To the editor:
Radiotherapy forms the cornerstone of the curative treatment of
nasopharyngeal carcinoma. Relatively high doses of radiotherapy are used
and as such, late toxicity is a concern in children and adolescents with
nasopharyngeal carcinoma who are treated with radiotherapy. We report on
a patient with a long disease-free survival of 5 years after treatment
despite receiving a reduced dose of radiotherapy.
A 15-year-old girl presented with a 4-cm left-sided neck mass of 2
weeks’ duration. Nasoendoscopic evaluation demonstrated a mass in the
right nasopharynx. Magnetic resonance imaging (MRI) and
18F-fluorodeoxyglucose (FDG) positron emission tomography with computed
tomography (PET/CT) demonstrated a nasopharyngeal mass, which was more
prominent on the right side, and conglomerate lymph nodes, more
prominent on the left, involving bilateral levels II, III, IV, V, and
VII, with no distant metastases (Fig. 1). Findings from a biopsy of the
posterior nasal space mass and fine needle aspiration cytology of a neck
node were consistent with undifferentiated carcinoma with nodal
metastases. Quantitative polymerase chain reaction (PCR) for
Ebstein-Barr Virus (EBV) deoxyribonucleic acid (DNA) yielded 5,395
copies. She disease was staged as T1 N3b M0, Stage IVB, nasopharyngeal
undifferentiated carcinoma, World Health Organization (WHO) type 3,
using the American Joint Committee on Cancer (AJCC)
7th Edition Staging Manual. Despite counselling, her
parents and her declined standard treatment and sought alternative
medicine. She also received 1 cycle of the humanized monoclonal
programmed cell death-1 (PD-1) antibody pembrolizumab at an external
institution.
She was lost to follow-up, but returned 10 months later with progressive
neck nodal disease. Repeat investigations with MRI and FDG PET/CT
demonstrated bulkier locally advanced disease without distant
metastases, with the same stage of T1 N3b M0, Stage IVB. Quantitative
PCR for EBV DNA yielded 175,575 copies, which was much higher than her
prior result. She was treated with 3 cycles of induction chemotherapy
with cisplatin/5-fluorouracil followed by concurrent cisplatin
chemoradiotherapy. The original intention was to deliver a total dose of
70 Gy to gross disease using volumetric-modulated arc radiotherapy
(VMAT), which is consistent with our standard practice in adult
nasopharyngeal carcinoma. We had considered a reduction of radiotherapy
dose based on the protocol of a Children’s Oncology Group (COG) study
that was ongoing at that time, but she did not meet the criteria for
dose reduction.1 After just 50 Gy was delivered, the
patient refused further treatment due to dermatitis with dry
desquamation, although this was within expectations due to the large
volume of disease and anticipated skin dose (Fig. 2). Our patient has
continued to be disease-free for 5 years since completion of
reduced-dose radiotherapy. Late toxicity from radiotherapy has been
mild- she has had infrequent episodes of epistaxis due to bleeding at
Little’s area as well as mild dryness of the skin of the neck. She has
developed Graves’ disease, which is a known complication of
pembrolizumab.
As the severity of late toxicity after radiotherapy is strongly
correlated with the dose received, reduction of dose presents an
opportunity to reduce the severity of late toxicity. Retrospective
studies have suggested that lower doses can be used in children compared
to adults.2,3,4 Prospective evidence has also been
provided by the COG study ARAR 0331 on childhood nasopharyngeal cancer,
which has demonstrated excellent outcomes with a reduction in total dose
from 70.2 Gy to 61.2 Gy in patients achieving an adequate response to
induction chemotherapy.1 Our patient’s long-term
survival is remarkable given that she had advanced disease at
presentation, a prolonged delay in starting standard treatment, and a
high pre-treatment EBV DNA load, which has been inversely correlated
with survival.5 Notably, she had stopped radiotherapy
treatment prematurely and received a radiotherapy dose of just 50 Gy,
which is significantly lower than the dose of 61.2 Gy used in the COG
ARAR 0331 study. Although not our standard practice, our patient
received 1 cycle of pembrolizumab 6 months before irradiation in an
external institution, which bears mentioning as immunotherapy has
demonstrated promising activity against nasopharyngeal
carcinoma.6 While we recognize that this is a case
report and that the findings cannot be generalized, it is
thought-provoking that the required dose of radiotherapy for disease
control may be lower than expected, at least in some patients.