Joseph H Kuei, M.D.;([unkeyable]) D...

Joseph H Kuei, M.D.;([unkeyable]) Donald P Tashkin, MD FC C.P.;([unkeyable]) and Robert A. Figlin, M.D.(Section)

Tumor necrosis factor is a cytokine produc by means of activated macrophages that causes hemorrhagic necrosis in various tumors. In preliminary clinical trials, patients have unraveled various degress of respiratory insufficiency following administration of rTNF Twenty-seven patients were studied prospectively to evaluate the import of administration of rTNF in succession pulmonary function. Sixteen of the 27 patients complet the eight-week course of daily IM injection of rTNF Spirometric data and Dsb were measured at baseline and in succession days 8, 15, and 56 of treatment. the two patients with and without progressive pulmonary metastases demonstrated a comparable mean decline in Dsb (- 107 [+ or -] 96 percent [+ or -] SD and 147 [+ or -] 100 percent respectively; p<001) not accounted for at either a decline in the hemoglobin appease of the blood or a reduction in alveolar whirl Marked interindividual variability in the replication of Dsb to rTNF therapy was noted. The reduction in Dsb reached a plateau by the agency of day 15. In contrast, alveolar dimensions and FVC remained essentially unchanged through every part of the course of treatment. Measurements of Dsb performed sum of two units weeks after cessation of rTNF therapy in seven of the 27 patients showed solely a modest trend toward recuperation which was not statistically significant. We finish that the administration of rTNF for the treatment of malignant neoplasms in this dosage and schedule can cause significant pulmonary injury meditateed by a reduction in Dsb which reaches a plateau through two weeks after initiation of therapy.

The phenomenon of tumor necrosis was first observ from Coley.[1] Subsequently, Shear et al[2] reported that endotoxin could induce tumor necrosis. In 1975 Carswell and associates[3] first described the existence of an endotoxin-induced serum factor that caused tumor necrosis (TNF) These authors showed that TNF had as well-as; not only-but also; not only-but; not alone-but cytolytic and cytostatic properties against tumor enclosed space lines in vitro and could induce hemorrhagic necrosis of certain murine sarcomas in vivo.[3,4] The activity of TNF was not species-specific.[5] In addition, it was highly selective against malignant cells[34] These properties of TNF activity generated considerable interest in its therapeutic potential for therapy for tumors.

Several patients participating in phase 1 clinical trials of rTNF for treatment of malignant neoplasms have been reported to evolve respiratory insufficiency following administration of rTNF[67] In a freshly reported series of 19 patients, Morice et al[8] ground that rTNF administered either subcutaneously or intravenously induced a dose-related decline in D The plan of the present study was to further evaluate the powers of rTNF on pulmonary function throughout time during the course of treatment of malignant neoplasms with rTNF

MATERIALS AND METHODS

Preparation of TNF

The rTNF was produc in Escherichia coli which intimateed the gene coding human TNF The rTNF was purified to more than 99 percent with a specific activity of approximately 4 x [10sup7] units/mg of protein as defined in the L929 cytotoxicity assay. Sterility, general safety, and purity studies met Office of Biologic standards.

Selection of Patients

Patients with histologic confirmation of disseminated malignant melanoma or renal solitary abode; squalid carcinoma who had not received antitumor therapy for at least three weeks were eligible for the investigation after giving an informed concord Participants were also required to have a performance status of 60 percent or more forward the Karnofsky scale, a life expectancy of at least three month and preserv cardiopulmonary, hepatic, renal, and hematologic function. Patients with lipoprotein disorders, known diffuse lymphangitic pulmonary metastasis, or CN metastasis were exclud from the consideration as were patients requiring treatment for active cardiac disease or receiving nonsteroidal anti-inflammatory medicines or anticoagulants. Twenty-seven patients (18 men and nine women) 34 to 78 years of age (mean, 56 [+ or -] 12 years), were chronicleed in the study. Thirteen of the make liables had melanoma, and 14 had renal carcinoma. Six of the enslaves were current cigarette smokers, 15 were ex-smoker and six were nonsmokers. Baseline pulmonary function is shown in Table 1 for all 27 patients studied.

Treatment

The rTNF was administered IM one time per day for eight weeks, starting at 25[unkeyable]g/[m.sup.2]/day and escalated to 50[unkeyable]g/[m.sup.2[/day forward day 8 and to 75[unkeyable]/[m.sup.2]/day upon day 15. Daily administration of rTNF was continued in the absence of any of the following manifestations of toxicity: significant leukopenia; thrombocytopenia; coagulopathy; hyperbilirubinemia; evulated hepatic enzymes; renal insufficiency; emesis; diarrhea; weight loss; neurologic symptoms; heat (temperature of 103 [degrees] F [394 [degrees] C or more); hypotension; or plain local reaction at the site of injection. Patients were monitored daily; all symptoms and signs were recorded. Patients received cumulative doses of rTNF ranging from 725[unkeyable]g/[m.sup.2] to 3,675[unkeyable]g/[m.sup.2] (mean, 2,234[unkeyable]g/[m.sup.2] [+ or -] 904[unkeyable]g/[m.sup.2] [+ or -] SD]) athwart the eight-week course of treatment. Sixteen of the 27 patients, complet the eight-week course of treatment. In 11 of the 27 patients, therapy with rTNF was discontinued early fit to the development of either dose-limiting rTNF-induced systemic toxicity or objective clinical progression of the primary tumor; however, all 27 enthralls had received rTNF therapy for at least 15 days.