Nasopharyngeal Cancer

Nasopharyngeal cancer may also be called nasopharyngeal carcinoma or NPC. It is 1 of 5 main types of cancer in the head and neck region, a grouping called head and neck cancer.

NPC is a disease of the nasopharynx, which is the air passageway at the upper part of the pharynx, or throat, behind the nose. The nostrils lead through the nasal cavity into the nasopharynx, and an opening called the Eustachian tube, which is located on each side of the nasopharynx, leads into the middle ear on each side.

The nasopharynx contains several types of tissue, and each tissue type contains several types of cells. Different cancers can develop from each kind of cell. For example, many types of NPC contain white blood cells, called lymphocytes. The cancer is named after these lymphocytes: lymphoepithelioma. These differences are important because they determine the seriousness of the cancer and the type of treatment needed.
(ASCO)

The nasopharynx has a cuboidal shape. The lateral walls are formed by the eustachian tube and the fossa of Rosenmuller. The roof, sloping downward from anterior to posterior, is bordered by the pharyngeal hypophysis, pharyngeal tonsil, and pharyngeal bursa with the base of the skull above. Anteriorly, the nasopharynx abuts the posterior choanae and nasal cavity, and the posterior boundary is formed by the muscles of the posterior pharyngeal wall. Inferiorly, the nasopharynx ends at an imaginary horizontal line formed by the upper surface of the soft palate and the posterior pharyngeal wall.
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Clinical Evaluation   Staging   Treatment (NCI)   Treatment Overview (ASCO)   Drug Rx for Head & Neck Cancers (PDR)   NCCN Guidelines   Treatment Summary  

Statistics

NPC is uncommon in the United States. Less than 1 person out of 100,000 people is diagnosed with NPC each year. NPC is more common in Asians/Pacific Islanders, who are diagnosed 6 times more often than white people and Hispanic people. Alaska Natives are also more likely to develop NPC. About 50% of people with the disease are 55 or younger.

During the past few years, the rate at which Americans have been developing this cancer has been slowly decreasing. NPC is much more common in certain parts of Asia and North Africa. For instance, it is a fairly common cancer in southeast China.

The 5-year survival rate tells you what percent of people live at least 5 years after the cancer is found. Percent means how many out of 100. The 5-year survival rate for people with NPC is 60%. Approximately 44% of NPC is diagnosed at the regional stage, which means the cancer has spread to surrounding tissues or organs and/or the regional lymph nodes. About 39% of NPC is diagnosed at the distant stage, which means the cancer has spread to a distant part of the body.

Survival rates depend on many factors, including the location of the tumor and if or where it has spread, called the stage. Talk with your doctor about what to expect with your specific diagnosis.
(ASCO)

Risk Factors

Unlike other squamous cell cancers of the head and neck, nasopharyngeal cancer does not appear to be linked to excess use of tobacco or moderate alcohol intake (up to 15 drinks a week). Factors thought to predispose to this tumor include the following:
• Chinese (or Asian) ancestry.
• Epstein-Barr virus (EBV) exposure.
• Unknown factors that result in very rare familial clusters.
• Heavy alcohol intake.

Anatomy

Immune checkpoint inhibitors, PD-1/PD-L1

 

Signs and Symptoms

• Painless, enlarged lymph nodes in the neck (present in approximately 75% of patients and often bilateral and posterior).
• Nasal obstruction.
• Epistaxis.
• Diminished hearing.
• Tinnitus.
• Recurrent otitis media.
• Cranial nerve dysfunction (usually II–VI or IX–XII).
• Sore throat.
• Headache.

In the patient who presents with only cervical adenopathy, the finding of EBV genomic material in the tissue after amplification of DNA with the polymerase chain reaction lends strong evidence for a nasopharyngeal primary tumor, and a concerted search should be conducted in that area.

Diagnostic Tests

Diagnosis is made by biopsy of the nasopharyngeal mass. Workup includes the following:
• Careful visual examination (by fiberoptic endoscopic examination or examination under anesthesia [EUA]).
• Documentation of the size and location of the tumor and neck nodes.
• Evaluation of cranial nerve function including neuro-ophthalmological evaluation and audiological evaluation.
• Computed tomographic (CT) scan or positron emission tomography (PET)-CT scan.
• Magnetic resonance imaging (MRI) to evaluate skull base invasion.
• Hemogram.
• Chemistry panel.
• EBV titers.
Any clinical or laboratory suggestion of distant metastasis may prompt further evaluation of other sites. Careful dental and oral hygiene evaluation and therapy is particularly important prior to initiation of radiation treatment. MRI is often more helpful than CT scans in assessing skull base involvement and in defining the extent of abnormalities detected.

Prognosis

Major prognostic factors adversely influencing outcome of treatment include the following:
• Large tumor size.[Level of evidence: 3iiiA]
• A higher tumor (T) stage.
• The presence of involved neck nodes.

Other factors linked to diminished survival that were present in some, but not all, studies include the following:
• Age.
• World Health Organization (WHO) grade I.
• Long interval between biopsy and initiation of radiation therapy.
• Diminished immune function at diagnosis.
• Incomplete excision of involved neck nodes.
• Pregnancy during treatment.
• Locoregional relapse.
• Certain EBV antibody titer patterns.

Small cancers of the nasopharynx are highly curable by radiation therapy, and patients with these small cancers have shown survival rates of 80% to 90%.

Moderately advanced lesions without clinical evidence of spread to cervical lymph nodes are often curable, and patients with these lesions have shown survival rates of 50% to 70%.

Follow-up

Follow-up for patients includes the following:
Routine periodic examination of the original tumor site and neck.
• CT or PET-CT scan.
• MRI scan.
• Blood work.
• EBV titers.

Monitoring of patients should include the following:
• Surveillance of thyroid and pituitary function.
• Dental and oral hygiene.
• Jaw exercises to avoid trismus.
• Evaluation of cranial nerve function, especially as it relates to vision and hearing.
• Evaluation of systemic complaints to identify distant metastasis.

Although most recurrences occur within 5 years of diagnosis, relapse can be seen at longer intervals. The incidence of second primary malignancies is less than after treatment of tumors at other head and neck sites.

Poorly differentiated squamous cell cancer has been associated with EBV antibodies. High-titer antibodies to virus capsid antigen and early antigen, especially of high IgA class, or high titers that persist after therapy, have been associated with a poorer prognosis. This finding remains under evaluation.

Tumors of many histologies can occur in the nasopharynx, but this discussion, like the American Joint Committee on Cancer nasopharynx staging, refers exclusively to WHO grade I-, II-, and III-type nasopharyngeal carcinoma.

Cellular Classification of Nasopharyngeal Cancer

Although a wide variety of malignant tumors may arise in the nasopharynx, only squamous cell carcinoma is considered in this discussion because management of the other types varies substantially with histology. Subdivisions of squamous cell carcinoma in this site include the following:

World Health Organization (WHO) histopathological grading system describes three types of nasopharyngeal cancer:
• Keratinizing squamous cell carcinoma.
• Nonkeratinizing squamous cell carcinoma.
• Undifferentiated carcinoma (most common subtype).

Previous subdivisions of nasopharyngeal carcinoma included lymphoepithelioma, which is now classified as WHO grade III characterized by lymphoid infiltrate.

