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Mucositis

Introduction

Mucositis occurs when cancer treatments break down the rapidly divided epithelial cells lining the gastro-intestinal tract (which goes from the mouth to the anus), leaving the mucosal tissue open to ulceration and infection.  Mucosal tissue, also known as mucosa or the mucous membrane, lines all body passages that communicate with the air, such as the respiratory and alimentary tracts, and have cells and associated glands that secrete mucus. The part of this lining that covers the mouth, called the oral mucosa, is one of the most sensitive parts of the body and is particularly vulnerable to chemotherapy and radiation. The oral cavity is the most common location for mucositis.

Oral mucositis is probably the most common, debilitating complication of cancer treatments, particularly chemotherapy and radiation. It can lead to several problems, including pain, nutritional problems as a result of inability to eat, and increased risk of infection due to open sores in the mucosa. It has a significant effect on the patient’s quality of life and can be dose-limiting (i.e., requiring a reduction in subsequent chemotherapy doses).

Signs of Mucositis

Signs and symptoms of mucositis include:

-Red, shiny, or swollen mouth and gums

-Blood in the mouth

-Sores in the mouth or on the gums or tongue

-Soreness or pain in the mouth or throat

-Difficulty swallowing or talking

-Feeling of dryness, mild burning, or pain when eating food

-Soft, whitish patches or pus in the mouth or on the tongue

-Increased mucus or thicker saliva in the mouth

An extreme case of the condition is called confluent mucositis.  In a worst case, the mucous membrane of the patient’s entire mouth and tongue can be coated by a white mucus coating that is up to a millimeter thick.  The combination of mucus, excess saliva and pain can make it difficult or even impossible to eat.

Who Gets Mucositis?

The majority of oral cancer patients receiving chemotherapy in combination with radiation will experience at least some degree of mucositis. When caused by chemotherapy, mucositis is usually due to the low white blood cell count; when caused by radiation, mucositis is usually due to the necrotic and inflammatory effect of radiation energy on oral mucosa.

Factors that can increase the likelihood of developing mucositis, or that can make it worse if it does occur, include:

-Poor oral or dental health.

-Smoking or chewing tobacco and drinking alcohol.

-Gender (females appear to be more likely than males to develop mucositis)

-Dehydration.

-Low body mass index.

-Diseases such as kidney disease, diabetes or HIV/AIDS.

-Previous cancer treatment.

-Chronic irritation from ill-fitting prostheses or faulty restorations can predispose patients to the development of oral mucositis due to local irritation and trauma.

-Generally, patients with hematologic malignancies have an increased rate of oral mucositis compared with those with solid tumors. This is to some extent related to the treatment regimens.

-Hyposalivation prior to and during treatment is associated with an increased risk of oral mucositis.

-The use of methotrexate for chronic GVHD prophylaxis may exacerbate lesions of oral mucositis, although this is less of a concern with newer prophylaxis regimens.

-Oral mucositis occurs independently of oral mucosal infections of viral and fungal etiology, but it may be exacerbated by such concomitant infections.

Younger patients tend to develop oral mucositis more often than older patients being treated for the same malignancy with the same regimen. This appears to be due to the more rapid rate of basal cell turnover noted in children. However, the healing of oral mucositis is also more rapid in the younger age group.

Consequences of Mucositis

It is important that cancer patients be on the lookout for signs of mucositis, which should be treated as soon as possible once diagnosed. The consequences of mucositis can be mild, requiring little intervention, but they can also be severe--such as hypovolemia, electrolyte abnormalities, and malnutrition--and even result in fatality. Oral mucositis can:

-Cause pain

-Restrict oral intake

-Act as a portal of entry for organisms

-Contribute to interruption of therapy

-Increase the use of antibiotics and narcotics

-Increase the length of hospitalization

-Increase the overall cost of treatment.

Patients with oral mucositis and neutropenia (a type of white blood cell deficiency) have a relative risk of septicemia (a systemic, toxic illness caused by the invasion of the bloodstream by virulent bacteria coming from a local infection) more than 4 times that of patients with neutropenia only.

Mucositis is further complicated by the nausea and vomiting that often occur with treatment. Chemotherapy and radiation therapy can affect the ability of cells to reproduce, slowing healing of the oral mucosa, often extending the duration of present mucositis. Patients with damaged oral mucosa and reduced immunity are also prone to mouth infections.

Taste loss tends to increase in proportion to the aggressiveness of treatment. Nausea, pain, vomiting, diarrhea, a sore or dry mouth may make eating difficult. Thus, maintaining adequate nutrition is an important challenge for oral cancer patients. Reduction of caloric intake can lead to weight loss, loss in muscle mass strength and other complications, including a decrease in immunity and a longer healing time from treatments.

Physical problems may interfere with food intake and proper nutrition. Patients with head and neck tumors may have mouth or throat pain that can interfere with chewing and compound difficulties in swallowing. Tooth and gum disease can also exacerbate issues.

Chemotherapy can inhibit appetite by the same mechanisms as radiation. This is often worsened because of accompanying nausea. Decreased food intake is common for a short period around the time of treatment. It is important to try to compensate for weight loss during this time by making a conscious effort to eat more or, if this is not possible, to use feeding tubes or food pumps.

When you experience any of these problems, first consult your physician, nurse or the registered dietitian on your health care team. With their help and with the suggestions below, you should be able to plan a diet designed to minimize these problems. Prescription medications may be required. Your dentist, dental hygienist, nurse, dietitian, and pharmacist may also be of assistance.

Duration

Oral mucositis generally begins 5-10 days following the initiation of chemotherapy and lasts anywhere from one week to six weeks or more.  Resolution (in the case of HCT) coincides with recovery of the white blood cell count, specifically when the absolute neutrophil count becomes greater than 500 cells/µL. In patients being treated for solid tumors, the duration of oral mucositis depends on the type, dose, and course of treatment.

Preventive Steps

You may not be able to stop mucositis from occurring, but there are steps you can take before beginning radiation or chemotherapy treatment to help alleviate its side effects and symptoms. The first step is to see if your doctor can recommend a dentist who deals with cancer patients.  If you wear dentures, you will need to make sure they fit properly. If any work is needed (tooth extractions or refitting of dentures), it should be completed at least one month prior to starting therapy to make sure your mouth has completely healed and prevent damage to your existing teeth, gums or jaw bones.

It is known that a good oral care regimen can help prevent or decrease the severity of mucositis and, just as important, help prevent the development of infection through open mouth sores. The mainstay of an effective oral care regimen is mouth rinses, and numerous studies have determined that just plain old salt water is one of the best and most cost effective mouth rinses available. A mouth rinse aides in removing debris and keeping the oral tissue moist and clean.

Another important aspect of caring for your mouth is proper brushing techniques and oral hygiene. You should also avoid alcohol and irritating foods, such as those that are spicy, hot, acidic or coarse.  You should use a soft bristle toothbrush and brush your teeth after eating 2 to 3 times each day. If you experience sensitivity or mouth sores, you may need to use foam toothbrushes with an antibacterial rinse. You should use a mild tasting toothpastes with fluoride, such as Biotene enzyme based products, as some flavorings and foaming agents such as SLS in toothpaste may irritate the mouth. You may augment these with Rx strength fluoride ones such as Prevident from Colgate. If your toothpaste is still too irritating, you can use a solution made by dissolving 1 teaspoon of salt in 4 cups of water, or mixing 1 teaspoon baking soda in 2 cups of water. You should also gently floss your teeth once daily.

Other ways of maintaining a healthy oral care protocol include:

-Rinse mouth (swish and spit) before and after meals and at bedtime with either normal saline (1 tsp of table salt to 1 quart of water), or salt and soda (one-half teaspoon of salt and 2 tablespoons of sodium bicarbonate in 1 quart of warm water).

-If you smoke, it is extremely important that you stop. Your doctor will be able to help you with smoking cessation products and programs.

-Avoid toothpastes with whitening agents.

-Avoid products that irritate the mouth and gums, such as strong flavored commercial mouthwashes and those with alcohol.

-Keep lips moist with moisturizers. Avoid using Vaseline (the oil base can promote infection).

-Limit use of dental floss. Do not use if your platelet count is below 40,000.

-Do not use lemon or glycerin swabs or toothbrushes without soft bristles.

-Increase your fluid intake.

-Try to include foods high in protein in your diet.

-If you wear dentures, remove them whenever possible to expose gums to air.  Loose fitting dentures can irritate the mouth and gums and should not be worn.  Do not wear dentures if mouth sores are severe.

