Medical Care
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]
In November 2016, nivolumab (Opdivo) was approved by the 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. It’s approval was based on the phase 3 CheckMate-141 trial. Results from the trial showed nivolumab significantly improved overall survival when compared with the comparator (investigator's choice of methotrexate, docetaxel, or cetuximab). The 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 the estimates for the 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. [27]
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. [28]
A multi-institutional study showed that doses of at least 66 Gy to gross disease are needed for optimal local control. [29] 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%. [30] 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%. [31]
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. [32, 33]
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 towards 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. [34]
Some centers use amifostine, a radioprotective agent, to help reduce radiation-related xerostomia. Possible adverse effects of amifostine such as flulike symptoms, nausea, low calcium levels, and hypotension have limited its widespread use in the oncologic community.
Surgical Care
Surgical therapy for these patients is often limited to a biopsy for tissue diagnosis. Nearly all tumors are unresectable at diagnosis because of their location.
Consultations
Consultation with an otolaryngologist is often required in the initial management to obtain tissue diagnosis and in follow-up endoscopic examinations to rule out recurrence. An otolaryngologist may also be involved if the child develops sensorineural hearing loss from cisplatin and radiotherapy.
Consultation with an endocrinologist may be required in the future if the child shows signs of growth retardation or hypothyroidism secondary to radiotherapy. [32] Occasionally, children develop panhypopituitarism.
Consultation with a dentist familiar with radiation effects should be performed prior to initiation of radiotherapy to minimize risk of osteoradionecrosis. Patients also need to be followed after treatment as xerostomia and change in salivary consistency may predispose the patient to dental caries.
Diet and Activity
Diet
Many patients experience severe mucositis during radiotherapy. Certain foods may irritate irradiated mucosa, causing pain or difficulty swallowing or chewing. Soft foods such as milkshakes, mashed potatoes, and pureed meats are advisable during the course of radiotherapy. Citrus fruits, spicy foods, salty foods, and coarse foods can make the irritated mucosa worse. Gastrostomy tube placement allows adequate hydration and calorie intake during radiotherapy.
Activity
Activity depends on the child's condition. During periods of chemotherapy-induced thrombocytopenia, some limitation of strenuous activity and avoidance of contact sports is necessary. Infectious contacts should be avoided where possible, especially during periods of neutropenia.
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MRI of the head and neck in a patient with nasopharyngeal carcinoma showing the primary tumor and cervical lymph node metastases
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Intensity modulated radiotherapy images for a patient with nasopharyngeal carcinoma
Tables
Stage |
T |
N |
M |
0 |
Tis |
No |
M0 |
I |
T1 |
N0 |
M0 |
II |
T1 |
N1 |
M0 |
T2 |
N0 |
M0 |
|
T2 |
N1 |
M0 |
|
III |
T1 |
N2 |
M0 |
T2 |
N2 |
M0 |
|
T3 |
N0 |
M0 |
|
T3 |
N1 |
M0 |
|
T3 |
N2 |
M0 |
|
IVA |
T4 |
N0 |
M0 |
T4 |
N1 |
M0 |
|
T4 |
N2 |
M0 |
|
IVB |
Any T |
N3 |
M0 |
IVC |
Any T |
Any N |
MI |
TX |
Primary tumor cannot be assessed |
T0 |
No evidence of primary tumor |
Tis |
Carcinoma in situ |
T1 |
Tumor confined to the nasopharynx or extends to oropharynx and/or nasal cavity without parapharyngeal extension |
T2 |
Tumor with parapharyngeal extension |
T3 |
Tumor involves bony structures of skull base and/or paranasal sinuses |
T4 |
Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, or with extension to the infratemporal fossa/masticator space |
NX |
Regional lymph nodes cannot be assessed |
N0 |
No regional lymph node metastasis |
N1 |
Unilateral metastasis in cervical lymph node(s), less than or equal to 6 cm in greatest dimension, above the supraclavicular fossa, and/or unilateral or bilateral retropharyngeal lymph nodes, less than or equal to 6 cm in greatest dimension |
N2 |
Bilateral metastasis in a cervical lymph node (s), less than or equal to 6 cm in greatest dimension, above the supraclavicular fossa |
N3 |
Metastasis in a lymph node(s) greater than 6 cm and/or to supraclavicular fossa |
N3a |
Greater than 6 cm in dimension |
N3b |
Extension to supraclavicular fossa |
M0 |
No distant metastasis |
M1 |
Distant metastasis |
