Treatment of metastatic renal cell carcinoma with subcutaneous interleukin 2: evidence for non-renal clearance of cytokines

Abstract

Summary The circulating cytokine concentrations following administration of subcutaneous recombinant interleukin 2 (IL-2) in combination with interferon a and 5-fluorouracil used to treat advanced renal cancer were studied. One patient was anephric and on dialysis, and seven had normal biochemical renal function, although five had undergone single nephrectomy. The pharmacokinetics of IL-2 and changes in IL-6 and tumour necrosis factor (TNF)-a were essentially similar in all patients including the anephric patient, irrespective of the periods of dialysis, although at some time points, IL-2 concentrations were slightly higher in the anephric patient than in the others. These results show that for subcutaneous administration of low-dose IL-2, renal clearance of IL-2 is not important. This contrasts with high-dose, intravenous IL-2 where blood concentrations are higher and renal clearance seems to occur, perhaps because of saturation of the non-renal mechanisms of clearance. The subcutaneous route is certainly preferred if IL-2 is used in anephric patients and in those with impaired renal function, and it may be generally preferred for most purposes.Keywords: interleukin 2; renal; anephric; cytokine; clearance; therapy The use of interleukin 2 (IL-2) as a biological anti-cancer therapy is based on its ability to activate and enhance the cytotoxic activity of T lymphocytes and to stimulate natural killer cell-and lymphokine-activated killer cell activity. These actions are probably mediated both directly and via secondary induction of a cascade of cytokines including tumour necrosis factor (TNF)-a and IL-6 (Whittington and Faulds 1993; Janssen et al, 1994). Multiple regimens with IL-2 have been developed, but progress has been hampered by the marked toxicity associated with many of the higher dose intravenous (i.v.) regimens employed, most notably a capillary leak syndrome (similar to that seen in patients with septic shock) manifest by hypotension, weight gain, acute renal failure and pulmonary oedema (Whittington and Faulds, 1993). Newer approaches using lower dose subcutaneous (s.c.) IL-2 have been promising with, for example, recent combination regimens producing objective responses with less accompanying toxicity in 30-40% of patients with metastatic renal cell carcinoma (Atzpodien et al, 1990;Atzpodien-et al, 1993;Joffe et al, 1996).An understanding of cytokine metabolism is important for ensuring a rational approach to the design of therapeutic strategies, particularly with regard to route of administration and dosage. The mechanism of clearance is an important consideration as IL-2, for example, may be administered to patients who have undergone a nephrectomy, occasionally bilateral nephrectomies, and IL-2 itself may cause renal dysfunction. The Correspondence to: RE Banks following i.v. administration is generally thought to be consistent with a two-compartment model with first-order elimination kinetics. In rodents, an initial rapid clearance with a half-life (t,2) of approximately 1-5 min is followed by ...

Inflammatory Cytokines as Uremic Toxins: “Ni Son Todos Los Que Estan, Ni Estan Todos Los Que Son”

“…For IL-6, up to 80% may be cleared by the rat liver [ 132 ]. In humans on dialysis, the pharmacokinetics of low dose IL-2 and changes in IL-6 and TNF-α were essentially similar in all patients studied, including one anephric patient, irrespective of the periods of dialysis [ 133 ]. However, higher doses of IL-2 may have renal clearance and this was attributed to saturation of physiological clearance mechanisms.…”

Pharmacokinetic Study of Interleukin‐2 Following Intravenous Injection in Hemodialysis Patients With Renal Cell Carcinoma

“…Banks et al. (7), who also administered subcutaneous injections of IL‐2 at low doses to anephric hemodialysis patients, suggested the possibility of non‐renal clearance of IL‐2 and reported that IL‐2 could be used safely in these patients. In the present study, we measured serum concentrations of IL‐2 and calculated pharmacokinetic parameters of IL‐2 to determine whether intravenous injection of low‐dose IL‐2 is possible and safe in hemodialysis patients.…”

“…Particularly in patients with impairment of renal function, IL‐2 may cause serious adverse reactions. Although there have been some reports on its pharmacokinetics after subcutaneous injection (6,7), few reports have been published concerning the pharmacokinetics of IL‐2 administered intravenously to hemodialysis patients. We therefore determined the changes in blood concentration of IL‐2 following intravenous injection in hemodialysis patients and compared the results obtained with those in non‐hemodialysis patients to assess the safety of intravenous IL‐2 injection in patients undergoing hemodialysis.…”