Proton therapy following induction chemotherapy for pediatric and adolescent nasopharyngeal carcinoma.

PURPOSE: In children treated for nasopharyngeal carcinoma, proton therapy and postchemotherapy target volumes can reduce the radiation dose to developing tissue in the brain and the skull base region. We analyzed outcomes in children with nasopharyngeal carcinoma treated with induction chemotherapy followed by moderate-dose proton therapy. METHODS/MATERIALS: Seventeen patients with nonmetastatic nonkeratinizing undifferentiated/poorly differentiated nasopharyngeal carcinoma underwent double-scattered proton therapy between 2011 and 2017. Median age was 15.3 years (range, 7-21). The American Joint Committee on Cancer T and N stage distribution included the following: T1, one patient; T2, five patients; T3, two patients; and T4, nine patients; and N1, six patients; N2, nine patients; and N3, two patients. Median radiation dose to the primary target volume and enlarged lymph nodes was 61.2 Gy (range, 59.4-61.2). Uninvolved cervical nodes received 45 Gy (range, 45-46.8). All radiation was delivered at 1.8 Gy/fraction daily using sequential plans. In 11 patients, photon-based intensity-modulated radiotherapy was used for elective neck irradiation to optimize dose homogeneity and improve target conformity. All patients received induction chemotherapy; all but one received concurrent chemotherapy. Five received adjuvant beta-interferon therapy. RESULTS: Median follow-up was 3.0 years (range, 1.6-7.9). No patients were lost to follow-up. Overall survival, progression-free survival, and local control rates were 100%. Fifteen patients developed mucositis requiring enteral feeding (n = 14) or total parenteral nutrition (n = 1) during radiotherapy. Serious late side effects included cataract (n = 1), esophageal stenosis requiring dilation (n = 1), sensorineural hearing loss requiring aids (n = 1), and hormone deficiency (n = 5, including three with isolated hypothyroidism). CONCLUSION: Following induction chemotherapy, moderate-dose proton therapy can potentially reduce toxicity in the brain and skull base region without compromising disease control. However, further follow-up is needed to fully characterize and evaluate any reduction in long-term complications.

Molecular characteristics of pediatric nasopharyngeal carcinoma using whole-exome sequencing.

OBJECTIVES: While a number of genetic and epigenetic events contributing to adult nasopharyngeal carcinomas (aNPC) development has been established, the scarcity of pediatric nasopharyngeal carcinoma (pNPC) hinders the understanding of the biology of the disease and rational treatment approach. We aim to identify the molecular characteristics of pNPC. MATERIALS AND METHODS: pNPC primary tumors with paired blood samples were collected and sequenced using whole-exome sequencing. Samples were collected from four tertiary academic medical centers in China. A total of 30 patients (25 male and 5 female) with pathologically confirmed NPC under the age of 20 were enrolled. RESULTS: Several genes such as C9orf84 (20 %), ZFHX4 (16.7 %), ZC3H6 (16.7 %), RBM38 (16.7 %) were frequently mutated in pNPC. Copy number analysis revealed highly recurring gain/amplification of the HLA class II genes at 6p21.32 (63.3 %) and losses of TOLLIP at 11p15.5 (20 %). Recurrent NUTM1 (16.7 %) fusion variants were found for the first time with pNPC. We also investigated germline genomic signatures and showed 8 of 30 (26.7 %) of the pNPC patients carrying germline pathogenic and/or likely pathogenic variants in known cancer-predisposing genes. Multi-dimensional comparison suggested that pNPC might exhibit distinct genomic profile compared to aNPC. In addition, pNPC exhibited significantly elevated level of PD-L1 expression than aNPC (percent of patients with >50 % PD-L1 expression: 92.0 % vs 32.1 %), suggesting high possibility of benefit from immunotherapy. CONCLUSION: Our results provide the first insight into the molecular basis of pNPC, and might offer novel targets and therapeutic approaches such as immunotherapy for this rare disease.

Pediatric Nasopharyngeal Cancer: Case Report and Review of the Literature.

Pediatric nasopharyngeal carcinoma, also referred to as cavum carcinoma, is a rare pediatric disease with an infrequent incidence rate. We present the case of a pediatric patient with nasopharyngeal cancer who received an adult schedule of concomitant chemotherapy and conformal radiotherapy with a brachytherapy boost. Adult protocols with high radiotherapy doses are not commonly used in pediatric patients due to the high comorbidity associated with this practice. In this case, the patient displayed excellent overall survival, a longer disease-free period, and fewer side effects and comorbidities, even in the absence of interferon therapy, which is not easily available in low-income countries. In addition, this case shows that conformal radiotherapy and brachytherapy are options that can be used to escalate the radiotherapy dose and decrease side effects. A 12-year-old female pediatric patient presented to our outpatient clinic with an eight-month history of moderate-to-severe otalgia, intermittent hyaline rhinorrhea, asthenia, adynamia, nasal congestion, epistaxis in the previous months, and local pruritus. Upon physical examination, a 60x60 mm mass was detected at level II of the neck, and a biopsy of the lesion confirmed a histopathological diagnosis of undifferentiated carcinoma compatible with nasopharyngeal carcinoma. The patient was considered to have clinical Stage III cancer, and she received an adult Al-Sarraf protocol with chemoradiotherapy and an intracavitary brachytherapy boost. The patient had a complete response, and she remains without local or distance relapse. Treating pediatric nasopharyngeal carcinoma patients with the Al-Sarraf protocol could be a feasible modality, as observed in this clinical case, despite the elevated cost of using interferon-beta in low-income countries when using more advanced radiotherapy techniques such as conformal radiotherapy and now, modulated intensity radiotherapy. It should be noted that brachytherapy boosts should be used with caution in pediatric patients; the potential side effects should be weighed against improved local control.

International randomized phase 2 study on the addition of docetaxel to the combination of cisplatin and 5-fluorouracil in the induction treatment for nasopharyngeal carcinoma in children and adolescents.

PURPOSE: Nasopharyngeal carcinoma (NPC) is a rare but aggressive malignancy in children and adolescents. An international, randomized phase 2 trial was conducted to compare induction chemotherapy with docetaxel plus cisplatin and 5-fluorouracil (TPF) with cisplatin and 5-fluorouracil (PF) in NPC patients under the age of 21. METHODS: Patients with stage IIB-IV NPC were randomly assigned, in a 2:1 ratio, to receive TPF or PF 3-weekly for three cycles, followed by chemoradiotherapy. The primary endpoint was the complete response rate achieved with TPF or PF. Docetaxel pharmacokinetics was also evaluated. RESULTS: Seventy-five patients (median 16 years old) were randomized, with 50 assigned to the TPF group and 25 to the PF group. Overall response was assessed after induction treatment: one patient in the TPF group and none in the PF group had a complete response. Partial response was achieved in 76.0 and 80.0 % in the TPF and PF groups, respectively. The overall safety profile was consistent with findings in adults. The estimated 3-year overall survival rate was 78.0 % for the PF group and 85.7 % for the TPF group (median follow-up 3.3 years). Mean docetaxel area under the curve was 3.41 µg h/mL, compared with 3.51 µg h/mL seen in adult patients. CONCLUSION: This study demonstrated the feasibility of prospective randomized protocols, even for such rare tumors as pediatric NPC. Overall, there were no differences between the two treatment arms in terms of efficacy and toxicity. The pharmacokinetics of docetaxel in pediatric patients at 75 mg/m(2) was similar to those observed in adults.