:163-171. https://doi.org/10.1016/S1470-2045(11)70320-5.
                                                                                38
                                                                                     Liu X, Wu B, Huang J, et al. Tumor factors associated with in-field
                                                                                     failure for nasopharyngeal carcinoma after intensity-modulated ra-
23
     Zhang Y, Chen L, Hu GQ, et al. Gemcitabine and cisplatin induc-                 diotherapy. Head Neck 2022;44:876-888. https://doi.org/10.1002/
     tion chemotherapy in nasopharyngeal carcinoma. N Engl J Med
                                                                                     hed.26983
     2019;381:1124-1135. https://doi.org/10.1056/NEJMoa1905287
                                                                                39
                                                                                     Zhang W, Li L, Guo E, et al. Inhibition of PDK1 enhances radio-
24
     Liu T, Dai S, Zhang H, Zhong X, et al. The best choice of induction
                                                                                     sensitivity and reverses epithelial-mesenchymal transition in naso-
     chemotherapy for patients with locally advanced nasopharyngeal car-
                                                                                     pharyngeal carcinoma. Head Neck 2022;44:1576-1587. https://doi.
     cinoma: Bayesian network meta-analysis. Head Neck 2022;44:518-
     529. https://doi.org/10.1002/hed.26932                                          org/10.1002/hed.27053
25
     Li WZ, Lv X, Hu D, et al. Effect of induction chemotherapy with
                                                                                40
                                                                                     Wessberg GA, Hill SC, McBride KL. Median labiomandibular glos-
     paclitaxel, cisplatin, and capecitabine vs cisplatin and fluorouracil on        sotomy. Int J Oral Surg 1981;10:333-337. https://doi.org/10.1016/
     failure-free survival for patients with stage IVA to IVB nasopharynge-          s0300-9785(81)80030-0
     al carcinoma: a multicenter phase 3 randomized clinical trial. JAMA        41
                                                                                     Fisch U. The infratemporal fossa approach for nasopharyn-
     Oncol 2022;8:706-714. https://doi.org/10.1001/jamaoncol.2022.0122               geal     tumors.     Laryngoscope       1983;93:36-44.       https://doi.
26
     Li M, Zhang B, Chen Q, et al. Concurrent chemoradiotherapy with ad-             org/10.1288/00005537-198301000-00007
     ditional chemotherapy for nasopharyngeal carcinoma: a pooled analy-        42
                                                                                     Janecka IP, Sen CN, Sekhar LN, et al. Facial translocation for cranial
     sis of propensity score-matching studies. Head Neck 2021;43:1912-               base surgery. Keio J Med 1991;40:215-220. https://doi.org/10.2302/
     1927. https://doi.org/10.1002/hed.26664                                         kjm.40.215
27
     Zhao C, Miao JJ, Hua YJ, et al. Locoregional control and mild late         43
                                                                                     Wei WI, Lam KH, Sham JS. New approach to the nasopharynx: the
     toxicity after reducing target volumes and radiation doses in patients          maxillary swing approach. Head Neck 1991;13:200-207. https://doi.
     with locoregionally advanced nasopharyngeal carcinoma treated with              org/10.1002/hed.2880130306
     induction chemotherapy (ic) followed by concurrent chemoradiother-         44
                                                                                     Chan JY, Tsang RK, Wei WI. Morbidities after maxillary swing naso-
     apy: 10-year results of a phase 2 study. Int J Radiat Oncol Biol Phys
                                                                                     pharyngectomy for recurrent nasopharyngeal carcinoma. Head Neck
     2019;104:836-844. https://doi.org/10.1016/j.ijrobp.2019.03.043
                                                                                     2015;37:487-492. https://doi.org/10.1002/hed.23633
28
     Jiang YT, Chen KH, Liang ZG, et al. A nomogram based on tumor re-          45
                                                                                     Yoshizaki T, Wakisaka N, Murono S, et al. Endoscopic nasopharyn-
     sponse to induction chemotherapy may predict survival in locoregion-
     ally advanced nasopharyngeal carcinoma. Head Neck 2022;44:1301-                 gectomy for patients with recurrent nasopharyngeal carcinoma at the
     1312. https://doi.org/10.1002/hed.27020                                         primary site. Laryngoscope 2005;115:1517-1519.
29
     Jiang YT, Chen KH, Yang J, et al. Prognostic significance of wait time
                                                                                46
                                                                                     Yang J, Song X, Sun X, et al. Outcomes of recurrent nasopharyngeal
     for radical radiotherapy in locoregionally advanced nasopharyngeal              carcinoma patients treated with endoscopic nasopharyngectomy: a
     carcinoma. Head Neck 2022;44:1182-1191. https://doi.org/10.1002/                meta-analysis. Int Forum Allergy Rhinol 2020;10:1001-1011. https://
     hed.27011                                                                       doi.org/10.1002/alr.22552
30
     He Y, Zhao Z, Wang Y, et al. Optimizing number of cycles of induc-
                                                                                47
                                                                                     Liu YP, Wen YH, Tang J, et al. Endoscopic surgery compared with
     tion chemotherapy for patients with nasopharyngeal carcinoma: ret-              intensity-modulated radiotherapy in resectable locally recurrent na-
     rospective survival analysis. Head Neck 2020;42:2067-2076. https://             sopharyngeal carcinoma: a multicentre, open-label, randomised,
     doi.org/10.1002/hed.26141                                                       controlled, phase 3 trial. Lancet Oncol 2021;22:381-390. https://doi.
                                                                                     org/10.1016/S1470-2045(20)30673-2
31
     Ribassin-Majed L, Marguet S, Lee AWM, et al. What is the best treat-
     ment of locally advanced nasopharyngeal carcinoma? An individual
                                                                                48
                                                                                     Ozer E, Waltonen J. Transoral robotic nasopharyngectomy: a novel
     patient data network meta-analysis. J Clin Oncol 2017;35:498-505.               approach for nasopharyngeal lesions. Laryngoscope 2008;118:1613-
     https://doi.org/10.1200/JCO.2016.67.4119                                        1616. https://doi.org/10.1097/MLG.0b013e3181792490
32
     Tang L, Mao Y, Liu L, et al. The volume to be irradiated during se-        49
                                                                                     Tsang RK, To VS, Ho AC, et al. Early results of robotic assisted naso-
     lective neck irradiation in nasopharyngeal carcinoma: analysis of the           pharyngectomy for recurrent nasopharyngeal carcinoma. Head Neck
     spread patterns in lymph nodes by magnetic resonance imaging. Can-              2015;37:788-793. https://doi.org/10.1002/hed.23672
     cer 2009;115:680-688. https://doi.org/10.1002/cncr.24049                   50
                                                                                     Tsang RK, Holsinger FC. Transoral endoscopic nasopharyngectomy
33
     Liu YP, Lv X, Zou X, et al. Minimally invasive surgery alone com-               with a flexible next-generation robotic surgical system. Laryngoscope
     pared with intensity-modulated radiotherapy for primary stage I naso-           2016;126:2257-2262. https://doi.org/10.1002/lary.25970




                                                                                                                                                         167
G. Cantù




51
     Tsang RK, Chan WCP, Holsinger FC, et al. Long-term results of             67
                                                                                    Vikram B, Strong EW, Manolatos S, et al. Improved survival in carci-
     robotic-assisted nasopharyngectomy for recurrent nasopharyngeal                noma of the nasopharynx. Head Neck Surg 1984;7:123-128. https://
     carcinoma. Head Neck 2022;44:1940-1947. https://doi.org/10.1002/               doi.org/10.1002/hed.2890070206
     hed.27115                                                                 68
                                                                                    Yeh SA, Hwang TZ, Wang CC, et al. Outcomes of patients with naso-
52
     Li JG, Venigalla P, Leeman JE, et al. Patterns of nodal failure after          pharyngeal carcinoma treated with intensity-modulated radiotherapy.
     intensity modulated radiotherapy for nasopharyngeal carcinoma. La-             J Radiat Res 2021;62:438-447. https://doi.org/10.1093/jrr/rrab008
     ryngoscope 2017;127:377-382. https://doi.org/10.1002/lary.26139           69
                                                                                    Lee AW, Sze WM, Au JS, et al. Treatment results for nasopharyngeal
53
     Zhang L, Zhu YX, Wang Y, et al. Salvage surgery for neck resi-                 carcinoma in the modern era: the Hong Kong experience. Int J Ra-
     due or recurrence of nasopharyngeal carcinoma: a 10-year experi-               diat Oncol Biol Phys 2005;61:1107-1116. https://doi.org/10.1016/j.
