Management of chemotherapy and radiation induced oral mucositis. An update

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MANAGEMENT OF CHEMOTHERAPY AND RADIATION INDUCED ORAL MUCOSITIS. AN UPDATE. Velez I, Tamara L.

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Authors Luis Tamara MD. Board Certified In Internal Medicine. Fellow Nuclear Medicine Board Certified in Nuclear Medicine Board Certified in Nuclear Cardiology Email: thetamarafamily@yahoo.com Veterans Hospital. San Petersburg Florida Phone (727) 399 6661 Ines Velez DDS MS Oral and Maxillofacial Pathologist Associate Professor College of Dental Medicine Nova Southeastern University Fort Lauderdale, Florida Address: 3200 S University Dr. Fort Lauderdale, Fl , 33328 Phone: 954 262 7382 Email: ivelez@nova.edu

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Response to chemotherapy is different for each tissue. The cell cycle: G1 phase: preliminary preparation of the cell for division; S phase: DNA synthetic phase; G2 phase: resting period; M phase: condensation and separation of chromosomes and division of the cell. Most of the chemotherapeutic agents act in rapidly reproducing cells.1

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It is important to have in mind that there are three sub-populations of cells: A Non dividing and terminally differentiated cells. B Continually proliferating cells C Resting cells, that may be recruited into the cell cycle.

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The toxicity of chemotherapy exceeds that of any other pharmacologic group2. As a difference, with radiotherapy, the chemotherapy - induced toxicity is not confined to the tissues of the area being treated.

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Toxicity due to Chemotherapy2 - Emesis - Myelotoxicity - Infection - Anemia - Anorexia Cachexia Asthenia Fatigue Mucositis GI tract ulcerations Diarrhea

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Radiation Therapy A. Brachytherapy: localized radiation is delivered directly into the tumor area, by small fragments of radioactive sources. Low toxicity is associated with this treatment3. B Radioimmunotherapy it delivers a tumor-targeted radiation many times higher than the highest radiation dose permitted for normal tissue. It uses a radio-labeled antibody that reacts with a tumor specific antigen. Mild to moderate clinical toxicity.4 C Radioactive Iridium implant: Under general anesthesia, catheters are placed into the tumor, and radioactive 192 Iridium is delivered into the area. D Megavoltage external beam radiation: it is used with extensive lesions, Different radiation doses are required depending on tumor type and volume. Toxicity is related to the kinetic properties of the cells, and dose given.5

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Radiation Injuries A Early effects: are very common. Usually seen during treatment. They can be very symptomatic and residual damage is often present. B Intermediate effects: occur several weeks or months after treatment. C Late effects: are rare and may appear months to years after the treatment. Oncogenesis is a late effect of radiation therapy 3.

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Toxicity due to Radiotherapy Dysphagia, mucositis, hoarseness, ulceration, necrosis, fibrosis, xerostomia, dysgeusia, dysphonia and delayed wound healing, are sequelae of the damage of the oral tissues and the salivary glands during radiation treatment. These effects are usually confined to the area being treated.

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The mucositis results from death of the basal cells of the oral epithelium, usually two weeks after initiation of radiotherapy. It can be a very debilitating complication of cancer treatment6 The damaged oral mucosa and the reduced immunity resulting from cancer therapy also make patients prone to opportunistic infections. Complications of salivary gland dysfunction and trauma can also modify the evolution of mucositis.

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Therapeutic Approach

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Antioxidants Radiotherapy and chemotherapy generate free radical species which require antioxidants to be neutralized. Beta-carotene: has been proven to be useful in chemotherapy induced mucositis. In one trial, chemotherapy patients were given 400,000 I.U per day for three weeks and then 125,000 I.U. for an additional four weeks. In these patients the mucositis developed later and tended to be less severe than mucositis that appeared in controls .7 Vitamin E along with Vitamin C: act on a cellular level by protecting the cell membrane and preventing peroxidation. Studies have found the tocopherol form of Vitamin E to be effective when it is applied topically twice per day.2

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Antioxidants Glutamine, glutamine seems to play the roll of an immunomodulator and mucosal barrier in patients with advanced esophageal cancer8. It may work as a cellular fuel; as a precursor for nucleotides needed for cell regeneration and as a source of glutathione which is a potent antioxidant.9 The use of 4 grams of powdered glutamine in oral rinse, swish and swallow suspension, twice / day, decreases the intensity of the mucositis and it is cost-effective. Topical action also has been proven to be beneficial. Glutathione: is the body’s main antioxidant and protects cells from free radical damage. Blood levels of glutathione are reduced by radiotherapy and by severe inflammation which occur in mucositis4. Lysofylline: is a protectant that reduces lipid peroxidation and decreases oxidative injury. It is tested in chemoradiation trials of head and neck cancer3

