Outpatient treatment with subcutaneous histamine dihydrochloride in combination with interleukin-2 and interferon-α in patients with metastatic renal cell carcinoma:: results of an open single-armed multicentre phase II study

Objectives: Histamine inhibits formation and release of monocyte/macrophage-derived reactive oxygen metabolites and thereby protects natural killer (NK) and T cells against oxidative inhibition. Efficacy and safety of histamine, when given in combination with interleukin-2 (IL-2) and interferon-alpha (IFN-alpha), were evaluated in patients with metastatic renal cell carcinoma (mRCC). Patients and methods: Forty-eight mRCC patients were included. The self-administered, outpatient regimen included IFN-alpha, 3 MIU s.c., once daily for 1 week, followed by up to nine 4 week cycles of IFN-alpha, 3 MIU s.c., days 1-7, weeks 1-4; interleukin-2, 2.4 MIU/m(2) s.c., b.i.d., days 1-5 weeks 1 and 2, and histamine dihydrochloride, 1 mg s.c.. b.i.d. days 1-5, weeks 1-4. Results: Forty-six patients were eligible. Forty-two patients were evaluable for response with four partial responses (9% of eligible patients, 10% of evaluable patients), Fifteen patients (36%) had stable disease. After subsequent surgery of residual tumours. three patients (7%) had no evidence of disease at 14+, 21+ and 21+ months. Median survival time for all patients was 16.3 months. One grade 4 toxicity (thrombocytopenia) was observed. Most frequent grade 3 toxicities were fatigue/malaise (26%). dyspnoe (11%), nausea (9%) and stomatitis (9%). Four patients discontinued due to treatment-related toxicity. There were no treatment-related deaths. Conclusions: The present combination of histamine with IL-2 and IFN-alpha as self-administered outpatient therapy is a safe and well-tolerated regimen. However, histamine does not appear to add efficacy with respect to response in this low-dose schedule of IL-2 and IFN-alpha. Whether histamine might improve efficacy with higher doses of IL-2 and IFN-alpha requires further investigation.