Introduction
The primary treatment for nasopharyngeal cancer
(NPC) is radiotherapy (RT) ± chemotherapy (CT). Intensity-
modulated radiotherapy (IMRT) has been used in NPC for the past two decades. Local control (LC)
rates are over 90% with IMRT and CT.[] In addition,
IMRT reportedly decreases toxicity rates and provides
better survival rates in NPC cases. Therefore chronic
side effects are becoming increasingly important, especially as overall survival has improved with IMRT.[]
Chronic injury is possible as the lower cranial nerves
usually remain within the primary high-dose volume
during treatment. Lower cranial nerve injury may result
in a significant reduction in the patient's quality
of life. There is limited evidence on the relationship
between the dose to which the lower cranial nerves
are exposed and nerve damage.[] Some of the published
data focus on Dmax for nerves considered serial
organs, while others focus on the mean dose.[,] Furthermore,
lower cranial nerve contouring in treatment
planning is uncommon. In this study, the dosimetric
differences in the lower cranial nerves and the dosevolume
relationship in cases with side effects will be
evaluated by contouring the lower cranial nerves and
retrospectively analyzing the radiotherapy plans.
Methods
Patient Characterictics
A total of 125 patients diagnosed with nasopharyngeal
cancer who underwent definitive RT with or without
CT at our institution between 2010 and 2024 were included
in the study. The patient characterictics is presented
in Table 1. The inclusion criteria were patients
with histopathologically confirmed nasopharyngeal
cancer who underwent curative RT ± CT, had at least 6
months" follow-up after treatment, had been followedup
with magnetic resonance imaging (MRI) scans, had
no primary recurrence, and had no involvement of the
lower cranial nerves before treatment. The exclusion
criteria were patients who did not undergo treatment
or follow-up at our institution; those who did not follow
with MRI scans; and those with recurrence were
excluded from the study. All patients underwent a
standard diagnostic radiological assessment, which included
nasopharyngeal and neck magnetic resonance
imaging (MRI) on admission and after three courses
of neoadjuvant chemotherapy. In cases diagnosed after
2010, an additional procedure was conducted as
a routine part of the radiologic evaluation: 18-Fluorodeoxyglucose
positron emission tomography-computed
tomography (18-FDG PET-CT). Tumour-nodemetastasis
staging was performed under the eighth
edition of the American Joint Committee on Cancer
(AJCC) classification. The 5th version of the Common
Terminology Criteria for Adverse Events (CTCAE)
was used to classify the adverse effects. This study was
approved by the Istanbul University-Cerrahpaşa Rectorate
Ethics Committee and adhered to the principles
of the Declaration of Helsinki.
Table 1: Patient characteristics
Chemotherapy
In patients with T3, T4, and N3 tumors, chemoradiotherapy
is typically initiated following three cycles of
induction chemotherapy. Before 219, the induction
CT regimen was TPF (5-FU 750 mg/m2 by 24-h continuous
infusion d1-5, cisplatin 75 mg/m2 d1, and
docetaxel 75 mg/m2 d1 for three cycles every 3 weeks).
Subsequently, GP (gemcitabine 1 g/m2 d1 and d8 with
cisplatin 80 mg/m2 d1, for three cycles every 3 weeks)
was used as the induction CT regimen. Cisplatin chemotherapy
was administered at a dose of either 75-100
mg/m2 every three weeks or 40 mg/m2 every week, according
to the patient's performance status, concomitantly
with RT. Of the patients, 38% underwent induction
chemotherapy. The proportion of patients who
received cisplatin above 200 mg, either with or without
induction chemotherapy, is as follows 76.7 %.
Radiotherapy
The patients were all immobilized with the use of a
thermoplastic head and shoulder mask. A series of
computed tomography (CT) scans were obtained at
a slice thickness of 1.25-2.5 mm, extending from the
cranial vertex to the bifurcation of the carina in the supine
position. The planning CT scan was fused with the
MRI and PET/CT images.
Target delineation, dose planning, and treatment volume
definitions were performed in accordance with the
methodology established in our previous study. The same
contouring protocols and dose constraints were applied
in a consistent approach, without any modifications.
