Hyperthermic Isolated Limb Perfusion with Tumor Necrosis Factor-α and Melphalan in Patients with Locally Advanced Soft Tissue Sarcomas: Treatment Response and Clinical Outcome Related to Changes in Proliferation and Apoptosis

• Published in: Clinical cancer research 1999-07, Vol.5 (7), p.1650-1657
• Main Authors: PLAAT, B. E. C, MOLENAAR, W. M, MASTIK, M. F, KOUDSTAAL, J, VAN DEN BERG, E, KOOPS, H. S, HOEKSTRA, H. J
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Biological and medical sciences; Cell Division; Chemotherapy, Cancer, Regional Perfusion; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Female; Follow-Up Studies; Foot Diseases - drug therapy; Foot Diseases - mortality; Humans; Hyperthermia, Induced; Interferon-gamma - administration & dosage; Male; Medical sciences; Melphalan - administration & dosage; Melphalan - therapeutic use; Middle Aged; Pharmacology. Drug treatments; Sarcoma - drug therapy; Sarcoma - mortality; Sarcoma - pathology; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha - administration & dosage; Tumor Necrosis Factor-alpha - therapeutic use
• ISSN: 1078-0432; 1557-3265

Hyperthermic isolated limb perfusion with tumor necrosis factor-α and melphalan (HILP-TM) with or without IFN-γ is a promising local treatment in patients with locally advanced extremity soft tissue sarcomas (STSs), with response rates of up to 84%. The mechanisms of the treatment response are poorly understood. Here, we determined the HILP-TM-induced changes in mitotic activity, proliferation, and apoptosis in 37 STSs; the additional effect of IFN-γ; and the association of HILP-TM with treatment response and clinical outcome. On archival material, obtained before and 6–8 weeks after HILP-TM with ( n = 15) or without ( n = 22) IFN-γ, the number of mitoses was counted, and the proliferation fraction was determined by immunohistological staining for the proliferation associated Ki-67 antigen (MIB1). Apoptosis was visualized by enzymatic detection of DNA fragmentation (terminal deoxynucleotidyl transferase-mediated nick end labeling method). Clinical and histological response, follow-up status, and survival were recorded. The number of mitoses dropped 57% and proliferation rate decreased with 40% after HILP-TM, whereas the amount of apoptosis after HILP-TM more than doubled as before HILP-TM. The addition of IFN-γ to HILP-TM did not influence the changes in tumor parameters and did not affect treatment response. A better clinical response to HILP-TM was correlated with high mitotic activity and low amount of apoptosis in tumor samples before HILP-TM. Patients with highly proliferative STS before and after HILP-TM had a relatively poor prognosis. Furthermore, patients who developed distant metastases after HILP-TM had a relatively high number of dividing cells in the tumor remnants after treatment.