-Cryotherapy, which involves sucking on ice chips during chemotherapy administration, has shown some effect in preventing mucositis caused by 5-FU (fluorouracil) chemo treatments.

Oral cancer patients receiving radiation therapy should examine their mouths at least once a day for redness, sores, or signs of infection. The healthcare team should be notified if you notice worsening sores, white patches, pus, a “hairy” or thick feeling tongue, bleeding in the mouth, or development of a fever (temperature greater than 100.4).

In addition, two agents, Gelclair® and Zilactin®, are mucosal protectants that work by coating the mucosa, forming a protective barrier for exposed nerve endings. In clinical trials, these agents improved pain control and the ability to eat and speak.

Amifostine (Ethyol®), a drug that offers some protection against the damage to the mucosa caused by radiation, is approved by the FDA for patients receiving radiation therapy for cancers of the head and neck. Studies have demonstrated that Amifostine can reduce dry mouth and may prevent or lessen the degree of the mucositis. Amifostine is frequently prescribed to oral cancer patients as a chemoprotective agent to spare salivary gland damage during radiation treatments. While it has one significant negative side effect in many patients, which is nausea, it is certainly worth seeing if a patient is able to tolerate it for the many potentially positive effects that it has. Other agents that have been studied include: capsaicin (derived from chili peppers), glutamine, prostaglandin E2, Vitamin E, sucralfate, and allopurinol mouthwash with varying degrees of success.

In March 2007, the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology announced their latest guidelines for preventing mucositis:

-To prevent radiotherapy-induced mucositis, they recommend using midline radiation blocks and 3-D radiation treatment.  They recommend using benzydamine to prevent mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy.

-To prevent standard-dose and high-dose chemotherapy-induced mucositis, they recommend using either ranitidine or omeprazole ( a stomach ascid reducer / proton pump inhibitor) to prevent epigastric pain after cyclophosphamide, methotrexate, and 5-fluorouracil or treatment with 5-fluorouracil with or without folinic acid chemotherapy. 

-They advocate not using chlorhexidine in patients with solid tumors of the head and neck who are undergoing radiotherapy.   They also say you should not use antimicrobial lozenges or systemic glutamine to prevent mucositis.

In late 2008, palifermin, a recombinant keratinocyte growth factor, was approved by the American Society for Clinical Oncology for protection against severe mucositis associated with hematopoietic stem-cell transplantation in hematologic malignancies. It represents "an advance for the field," write the guideline authors, cochaired by Martee L Hensley, MD, from Memorial Sloan-Kettering Cancer Center, in New York City, and Lynn M. Schuchter, MD, from the University of Pennsylvania, in Philadelphia.  Whether palifermin will be approved for protection against mucositis caused by other factors remains to be seen.

Treating Mucositis

If you develop mucositis or it worsens, you may need to increase brushing (with the softest tooth brush possible) to every 4 hours and at bedtime. This will help keep the mouth moisturized and help prevent any infections. It is important to brush and floss very gently. You will want to rinse your mouth frequently with antiseptic mouth rinses, such as Peridex or Periogard, to prevent periodontal (gum) infections and inflammation. You can make your own rinse by mixing 1 teaspoon of baking soda in 8 ounces of water or ½ teaspoon salt and 2 tablespoons of sodium bicarbonate dissolved in 4 cups of water. This solution has a double benefit of also cutting through some of the severe phlegm / mucous production that is a by-product of the treatments, and helping to clear it.

If you are being treated with high dose chemotherapy or a bone marrow transplant, your doctor may be able to prescribe medication that can prevent or shorten the duration of mucositis. Your mouth may become dry and you will want to keep it moisturized.  Some easy remedies include chewing ice chips, chewing sugarless gum, or sucking tart sugarfree candy. If these do not work there are artificial saliva products that your physician can prescribe for you or some over-the-counter products are available such as enzyme based Oral Balance, which is used by huge numbers of OCF members in treatment as well as their collateral products, Biotene toothpaste and mouthwash that are free of the strong flavors and foaming agents that can be very irritating to sensitive tissues under treatment. Since your saliva barrier is compromised, you should avoid eating or drinking products containing sugar to prevent cavities.