The radiotherapy dose was reduced for pediatric
patients. The dose for PTV high-risk was 61.2-63Gy,
for PTV intermediate-risk was 54Gy, and PTV lowrisk
was 45Gy. Of these 80% underwent the simultaneous
integrated boost (SIB) technique.[]
Treatment and Follow-up
The IMRT or volumetric modulated arc therapy (VMAT)
plan was generated for each patient using the Eclipse version
8.6 treatment planning system with 6-MV photon
beams from a LINAC (linear accelerator; Varian Medical
Systems, Palo Alto, USA). Verification of the radiotherapy
volume was conducted on each fraction using
either a cone beam CT scan or a kilovoltage (kV) imaging
modality for image-guided radiation therapy (IGRT).
A dose-volume histogram (DVH) was used to define
the target dose and the dose to organs at risk (OAR).
The patients were examined every week to evaluate any
acute adverse effects. All patients completed the planned
course of treatment. At each visit, patients underwent both endoscopic examination and MRI of the nasopharynx
and neck. This follow-up schedule was conducted
every 3 months for the first two years, every 6 months for
the next three years, and annually thereafter.
Dosimetric Data and Statistical Analysis
A total of 125 patients with histologically confirmed
NPC who underwent radiotherapy with or without chemotherapy between 2010 and 2024 were retrospectively
reviewed. For a detailed dosimetric analysis, we
selected a subset of 96 patients from this cohort. The
remaining 29 patients were excluded due to technical
limitations, such as the unavailability of complete
treatment planning for accurate contouring, thereby
minimizing the potential for selection bias. For these 96
patients, the lower cranial nerves (CN9, CN10, CN11,
and CN12) were separately and bilaterally delineated
on treatment planning CT scans that were fused with
MRI and PET/CT images (Fig. 1). This contouring was
performed by a single experienced radiation oncologist
using a published CT-based atlas as an anatomical reference
by Mourad et al.[] to ensure consistency. The
relationship between several dosimetric parameters
(Dmax, Dmean, D2cc, D1cc, and D0.5cc) and lower cranial nerve palsy was then analyzed. The diagnosis was primarily
based on clinical findings, as documented in patient
records. To ensure diagnostic accuracy, all patient
files were reviewed for physical examination findings,
and all MRI reports interpreted by a neuroradiologist
were carefully examined to identify patients with nerve
palsy. The findings in the nerve-palsied patients were
then confirmed by a physical examination performed
by a physician experienced in neuro-oncology during
a follow-up appointment. Regarding electromyography
(EMG), we confirmed that routine EMG was not
performed. The trapezius muscle was examined for the
presence of multiple cranial palsy on magnetic resonance
imaging (MRI) in patients presenting cranial
nerve (CN) 12 palsy. The patient characteristics were
determined using descriptive statistical methods. The
Mann-Whitney U test was performed for the purpose
of evaluating the data associated with the nerve palsy
and the exposed doses. Cox regression analysis was
performed using univariate analyses for diabetes mellitus
(DM), hypertension (HT) and smoking. A p-value
of 0.05 was used to determine the statistical significance
of the results. All analyses were conducted using
SPSS version 22.0 (IBM Corp., Armonk, NY, USA).
Fig 1: Bilateral lower cranial nerves" volume on axial and coronal slices
Results
The patient cohort was 77.6% male and 22.4% female.
Upon analysis of the comorbidities of the patients, it
was observed that the percentage of smokers, diabetes,
and hypertension were 44.8%, 11.2%, 23.2% respectively.
The percentage of patients with T3-T4 tumors and
tumors with positive lymph nodes is as follows: 34.4%,
81.6%. The number of patients presenting with disease- related nerve palsies (with the exception of the CN 9-12
involvement) at the initiation of therapy was 12.
No patients developed grade 3-4 toxic effects associated
with the therapeutic regimens. The overall median
follow-up period for the sample was 44 months. The
median follow-up period was 58 months (range 6-151)
among the surviving patients. All patients evaluated for
nerve palsy showed no evidence of locoregional recurrence.
The number of patients who developed distant
metastasis is as follows: 20 (16%). The median overall
survival was observed to be 53 months. Thirty-eight
patients (30.4%) died during the follow-up period. Of
these patients,17 died of disease-related causes, while
21 died of non-disease-related causes. Nerve palsy was
observed in 8 out of the 125 patients who underwent
definitive IMRT. Five patients exhibited CN9-11 palsy
while all patients who developed 9-11. nerve palsy also
had CN12 palsy. The median time to the onset of nerve
palsy was 75 months (range 14-133)
When the patients were evaluated in terms of clinical
characteristics such as smoking, DM, HT, age and stage
no statistically significance was found with lower cranial
nerve palsy including CN12 and CN 9-11. The impact
of smoking, DM, HT and age on the time interval
following RT and the occurrence of lower cranial nerve
palsy was evaluated. However, the findings revealed that
these factors were not statistically significant.
