Side effects of chemotherapy & immunotherapy for head & neck cancer

Chemotherapy for head and neck cancer

Chemotherapy for head and neck cancer is used in conjunction with supportive care for most patients with metastatic or advanced recurrent head and neck cancer. The choice of specific systemic therapy is influenced by the patient's prior treatment with chemotherapeutic agents and the general approach to preserve the affected organs. Supportive care includes the prevention of infection due to severe bone marrow suppression and the maintenance of adequate nutrition. 

  

There are many different types of chemotherapy medications that differ in how they kill the cancer cells. The choice of agents(s) is based on clinical trials that have shown which ones are effective. Therapeutic options include treatment with a single agent and combination regimens with conventional cytotoxic chemotherapy and/or molecularly targeted agents, combined with optimal supportive care. Chemotherapy is given in cycles, alternating between periods of treatment and rest. Treatment can last several months or even longer. 

The specific chemotherapy regimen, including the drugs used, dosage, and administration schedule, is tailored to each patient's individual case based on factors like the type and stage of cancer. One’s oncologist will determine the most appropriate chemotherapy plan for each patient.

Chemotherapy for head and neck cancer can be administered through several routes: 

1.         Intravenous (IV) Administration is the most common method of delivering chemotherapy for head and neck cancer is intravenously. This involves:

• Injecting the drugs directly into a vein through a cannula (short, thin tube) in the arm or hand
• Using a central line - a long, thin tube inserted into a vein in the chest
• Using a PICC (peripherally inserted central catheter) line - a flexible tube inserted into a vein in the arm and threaded to a vein in the chest
• Using a portacath - an implantable catheter with an opening under the skin on the chest or arm

2.         Oral Administration

Some chemotherapy drugs, such as capecitabine, can be taken orally as tablets.

 

3.         Continuous Infusion

In some cases, intravenous chemotherapy may be administered continuously over a few days using a small, portable pump attached to a central line or PICC line. This allows patients to receive treatment at home. See picture below how the opening of the portacath opening under the chest can be protected during continuous administration with a portable pump.

Improvised protection of the portacath opening under the chest

The agents commonly used in treatment head and neck cancer include: Cisplatin, carboplatin, 5-fluorouracil, hydroxyurea, paclitaxel and docetaxel, and epirubicin. Other less commonly agents include: gemcitabine, vinorelbine and irinotecan, methotrexate and edatrexate, and ifosfamide. Cetuximab, vandetanib, trametinib and bevacizumab, are newer drug that target a specific receptor molecule that is found on some head and neck cancer cells. Enclosed is link to a site that lists all the chemotherapeutic agents and their side effects.

Chemotherapeutic drugs work throughout the whole body by disrupting cancer cells’ growth. The drugs can be given intravenously (most common), intra-muscularly, and by mouth.   Chemotherapy for the treatment of head and neck cancers is usually given at the same time as radiation therapy and is known as chemoradiation. It can be given as adjuvant chemotherapy or as neoadjuvant chemotherapy. 

Adjuvant chemotherapy is used for treatment after surgery to reduce the risk of cancer returning, and to kill cells that may have spread. 

Neoadjuvant chemotherapy is administered before surgery to shrink the size of the tumor thus making it easier to remove.

Chemotherapy administered prior to chemoradiation treatment is known as induction chemotherapy. 

 

                                                               

                                                         Chemotherapy drugs

Side effects of chemotherapy

The kind and type of possible side effects of chemotherapy depend on the individual. Some have few side effects, while others have more. Many individuals do not experience side effects until the end of their treatments; for many individuals, these side effects do not last long. 

Chemotherapy can, however, cause several temporary and long term side effects. Although these may be worse with combined radiation therapy, they generally disappear gradually after the treatment has ended.

Side effects depend on the chemotherapeutic agent(s) used. These occur because chemotherapy drugs work by killing all actively growing cells. These include cells of the digestive tract, hair follicles, and bone marrow (which makes red and white blood cells), as well as the cancer cells.

The more common side effects are nausea, vomiting, taste alteration, diarrhea, sores (mucositis) in the mouth (resulting in problems swallowing and sensitivity in the mouth and throat), increased susceptibility to infection, anemia, hair loss, general fatigue, numbness in the hands and feet (neuropathy), hearing loss, kidney damage, radiation recall dermatitis, bleeding problems, malaise, and dysautonomia including balance problem. Some side effects (e.g., nausea, mucositis) are generally more pronounced in those who receive radiation in combination with chemotherapy. An oncologist and other medical specialist watch for and treat these side effects. 

