KGF Reduces Severe Painful Oral Mucositis After Transplantation

SAN FRANCISCO—In a phase II trial, recombinant human keratinocyte growth factor (rHuKGF, or KGF) significantly reduced severe mucositis and improved quality of life for patients with hematologic malignancies who underwent autologous peripheral blood progenitor cell transplantation.

Ricardo Spielberger, MD, of the City of Hope National Medical Center, Duarte, California, presented the results at the 37^th Annual Meeting of the American Society of Clinical Oncology.

Dr. Spielberger said that about 80% of patients undergoing transplantation for hematologic cancers using a conditioning regimen of total body irradiation (TBI), etoposide (VePesid), and cyclophosphamide develop severe (WHO grade 3-4) mucositis. Patients with grade 3 mucositis cannot swallow solid food; at grade 4, alimentation is not possible, he said. "Currently, there is no standard therapy available to prevent or reduce severe oral mucositis," he added.

The trial drew upon in vitro data showing that KGF stimulates the proliferation and differentiation of epithelial cells in animal models.

Eleven centers in the United States and Canada enrolled 129 patients; 80% had non-Hodgkin’s lymphoma or Hodgkin’s disease. The rest had multiple myeloma, acute myelogenous leukemia, or acute lymphocytic leukemia. All were in complete remission, Dr. Spielberger said.

All patients received the same conditioning regimen of 12 Gy of TBI plus 60 mg/kg of etoposide and 75 or 100 mg/kg of cyclophosphamide. One group received three doses of placebo for 3 days prior to TBI followed by three more placebo doses after transplant. The second group had three daily doses of KGF before TBI and three placebo doses after transplant. The third group received three doses of KGF both pre-TBI and after transplant. Each dose was administered intravenously at 60 µg/kg/d. The study period began 11 days prior to transplant and continued 28 days afterward.

KGF Prevents Mucositis in Colon Cancer Patients

In another phase II trial of KGF reported at ASCO, 64 patients with advanced colorectal cancer were randomized to receive two 28-day cycles of KGF (40 µg/kg/d on days 1 to 3) or placebo by IV bolus, followed by chemotherapy (fluorouracil/leucovorin) on days 4 to 8.

Results showed significant reductions in the incidence of moderate-to-severe oral mucositis (WHO grades 2-4) over the two cycles—from 78% for placebo to 32% for KGF—and in the duration of mucositis (from 10.2 days for placebo to 3.4 days for KGF).

The mean number of days with severe mucositis was 7.7 for patients who received only placebo and 5 for those who received KGF pre-TBI followed by placebo after transplant (relative reduction of 35%). For the arm that received KGF pre-TBI and post-transplant, the mean number of days with severe mucositis was 4—a relative reduction of 48%, compared with placebo-only results.

The incidence of severe mucositis was also reduced, he said, with the most impressive results registered for grade 4 mucositis. While half of the patients in the placebo-only arm had grade 4 mucositis, incidence declined to 33% in the group that received KGF followed by placebo and to 26% in the group given KGF pre-TBI and post-transplant.

The KGF-only patients reported 36% less mouth and throat soreness than the placebo-only group, Dr. Spielberger said. Use of opiate analgesics was also lower (a mean of 8.3 days vs 12.1 days), as was use of total parenteral nutrition (a mean of 7.7 days vs 11.3 days).

About one fourth of patients receiving KGF had adverse events, including mild to moderate skin and oral erythema with or without edema, but the regimen was described as well tolerated overall.

Phase III Trial Underway

A two-arm phase III trial is already underway to evaluate KGF’s effect on duration of severe mucositis, Dr. Spielberger said. While the investigation is primarily focused on supportive care, he suggested that KGF’s effect on outcomes might also be evaluated. "Mucositis does have an impact on morbidity and, if extremely severe, could have an impact on mortality," he said. Mucositis could increase the risk of other complications by becoming "a port of entry for other infections."

Commentator Scott I. Bearman, MD, of the University of Colorado Health Sciences Center, Denver, said the results suggest that KGF’s effect on early regimen-related toxicity could make the regimen "easier, possibly cheaper, and safer." He cautioned that whether the ability to escalate doses further with cytoprotective agents leads to an improved antitumor effect is unclear and needs to be studied.

Dr. Bearman also suggested that surrogate endpoints, such as number of hospital days, hospital costs, and quality of life, be included in future investigations. "I would suggest that improvement in these surrogate endpoints alone would justify the routine use of cytoprotective agents regardless of whether additional antitumor benefits result from further dose escalation," he said.