Radiation therapy is the mainstay of treatment, with chemotherapy used in advanced cases. Concurrent cisplatin, 5-fluorouracil, and radiotherapy have been shown to improve survival. [8, 22, 23] Sequential chemoradiotherapy with gemcitabine and cisplatin has been shown to improve survival in locoregionally advanced nasopharyngeal carcinoma. [24] Many pediatric studies have used neoadjuvant chemotherapy followed by radiation therapy with improvement in local control or progression-free survival rates over radiotherapy alone. [25, 12, 26]
Pharmacologic therapy
Toripalimab
Toripalimab (Loqtorzi) is a programmed death receptor 1–blocking antibody indicated for nasopharyngeal carcinoma (NPC). It gained approval as first-line treatment of metastatic or recurrently locally advanced NPC in combination with cisplatin and gemcitabine. Additionally, it is approved as monotherapy for treatment of recurrent, unresectable, or metastatic NPC with disease progression on or after platinum-containing chemotherapy.
Approval for first-line treatment was supported by results of the phase 3 JUPITER-02 trial (n = 289). Patients were randomly assigned 1:1 to either toripalimab or placebo on a background of cisplatin and gemcitabine, followed by toripalimab or placebo continuation. Significantly longer progression-free survival (PFS) was observed with toripalimab (11.7 months) compared with placebo (8 months) (P = .0003). Additionally, at the time of analysis, a 40% reduction in risk of death was reported with toripalimab vs placebo. [27]
The POLARIS-02 trial (n = 190) demonstrated the efficacy of toripalimab as a single agent in patients with unresectable or metastatic NPC who had received prior platinum-based chemotherapy or had progressed within 6 months of neoadjuvant, adjuvant, or chemoradiation therapy. The overall response rate was 20.5%, with median duration of response 12.8 months, median PFS 1.9 months, and median overall survival 17.4 months. [28]
Nivolumab
In 2016, nivolumab (Opdivo) was approved by the US Food and Drug Administration (FDA) for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy. Nivolumab is a monoclonal antibody that inhibits PD-1 and blocks interaction between PD-1 and its ligands, PD-L1 and PD-L2.
FDA approval for this indication was based on the phase 3 CheckMate-141 trial, in which nivolumab significantly improved overall survival compared with the comparator (investigator's choice of methotrexate, docetaxel, or cetuximab). Median overall survival was 7.5 months for nivolumab compared with 5.1 months for investigator's choice (hazard ratio, 0.70; P = .0101), and estimated 1-year survival rate were 36% with nivolumab vs 16.6% with investigator's choice. The trial was stopped early after this benefit was shown in a preplanned analysis. [29]
Radiation therapy
Radiotherapy is administered to the gross tumor volume (GTV) or disease in the primary site and neck adenopathy. The initial clinical target volume (CTV) includes the GTV and all sites of potential subclinical disease to a dose of 45-50.4 Gy at 1.8-2 Gy/fraction. It is anticipated that in most patients, levels I to V neck nodes are included in the initial CTV. For the boost CTV, the GTV with a margin is treated to a dose of 15-25 Gy. The total dose to the GTV usually ranges from 65-70 Gy. A planning target volume (PTV) takes into account the CTV and daily set-up variation; in most cases with an immobilization mask for the head and neck, a 0.5-cm margin is added to the CTV to create the PTV. The PTV receives the same prescription dose as the CTV.
In the past, the initial radiotherapy fields were treated with 2 parallel opposed lateral fields that encompassed the nasopharynx and upper cervical nodes. The lower cervical nodes were treated with an anterior field, which abuts the upper lateral fields superiorly. These patients are now commonly treated with intensity-modulated radiation therapy (IMRT). IMRT may be used to spare neighboring critical structures next to the nasopharynx, such as the brain, pituitary gland, optic chiasm, optic nerve, and spinal cord.
A randomized controlled trial compared the clinical outcomes of upper versus whole-neck prophylactic irradiation in the treatment of patients with node-negative nasopharyngeal carcinoma (NPC). The study concluded that prophylactic upper neck irradiation is sufficient for patients with node-negative NPC. Larger studies are needed to confirm the study’s findings. [30]
A multi-institutional study showed that doses of at least 66 Gy to gross disease are needed for optimal local control. [31] Others have used a radiotherapy dose adaptation strategy with which children responding well to chemotherapy receive less radiotherapy dose. In the Italian Rare Tumors in Pediatric age (TREP) Project, 3 courses of cisplatin and 5-fluorouracil followed by radiotherapy, with doses ranging from 60-65 Gy to gross disease, resulted in a 5-year progression-free survival rate of 79.3%. [32] In another study, cervical nodal irradiation was reduced to less than 50 Gy, with good response to chemotherapy (>90% shrinkage of original tumor) with a 5-year, event-free survival rate of 75%. [33]
Data using IMRT reveal equivalent or better locoregional control compared with conventional radiotherapy and sparing of the parotid glands from high doses of radiation therapy. [34, 35]
During the course of radiotherapy, several immediate effects may occur, usually after the first 2 weeks of treatment. Confluent mucositis usually occurs, especially in children receiving both radiotherapy and cisplatin. Dry mouth and thick saliva are also likely secondary to irradiation of the salivary glands. Because of this oropharyngeal mucositis, consideration of placement of a gastrostomy tube prior to initiation of radiotherapy. If a gastrostomy tube is not placed, poor nutrition and dehydration are quite common, and intravenous fluids may need to be administered. Redness, itching, and peeling of the treated skin can occur toward the end of radiotherapy and may need to be treated with topical antibiotics and Silvadene. A study of children treated with IMRT showed less acute toxicity (skin, mucous membrane, pharynx) compared with conventional radiotherapy. [36]
Some centers use amifostine, a radioprotective agent, to help reduce radiation-related xerostomia. Possible adverse effects of amifostine (eg, flulike symptoms, nausea, low calcium levels, hypotension) have limited its widespread use in the oncologic community.
