SAN FRANCISCO—Recombinant human keratinocyte growth factor (rHuKGF) reduces the risk of dose-limiting oral mucositis in patients with advanced colorectal cancer according to Stephen J. Clarke, MD, of Royal Prince Alfred Hospital, Camperdown, Australia. Reviewing results of a randomized, placebo-controlled trial of rHuKGF, Dr. Clarke also called for further study of the growth factor as an adjunct to standard chemotherapy.
The phase II trial was conducted by investigators in Australia and in the United States. Although treatment with rHuKGF reduced WHO grade 2-4 oral mucositis by nearly half compared to no treatment, two factors limit the applicability of these results:
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Treatment was compared to placebo rather than to more commonly used therapy, which is oral ice.
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The Mayo Clinic fluorouracil(Drug information on fluorouracil) (5-FU)/leucovorin regimen that was standard therapy for colorectal cancer at the time this study was designed has been largely superseded by irinotecan(Drug information on irinotecan) (Camptosar, CPT-11)-based regimens.
Extended Earlier Study
This study was an extension of a previously reported randomized phase I clinical trial in patients with advanced colorectal cancer (Meropol et al: J Clin Oncol, 19:2374, 2000). According to Dr. Clarke, the earlier study had shown that rHuKGF at doses ³ 10 µg/kg reduced the incidence of grade 2 to 4 oral mucositis caused by 5-FU to 43%, as compared to 67% for placebo (P = 0.06).
"To establish efficacy, we enrolled 64 additional patients with advanced colorectal cancer," Dr. Clarke explained. Patient characteristics were as follows:
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42 males, 22 females;
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median age 65, range 37-88;
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median Eastern Cooperative Oncology Group (ECOG) performance status 1, range 0 to 2.
"The patients were randomly assigned to receive two cycles of either rHuKGF 40 µg/kg/day or placebo by IV bolus on days 1 to 3, followed by bolus 5-FU 425 mg/m2/day plus leucovorin 20 mg/m2/day on days 4 to 8 of a 28-day cycle," Dr. Clarke continued.
Dr. Clarke said this study was designed with a 90% power to detect a 50% decrease in the incidence of oral mucositis. Specially trained research nurses assessed ulcerative oral mucositis. The incidence of grade 2 to 4 oral mucositis was 32% in patients treated with rHuKGF vs 78% with placebo (P = 0.001). The duration of grade 2 to 4 mucositis dropped to 3.4 days in treated patients from 10.2 days with placebo (P = 0.001).
"Patients had a week less oral mucositis when treated with rHuKGF," Dr. Clarke pointed out. This translated into a significant decrease in the number of patients requiring chemotherapy dose reductions of greater than 10%, from 31% with placebo to 14% with rHuKGF.
Mild Adverse Events
Recombinant rHuKGF had no effect on median survival, which was 71 weeks for the rHuKGF group (95% CI 54-81) vs 66 weeks for the placebo group (95% CI 41-135).
"Treatment with rhuKGF was well tolerated and had no adverse impact on response to chemotherapy or on survival," Dr. Clarke said. The most common treatment-related adverse events were mild to moderate skin problems (36% in rHuKGF-treated subjects and 22% in the placebo group), including facial rash, flushing, and edema. The researchers also observed asymptomatic and reversible increases in amylase and lipase after rHuKGF administration.
"These results confirm and extend our previous clinical observations of the efficacy and safety profile of rHuKGF—reducing the incidence, severity and duration of chemotherapy-induced mucositis," Dr. Clarke concluded.
