Treatment and Prevention of Mucositis Secondary to Cancer Treatment

Introduction

Mucositis is one of the most significant and debilitating adverse reactions from cancer treatment. It may occur as a result of chemotherapy or radiation therapy (RT), and can affect any part of the gastrointestinal tract from the oral cavity to the rectum. Oral mucositis presents as mouth pain, erythema and ulceration, which may extend to the pharynx and larynx. Gastrointestinal (GI) mucositis presents with symptoms such as significant GI pain, diarrhoea and nausea. Mucositis was reported as the most significant adverse symptom reported by patients in a 2008 paper from the National Comprehensive Cancer Network (NCCN). It is commonly associated with delays or dose reductions of cancer treatment, which can in turn negatively affect the prognosis of patients. Mucositis is also associated with a substantial economic impact due to symptom management, nutritional management, hospitalisations and the possibility of secondary infections.

Risk Factors

The risk of mucositis in patients receiving cancer therapy varies depending on the regimen and the treatment intensity. Mucositis occurs in 20-40% of patients receiving conventional doses of chemotherapy and 80% of patients receiving high dose chemotherapy immediately prior to a haematopoietic stem cell transplantation (HSCT). Almost all patients receiving RT for head and neck cancers will experience mucositis to some degree. Cisplatin, 5-fluorouracil, methotrexate and cyclophosphamide are all associated with a particularly high risk of oral mucositis, whereas the combination of chemotherapy and RT is associated with higher risk and severity of oral mucositis then either therapy alone, with 43% of patients on combination therapy presenting with high grade (WHO grade 3-4) oral mucositis.

There are also patient related risk factors, for instance, data shows that women are at higher risk than men of developing severe mucositis. Other factors such as dental appliances (including dentures) and poor nutritional status are thought to contribute, however are more difficult to study. As such, all patients should be individually assessed for their risk, and appropriate management, of mucositis when cancer regimens and doses are being determined and revised.

Proposed Mechanism

The pathogenesis of mucositis secondary to chemotherapy or radiation therapy is thought to be the result of various pathways, which has led to the testing of a very diverse range of treatment options. Al-Dasooqi et al. (2013) have proposed a five stage model for the pathogenesis as follows:

1. Direct cell damage from cytotoxic agents initiates mucositis; rapidly proliferating cells such as those in the oral and GI mucosa being particularly susceptible.
2. RT has been shown to impact of the production of saliva which may increase the vulnerability of the oral mucosa.
3. Evidence suggests that initial injury is amplified by the upregulation of inflammatory pathways, microorganisms, reactive oxygen species, and metabolic by products.
4. Nuclear factor kappa B (NF-ĸB) transcription factors are thought to upregulate a number of inflammatory pathways including pro-inflammatory cytokines and the cyclooxygenase-2 (COX-2) enzyme.
5. It has been shown that pro-inflammatory cytokines play an important role in both oral and GI mucositis.

Oral Mucositis

It is of paramount importance to identify patients at high risk of developing mucositis and to put preventative measures in place prior to the commencement of treatment. It is considered good clinical practice to ensure a high standard of oral hygiene in all chemotherapy and radiation therapy patients. Such measures include regular tooth brushing with a soft toothbrush (at least twice daily), regular replacement of the toothbrush, flossing once a day, and using oral moisturisers and mouthwashes. The preferred mouthwash is normal saline. It is further suggested that mouthwashes containing chlorhexidine, alcohol, hydrogen peroxide, and sucralfate not be used to prevent mucositis in chemotherapy patients and patients receiving RT for head and neck cancer.

The Multinational Association of Supportive Care in Cancer (MASCC) have also published guidelines, including the prevention of mucositis in high risk patient groups in particular. Oral cryotherapy, which involves holding ice chips in the mouth from shortly prior to, and continuing beyond, the dose administration for a total of 30 minutes when a 5-fluorouracil bolus is given without oxaliplatin. In patients receiving high dose chemotherapy being conditioned for HSCT, it is recommended that low level laser therapy be used to prevent oral mucositis and that oral cryotherapy may be useful in preventing mucositis in patients receiving melphalan. Additionally, in HSCT patients undergoing conditioning, it is not recommended that intravenous glutamine or systemic pilocarpine be used for the prevention of oral mucositis.