The most common side effects include:

Lowered resistance to infection

Chemotherapy can temporarily reduce the production of white blood cells (neutropenia), making the patient more susceptible to infections.

This effect may begin about seven days following treatment and the decline in resistance to infection is maximal usually about 10–14 days after chemotherapy has ended. At that point the blood cells generally begin to increase steadily and return to normal before the next cycle of chemotherapy is administered. Signs of infection include fever above 100.4°F (38°C) and or a sudden feeling of being ill. Prior to resuming chemotherapy blood test are performed to ensure the recovery of the white blood cells has occurred. Further administration of chemotherapy may be delayed until recovery of blood cells has taken place.

Fever

                                                                     
Bruising or bleeding

Chemotherapy can promote bruising or bleeding because the agents given reduce the production of platelets which help the blood clotting. Nosebleeds, blood spots or rashes on the skin, and bleeding gums can be a sign that this has occurred.

Skin bruising

Nose bleeding

Anemia

Chemotherapy can lead to anemia (low number of red blood cells). The patient generally feels tired and breathless. Severe anemia can be treated by blood transfusions or medications that promote red cells production.

Red blood cells

Kidney problems (nephropathy)

A variety of renal disease can be caused by many chemotherapeutic agents. These agents can affect the glomerulus, tubules, and the interstitium of the kidney. Individuals can exhibit a variety of clinical manifestations ranging from an asymptomatic increase of their serum creatinine to acute renal failure requiring dialysis.

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Hair loss

Some chemotherapy agents cause hair loss all over the body. The hair almost always grows back over a period of 3-6 months once the chemotherapy has ended. Meanwhile, a wig, bandana, hat or scarf can be worn. 

These steps can minimize the frustration and anxiety associated with hair loss:

Before treatment:

• Do not bleach, color or perm the hair
• Do not dry the hair with heating devices such as curling irons and hot rollers.
• Considering cutting or shortening the. Short hair tends to look fuller than long hair.
• Plan for a wig, scarves or other head coverings. The cost of a wig may be covered by health insurance if one’s doctor writes a prescription for it.

During treatment:

• Use a soft brush
• Wash your hair only as often as necessary with a gentle shampoo.
• Consider shaving the head. Some people report that their scalps feel itchy, sensitive and irritated during their treatments and while their hair is falling out. Shaving the head can reduce the irritation and save the embarrassment of shedding. Some men shave their heads because they feel it looks better than the patchy hair loss they might be experiencing.
• Protecting the scalp from to the sun or to cold air, with sunscreen or a head covering. The scalp may be sensitive during the treatment, and extreme cold or sunshine can easily irritate it.

•          Consider wearing a “cooling hat”.

After treatment:

• Continue gentle hair care as the new hair growth is fragile and vulnerable to the damage caused by styling products and heating devices.
• Hold off on coloring or bleaching until the hair grows stronger. Processing could damage the new hair and irritate the sensitive scalp.
• Be patient. The hair may come back slowly and might not look normal right away. Growth takes time, and it takes time to repair the damage caused by the cancer treatment.

Hair loss

Hearing loss

Hearing loss is a special common for platinum-based chemotherapy drugs (i.e., cisplatin). Associated symptoms my include ringing in the ears (tinnitus). The hearing loss begins in the upper hearing frequencies; often well above the range for speech recognition. The patient often doesn’t realize that the damage has begun until ototoxicity has irrevocably impacted the cochlear hair cells and other critical parts of the inner ear. 

Chemoradiation therapy can cause progressive hearing impairment especially in those receiving the chemotherapy intravenously, with an average of 5 decibel decrease in hearing 4.5 years after treatment.

It is advisable that patients have a hearing test prior to treatment with a platinum-based chemotherapy, followed by repeated tests throughout their treatment.

Hearing loss may make individuals perceive that their voice is weaker than it actually is. It may contribute to social isolation and make laryngectomees try to speak louder. In those who use tracheoesophageal speech generating greater expiratory effort can lead to separation of the HME base plate from the skin. Wearing a hearing aid enables a laryngectomee to hear their actual voice. 

