Regional toxicity after isolated limb perfusion with melphalan and tumour necrosis factor- α versus toxicity after melphalan alone

Abstract

Aims To determine whether the addition of high-dose tumour necrosis factor- α (TNFα ) to isolated limb perfusion (ILP) with melphalan increases acute regional tissue toxicity compared to ILP with melphalan alone. Methods A retrospective, multivariate analysis of toxicity after normothermic (37–38°C) and «mild» hyperthermic (38–40°C) ILPs for melanoma was undertaken. Normothermic ILP with melphalan was performed in 294 patients (70.8%), «mild» hyperthermic ILP with melphalan in 71 patients (17.1%) and «mild» hyperthermic ILP with melphalan combined with TNF α in 50 patients (12.0%). Toxicity was nil or mild (grades I–II according to Wieberdink et al.) in 339 patients (81.7%), and more severe acute regional toxicity (grades III–V) developed in 76 patients (18.3%). A stepwise logistic regression procedure was performed for the multivariate analysis of prognostic factors for more severe toxicity. Results On univariate analysis, «mild» hyperthermic ILP with melphalan plus TNF α significantly increased the incidence of more severe acute regional toxicity compared to normothermic and «mild» hyperthermic ILP with melphalan alone (36%vs 16% and 17%P=0.0038). However, after ILP using TNF α no grade IV (compartment compression syndrome) or grade V (toxicity necessitating amputation) reactions were seen. Significantly more severe toxicity was seen after ILPs performed between 1991 and 1994 compared with earlier ILPs (33%vs 14%P=0.0001). Also, women had a higher risk of more severe toxicity than men (22%vs 7%P=0.0007). After multivariate analysis, prognostic factors which remained significant were: sex (P=0.0013) and either ILP schedule (P=0.013) or treatment period (P=0.0003).Conclusions Regional toxicity after «mild» hyperthermic ILP with melphalan and TNF α was significantly increased compared to ILP with melphalan alone. This may be caused by increased thermal enhancement of melphalan due to the higher tissue temperatures (39–40°C) at which the melphalan in the TNF α -ILPs was administered or by an interaction between high-dose TNF α and melphalan.