title: Local intratumoral tumor necrosis factor-alpha and systemic IFN-alpha 2b in patients with locally advanced prostate cancer.
abstract: To examine tolerability and activity of local, intratumoral tumor necrosis factor-alpha (TNF-alpha) and systemic interferon-alpha2b (IFN-alpha2b) in locally advanced, hormone-resistant prostate cancer (LA-HRPC), 10 patients with LA-HRPC (T4N x M0, n = 3, T4N x M1, n = 5; T4N1M1, n = 2) were treated with recombinant TNF-alpha injected locally into prostate tumor tissue at 4-week intervals (maximum of four cycles) combined with intermittent subcutaneous (s.c.) administration of 5 x 10(6) IU IFN-alpha2b. Twenty-nine TNF-alpha cycles were administered. Despite significant TNF-alpha leakage into the systemic circulation 2 h after intraprostatic application (from a mean of 9 to a mean of 416 pg/ml; p = 0.0034), TNF-alpha (and IFN-alpha2b) was well tolerated (WHO grade 1-2 toxicity), possibly because of its rapid neutralization by increasing soluble 55-kDa and 75-kDa TNF receptor levels in the serum (mean increase 268% and 91%, respectively) at the same time. TNF-alpha induced prostate tumor cell necrosis in all patients, leading to a significant reduction of prostate volume in 9 of 10 cases (mean 38%; p = 0.0025). The significant short-term increase of prostate-specific antigen (PSA) (mean 65%; p < 0.001), tissue polypeptide-specific antigen (TPS) (mean 85%; p = 0.001), and possibly interleukin-8 (IL-8) (mean 2687%; p < 0.009) serum levels within 4 h after TNF-alpha confirmed the cytotoxic effect in vivo. In the long term, serum PSA levels dropped by 18%-87%, reaching the nadir value 7 weeks after baseline. Objective responses of metastases were not seen. Intraprostatic administration of TNF-alpha is feasible at a tolerable toxicity in patients with LA-HRPC and, thus, may be a new treatment option for these patients.
authors.affiliation: Department of Urology, University of Vienna, Austria. uroldep@akh-wien.ac.at
authors.forename: G
authors.initials: G
authors.lastname: Kramer
authors.forename: G E
authors.initials: GE
authors.lastname: Steiner
authors.forename: P
authors.initials: P
authors.lastname: Sokol
authors.forename: A
authors.initials: A
authors.lastname: Handisurya
authors.forename: H C
authors.initials: HC
authors.lastname: Klingler
authors.forename: U
authors.initials: U
authors.lastname: Maier
authors.forename: M
authors.initials: M
authors.lastname: Földy
authors.forename: M
authors.initials: M
authors.lastname: Marberger
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D006801:Humans; D015552:Injections, Intralesional; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000097:blood / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010455:Peptides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C089984:tissue polypeptide specific antigen; D017430:Prostate-Specific Antigen