title: Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma.
abstract: Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The self-administered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P = 0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P = 0.07), time to PD (4.5 vs 2.2 months, P = 0.13) and clinical benefit (CR + PR + SD) (58 vs 37%, P = 0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC.
authors.affiliation: Department of Oncology, Aarhus University Hospital, Denmark. fd@microbiology.au.dk
authors.forename: F
authors.initials: F
authors.lastname: Donskov
authors.forename: M
authors.initials: M
authors.lastname: Middleton
authors.forename: K
authors.initials: K
authors.lastname: Fode
authors.forename: P
authors.initials: P
authors.lastname: Meldgaard
authors.forename: W
authors.initials: W
authors.lastname: Mansoor
authors.forename: J
authors.initials: J
authors.lastname: Lawrance
authors.forename: N
authors.initials: N
authors.lastname: Thatcher
authors.forename: H
authors.initials: H
authors.lastname: Nellemann
authors.forename: H
authors.initials: H
authors.lastname: von der Maase
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006632:Histamine / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D016019:Survival Analysis
chemical_list: D007376:Interleukin-2; D006632:Histamine