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Mucosal Barriers Sucralfate is a sucrose aluminum hydroxide compound that forms a sort of bandage, and acts through a topical protectant effect in patients at risk for developing mucositis. In addition, local production of Prostaglandin E2 is stimulated. Sucralfate must be given four times daily (swish and swallow) Its use has been successful in esophagitis and gastric ulceration.3 Clobetasol 0.05% ointment 1:1 with Orabase. As a topical corticosteroid it plays a role in inflammation and immunosuppression. It is contraindicated in infection. Clobetasol must be applied as a thin film, and patient must not have anything by mouth for ½ hour.

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Mouthwashes Benzydamine hydrochloride: benzydamine oral rinse is effective, safe and well tolerated in ameliorating the symptoms of cancer treatment induced-mucositis. A 0.15% oral rinse. 15 ml every two hours, with expectorating the solution, will help with the painful inflammation of mouth and throat. Benzydamine has local analgesic, antimicrobial and anti-inflammatory properties. It prevents the release of the arachidonic acid cycle which is an initiator of the inflammatory process.10 Corticosteroid mouthwashes: These medications are contraindicated if the patient has bacterial or viral infection43. Triamcinolone acetonide 0.2% aqueous suspension can be used as a rinse for 1 minute/twice a day and expectorated.

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Mouthwashes Chamomile mouthwashes rinsing with 15 drops in 10 ml of warm water, three times a day, has reduced the incidence and severity of mucositis in cancer patients.11 It is said to have anti-inflammatory and healing effects. Glycerin-containing mouthwashes are not effective. Glycerin can produce dryness of the mouth over a period of time. Local anesthetic mouthwashes may help to relieve the pain on a temporary basis.

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Analgesics Capsaicin is found in chili peppers and acts upon nerve tissue endings to provide temporary pain relief. Morphine, a central nervous system analgesic that depresses pain impulse transmission. It is effective for managing mucositis pain in cancer patients, but dry mouth is one of its adverse reactions. It does not improve the health of the mucosa.

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Analgesics Cannabinoids relieve severe pain and there is also anti-inflammatory activity. It has been recommended that cannabinoids be made available for patients with chronic severe pain that may include mucositis. Fentanyl (Duragesic transdermal patches): is a very potent short acting opioid. It is available in a sustained-release trans-dermal delivery system with a half-life of 22 hours and it is especially useful in patients unable to take oral medications3. Dry mouth is an adverse reaction.

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Anti-inflammatory Agents Prostaglandins E1 and E2 are known to have many properties including the protection of the gastric mucosa from injuries. However, we did not find evidence to support its use to prevent or ameliorate cancer treatment induced-mucositis. Steroids

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Growth Factors Recombinant keratinocyte growth factor influence the growth, development and repair of epidermal tissues and accelerates wound healing.12 increases the number of stem cells that survive a dose of radiation therapy. Fibroblastic growth factor (Repifermin) is known to be able to stimulate salivary gland hyperplasia and salivary gland output2

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Growth Factors Epidermal growth factor (EGF) : Epidermal growth factor is present in biologic fluids including saliva. Its level decreases in patients receiving radiation therapy. EGF plays a role in healing of damaged mucosa.

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Immnunomodulators Thalidomide is an immunomodulatory and antiangiogenic agent, that inhibits tumor necrosis–alpha, which is associated with oro-pharyngeal ulcers. In one trial, 92%of patients had complete healing after 4 weeks of thalidomide. (4 weeks of thalidomide 200 mg by mouth at bed time) To prescribe thalidomide, the doctor must register with the System for Thalidomide Education and Prescribing Safety (STEPS) to minimize the substantial risks of teratogenicity.

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Immnunomodulators Pentoxiphylline is also an inhibitor of tumor necrosis–alpha (Trental, one tablet three times/day with food) However, the studies regarding prevention of mucositis with this medication are contradictory.

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Immnunomodulators Granulocyte colony-stimulating factor (GCSF) has been reported to shorten the white blood cell recovery time and decrease the incidence of infection and mucositis in bone marrow transplantation patients. (Filgrastim, 10 mcg/kg per day for 7 days, followed by 5 mcg/kg per day for 4 days).

