In patients with stage IIB-III disease, adjuvant high-dose
interferon-alpha2b has shown clinical benefit, although metastatic
melanoma is currently without any known survival-prolonging
therapy. Angiogenesis has been considered important in
melanoma progression, and
endostatin is an
angiogenesis inhibitor with antitumor activity that has shown promising results in murine model systems, prompting investigation of a formulation of rh-
Endostatin (EntreMed, Rockville, Maryland, USA) alone and with
interferon in metastatic
melanoma. Patients were randomly assigned to receive
interferon alpha2b (Schering-Plough) 10 million units/m(2) subcutaneously three times a week plus rh-
Endostatin 45 mg/m(2) subcutaneously every 12 h (arm A) vs. rh-
Endostatin alone (arm B). Twenty-one patients (age range 31-77 years, median age 54, 12 men and nine women, 17 cutaneous, and four ocular
melanomas) were enrolled. No antitumor responses were observed, and no significant differences were noted in time to progression or overall survival. Two patients had stable disease enduring more than 30 weeks on treatment. Serum
endostatin levels increased significantly 4 weeks
after treatment in both groups.
Basic fibroblast growth factor levels in urine were significantly lower following treatment in patients on arm B (P=0.043). The percentage of circulating endothelial cells was increased in five evaluable patients 4 weeks
after treatment. Low titer (<or=1:25)
IgG antibodies against the rh-Endo formulation were detected in two patients (one per arm) in cycle 4. In conclusion,
interferon did not improve response rate of rh-Endo although prolonged disease stability was observed in two patients. Better laboratory correlates of antiangiogenic response are needed, and the predictive value of circulating endothelial cells warrants further evaluation.