To help clean oral sores you can rinse with a solution consisting of 1 part of 3% hydrogen peroxide with 2 parts of saltwater (1 teaspoon of salt dissolved in 4 cups of water).  For mild fungal infections, topical oral suspensions or dissolving tablets can be prescribed that contain anti-fungals. You will need to swish or dissolve the medicine in your mouth and, depending on your doctor’s directions, either swallow or spit out the medicine. It is important to not use any medicine containing alcohol because it will burn the mouth. For worsening fungal, bacterial and viral infections, your physician will need to prescribe oral medications, such as antibiotics or antifugals, to eradicate them. Also, if you wear any dental appliances, you should soak them in antiseptic solutions.

Keratinocyte growth factor (KGF) is a substance produced naturally in the body that stimulates the growth, repair, and survival of cells that protect the lining of the mouth and GI tract. A manmade version of human KGF has been developed as the drug palifermin, and is currently indicated for use in patients with hematologic malignancies or blood cancers (leukemias, lymphomas and myelomas) who are undergoing bone marrow or stem cell transplant. Palifermin was found to decrease the length and severity of mucositis in these patients. As noted earlier, it remains to be seen whether palifermin will be indicated for use among oral cancer patients.

Controlling Pain from Mucositis

Pain is a significant problem related to mucositis and warrants early intervention. Actions that may help reduce the pain from mucositis:

-In mild cases, ice pops, water ice, or ice chips may help numb the area, but most cases require more intervention for relief or pain.

-Topical pain relievers include lidocaine, benzocaine, dyclonine hydrochloride (HCl), and Ulcerease® (0.6% Phenol).

-Corticosteroids such as prednisone may be effective.

-Benadry® elixir, lozenges and analgesics may help reduce mouth pain.

-Swishing and gargling the anesthetic gel viscous Xylocaine 2% can help you eat if you have pain in your mouth, pharynx or esophagus. Use 1 tsp.(5 mL) viscous Xylocaine before meals. (Hold in mouth for one minute, then spit out.) This may increase your ability to eat by mouth while the anesthetic effects are working.

-Cepacol Lozenges, Chloraseptic spray and lozenges, or the use of tea (particularly chamomile) for swishing and gargling may be of some help.

-Frequent use of a gentle mouthwash may help reduce discomfort or pain. Biotene mouthwashes, which combine enzyme based protection with soothing mouth moisturizers are available over the counter at drug stores.

-Swish diluted milk of magnesia, Carafate slurry or Mylanta around your mouth.

-Oral Balance is a dental gel that moistens the mouth while sores are healing and also has enzymes that help control oral bacteria. You may have to apply it often during the day. It can be obtained over the counter.

-GI Cocktail: 1 tbsp (15mL) Cherry Maalox (acid reducer) + 1 tsp. (5mL) + Nystatin (antifungal) + 1/2 tsp. (2mL) Hurricane Liquid (analgesic) original flavor. Mix ingredients thoroughly. Swish and gargle for one minute, and then swallow immediately before each meal.

-Orabase B (OTC) is an adhesive paste with a topical anesthetic (benzocaine) that may be helpful.

Advil, Tylenol and opioid pain killers are often required to ease pain/discomfort.

You can also use topical products like Orajel or some prescription products like viscous lidocaine to eliviate discomfort temporarily.

-If the pain becomes more severe, you may need your doctor to prescribe you stronger pain medications. In oral cancer cases, it is not uncommon for the pain to be severe enough to require opiates for control.

Aspirin containing products and nonsteroidal anti-inflammory products like Motrin or Naprosyn should be avoided due to their effect on platelets, which can increase the risk of bleeding.

One popular topical agent that appears to get mixed reviews is a so-called “magic mouthwash”.  Some patients report good results with a combination of Lidocaine (a numbing agent), Benadryl, Maalox, and Nystatin (an antifungal).

One of the issues of using topical agents is the inability to effectively coat all areas and that the pain relief may be brief. In patients with mucositis who do not achieve pain relief with topical agents, narcotic analgesia is often necessary. This will require an Rx from your treating staff, until the mucosa begins to heal, particularly in patients unable to swallow. It is important to note that mucositis is transient during the treatment phases themselves, and narcotics for the relief of pain caused by mucositis will be temporary as well. Patients should not “suffer through it” to avoid using narcotics; they will not become addicted to them when used properly for this very real pain. Narcotics for pain will also cause constipation, and appropriate stool softeners will need to be taken with them.