WHO grade I-type cancer accounts for 20% of cases in United States and is associated with alcohol and tobacco use; WHO grade II and III represent the endemic form seen in Southern China.

The presence of keratin has been associated with reduced local control and survival.

Subtypes of NPC

According to the World Health Organization (WHO), NPC is classified into 3 subtypes:
• Keratinizing squamous cell carcinoma (WHO type 1)
• Nonkeratinizing squamous cell carcinoma (WHO type 2)
• Undifferentiated or poorly differentiated carcinoma, including lymphoepithelioma and anaplastic variants (WHO type 3)
Recently, doctors have found that other factors, such as the presence of Epstein-Barr virus (EBV), can be more important for determining the seriousness of NPC and how to treat it. This means that the WHO types are being used less often in the treatment of NPC.
(ASCO)

 

Stage Information for Nasopharyngeal Cancer

Staging systems are all clinical staging and are based on the best possible estimate of the extent of disease before treatment. Assessment of the primary tumor is based on inspection and palpation, and fiberoptic endoscopic evaluation. The tumor must be confirmed histologically, and any other pathologic data obtained on biopsy may be included. Evaluation of the function of the cranial nerves is especially appropriate for tumors of the nasopharynx. The appropriate nodal drainage areas are examined by careful palpation and radiologic evaluation. The retropharyngeal lymph nodes are the first echelon of drainage. Information from diagnostic imaging studies may be used in staging. Magnetic resonance imaging provides additional information to computed tomographic scanning in the evaluation of skull base invasion and intracranial spread. Positron emission tomography scans combined with CT are helpful in radiation treatment planning for target delineation of the primary tumor, aids in detection of metastatic nodal involvement and metastatic spread such as lung or skeletal metastases in patients with advanced nasopharyngeal cancer.

If a patient has a relapse, a complete reassessment must be done to select the appropriate additional therapy.

Definitions of TNM
The AJCC has designated staging by TNM (tumor, regional lymph node, metastasis) classification to define nasopharyngeal cancer.

Primary Tumor (T)
TX Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
Tis = Carcinoma in situ.
T1 = Tumor confined to the nasopharynx, or tumor extends to oropharynx and/or nasal cavity without parapharyngeal extension.
T2 = Tumor with parapharyngeal extension. (Parapharyngeal extension denotes posterolateral infiltration of tumor)
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.

Regional Lymph Nodes (N)
(Note: The distribution and the prognostic impact of regional lymph node spread from nasopharyngeal cancer, particularly of the undifferentiated type, are different from those of other head and neck mucosal cancers and justify the use of a different N classification scheme.)

NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Unilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the supraclavicular fossa, and/or unilateral or bilateral, retropharyngeal lymph nodes, ≤6 cm in greatest dimension. (Note: Midline nodes are considered ipsilateral nodes.)
N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the supraclavicular fossa.
N3 = Metastasis in a lymph node(s)c >6 cm and/or to supraclavicular fossa.
N3a = >6 cm in dimension.
N3b = Extension to the supraclavicular fossa.
    (Note: Supraclavicular zone or fossa is relevant to the staging of nasopharyngeal carcinoma and is the triangular region originally described by Ho. It is defined by three points: (1) the superior margin of the sternal end of the clavicle, (2) the superior margin of the lateral end of the clavicle, (3) the point where the neck meets the shoulder. Note that this would include caudal portions of levels IV and VB. All cases with lymph nodes (whole or part) in the fossa are considered N3b.)

Distant Metastases (M)
M0 = No distant metastasis.
M1 = Distant metastasis.

Anatomic Stage/Prognostic Groups


Stage T N M
0 Tis N0 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 M1

 

 

Nasopharyngeal Cancer - Treatment Options

Treatment Option Overview

Standard treatments for patients with nasopharyngeal cancer include the following:
• Radiation therapy alone.
• Concurrent chemoradiation followed by adjuvant chemotherapy.
• Surgery for residual nodal disease.
• Chemotherapy alone for metastatic disease.

High-dose radiation therapy with chemotherapy is the primary treatment of nasopharyngeal cancer, both for the primary tumor site and the neck.
When feasible, surgery is usually reserved for nodes that fail to regress after radiation therapy or for nodal recurrence following clinical complete response.
Radiation therapy dose and field margins are individually tailored to the location and size of the primary tumor and lymph nodes.
Although most tumors are treated with external-beam radiation therapy (EBRT) exclusively, in some tumors radiation therapy may be boosted with intracavitary or interstitial implants or by the use of stereotactic radiosurgery when clinical expertise is available and the anatomy is suitable.
Intensity-modulated radiation therapy (IMRT) results in a lower incidence of xerostomia and may provide a better quality of life than conventional three-dimensional or two-dimensional radiation therapy.[Level of evidence: 1iiC]
Results of a phase II RTOG study (RTOG-0225) showed the feasibility of IMRT in a multi-institutional setting and minimal grade III and IV xerostomia rates. The rate of grade 2 xerostomia at 1 year from start of IMRT was 13.5%. Only 2 of 68 patients were reported with grade 3 xerostomia, and none had grade 4 xerostomia.[Level of evidence: 2C]

Accumulating evidence has demonstrated a high incidence (>30%–40%) of hypothyroidism in patients who have received radiation therapy that delivered EBRT to the entire thyroid gland or to the pituitary gland. Thyroid-function testing of patients should be considered before therapy and as part of posttreatment follow-up.

Treatments under clinical evaluation for patients with nasopharyngeal cancer include the following:
• Dose escalation with new radiation therapy techniques such as stereotactic radiation therapy boost.[Level of evidence: 3iiiDiv]
• Brachytherapy.[Level of evidence: 3iiiDii]

 

Treatment Options for Stage I Nasopharyngeal Cancer

Standard treatment options:
• High-dose radiation therapy to the primary tumor site and prophylactic radiation therapy to the nodal drainage.

 

 

Treatment Options for Stage II Nasopharyngeal Cancer

Standard treatment options:
1. Chemoradiation therapy followed by adjuvant chemotherapy, as was used in the INT-0099 trial, for example.[Level of evidence: 3iiiA]
(Patients with parapharyngeal extension were originally staged as T3 in the INT-0099 study and are now considered T2 in the current staging.)
2. High-dose radiation therapy to the primary tumor site and prophylactic radiation therapy to the nodal drainage.

 

 

Treatment Options for Stage III Nasopharyngeal Cancer

Standard treatment options:
1. Combined chemoradiation therapy.
2. Combined chemoradiation therapy followed by adjuvant chemotherapy, as evidenced in INT-0099, for example.
3. Altered fractionation radiation therapy.
4. Neck dissection may be indicated for persistent or recurrent nodes if the primary tumor site is controlled.

Treatment options under clinical evaluation:
• Neoadjuvant chemotherapy. Neoadjuvant chemotherapy as given in clinical trials has been used to shrink tumors, which renders them more definitively treatable with radiation therapy. Chemotherapy is given prior to the other modalities, hence the designation neoadjuvant to distinguish it from standard adjuvant therapy, which is given after or during definitive therapy with radiation or after surgery. Many drug combinations have been used in neoadjuvant chemotherapy.

