Chemotherapy and Hematopoietic Stem Cell Transplantation Patients
        Management of mucositis

The terms oral mucositis and stomatitis are often used interchangeably at the clinical level, but they do not reflect identical processes. Oral mucositis describes inflammation of oral mucosa resulting from chemotherapeutic agents or ionizing radiation.[1-5] Mucositis typically manifests as erythema or ulcerations. It may be exacerbated by local factors. Stomatitis refers to any inflammatory condition of oral tissue, including mucosa, dentition/periapices, and periodontium. Stomatitis thus includes infections of oral tissues, as well as mucositis as defined above.

Relationships between cancer therapy–induced compromise of systemic immune constituents and functionally distinct mucosal immune components are not well understood.[6-9] Additionally, the role of cytokines and oral mucosal lymphocyte subsets in mucositis has not been investigated systematically. Evidence now supports the impact of derangements in selected cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) as possible key contributors to development of oral mucositis.

As noted above, erythematous mucositis typically appears 7 to 10 days after initiation of high-dose cancer therapy. Clinicians should be alert to the potential for increased toxicity with escalating dose or treatment duration in clinical trials that demonstrate gastrointestinal mucosal toxicity. High-dose chemotherapy, such as that utilized in the treatment of leukemia and hematopoietic stem cell transplant regimens, may produce severe mucositis. Mucositis is self-limited when uncomplicated by infection and typically heals within 2 to 4 weeks after cessation of cytotoxic chemotherapy.

Systematic assessment of the oral cavity following treatment permits early identification of lesions.[10-17] Oral hygiene and other supportive care measures are important to minimizing the severity of the lesion.

In an effort to standardize measurements of mucosal integrity, oral assessment scales have been developed to grade the level of stomatitis by characterizing alterations in lips, tongue, mucous membranes, gingiva, teeth, pharynx, quality of saliva, and voice.[12-14] Specific instruments of assessment have been developed to evaluate the observable and functional dimensions of mucositis. These evaluative tools vary in complexity.

Oral mucositis in hematopoietic stem cell transplantation (HSCT) patients produces clinically significant toxicities that require multiprofessional interventions. The lesion can increase risk for systemic infection,[1] produce clinically significant pain,[18] and promote oral hemorrhage. It can also compromise the upper airway such that endotracheal intubation is required. Use of total parenteral nutrition is often necessary because of the patient’s inability to receive enteral nutrition.

Once mucositis has developed, its severity and the patient’s hematologic status govern appropriate oral management. Meticulous oral hygiene and palliation of symptoms are essential. In the absence of controlled clinical trials, many of the management recommendations are anecdotal. Some established guidelines for oral care include oral assessments twice daily for hospitalized patients and frequent oral care (minimum of every 4 hours and at bedtime) that increases in frequency as the severity of mucositis increases.

Oral care protocols generally include atraumatically cleansing the oral mucosa, maintaining lubrication of the lips and oral tissues, and relieving pain and inflammation.

Palifermin (Kepivance), also known as keratinocyte growth factor-1, has been approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic cancers undergoing high-dose chemotherapy, with or without radiation therapy, followed by a bone marrow transplant.[19] Palifermin has also been shown in a randomized, placebo-controlled trial to reduce the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy.[20]

Mucositis Management

• Bland rinses:
  • 0.9% saline solution.
  
  
  
  • Sodium bicarbonate solution.
  
  
  
  • 0.9% saline/sodium bicarbonate solution.
  
  
  



• Topical anesthetics:
  • Lidocaine: viscous, ointments, sprays.
  
  
  
  • Benzocaine: sprays, gels.
  
  
  
  • 0.5% or 1.0% dyclonine hydrochloride (HCl).
  
  
  
  • Diphenhydramine solution.
  
  
  



• Mucosal coating agents:
  • Amphojel.
  
  
  
  • Kaopectate.
  
  
  
  • Hydroxypropyl methylcellulose film-forming agents (e.g., Zilactin).
  
  
  
  • Cyanoacrylate mucoadherent film.
  
  
  
  • Gelclair (approved by the FDA as a device). This gel soothes oral mucositis pain by forming a protective coating that shields exposed and overstimulated nerve endings.
  
  
  



• Analgesics:
  • Benzydamine HCl topical rinse (not approved in the United States).
  
  
  
  • Opioid drugs: oral, intravenous (e.g., bolus, continuous infusion, patient-controlled analgesia [PCA]), patches, transmucosal.
  
  
  



• Growth factor (keratinocyte growth factor-1):
  • Palifermin (approved by the FDA in December 2004 to decrease the incidence and duration of severe oral mucositis in patients undergoing high-dose chemotherapy with or without radiation therapy followed by bone marrow transplant for hematologic cancers).

Management of oral mucositis via topical approaches should address efficacy, patient acceptance, and appropriate dosing. A stepped approach is typically utilized, with progression from one level to the next as follows:

• Bland rinses (e.g., 0.9% normal saline and/or sodium bicarbonate solutions).



• Mucosal coating agents (e.g., antacid solutions, kaolin solutions).



• Water-soluble lubricating agents, including artificial saliva for xerostomia.



• Topical anesthetics (e.g., viscous lidocaine, benzocaine sprays/gels, dyclonine rinses, diphenhydramine solutions).



• Cellulose film-forming agents for covering localized ulcerative lesions (e.g., hydroxypropyl cellulose).

Normal saline solution is prepared by adding approximately 1 tsp of table salt to 32 oz of water. The solution can be administered at room or refrigerated temperatures, depending on patient preference. The patient should rinse and swish approximately 1 tbsp, followed by expectoration; this can be repeated as often as necessary to maintain oral comfort. Sodium bicarbonate (1–2 tbsp/qt) can be added, if viscous saliva is present. Saline solution can enhance oral lubrication directly as well as by stimulating salivary glands to increase salivary flow.

A soft toothbrush that is replaced on a regular basis (see the 2005 Oral Mucositis Guidelines Update ¹) should be used to maintain oral hygiene. Foam-swab brushes do not effectively clean teeth and should not be considered a routine substitute for a soft nylon-bristled toothbrush. Options for cleansing and debriding agents include salt and soda (½ tsp of salt and 2 tbsp of sodium bicarbonate in 32 oz of warm water), normal saline, sodium bicarbonate (1 tsp in 8 oz of water), and sterile water. Based on nonoral mucosa wound-healing studies, the repeated use of hydrogen peroxide rinses for daily preventive oral hygiene is not recommended, especially if mucositis is present. This is because of the potential for damage to fibroblasts and keratinocytes, which can cause delayed wound healing.[21-27] Using 3% hydrogen peroxide diluted 1:1 with water or normal saline to remove hemorrhagic debris may be helpful; however, this approach should only be used for 1 to 2 days since more extended use may impair timely healing of mucosal lesions associated with bleeding.[28]

Focal topical application of anesthetic agents is preferred over widespread oral topical administration, until the patient requires more extensive pain relief. Products such as 2% viscous lidocaine, diphenhydramine solution, or one of the many extemporaneously prepared mixtures incorporating coating agents such as milk of magnesia, kaolin with pectin suspension, mixtures of aluminum, and/or magnesium hydroxide suspensions (many antacids) combined with topical anesthetic agents may provide relief.

Irrigation should be performed prior to topical medication because removal of debris and saliva allows for better coating of oral tissues and prevents material from accumulating. Frequent rinsing cleans and lubricates tissues, prevents crusting, and palliates painful gingiva and mucosa.

Systemic analgesics should be administered when topical anesthetic strategies are not sufficient for clinical relief. Opiates are typically used;[18] the combination of chronic indwelling venous catheters and computerized drug administration pumps to provide PCA has significantly increased the effectiveness of controlling severe mucositis pain while lowering the dose and side effects of narcotic analgesics. Nonsteroidal anti-inflammatory drugs that affect platelet adhesion and damage gastric mucosa are contraindicated, especially if thrombocytopenia is present.

Although mucositis continues to be one of the dose-limiting toxicities of fluorouracil (5-FU), cryotherapy may be an option in prevention of oral mucositis. Because 5-FU has a short half-life (5–20 minutes), patients are instructed to swish ice chips in their mouths for 30 minutes, beginning 5 minutes prior to 5-FU administration.[29]

Many agents and protocols have been promoted for management or prevention of mucositis.[30-54] Although not adequately supported by controlled clinical trials, allopurinol mouthwash and vitamin E have been cited as agents that decrease the severity of mucositis. Prostaglandin E2 was not effective as a prophylaxis of oral mucositis following bone marrow transplant,[45] although more recent studies indicate possible efficacy when administered via a different dosing protocol.[34]

Capsaicin preparations may be effective in controlling oral mucositis pain.[51-54] Capsaicin and its analogues are the active ingredients in chili peppers that produce burning pain by stimulating polymodal nociceptors, which are the predominant pain receptors found in skin and mucous membranes. It has been demonstrated experimentally that after ingesting capsaicin-containing foods or after capsaicin application to the oral mucosa, severity of pain is directly proportional to concentration of capsaicin present. Capsaicin’s clinical potential derives from the fact that it elevates the threshold for pain in areas to which it is applied. The pain threshold can be further elevated by gradually increasing the capsaicin concentration in a series of repeated applications. This approach to mucositis pain control is not convenient, and some patients are clearly not candidates for its use. Thus far, evidence that capsaicin produces symptomatic relief for mucositis pain is encouraging but limited to anecdotal reports and a small case series. It is not yet known what effects capsaicin may have on compromised human gastrointestinal mucosa at doses and durations that may be useful in treating mucositis. Further evaluation is warranted.

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