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Management of oral mucositis

PRACTICAL THERAPEUTICS
Current clinical management of oral mucositis is largely focused on palliative measures but a number of promising therapeutic agents and interventions are available for the management of this condition
Tiene Bauters PharmD PhD 
Department of Pharmacy,
Ghent University Hospital, Ghent, Belgium
Email: Tiene.Bauters@uzgent.be
Oral mucositis is a frequent, clinically important, and often dose-limiting, complication of cancer therapy. It results from injury to epithelial cells that line the oral cavity and can affect the entire alimentary tract. Damage causes changes ranging from mild atrophy to severe ulceration.(1-4) 
On average, it affects 35-40% of patients receiving chemotherapy and, in patients undergoing conditioning regimens for haematopoietic stem cell transplantation (HSCT) with melphalan or in patients treated with radiotherapy regimens, it can affect up to 100% of patients.(1-4) 
Multiple risk factors influence the severity and extent of mucositis including: specific drugs, dose, frequency, the route of administration and individual tolerance of the patient. Antineoplastic agents that are DNA cycle-specific (for example, methotrexate, bleomycin) are more stomatotoxic than those that are cell phase non-specific.(2) Although of a lesser severity than with conventional antineoplastic agents, oral mucositis is reported in 30-40% of patients receiving oral tyrosine kinase inhibitors that target vascular endothelial growth factor receptors and in 10-20% of patients treated with drugs that target epidermal growth factor receptors.(3) 
Clinical manifestation
Symptoms of mucositis vary from severe pain requiring opioid analgesia to discomfort and inadequate nutritional intake, necessitating parenteral feeding until patients are able to maintain adequate nutrition orally. Mucositis may be so severe as to delay treatment, thereby limiting the effectiveness of cancer therapy, which can affect patients' survival. In addition, it might be the principal reason of prolonged hospitalisation.
An intact mucous membrane forms a physical barrier to pathogens and provides clearance of adhering microbes, so patients with damaged oral mucosa and reduced immunity are prone to infectious complications, especially during periods of deep neutropenia. 
Management
Clinical management of oral mucositis is the result of the combination of a number of factors.
Nutritional support
Nutritional intake and patient weight should be closely monitored during episodes of mucositis and soft diet or liquid food might be preferred. In cases of severe mucositis, enteral or parenteral feeding should be considered.
Adequate pain control
Pain is often the first symptom of oral mucositis and should be treated adequately, especially as it affects nutritional intake of the patient, oral care and quality of life. 
Palliation of dry mouth
Patients treated with chemotherapy or radiation therapy may develop transient or permanent xerostomia (subjective symptom of dryness) and hyposalivation (reduction in salivary flow).
Oral decontamination
As microbial colonisation of oral mucositis lesions exacerbates the severity of oral mucositis, oral decontamination may reduce infection of the oral cavity by opportunistic pathogens. 
Management of oral bleeding
Bleeding may occur from ulcerations of oral mucositis in thrombopenic patients because of chemotherapy. Topical haemostatic agents (for example, gelatin sponges) can be used. 
 