Hearing loss

Sore mouth (mucositis), thrush and small mouth ulcers

Some chemotherapeutic agents cause sore mouth (mucositis) which can interfere with mastication and swallowing, oral bleeding, difficulty in swallowing (dysphagia), dehydration, heartburn, vomiting, nausea, and sensitivity to salty, spicy, and hot/cold foods. These agents can also cause chemotherapy-related oral cavity ulcers (stomatitis), and thrush that result in eating difficulty. Mucositis generally develop 5-10 days after receiving the chemotherapeutic drugs. It lasts an average of 1-2 weeks and will get better once the white blood cell counts return to normal.  

The cytotoxic agents most often associated with oral, pharyngeal, and esophageal symptoms of swallowing difficulty (dysphagia) are the antimetabolites such as methotrexate and fluorouracil. The radiosensitizer chemotherapies, designed to heighten the effects of radiation therapy, also increase the side effects of the radiation mucositis.

Nausea and vomiting can be treated by anti-nausea (anti-emetic) drugs. Regular mouthwashes can also help. These side effects can impact swallowing and nutrition. Accordingly, it is important to supplement one’s diet with nutritious drinks or soups. A dietitian's advice may be helpful to maintain adequate nutrition. Mucositis can lead to nutritional deficiency. Those who experience significant weight loss or recurrent episodes of dehydration may require feeding through a gastrostomy feeding tube.

Management includes meticulous oral hygiene, dietary modification, and topical anesthetics combined with an antacid and antifungal suspension ("cocktail"). Spicy, acidic, sharp, or hot food as well as alcohol should be avoided. Secondary bacterial, viral (i.e., Herpes), and fungal (i.e., Candida) infections are possible. Control of the pain (using opiates or gabapentin) may be needed.

Prevention and treatment of thrush can be found in the Preventive Care Section.

Alterations in taste (dysgeusia)

Chemotherapy as well as radiation therapy can impair the sense of taste because of their effects on the in the tongue and nasal epithelium receptors. Additional factors that may contribute to an altered sense of taste include a bitter taste from chemotherapy drugs, poor oral hygiene, infection, and mucositis. These side effects can further decrease food intake and contribute to weight loss. 

The altered taste and tongue pain gradually dissipate in most patients over a six month period, although in some cases taste recovery is incomplete. Many individuals experience a permanent alteration in their taste. 

In most instances, there are no specific treatments for taste problems.

These tips may help to cope with taste changes:

• Choosing foods that smell and taste good, even if the food is not familiar.
• Eliminating cooking smells by using an exhaust fan, cooking on an outdoor grill, or buying precooked foods. Cold or room-temperature foods also smell less.
• Eating cold or frozen food, which may taste better than hot foods. This is not the case in those receiving oxaliplatin (Eloxatin), which makes it difficult to ingest anything cold.
• Using plastic utensils and glass cookware to lessen a metallic taste.
• Trying sugar-free, mint gum or hard candies (with flavors such as mint, lemon, or orange) to mask a bitter or metallic taste in the mouth.
• Trying other protein sources (such as poultry, eggs, fish, peanut butter, beans, or dairy products) if red meats don't taste good.
• Marinating meats in fruit juices, sweet wines, salad dressings, or other sauces.
• Flavoring foods with herbs, spices, sugar, lemon, or sauces.
• Not eating one to two hours before and up to three hours after chemotherapy to prevent food aversions caused by nausea and vomiting. Additionally, avoiding favorite foods before chemotherapy helps prevent aversions to those foods.
• Rinsing with a salt and baking soda solution (½ teaspoon of salt and ½ teaspoon of baking soda in 1 cup of warm water) before meals, which may help neutralize bad tastes in the mouth.
• Keeping a clean and healthy mouth by brushing frequently and flossing daily.
• Considering zinc sulfate supplements, which may help improve taste in some people. However, one should consult with their physician before taking any dietary supplements, especially during active treatment.

Photobiomodulation therapy employing light at red and near-infrared wavelengths has been used for the treatment of taste alteration. 

Nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) may be very distressing. CINV is a common problem with all chemotherapeutic agents. It can be acute (beginning within 1-2 hours of chemotherapy, peaking in 4-6 hours); delayed (beginning within 24 hours); chronic and anticipatory (occurring prior to treatment).

There are available therapeutic modalities that include medications and acupuncture aimed at the prevention and treatment of CINV.  Acupuncture can be used to help relieve nausea) caused by chemotherapy or other cancer drugs. Seabands (acubands) are bracelets that apply pressure to acupuncture points on the wrist and can help to reduce sickness due to chemotherapy or following surgery.

