Evaluation and Treatment of Chemo- or Radiation-Induced Painful Complications
Chemotherapy (CT), radiation therapy (RT), and their combination are commonly prescribed for patients with cancer. These life-saving treatments, however, often cause systemic side effects including bone marrow suppression, immunosupression, nausea, vomiting, diarrhea, fever, anorexia, asthenia, cachexia, cardiovascular, renal and hepatic toxicity, alopecia, sloughing of skin and mucosal membranes (related to its effects on rapidly mitotic cellular function), as well as central and peripheral neuropathic toxicities.
Mucositis and peripheral polyneuropathy are amongst the most common painful side effects from these treatments, and will be the focus of this article. Painful mucositis can be disabling and affect the future course of CT and/or RT. Painful peripheral polyneuropathy may occur as delayed sequelae of effective treatment. To follow are some strategies to minimize side effects and morbidity, as well as effective analgesics to control symptoms.
Mucositis and xerostomia (stomatitis) are common side effects following CT and/or RT. Mucositis affects 400,000 cancer patients annually, is associated with infection in 80% of patients, and has a mortality rate of 10% due to sepsis.1 There is a significantly increased cost of care for patients who develop mucositis, including hospitalizations requiring parenteral or gastric feedings, and higher utilization of opioids.2
Mucositis and xerostomia occur most commonly following the treatment of blood dyscrasias (hematologic cancers) or transplantation, followed by colorectal cancer treatment (if CT is used only). In head and neck cancers, mucositis has a prevalence of up to 80%, and occurs more commonly following combined CT and RT, especially if patients receive more than 5,000 cGy of radiation.
Mucositis may occur anywhere in the GI tract including the esophagus, small and large intestine, but is more commonly symptomatic in the oral mucosa. The ulcers may occur on the lip, buccal mucosa, palate, or tongue.3 The pathophysiology of mucositis includes initial inflammation with disruption of the epithelial cells followed by damage to the subepithelial layers of mucosa caused by free radicals released by cytokines. This is followed by ulceration and secondary infection. Secondary infections with leukoplakia include bacterial and yeast (thrush) infections, as well as viral infection, particularly recrudescent herpes simplex virus (HSV). A pseudomembrane formation is initiated by fibroblasts, and then subsequent healing occurs.1
Initial symptoms include xerostomia with highly viscous saliva, followed by very painful oral mucosal ulcers with surrounding inflammation (erythema) of the mucosal membranes with odynophagia, dysphagia, and dysgeusia (alteration in taste perception), dysarthria, and insomnia (due to pain). The loss of salivary gland secretion may occur as a result of dehydration, anticholinergic medications, CT (usually occurs after 4-10 days, lasting 7-14 days), and RT (usually occurs after 3 to 4 weeks).1 Xerostomia also carries an increased incidence of dental caries.
Severity of Mucositis
The severity of oral mucositis can be graded from 0-4 based on the World Health Organization oral toxicity scale. National Cancer Institute Common Toxicity Criteria (NCI CTC) is another scale based solely on functional deficits (Table 1). Alternative nutritional support should be considered if malnutrition results in >5% weight loss.
Mucositis is commonly caused by CT agents including melphalan (Alkeran), fluorouracil (5-FU, Efudex), doxorubicin (Doxil), cisplatin, paclitaxel, bleomycin, rapalogs (rapamycin derivatives), and cytarabine. These agents generally result in the highest frequency of side effects, particularly if combined with RT. Methotrexate and etoposide (Etopophos) are secreted into the saliva, with direct toxic effects on the mucosa (Table 2).4
Prevention of Mucositis
Risk factors for the development of mucositis include poor oral hygiene, dental caries, periodontal disease, high titers of HSV, and positive cultures for Candida.4 A dental assessment including regular inspection of the oral cavity is recommended. Patients are told to avoid smoking, alcohol, and spices. Proper nutrition, including a high protein diet for wound healing and hydration to prevent dehydration, also are recommended.
For the prevention of mucositis, oral hygiene protocols include brushing with toothpaste and warm water using a soft toothbrush or foam swab, use of Biotène products, use of non-alcoholic mouthwashes and rinses, baking soda, and flossing. Mucositis is commonly pretreated with cryotherapy (ice chips), which causes local vasoconstriction, thus decreasing the delivery of CT to the oral mucosa. It may be given prophylactically, 5 minutes prior to the administration of CT.
To prevent mucositis following RT, there is an innovative surgery that transposes the submandibular salivary gland out of the field of radiation, thus preserving most salivary function.5 Most recently, intensity-modulated RT has been developed that more specifically targets the cancer, without affecting the adjacent salivary glands.6
Treatment of Mucositis And Xerostomia
There are a number of agents available to treat or reduce painful mucositis. One area of research has been the development of agents that go to the core of CT or RT-induced mucositis—inflammation. Glutamine supplementation in the form of AES-15 (Saforis) has recently shown promise by improving amino acid replacement in the damaged epithelium.7 Palifermin (Kepivance), a keratinocyte growth factor preparation, has been approved by the FDA for use with high-dose CT regimens associated with high rates of mucositis.8 Clinical studies of the agent found that it improved mucositis scores by approximately 33%, as well as reduced the need for opioids.9,10 The side effects include local mucosal toxicity, rash, and hypotension. Velafermin (rhFGF-20) is a recombinant fibroblast growth factor under investigation for the treatment of mucositis.11
MuGard is FDA-approved for the management of mucositis and stomatitis.12 When swirled around the mouth, the mucoadhesive protectant forms a hydrogel coating over the oral mucosa. Episil is another mucoadhesive protectant that creates a lipid membrane that bonds to the mucosa for pain relief of oral mucositis and stomatitis.13 Other oral protectants include Gelclair, another mucoadhesive thin gel, with a soothing effect.14 NeutrSal is an FDA-approved calcium phosphate mouth rinse for the management of mucositis.1 The agent is started at the beginning of CT or RT and is designed to replace the normal ionic and pH balance in mouth.