Regional toxicity after isolated limb perfusion with melphalan and tumour necrosis factor- alpha versus toxicity after melphalan alone.
OBJECTIVE
To determine whether the addition of high-dose tumour necrosis factor-alpha (TNF alpha) 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 degrees C) and 'mild' hyperthermic (38--40 degrees 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 alpha 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 alpha 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 alpha 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 alpha 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 degrees C) at which the melphalan in the TNF alpha-ILPs was administered or by an interaction between high-dose TNF alpha and melphalan.
Vrouenraets
B C
BC
Department of Surgery, The Netherlands Cancer Institute/Antoni van Leeuwenhoek ziekenhuis, Amsterdam, The Netherlands.
Eggermont
A M
AM
Hart
A A
AA
Klaase
J M
JM
van Geel
A N
AN
Nieweg
O E
OE
Kroon
B B
BB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects*; D001768:Blister / Q000139:chemically induced; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D003161:Compartment Syndromes / Q000139:chemically induced; D004487:Edema / Q000139:chemically induced; D004890:Erythema / Q000139:chemically induced; D005121:Extremities; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects*; D008875:Middle Aged; D015999:Multivariate Analysis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D012737:Sex Factors; D012878:Skin Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects*
D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan