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

Aims: To determine whether the addition of high-dose tumour necrosis factor -alpha (TNF alpha) to isolated limb perfusion (ILP) with melphalan increase s acute regional tissue toxicity compared to ILP with melphalan alone. Methods: A retrospective, multivariate analysis of toxicity after normother mic (37-38 degreesC) and 'mild' hyperthermic (38-40 degreesC) ILPs for mela noma. 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 (LP with melphalan combined with TNF alpha in 5 0 patients (12.0%). Toxicity was nil or mild (grades I-II according to Wieb erdink ct al.) in 339 patients (81.7%), and more severe acute regional toxi city (grades III-V) developed in 76 patients (18.3%). A stepwise logistic r egression procedure was performed for the multivariate analysis of prognost ic factors for more severe toxicity. Results: On univariate analysis, 'mild' hyperthermic ILP with melphalan plu s TNF alpha significantly increased the incidence of more severe acute regi onal toxicity compared to normothermic and 'mild' hyperthermic ILP with mel phalan alone (36% vs 16% and 17%; P = 0.0038). However, after ILP using TNF alpha no grade IV (compartment compression syndrome) or grade V (toxicity necessitating amputation) reactions were seen. Significantly more severe to xicity was seen after ILPs performed between 1991 and 1994 compared with ea rlier 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 analys is, prognostic factors which remained significant were: sex (P = 0.0013) an d either ILP schedule (P = 0.013) or treatment period (P = 0.0003). Conclusions: Regional toxicity after 'mild' hyperthermic ILP with melphalan and TNF alpha was significantly increased compared to ILP with melphalan a lone. This may be caused by increased thermal enhancement of melphalan due to the higher tissue temperatures (39-40 degreesC) at which the melphalan i n the TNF alpha -ILPs was administered or by an interaction between high-do se TNF alpha and melphalan. (C) 2001 Harcourt Publishers Ltd.