The Impact of Interleukin-2 on Survival in Renal Cancer: A Multivariate Analysis

Abstract

The purpose of this analysis was to compare the survival of patients with advanced renal carcinoma treated with intravenous recombinant interleukin-2 to the survival of matched patients taken from the large and well characterised database of the Eastern Cooperative Oncology Group (ECOG). Recombinant interleukin-2 (rIL-2) given by continuous intravenous infusion was used to treat 387 patients with advanced adenocarcinoma of the kidney in five multi-centre studies and 327 of these patients fulfilled the study eligibility criteria and were evaluable for response, toxicity and survival. The survival of patients treated with rIL-2 was compared in a multi-variate survival analysis taking account of all identified prognostic factors to 390 control patients receiving chemotherapy derived from the database. Thirteen patients treated with rIL-2 achieved a complete remission of their disease and 32 a partial remission giving an overall response rate of 14%. Remissions were durable with a median duration of 357 days for partial remissions and a median duration in excess of 926 days for complete remissions. Most patients experienced fever or mild to moderate hypotension and other toxicities are described. However, only 11 patients required admission to intensive care and in only five cases was this judged to be due to treatment toxicity. There were three deaths judged to be probably due to treatment toxicity. rIL-2 treatment was associated with significantly prolonged survival compared to the ECOG control patients. Patients with good prognostic features appeared to have a greater survival benefit from rIL-2 than those with poor prognostic features. This analysis provides the first evidence that rIL-2 prolongs survival in patients with advanced renal cancer but cannot provide proof which should be sought in randomised prospective trials drawing on the hypotheses generated herein.

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

“…First, patient selection based on known and unknown factors can be an important cause. Half of our patients belonged to the good prognostic subgroup according to the criteria of Jones et al (1993). Five of the six responders belonged to that group and the other to the intermediate prognostic subgroup.…”

“…Nine patients received radiotherapy and three patients underwent a metastasectomy in the period prior to entry of the study. When the patients were separated in prognostic subgroups according to the model of Jones, approximately half of the patients belonged to the good prognostic group (Jones et al, 1993).…”

Establishment of combined immuno-chemotherapy with systemically administered gemcitabine and intra-portal administration of interleukin-2 in murine models of liver metastases of pancreatic cancer

“…One report showed liver metastasis of sarcoma to be suppressed by AIT (32) (12 and 21) and partial response in 37 (15 and 22). However, some reports have noted a high incidence of influenza-like symptoms with systemic administration, including pyrexia, chills, arthralgia, and nausea, and some cases had severe side-effects, i.e., capillary leak syndrome induced by intravascular hyperpermeability of IL-2 can result in remarkable systemic edema (due to retention of humoral fluid in the third space), pulmonary edema, hypotension, oliguria, and disturbance of consciousness, and may have a fatal course due to rapidly worsening circulatory insufficiency or respiratory failure (14)(15)(16)(17). Furthermore, it is difficult for an adequate local concentration of systemically administered IL-2 to be maintained, which limits the anti-tumor effect.…”

“…When IL-2 is administered systemically, its concentrations at local tumor sites possibly remain suboptimal, thereby limiting the antitumor effect. Furthermore, systemic administration leads to side-effects, i.e., influenza-like symptoms and capillary leak syndrome (14)(15)(16)(17). Thus, local administration of a cytokine is considered an efficient means of attaining adequate cytokine concentrations at local tumor sites and of minimizing toxic side-effects.…”

Safety and efficacy of subcutaneous and continuous intravenous infusion rIL-2 in patients with metastatic renal cell carcinoma

“…The response rate to chemotherapy is low and responses are of short duration (Heinzer et al, 2001). Immunotherapeutic agents are more successful, and studies with recombinant human interleukin-2 (rIL-2), the first cytokine registered for this indication, have demonstrated survival benefits over chemotherapy for the majority of patients with mRCC (Jones et al, 1993;Bordin et al, 2000;Fisher et al, 2000;Atzpodien et al, 2002;Lissoni et al, 2002;Pantuck et al, 2002).…”