SAN FRANCISCORecombinant 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:
Treatment was compared to placebo rather than to more
commonly used therapy, which is oral ice.
The Mayo Clinic 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designed has been largely superseded by irinotecan (Camptosar, CPT-11)-based
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:
42 males, 22 females;
median age 65, range 37-88;
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
"These results confirm and extend our previous clinical
observations of the efficacy and safety profile of rHuKGFreducing the
incidence, severity and duration of chemotherapy-induced mucositis," Dr.