AcuBand - nausea releaving band

Radiation recall dermatitis

“Radiation recall” - also called “radiation recall dermatitis” - is an inflammatory reaction that occurs when an individual receives chemotherapy following radiation therapy for cancer. Its estimated frequency is in 9% of individuals. Symptoms of radiation recall are induced by inflammation in a region that was previously treated with radiation. The reaction is characterized by a skin rash typified by redness, swelling, and/or blistering of the skin. The rash is often painful and can resemble a severe sunburn.

The chemotherapy agents most commonly associated with radiation recall include: Docetaxel (Taxotere), Paclitaxel (Taxol), Gemcitabine (Gemzar), Capecitabine (Xeloda), and Doxorubicin (Adriamycin).

Treatment for the reaction is mostly supportive, initially by eliminating the source of the reaction (i.e., discontinuing the responsible chemotherapy drug). Medications such as corticosteroids and anti-inflammatory agents may be used.

Unfortunately, it is difficult to predict who will react to a particular chemotherapy drug following radiation therapy. Radiation recall occurs less often when the time interval between the radiation therapy and chemotherapy is longer. However, considerations other than radiation recall are often more important in making decisions about timing of chemotherapy treatments.

Radiation recall dermatitis

Chemotherapy-induced peripheral neuropathy and nerotoxicity

Disorders of peripheral nerves are frequent complications of chemotherapy. Chemotherapy can cause degeneration of peripheral sensory and motor nerves and cause patients to present with sensory disturbances, balance problems or weakness. Signs and symptoms of peripheral neurotoxicity involve the upper and lower extremities and include loss of vibration sense, loss of position sense, tingling paraesthesia, weakness, tremor, and loss of taste. These problems usually get better after treatment.

Specific types of chemotherapeutic agents, particularly in high doses, can injure peripheral nerves. These drugs include: Bortezomib (Velcade); Platinums, including cisplatin (Platinol), oxaliplatin (Eloxatin), and carboplatin (Paraplatin); Taxanes, including docetaxel (Docefrez, Taxotere) and paclitaxel (Taxol); Thalidomide (Synovir, Thalomid); and Vinca alkaloids, including vincristine (Vincasar), vinorelbine (Navelbine), and vinblastine (Velban). Treatment of chemotherapy-induced peripheral neuropathy may involve discontinuation or lowering the dose of the anti-cancer drug. Currently, there is no good evidence that any medications, vitamins, or supplements can help you avoid neuropathy.

There are three types of peripheral nerves that can become damaged, causing a wide range of symptoms:

Sensory nerves. Peripheral neuropathy usually affects the sense of touch and feeling in the nerves in the hands and feet. Most individuals feel tingling, burning, pinching, sharp stabs, a buzzing “electrical” sensation, or numbness. It usually starts in the toes and fingers and can continue along the hands and feet toward the body’s center. A feeling of wearing tight gloves or stockings is common. An uncomfortable sensation in the hands or feet that may be worse when you touch something is common. Additionally, objects on the feet, such as a shoe or bed covers, may cause pain. The loss of sensation, may make it difficult to feel hot and cold temperatures or perceive an injury. Another symptom is loss of position sense, which knows where one’s feet and hands are in space. This may make walking or picking up objects hard, especially if in a dark room or when working with small objects.

Motor nerves. These nerves send information between the brain and muscles. Damage to these nerves can cause difficulty in walking and moving around, and the legs and arms may feel heavy or weak, causing balance and coordination problems. Using the hands and arms may become hard, making everyday tasks, such as brushing teeth more difficult. In addition, muscle cramps and weakening of muscle strength in the hands and feet can occur.

Autonomic nerves. These nerves control involuntary body functions, such as blood pressure and bowel and bladder function. Damage to the autonomic system is called dysautonomia (see section Late effects of Radiation).Symptoms include an inability to sweat normally; gastrointestinal issues, such as diarrhea and constipation; dizziness or lightheadedness; trouble swallowing; and sexual dysfunction.

For some individuals, chemotherapy - induced peripheral neuropathy is just a little bothersome and they learn to deal with it. In others, however, it can be so severe that it can lead to stopping chemotherapy or reducing the dosages of the chemotherapeutic agents. Patients experiencing any of these symptoms, are encouraged to talk with their physicians or other members of their health care team so that they can get help managing these symptoms.

Persistent neuropathic pain can become a long term problem. Management includes relieving the side effects (also called symptom management), and providing palliative care (supportive care). Treatment depends on the cause and the related symptoms. Many individuals recover fully from the condition over time, in a few months or a few years. Sometimes, the disorder may be more difficult to treat and may require long-term management. There are a number of methods available that may provide some relief:

Medications. Although medications cannot reverse neuropathy, they may relieve the pain. However, they do not relieve the numbness. The most common medications to treat neuropathic pain are anticonvulsants and antidepressants. Over-the-counter pain medications may be recommended for mild pain. Prescription nonsteroidal anti-inflammatory drugs or very strong analgesics may be prescribed for severe pain. Topical treatments, such as lidocaine patches and creams, may also help. However, the medications used to manage neuropathy are related to the specific clinical situation and the cause of the neuropathy.

Nutrition. Eating a diet rich in B vitamins (including B1 and B12), folic acid, and antioxidants may help manage neuropathy. Eating a balanced diet and avoiding excessive alcohol ingestion is recommended.

Physical and/or occupational therapy. Physical and/or occupational therapy can keep muscles strong and improve coordination and balance. Therapists can often recommend assistive devices that can be helpful in completing one’s daily activities. Regular exercise may also help reduce pain.

Complementary medicine. Massage, acupuncture treatment,  and relaxation techniques may help decrease pain and reduce mental stress. 

In severe painful conditions patients may be referred to a pain management clinic for a multidisciplinary approach to pain management. Patients who have severe balance problems often benefit from balance (vestibular) rehabilitation.

Home safety can be very important. Enclosed are tips that may help avoid injury in the home for those with sensory or motor difficulties:

• Keeping all rooms, hallways, and stairways well lit
• Installing handrails on both sides of stairways
• Removing small area rugs and any other clutter that could cause one to trip or slip
• Installing grab bars in the shower or hand-grips in the tub, and laying down skid-free mats
• Using a thermometer to check that any water used is below 110 ⁰ F, or setting the water heater accordingly
• Cleaning up any spilled water or liquids immediately
• Using non-breakable dishes
• Using potholders while cooking and rubber gloves when washing dishes
• If driving, making sure that one can fully feel the gas and brake pedals and the steering wheel and that one can quickly move their foot from the gas pedal to the brake pedal
• If prescribed, using a cane or walker when moving from one room to the other

Attention, thinking, and memory problems (cognitive problems)

Many patients who received RT to the head and neck and/or chemotherapy experience attention, thinking, or short-term memory problems (cognitive problems). Neurocognitive function, although not immediately affected after treatment, progressively declines in 38% of the patients in the 2 years after definitive treatment with chemotherapy or radiation.
Other causes for these issues are pain and other medications, emotional state, and other medical problems.

This includes the following symptoms or changes:

• Trouble concentrating, focusing, or paying attention
• Mental fog or disorientation
• Difficulty with spatial orientation
• Memory loss or difficulty remembering things, especially names, dates, or phone numbers
• Problems with understanding
• Difficulties with judgment and reasoning
• Impaired math, organizational, and language skills. This includes tasks such as not being able to organize thoughts, find the right word, or balance a checkbook.
• Problems multitasking
• Processing information slower
• Behavioral and emotional changes, such as irrational behavior, mood swings, inappropriate anger or crying, and socially inappropriate behavior
• Severe confusion

Management of these cognitive problems may include:

• Medications, including stimulants, cognition-enhancing drugs, antidepressants, and drugs that block the actions of narcotics
• Occupational therapy and vocational rehabilitation, to help people with the activities of daily living and job-related skills
• Cognitive rehabilitation and cognitive training, to help patients improve their cognitive skills and find ways to cope with these issues.