     ence. Ann Surg Oncol 2011;18:233-238. https://doi.org/10.1245/                 ijrobp.2004.07
     s10434-010-1292-9                                                         70
                                                                                    Yang K, Li M, Zhu J, et al. Nomograms for predicting survival out-
54
     Wei WI, Ho CM, Wong MP, et al. Pathological basis of sur-                      comes in intensity-modulated radiotherapy era of nasopharyngeal
     gery in the management of postradiotherapy cervical metasta-                   carcinoma: a study based on Epstein-Barr virus DNA biological re-
     sis in nasopharyngeal carcinoma. Arch Otolaryngol Head Neck                    sponses. Head Neck 2021;43:1838-1847. https://doi.org/10.1002/
     Surg 1992;118:923-929; discussion 930. https://doi.org/10.1001/                hed.26654
     archotol.1992.01880090039012                                              71
                                                                                    He SS, Wang CT, Peng ZW, et al. Development and external vali-
55
     Yen KL, Hsu LP, Sheen TS, et al. Salvage neck dissection for cer-              dation of a nomogram for predicting the overall survival of patients
     vical recurrence of nasopharyngeal carcinoma. Arch Otolaryn-                   with stage II nasopharyngeal carcinoma after curative treatment. Can-
     gol Head Neck Surg 1997;123:725-729. https://doi.org/0.1001/                   cer Manag Res 2019;11:4403-4412. https://doi.org/10.2147/CMAR.
     archotol.1997.01900070069011                                                   S202151
56
     Wang SY, Lou JL, Chen J, et al. Salvage surgery for neck residue          72
                                                                                    Siti-Azrin AH, Norsa’adah B, Naing NN. Prognostic factors of na-
     or recurrence of nasopharyngeal carcinoma after primary radiother-             sopharyngeal carcinoma patients in a tertiary referral hospital: a ret-
     apy: options of surgical methods and regions. World J Surg Oncol               rospective cohort study. BMC Res Notes 2017;10:705. https://doi.
     2016;14:89. https://doi.org/10.1186/s12957-016-0822-8                          org/10.1186/s13104-017-2990-1
57
     Khor TH, Tan BC, Chua EJ, et al. Distant metastases in nasopharyn-        73
                                                                                    Jiang Y, Qu S, Pan X, et al. Prognostic nomogram for locoregionally
     geal carcinoma. Clin Radiol 1978;29:27-30. https://doi.org/10.1016/            advanced nasopharyngeal carcinoma. Sci Rep 2020;10:861. https://
     s0009-9260(78)80160-3                                                          doi.org/10.1038/s41598-020-57968-x
58
     Ai QY, Hu CW, Bhatia KS, et al. Nasopharyngeal carcinoma: rela-           74
                                                                                    OuYang PY, Zhang LN, Lan XW, et al. The significant survival ad-
     tionship between invasion of the prevertebral space and distant me-            vantage of female sex in nasopharyngeal carcinoma: a propensity-
     tastases. Eur Arch Otorhinolaryngol 2018;275:497-505. https://doi.             matched analysis. Br J Cancer 2015;112:1554-1561. https://doi.
     org/10.1007/s00405-017-4825-z                                                  org/10.1038/bjc.2015.70
59
     Liu GY, Li WZ, Wang DS, et al. Effect of capecitabine maintenance         75
                                                                                    Zhang Y, Yi JL, Huang XD, et al. Inherently poor survival of elderly
     therapy plus best supportive care vs best supportive care alone on pro-        patients with nasopharyngeal carcinoma. Head Neck 2015;37:771-
     gression-free survival among patients with newly diagnosed metastat-           776. https://doi.org/10.1002/hed.23497
     ic nasopharyngeal carcinoma who had received induction chemother-         76
                                                                                    Stepan KO, Mazul AL, Skillington SA, et al. The prognostic signifi-
     apy: a phase 3 randomized clinical trial. JAMA Oncol 2022;8:553-
                                                                                    cance of race in nasopharyngeal carcinoma by histological subtype.
