Side Effects of Cancer Treatment: Mouth Sores or Mucositis

Reduce mucositis associated pain and inflammation resulting from chemotherapy and radiation - ice chips still supreme!

Medically reviewed by C.H. Weaver M.D. Medical Editor updated 5/2019

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. Treatment for mucositis consists of supportive therapies, such as mouthwashes, aimed at reducing discomfort until the cells regenerate themselves and cryotherapy (ice chips) although new medications are under investigation.(1-5)

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.(list of medications at bottom of article)

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

The main ways to manage oral mucositis include 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.

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)

A study in the April 2019 issue of JNCCN—Journal of the National Comprehensive Cancer Network supports oral cryotherapy as a cost effective easy way to reduce mucositis related side effects.

This current study enrolled 50 patients, half of which were provided with with ice chips to be chewed continuously during oxaliplatin chemotherapy infusions. Patients were encouraged to keep the ice chips in their mouths as long as possible. The two groups were then directly compared.

At baseline, none of the patients in either group reported any ongoing oral symptoms. After the first treatment cycle, only 32% of cryotherapy patients experienced oral symptoms, compared with 72% not chewing the ice chips. By the second cycle, the “oral cryotherapy” patients had significantly fewer oral symptoms, less difficulty eating or drinking cold items, and less difficulty eating or drinking overall than those in the control group.(5)

What else might work to control mucositis?

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.

Intravenous Glutamine

Among patients with advanced head and neck cancer treated with chemotherapy and radiation therapy, intravenous treatment with a derivative of the amino acid glutamine may reduce the severity of oral mucositis. These results were published in the International Journal of Radiation Oncology Biology Physics.

Glutamine is an amino acid that plays a role in cellular repair. To evaluate the safety and effectiveness of intravenous administration of a derivative of glutamine-L-alanyl-L-glutamine-researchers in Argentina conducted a clinical trial among 29 patients with advanced head and neck cancer. Half the patients received intravenous L-alanyl-L-glutamine and half the patients received intravenous saline (the placebo).

  • Severe oral mucositis developed in 14% of patients treated with L-alanyl-L-glutamine and 67% of patients treated with the placebo.
  • A feeding tube was required by 14% of patients treated with L-alanyl-L-glutamine and 60% of patients treated with the placebo.
  • Patients treated with L-alanyl-L-glutamine reported less pain than patients treated with the placebo.
  • L-alanyl-L-glutamine did not appear to produce any adverse side effects.

The researchers conclude that intravenous treatment with the glutamine derivative L-alanyl-L-glutamine may reduce the severity of oral mucositis in patients with advanced head and neck cancer.

Doxepin Reduces Mouth Pain from Radiation for Head and Neck Cancer

The tricyclic antidepressant doxepin reduces oral mucositis in patients who receive radiation for head and neck cancer, according to the results of a study presented at the 54th annual meeting of the American Society for Radiation Oncology in Boston, Massachusetts.

Researchers conducted a multi-institution, randomized, double-blind, placebo-controlled, phase III trial to evaluate the efficacy of a doxepin oral rinse for the treatment of OM associated with radiation therapy. The study included 140 patients who received radiation therapy for head and neck cancer that involved more than one-third of the oral cavity. Patients had all reported OM pain scores above four (on a scale of 1-10) prior to the study. Throughout the study, patients completed OM pain questionnaires.

On the first day of the study, patients received a single, blinded dose of either doxepin rinse or placebo and then crossed over to the other study group on a subsequent day. In order to assess OM-related pain after the doxepin or placebo rinse, patients responded to a pain questionnaire at baseline and at 5, 15, 30, 60, 120, and 240 minutes. The study’s primary endpoint was total OM pain reduction as measured by the area under the curve (AUC) of the pain scale over time using data from day one.

Results indicated that doxepin significantly decreased pain on the pain scale over time. Analysis of the primary endpoint revealed that the pain reduction AUC was greater for doxepin (-9.1) vs. placebo (-4.7). Analysis of the crossover data revealed similar findings, with an AUC score of -7.9 in the doxepin group versus-5.6 in the placebo group.

Doxepin was well tolerated. Patients who took doxepin reported increased stinging/burning, unpleasant taste, and increased drowsiness. After the study was completed, 64 percent of patients elected to continue taking doxepin.

The researchers concluded that OM pain was significantly reduced after doxepin compared to placebo. They suggest that this sets a new standard of care for the treatment of mouth pain associated with radiation therapy.(10)

Laser Therapy Reduces Oral Mucositis in Head and Neck Cancer

The use of low-level laser therapy (LLLT) may reduce the incidence and severity of oral mucositis caused by chemotherapy and/or radiation therapy among patients with head and neck cancer.

LLLT has been evaluated for the treatment and prevention of mucositis among patients with head and neck cancer undergoing radiation and/or chemotherapy, demonstrating potential promise for reducing severity and incidence of oral mucositis in this group of patients. The laser is directed at affected areas of the mouth and is thought to stimulate healing.

Researchers from Brazil recently conducted a Phase III trial to evaluate LLLT in reducing the incidence and severity of OM in head and neck cancer patients. This trial included 94 patients who were treated with chemotherapy and radiation therapy. One group received LLLT and the other group received a placebo (inactive substitute).

  • Severe OM occurred in 48% of the placebo group and 6% of the LLLT group.
  • Mouth sores occurred in 83% of the placebo group and 49% of the LLLT group.
  • Patients in the LLLT group experienced significantly less pain, fatigue, problems swallowing, and emotional disturbances than those in the placebo group. Importantly, not one patient in the LLLT group had a reduction or delay in treatment.

These results suggest that LLLT may reduce OM among head and neck cancer patients. Direct comparisons of LLLT to other treatments for OM are warranted.(11)

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®)

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.
  2. Dodd MJ, Dibble SL, Miaskowski C, et al. Randomized clinical trial of the effectiveness of 3 commonly used mouthwashes to treat chemotherapy-induced mucositis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:39-47.
  3. Pitten FA, Kiefer T, Buth C, et al. Do cancer patients with chemotherapy-induced leukopenia benefit from an antiseptic chlorhexidine-based oral rinse? A double-blind, block-randomized, controlled study. J Hosp Infect 2003;53:283-91.
  4. Clarkson JE, Worthington HV, Eden, et al. Prevention of Oral Mucositis or Oral Candidisis for Patients with Cancer Receiving Chemotherapy (Excluding Head and Neck Cancer). Cochrane Database Sys Rev2000;(2):CD000978.
  5. Bellm LA, Epstein JB, Rose-Ped A, et al. Patient Reports of Complications of Bone Marrow Transplantation. Support Care Cancer 2000;8:33-39.
  6. Spielberger R, Emmanouilides C, Stiff P. Use of recombinant human keratinocyte growth factor (rHuKGF) can reduce severe oral mucositis in patients (pts) with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation (auto-PBPCT) after radiation-based conditioning – results of a phase 3 trial. Proceedings of the 39th meeting of the American Society of Oncology 2003;22: Abstract #3642.
  7. 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.
  8. Cerchietti LCA, Navigante AH, Lutteral MA et al. Double-Blinded, Placebo-controlled Trial on Intravenous L-alanyl-L-glutamine in the Incidence of Oral Mucositis Following Chemoradiotherapy in Patients with Head and Neck Cancer. International Journal of Radiation Oncology Biology Physics. 2006;65:1330-1337.
  9. Miller RC, Leenstra J, Qun R, et al. N09C6 (Alliance) – A Phase III, Randomized Double-Blind Study of Doxepin Rinse versus Placebo in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Head and Neck Radiotherapy with or without Chemotherapy. Presented at the 54th Annual Meeting of the American Society for Radiation Oncology. October 28-31, 2012 Boston, Mass. Abstract LBA2.
  10. Reference: Antunes H, Herchenhorn C, Arajugo E, et al. Phase III trial of low-level laser therapy to prevent induced oral mucositis in head and neck cancer patients submitted to concurrent chemoradiation. Paper presented at: 2011 Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. Abstract LBA5524.
  11. 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.
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