Introduction
Nasopharyngeal cancer (NPC) is a radiosensitive disease.[] A recent series reported local control (LC)
rates over 90% with intensity-modulated radiotherapy (IMRT) and chemotherapy (CC).[-] Alongside LC,
acute and late treatment complications increase in a
dose-dependent manner. Some studies have used dose
reduction and contour modification for NPC to minimize
side effects in adults. While tumor control is similar using these treatment adjustments, according to the
literature, results show a decrease in acute and chronic
side effects.[,] In addition, IMRT reportedly decreases
toxicity rates and provides better survival rates
in NPC cases.[-] Therefore, current guidelines suggest
IMRT for NPC.
NPC in childhood is rare, with an incidence rate
of <1% among all childhood tumors.[] When compared
to adults with NPC, while treatment is similar,
tumor LC and disease-free survival (DFS) are better for
children.[] However, toxicities such as dental caries,
growth development abnormalities, endocrine irregularities,
and secondary malignancies were observed
more frequently in children than in adults.[,] Thus,
dose reduction studies to reduce side effects without
compromising LC have been performed.[,]
Our primary purpose in this study was to analyze
the outcomes of different doses of radiotherapy (RT)
by retrospectively reporting results from adolescent
and childhood NPC cases treated with IMRT and 3Dconformal
RT (3D-RT).
Methods
Study Population
All children and adolescents ?22 years old with NPC,
treated at the Cerrahpasa Medical School Radiation
Oncology Department between 2007 and 2021, were
included in this retrospective study. Patients" medical
records were reviewed for demographics, clinical presentation,
laboratory results, radiology records, pathology
data, treatment details, outcomes, and longterm
sequelae. On admission, all patients underwent
a thorough physical examination, nasopharyngeal endoscopy,
and laboratory evaluation (complete blood
count, liver and kidney function tests, and serum Epstein?
Barr virus [EBV] DNA level, if possible). The
standard diagnostic radiological assessment for all
patients included nasopharyngeal and neck magnetic
resonance imaging (MRI) on admission and after 3
courses of neoadjuvant CC. For those diagnosed after
2010, 18-fluorodeoxyglucose positron emission tomography-
computed tomography (18-FDG PET-CT)
was also performed as a routine part of the radiological
evaluation. Tumor-node-metastasis was staged
according to the 8th edition of the American Joint
Committee on Cancer. Adverse effects were evaluated
according to the Common Terminology Criteria for
Adverse Events version 5. This study was approved by
the local ethics committee (No: 404194).
CC
All but 2 patients (n=18) started treatment with neoadjuvant
CC followed by RT. Different induction chemotherapy
(IC) regimens were administered every 3
weeks for 3-4 cycles during the study period. Patients
diagnosed between 2007 and 2009 received cisplatin,
80 mg/m2 on day 1 and 5-fluorouracil 800?1000 mg/m2
for a 96 h continuous intravenous infusion (PF). From
2009 to 2019, patients received docetaxel 75 mg/m2 on
day 1 and cisplatin 75 mg/m2 on day 1 with 5-fluorouracil
750 mg/m2 for a 96 h continuous intravenous infusion
(TPF). After 2019, gemcitabine 1 g/m2 on days
1 and 8 and cisplatin 80 mg/m2 on day 1 or 25 mg/m2/
day on days 1?3 (GP) and concomitant chemotherapy
(CCT) with RT consisting of cisplatin weekly 20 mg/m2
by intravenous infusion were the preferred regimen.
Two patients were administered only CCT with RT
(no prior IC), one of whom had a diagnosis of cystic
fibrosis and chronic lung disease. The other patient had
early-stage disease (T2N1) and was >20 years of age.
RT
For RT, all patients were immobilized using a thermoplastic
head and shoulder mask in a supine position. The
planning CT was obtained with a 2.5 mm slice thickness
from the head to the carina. Both PET-CT and MRI fusion
with the RT planning CT were used to detect the
primary tumor and metastatic lymph nodes. Organs at
risk and target volumes were contoured according to
radiation therapy oncology group (RTOG) guidelines.