Some evidence suggests that oral zinc supplements may be of benefit in preventing oral mucositis in patients receiving chemotherapy or radiation for oral cancer. Furthermore, patients with head and neck cancer who are receiving RT without chemotherapy should use benzydamine mouthwash and receive low level laser therapy to prevent oral mucositis. However, these patients are not recommended to use PTA (polymyxin, tobramycin and amphotericin B) lozenges and paste, BCoG (bacitracin, clotrimazole and gentamicin) lozenges, misoprostol mouthwash, or systemic pilocarpine.

For patients with a haematological malignancy who are receiving high dose chemotherapy and total body irradiation followed by an autologous stem cell transplant, it is recommended that recombinant human keratinocyte growth factor-1 be used to prevent oral mucositis. Granulocyte macrophage colony stimulating factor is not recommended in patients on high dose chemotherapy prior to autologous or allogeneic stem cell transplantation, and oral pentoxifylline is not recommended to prevent oral mucositis in cancer patients that are undergoing bone marrow transplantation.

All of the evidence based MASCC guidelines for the treatment of mucositis detail recommended analgesia options. Transdermal fentanyl patches and 0.5% doxepin mouthwash may be used to treat pain secondary to oral mucositis in cancer patients of all treatment modalities. Morphine mouthwash 2% has been shown to be effective in patients receiving RT for head and neck cancer, and patient controlled morphine is recommended to treat mucositis pain in patients undergoing HSCT.

Patients with oral mucositis may benefit from other topical or systemic management, however, the choice to use such agents is driven by patient preference rather than compelling evidence that recommends a specific product. Patients may gain some relief by continuing with bland rinsing to remove debris from the oral cavity and moisturising the area with oral lubricants. Topical anaesthetics (often containing lignocaine) may also provide temporary relief from oral mucositis pain. When using these products, patients should be advised to take care to avoid further damage through eating or performing oral hygiene while the area is anaesthetised. A stepwise management approach is recommended by the NCCN, which involves starting with bland rinses, moving to other topical agents and, when ineffective, treating with narcotics.

Gastrointestinal (GI) Mucositis

MASCC have published a number of guidelines for the prevention and treatment of gastrointestinal mucositis; here defined as mucositis not including the oral cavity. Intravenous amifostine is recommended to prevent radiation proctitis in patients receiving any form of RT. It may also be used to prevent oesophagitis in patients treated with both chemotherapy and RT for non-small cell lung carcinoma. For patients receiving RT for solid tumours, hyperbaric oxygen may help to treat radiation induced proctitis. Orally administered systemic sucralfate is also not recommended to treat GI mucositis, however chronic radiation induced proctitis with rectal bleeding may be treated with sucralfate enemas. Misoprostol suppositories are not recommended to prevent proctitis due to RT for prostate cancer.

Probiotics containing Lactobacillis may be used to prevent diarrhoea secondary to chemotherapy and/or radiation for a pelvic malignancy and subcutaneous octreotide is recommended to treat diarrhoea due to HSCT chemotherapy if loperamide is unsuccessful.

Oral 5-aminosalicylates including balsalazide, mesalazine, olsalazine and sulfasalazine are not recommended to prevent diarrhoea due to RT for pelvic malignancy. However, oral sulfasalazine may be used to prevent radiation induced enteropathy in patients receiving RT to the pelvis.

In addition to these guidelines, the European Society for Medical Oncology (ESMO) recommends good bowel hygiene including adequate hydration throughout treatment.

Patient Counselling

All cancer patients and their carers should receive sufficient education on the risk of mucositis, with particular emphasis to those at highest risk. Nurses and pharmacists are well positioned to provide patients and carers with education. Additional education and supportive care is exceptionally important for patients suffering from mucositis. Some measures include monitoring affected sites for infection, the patient’s swallowing ability (which may require adjustment of regular medications), access to dietary advice and artificial nutrition interventions. Patient education and monitoring should occur prior to and on a regular basis during patients’ treatments to increase awareness and the benefits of early intervention.