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Radioprotectants Amifostine: (Ethyol). Amifostine cytoprotective mechanism involves DNA protection, repair acceleration and anti-oxidant function. It has been reported to prevent salivary gland injury from radiation, xerostomia and mucositis.2 Amifostine is approved by FDA for the prevention of xerostomia in the head and neck cancer patients receiving radiotherapy when administered intravenously. However, subcutaneous administration of Amifostine give radioprotection comparable to IV administration. In a controlled trial a significant influence of cytoprotection was found in xerostomia, fibrosis, loss of taste, mucositis and dysphagia.13 Anaphylactoid reaction, nausea, vomiting, hypotension and hypocalcemia associated to Amifostine treatment have been reported.

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Non Pharmacologic Approach Cryotherapy: Vasoconstriction reduces blood flow and diminishes the distribution of the chemotherapeutic agent to the oral mucosa. It results in the reduction of the mucositis intensity caused by local cytotoxic activity. Ice swishing for 30 minutes following cancer therapy has been shown to be beneficial for these patients.2 Low Intensity Laser may improve wound healing and accelerate replication of the cells. Low energy Helium-Neon (He-Ne) laser seems to be a safe, simple, a-traumatic and efficient method for prevention and treatment of chemotherapy-radiotherapy-induced mucositis, activation of the epithelial healing is the most commonly recognized effect of low energy laser and it is capable of reducing the severity and duration of mucositis of various origins

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Recommendations -Before cancer therapy the patient must receive a complete dental treatment, to achieve and maintain an infection free mouth. -Patients should have a routine of gently brushing at least three times per day with a fluoride toothpaste and floss. -Regular rinse with bicarbonate of soda. -Removal and cleaning of dentures -Use of melting ice chips for a duration of 30 minutes following cancer therapy and periodically throughout the day. -Pilocarpine (Salagen 5mg Potid-qid) or artificial saliva when necessary. -Anti-fungal, antiviral or antibiotic medications. These may include clorhexidine (10-15 ml rinse/3/day), acyclovir (250 mg I.V. every 8 hours, in day –3 to day +12 in HSV seropositive patients) and nystatin (5-10 ml. swish-expectorate every 4 hours) to reduce the risk of mucotoxicity from bacteria, virus and fungus. -Avoidance of caffeine, tobacco, alcohol

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References 1. Verdi CJ. Cancer therapy and oral mucositis, Drug Saf. 1993;9:185-95 2. Richard Pazdur, Lawrence Coia, Willim J Hoskins, Lawrence Wagman: Cancer Management : A Multidisciplinary Approach. 5th Edition. Melville NY PRR 2001 pag754, 805, 810-13 3. K.S. Clifford Chao,Carlos A Perez, Luther W. Brady: Radiation Oncology. Management decisions. 2nd Ed. Philadelphia: Lippincott Williams and Wilkins. 2002 pag.1 4. Iraj Khalkhali, Jesan C. Maublant, Stanley J Goldsmith: Nuclear Oncology. Diagnosis & Therapy. Philadelphia: Lippincott Williams & Wilkins 2001 p. 3-12, 60-68 5 Dorr W, Hamilton CS, BoydT, Reed B Denham JW.:Radiation induced changes in cellularity and proliferation in human oral mucosa. Int J Radiat Oncol Biol Phys 2002. 52:911-17. 6 Neville, Damm, Allen, Bouquot. Oral and Maxillofacial Pathology. WB Saunders, Philadelphia Second edition 2002;262 7. Mills EED. The modifying effect of beta carotene on radiation and chemotherapy induced oral mucositis. Brit J Cancer 1988;57:416-7

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References 8. Furst P et al, Evidence for a nutritional need for glutamine in catabolic patients. Kidney Int. 1989;36:5287-92. 9. Klimberg VS. How glutamine protects the gut during irradiation; 1996 ICCN,3:21. Epstein JB, et al.;Benzydamine HCL for prophylaxis of radiation-induced oral mucositis: results from a multicenter, randomized, double blind, placebo-controlled clinical trial.Cancer. 2001;92:875-85 Carl W, Emrich LS. Management of oral mucositis during local radiation and systemic chemotherapy: A study of 98 patients J prosthet Dent 1991;66:361- Tseng S, Pak G, Washenik K et al. Rediscovering thalidomide . A review of mechanism of action, side effects, and potential uses. J Am Acad Dermatol 1996;35:969-79 13. Buntzel J, Glatzel M, Kuttner K, Weinaug R, Frohlich D. Amifostine in simultaneous radiochemotherapy of advanced head and neck cancer. Semin Radiat Oncol 2002:12:4-13

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