Understanding Mucositis - Cause and Solutions
by Dr. C.H. Weaver M.D. updated 11/2018
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.
Mucositis is a condition characterized by damage to the epithelium of the oral-pharyngeal cavity and gastrointestinal (GI) tract from radiation and/or chemotherapy. One of the reasons that epithelial cells are more susceptible to the cytotoxic effects of radiation and chemotherapy is because of their relatively high rate of turnover compared to cells in other organs. In most instances, epithelial cells of the mucous membranes have a more rapid turnover than the cancer being treated and are vulnerable to damage by cytotoxic agents and radiation.
In patients with mucositis, there is a breakdown in the saliva barrier, a disruption of epithelial cells, and a thinning of the epithelium often with ulceration. Mucositis can be severe enough to require narcotics for pain and can significantly interfere with oral nutrition resulting in weight loss. Mucositis is particularly acute in patients with head and neck cancer receiving chemotherapy and radiation therapy. Severe mucositis can result in hospitalization and delay of scheduled treatment, compromising therapeutic efficacy.
What are the Mechanisms of Normal Tissue Damage from Radiation Therapy?
Radiation therapy depletes stem cells of the basal epithelium resulting in a reduction of epithelial cell replacement. Damaged epithelial cells release cytokines which increase local vascularity and cause inflammation. This process leads to ulceration, pain, and breakdown of the mucosal barrier leading to entry of bacteria, fungi, and viruses. Based on animal and human studies, researchers believe that evidence for epithelial damage can be detected within 24 hours of beginning treatment with chemotherapy or radiation therapy.3 Once the chemotherapy and radiation therapy are completed there is relatively rapid recovery of epithelial cells. In most cases, oral mucositis treatments are utilized until natural healing occurs.
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.
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. 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.
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.
Palifermin (Kepivance®) (keratinocyte growth factor)
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.,,,
Palifermin not only reduced the incidence and severity of oral mucositis, but improved overall patient quality of life and decreased the days spent in the hospital, the time spent on analgesics and the proportion of patients who need to get fed through a vein, compared to placebo, in patients undergoing a stem cell transplant. Patients who are to undergo a stem cell transplant or treatment with a chemotherapy agent that is highly associated with oral mucositis may wish to speak with their physician about the risks and benefits of participating in a clinical trial further evaluating palifermin.
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. Amifostine works by promoting the repair of damaged tissue and binding to harmful free radicals released by cells.
Pivotal trial of Ethyol® in head and neck cancers:
The large multi-center clinical trial by Brizel and colleagues that lead to FDA approval of Ethyol® for xerostomia in head and neck cancers showed that while Ethyol® reduced the incidence or severity of xerostomia, there was no effect on the incidence, severity, or duration of oral mucositis. In this study, 300 patients with cancer of the head and neck were assigned to receive either radiation therapy combined with Ethyol® 200 mg/m2 or radiation therapy alone. The incidence of severe xerostomia for patients receiving Ethyol® was 51%, compared to 78% for patients receiving radiation therapy alone. One year following completion of radiation therapy, only 35% of patients who had received Ethyol® were still experiencing symptoms of xerostomia, whereas 57% of patients who had received radiation therapy alone were still experiencing symptoms.
Acupuncture for Xerostomia
An educational session held at ASTRO 2003 on complementary medicine in radiation oncology practice evaluated the evidence for acupuncture in the treatment of xerostomia. Acupuncture has been shown to increase parotid gland blood flow, release neuropeptides involved in salivary gland function, and may stimulate tissue regeneration in parotid glands damaged by radiotherapy. In a randomized study of acupuncture, 38 patients with radiation-induced xerostomia were randomized to classical accupunture (20) or superficial acupuncture as placebo (18). Among those patients who had had all their salivary glands irradiated, 50% in both groups showed increased salivary flow rates (>20%) by the end of the observation period of 1 year.16
What Cancer Medications Cause Mucositis?
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®)
- Syrjala KL, Hays RD, Kallich JD, Farivar SS, et al. Impact of Oral Mucositis and Its Sequelae on Quality of Life. Proc Am Soc Hem. Blood. 2003;102(11):751a, Abstract #2771.
- Emmanouilides C, Spielberger R, Stiff P, Rong A, et al. Palifermin Treatment of Mucositis in Transplant Patients Reduces Health Resource Use: Phase 3 Results. Proc Am Soc Hem. Blood. 2003;102(11):251a, Abstract #883.
- Speilberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351:2590-8.
- Barasch A, Peterson DE. Risk factors for ulcerative oral mucositis:unanswered questions. Oral Oncol. 2003;39:91-100.
- Brizel DM, Wasserman TH, Henke M, et al. Phase III Randomized Trial of Amifostine as a Radioprotector in Head and Neck Cancer. J Clin Oncol 2000;18:3339-3345.
- Antonadou D, Pepelassi M, Synodinou M, Puglisi M, Throuvalas N, et al. Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head and neck cancer. Int J Radiat Oncol Biol Phys. 2002;52(3):739-47.
- Blom M, Dawidson I, Fernberg JO, Johnson G, et al. Acupuncture treatment of patients with radiation-induced xerostomia. Eur J Cancer B Oral Oncol. 1996 May;32B(3):182-90
- Wong RK, Jones GW, Sagar SM, Babjak AF, et al. A Phase I-II study in the use of acupuncture-like transcutaneous nerve stimulation in the treatment of radiation-induced xerostomia in head-and-neck cancer patients treated with radical radiotherapy. Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):472-80.
- Johnstone PA, Peng YP, May BC, Inouye Ws, et al. Acupuncture for pilocarpine-resistnat xerostomia following radiotherapy for head and neck malignancies. Int J Radiat Oncol Biol Phys. 2001 Jun 1;50:353-7.
- 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.