AUGMENTED CAPILLARY LEAK DURING ISOLATED HEPATIC PERFUSION (IHP) OCCURS VIA TUMOR NECROSIS FACTOR-INDEPENDENT MECHANISMS

Isolated organ perfusion of the liver or extremity with tumor necrosis factor (TNF) and melphalan results in regression of bulky tumors in t he majority of patients, The efficacy of TNF in this setting is not kn own, although data suggest that it may exert antitumor effects primari ly on tumor-associated neovasculature. We studied the effects of TNF o n capillary leak in liver and tumor tissue during isolated hepatic per fusion (IHP) with melphalan, Twenty-seven patients with unresectable c ancer confined to the liver underwent a 60-min hyperthermic IHP using 1.5 mg/kg melphalan alone (n = 7) or with 1.0 mg of TNF (n = 20), Comp lete vascular isolation was confirmed in all patients using an intraop erative leak monitoring I-131 radiolabeled albumin technique. Samples of tumor and liver were collected just prior to and immediately after IHP, There was no difference in I-131 radiolabeled cpm/g of tissue (cp m) in liver versus tumor at baseline (P-2 = 0.44), After IHP, I-131 al bumin cpm were higher in tumor versus liver (10,999 a 1,976 versus 3,8 21 +/- 780, respectively; P-2 < 0.005), However, I-131 albumin cpm in tumor were not effected by TNF (11,636 +/- 2,518 with TNF versus 9,180 +/- 2,674 without TNF; P-2 = 0.59), TNF did not affect melphalan conc entrations in tumor (1,883 +/- 540 ng/g versus 1,854 +/- 861 ng/g with out TNF; P-2 = 0,9), Capillary leak, as reflected by diffusion of I-13 1 radiolabeled albumin into the interstitial space, is comparable in l iver and tumor before IHP but is significantly higher in tumor after I HP, The increased diffusion in the capillary tumor bed must occur thro ugh TNF-independent mechanisms such as intrinsic features of tumor neo vasculature, hyperthermia, or other unrecognized perfusion-related fac tors. These data indicate that TNF must continue to be critically eval uated in clinical trials before it is routinely used with melphalan in isolated organ perfusion.