Oral mucositis (OM) is a frequent and, occasionally severe complication of chemotherapy and radiation therapy to treat cancer. The patient’s experience of OM can range from mild odynophagia to severe tissue inflammation, edema, and mucosal bleeding which prevents all alimentation, and can require -- in its most severe form -- intubation to protect a patient’s airway. As patients experience progressive mucositis during treatment, a vicious cycle can ensue, including worsening pain and dysphagia, resulting in reduced oral intake, leading to malnutrition, weight loss, fatigue and deconditioning. At the same time, ulceration in the oral cavity can lead to bacterial and fungal colonization and local infection, putting immune compromised patients at risk for systemic infection.
While best characterized in the setting of myeloablative high-dose chemotherapy for patients undergoing hematological stem cell transplantation (HCST), OM is a common toxicity of a wide range of chemotherapy agents used to treat cancers such as breast, lung, colorectal, and lymphoma.(1) The World Health Organization’s scoring for grading OM ranges from 0 to 4, with 0 being no evidence of mucositis, grade 1 including soreness with or without erythema but no ulcerations, while grade 2 to 4 includes erythema and ulceration and a progressive loss of the ability to eat. Grade 2 classifies patients who can still swallow some solid foods, while grade 3 characterizes patients who cannot swallow any solid food. Grade 4 is reserved for those patients who are not able to tolerate any p.o. intake. (2) Despite its clinical impact, OM has not been studied with the fervor and intensity of new anti-cancer agents that are designed to eliminate tumor burdens and cure patients or prolong their survival. Hence, it has been viewed as the “icing on the cake” of cancer therapy, to the detriments of cancer patients who suffer from the complications of this very real clinical problem.
Given the severity and significant complications from oral mucositis, a number of interventions have been developed and tested to reduce the severity of this complication. Good oral hygiene, aggressive use of narcotic analgesics, and frequent physician evaluations are critical. Additional interventions that have been studied include cryotherapy using ice chips, and drugs such as benzydamine, amifostine, and more recently palifermin. Palifermin is a recombinant human keratinocyte growth factor (KGF) which targets the KGF/FGFR2b receptor. Stimulating this growth factor receptor can have a potent stimulating effect on epithelial cell proliferation. When initially tested in patients undergoing autologous HCST, palifermin was found to reduce the percentage of patients experiencing severe (grade 3/4) OM as well as its duration. (3) This positive study led to FDA approval in December, 2004. Subsequent studies of palifermin in colorectal patients treated with 5-fluorouracil as well as head and neck patients treated with radiation therapy have found improvements in mucositis, dysphagia and xerostomia in select patient groups. However, while approved as part of the conditioning regimen in HSCT, palifermin is not currently recommended for inclusion in other treatment modalities based on the consensus statements from groups such as the American Society of Clinical Oncology and the Multinational Association of Supportive Care in Cancer (1,2).
In this issue of the Annals, Vadhan-Raj and colleagues describe the effects of palifermin therapy in patients undergoing intensive treatment for solid tumor malignancies. (4) Using a randomized placebo-controlled phase II study design, they found that patients treated with doxorubicin-based chemotherapy for sarcomas had a significant improvement in the severity and duration of grade 2-4 mucositis. Patients in the trial received a single dose of 180 micrograms//kg instead of the standard three daily dosages prior to chemotherapy. Further, patients on the placebo arm were allowed to cross over to palifermin after treatment assignments were unblinded; all such patients experienced improvement in their OM in subsequent rounds of chemotherapy. In short, this is a positive study that met its endpoint.
The importance of supportive care in assisting patients undergoing intensive anticancer therapy cannot be overemphasized. Accordingly, we believe such supportive care interventions such as the use of palifermin should be assessed based on four principles.