Decreased tolerance to interleukin-2 with repeated courses of therapy in patients with metastatic melanoma or renal cell cancer

High-dose interleukin-2 (IL-2) therapy has a response rate of approximately 20% in patients with metastatic melanoma and renal cell cancer. Animal mod els have shown that the anti-rumor effects of IL-2 are dose and schedule de pendent, and one report has shown that patients with melanoma who responded to IL-2 therapy received more doses of IL-2 than did those who did not res pond. The current study evaluated patients' tolerance to IL-2 over multiple courses of therapy and the factors that affected the number of doses deliv ered. Patients with metastatic melanoma or renal cell cancer who received a t least two consecutive courses of high-dose intravenous IL-2 alone from Oc tober 1, 1985 through December 31, 1996 were evaluated. Patients served as their own controls in paired analyses. The number of doses tolerated from o ne course to the next and the reasons for stopping therapy were analyzed. O ne hundred fifty-nine patients received two or more courses of therapy duri ng the study. The median number of doses of high-dose IL-2 decreased from c ourse 1 (15 doses) to course 2 (12 doses) (p2 = 0.0001). Pretreatment facto rs were not found to significantly influence the decrease in the number of doses delivered. Only 2 of 33 separate toxic effects resulting in discontin uation of IL-2 dosing were found to be significantly different between cour ses. After adjusting for multiple tests of statistical significance, serum aspartate aminotransferase elevations were more likely to stop course 1 (p2 = 0.0033) and creatinine elevations were more Likely to stop course 2 (p2 = 0.00007). The influence of renal toxicity was further assessed by compari ng the median creatinine value at the time IL-2 dosing was discontinued. Th is difference was found to be significant when cycle 1 of course 1 (1.5 mg/ dL) was compared with cycle 1 of course 2 (1.8 mg/dL; p2 = 0.0001). When pr etreatment factors were analyzed, male sex (p2 = 0.006), a diagnosis of ren al cell cancer (p2 = 0.008), previous nephrectomy (p2 = 0.001), and older a ge (p2 = 0.0055) were significantly associated with the development of rena l toxicity that resulted in discontinuation of IL-2 therapy. Furthermore, t he same four patient subsets had higher baseline creatinine values in indiv idual univariate analyses. This study identified subsets of patients who to lerated less IL-2 with repeated courses. The decreasing tolerance to IL-2 w as associated primarily with elevations in creatinine. Finding ways to amel iorate the renal toxicity seen during IL-2 therapy in this patient populati on may allow an increase in the number of IL-2 doses administered and poten tially an increase in clinical response.