A total of 250 lower cranial nerves were evaluated
from a dosimetric perspective. The median CN 12 volume
was 9.4 cc (range 4.2-17.4) while 9.9 cc (range
4.2-17.8) was for CN 9-11 unilaterally. There was no
statistically significant with nerve palsy and dosimetric data. The dosimetric data of the patients and the incidence
of nerve palsy are presented in Table 2.
Table 2: The dosimetric data of the patients and the incidence of nerve palsy
The evaluation of the dosimetric characteristics of
the patients in terms of time following RT and nerve
palsy revealed no significant findings.
Discussion
The prevalence of severe adverse effects that lead to a reduction
in the quality of life of survivors has increased
with the enhanced efficacy of cancer treatments. In the
majority of cases, clinically asymptomatic conditions
do not have an negative impact on the quality of life
of patients.[] However, depending on the irradiated
tissue and administered dose, serious adverse effects,
such as damage to the cranial nerves, may occur in the
long term. As is widely acknowledged, RT carries out
its effects on tissue through the generation of free oxygen
radicals as a consequence of ionization. Radicals
typically participate in physiological processes such as
cell differentiation, proliferation, and inflammation.
However, excessive production can result in physical
and chemical damage, as well as pathological stress,
when antioxidant defences are inadequate. As the concentration
of radicals in the tissue increases with RT,
direct toxicity for cells and a fibrotic process are initiated.[] The short-term damage becomes chronic by
overcoming the repair mechanisms of the tissue via the
regenerative processes of stem cells. The delayed local
damage initially attributable to microvascular damage
in mature nerve tissue is defined as radiotherapyinduced
neuropathy (RIN). This phenomenon is characterized by a prolonged and consistent progression
over an extended period. The initial phase is marked
by the presence of chronic inflammation, often without
overt symptoms, and is referred to as the "prefibrotic"
phase. Subsequent to this initial phase, a fibrotic phase
becomes apparent, in which there is an organized deposition
of extracellular matrix. The final phase is a late
fibroatrophic phase, distinguished by a lack of vascularization
and retractile fibrosis. The delayed effects are
a consequence of several factors, including fibroblast
proliferation induced by cytokines such as TGF-β1, extracellular
matrix deposition, direct axonal injury and
demyelination, extensive fibrosis, and irregular neovascularisation
in and around nerve trunks, and ischemia
in the capillary networks supplying the nerves.[] These
factors result in an irregular structure in the irradiated
volume. Consequently, the symptomatic nerve damage
observed in the chronic phase is no longer reversible.
Although factors influencing RIN risk and severity are
unclear, several RT-related factors are currently known:
High total dose (>50 Gy to plexus, >60 Gy to cranial
nerves),[] high dose per fraction,[11] RT volume with
large part of nerve fibres,[] inhomogeneous high dose
distribution,[] high dose at hot spots, salvage RT of
sites previously treated, intracavitary radium source[]
or after IORT boost. Cases of lower cranial nerve damage were observed to be in the range of 1 to 11 years in our
study and we found that 6% of patients had lower cranial
nerve palsy after treatment, compared with 5.1-8.7% in
the literature.[] The doses administered to the nerves are
at the apex of the sigmoidal dose-effect curve, where the
probability of complications is subject to significant variation
with even a minor alteration in radiation dose. The
lower cranial nerves are subjected to exceptionally high
doses during nasopharyngeal treatment, primarily due to
their close proximity to the high-dose target volume. It is
established that peripheral nerves are more radioresistant
than other neural structures.[] Nevertheless, it is essential
to minimise hot spots in these structures in order to
reduce the incidence of neuropathy, which has a significant
impact on quality of life. There is a lack of data in
the existing literature regarding the doses to which these
nerves are exposed. Chow and colleagues demonstrated
that Dmax, Dmean, D2cc, D1cc and D0.5cc were significantly associated
with the development of nerve palsy. Of these,
D1cc was identified as the most effective factor for predicting
radiation-induced hypoglossal nerve palsy. Furthermore,
they established that a D1cc limit of EQD2 <74 Gy
could reduce the risk of this toxicity to less than 5%.[] In
our study, we implemented these established constraints
for the analysis of nerves however no statistical significance
was found between doses and RIN.