Therapeutic interventions
Cryotherapy
Cryotherapy involves topical administration of dissolving ice chips, which are swilled around the mouth for 30 minutes during administration of chemotherapy. This might be a cost-effective method of reducing the severity of oral mucositis. Cryotherapy is studied in mucositis induced by antineoplastic drugs, such as 5-FU (with short half-life) administered as a bolus injection, and in melphalan, showing consistent results in favour of using cryotherapy. Evidence continues to support the application of oral cryotherapy for prevention of oral mucositis in patients receiving bolus 5-FU chemotherapy or high-dose melphalan.(4,5) Cryotherapy rapidly cools the oral cavity, resulting in local vasoconstriction and reduced blood flow to the oral mucosa. Application in paediatrics is not considered, for practical reasons. Cryotherapy does not have a role in radiotherapy-induced oral mucositis. For some patients, the uncomfortable sensation of holding ice in the mouth might prevent them from using it.
Growth factors
Palifermin (recombinant human keratinocyte growth factor) protects the mucosal epithelium and promotes the early regeneration after chemotherapy and radiation induced injury, inhibition of epithelial cell apoptosis and DNA damage, upregulation of detoxifying enzymes and downregulation of pro-inflammatory cytokines, as well as enhancing migration, proliferation and differentiation of epithelial cells. Palifermin significantly reduces the incidence, severity and duration of oral mucositis in patients with haematological malignancies undergoing myelotoxic conditioning therapy and haematopoietic stem cell transplantation (HSCT). Guidelines established by international organisations such as the Multinational Association of Supportive Care in Cancer (MASCC) recommend the use of palifermin in this specific population.(4) Other growth factors (for example, velafermin, a recombinant human fibroblast growth factor-20 (rhFGF-20) protein) are under investigation for the prevention of oral mucositis (www.clinicaltrials.gov). Studies with human KGF2 (repifermin) have been withdrawn from study because of poor performance.(4) 
Antioxidants
Amifostine, an organic thiophosphate used as a normal tissue protector during cytotoxic therapy, is thought to act as a scavenger for harmful reactive oxygen species, known to potentiate mucositis. However, owing to insufficient evidence of benefit, its use is not supported in any cancer treatment setting for this purpose. Additional, well-designed research is needed to clarify the role of amifostine as an intervention for oral mucositis.(6) 
Anti-inflammatory agents
Benzydamine hydrochloride, a non-steroidal anti-inflammatory drug that inhibits pro-inflammatory cytokines including TNF-α, has been used in mouthwashes to reduce the severity of mucositis in patients with head and neck cancer undergoing radiation therapy. This agent requires further study before treatment recommendations can be made.(4) 
L-glutamine is an amino acid necessary for cell respiration in rapidly dividing cells. Glutamine may reduce mucosal injury by reducing the production of proinflammatory cytokines and cytokine-related apoptosis and can promote healing by increasing fibroblast and collagen synthesis. Systemic glutamine is not recommended for the prevention of GI mucositis because of severe toxicity.(4,6)
The use of L-glutamine in an oral drug delivery system may provide greater bioavailability to the oral mucosa. It showed a reduction in oral mucositis among patients who were receiving anthracycline-based chemotherapy. Independent confirmation of benefit is needed before its routine prophylactic use in any setting.(7)   
Low-level laser therapy
Low-level laser therapy (LLLT) generates power ranging from 5 to 200mW with helium/neon or diode lasers using various wavelengths. LLLT has been reported to be an effective, atraumatic and simple technique in the treatment of oral mucositis. Although the mechanism of the effect is not fully understood, it has been speculated that LLLT may reduce levels of reactive oxygen species and/or pro-inflammatory cytokines that contribute to the pathogenesis of mucositis. 
The laser is used for local application and has analgesic, anti-inflammatory and wound healing properties. No side effects are reported so far, and there is evidence in favour of LLLT for prevention and treatment of cancer therapy induced oral mucositis when used in the right dose and duration. In those centres that are able to support the required technology, LLLT will soon become part of routine oral supportive care in cancer.(8) 
Mouthwashes
Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) have been studied to reduce the incidence and severity of mucositis. However, the evidence is insufficient to support their use.(4)
 
Many mouth rinses are available to alleviate symptoms of pain. Topical anaesthetics (for example, lidocaine) may be incorporated in suspensions (the 'magic' cocktails) with diphenhydramine (for local drying effect) with or without nystatin, including or not steroids and antibiotics. Formulations may vary considerably from one hospital to another. However, data are insufficient to recommend any particular formulation.
Many oral care regimens include prophylactic antibacterial (tobramycin, polymyxin B) and/or antifungal (nystatin, clotrimazole) treatments to clear the mouth of oral microflora before and during chemo/radiotherapy. Antibiotic lozenges designed to dissolve in the mouth and to decontaminate the oral mucosa have been developed and have been widely recommended to reduce oral infections associated with mucositis. 
Calcium phosphate rinse is a preparation comprising two separately packaged aqueous solutions, a phosphate solution and a calcium solution, which, when both solutions are combined in equal volumes, forms a neutral supersaturated solution with respect to both calcium and phosphate ions. It acts as an electrolyte solution designed to moisten, lubricate and clean the oral cavity including the mucosa of the mouth, tongue and oropharynx. The supersaturated calcium phosphate rinse was used in a double-blind, placebo-controlled trial in which 95 patients undergoing HSCT were randomly assigned to calcium phosphate rinse plus a topical fluoride versus topical fluoride alone. Patients using the calcium phosphate rinse had a significantly shorter duration of mucositis (3.7 versus 7 days), and less pain and morphine use. This approach may offer benefit by decreasing oral mucositis during highly toxic regimens (for example, allogeneic HSCT).(9) 
Barriers and coating agents
Many agents have been used to act as a mucosal barrier. Among them, sucralfate has been most studied. Sucralfate, non-absorbed sulfated disaccharide, binds electrostatically to gastric ulcers, acting as a barrier to irritants and promoting healing. Sucralfate might also protect oral mucosal surfaces in patients at risk of developing mucositis. However, so far, the available evidence does not support its use.(4)
 
A variety of mucosal coating agents have been used to protect the mucosal surfaces of the oral cavity; however, there is little evidence from randomised trials to support benefit from any of these preparations.
A bioadherent gel consisting of sodium hyaluronate, polyvinylpyrrolidone, and glycyrrhetinic acid appears to have a role in (prolonged) pain relief and approved as a medical device. It provides a physical adherent barrier over mucosal surfaces, thereby shielding oral lesions from the effect of food, liquids, and saliva.  
Others
A wide range of antiseptic solutions have been used including chlorhexidine, povidone iodine and hydrogen peroxide. Chlorhexidine is one of the most commonly used mouthwash solutions used as prophylaxis for both chemo/radiotherapy induced mucositis. However, the benefit of chlorhexidine mouth rinses for mucositis remains uncertain so far.(10)  
While a preliminary trial suggested that administration of manuka honey (multiple times daily) limited radiation mucositis in patients receiving chemo/radiotherapy, a placebo-controlled trial failed to demonstrate a similar benefit.(11)
 
Topical application of morphine sulfate (2mg/ml in water, 15ml swish for two minutes and expectorate) may shorten the duration and intensity of mouth pain even in the absence of significant systemic absorption. Cytoprotectants (beta-carotene, vitamin E and oxpentifylline) have been used in cancer patients in an attempt to ameliorate the mucositis resulting from cytotoxic treatments. Currently there is no evidence to support their use. Azelastine hydrochloride has membrane-stabilising and leukocyte-suppressing activities and was suggested to significantly reduce the duration and severity of mucositis. There is no evidence to support the use of prostaglandins E1 and E2 (having cytoprotective actions) in patients with mucositis.(10)  
Conclusions
Oral mucositis is a clinically important and sometimes dose-limiting complication of cancer therapy and its pathogenesis is complex. Lesions can be painful, and affect nutrition and quality of life. Current clinical management of oral mucositis is largely focused on palliative measures such as pain management, nutritional support and maintenance of good oral hygiene. However, several promising therapeutic agents are in various stages of clinical development for the management of oral mucositis.

Key points
  • Mucositis is a common complication during chemotherapy and radiotherapy, with a complex underlying pathophysiology. It might be very difficult for physicians and pharmacists to choose from the wide array of often-defined 'magic' treatment options, especially as many interventions have scant evidence to support their effectiveness.
  • Although several promising agents are in clinical development for management of oral mucositis, further research in this area is still necessary. In addition, it is important to evaluate if agents acting by different mechanisms can be used in combination for greater clinical effectiveness. 
  • Novel drug delivery technologies providing increased uptake of the active agent (for example, glutamine) need to be explored. 
  • In the meantime, physicians and pharmacists can improve mucositis management by patient education, appropriate assessment and adequate therapeutic interventions.
References
  1. Lalla R, Sonis S, Peterson D. Management of oral mucositis in patients with cancer. Dent Clin North Am 2008;52(1):61-77.
  2. Rubenstein EB et al. Mucositis Study Section of the Multinational Association for Supportive Care in Cancer; International Society for Oral Oncology. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 2004;100(9 Suppl):2026-46.
  3. Watters AL, Epstein JB, Agulnik M. Oral complications of targeted cancer therapies: a narrative literature review. Oral Oncol 2011;47(6):441-8. 
  4. Keefe DM et al. Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007;109(5):820-31.
  5. Peterson DE et al. Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of oral cryotherapy for management of oral mucositis caused by cancer therapy. Support Care Cancer 2013;21(1):327-32.
  6. Nicolatou-Galitis O et al. Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of amifostine for the management of oral mucositis in cancer patients. Support Care Cancer 2013;21(1):357-64. 
  7. Chicago Supportive Oncologu Conference. Experimental L-glutamine agent  shown effective in oral mucositis. www.oncologypractice.com/jso/journal/articles/0306414.pdf (accessed 31 May 2013).
  8. Migliorati C et al. Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of laser and other light therapy for the management of oral mucositis in cancer patients. Support Care Cancer 2013;21(1):333-41. 
  9. Papas AS et al. A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;31:705-12.
  10. Negrin RS, Bedard JF, Toljanic JA. Oral toxicity associated with chemotherapy. www.uptodate.com/contents/oral-toxicity-associated-with-chemotherapy? (accessed 31 May 2013).
  11. Bardy J et al. A double-blind, placebo-controlled, randomised trial of active manuka honey and standard oral care for radiation-induced oral mucositis. Br J Oral Maxillofac Surg 2012;50:221-6.

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