April 2006
Volume 5
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April 2006
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Contents
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Keratinocyte Growth Factor Decreases Oral Mucositis Resulting from Intensive Therapy for Hematologic Malignancies
KGF functions as a mesenchymally derived, paracrine mediator of epithelial homeostasis, with remarkable cytoprotective effects. The upregulation of KGF after epithelial injury suggests that it has an important role in tissue regeneration. In addition to stimulating repair, other studies demonstrated that the timely administration of recombinant KGF could prevent or reduce damage from a variety of toxic agents, including chemotherapy and radiation. In 1992, KGF technology was licensed to Amgen, Inc., for the development of therapeutic products. Among several potential applications, the decision was made to initially focus on the reduction of damage to the oral cavity that results from high-dose chemo/radiotherapy. Oral mucositis is a major debilitating side effect of intensive cancer treatments. Severe oral mucositis is associated with pain, difficulty eating and speaking, and gastrointestinal bleeding. It has a negative effect on patients’ quality of life and often results in a delay or reduction in cancer therapy. Until now, there has been no effective way to prevent or limit this condition. Encouraging results were obtained with KGF in a series of clinical trials, leading to a pivotal phase 3 trial reported in the New England Journal of Medicine (referenced above). Patients in this study received autologous peripheral blood progenitor cell transplants for hematologic malignancies. Prior to the transplants, they were treated with a standard combination of fractionated total body irradiation for 3 or 4 days, followed by VP-16 and cyclophosphamide. Patients received either the vehicle control or KGF (60 micrograms/kg/day) in three daily intravenous injections both before the start of radiation and after chemotherapy. Clinical staff monitored the appearance of the patients’ mouths on a daily basis. Severe mucositis was characterized by widespread erythema and ulceration in the oral cavity, and the ability to eat either only a liquid diet or nothing at all. Additional information was gathered from hospital records and from patients’ diaries about their health. KGF markedly reduced the duration of severe oral mucositis: the placebo group averaged 9.0 days, whereas the KGF cohort averaged only 3.0 days (P < 0.001). The incidence of severe oral mucositis also was significantly lower in the KGF group, 63% versus 98% for the placebo. This effect was due to a decline in the most debilitating form of mucositis, associated with an inability to eat, that corresponded to 62% of the placebo population but only 20% of the KGF group. Consistent with the decline in mucositis, there was a substantial reduction in the amount of analgesic medicine required by patients treated with KGF (P < 0.001), and a decrease in the use of total parenteral nutrition to supplement oral intake (P < 0.001). These favorable results were corroborated by the patients’ reports of mouth/throat soreness and functional status (e.g., ability to drink, eat, talk, and sleep). Furthermore, patients treated with KGF were less likely to experience episodes of febrile neutropenia, reinforcing the idea that a decrease in damage to the mucosa would reduce infection. Side effects of KGF were mild to moderate in severity, transient, and attributable to its pharmacologic action on skin and oral epithelium (e.g., rash, pruritis, erythema, and taste alteration). Based on these results, the U.S. Food and Drug Administration (FDA) approved KGF1 to reduce severe oral mucositis in patients with hematologic malignancies who were receiving chemotherapy and radiation prior to autologous bone marrow/peripheral blood progenitor cell transplants. Approximately 10,000 adults in the United States undergo transplantation each year. Additional clinical trials have been initiated to test the safety and efficacy of KGF in the solid tumor setting, particularly head/neck, lung, and colorectal carcinomas. Positive results in these populations could lead to a substantial increase in the number of patients treated with KGF. By decreasing the toxicity of therapeutic agents, KGF might also foster the development of more potent and effective cancer treatments. 1 Palifermin is the generic name for KGF in the clinic, and KepivanceTM is the trade name of the product from Amgen that went on the market in January 2005. Note: as a co-inventor on patents pertaining to KGF, the author acknowledges that he has a financial interest in its commercial development.
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eratinocyte
growth factor (KGF) was identified and cloned in the Laboratory of Cellular
and Molecular Biology, Division of Cancer Etiology, NCI, in the late 1980s.
It was purified from fibroblast culture fluid based on its ability to stimulate
DNA synthesis in a keratinocyte cell line and was subsequently shown to be active
on a variety of epithelial cells, but not other cell types. KGF is a member
of the fibroblast growth factor (FGF) family (FGF-7) and acts through a subset
of FGF receptor isoforms (FGFR2b) that are expressed almost exclusively by epithelial
cells.