Strategies for coping with cognitive problems include:

• Keeping a checklist of daily reminders
• Doing one task at a time without distractions
• Carry around a small pad and a pen or pencil to easily write down notes and reminders. Or, download a note-making app on your smartphone and tablet.
• Using a calendar and a notebook with questions and a to-do list.
• Letting friends, family, work place, and health-care team about one’s memory loss
• Getting counseling and other resources to improve memory.
• Placing sticky notes around the house and workplace to remind about important tasks.
• Use word play, such as rhyming, to help you remember things.
• Get plenty of rest.
• Keeping physically activity to increase mental alertness.
• Conduct brain-strengthening mental activities (i.e. hobbies, solving puzzles, and painting)
• Prepare for the next day by setting out the things you will need the night before.
• Color code or label certain cabinets or drawers where you store things around your home.
• Eliminating clutter, and placing things back in the same place

Tiredness (fatigue)

Chemotherapy affects different individuals in different ways. Some people are able to lead a normal life during their treatment, while others may find they become very weak and tired (fatigue) and have to take things more slowly. Any chemotherapy drug may cause fatigue. It can last for a few days or persists through and beyond completion of treatment. Drugs such as vincristine, vinblastine, and cisplatin often cause fatigue.

Factors that contribute to fatigue are anemia, decrease food and liquid intake, medications, hypothyroidism, pain, stress, depression, and lack of sleep (insomnia) and rest.

Rest, energy conservation, and correcting the above contributing factors may ameliorate the fatigue.  

The following strategies can reduce fatigue and improved quality of life:

• Assess and document the level of fatigue daily by using a diary or worksheet to monitor fatigue daily. The fatigue level assessment includes monitoring its severity (none, minor, moderate, advanced) over the times the day.
• Perform regular daily tasks and activities especially during the time of day when feeling less fatigue. (based upon one’s diary or worksheet)
• Drink plenty of fluids and eat as nutritious as possible.
• avoid caffeine which dries the mouth and can disrupt sleep.
• Maintain a daily exercise program.
• Allow plenty of time for sleep each night.
• Consult a social worker or psychologist, and seek support from family and friends.
• Seek evaluation and treatment of underlying medical and psychological conditions (i.e., anemia, hypothyroidism).
• Try to maintain a positive outlook. 

Accupuncture may be helpful in relieving the tiredness. 

More information about the side effects of chemotherapy can be found at the National Cancer Institute and Healthline Web sites.

Immunotherapy for head and neck cancer

Immunotherapy enhances a patient’s immune system to fight disease including cancer. Among the many immunotherapeutic strategies, immune checkpoint blockade drugs has shown significant benefit in the treatment of a variety of cancer types including head and neck one. The U.S. Food and Drug Administration has approved  two checkpoint inhibitors drug (pembrolizumab or Keytruda® and nivolumab or Opdivo®) to treat advanced head and neck squamous cell carcinoma.  These agents are monoclonal antibody targeting the PD-1 cell receptor, which helps to regulate immune responses.

Adverse effects associated with immune checkpoint blockade drugs

Because immune checkpoint blockade increase the activity of the immune system, these agents can have inflammatory side effects, termed as immune-related adverse events. Although any organ system can be affected, immune-related adverse events most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. Less often, the central nervous system and cardiovascular, pulmonary, musculoskeletal, and hematologic systems are involved. 

Click to find the side effects of  pembrolizumab (Keytruda®) and nivolumab (Opdivo®)

The commonest adverse side effects are: immune-mediated pneumonitis, Immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis and renal dysfunction, immune-mediated skin adverse reactions, and infusion-related reactions.

The common adverse reaction symptoms of these agents include: fatigue, cough, shortness of breath, upper respiratory infection, itching, swelling of the extremities (edema), muscle pain, skin redness and peeling, loss of skin pigmentation (vitiligo), psoriasis, decreased appetite, headache, numbness and tingling, dizziness, joint pain, back pain, nausea, constipation, diarrhea, weight loss, irregular heartbeat,  eye inflammation, increased amylase, and increased lipase,

Most of the toxic effects are reversible, aside from effects on the endocrine system, which may be permanent. Fortunately, deaths from immune-related adverse events are exceptionally rare, but deaths due to myocarditis, pneumonitis, colitis, and neurologic events, among others, can occur.

Ipilimumab, nivolumab, and pembrolizumab are checkpoint-blocking antibodies that target the PD-1 and PD-L1 receptors and CTLA-4. These agents are used for the treatment of head and neck cancer. (Ipilimumab is not approved for the treatment of head and neck cancer).

The systemic and local side effects of these agents summarized below:

Fatigue: Mild fatigue occurs in 16-40% of patients. Other potential causes of fatigue should be excluded (i.e. thyroid, pituitary, primary adrenal insufficiencies).

