Injection of recombinant tumor necrosis factor directly into liver metastases: an experimental and clinical approach

Abstract

Systemic treatment with tumor necrosis factor (TNF) is associated with side-effects, limiting its clinical use in the treatment of malignancies. To investigate the feasibility of other routes of administration experimental and clinical studies were started to establish the toxicity and antitumor activity of TNF after intratumoral (i.t.) injection. In a rat model for colon adenocarcinoma, tumor fragments, implanted subcutaneously or under the hepatic capsule, were treated with TNF injected i.v. or i.t. A dosage of 40 micrograms/kg was lethal when given i.v., but not i.t. Injection of TNF (40 micrograms/kg) directly into the tumor resulted in inhibition of tumor growth in the subcutaneous as well as subhepatic tumor model. A phase I study was started in patients with advanced malignancies to determine the toxicity of TNF injected into liver metastases. Injection of TNF into liver metastases was accomplished by ultrasonography. A 50 microgram-dose escalating schedule (3 patients/dosage) was chosen, starting at a dose of 100 micrograms TNF/injection. Up to now, 12 patients have been treated, the highest dosage of TNF injected being 250 micrograms. Chills, fever, nausea and vomiting were the main side-effects. No significant changes were found in circulatory, hematologic, renal and liver parameters. In summary, i.t. administration of TNF is associated with antitumor efficacy in experimental models and well-tolerated in man. The antitumor efficacy of TNF i.t. in man awaits evaluation in a phase II study.

Anti-tumor action of tumor necrosis factor against Bomirski Ab melanoma in hamsters

“…We chose this mode of application because of its lower toxicity at high doses of TNF. Intratumoral application of TNF is used in clinical applications, for example in the local treatment of liver metastases [ 28 , 31 ] and in the treatment of advanced prostate cancer [ 36 ], with a significant anti-tumor effect and mild and transient toxic effects. Additionally, in some experimental models, TNF applied intratumorally or intravenously affected tumor growth similarly, even with a stronger dependence of its anti-tumor effect of intravenous application on the immune system [ 21 ].…”

Tumor Necrosis Factor for the Treatment of Malignancies

“…Rigors after TNF adminis tration are common, but not observed by all investigators [70,73]. Fever follows generally rapidly after i.v.…”

“…Equal doses were lethal when given i.v., but injection i.t. resulted in inhibi tion of tumor growth in the s.c. as well as subhepatic tumor model [65],…”

“…infusion of TNF [69,70,72,79] and also occurs after i.t. adminis tration [73]. Antipyretic drugs can ameliorate fever, espe cially when they are given before TNF infusion; an effect on rigor has not be seen [67,73], Myalgias and fatigue occur in most patients, nausea and vomiting in 20-40%.…”

“…adminis tration [73]. Antipyretic drugs can ameliorate fever, espe cially when they are given before TNF infusion; an effect on rigor has not be seen [67,73], Myalgias and fatigue occur in most patients, nausea and vomiting in 20-40%. After administration of TNF into skin, soft tissue, or mus cle, local effects are seen, which are in some cases dose limiting [67,72].…”