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Hyperthermic Isolated Limb Perfusion with Tumor Necrosis Factor- and Melphalan in Patients with Locally Advanced Soft Tissue Sarcomas: Treatment Response and Clinical Outcome Related to Changes in Proliferation and Apoptosis¹

Departments of Pathology [B. E. C. P., W. M. M., M. F. M., J. K.] and Surgical Oncology [H. S. K., H. J. H.], University Hospital Groningen, 9700 RB Groningen, the Netherlands, and Department of Medical Genetics, University of Groningen, 9713 AW Groningen, the Netherlands [E. v. d. B.]

Hyperthermic isolated limb perfusion with tumor necrosis factor- and melphalan (HILP-TM) with or without IFN- 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-; 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-, 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- 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.

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