Local Intratumoral Tumor Necrosis Factor- α and Systemic IFN- α 2b in Patients with Locally Advanced Prostate Cancer

Abstract

To examine tolerability and activity of local, intratumoral tumor necrosis factor-α (TNF-α) and systemic interferon-α2b (IFN-α2b) 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 with recombinant TNF-α injected locally into prostate tumor tissue at 4-week intervals (maximum of four cycles) combined with intermittent subcutaneous (s.c.) administration of 5 × 10⁶ IU IFN-α2b. Twenty-nine TNF-α cycles were administered. Despite significant TNF-α 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-α (and IFN-α2b) 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-α 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-α 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-α is feasible at a tolerable toxicity in patients with LA-HRPC and, thus, may be a new treatment option for these patients.