Two randomized, prospective trials compared combination chemotherapy (i.e., cisplatin, epirubicin, and bleomycin or cisplatin plus fluorouracil [5-FU] infusion) plus radiation therapy to radiation therapy alone.[Level of evidence: 1iiA];[Level of evidence: 1iiDii]
Although disease-free survival was improved in the chemotherapy group for both groups, improvement in overall survival was reported only from the Intergroup trial in which chemotherapy with cisplatin was ever concurrently given.

Clinical trials for advanced tumors evaluating the use of chemotherapy before radiation therapy, concomitant with radiation therapy, or as adjuvant therapy after radiation therapy should be considered

 

 

Treatment Options for Stage IV Nasopharyngeal Cancer

Standard treatment options:
1. Chemoradiation therapy followed by adjuvant chemotherapy, as evidenced in INT-0099, for example.
2. Altered fractionation including hyperfractionated radiation therapy.
3. Neck dissection should be reserved for persistent or recurrent nodes.
4. Chemotherapy for patients with stage IVC disease.

Treatment options under clinical evaluation:
1. Neoadjuvant chemotherapy.
Neoadjuvant chemotherapy has been used to shrink tumors, which renders them more definitively treatable with radiation therapy.
Many drug combinations have been used in neoadjuvant chemotherapy.
Clinical trials for advanced tumors to evaluate the use of chemotherapy before radiation therapy, concomitant with radiation therapy, or as adjuvant therapy after radiation therapy should be considered.

A phase II, randomized study of 65 patients with stage III and IV nasopharyngeal carcinoma were randomly assigned to neoadjuvant docetaxel (75 mg/m2) and cisplatin (75 mg/m2) every 3 weeks for two cycles followed by cisplatin (40 mg/m2) every week versus chemoradiation alone.
Rates of grade 3 or 4 neutropenia were 97% during the neoadjuvant arm with no difference in toxicities between the two groups during the chemoradiation portion of treatment.
The 3-year progression-free survival for neoadjuvant docetaxel versus the control arm was 88.2% and 59.5% (HR, 0.49; 95% CI, 0.20–1.19; P = .12). The 3-year overall survival (OS) for neoadjuvant docetaxel versus the control arm was 94.1% and 67.7% (HR, 0.24; 95% CI, 0.078–0.73; P = .012).[Level of evidence: 1iiDiii] These data have to be confirmed in a definitive phase III trial.

Three randomized, prospective trials compared combination chemotherapy (i.e., cisplatin, epirubicin, and bleomycin or cisplatin plus fluorouracil [5-FU] infusion) plus radiation therapy to radiation therapy alone.[Level of evidence: 1iiA]; [Level of evidence: 1iiDii]
Although disease-free survival (DFS) was improved in the chemotherapy group for both groups, improvement in OS was reported only from the Intergroup trial in which chemotherapy with cisplatin was ever concurrently given.

2. Concurrent radiation therapy with chemotherapy.
A study of 1,355 patients compared concurrent radiation therapy with carboplatin or cisplatin administered with 96-hour infusion of 5-FU monthly for three cycles. The 3-year DFS rate was 63.4% for patients in the cisplatin arm and 60.9% for patients in the carboplatin arm (P = .961; HR, 0.70; 95% CI, 0.50–0.98). OS rates were 77% for patients in the cisplatin arm and 79% for patients in the carboplatin arm (P = .988; HR, 0.83; 95% CI, 0.63–1.010).[Level of evidence: 1iiA] Toxicity to kidneys and red blood cell count was greater in patients in the cisplatin group.

 

 

Treatment Options for Recurrent Nasopharyngeal Cancer

Standard treatment options:
1. Selected patients with local recurrence may be retreated with moderate-dose external-beam radiation therapy using intensity-modulated radiation therapy, stereotactic radiation therapy, or intracavitary or interstitial radiation to the site of recurrence.
2. In highly selected patients, surgical resection of locally recurrent lesions may be considered.
3. If a patient has metastatic disease or local recurrence that is no longer amenable to surgery or radiation therapy, chemotherapy should be considered.

Treatment options under clinical evaluation:
• Clinical trials evaluating chemotherapy should be considered.
• Stereotactic radiation for locally recurrent disease or persistence.[Level of evidence: 3iiiDiv]

 

 

 

Nasopharyngeal Cancer - Treatment Overview and Options

(Updated 07/2017)
Treatment overview
Many cancers of the nasopharynx can be cured, especially if they are found early. Descriptions of the most common treatment options for NPC are listed below. Treatment options and recommendations depend on several factors, including the type and stage of cancer, possible side effects, and the patient’s preferences and overall health.

The main treatment for NPC is radiation therapy. It is often given in combination with chemotherapy. This approach may be called concomitant chemoradiotherapy. Surgery for NPC is occasionally used, mainly to remove lymph nodes after chemoradiotherapy or to treat NPC that has come back after initial treatment. Your care plan may also include treatment for symptoms and side effects, an important part of cancer care.
Although curing the cancer is the primary goal of treatment, preserving the function of the nearby organs and tissues is also very important. When doctors plan treatment, they consider how it might affect a person’s quality of life, including how a person feels, looks, talks, eats, and breathes.

Radiation therapy

There are different types of radiation therapy for NPC.
• External-beam radiation therapy. The most common type of radiation therapy used to treat NPC is called external-beam radiation therapy, which aims radiation from a machine outside the body at the tumor. A method of external-beam radiation therapy, known as intensity-modulated radiation therapy (IMRT), allows more effective doses of radiation therapy to be delivered, while reducing damage to healthy cells and causing fewer side effects.

• Proton therapy. Proton therapy is a type of external-beam radiation therapy that uses protons rather than x-rays. At high energy, protons can destroy cancer cells. Proton therapy may be used as part of the treatment for some skull-base tumors to further limit the radiation dose to nearby structures, such as the optic nerves in the eye and the brainstem. Proton therapy may also be an option for later-stage NPC that is located close to parts of the central nervous system, which includes the brain and spinal cord.

• Stereotactic radiosurgery. Stereotactic radiosurgery delivers radiation therapy precisely to the tumor. This can be used to treat a tumor that has grown into the base of the skull or a tumor that has recurred at the base of the brain or skull.

• Brachytherapy. When radiation treatment is given using implants, it is called internal radiation therapy or brachytherapy. To treat NPC with internal radiation therapy, a doctor surgically implants tiny pellets or rods that contain radioactive materials in or near the cancer location. The implant is left in place for several days while the person stays in the hospital. This approach is most often used to treat NPC that has come back after the first treatment. It may also be used to treat the original tumor.

Before starting radiation treatment for any head and neck cancer, people should receive a thorough examination from a dentist experienced in treating people with head and neck cancer, called an oncologic dentist. Since radiation therapy can cause tooth decay, damaged teeth may need to be removed. Often, tooth decay can be prevented with proper treatment from a dentist before cancer treatment begins. After radiation therapy for NPC, dental care should continue to help prevent further dental problems. People may receive fluoride treatment to prevent dental cavities. Read more about dental and oral health.

Other side effects of radiation therapy to the head and neck may include redness or irritation of the skin in the treated area, dry mouth or thickened saliva from damage to salivary glands, bone pain, nausea, fatigue, mouth sores, sore throat, pain or difficulty swallowing, appetite loss because of changes in a person's sense of taste, hearing loss because of a buildup of fluid in the middle ear, and earwax buildup that dries out because of the radiation therapy’s effect on the ear canal.

