title: Decreased tolerance to interleukin-2 with repeated courses of therapy in patients with metastatic melanoma or renal cell cancer.
abstract: High-dose interleukin-2 (IL-2) therapy has a response rate of approximately 20% in patients with metastatic melanoma and renal cell cancer. Animal models have shown that the anti-tumor effects of IL-2 are dose and schedule dependent, 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 respond. The current study evaluated patients' tolerance to IL-2 over multiple courses of therapy and the factors that affected the number of doses delivered. Patients with metastatic melanoma or renal cell cancer who received at least two consecutive courses of high-dose intravenous IL-2 alone from October 1, 1985 through December 31, 1996 were evaluated. Patients served as their own controls in paired analyses. The number of doses tolerated from one course to the next and the reasons for stopping therapy were analyzed. One hundred fifty-nine patients received two or more courses of therapy during the study. The median number of doses of high-dose IL-2 decreased from course 1 (15 doses) to course 2 (12 doses) (p2 = 0.0001). Pretreatment factors were not found to significantly influence the decrease in the number of doses delivered. Only 2 of 33 separate toxic effects resulting in discontinuation of IL-2 dosing were found to be significantly different between courses. 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 comparing the median creatinine value at the time IL-2 dosing was discontinued. This 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 pretreatment factors were analyzed, male sex (p2 = 0.006), a diagnosis of renal cell cancer (p2 = 0.008), previous nephrectomy (p2 = 0.001), and older age (p2 = 0.0055) were significantly associated with the development of renal toxicity that resulted in discontinuation of IL-2 therapy. Furthermore, the same four patient subsets had higher baseline creatinine values in individual univariate analyses. This study identified subsets of patients who tolerated less IL-2 with repeated courses. The decreasing tolerance to IL-2 was associated primarily with elevations in creatinine. Finding ways to ameliorate the renal toxicity seen during IL-2 therapy in this patient population may allow an increase in the number of IL-2 doses administered and potentially an increase in clinical response.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1502, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Marroquin
authors.forename: D E
authors.initials: DE
authors.lastname: White
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: S A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: D J
authors.initials: DJ
authors.lastname: Schwartzentruber
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001219:Aspartate Aminotransferases / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000473:pathology* / Q000628:therapy*; D003404:Creatinine / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects*; D007680:Kidney Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008297:Male; D008545:Melanoma / Q000097:blood / Q000473:pathology* / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009392:Nephrectomy; D051437:Renal Insufficiency / Q000139:chemically induced; D012189:Retrospective Studies; D012737:Sex Factors
chemical_list: D007376:Interleukin-2; D003404:Creatinine; D001219:Aspartate Aminotransferases