title: Phase-I trial of intravenous continuous infusion of tumor necrosis factor in advanced metastatic carcinomas.
abstract: Fifteen patients with advanced metastatic adenocarcinomas were treated in a phase-I study with continuous intravenous 24 h infusion of recombinant tumor necrosis factor alpha (TNF-alpha) in order to determine the maximum tolerated dose (MTD) and associated side-effects. Patients received 40-400 micrograms/m2 TNF-alpha once (arm A) or twice (arm B) weekly for a scheduled treatment period of 2 months. The observed systemic side-effects resembled those reported for interferons and included fever, chills, fatigue, headaches, myalgias, thrombocytopenia, prostration, and malaise. Dose-limiting toxicities, resulting in a median MTD of 200 micrograms/m2 for 24 h, were fever, chills, fatigue, myalgias, and thrombocytopenia. Out of 15 patients, 11 showed tumor progression, and 3 sustained in no change for over 2 months of treatment. A minor response was seen in 1 patient with a colorectal carcinoma and liver metastases. To reduce side-effects, patients were treated either with paracetamol or indomethacin. Higher MTDs were observed in patients treated with indomethacin. No detectable plasma TNF-alpha levels or TNF antibodies were measured under therapy (plasma TNF-alpha less than 20 pg/ml). We conclude that TNF-alpha appears to have some antineoplastic activity in patients with adenocarcinomas since 4 patients remained in no change or showed a minor response.
authors.affiliation: Medizinische Klinik der Universität Heidelberg, Federal Republic of Germany.
authors.forename: B
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: P
authors.initials: P
authors.lastname: Reichardt
authors.forename: U
authors.initials: U
authors.lastname: Räth
authors.forename: L
authors.initials: L
authors.lastname: Theilmann
authors.forename: B
authors.initials: B
authors.lastname: Schüle
authors.forename: A D
authors.initials: AD
authors.lastname: Ho
authors.forename: E
authors.initials: E
authors.lastname: Schlick
authors.forename: J
authors.initials: J
authors.lastname: Kempeni
authors.forename: W
authors.initials: W
authors.lastname: Hunstein
authors.forename: B
authors.initials: B
authors.lastname: Kommerell
mesh_terms: D000906:Antibodies / Q000032:analysis; D000970:Antineoplastic Agents; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D002986:Clinical Trials as Topic; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha