Head and Neck Cancer: Treatment & Management

Head and neck cancer refers to a group of cancers that affect structures in the head and neck region, including the oral cavity, pharynx, larynx, nasal cavity, and salivary glands.¹ Head and neck cancer is the seventh most common cancer worldwide² and accounts for approximately 4% of all cancers in the United States.³ The global incidence of head and neck cancer is increasing and is projected to exceed 1 million new cases annually by 2030.⁴ Approximately 90% of all head and neck cancers are squamous cell carcinomas (HNSCC) that originate from the mucosal surfaces of the oral cavity, pharynx, and larynx, while cancers of the nasal cavity and salivary glands are much less frequently encountered.⁵ Head and neck cancers are classified into the following subtypes, according to their anatomical location: 

• Laryngeal cancer
• Hypopharyngeal cancer 
• Lip and oral cavity cancer 
• Oropharyngeal cancer 
• Nasopharyngeal cancer 
• Nasal cavity and paranasal sinus cancer 
• Salivary gland cancer 

Major risk factors contributing to the development of head and neck cancer include smoking, exposure to tobacco products, and alcohol consumption, and these factors are frequently associated with cancers of the oral cavity and larynx. Infection with oncogenic strains of human papillomavirus (HPV) has been identified as a burgeoning risk factor for the development of oropharyngeal cancer.⁴

Other risk factors contributing to head and neck cancer include use of betel quid (a chewing product often containing betel leaf, areca nut, and tobacco), occupational exposure to potential carcinogens, infection with the Epstein-Barr virus (EBV), and genetic predisposition.⁴ No successful screening strategies exist, and early detection of HNSCC has relied on careful physical examination. If detected in early stages, some head and neck cancers — especially those of the oral cavity and larynx — can be successfully treated with surgery and/or radiation. However, the majority of head and neck cancer cases are diagnosed at advanced stages with no history of premalignant lesions. The prognosis for recurrent or metastatic HNSCC is generally poor, with survival dependent on cancer stage and location.⁶

Types of Head and Neck Cancer

Laryngeal Cancer

Laryngeal cancer affects the larynx, which is located between the base of the tongue and the trachea. The larynx contains the vocal cords. Smoking, tobacco use, and heavy alcohol consumption are factors that increase the risk of developing laryngeal cancer. 

Symptoms of laryngeal cancer include:

• Sore throat 
• Odynophagia (pain on swallowing)
• Ear pain
• Dysphonia (hoarseness and other changes in voice quality)
• Cervical lymphadenopathy (enlarged lymph nodes in the neck)

Depending on the regions of the head and neck affected by the malignancy, lymph nodes are involved in approximately 25% to 50% of cases of laryngeal cancer.⁷ If there is no lymph node involvement, prognosis for small laryngeal cancers is good, with cure rates ranging from 75% to 95%.⁷ Surgery and/or radiation therapy may be curative for small superficial cancers without lymph node involvement.

The goal of preserving vocal function should be considered when determining treatment. Advanced-stage tumors require a combination of radiation therapy and chemotherapy with or without surgery. The development of a second primary tumor can occur in up to 25% of patients with laryngeal cancer whose primary tumor has been controlled. The risk of recurrence of laryngeal cancer is highest within the first 2 to 3 years of treatment.⁷ 

Hypopharyngeal Cancer 

Hypopharyngeal cancers originate from hypopharynx, which is located at the bottom part of the pharynx. Hypopharyngeal cancer is uncommon, with approximately 2500 new cases diagnosed in the United States annually.⁸ Because the symptoms of hypopharyngeal cancer often are not noticeable until it is in the late phase and it metastasizes early, survival rates are the lowest of all head and neck cancers. Risk factors contributing to the development of hypopharyngeal cancer include smoking and tobacco use, heavy alcohol consumption, and nutritional deficiencies.⁸ 

Symptoms associated with hypopharyngeal cancer include:

• Neck mass 
• Persistent sore throat 
• Odynophagia
• Ear pain
• Dysphonia 

Except for cases identified in the very early stage, treatment for hypopharyngeal cancer has been surgery, usually followed by postoperative radiation therapy.⁸ 

Lip and Oral Cavity Cancer

Most cancers of the lip and oral cavity originate as squamous cell carcinomas and affect the lip, tongue, gums, lining inside the mouth, floor and the roof of the mouth, and the area behind the wisdom teeth. Risk factors for lip and oral cavity cancer include smoking and tobacco use, heavy alcohol consumption, and exposure to ultraviolet (UV) light. 

Symptoms of lip and oral cavity cancer include:

• Sore on the  mouth or lip
• Lump on the lips or in the mouth
• White or red patch inside the mouth
• Difficulty chewing or swallowing
• Jaw swelling
• Sore throat
• Dysphonia
• Loose teeth or dentures that no longer fit

Regular dental examinations are beneficial for identifying symptoms of lip and oral cavity cancer that often go unnoticed. Early-stage cancers of the lip and oral cavity are highly curable by surgery or radiation therapy. Patients with late-stage tumors may be treated with a combination of surgery and radiation therapy. In their early stages, cancers of the lip and oral cavity have high cure rates ranging from 90% to 100%.⁹     

Oropharyngeal Cancer 

Oropharyngeal cancer affects the soft palate, walls of the throat, tonsils, and base of the tongue. Most oropharyngeal cancers are squamous cell carcinomas. Risk factors include history of smoking (more than 10 pack-years), tobacco use, heavy alcohol consumption, HPV-16 infection, personal history of head and neck cancer, and betel quid chewing. With the rise in the number of HPV-associated cases, the incidence of oropharyngeal cancer has been steadily increasing. 

As many as 55,000 new cases of oral and oropharyngeal cancer are anticipated in the United States in 2023.¹⁰ According to researchers who evaluated data from the Surveillance, Epidemiology, and End Results (SEER) program, the prevalence of HPV-negative cancer declined by 50% from 1988 to 2004, while the rate of HPV-positive oropharyngeal cancers increased by 225% during that same time period.¹¹ Researchers also determined that HPV vaccination prevented 88% of oral HPV infections that can cause oral cavity and oropharyngeal cancers.¹² 

Symptoms of oropharyngeal cancer include:

• Persistent sore throat
• Difficulty swallowing
• Difficulty moving the tongue or opening the mouth fully
• Ear pain
• Lump in the back of the mouth, throat, or neck
• White patch on the tongue or lining of the mouth
• Weight loss

Prognosis of oropharyngeal cancer depends on the patient’s HPV status, smoking history, stage of the cancer, and lymph node involvement. HPV-positive oropharyngeal tumors are associated with a better prognosis and have lower likelihood of recurrence. Treatment options for oropharyngeal cancer include surgery, radiation therapy, chemotherapy in different combinations depending on stage and metastasis status, and consideration for preserving speech and swallowing function. The standard of care for oropharyngeal cancer has been surgery and radiation therapy.¹¹ 

Nasopharyngeal Cancer

Nasopharyngeal cancer affects the nasopharynx, which is a small tubular structure located above the soft palate that connects the nose to the oropharynx. Nasopharyngeal cancer is rare among White individuals, with less than one person out of 100,000 affected each year in North America.¹³ The frequency of nasopharyngeal cancer in ethnic Chinese individuals in Southeast Asia is much higher at 15 to -30 per 100,000 each year.¹⁴ Risk factors contributing to nasopharyngeal cancer include smoking, heavy alcohol consumption, exposure to Epstein-Barr virus, and Chinese or Asian ancestry. 

Symptoms of nasopharyngeal cancer include:

• Lump in the nose or neck
• Difficulty breathing or speaking
• Diminished hearing
• Tinnitus (ringing in the ears)
• Facial numbness
• Epistaxis (nosebleed)
• Diplopia (double vision)
• Ear infection
• Sore throat
• Headache 

Treatment for nasopharyngeal cancer is dependent on stage of disease. High-dose radiation therapy is the recommended treatment for patients with stage I nasopharyngeal cancer. High-dose radiation therapy combined with chemotherapy is the initial treatment for patients with stages II through IV nasopharyngeal cancer, and chemotherapy is recommended for patients with late-stage nasopharyngeal cancer. Surgery may be considered for locally recurrent tumors in a select population of patients.¹³ 

Nasal Cavity and Paranasal Sinus Cancer 

Most cancers of the nasal cavity and paranasal sinuses are squamous cell carcinomas that arise from the cells lining the inside of the paranasal sinuses and nasal cavity. As most cases of nasal cavity and paranasal sinus cancer are at advanced stages when first diagnosed, rates of cure are generally poor at less than 50%.¹⁵ Cancers of the paranasal sinus are most commonly located in the maxillary sinus. Risk factors contributing to cancers of the nasal cavity and paranasal sinus include smoking, occupational exposure to chemicals or dust, and HPV infection. 

Symptoms of paranasal sinus and nasal cavity cancer include:

• Blocked sinuses
• Headache
• Sinus pain
• Lump or sore inside the nose
• Lump on the face or roof of the mouth
• Numbness or tingling in the face
• Diplopia
• Ear pain
• Epistaxis
• Pain in the upper teeth 

A combination of surgery and radiation therapy is recommended for treatment of most nasal cavity and paranasal cancers. Due to the complexity of the treatment, management should be planned on an individual basis based on operability, the size of the affected area, and lymph node involvement. If surgery is warranted, the tumor is removed to first enable drainage of the affected sinus or sinuses, followed by radiation therapy.¹⁵ 

Salivary Gland Cancer 

Cancer of the salivary gland is a rare type of head and neck cancer that affects the tissues of the major and minor salivary glands. Most of these malignancies originate from the parotid gland, and the palate is the most common location for minor salivary gland tumors. More than 50% of salivary gland tumors are benign.¹⁶ Factors that may contribute to the development of salivary gland tumors include exposure to ionizing radiation (radiation therapy of the head and neck area) and occupational exposure to chemicals or dust. 

Symptoms of salivary gland cancer include:

• Lump in the area of the ear, cheek, jaw, or lip, or inside the mouth
• Numbness or weakness in the face
• Persistent facial pain
• Difficulty swallowing or opening the mouth widely

In many cases, symptoms of salivary gland tumors are not accompanied by pain. 

Surgery is effective in treatment of early-stage, low-grade, malignant salivary gland tumors. Prognosis is largely dependent on tumor size and is more favorable for tumors in a major salivary gland and less favorable for tumors in the sublingual and minor salivary glands. Large tumors may be treated with surgery followed by radiation therapy.¹⁶ 

Treatment of Head and Neck Cancers

Main treatment modalities for head and neck cancers include surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Surgery is often the first-line treatment for localized head and neck cancers and may be used alone or in combination with other treatment modalities. Size, location, and stage of tumor, as well as metastasis status are factors to be considered when determining operability and outcome. However, surgery may not be of benefit in patients with advanced HNSCC, and the desire to preserve organs may make surgery unsuitable. Radiotherapy and systemic therapy with pharmacologic agents may be better treatment options in these cases. 

Radiation therapy is an effective treatment option for small, localized head and neck cancers. It is often combined with surgery and/or chemotherapy to improve outcome in advanced, late-phase malignancies. Systemic therapies, which include chemotherapy, targeted therapy, and immunotherapy, are indicated for most patients with metastatic or advanced recurrent HNSCC. Treatment decisions are made based on multiple factors: location and stage of the tumor, presence of comorbidities, swallowing and airway considerations, and the patient’s desire to preserve organs. 

Systemic Therapy for Head and Neck Cancer: Pharmacotherapy

With the recent development of immunotherapeutic agents and targeted therapeutics against biomarkers, systemic therapy options for HNSCC have expanded considerably. Incorporation of systemic therapy to treatment regimens with surgery and/or radiation therapy has led to improved prognosis in many types of head and neck cancers. Treatment decision is based on multiple factors, including patient comorbidities, previous therapy, and the biomarker status of the tumor. 

Options for systemic therapy for head and neck cancer include the following: 

• Chemotherapy
• Targeted therapy
• Immunotherapy

Chemotherapy

Cisplatin. Cisplatin is a chemotherapeutic agent that induces cell death in cancer cells by causing damage to their DNA. It is commonly used in combination with radiation therapy to treat locally advanced head and neck cancers. Compared with radiation therapy alone, cisplatin improves overall survival (13% higher) and locoregional control (freedom from first local or regional recurrence), in patients with head and neck cancer.¹⁷ Cisplatin as a single agent is given as an intravenous injection at 100 mg/m² every 3 weeks, for up to 3 to 4 cycles.¹⁸ The dosage may be reduced to 40 mg/m² every week for patients with kidney injury or comorbidities. 

Pregnancy status of female patients should be checked before treatment with cisplatin. Female patients should be warned of the risk of fetal harm and advised to use effective contraception during treatment and for 14 months after the last dose of cisplatin injection. Effective contraception should be used by male patients with female partners of reproductive potential during treatment and for 11 months after the last dose. Because cisplatin can cause cumulative kidney toxicity and hearing damage, nephrotoxic and ototoxic drugs should be avoided during treatment with cisplatin. 

Docetaxel. Docetaxel is a chemotherapeutic agent that prevents cell division of cancer cells by inhibiting microtubule formation. It is used for the treatment of locally advanced and recurrent or metastatic HNSCC in combination with cisplatin and fluorouracil.¹⁹ Docetaxel has been shown to improve overall survival compared with cisplatin and fluorouracil alone. 

