Overview

Chemotherapy- or radiation-induced damage to the cells lining the mouth, throat and gastrointestinal (GI) tract is called mucositis. This side effect of cancer treatment can significantly affect patient quality of life and may cause delays in treatment. Historically, treatment for mucositis has consisted of supportive therapies, such as mouthwashes, aimed at reducing discomfort until the cells regenerate themselves, which takes about 7 to 14 days. However, a new biological therapy called Kepivance™, which is the recombinant form of human keratinocyte growth factor, appears to reduce mouth and throat soreness and improve function by stimulating cells that protect the lining of the mouth and GI tract.[1]

What causes mouth sores?

Mouth sores are a common side effect of radiation and certain chemotherapy drugs. Chemotherapy and radiation kill rapidly dividing cells, a hallmark characteristic of some cancers. The GI tract, including the mouth and the throat, is made up of cells that divide rapidly. For this reason, the GI tract is particularly susceptible to damage by chemotherapy and radiation treatment. Chemotherapy- or radiation-induced damage to the cells lining the mouth, throat and gastrointestinal tract is called mucositis.

What are the signs and symptoms of mouth sores?

Symptoms of mouth sores commonly occur three to ten days following your treatment with chemotherapy.  You may experience a burning sensation followed by ulcers, and your mouth may appear red (inflammation) with sores (ulcerations).  There may be associated discomfort and pain.

Mouth sores can make chewing and swallowing difficult, thereby interfering with your nutrition and food intake, resulting in weight loss. Your speech may also be compromised because of the soreness.  Furthermore, the lining of your mouth serves to protect you against infection, so mouth sores may make you more susceptible to bacterial, fungal, or viral infections in the mouth. Ultimately, mouth sores can become severe enough that it is necessary to reduce your dosage or delay your treatment in order to allow your mouth to heal.

What treatments are more likely to cause mouth sores?

Most chemotherapy drugs can cause mucositis, but this side effect is more frequent with some treatments.

The chemotherapy drugs that have been reported to cause mucositis in 30% or more of patients are:

• Actinomycin (Cosmegen)
• Busulfan (Myleran®, Busulfex®)
• Cytarabine (Cytosar-U®)
• Daunorubicin (Cerubidine®)
• Docetaxel (Taxotere®)
• Doxorubicin (Adriamycin®, Rubex®)
• Epirubicin (Ellence®)
• Floxuridine (FUDR®)
• Fluorouracil (5-FU, Adrucil®, Carac®, Efudex®, Fluoroplex®)
• Idarubicin (Idamycin®, Idamycin PFS®)
• Isotretinoin (Accutane®)
• Liposomal doxorubicin (Doxil®)
• Methotrexate (Rheumatrex®, Trexall™)
• Mitomycin (Mutamycin®)
• Mitoxantrone (Novantrone®)
• Mechlorethamine (Mustargen®)
• Oprevelkin (Neumega®)
• Paclitaxel (Taxol®, Onxal™)
• Pemetrexed (Alimta®)
• Plicamycin (Mithracin®)
• Procarbazine (Matulane®)
• Teniposide (Vumon®)
• Trimetrexate (Neutrexin®, TMQ®, TMTX®)
• Tretinoin (Vesanoid®)

The chemotherapy drugs that have been reported to cause mucositis in 10%-29% of patients are:

• Alemtuzumab (Campath®)
• Asparaginase (Elspar®, Kidrolase®)
• Bleomycin (Blenoxane®)
• Capecitabine (Xeloda®)
• Carboplatin (Paraplatin®)
• Cyclophosphamide (Cytoxan®, Neosar®)
• Etoposide (VePesid®, Toposar®, Etopophos®)
• Gemcitabine (Gemzar®)
• Gemtuzumab ozogamicin (Mylotarg®)
• Hydroxyurea (Hydrea®)
• Interleukin 2 (Proleukin®)
• Irinotecan (Camptosar®)
• Liposomal daunorubicin (DaunoXome®)
• Lomustine (CeeNU®)
• Melphalan (Alkeran®)
• Oxaliplatin (Eloxatin®)
• Pentostatin (Nipent®)
• Rasburicase (Elitek®)
• Thiotepa (Thioplex®)
• Topotecan (Hycamtin®)
• Trastuzumab (Herceptin®)
• Tretinoin (Vesanoid®)
• Vinblastine (Velban®, Alkaban AQ®)
• Vincristine (Oncovin®, Vincasar PFS®)

Furthermore, while mouth sores can occur with any treatment for cancer, mucositis is more severe if you are treated with the following:

• Stem cell transplants
• Radiation for head and neck cancer
• Combined chemotherapy and radiation therapy
• High-dose treatment
• Frequent dosing schedules, such as weekly chemotherapy

The technique used to administer radiation may also impact the severity and duration of mouth sores. The following radiation techniques tend to produce less severe side effects:

• Hyperfractionated radiation involves lower doses administered more frequently, resulting in less severe side effects.
• Intensity-modulated radiation therapy (IMRT) spares normal tissues, reducing mouth sores, while still delivering the full radiation dose or even an increased dose to the cancer.

What makes mouth sores worse?

A number of factors contribute to the severity of mouth sores, including:

• Poor oral and dental health prior to treatment
• Kidney disease
• Younger or older adults
• Smoking and the use of chewing tobacco during episodes of mucositis
• Harsh foods and alcohol
• Concomitant disease such as diabetes or AIDS

How are mouth sores treated?

Until recently, the only approaches to managing oral mucositis included good oral care; mouthwashes; cryotherapy (sucking on ice chips) to minimize the damage from chemotherapy drugs; Salagen®, a drug that stimulates salivary flow; and other investigational treatments. A promising new approach to the prevention and treatment of mouth sores is the use of growth factors. Growth factors are natural substances produced by the body to stimulate cell growth. The new drug Kepivance™ is a growth factor that is produced in a laboratory and designed to protect the cells in the mouth and GI tract from mucositis.

Oral care: Good oral care, defined as frequently rinsing the mouth with saline and brushing teeth 2-3 times per day, may help prevent mouth sores.

Mouthwashes: Salt and soda mouthwash has been shown to relieve mouth sores as well as medicated mouth washes, and is less expensive.[2] In fact, some researchers suggest that rinsing with chlorhexidine, an antimicrobial drug used to treat gum disease, did not provide benefit, and actually increased the risk of mouth sores in chemotherapy patients.[3]

Rinsing with a mouthwash containing the ulcer drug sucralfate has produced varied results in the treatment of mouth sores. Sucralfate has been shown to reduce mouth sores, but other researchers have found salt and soda to be equally effective.

Cryotherapy (ice chips): Symptomatic relief from mouth pain can be achieved by sucking ice chips when the chemotherapy drug is most concentrated in the body. This technique, called cryotherapy, works by decreasing blood flow to the cells in the mouth, reducing exposure to the drug and decreasing the risk of developing mouth sores. Furthermore, according to a recent Cochran review, sucking ice is the only measure proven to prevent mouth sores.[4]

Kepivance™ (keratinocyte growth factor, palifermin): Keratinocyte growth factor is a naturally produced substance that stimulates the growth of cells which are involved in protecting the lining of the mouth. Kepivance™ is produced in a laboratory and is designed to mimic natural keratinocyte growth factor that is made in the body. By stimulating growth in the cells that line the mouth and GI tract, Kepivance™ may help to reduce mucositis.

Kepivance™ is the first FDA-approved drug for the prevention and treatment of oral mucositis. In clinical trials, Kepivance™ has demonstrated the ability to protect the epithelial cells from the damaging effects of radiation and chemotherapy in patients undergoing autologous stem cell transplantation.[5],[6],[7],[8] Research is underway to determine whether Kepivance™ may benefit other patients.

Amifostine (Ethyol®): Ethyol® is a drug that protects against the damage of radiation and is the first drug to be approved by the FDA for the treatment of patients with head and neck cancers receiving radiation therapy. Clinical trials have demonstrated that Ethyol® can reduce dry mouth and may prevent mouth sores; however, more research is needed to prove the affect of this drug on mouth sores.

References

---

[1] Stiff P, Bensinger W, Emmanouilides C, Gentile T, et al. Treatment of Mucositis with Palifermin Improves Patient Function and Results in a Clinically Meaningful Reduction in Mouth and Throat Soreness (MTS): Phase 3 Results. Proc Am Soc Hem 2003;102(11):194a, Abstract #676.