Home therapy with recombinant interleukin-2 and interferon-$alpha;2b in advanced human malignancies

The purpose of this study was to evaluate in a randomized phase II trial the efficacy and toxicity of combination biochemotherapy compared with chemotherapy alone in patients with metastatic melanoma. Sixty-five patients with metastatic melanoma (ECOG performance status 0 or 1) were randomized to receive intravenous BCNU 100 mg m(-2) (day 1, alternate courses), cisplatin 25 mg m(-2) (days 1-3), DTIC 220 mg m(-2) (days 1-3) and oral tamoxifen 40 mg (BCDT regimen) with (n = 35) or without (n = 30) subcutaneous interleukin 2 (IL-2) 18 x 10(6) iu t.d.s. (day - 2), 9 x 10(6) iu b.d. (day - 1 and 0) and interferon 2 alpha (IFN-alpha) 9 MU (days 1-3). Evidence for immune activation was determined by flow cytometric analysis of peripheral blood lymphocytes. Treatment was repeated every 4 weeks up to six courses depending on response. The overall response rate of BCDT with IL-2/IFN-alpha was 23% [95% confidence interval (CI) 10-40%] with one complete response (CR) and seven partial responses (PR), and for BCDT alone 27% (95% CI 12-46%) with eight PRs; the median durations of response were 2.8 months and 2.5 months respectively. Sites of response were similar in both groups. There was no difference between the two groups in progression-free survival or overall survival (median survival 5 months for BCDT with IL-2/IFNalpha and 5.5 months for BCDT alone). Although 3 days of subcutaneous IL-2 resulted in significant lymphopenia, evidence of immune activation was indicated by a significant rise in the percentage of CD56- (NK cells) and CD3/HLA-DR-positive (activated T cells) subsets, without any change in the percentage of CD4 or CD4 T-cell subsets. Toxicity assessment revealed a significantly higher incidence of severe thrombocytopenia in patients treated with combination chemotherapy than with chemotherapy alone (37% vs 13%, P = 0.03) and a higher incidence of grade 3/4 flu-like symptoms (20% vs 10%) and fatigue (26% vs 13%). The addition of subcutaneous IL-2 and IFNalpha to BCDT chemotherapy in a randomized phase II trial resulted in immune activation but did not improve response rates in patients with metastatic melanoma, and indeed may increase some treatment-related toxicity.

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confidence: 78%

Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-α) and interleukin (IL-2) in patients with metastatic melanoma

Johnston

Constenla²,

Moore³

et al. 1998

“…While renal-cell carcinoma responds poorly to single-agent chemotherapy or hormonal therapy, immunotherapies with subcutaneous (s.c.) recombinant interleukin-2 (IL-2) alone or in combination with s.c. recombinant interferon-a (INF-a) yielded significant therapeutic efficacy in renal-cell carcinoma (Atzpodien et al, 1990(Atzpodien et al, , 2001(Atzpodien et al, , 2002Sleijfer et al, 1992).…”

