title: Prospective pilot study of recombinant granulocyte-macrophage colony-stimulating factor and interferon-gamma in patients with inoperable hepatocellular carcinoma.
abstract: Interferon (IFN)-gamma and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) enhance tumor immunogenicity. The authors assessed tolerability and effectiveness of a combination therapy of these recombinant human (rh) cytokines in patients with inoperable hepatocellular carcinoma (HCC). In a monocentric, open, nonrandomized pilot study, rhGM-CSF (5 microg/kg qd, Monday and Tuesday) and rhIFN-gamma (100 microg qd, Wednesday and Thursday) were subcutaneously administered in 9-week cycles. Primary objective was survival, as secondary outcomes volumetric changes of tumor mass and biologic parameters reflecting systemic immunologic or local tumor responses were measured. Only patients with complete response (CR), partial response (PR), or stable disease (SD) proceeded to new treatment cycles. Fifteen patients (median 63 years, range 46-74 years, all men) were enrolled. Survival after the first cycle was 80% with SD in 9 of 15 patients (60%). PR was detected in one patient after the second cycle. Two patients finished five treatment cycles. Overall survival at 26 and 52 weeks was 40% and 20%, respectively. Median survival in patients with inducible HLA-DR on hepatoma cells (40%) was increased (42 weeks, 27-100) as compared with HLA-DR negative cases (60%; 13 weeks, 8-23; p < 0.0001), and a control group (p = 0.01). Parameters reflecting systemic immunomodulatory activities were not associated with clinical outcome. In 13 of 15 patients (87%), adverse events were reported, all less than grade 2 and none requiring therapy discontinuation. Immunotherapeutic approaches hold promise to prolong survival in selected patients with advanced HCC who respond by enhanced tumor immunogenicity.
authors.affiliation: Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. walter.reinisch@akh-wien.ac.at
authors.forename: Walter
authors.initials: W
authors.lastname: Reinisch
authors.forename: Margareta
authors.initials: M
authors.lastname: Holub
authors.forename: Andreas
authors.initials: A
authors.lastname: Katz
authors.forename: Andreas
authors.initials: A
authors.lastname: Herneth
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lichtenberger
authors.forename: Maximilian
authors.initials: M
authors.lastname: Schoniger-Hekele
authors.forename: Thomas
authors.initials: T
authors.lastname: Waldhoer
authors.forename: Georg
authors.initials: G
authors.lastname: Oberhuber
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.forename: Alfred
authors.initials: A
authors.lastname: Gangl
authors.forename: Christian
authors.initials: C
authors.lastname: Mueller
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000097:blood; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000097:blood; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D006680:HLA Antigens / Q000097:blood; D006801:Humans; D007157:Immunologic Surveillance / Q000187:drug effects; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000008:administration & dosage / Q000627:therapeutic use*; D017567:Karnofsky Performance Status; D007958:Leukocyte Count; D015993:Life Tables; D008103:Liver Cirrhosis / Q000150:complications; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood; D010166:Palliative Care; D010865:Pilot Projects; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012074:Remission Induction; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D015415:Biomarkers; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D006680:HLA Antigens; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor