On December 15, 2004 the U.S. Food and Drug Administration approved the use of keratinocyte growth factor (palifermin, Kepivance™) for the treatment of patients undergoing high-dose chemoradiotherapy for hematologic malignancies. The details of the pivotal study leading to approval were published in the December 16, 2004 issue of the New England Journal of Medicine .[1]

Oral mucositis is a frequent clinical problem in patients receiving chemotherapy and/or radiation therapy. Mucositis can be a severe dose-limiting toxicity, especially in patients receiving autologous or allogeneic stem cell transplants or radiation therapy for head and neck cancers. Patients who have undergone stem cell transplants frequently rate mucositis as the most debilitating side effect of the treatment. Although oral mucositisis is the most obvious manifestation of mucosal injury from chemotherapy and radiation therapy, the damage extends throughout the oropharynx, exophgitis, and perirectal areas. Damaged mucosa is also the portal of entry of bacteria and fungi and mucositis is associated with febrile neutropenia. Although many specific and non-specific prophylactic and therapeutic treatments have been evaluated, there is no proven therapy for the prevention or treatment of mucositis. Prior to the approval of Kepivance™, there were no FDA-approved systemic drugs for the treatment or prevention of mucositis due to chemotherapy or radiation therapy.

Kepivance™ has been effective in animal models and in one preclinical phase I-II clinical trial in reducing the severity and incidence of severe mucositis induced by radiation and/or chemotherapy. The results of the multi-center randomized trial leading to approval of Kepivance™ have been reported at scientific meetings, but only appeared today in a definitive form in the NEJM. This relatively large placebo-controlled trial demonstrated that Kepivance™ reduced the incidence and severity of oral mucositis in patients receiving a total body irradiation (TBI)-based regimen followed by autologous stem cell rescue.

In this study, 129 patients with hematological malignancies receiving a regimen of TBI and etoposide were randomly allocated to receive Kepivance™ 50 micrograms/kg for each of 3 days before stem cell infusion and 3 days following. Mucositis was graded on a WHO scale of 0-4. Grade 3-4 is considered severe. Grade 3 consisted of ulcerations with inability to eat solid food. Grade 4 is the inability to take in any nutrition. Patients in this study were evaluated daily for 28 days.

Grade 3-4 mucositis developed in 98% of the placebo group and lasted an average of 9 days. Grade 3-4 mucositis developed in 63% of the Kepivance™-treated patients and lasted an average of 6 days. Grade 4 mucositis occurred in 62% of the placebo group and lasted an average of 6.2 days. In the Kepivance™ group, only 20% developed Grade 4 mucositis, which lasted an average of 3.3 days. The number of days receiving narcotics for pain was less in the treated group and the total quantity of narcotics taken was significantly less for those taking Kepivance™. In addition, febrile neutropenia occurred in 92% of the placebo group, compared to 75% in the Kepivance™ group. There were no adverse effects on relapses or secondary leukemias. Toxicities of Kepivance™ included skin rash, pruritis, erythema, cough, edema, taste alteration, white film coating mouth or tongue, rhinitis, arthralgia, sensation of tongue thickness, perianal pain numbness, taste loss and paresthesia. However, these side effects were reversible and did not interfere with treatment.

Comments: Kepivance™ appears to be a true advance in the prevention of chemotherapy-induced mucositis associated with high-dose therapy. There are ongoing studies to determine the effect of Kepivance™ in other mucositis-induced settings. However, many patients receiving Kepivance™ still had severe mucositis, suggesting the need for additional preventive measures. An accompanying editorial in the NEJM pointed out that “keratinocyte growth factor should be considered one component of the multi-drug therapies. A combination of protocols could provide the much needed solution.”[2]

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