Infusion - related reactions: Mild infusion-related side effects have been reported in up to 25% of patients, and severe or life-threatening ones have been observed in about 2%. Symptoms can include: flushing, alterations in heart rate and blood pressure, dyspnea, bronchospasm, back pain, fever, urticaria, peripheral edema, nausea and all types of rashes.

Dermatologic toxicity can occur in about a third to half of patients. Hair loss (alopecia) has been reported in less than 2% percent of cases. This toxicity generally start in the third week of treatment and include a reticular, maculopapular, faintly erythematous rash on the trunk or extremities that is often accompanied with itching (pruritus), and loss of skin color in blotches (vitiligo).  (see pictures below)  Severe rashes such as Stevens-Johnson syndrome/toxic epidermal necrolysis are rare and require hospitalization. 

Rashes can be treated with topical corticosteroid creams, and agents against itching (e.g., hydroxyzine, diphenhydramine). Suspension of treatment with checkpoint blockade may be required in severe cases.

 Vitiligo 

 A rash associated with checkpoint administration 

Oral mucositis and/or dry mouth occurs in less than10%. Oral corticosteroid rinses and lidocaine can be effective treatment. Oral candidiasis should be considered especially in those who receive corticosteroids.

Diarrhea and colitis usually present about six weeks into treatment. It occurs in less than 2% of patients. Clostridium difficile or other bacterial/viral pathogens need to be excluded.  Management of mild symptoms includes maintaining oral hydration, colitis diet and anti-motility agents (loperamide or oral diphenoxylate atropine sulfate). If symptoms increase or persist for > 3 days and no infectious causes are detected, corticosteroids may be administered.

Liver toxicity (Hepatotoxicity) is generally manifested by symptomatic elevation of serum levels of the liver enzymes, and rarely also of bilirubin.  Onset is usually 8 to 12 weeks after initiation of treatment and occur in up to 5% of patients. Treatment with corticosteroids can be initiated in those without infectious etiology.  

Pneumonitis is a rare ( less than 5%) and potential serious complication. The most common presenting symptoms are dyspnea and cough, and it occurs between 9 days and 19 months after initiation of treatment. Steroids can be administered in those without an infectious etiology. Treatment with check inhibitors is withheld in refractory case. 

Endocrine gland inflammation:  The pituitary, thyroid, and/or adrenal glands can become inflamed in about 10% of patients. Patients usually present with nonspecific symptoms such as fatigue, nausea, headache, and disturbances in vision. The most common endocrine gland diseases are hypothyroidism, hyperthyroidism, and inflammation of the pituitary gland or pituitary stalk (hypophysitis).

Hypothyroidism is managed by administering thyroid hormone (levothyroxine) and hypophysitis is managed with corticosteroids.

Adrenal insufficiency is rare (less than 0.1%) and constitutes a medical emergency. It can cause dehydration, hypotension, and electrolyte imbalances (hyperkalemia, hyponatremia). Hospitalization is required and this condition is treated with intravenous corticosteroids.

Type 1 diabetes mellitus is associated with checkpoint inhibitors in approximately 0.2% of cases.  Monitor serum glucose is important with each dose of administered immunotherapy.

Rare adverse effects include:

Acute kidney toxicity was observed in 1-2% of cases, emerging 21 to 245 days after initiation of therapy.

Pancreatitis is generally manifested with elevated pancreatic enzymes (amylase and lipase).

Neurotoxicity can occurs in 1 to 3% of patients. These include Guillain-Barre syndrome, aseptic meningitis, myasthenia gravis, posterior reversible encephalopathy syndrome, enteric neuropathy, transverse myelitis, pancerebellitis, and autoimmune encephalitis. Serious adverse effects are treated with corticosteroids, plasmapheresis and intravenous immunoglobulin.

Cardiovascular toxicities include myocarditis, myositis and venous thromboembolism. High-dose steroids have been used to treat cardiac complications.

Hematologic toxicities include red cell aplasia, neutropenia, thrombocytopenia, acquired hemophilia A, and cryoglobulinemia. Management includes corticosteroid treatment and other immune-suppressing agents if symptoms persist.

Eye inflammation can occur in 1% of patients and include: episcleritis, conjunctivitis, uveitis, or orbital inflammation. Patient can present with photophobia, pain, dryness of the eyes, and blurred vision. Oral corticosteroids can be administered to severe cases.

Rheumatologic and musculoskeletal side effects include inflammatory arthritis and myositis, and salivary gland dysfunction (sicca syndrome).