Interleukin-2 in combination with interferon-α and 5-fluorouracil for metastatic renal cell cancer

In patients with metastatic renal cell carcinoma response rates of 7–26% have been achieved with immunotherapy. A high response rate of 48% in 35 patients has been reported for treatment with the combination of interferon-α (IFN-α), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) (Atzpodien et al (1993 a ) Eur J Cancer 29A : S6–8). We conducted a multicentre phase II study to confirm these results. Metastatic renal cell carcinoma patients were treated as outpatients with an 8-week treatment cycle. Recombinant human IL-2 20 MU m −2 was administered subcutaneously (s.c.) three times a week (t.i.w) in weeks 1 and 4 and 5 MU m −2 t.i.w. in weeks 2 and 3. Recombinant human IFN-α 2a 6 MU m −2 was administered s.c. once in weeks 1 and 4 and t.i.w. in weeks 2 and 3, and 9 MU m −2 t.i.w. in weeks 5–8. 5-FU (750 mg m −2 ) was given as a bolus injection intravenous once a week in weeks 5–8. The treatment cycle was repeated once in case of response or minor response. Fifty-two patients entered the study. All had undergone a nephrectomy and had progressive metastatic disease. The median WHO-performance status was 1, the median number of metastatic sites was 2 (range 1–5) and the median time between the diagnosis of the primary tumour and the start of treatment was 12.9 months (range 1–153). Among the 51 patients, including four patients with early progressive disease, who were evaluable for response, the response rate was 11.8% (95% confidence interval (CI) 2.9–20.7%), with no complete responses. Median duration of response was 8.3 (range 3.8–22.4+) months. Median survival was 16.5 (range 1.8–30.5+) months. Grade 3/4 toxicity (WHO) occurred in 29/52 (55.8%) of the patients in cycle 1 and in 6/16 (37.5%) of the patients in cycle 2. It consisted mainly of anorexia, fatigue, nausea, fever and leucocytopenia. We cannot confirm the high response rate in patients with metastatic renal cell carcinoma treated with the combination of IFN-α, IL-2 and 5-FU, as described by Atzpodien et al. © 2000 Cancer Research Campaign

Section: Discussionmentioning

confidence: 77%

Immunochemotherapy with interleukin-2, interferon- α and 5-fluorouracil for progressive metastatic renal cell carcinoma: a multicenter phase II study

Herpen¹,

Jansen

Kruit

et al. 2000

“…Patients were treated with a combination of IFN-a, IL-2 and 5-FU in an 8-week schedule as described previously (Atzpodien et al, 1993 concentration of IL-2 in the samples was calculated using parallelline analysis (Wadhwa et al, 1995). TNF-a was measured in citrated plasma samples by a cytotoxicity assay using the murine WEHI 164 clone 13/2F2 (Meager et al, 1989).…”

Section: Treatmentmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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confidence: 99%

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

Banks

Forbes²,

Hallam³

et al. 1997

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 ...

“…Those who were treated with IL-2 alone survived for a median of The increased toxicity of this cytokine combination suggests either that further evaluation of the IL-2/IFN-aL, combination should be confined to large prospective randomized trials or that the less toxic but more active 5-fluorouracil /IL-2/IFN-a,, combinations (Atzpodien et al, 1993) should be fiunher explored.…”

Section: Toxicity Of Treatmentmentioning

confidence: 99%

A randomized phase II trial of interleukin 2 and interleukin 2-interferon alpha in advanced renal cancer

Jayson

Middleton²,

Lee³

et al. 1998

Summary A randomized phase 11 trial was performed to compare the efficacy and toxicity of interleukin 2 (IL-2) with an IL-2 and interferon alpha (IFN-a) regimen for the treatment of metastatic renal carcinoma. Sixty patients with recurrent renal cell carcinoma (RCC) who had previously undergone a nephrectomy were randomized to receive three cycles of IL-2 or IL-2 with IFN-a,. Eighteen al. 1996).Experimental data suggested that a combination of IL-2 and IFN-a might offer superior efficacy. Interferon enhances the cell membrane expression of major histocompatibility complex (MHC) antigens to %%-hich IL-2-activated T cells can respond (Guadagni et al. 1989). A sxnergistic response was confirmed in mice (Cameron et al. 1988) and this led to the development of combination regimens that were associated wvith an ox erall response rate of up to 29%7 (Atzpodien et al. 1990. 1991: Palmer et al. 1993: Canobbio et al. 1996b: Gause et al. 1996 Savage et al. 1996) wxith a median survival of 8-12 months (Facendola et al. 1995: Canobbio et al. 1996a Correspondence to: GC Jayson hN-potension and creatinine elexvation (Atkins et al. 1993: Gause et al. 1996. factors that led to the premature discontinuation of therapy in 14% of patients (Facendola et al. 1995).We haxe performed a phase I trial to determine the maximum