mentioning

confidence: 99%

Metastatic renal carcinoma comprehensive prognostic system

Atzpodien

Royston

Wandert³

et al. 2003

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226

145

The purpose of the study was to identify a comprehensive prognostic system of pretreatment clinical parameters in 425 patients (pts) with metastatic renal-cell carcinoma treated with different subcutaneous (s.c.) recombinant cytokine-based home therapies in consecutive trials. Treatment consisted of (A) s.c. interferon-a2a (INF-a), s.c. interleukin-2 (IL-2) (n ¼ 102 pts), (B) s.c. IFN-a2a, s.c. IL-2, and i.v. 5-fluorouracil (5-FU) (n ¼ 235 pts) or (C) s.c. IFN-a2a, s.c. IL-2, and i.v. 5-FU combined with p.o. 13-cis-retinoic acid (13cRA) (n ¼ 88 pts). Kaplan -Meier survival analysis, log-rank statistics, and Cox regression analysis were employed to identify risk factors and to create a multiple risk factor model. The following pretreatment risk factors were identified by univariate analysis: (1) three and more metastatic sites, (2) presence of liver, lymph node or bone metastases, (3) neutrophil count X6500 cells ml À1 , (4) serum lactate dehydrogenase level (LDH) X220 U l À1 , and (5) serum C-reactive protein level (CRP) X11 mg l À1 . Cox regression analysis with forward stepwise variable selection identified neutrophil count as the major prognostic factor (hazard ratio ¼ 1.9, Po0.001), while serum levels of LDH and CRP, time between diagnosis of tumour and onset of metastatic disease, number of metastatic sites, and bone metastases were significant but somewhat less important prognostic variables within the multiple risk factor model (hazard ratio p1.5). Patients were assigned to one of the three risk groups according to cumulative risk defined as the sum of simplified risk s.c.ores for six pretreatment variables. Low-, intermediate-, and high-risk patients achieved a median overall survival of 32+ months (95% CI 24, 43; 5-year survival of 27%), 18+ months (95% CI 15, 20; 5-year survival of 11%), and 8+ months (95% CI 6, 10; 5-year survival of 5%), respectively. These prognostic categories are helpful both in individual patient care and in the assessment of patients entering prospective clinical trials.

“…Immunotherapy with cytokines, notably subcutaneous recombinant interleukin-2 (s.c. IL-2) alone or in combination with subcutaneous recombinant interferon-a2a (s.c. IFN-a2a) at doses far below the maximum tolerated dose, yields significant therapeutic efficacy in RCC patients (Atzpodien et al, 1990;Sleijfer et al, 1992). Although subcutaneous application of IL-2 and IFN-a is associated with reduced treatment-related toxicity compared to intravenous application, worsening of quality of life in patients receiving systemic combination immunochemotherapy are described by several authors (Atzpodien et al, 1995;Joffe et al, 1996).…”

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confidence: 99%

Rapid deterioration in quality of life during interleukin-2- and α-interferon-based home therapy of renal cell carcinoma is associated with a good outcome

Atzpodien

Küchler

Wandert³

et al. 2003

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We conducted a prospective quality-of-life analysis during outpatient immunotherapy in 22 patients with progressive metastatic renal cell carcinoma (RCC) treated with subcutaneous interferon-a2a and subcutaneous interleukin-2. Patients' quality of life was assessed by the European Organization for Research and Treatment of Cancer quality-of-life questionnaire QLQ-C30 before (week 0) and once during immunotherapy (week 3). Advanced renal cancer patients completed a total of 30 questionnaires before therapy (week 0) and after 3 weeks of therapy. Their mean quality of life (global-quality-of-health status) deteriorated significantly, from 64 to 41 (Pp0.001) during the first 3 weeks after treatment initiation, due to a mean reduction in physical (from 82 to 65; Pp0.001), emotional (from 77 to 61; Pp0.01), social (from 78 to 55; Pp0.01), and role functioning (from 82 to 58; Pp0.01). In contrast, cognitive functioning did not differ significantly from pretreatment scores after 3 weeks of therapy. In addition, during the first 3 weeks, appetite loss (from 18 to 59; Pp0.01), fatigue (from 33 to 56; Pp0.01), nausea/vomiting (from 10 to 26; Pp0.01), sleep disturbance (from 27 to 47; Pp0.01), diarrhoea (from five to 27; Pp0.01), and pain (from 20 to 32; Pp0.05) were significantly increased, while quality-of-life symptoms such as dyspnoea, and constipation were not significantly influenced by therapy. Complete response to RCC outpatient immunotherapy was associated with the most predominant reduction in functional quality of life when compared against patients in progressive or stable disease or partial tumour response. In conclusion, quality-of-life analysis during outpatient immunotherapy yielded modest changes in patients' health status 3 weeks after therapy initiation. Since the rapid decline in functional quality-of-life was associated with therapeutic efficacy, it is suggested that quality-of-life analysis might serve as an early indicator for immunotherapy response in metastatic RCC.