melphalan and Shock--Septic

Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan harbors the risk of septic shock-like syndrome. Pentoxifyllin (PTX) produced a beneficial effect on cytokine response and survival in animal experiments of septic shock, and we were interested to explore its effect during TNF-ILP in humans.. Eighteen consecutive patients underwent TNF-ILP and received PTX (30 mg/kg/day), whereas another 13 consecutive patients did not. PTX was given systemically after the limb extracorporeal circulation was started. Cardiac index, systemic vascular resistance (SVR), and pulmonary vascular resistance were recorded via a Swan-Ganz catheter. Blood levels of TNF-alpha, interleukin-6, procalcitonin, and lipopolysaccharide-binding protein were determined before, during, and after ILP.. After reperfusion, systemic levels of TNF-alpha were significantly less increased in the PTX group (peak, 2.8 vs. 1.3 ng/mL; P <.05), as were interleukin-6 values (peak, 68 vs. 22 pg/mL; P <.02) and lipopolysaccharide-binding protein plasma levels (peak, 215 vs. 105 micro g/mL; P <.03). Differences in cardiac index, SVR, and mean arterial blood pressure were not significantly different. Norepinephrine or dobutamine to maintain SVR was less required in the PTX group.. PTX attenuates systemic cytokine production and influences components of the systemic inflammatory response after TNF-ILP. PTX may play a beneficial role in the management of septic shock-like syndrome, particularly in patients with leakage from the ILP circuit.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Enzyme Inhibitors; Extremities; Female; Humans; Inflammation; Male; Melanoma; Melphalan; Middle Aged; Pentoxifylline; Sarcoma; Shock, Septic; Skin Neoplasms; Soft Tissue Neoplasms; Syndrome; Tumor Necrosis Factor-alpha

Isolated perfusion of the extremities with high-dose tumour necrosis factor alpha (TNF-alpha) plus melphalan leads to dramatic tumour response in patients with irresectable soft tissue sarcoma or multiple melanoma in transit metastases. We developed in vivo isolated organ perfusion models to determine whether similar tumour responses in solid organ tumours can be obtained with this regimen. Here, we describe the technique of isolated kidney perfusion. We studied the feasibility of a perfusion with TNF-alpha and assessed its anti-tumour effects in tumour models differing in tumour vasculature. The maximal tolerated dose (MTD) proved to be only 1 microg TNF-alpha. Higher doses appeared to induce renal failure and a secondary cytokine release with fatal respiratory and septic shock-like symptoms. In vitro, the combination of TNF-alpha and melphalan did not result in a synergistic growth-inhibiting effect on CC 531 colon adenocarcinoma cells, whereas an additive effect was observed on osteosarcoma ROS-1 cells. In vivo isolated kidney perfusion, with TNF-alpha alone or in combination with melphalan, did not result in a significant anti-tumour response in either tumour model in a subrenal capsule assay. We conclude that, because of the susceptibility of the kidney to perfusion with TNF-alpha, the minimal threshold concentration of TNF-alpha to exert its anti-tumour effects was not reached. The applicability of TNF-alpha in isolated kidney perfusion for human tumours seems, therefore, questionable.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Kidney; Male; Melphalan; Neoplasm Transplantation; Neoplasms, Experimental; Osteosarcoma; Rats; Renal Insufficiency; Shock, Septic; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

To describe the systemic effects of high-dose recombinant tumor necrosis factor alpha (rTNF-alpha), recombinant interferon gamma (rIFN-gamma), and melphalan administered through hyperthermic isolation perfusion of the limbs (IPL) in patients with melanoma and malignant soft-tissue tumors.. The clinical, hemodynamic, and biologic parameters were recorded after IPL during the postoperative period.. Surgical intensive care service of a 1,000-bed tertiary university medical center.. Nineteen patients referred to a pluridisciplinary Center for Oncology after relapse of regionally advanced melanoma or soft-tissues tumors, included in a phase 2 therapeutic study.. Major systemic and hemodynamic changes were observed after IPL in all patients. Ninety-four percent (17/18) of the evaluable patients presented a shock unresponsive to fluid challenge, requiring the continuous perfusion of vasopressors, inotropic agents, or both. Analysis of hemodynamic data showed two distinctive patterns: a pure distributive shock in nine patients requiring norepinephrine, and a mixed distributive and cardiogenic shock in eight patients requiring vasopressor and inotropic agents. The oxygen parameters were characterized by an increase in both the delivery and the uptake of oxygen, with a prolonged reduced oxygen extraction ratio for most patients. The other observed effects were as follows: transient bilateral or mixed pulmonary infiltrates in all patients; some hematologic disturbances in 83% of patients; infection requiring a modification of the antibiotic prophylaxis in 61% of patients; and some liver toxic reactions in 50% of patients. Very high systemic TNF-alpha serum bioactivity was found in 12 patients for whom serum samples were available, indicating an early and important rTNF-alpha leakage from the IPL. No correlations could be found between the levels of TNF-alpha and the observed systemic effects. Despite the severity of the hemodynamic disturbance, no patient died.. Major systemic effects, consisting mainly in cardiovascular, respiratory, and hematologic disturbances, were observed in patients after IPL with high-dose of rTNF-alpha. The likely explanation for these observations is an early rTNF-alpha leakage related to inadequate IPL technique. These data show that the iatrogenic administration of high circulating TNF levels lead to a "septic shock-like" syndrome without resulting in lethal organ dysfunction.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase II as Topic; Extremities; Hemodynamics; Humans; Interferon-gamma; Melanoma; Melphalan; Recombinant Proteins; Retrospective Studies; Sarcoma; Shock, Septic; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha