Local intratumoral tumor necrosis factor-alpha and systemic IFN-alpha 2b in patients with locally advanced prostate cancer

To examine tolerability and activity of local, intratumoral tumor necrosis factor-alpha (TNF-alpha) and systemic interferon-alpha 2b (IFN-alpha 2b) in locally advanced, hormone-resistant prostate cancer (LA-HRPC), 10 patients with LA-HRPC (T4NxM0, n = 3, T4NxM1, n = 5; T4N1M1, n = 2) were treated wi th recombinant TNF-alpha injected locally into prostate tumor tissue at 4-w eek intervals (maximum of four cycles) combined with intermittent subcutane ous (s.c.) administration of 5 x 10(6) IU IFN-a2b. Twenty-nine TNF-alpha cy cles were administered. Despite significant TNF-alpha leakage into the syst emic 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-alpha 2b) was well tol erated (WHO grade 1-2 toxicity), possibly because of its rapid neutralizati on 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 ind uced 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 = 0.00 1), and possibly interleukin-8 (IL-8) (mean 2687%; p, 0.009) serum levels w ithin 4 h after TNF-alpha confirmed the cytotoxic effect in vivo. In the lo ng term, serum PSA levels dropped by 18%-87%, reaching the nadir value 7 we eks after baseline. Objective responses of metastases were not seen. Intrap rostatic 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 p atients.