Radiation therapy may also cause a condition called hypothyroidism. As a result, every person who receives radiation therapy to the neck area should have his or her thyroid checked regularly.

There are numerous studies underway to find ways to reduce or better relieve the side effects of radiation therapy.

Chemotherapy

Chemotherapy is the use of drugs to destroy cancer cells, usually by ending the cancer cells’ ability to grow and divide.

A chemotherapy regimen, or schedule, usually consists of a specific number of cycles given over a set period of time. A combination of chemotherapy and radiation therapy is commonly used to treat NPC. The use of chemotherapy before radiation therapy is also being studied.

Each drug or combination of drugs can cause specific side effects, and it is important to talk with your doctor about which side effects to expect and if any may become permanent. Side effects of chemotherapy may include fatigue, nausea, vomiting, hair loss, dry mouth, diarrhea, constipation, and loss of appetite, often due to a change in a person's sense of taste.

In addition, chemotherapy can weaken the immune system and cause open sores in the mouth, which can lead to infection. In general, chemotherapy in combination with radiation therapy increases these side effects. Nutritional support may be necessary during treatment due to these side effects.

Learn more about the basics of chemotherapy and preparing for treatment. The medications used to treat cancer are continually being evaluated. Talking with your doctor is often the best way to learn about the medications prescribed for you, their purpose, and their potential side effects or interactions with other medications. Learn more about your prescriptions by using searchable drug databases.

Surgery

Surgery is the removal of the tumor and some surrounding healthy tissue during an operation. It is occasionally used for NPC, but it is not a common treatment choice because the area is hard to reach and lies close to cranial nerves and blood vessels.

If the doctor suspects that the cancer has spread to the lymph nodes, surgical removal of lymph nodes in the neck may be recommended. This type of surgery is called a neck dissection. For undifferentiated carcinoma of the nasopharynx, neck dissection is sometimes needed.

A neck dissection may cause numbness of the ear, weakness when raising the arm above the head, and weakness of the lower lip. These side effects are caused by damage to nerves in the area. Depending on the type of neck dissection, weakness of the lower lip and arm may go away after a few months. However, it is possible that weakness will be permanent if a nerve is removed or damaged as part of a dissection. Facial disfigurement may need to be addressed using reconstructive or plastic surgery.

Getting care for symptoms and side effects

Cancer and its treatment often cause side effects. In addition to treatments intended to slow, stop, or eliminate the cancer, an important part of cancer care is relieving a person’s symptoms and side effects. This approach is called palliative or supportive care, and it includes supporting the patient with his or her physical, emotional, and social needs.

Palliative care is any treatment that focuses on reducing symptoms, improving quality of life, and supporting patients and their families. Any person, regardless of age or type and stage of cancer, may receive palliative care. It works best when palliative care is started as early as needed in the cancer treatment process. People often receive treatment for the cancer at the same time that they receive treatment to ease side effects. In fact, patients who receive both at the same time often have less severe symptoms, better quality of life, and report they are more satisfied with treatment.

Palliative treatments vary widely and often include medication, nutritional changes, relaxation techniques, emotional support, and other therapies. You may also receive palliative treatments similar to those meant to eliminate the cancer, such as chemotherapy, surgery, or radiation therapy.

Metastatic NPC

If cancer spreads to another part in the body from where it started, doctors call it metastatic cancer. If this happens, it is a good idea to talk with doctors who have experience in treating it. Doctors can have different opinions about the best standard treatment plan. Also, clinical trials might be an option. Learn more about getting a second opinion before starting treatment, so you are comfortable with your chosen treatment plan.

Your treatment plan may include a combination of radiation therapy and chemotherapy. Sometimes, surgery may be recommended as well. Palliative care will also be important to help relieve symptoms and side effects.

For most patients, a diagnosis of metastatic cancer is very stressful and, at times, difficult to bear. Patients and their families are encouraged to talk about the way they are feeling with doctors, nurses, social workers, or other members of the health care team. It may also be helpful to talk with other patients, including through a support group.

Remission and the chance of recurrence

A remission is when cancer cannot be detected in the body and there are no symptoms. This may also be called having “no evidence of disease” or NED.

A remission may be temporary or permanent. This uncertainty causes many people to worry that the cancer will come back. While many remissions are permanent, it’s important to talk with your doctor about the possibility of the cancer returning. Understanding your risk of recurrence and the treatment options may help you feel more prepared if the cancer does return. Learn more about coping with the fear of recurrence.

If the cancer does return after the original treatment, it is called recurrent cancer. It may come back in the same place (called a local recurrence), nearby (regional recurrence), or in another place (distant recurrence).

When this occurs, a new cycle of testing will begin again to learn as much as possible about the recurrence. After this testing is done, you and your doctor will talk about your treatment options. Recurrent NPC is usually treated with radiation therapy and/or chemotherapy, and sometimes with surgery. Chemotherapy is used for NPC that has come back in distant sites and was previously treated only with radiation therapy. Chemotherapy may also be used together with radiation therapy to improve the effectiveness of the radiation therapy. This approach is called chemoradiotherapy. Your doctor may suggest clinical trials that are studying new ways to treat this type of recurrent cancer. For instance, a clinical trial of biologic therapy, also called immunotherapy, may be an option. Learn more in the Latest Research section.

Whichever treatment plan you choose, palliative care will be important for relieving symptoms and side effects.

People with recurrent cancer often experience emotions such as disbelief or fear. Patients are encouraged to talk with their health care team about these feelings and ask about support services to help them cope. Learn more about dealing with cancer recurrence.

 

 

Drug Therapy for head and neck cancer

† For the treatment of advanced or recurrent head and neck cancer.
cisplatin/fluorouracil vs cisplatin/paclitaxel
cisplatin 100 mg/m2 IV on day 1 in combination with fluorouracil (5-FU) (1000 mg/m2/day continuous IV infusion on days 1, 2, 3, 4), repeated every 3 weeks has been studied.
No difference in overall survival was seen when compared to cisplatin and paclitaxel.

† For induction treatment of inoperable, locally advanced squamous cell head and neck cancer.
(NOTE: Docetaxel is FDA-approved for this indication.)
cisplatin/docetaxel/5-FU
cisplatin 75 mg/m2 IV over 1 hour immediately before docetaxel (75 mg/m2 IV over 1 hour) on day 1, followed by 5-FU continuous IV infusion (750 mg/m2/day continuous IV infusion for 5 days); this regimen is given every 3 weeks for 4 cycles.
After completion of chemotherapy, patients should receive radiation therapy.
All patients must receive prophylaxis for neutropenic infections, premedication with antiemetics, and appropriate hydration (before and after cisplatin administration).
During clinical trials, colony-stimulating factors were recommended during the second and/or subsequent cycles for prophylaxis of febrile neutropenia, documented infections with neutropenia, or neutropenia lasting > 7 days.

In a randomized trial of 358 patients with inoperable, locally advanced squamous head and neck cancer, patients were treated with the FDA-approved regimen of docetaxel/cisplatin/5-FU or cisplatin (100 mg/m2 IV day 1) and 5-FU (1000 mg/m2/day continuous IV infusion for 5 days) every 3 weeks for 4 cycles.
Progression-free survival (PFS), the primary end-point of the study, was significantly longer in the docetaxel/cisplatin/5-FU arm as compared to the cisplatin/5-FU (median PFS, 11.4 months vs. 8.3 months, respectively) with a median follow-up of 33.7 months.
With a follow-up of 51.2 months, the median overall survival also favored patients treated with docetaxel/cisplatin/5-FU as compared to those treated with cisplatin/5-FU (18.6 months vs. 14.2 months, respectively).

† For induction treatment of locally advanced squamous cell head and neck cancer in combination with docetaxel and 5-fluorouracil (5-FU) for unresectable disease, low surgical cure, or organ preservation.
(NOTE: Docetaxel is FDA-approved for this indication.)
cisplatin/docetaxel/5-FU + chemoradiotherapy
cisplatin 100 mg/m2 IV over 1 hour immediately before docetaxel (75 mg/m2 IV over 30 minutes to 3 hours) on day 1, followed by 5-FU continuous IV infusion (1000 mg/m2/day continuous IV infusion for 4 days, i.e., day 1—4); this regimen is given every 3 weeks for 3 cycles.
After completion of chemotherapy, patients should receive chemoradiotherapy.
All patients must receive prophylaxis for neutropenic infections, premedication with antiemetics, and appropriate hydration (before and after cisplatin administration).

NOTE: Survival was significantly improved among patients who got the 3 drugs as compared with receipt of only cisplatin 100 mg/m2 IV on day 1 and 5-fluorouracil 1000 mg/m2/day by continuous IV infusion for 5 days.
Specifically, the relative risk of death was 30% lower.
Also, the median overall survival was 70.6 months as compared with 30.1 months for patients receiving only cisplatin and 5-fluorouracil.

Three to 8 weeks after the start of the last cycle, all patients in both treatment arms who did not have progressive disease got carboplatin (AUC 1.5 weekly x 7 doses) and radiation therapy (2 Gy per day, 5 days per week for 7 weeks) followed by surgery, if appropriate.

† For the treatment of advanced nasopharyngeal head and neck cancer.
cisplatin/radiation + cisplatin/5-FU
cisplatin 100 mg/m2 IV over 15—20 minutes on days 1, 22, and 43 concurrently with radiation therapy (RT)
followed by cisplatin 80 mg/m2 IV on days 71, 99, and 127 in combination with 5-fluorouracil (5-FU) (1000 mg/m2/day IV over 4 days on days 71—74, 99—102, and 127—130).

In a phase III trial of 147 patients with advanced nasopharyngeal cancer, chemoradiotherapy significantly improved 3-year progression-free (69% vs. 24%, p < 0.001) and overall survival (76% vs. 46%, p < 0.001) rates versus RT alone.

† For the treatment of previously untreated resectable squamous cell head and neck cancer of the larynx.
cisplatin/radiation
cisplatin 100 mg/m2 IV on days 1, 22, and 43 during radiation therapy (70 Gy; delivered in 35 fractions over 7 weeks). In a phase III trial of 547 patients,
cisplatin/radiation resulted in a significantly higher percentage of patients with an intact larynx at 3.8 years median follow-up compared to induction cisplatin/fluorouracil followed by radiation (88% vs. 75%, p = 0.005), or radiation alone (88% vs. 70%, p < 0.001).
Overall survival was not significantly different between the treatment groups.
Toxicity was increased in each of the chemotherapy arms; mucosal toxicity was significantly worse in the cisplatin/radiation arm.

† For the treatment of previously untreated unresectable squamous cell head and neck cancer, excluding cancers of the nasopharynx, paranasal sinus, or parotid gland.
cisplatin/radiation
cisplatin 100 mg/m2 IV on days 1, 22, and 43 during radiation therapy (XRT) (70 Gy; delivered in 35 fractions over 7 weeks).
In a phase III trial of 295 patients, cisplatin/XRT was compared to XRT alone and a split course of cisplatin/5-FU with XRT.
Overall survival at 3 years was significantly higher in the cisplatin/XRT arm compared to XRT alone (37% vs. 23%, p = 0.014). Cisplatin/5-FU with XRT was not significantly different than XRT alone.

† For the treatment of previously untreated squamous cell head and neck cancer of the oral cavity, oropharynx, hypopharynx, or larynx.
cisplatin/radiation
cisplatin 100 mg/m2 IV on days 1, 22, and 43 during radiation therapy (XRT) has been studied.
In a phase III trial of 334 patients, cisplatin/XRT significantly improved progression-free survival, the primary endpoint, compared to XRT alone at a median follow-up of 60 months (HR, 0.75; 95% CI, 0.56—0.99, p = 0.02).
Overall survival was also significantly longer in the combination therapy arm (HR, 0.70; 95% CI, 0.52—0.95, p = 0.04).
Grade 3 and 4 adverse events occurred more frequently with combination therapy than with XRT alone (41% vs. 21%, p = 0.001).

In another phase III trial, 459 patients with high-risk squamous cell carcinoma of the head and neck were randomized to receive adjuvant cisplatin/XRT or XRT alone.
Local and regional tumor control, the primary endpoint, was significantly improved in the combination therapy arm (HR, 0.61, 95% CI 0.41—0.91, p = 0.01).
Disease-free survival was also significantly improved in the combination therapy arm (HR, 0.78, 95% CI 0.61—0.99, p = 0.04), but overall survival was similar.
Grade 3 and 4 adverse events occurred more frequently with combination therapy than with XRT alone (77% vs. 34%, p < 0.001).

 

Targeted Therapy

† For the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck.
cisplatin/cetuximab vs cisplatin
cisplatin 100 mg/m2 IV on day 1 in combination with cetuximab (400 mg/m2 IV over 120 minutes on day 1, then 250 mg/m2 IV over 60 minutes weekly from day 8); the treatment regimen was repeated every 4 weeks until disease progression or for 2 treatment cycles after the achievement of a complete response.

A phase III trial compared cisplatin with or without cetuximab in 117 patients with recurrent or metastatic head and neck cancer.
Neither progression-free survival (4.2 months vs. 2.7 months, p = 0.09), the primary endpoint, or overall survival (9.2 months vs. 8 months, p = 0.21) was significantly improved with the addition of cetuximab;
however the objective response rate was improved (26% vs. 10%, p = 0.03).

† For the first-line treatment of recurrent locoregional or metastatic squamous cell carcinoma of the head and neck.
(NOTE: Cetuximab is FDA-approved for this indication.)
cisplatin/5-fU/cetuximab vs cisplatin
cisplatin 100 mg/m2 IV on day 1 in combination with cetuximab (400 mg/m2 IV over 120 minutes on day 1, then 250 mg/m2 IV over 60 minutes weekly from day 8) and fluorouracil (1000 mg/m2/day IV infusion over days 1, 2, 3, 4). Cycles are repeated every 3 weeks; continue until disease progression or unacceptable toxicity.
Complete cetuximab administration 1 hour before platinum-based therapy and 5-FU.

In a phase III trial, 442 patients were randomized to receive a platinum (cisplatin or carboplatin) and fluorouracil with or without cetuximab for 6 cycles.
Overall survival, the primary endpoint, was significantly greater with the addition of cetuximab (10.1 months vs. 7.4 months, p = 0.04).
However, sepsis, hypomagnesemia, grade 3 skin reactions, and grade 3 or 4 infusion reactions occurred more frequently with the addition of cetuximab.

Immunotherapy

For the treatment of recurrent or metastatic head and neck cancer (squamous cell) with disease progression on or after platinum-containing chemotherapy.
Nivolumab
Standard Nivolumab regimen:
240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity.
Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions.
Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions.

In a multicenter, randomized, open-label clinical trial, nivolumab significantly improved overall survival compared with investigator’s choice of weekly monotherapy with cetuximab, methotrexate, or docetaxel (7.5 months vs. 5.1 months; HR 0.7; p = 0.01) in patients with recurrent, platinum-resistant, squamous-cell cancer of the head and neck.

For the treatment of recurrent or metastatic head and neck cancer (squamous cell) with disease progression on or after platinum-containing chemotherapy.
Pembrolizumab
Standard Pembrolizumab regimen:
200 mg IV over 30 minutes repeated every 3 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions.

After a median follow-up of 8.9 months, treatment with pembrolizumab resulted in an objective response rate (ORR) of 16% with complete response rate of 5%.
The median duration of response was not reached, but ranged from 2.4 months to more than 27.7 months; 23 of 28 responses lasted 6 months or longer. The ORR and duration of response were similar regardless of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.

 

 

NCCN Guidelines for Head and Neck Cancers

Among head and neck (H&N) cancers, NPC has one of the highest propensities to metastasize to distant sites. Regional recurrences are uncommon, occurring in only 10% to 19% of patients.

Patients with early-stage NPC should be treated with RT. For those with locoregionally advanced NPC, the panel recommends concurrent CRT with additional chemotherapy (either before or after CRT). For patients with M1 disease, recommended initial therapy options include either a platinum-based combination systemic therapy regimen or CRT for patients with limited metastatic burden and advanced locoregional disease. For the 2018 update, the panel voted to include pembrolizumab for patients with previously treated, PD-L1–positive recurrent or metastatic NPC (category 2B). When RT is used to treat patients with NPC, proton therapy may be considered when normal tissue constraints cannot be met by photon-based therapy, although IMRT is preferred.


Workup for NPC

Complete H&N examination. Nasopharyngeal endoscopic examination & biopsy.
MRI encompassing the skull base, face, and entire neck.
CT if needed for evaluation of bone invasion at the skull base.
FDG-PET/CT scan and/or chest CT may be used to evaluate for distant metastases, especially for locoregionally advanced disease.
If only a chest CT is ordered, a bone scan for distant bone metastasis is needed.
Epstein-Barr virus (EBV) DNA testing may also be considered.
Multidisciplinary consultation is encouraged. Dental, nutritional, speech and swallowing, and audiology evaluations should be performed as clinically indicated.
Ophthalmologic and endocrinologic assessments may also be considered.


Treatment of Locoregionally Advanced Disease

NCCN Recommendations: Patients with T1,N0,M0 nasopharyngeal tumors should be treated with definitive RT alone, including elective RT to the neck.
For patients with locoregionally advanced NPC (T1,N1–3; T2–T4,any N), enrollment in a clinical trial is preferred.
The panel recommends concurrent CRT (cisplatin) with adjuvant chemotherapy (cisplatin/5-FU) for locoregionally advanced NPC.
Concurrent CRT (cisplatin) without adjuvant systemic therapy is a category 2B recommendation based on a single randomized trial from China, which did not demonstrate a clear superiority over delivery of adjuvant chemotherapy.
Cisplatin for CRT is recommended for patients with no contraindication to the drug, because most randomized trials support the use of cisplatin in this setting.
If using adjuvant chemotherapy, adjuvant carboplatin/5-FU is a widely accepted option; however, this recommendation is a category 2B option due to the uncertainty about the benefits of adjuvant chemotherapy for all patients with NPC.

Induction chemotherapy (followed by CRT) is also recommended for patients with NPC with either T1,N1–3 or T2–T4,any N lesions.
Based on the results from randomized trials and a meta-analysis, the panel voted to change the category recommendation for induction chemotherapy followed by CRT from category 3 to category 2A for the 2018 update.
Besides TPF, several other induction/sequential chemotherapy regimens are recommended in the algorithm for NPC.

Treatment of Metastatic Disease

For patients with NPC who present with metastatic (M1) disease, enrollment in a clinical trial is preferred.
Initial therapy options: platinum-based combination systemic therapy regimen or CRT.
Patients who receive chemotherapy alone may receive subsequent RT to the primary and neck or concurrent CRT as clinically indicated.
Population-based data appear to support the role of earlier RT in the management of metastatic disease.

Active combination regimens for these patients include gemcitabine/cisplatin (category 1); cisplatin or carboplatin, plus a taxane; cisplatin/5-FU; or carboplatin/cetuximab.
Results from a trial that compared 5 different cisplatin-based regimens for NPC showed that a gemcitabine/cisplatin regimen was effective, although not better than either cisplatin/5-FU or cisplatin/paclitaxel.
However, results from a recent randomized phase III trial showed that patients with recurrent or metastatic NPC (N=362) who received gemcitabine/cisplatin had a greater median PFS compared with those who received cisplatin/5-FU (7.0 vs 5.6 months, respectively; HR, 0.55; 95% CI, 0.44–0.68; P<.001).
Gemcitabine/vinorelbine was removed from the list of recommendations for the 2018 update because there are more data to support use of other regimens.
Active and more commonly used single agents include cisplatin, carboplatin, paclitaxel, docetaxel, 5-FU, methotrexate, capecitabine, and gemcitabine.

In 2016, the anti–PD-1 antibody pembrolizumab received FDA approval for use in patients with recurrent or metastatic squamous cell H&N cancer who have progressed on or following platinum-based chemotherapy. The panel subsequently added pembrolizumab to the NCCN Guidelines for this indication, excluding NPC.
Pembrolizumab in patients with PD-L1–positive recurrent or metastatic NPC was assessed in the nonrandomized, multi-institutional, phase IB KEYNOTE-028 trial (N=27). All but 2 of the patients had previously received systemic therapy for recurrent or metastatic disease. The objective response rate (partial response only; none had a complete response) was 26%, with a median duration of response of 17.1 months. The OS rate at 6- and 12-months was 85% and 63%, respectively, with PFS rates of 39% and 34%, respectively.
Approximately 30% of patients experienced a grade 3–5 drug-related adverse event. The panel voted to include pembrolizumab for patients with previously treated, PD-L1–positive recurrent or metastatic NPC for the 2018 update, but this is a category 2B option based on panel consensus.

 

 

Treatment for Nasopharyngeal Cancer (Summary)

Radiation therapy (ASCO)
There are different types of radiation therapy for NPC.
• External-beam radiation therapy. The most common type of radiation therapy used to treat NPC is called external-beam radiation therapy, which aims radiation from a machine outside the body at the tumor. A method of external-beam radiation therapy, known as intensity-modulated radiation therapy (IMRT), allows more effective doses of radiation therapy to be delivered, while reducing damage to healthy cells and causing fewer side effects.

• Proton therapy. Proton therapy is a type of external-beam radiation therapy that uses protons rather than x-rays. At high energy, protons can destroy cancer cells. Proton therapy may be used as part of the treatment for some skull-base tumors to further limit the radiation dose to nearby structures, such as the optic nerves in the eye and the brainstem. Proton therapy may also be an option for later-stage NPC that is located close to parts of the central nervous system, which includes the brain and spinal cord.

• Stereotactic radiosurgery. Stereotactic radiosurgery delivers radiation therapy precisely to the tumor. This can be used to treat a tumor that has grown into the base of the skull or a tumor that has recurred at the base of the brain or skull.

• Brachytherapy. When radiation treatment is given using implants, it is called internal radiation therapy or brachytherapy. To treat NPC with internal radiation therapy, a doctor surgically implants tiny pellets or rods that contain radioactive materials in or near the cancer location. The implant is left in place for several days while the person stays in the hospital. This approach is most often used to treat NPC that has come back after the first treatment. It may also be used to treat the original tumor.

Radiation for Head/Neck Cancers (NCCN)
Intensity-modulated RT (IMRT) is now widely used in H&N cancers and is the predominant technique used at NCCN Member Institutions. It is useful in reducing long-term toxicity in H&N cancers and particularly NPC by reducing the dose to ≥1 major salivary glands, temporal lobes, mandible, auditory structures (including the cochlea), and optic structures. IMRT may help to preserve the optic pathway in patients with sinonasal malignancies. A prospective Korean study showed that 3-dimensional and IMRT techniques were superior to 2-dimensional radiation for both PFS and OS, and IMRT was associated with improved survival in multivariate analysis, particularly in T3–T4 tumors.

Proton therapy has also been used to treat sinonasal malignancies. A systematic review and meta-analysis of 41 noncomparative observation studies suggested that patients with malignant diseases of the nasal cavity and paranasal sinuses who received proton therapy had statistically superior disease-free survival at 5 years and locoregional control at longest follow-up than those receiving IMRT.
Compared with all photon-treated patients, patients with sinonasal malignancies who received charged particle therapy had significantly more neurologic toxic effects, although the authors noted a strong possibility of reporting bias, with significantly more particle therapy articles reporting toxic effects.
More recent reports show that proton-beam therapy for treatment of sinonasal cancer is associated with good locoregional control, freedom from distant metastasis, and acceptable toxicity. Specifically for NPC, proton therapy has established dosimetric superiority, although trials are ongoing to determine the level of clinical benefit. However, without high-quality prospective comparative data, it is premature to conclude that proton therapy has been established as superior to other modern radiation techniques, such as IMRT.
For the 2018 NCCN Guidelines update, the panel added a statement that proton therapy may be considered for treatment of NPC when normal tissue constraints cannot be met by photon-based therapy.

For early-stage high-risk NPC, radiation doses of 66 to 70.2 Gy given with standard fractions are necessary for control of the primary tumor and involved lymph nodes. Limited prospective evidence supports elective radiation volume reductions for very early-stage patients. The local control rate for these tumors ranges from 80% to 90%, whereas T3–T4 tumors have a control rate of 30% to 65% with RT alone. Radiation dose-fractionation schedules may vary slightly depending on institutional preference. Usually, these deliver between 2.0 and 2.12 Gy/fraction daily (Monday–Friday) for 33 to 35 fractions to all areas of gross disease to a total dose of approximately 70 Gy. Low-risk subclinical disease in the low neck is often treated with 44 to 54.1 Gy at 1.64 to 2.0 Gy per fraction, and for intermediate-risk disease 59.4 to 63 Gy in 1.8 to 2.0 Gy per fraction is often given with dose-painting to different regions of the skull base and neck. International guidelines have been recently published describing the design of radiation clinical target volumes.

Surgery (ASCO)
Surgery is the removal of the tumor and some surrounding healthy tissue during an operation. It is occasionally used for NPC, but it is not a common treatment choice because the area is hard to reach and lies close to cranial nerves and blood vessels.

If the doctor suspects that the cancer has spread to the lymph nodes, surgical removal of lymph nodes in the neck may be recommended. This type of surgery is called a neck dissection. For undifferentiated carcinoma of the nasopharynx, neck dissection is sometimes needed.


Treatment Option Overview (NCI)
Standard treatments for patients with nasopharyngeal cancer include the following:
• Radiation therapy alone (Stage I tumor).
• Concurrent chemoradiation followed by adjuvant chemotherapy (Locoregional tumor).
• Surgery for residual nodal disease.
• Chemotherapy alone for metastatic disease.

High-dose radiation therapy with chemotherapy is the primary treatment of nasopharyngeal cancer, both for the primary tumor site and the neck.
When feasible, surgery is usually reserved for nodes that fail to regress after radiation therapy or for nodal recurrence following clinical complete response.
Radiation therapy dose and field margins are individually tailored to the location and size of the primary tumor and lymph nodes.
Although most tumors are treated with external-beam radiation therapy (EBRT) exclusively, in some tumors radiation therapy may be boosted with intracavitary or interstitial implants or by the use of stereotactic radiosurgery when clinical expertise is available and the anatomy is suitable.
Intensity-modulated radiation therapy (IMRT) results in a lower incidence of xerostomia and may provide a better quality of life than conventional three-dimensional or two-dimensional radiation therapy.[Level of evidence: 1iiC]
Results of a phase II RTOG study (RTOG-0225) showed the feasibility of IMRT in a multi-institutional setting and minimal grade III and IV xerostomia rates. The rate of grade 2 xerostomia at 1 year from start of IMRT was 13.5%. Only 2 of 68 patients were reported with grade 3 xerostomia, and none had grade 4 xerostomia.[Level of evidence: 2C]

Accumulating evidence has demonstrated a high incidence (>30%–40%) of hypothyroidism in patients who have received radiation therapy that delivered EBRT to the entire thyroid gland or to the pituitary gland. Thyroid-function testing of patients should be considered before therapy and as part of posttreatment follow-up.

Treatments under clinical evaluation for patients with nasopharyngeal cancer include the following:
• Dose escalation with new radiation therapy techniques such as stereotactic radiation therapy boost.[Level of evidence: 3iiiDiv]
• Brachytherapy.[Level of evidence: 3iiiDii]

Follow-Up/Surveillance for NPC (NCCN)
Recommendations for surveillance following treatment of NPC include a complete H&N examination, endoscopic examination, and supportive care and rehabilitation.
Because the deep areas of the skull base may be inaccessible to clinical examination, periodic cross-sectional imaging may be necessary.
The clinical benefit of blood EBV DNA monitoring is currently uncertain, but it may be considered (category 2B).
Within the immediate several months after treatment with either RT or CRT, evaluation with imaging (eg, CT and/or MRI with contrast, FDG-PET/CT) guides the use of neck dissection. The rare patient who completes all therapy with residual disease in the neck and experiences a complete response at the primary should undergo a neck dissection.

 

Summary

Stage I disease (NCCN)
NCCN Recommendations: Patients with T1,N0,M0 nasopharyngeal tumors should be treated with definitive RT alone, including elective RT to the neck.

Locoregional disease (NCCN)
NCCN Recommendations: For patients with locoregionally advanced NPC (T1,N1–3; T2–T4,any N), enrollment in a clinical trial is preferred.
The panel recommends concurrent chemoradiation (cisplatin) with adjuvant chemotherapy (cisplatin/5-FU) for locoregionally advanced NPC (category 2A).
Concurrent (cisplatin) without adjuvant systemic therapy is a category 2B recommendation based on a single randomized trial from China, which did not demonstrate a clear superiority over delivery of adjuvant chemotherapy.
Cisplatin for CRT is recommended for patients with no contraindication to the drug, because most randomized trials support the use of cisplatin in this setting.
If using adjuvant chemotherapy, adjuvant carboplatin/5-FU is a widely accepted option; however, this recommendation in the 2018 update is a category 2B option due to the uncertainty about the benefits of adjuvant chemotherapy for all patients with NPC.
Induction chemotherapy (followed by concurrent chemoradiation) is also recommended for patients with NPC with either T1,N1–3 or T2–T4,any N lesions. (category 2A)
Besides TPF (docetaxel, cisplatin, and 5-FU ), several other induction/sequential chemotherapy regimens are recommended in the algorithm for NPC.

Metastatic Disease (Medical Journals)
Phase 3 trial in China: gemcitabine/cisplatin vs 5FU/cisplatin
gemcitabine igm/M2 on days 1 & 8 + cisplatin 80 mg/M2 on day 1, every 3 weeks for 6 cycles.
5 FU 4 gm/M2 continous IV infusion over 96h + cisplatin 80 mg/M2 on day 1, every 3 weeks for 6 cycles.
Resluts: Median progression-free survival was 7 months in the gemcitabine group and 5.6 months in the 5FU group, p<0.0001.

Phase 2 trial in Taiwan: gemcitabine/cisplatin
gemcitabine i.25 gm/M2 on days 1 & 8 + cisplatin 75 mg/M2 on day 1, every 3 weeks.
Resluts: 52 patients. The regimen was well-tolerated, i death.
RR 51.9%, CR 9.6%.
Median progression-free/overal survivals: 9.8 months/14.6 months,

Metastatic Disease (NCCN)
For patients with NPC who present with metastatic (M1) disease, enrollment in a clinical trial is preferred.
Other recommended initial therapy options include either a platinum-based combination systemic therapy regimen or concurrent chemoradiation; treatment depends on whether disease is mostly localized or widespread and if it is symptomatic or posing a clinical risk to the patient.
Patients who receive chemotherapy alone may receive subsequent RT to the primary and neck or concurrent CRT as clinically indicated.
Population-based data appear to support the role of earlier RT in the management of metastatic disease.

Active combination regimens for these patients include:
gemcitabine/cisplatin (category 1);
cisplatin or carboplatin, plus a taxane;
cisplatin/5-FU; or
carboplatin/cetuximab.

GoTo Drug Therapy for head and neck cancer for details.

Active and more commonly used single agents include cisplatin, carboplatin, paclitaxel, docetaxel, 5-FU, methotrexate, capecitabine, and gemcitabine.

Results from a trial that compared 5 different cisplatin-based regimens for NPC showed that a gemcitabine/cisplatin regimen was effective, although not better than either cisplatin/5-FU or cisplatin/paclitaxel.
However, results from a recent randomized phase III trial showed that patients with recurrent or metastatic NPC (N=362) who received gemcitabine/cisplatin had a greater median PFS compared with those who received cisplatin/5-FU (7.0 vs 5.6 months, respectively; HR, 0.55; 95% CI, 0.44–0.68; P<.001).

Targeted Therapy

† For the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck.
cisplatin/cetuximab vs cisplatin
cisplatin 100 mg/m2 IV on day 1 in combination with cetuximab (400 mg/m2 IV over 120 minutes on day 1, then 250 mg/m2 IV over 60 minutes weekly from day 8); the treatment regimen was repeated every 4 weeks until disease progression or for 2 treatment cycles after the achievement of a complete response.

A phase III trial compared cisplatin with or without cetuximab in 117 patients with recurrent or metastatic head and neck cancer.
Neither progression-free survival (4.2 months vs. 2.7 months, p = 0.09), the primary endpoint, or overall survival (9.2 months vs. 8 months, p = 0.21) was significantly improved with the addition of cetuximab;
however the objective response rate was improved (26% vs. 10%, p = 0.03).

† For the first-line treatment of recurrent locoregional or metastatic squamous cell carcinoma of the head and neck.
(NOTE: Cetuximab is FDA-approved for this indication.)
cisplatin/5-fU/cetuximab vs cisplatin
cisplatin 100 mg/m2 IV on day 1 in combination with cetuximab (400 mg/m2 IV over 120 minutes on day 1, then 250 mg/m2 IV over 60 minutes weekly from day 8) and fluorouracil (1000 mg/m2/day IV infusion over days 1, 2, 3, 4). Cycles are repeated every 3 weeks; continue until disease progression or unacceptable toxicity.
Complete cetuximab administration 1 hour before platinum-based therapy and 5-FU.

In a phase III trial, 442 patients were randomized to receive a platinum (cisplatin or carboplatin) and fluorouracil with or without cetuximab for 6 cycles.
Overall survival, the primary endpoint, was significantly greater with the addition of cetuximab (10.1 months vs. 7.4 months, p = 0.04).
However, sepsis, hypomagnesemia, grade 3 skin reactions, and grade 3 or 4 infusion reactions occurred more frequently with the addition of cetuximab.


Immunotherapy

For the treatment of recurrent or metastatic head and neck cancer (squamous cell) with disease progression on or after platinum-containing chemotherapy.
Nivolumab
Standard Nivolumab regimen:
240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity.
Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions.
Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions.

In a multicenter, randomized, open-label clinical trial, nivolumab significantly improved overall survival compared with investigator’s choice of weekly monotherapy with cetuximab, methotrexate, or docetaxel (7.5 months vs. 5.1 months; HR 0.7; p = 0.01) in patients with recurrent, platinum-resistant, squamous-cell cancer of the head and neck.

For the treatment of recurrent or metastatic head and neck cancer (squamous cell) with disease progression on or after platinum-containing chemotherapy.
Pembrolizumab
Standard Pembrolizumab regimen:
200 mg IV over 30 minutes repeated every 3 weeks until disease progression or up to 24 months in patients without progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions.

After a median follow-up of 8.9 months, treatment with pembrolizumab resulted in an objective response rate (ORR) of 16% with complete response rate of 5%.
The median duration of response was not reached, but ranged from 2.4 months to more than 27.7 months; 23 of 28 responses lasted 6 months or longer. The ORR and duration of response were similar regardless of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.


Immunotherapy (NCCN)
In 2016, the anti–PD-1 antibody pembrolizumab received FDA approval for use in patients with recurrent or metastatic squamous cell H&N cancer who have progressed on or following platinum-based chemotherapy.The NCCN panel voted to include pembrolizumab for patients with previously treated, PD-L1–positive recurrent or metastatic NPC for the 2018 update, but this is a category 2B option based on panel consensus.

Biomarkers (Multiple sources)
* HPV status in some study associated with better outcome with anti-PD-1 therapy, but not in others.
* Tumor mutational burden (TMB), a biomarker, in early data sets appears to have higher predictive value in HPV(-) tumors.
* At this point clinical utility of Tumor mutational burden and PD-L1 is unclear, but it is suggestive of increased chance response.
* PD-L1(-) tumors can still respond to immunotherapy, but the likelihood of benefit is lower.
* An inflammation signature (e.g. GEP) may be helpful.
However, at this time, a GEP/TIS inflammation score hasn't been proved to improve the predictive ability of all these biomarkers.

Conclusion