     561. https://doi.org/10.1001/jamaoncol.2021.7366
                                                                                    Head Neck 2021;43:1797-1811. https://doi.org/10.1002/hed.26639
60
     Xu H, Lu L, Lu T, et al. Identifying the optimal candidates for lo-       77
                                                                                    Wu SG, Lian CL, Wang J, et al. The effect of histological subtypes
     coregional radiation therapy in patients with de novo metastatic na-
                                                                                    on survival outcome in nasopharyngeal carcinoma after extensive
     sopharyngeal carcinoma. Head Neck 2021;43:2602-2610. https://doi.
     org/10.1002/hed.26726                                                          follow-up. Ann Transl Med 2019;7:768. https://doi.org/10.21037/
                                                                                    atm.2019.11.75
61
     Yang L, Xue Y, Wei Z, et al. Local radiotherapy versus nonradio-
     therapy to distant lesions for metastatic nasopharyngeal carcinoma:
                                                                               78
                                                                                    Lee JT, Ko CY. Has survival improved for nasopharyngeal carcinoma
     retrospective cohort study. Head Neck 2022;44:615-623. https://doi.            in the United States? Otolaryngol Head Neck Surg 2005;132:303-
     org/10.1002/hed.26953                                                          308. https://doi.org/10.1016/j.otohns.2004.09.018
62
     Qu W, Li S, Zhang M, et al. Pattern and prognosis of distant metas-
                                                                               79
                                                                                    Colaco RJ, Betts G, Donne A, et al. Nasopharyngeal carcinoma: a ret-
     tases in nasopharyngeal carcinoma: a large-population retrospective            rospective review of demographics, treatment and patient outcome in
     analysis. Cancer Med 2020;9:6147-6158. https://doi.org/10.1002/                a single centre. Clin Oncol (R Coll Radiol) 2013;25:171-177. https://
     cam4.3301                                                                      doi.org/10.1016/j.clon.2012.10.006
63
     Yang ZC, Luo MJ, Sun XS, et al. Definitive radiation therapy and
                                                                               80
                                                                                    Balkwill F, Mantovani A. Inflammation and cancer: back to
     liver local therapy in de novo liver metastatic nasopharyngeal carci-          Virchow? Lancet 2001;357:539-545. https://doi.org/10.1016/
     noma: large cohort study. Head Neck 2022;44:1057-1068. https://doi.            S0140-6736(00)04046-0
     org/10.1002/hed.26999                                                     81
                                                                                    Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation.
64
     Xu JY, Wei XL, Wang YQ, et al. Current status and advanc-                      Nature 2008;454:436-444. https://doi.org/10.1038/nature07205
     es of immunotherapy in nasopharyngeal carcinoma. Ther                     82
                                                                                    Lin W, Cao D, Dong A, et al. Systematic construction and external
     Adv Med Oncol 2022;14:17588359221096214. https://doi.                          validation of an immune-related prognostic model for nasopharyngeal
     org/10.1177/17588359221096214                                                  carcinoma. Head Neck 2022;44:1086-1098. https://doi.org/10.1002/
65
     Barnes L, Eveson JW, Reichart P, et al., eds. World Health Organiza-           hed.26996
     tion Classification of Tumours. Pathology and Genetics of Head and        83
                                                                                    Yang S, Zhao K, Ding X, et al. Prognostic significance of hematologi-
     Neck Tumours. Lyon: IARC Press; 2005.                                          cal markers for patients with nasopharyngeal carcinoma: a meta-anal-
66
     Haghbin M, Kramer S, Patchefsky AS, et al. Carcinoma of the naso-              ysis. J Cancer 2019;10:2568-2577. https://doi.org/10.7150/jca.26770
     pharynx. A 25-year study. Am J Clin Oncol 1985;8:384-392. https://        84
                                                                                    Takenaka Y, Kitamura T, Oya R, et al. Prognostic role of neutrophil-
     doi.org/10.1097/00000421-198510000-00009                                       lymphocyte ratio in nasopharyngeal carcinoma: a meta-analysis.




168
                                                                                                                     Nasopharyngeal carcinoma. Part B




     PLoS One 2017;12:E0181478. https://doi.org/10.1371/journal.           92
                                                                                Yang XL, Wang Y, Bao Y, et al. Additional cervical lymph node biop-
     pone.0181478                                                               sy is not a significant prognostic factor for nasopharyngeal carcinoma
85
     Zeng X, Liu G, Pan Y, et al. Development and validation of immune          in the intensity-modulated radiation therapy era: a propensity score-
     inflammation-based index for predicting the clinical outcome in pa-        matched analysis from an epidemic area. J Cancer 2018;9:2844-2851.
     tients with nasopharyngeal carcinoma. J Cell Mol Med 2020;24:8326-         https://doi.org/10.7150/jca.25505
     8349. https://doi.org/10.1111/jcmm.15097                              93
                                                                                Chan AT, Grégoire V, Lefebvre JL, et al. EHNS-ESMO-ESTRO
86
     Jin YN, Liu BQ, Peng KW, et al. The prognostic value of adding             Guidelines Working Group. Nasopharyngeal cancer: EHNS-ESMO-
     systemic inflammation response index to Epstein-Barr virus DNA in          ESTRO Clinical Practice Guidelines for diagnosis, treatment and
     childhood nasopharyngeal carcinoma: a real-world study. Head Neck          follow-up. Ann Oncol 2010;21 (Suppl. 5):V187-V189. https://doi.
     2022;44:1404-1413. https://doi.org/10.1002/hed.27033                       org/10.1093/annonc/mdq186
87
     Chen Y, Jiang W, Xi D, et al. Development and validation of nomo-     94
                                                                                Chen YP, Mao YP, Zhang et al. Prognostic value of wait time in naso-
     gram based on SIRI for predicting the clinical outcome in patients
     with nasopharyngeal carcinomas. J Investig Med 2019;67:691-698.            pharyngeal carcinoma treated with intensity modulated radiotherapy:
     https://doi.org/10.1136/jim-2018-000801                                    a propensity matched analysis. Oncotarget 2016;7:14973-14982. htt-
                                                                                ps://doi.org/10.18632/oncotarget.7789
88
     Dickson RI. Nasopharyngeal carcinoma: an evaluation of
     209 patients. Laryngoscope 1981;91:333-354. https://doi.              95
                                                                                Eskander A, Merdad M, Irish JC, et al. Volume-outcome associations
     org/10.1288/00005537-198103000-00001                                       in head and neck cancer treatment: a systematic review and meta-
89
     Cai WM, Zhang HX, Hu YH, et al. Influence of biopsy on the                 analysis. Head Neck 2014;36:1820-1834. https://doi.org/10.1002/
     prognosis of nasopharyngeal carcinoma – a critical study of bi-            hed.23498
     opsy from the nasopharynx and cervical lymph node of 649 pa-          96
                                                                                Lee CC, Huang TT, Lee MS, et al. Survival rate in nasopharyngeal
     tients. Int J Radiat Oncol Biol Phys 1983;9:1439-1444. https://doi.        carcinoma improved by high caseload volume: a nationwide popu-
     org/10.1016/0360-3016(83)90315-2                                           lation-based study in Taiwan. Radiat Oncol 2011;6:92. https://doi.
90
     Li W, Lu H, Wang H, et al. Establishment and validation of a novel         org/10.1186/1748-717X-6-92
     nomogram to predict overall survival in nasopharyngeal carcinoma      97
                                                                                Goshtasbi K, Abiri A, Lehrich BM, et al. The influence of facility vol-
     with lymph node metastasis. Head Neck 2021;43:2353-2363. https://
     doi.org/10.1002/hed.26687                                                  ume on patient treatments and survival outcomes in nasopharyngeal
                                                                                carcinoma. Head Neck 2021;43:2755-2763. https://doi.org/10.1002/
91
     Lv JW, Zhou GQ, Chen YP, et al. Refining the role of lymph node
                                                                                hed.26739
     biopsy in survival for patients with nasopharyngeal carcinoma:
     population-based study from the surveillance epidemiology and end-    98
                                                                                Yoshida EJ, Luu M, David JM, et al. Facility volume and sur-
     results registry. Ann Surg Oncol 2017;24:2580-2587. https://doi.           vival in nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys
     org/10.1245/s10434-017-5966-4                                              2018;100:408-417. https://doi.org/10.1016/j.ijrobp.2017.09.038




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