Docetaxel is given intravenously at 75 mg/m² every 3 weeks, for up to 3 to 4 cycles.²⁰ The dosage may be adjusted based on the patient’s kidney and liver function and comorbidities. For treatment of locally advanced HNSCC in patients who are not a candidate for surgery, the recommended dosage is 75 mg/m² given as a 1-hour intravenous infusion followed by 75 mg/m² cisplatin given intravenously over 1 hour on day 1, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m²/d for 5 days. This regimen is repeated every 3 weeks for 4 cycles. Radiation therapy should follow chemotherapy. 

For the induction treatment of patients with locally advanced HNSCC, the recommended dosage is 75 mg/m² as a 1-hour intravenous infusion on day 1, followed by cisplatin 100 mg/m² administered as a 30-minute to 3-hour infusion, followed by fluorouracil 1000 mg/m²/d as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles.²⁰ 

Female patients should be warned of the risk of fetal harm and advised to use effective contraception during treatment and for 6 months after the last dose of docetaxel injection. Docetaxel may impair fertility in male patients of reproductive potential. CYP3A4 inhibitors have been shown to increase the exposure of docetaxel. Ketoconazole and ritonavir should be avoided during treatment with docetaxel.    

Targeted Therapy

Epidermal growth factor receptor (EGFR), an oncogenic gene involved in cell growth, is overexpressed in 90% of head and neck tumors. Overexpression of EGFR is associated with decreased survival and increased metastasis. EGFR antagonists target EGFR and inhibit its activity to prevent tumor cell growth.^21,22   

Cetuximab. Cetuximab is an EGFR monoclonal antibody and is the only targeted therapy agent approved by the US Food and Drug Administration (FDA) for treatment of²³: 

• Locally advanced HNSCC in combination with radiation therapy
• Recurrent locoregional or metastatic HNSCC in combination with platinum-based therapy with fluorouracil
• Recurrent or metastatic HNSCC progressing after platinum-based therapy 

In the EXTREME (ClinicalTrials.gov Identifier: NCT00122460) study, the addition of cetuximab to standard platinum-based chemotherapy and fluorouracil treatment for the management of recurrent and metastatic head and neck cancer was shown to improve overall survival and reduce risk of death compared with treatment with chemotherapy alone.²⁴ Response to therapy was also improved with the addition of cetuximab to chemotherapy.

Since then, platinum-based chemotherapy combined with cetuximab has been the standard of care for patients with locally recurrent and/or metastatic head and neck cancer. As a single agent or in combination with chemotherapy, cetuximab is administered weekly at an initial dose of 400 mg/m² as a 120-minute intravenous infusion, with subsequent doses of 250 mg/m² infused over 60 minutes once weekly. Cetuximab can be administered biweekly at 500 mg/m² as a 120-minute infusion every 2 weeks. 

In combination with radiation therapy, an initial dose of cetuximab 400 mg/m² is administered intravenously over 120 minutes one week prior to initiating a course of radiation therapy, with the subsequent doses of 250 mg/m² administered as 60-minute infusions every week for the duration of radiation therapy (6 to 7 weeks).²³ Due to the potential to be transmitted to the fetus, pregnant patients should be warned of the risk of fetal harm. Breastfeeding should be discontinued during treatment with cetuximab.

Immunotherapy

Immune checkpoint inhibitors are monoclonal antibodies that target checkpoint proteins to release the brake on the immune response against tumor cells.²⁵ When programmed death-1 ligand-1 (PD-L1) binds to PD-1, a checkpoint protein on the T-cell surface, it prevents the T cell from attacking the cell presenting PD-L1. Many cancer cells, including head and neck tumors, express high levels of PD-L1, enabling them to evade the immune response.²⁶ 

Pembrolizumab. Pembrolizumab is a monoclonal antibody to the PD-1 receptor that blocks binding of PD-L1 on the surface of cancer cells to the PD-1 receptor.²⁷ Based on results of the KEYNOTE-040 (ClinicalTrials.gov Identifier: NCT02252042) study that demonstrated the survival benefit of pembrolizumab over standard chemotherapy,²⁸ the FDA approved the use of pembrolizumab for the treatment of recurrent or metastatic HNSCC with disease progression following platinum-based chemotherapy.

Subsequently, results of the KEYNOTE-048 (ClinicalTrials.gov Identifier: NCT02358031) study, which demonstrated the survival benefit of pembrolizumab over the conventional platinum-based combination chemotherapy and cetuximab (EXTREME regimen), led to the approval of pembrolizumab in 2019 as first-line treatment for recurrent or metastatic HNSCC alone or in combination with platinum-based chemotherapy.²⁹ Since then, pembrolizumab plus platinum plus fluorouracil has been the standard of care treatment for recurrent or metastatic HNSCC. 

Pembrolizumab is administered at 200 mg as an intravenous infusion over 30 minutes every 3 weeks until disease progression or for up to 24 months in patients without disease progression.²⁷ Due to the potential to be transmitted to the fetus, pregnant patients should be warned of the risk of fetal harm. Breastfeeding should be discontinued during treatment with pembrolizumab and for 4 months after the final dose. Effective contraception should be used during treatment with pembrolizumab and for at least 4 months after the final dose to avoid pregnancy.

Nivolumab. Nivolumab is a monoclonal antibody to the PD-1 receptor.³⁰ In the CHECKMATE-141 (ClinicalTrials.gov Identifier: NCT02105636) study, treatment with nivolumab was shown to improve survival in patients with recurrent HNSCC whose disease had progressed after platinum-based chemotherapy compared with standard, single-agent, systemic therapy with methotrexate, docetaxel, or cetuximab.³¹

Nivolumab is administered intravenously at 3 mg/kg over 60 minutes every 2 weeks.³⁰ Pregnant patients should be warned of the risk of fetal harm, and effective contraception should be used during and for 5 months following treatment with nivolumab. Breastfeeding should be discontinued during treatment with nivolumab.    

Complications of Systemic Therapy in Head and Neck Cancer

Chemotherapy

Cytotoxic chemotherapy agents target rapidly dividing cancer cells by inhibiting cell division. Chemotherapy can also affect noncancerous cells in the body that divide quickly, such as those in the digestive tract, hair follicles, and bone marrow, leading to an array of adverse reactions. 

Cisplatin. Adverse reactions to cisplatin include renal toxicity, neuropathy, myelosuppression, hearing damage, nausea, and vomiting.¹⁸  

Docetaxel. Adverse reactions to docetaxel include infections, low white blood cell count, low platelet level, anemia, nerve pain, altered sense of taste, labored breathing, inflammation of the lining of the digestive tract, mouth sores, fluid retention, lethargy, pain, nausea, diarrhea, vomiting, constipation, anorexia, alopecia, and skin reactions. The most serious adverse reactions associated with treatment with docetaxel are toxic deaths, hepatic impairment, hematologic effects, enterocolitis and neutropenic colitis, hypersensitivity reactions, fluid retention, second primary malignancies, cutaneous reactions, neurologic reactions, eye disorders, and asthenia (weakness).²⁰

Targeted Therapy

Targeted therapy works by inhibiting activities of specific proteins or genes that are involved in cancer cell growth and survival. However, targeted therapy can also affect healthy cells in the body and cause side effects.

Cetuximab. The most common adverse reactions with cetuximab as a single agent or in combination with radiation therapy or chemotherapy are rash, pruritus (itching), nail changes, headache, diarrhea, and infection. The most frequently reported adverse reactions when cetuximab is administered in combination with encorafenib are fatigue, nausea, diarrhea, acneiform rash, abdominal pain, decreased appetite, and joint pain. It should be noted that the incidence of late radiation toxicities was higher for patients receiving combination therapy with cetuximab and radiation compared with patients receiving radiation therapy alone.²³ 

Immunotherapy

Immunotherapy is a type of cancer treatment that harnesses the power of the immune system to fight cancer cells. However, it can also cause immune-related adverse events and lead to more serious autoimmune reactions.

Pembrolizumab. Acute infusion reactions such as fever, hypotension, hypoxemia, rigor, rash, wheezing, and anaphylaxis can occur during administration of pembrolizumab. Other adverse reactions include colitis, hypophysitis (inflammation of the pituitary gland), pneumonitis, nephritis, hepatitis, thyroid disorders, and severe skin reactions.²⁷ 

Nivolumab. The most frequent serious adverse reactions reported with nivolumab administration are pneumonia, dyspnea, confusion state, vomiting, pleural effusion, and respiratory failure. The most common adverse effects reported with nivolumab administration are fatigue, nausea, rash, decreased appetite, and pruritus.³⁰

Guidelines

Numerous guidelines are available to assist with head and neck cancer treatment decision-making:

• Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline
• Management of the Neck in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: ASCO Clinical Practice Guideline
• Human Papillomavirus Testing in Head and Neck Carcinomas: ASCO Clinical Practice Guideline Endorsement of the College of American Pathologists Guideline
• Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline
• Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline
• Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary

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Author Bio

Bora Lee, PhD earned a Bachelor of Science in biology from Boston College and a PhD in Molecular and Cellular Biology from the University of Massachusetts Amherst. She has more than 10 years of translational research experience in reproductive medicine and women’s health, with a focus on fertility and placental health. She is passionate about improving people’s lives by helping them to make informed health decisions.