A randomised dose escalation study of subcutaneous interleukin 2 with and without levamisole in patients with metastatic renal cell carcinoma or malignant melanoma.

We have examined the efficacy, toxicity and host immunological response of two different dose schedules of interleukin 2 (IL-2) given subcutaneously, daily for 3 months in patients with renal cell carcinoma (RCC) or metastatic melanoma (MM). We also examined the effect of adding the immune modulator levamisole to the two different schedules of IL-2. Thirty-nine patients were entered into two sequential phase I/II studies. Eighteen patients entered study 1 and were randomised to receive IL-2, 3 x 10(6) IU m-2 day-1, subcutaneously for 3 months with or without levamisole 50 mg t.d.s. p.o. on days 1-3 on alternate weeks. Twenty-one patients entered study 2 and were randomised to receive 5.4 x 10(6) IU m-2 day-1 subcutaneously for 3 months with or without levamisole 50 mg t.d.s. p.o. on days 1-3 on alternate weeks. Blood was taken for peripheral blood lymphocyte (PBL) phenotype analysis, and measurement of IL-2, soluble IL-2 receptor (sIL-2R) and neopterin concentration. Two patients with metastatic melanoma, one in each study, responded (11.8%); both received IL-2 alone. Observations of immunological parameters showed that treatment with subcutaneous IL-2 resulted in a significant rise in the percentage of PBLs bearing CD25, CD3/HLA-DR, CD56 and levels of IL-2 receptor and neopterin. The total white blood cell count (WBC) and total lymphocyte count rose significantly on day 18 compared with pretreatment levels. The addition of levamisole to either IL-2 schedule resulted in no significant changes in any immunological parameters. This study illustrates that prolonged subcutaneous IL-2 can be given safely in the outpatient setting. There was no evidence that levamisole acts as an immunomodulator in this study.

The use of cisplatin plus 5-fluorouracil chemotherapy in an unselected group of patients with recurrent squamous cell carcinoma of the head and neck.

Cisplatin and infusional 5-fluorouracil (5-FU) has become regarded as the standard chemotherapy for squamous cell carcinoma (SCC) of the head and neck. Results of phase II studies vary widely and do not always reflect the activity of regimen in general clinical practice. We have treated 20 consecutive patients with cisplatin 100 mg/m2 and 5-FU given as a 4-day infusion at 1 g/m2 for 24 h. In order to reflect more accurately the activity of this regimen in everyday practice we have followed as many patients as possible to relapse and death and measured the duration of remissions from the end of treatment. 6 patients responded (30%, 95% CI: 10-48%) with 1 patient achieving a complete remission. Partial remission lasted for 3-18 months and the complete remission lasted for 7 months. Median survival of patients from the date of first treatment was 7 months (range 1 week-20.5 months). The regimen was well tolerated but required hospitalisation. We conclude that this regimen is well tolerated, active and a good choice for treating recurrent SCC of the head and neck in an unselected population of patients with recurrent disease in the context of everyday oncological practice.

A phase II study of the sequential administration of dacarbazine and fotemustine in the treatment of cerebral metastases from malignant melanoma.

34 patients with cerebral metastases from malignant melanoma received sequential dacarbazine at 250 mg/m2 followed 2 h later by fotemustine at 100 mg/m2; this was repeated on day 8. Maintenance therapy was given every 4 weeks to patients with radiological evidence of response or stable disease until a maximum response was achieved plus two more cycles. A 12% response rate was obtained for cerebral metastases, with 2 complete responses lasting 12 and 36+ months, and 2 partial responses lasting 2.5 and 3.75 months. Toxicity was mainly haematological with grade 3-4 leucopenia and thrombocytopenia in 23.5% of patients. No pulmonary toxicity was seen. This schedule of sequential dacarbazine and fotemustine has low activity against metastatic melanoma, and the response rate for cerebral metastases is not superior to that shown in other studies with single agent fotemustine, but the treatment was well tolerated and can be delivered on an outpatient basis.

Immune changes in peripheral blood resulting from locally directed interleukin-2 therapy in squamous cell carcinoma of the head and neck.

Interleukin-2 (IL-2) was administered locally by constant intra-arterial infusion in four escalating doses from 3 x 10(4)-3 x 10(7) IU/day to 12 patients with squamous cell carcinoma of the head and neck (SCCHN) in a phase I trial. Lymphocyte phenotypic markers and serum cytokine concentrations were measured over the course of treatment. Serum IL-1-alpha, -beta and IL-6 were not induced at any dose level. Tumour necrosis factor (TNF)-alpha was induced in the 2 patients who showed a clinical response (at the lowest dose) as well as in 4/10 of the non-responders. In addition TNF-beta was induced in 3/10 and IFN-gamma in 5/10 non-responders. Soluble IL-2 receptor concentrations were increased at the two higher doses. The highest dose of IL-2 produced a lymphocytosis after day 5 until the end of administration reflected by a general rise in lymphocyte phenotypic markers. CD25, CD3/HLA-DR and CD56 showed an additional upregulation not accounted for by the lymphocytosis with a suggestion of a bell-shaped dose-response curve for CD25 and CD3/HLA-DR. Administration of IL-2 in this manner has been shown to be well tolerated and has some anti-tumour activity at low doses, with little toxicity.

A randomised phase II study of carmustine alone or in combination with tumour necrosis factor in patients with advanced melanoma.

Laboratory data suggest a synergistic interaction between carmustine (BCNU) and tumour necrosis factor (TNF) in melanoma. We therefore studied the activity of 200 mg/m2 BCNU given alone or in combination with 88 micrograms/m2 recombinant human TNF-alpha (rhTNF alpha) as a daily i.v. infusion for 5 days at 48-day intervals to patients with metastatic melanoma. In this randomised phase II trial, the rate of response to BCNU alone was 20% [95% confidence interval (CI), 2%-38%], and this was not improved by the addition of TNF (response rate, 10.5%; 95% CI, 1.3%-33%). Toxicity was higher in the combination arm, and there was no difference in survival.