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

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 TNFα 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 TNFα 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 TNFα 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 TNFα 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 TNFα-ILPs was administered or by an interaction between high-dose TNFα and melphalan.