[,] The gross tumor volume of the primary tumor
and metastatic lymph nodes were delineated according
to clinical and radiological findings. Three clinical target
volumes (CTV) were defined. The high-risk CTV was
delineated as the primary tumor volume (according to
pre-CT) and metastatic lymph nodes (according to post-
CT) plus a 5 mm margin. The intermediate-risk CTV
was defined as the high-risk CTV plus a 5 mm margin
and was modified to include the entire nasopharynx and
whole involved nodal level. The low-risk CTV had to
cover the intermediate-risk CTV and the entire vomer,
surrounding ethmoid sinus, sphenoid sinus (for T1-T2
stage tumors: Inferior part of sphenoid sinus, for T3-T4
stage tumors: Whole sphenoid sinus), cavernous sinus
(for T3-T4 stage tumors: Whole ipsilateral cavernous
sinus), skull base foramina (foramen ovale, foramen rotundum,
and foramen lacerum), posterior nasal cavity,
posterior maxillary sinus, clivus (if not involved: Anterior
1/3 part of clivus; clival involvement: Entire clivus),
parapharyngeal space, and elective bilateral cervical
lymph nodes. The planning target volume (PTV) was defined by adding 3 mm in all directions for IMRT and 5
mm for 3D-RT to all CTVs. Field verification (anatomical
match) for image-guided RT was carried out with
daily cone-beam CT and kV images for patients with
IMRT planning. The patients with 3D conformal planning
were treated with portal imaging every day.
IMRT was used in 16 patients, while 3D-RT was
used in 4 patients. The PTV 61.2 Gy/34 fr (complete or
good partial response) and PTV 63 Gy/ 35 fr -70 Gy/
35 fr (partial response or only concurrent chemoradiotherapy
[CCRT]) were delineated as the high-risk volumes,
while PTV 54 Gy/30 fr ?60 Gy/33 fr was delineated
as the intermediate-risk volume. For the low-risk
volume, PTV 45 Gy/25 fr -54 Gy/30 fr was delineated
for high-risk areas with the potential for microscopic
spread and elective bilateral cervical lymph nodes. The
treatment schedule is detailed in Table 1.
Table 1: The treatment schedule
Response Criteria
Tumor response was assessed with 18-FDG PET-CT or
MRI after IC and 12 weeks after the end of RT. A complete
or good partial response was defined as the disappearance
of the disease or >75% disease response. A
partial response was defined as a tumor volume reduction
between 75% and 50%, whereas a stable response
was defined as a reduction of up to 50%.[]
Follow-up
Follow-up time was calculated between the completion
of RT to the last visit. All patients were re-evaluated
with MRI at 1.5-2 months and with PET-CT at
3?4 months after completion of RT. Patients were followed
up every 3 months during the first 2 years and
every 6 months after that. Follow-up visits included a
complete physical and fiber-optic head and neck examination
and biochemical and hematological blood
tests. A nasopharyngeal/neck MRI was performed
every 6 months. All patients were assessed for chronic
side effects such as skeletal growth retardation,
bone necrosis, nasopharyngeal mucosa necrosis,
radiation-induced trismus, cranial nerve palsy, aspiration,
alopecia, xerostomia, hearing impairment,
dental caries, hypothyroidism, fibrosis of the neck,
hypopituitarism, esophageal stricture, and secondary
malignancy. Toxicity was evaluated by the results of
the patient"s self-reported complaints, physical examination,
hearing tests, and laboratory results.
Statistical Analysis
All analyses were performed with SPSS version 22.0
(IBM, NY, USA). Descriptive statistical methods were
used to determine patient characteristics. The overall survival (OS), DFS, metastasis-free survival (MFS),
and LC were defined from the completion of IMRT to
the last visit. Survival analyses were made using the Kaplan?
Meier method.
Results
Twenty children and adolescents with NPC were evaluated.
The median age at diagnosis was 16 years (range
11-22), and the male/female ratio was 3:1. Non-keratinizing
undifferentiated carcinoma was the most common
histopathology (n=19), as only one patient had
keratinizing carcinoma. The tumor stage was T1-2 in 9
(45%) and T3-4 in 11 (55%). The nodal stage was N1 in
10 (50%) and N2 in 7 (35%) (Table 2).
Table 2: Patient and disease characteristics
Serum EBV DNA was detected in 1 of 5 patients
and became non-detectable after IC.
Treatment Response
All patients were evaluated with MRI scans before and
after CC; however, PET-CT scans were used in 14 patients
for assessment.
Eighteen patients received IC (TPF, PF, GP) before
CRT (n=16) or RT (n=2). Two patients were treated
with only CRT. After IC, 11 out of 18 patients achieved
a complete or good partial response. The remaining 7
patients had a partial response (TPF n=6, GP n=1). All
patients achieved a complete response after RT. The intended
weekly CCRT could not be given regularly due
to hematological toxicity in 3 patients treated with GP.
Treatment Outcome
The median follow-up time was 107 months (range:
6-168). No local or regional relapse was detected during
follow-up. The 5-year LC, DFS, MFS, and OS were
all 100%, while the 8-year LC, DFS, and OS were 100%,
90.9%, and 100%, respectively.
One patient developed single bone metastasis,
which was confirmed with a biopsy 62 months after
the primary diagnosis. He was treated with 6 cycles
of CC followed by RT to the metastatic bone site and
achieved a complete response. He is still well without
any evidence of disease 26 months after completing
treatment.
Toxicity
Grade 2 mucositis, dysphagia, and dermatitis were observed
in the whole group. Grade 3 acute side effects observed were mucositis 25%, dysphagia 25%, and dermatitis
15%. There were no grade 4 acute side effects.
Similar acute side effects were observed when ≤61.2 Gy
and >61.2 Gy dose groups were compared.
Grade 2 chronic side effects of xerostomia 30%,
hearing impairment 25%, dental caries 50%, and hypothyroidism
45% were observed. For hearing impairment,
the cochlear doses for all patients (n=19) were
within the dose limits (mean dose <50Gy) except for
one patient. Fibrosis of the neck in one patient, hypopituitarism
in one patient, and an esophageal stricture
requiring endoscopic dilatation in another patient
were also observed.
More chronic side effects were observed in the
>61.2 Gy group compared to the ≤61.2 Gy group.
Dental caries and hypothyroidism were observed in
60% of patients, and hearing impairment and tinnitus
in 40% of patients in the >61.2 Gy group. However, in
the ≤61.2 Gy group, the percentage of patients with
dental caries was 40%, and hypothyroidism was 30%.
Hearing impairment and tinnitus were not observed
in this group (Table 3).
Table 3: Acute and chronic side effects of the doses
When we compared 3D-RT and IMRT groups who
were treated with ≤61.2 Gy, the occurrence of dental
caries and hypothyroidism was similar. On the other
hand, hearing impairment was reported at 25% (n=1)
with 3D-RT and 12.5% (n=2) with IMRT, and esophageal
stricture (n=1) was also observed with 3D-RT.
Discussion
The standard treatment for pediatric NPC is IC followed
by definitive RT ± CC according to the current
international guidelines.[] Although dose reduction
in RT is recommended for children, LC and OS were better for children compared to adults with NPC. In
this study, we reported the outcome of LC and OS in
patients with pediatric NPC.
NPC is a chemosensitive malignancy, and several
retrospectives and a few prospective studies have
documented the efficacy of CC in pediatric cases.[]
Cisplatin-based CC protocols are now considered the
standard of care in children and adolescents with NPC,
but the optimal CC combination has not yet been determined.
The current treatment plan for pediatric NPC is
IC followed by CC with RT, but there are no comparative
studies on the efficacy of different regimens. The treatment
center usually determines the IC scheme.[,,]
In our center, cisplatin has been the main backbone of
IC and CCRT for many years, and TPF has been the
standard IC protocol since 2009. We had to choose an
IC protocol with a shorter hospital stay. Due to a small
study population, it is impossible to compare the efficacy
of the 2 schemes, but 4 out of 5 patients treated with
first-line GP achieved a very good or complete response
before RT, whereas 5 out of 11 cases treated with TPF
had similar responses. In our study, 55% (n=11) of patients
had a near-complete response, and the remaining
had significant responses to IC. However, it is noteworthy
as a clinical observation that GP was more practical
in terms of both duration and application and less toxic
to use in resource-limiting settings like ours.
In our study, 2 patients were administered only
CCRT without prior IC. Cystic fibrosis is a genetic disease
affecting the lung and gastrointestinal tract with
an immune function deficit failing to eradicate pathogens,
so IC was omitted from this patient. The other
patient had early-stage disease (T2N1) NPC and was
>20 years of age. Their treatment protocol was similar
to that for adult NPC.
The indication and efficacy of CCRT are still debatable
in pediatric NPC. There are no randomized studies
to compare RT with or without CC, and all information
is based on retrospective data.[12] Some studies showed
improved survival rates with CCRT with increased
toxicity, and some suggest the omission of CC in the
presence of a very good partial or complete response
to IC.[] Considering the toxicity, a response-based
approach could be suggested in the future. Although
some studies reported T classification and treatment
response association with OS or DFS, only one distant
metastasis was reported as the predominant pattern of
failure in our study.[,] The study demonstrated that
radiation dose reduction adapted to the CC response
does not have a negative impact on OS and LC. Orbach
et al.[] treated 34 pediatric NPC patients according to their IC response. Of those patients, the overall response
rate to neoadjuvant CC was 78%. The cervical
nodal irradiation dose was reduced in 15 patients to
the median dose of 47 Gy (range: 45-50). The high-risk
volume was given 59.4 Gy (range: 45-66). The 5-year
OS was 73±8%, and local and distant failure rates were
10% and 18%, respectively. A French multicenter study
evaluated neoadjuvant platinum-based CC followed by
tumor response-adapted CRT results. For the primary
tumor, the dose was defined as 59,4Gy in patients with
a CC response ≥50%, while in patients with a CC response
<50% had a specified dose of 66.6 Gy. Involved
and uninvolved neck nodes were prescribed reduced
doses of 54 Gy and 45 Gy, respectively, after a favorable
tumor response. After a median follow-up of 4.5 years,
13 (13.6%) relapses and 7 (7.3%) deaths were observed.
[] In the ARAR0331 study, patients with complete
or partial response to IC received 61.2 Gy to the nasopharynx
and neck, and patients with stable disease
received 71.2 Gy. The 5-year event-free survival and OS
estimates were 84.3% and 89.2%, respectively.[] In our
study, 10 patients with complete response to IC were
treated with 61.2 Gy, whereas 6 patients with partial
response to IC were treated with 63 Gy. The other 4 patients
were treated at 66-70 Gy. Our standard treatment
protocol for adults (70 Gy to high-risk volume) was
administered to patients >18 years old. There was no
relapse or death after the median follow-up of 5 years.
This data supports the possibility of dose reduction for
pediatric NPC patients responding to IC.
Another issue involves treatment volume. The guide
recommended 2 volumes for primary tumors; one included
the primary tumor, and the other included the
sphenoid sinus-maxillary sinus and whole mucosa.[]
In another study using doses similar to ours, 2 RT volumes
were defined as 61.2 Gy for the primary tumor
and 45 Gy for the entire nasopharynx and cervical
lymph nodes.[] However, in our study, we determined
3 volumes: The first volume (high-risk) covered the primary
tumor, the second volume covered the whole nasopharynx,
and the third volume covered the sphenoid
sinus-maxillary sinus and the whole mucosa with tumor
spread risk. Although the whole mucosa was included
in the low-risk volume, no recurrence was observed.
The side effects of RT were compared to our historical
data.[] There were varying degrees of acute mucosal
and skin reactions, which were associated with
weight loss in both series. No patient required hospitalization
or tube feeding due to mucositis. On the other
hand, chronic side effects such as skeletal growth retardation
(15.6%), trismus (6.2%), and necrosis of the bone-nasopharyngeal mucosa (6.2%) were observed
in historical data. In the present data from our clinic,
radiation-induced trismus, cranial nerve palsy, aspiration,
and alopecia were not observed; however, there
was hearing impairment in 20% of patients. Ototoxicity
depends on several factors, including cumulative
cisplatin dose and RT dose as hearing impairment
may be affected not only by the cochlear RT dose but
also by cumulative cisplatin doses. In this study, over
60% of patients underwent IMRT with dose reduction,
and chronic side effects decreased. In another study in
which Sahai et al.[] evaluated 41 pediatric patients for
the outcome and treatment-related morbidity, 28 were
treated with IC followed by CCRT with a dose of 65?70
Gy in 35 fractions, 8 were treated with IMRT, 18 with
3D conformal radiation therapy, and 14 with 2D simulation.
Late side effects including xerostomia (88%),
hypothyroidism (82%), dental caries (65%), neck fibrosis
(59%), trismus (59%), dysphagia (47%), growth
restriction (35%), and hearing impairment (29%) were
reported. Only one patient was observed to have radiation
myelitis. These side effects were observed less
in our study. Xerostomia decreased with IMRT and
dose reduction compared to our historical data. In a
French study, 95 patients were evaluated with IC, followed
by doses of adapted CRT to the IC response. Of
those, 57 (60%) patients were treated with IMRT, while
the remaining were treated with 3D-RT. Odynophagia
was significantly reduced in patients treated by IMRT;
however, 2 patients developed a second malignancy in
the head and neck area.[] These studies indicate that
reduced-dose IMRT helps decrease side effects without
compromising locoregional control.
Limitations
Our study has several limitations, including its retrospective
design and small sample size. In addition, the
enrolled patients had heterogeneous baseline characteristics.
The brief follow-up period for chronic side
effects and recurrence, when compared with the first
historical data is also a study weakness.
Conclusion
In our study, over 60% of patients were treated with
the reduced-dose IMRT technique. Although lowerdose
RT was administered, local-regional control was
100%, and the rate of side effects was lower. Prospective
multicenter studies are needed to confirm the
safety of dose reduction, especially in patients with
complete responses after IC.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by
the İstanbul University-Cerrahpaşa Clinical Research Ethics
Committee (no: 404194, date: 10/06/2022).
Financial Support: None declared.
Authorship contributions: Concept - M.D., S.Ç.K., Ö.E.U.;
Design - M.D., S.Ç.K., Ö.E.U.; Supervision - M.D., Ö.E.U.;
Materials - M.D., M.V.H.; Data collection and/or processing
- T.K.Ç., E.S.A., S.K., M.V.H.; Data analysis and/or interpretation
- M.D., S.O., T.K.Ç., S.K., M.V.H.; Literature search
- M.D., S.O., Ö.E.U.; Writing - M.D., S.O., Ö.E.U.; Critical
review - M.D., S.O., Ö.E.U.
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