A possible explanation for this discrepancy could
be differences in treatment techniques and patient
populations between studies. For instance, our cohort
was treated exclusively with modern Intensity-Modulated
Radiotherapy (IMRT) techniques, which are designed
to deliver a highly conformal dose to the target
volume while sparing surrounding critical structures,
including the cranial nerves. This contrasts with some
earlier studies that may have included patients treated
with older, less conformal techniques, which could
have resulted in higher and more heterogeneous doses
to the nerves. Furthermore, differences in patient populations,
such as varying tumor stages, comorbidities
(e.g., diabetes mellitus and hypertension), or follow-up
durations, could also influence the observed outcomes.
While our study assessed the impact of these clinical
factors, the limited number of palsy events prevented
us from performing a robust statistical analysis to fully
account for these confounding variables. This highlights
the complexity of radiation-induced neuropathy
and the need for larger, multi-institutional studies to
identify consistent predictive factors.
In this study, T stage, N stage, age, gender, smoking,
DM, and HT were assessed as predictive factors. The incidence
of nerve damage increased in the advanced stages
of the disease due to the increased RT volume irradiated.
In literature, hypoglossal nerve damage was related
to advanced T and N stages however in our study we
did not find statistical significance.[,] In one of our
patients, unilateral CN 12 damage was observed due to
the retropharyngeal lymph node metastasis, although it
was in the early stage (T1N1). Side effects of radiotherapy
increased due to microvascular damage. When other
predictive factors were evaluated HT, DM, and smoking
were related to microvascular damage.[] Although
some studies demonstrated that this relations between
radiotherapy side effects and microvascular damage for
NPC patients, we did not show statistical significance.
Radiation-related neuropathy was an irreversible
chronic side effect. Also, high dose steroids, hyperbaric
oxygen, and pentoxifylline-tocopherol clodronate
were recommended for the treatment of this
complication. Pentoxifylline-tocopherol reduced
radiotherapy-induced fibrosis whereas clodronate reduced
inflammatory effects. In our clinical procedure,
clodronate combined with pentoxifylline-tocopherol
was prescribed for patients with RIN. However, we
did not observe any recovery in our patients, only stabilization
was observed. On the other hand, physical
therapy and surgical treatment might be recommended
for maintaining function.[,,]
Limitation and Strengths
This study has several limitations, including its retrospective
design and small sample size of only 8 palsy
events. The small sample size likely rendered our study
underpowered and precluded a meaningful multivariate
analysis, which limits our ability to identify independent
predictors of cranial nerve palsy. Furthermore,
the lack of a standardized neurological evaluation protocol
and a formal interobserver variability assessment
for contouring are acknowledged limitations.
Despite these limitations, our study has key strengths:
All treatments were administered with modern IMRT
techniques, and patients with primary or lymph node
recurrence were excluded, which ensures a more homogeneous
cohort. Additionally, all patients were consistently
followed up with MRI scans and physical examinations,
providing robust clinical data for evaluation.
Conclusion
In this study, there was no correlation between radiotherapy-
induced neuropathy in the lower cranial
nerves and doses or other factors. However, the lower
cranial nerves are vital for quality of life, and the nerves
should be contoured.
Ethics Committee Approval: The study was approved by
the Istanbul University-Cerrahpaşa Rectorate Ethics Committee
(no: 1069261, date: 21/08/2024).
Conflict of Interest Statement: The authors have no conflicts
of interest to declare.
Funding: The authors declared that this study received no
financial support.
Use of AI for Writing Assistance: No AI technologies utilized.
Author Contributions: Concept - O.E.U.; Design - M.D.,
O.E.U.; Supervision - M.D.; Materials - I.F.D.; Data collection
and/or processing - I.F.D., S.Y.; Data analysis and/or interpretation
- M.D., I.F.D., G.C.; Literature search - S.C.K.,
O.E.U.; Writing - I.F.D., M.D.; Critical review - O.E.U.
Peer-review: Externally peer-reviewed.
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