Endostatin plus interferon-alpha2b therapy for metastatic melanoma: a novel combination of antiangiogenic and immunomodulatory agents.
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.
Moschos
Stergios J
SJ
Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, PA 15213-2584, USA.
Odoux
Christine
C
Land
Stephanie R
SR
Agarwala
Sanjiv
S
Friedland
David
D
Volker
Kirk M
KM
Sidor
Carolyn
C
Wong
Michael
M
Kirkwood
John M
JM
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D043169:Endostatins / Q000008:administration & dosage; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010865:Pilot Projects; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D007155:Immunologic Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins