1. ¹Department of Oncology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark
2. ²Department of Medical Oncology, Christie Hospital, Manchester, UK
3. ³Department of Radiology, Aarhus University Hospital, Aarhus, Denmark
4. ⁴Department of Radiology, Christie Hospital, Manchester, UK

Correspondence: Dr F Donskov, E-mail: fd@microbiology.au.dk

⁵Current address: Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, UK

Received 15 June 2005; Revised 25 July 2005; Accepted 2 August 2005; Published online 30 August 2005.

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.