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.