1 Division of Pediatric Haematology/Oncology, Department of Pediatrics 2 Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
* Correspondence to: Dr W. Schwinger, Division of Pediatric Haematology/Oncology, Department of Pediatrics, Medical University of Graz, Auenbruggerplatz 30, A-8036 Graz, Austria. Tel: +43-316-385-83329; Fax: +43-316-385-3450; wolfgang.schwinger{at}meduni-graz.at
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Abstract |
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Methods:: We prospectively studied treatment-related toxicities, quality of life and laboratory parameters in 10 children with progressive or metastatic solid tumors (metastatic osteosarcoma, n=4; neuroblastoma stage IV, n=3; metastatic Ewing's sarcoma, n=2; metastatic Wilms' tumor, n=1) during IL-2 therapy. Patients were scheduled to receive five cycles of high-dose IL-2 by continuous infusion for 5 days every 3 weeks.
Results:: All patients developed fever >39°C and influenza-like symptoms, with a significant decrease in Karnofsky score. In two patients treatment had to be stopped after three cycles because of severe side-effects. During IL-2 therapy a statistical significant increase in white blood cells (WBC), creatinine, -glutamyltransferase, C-reactive protein, glucose and body weight was observed. In contrast, red blood cells, platelets, protein, albumin and cholinesterase significantly decreased. When results from day 1 of the first and of the fifth cycle were compared, an increase of WBC and a decrease of alkaline phosphatase was shown. No constant quantitative changes in total lymphocytes and subsets were observed during IL-2 therapy.
Conclusions:: IL-2 treatment in children with refractory and relapsed solid malignancies is associated with severe, but reversible, side-effects. However, five of the 10 patients with diseases of worst prognosis could be rescued by this treatment.
Key words: cancer, children, interleukin-2, side-effects, toxicity
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Introduction |
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IL-2 therapy is associated with a number of serious side-effects limiting its clinical use and potential benefit [15]. Capillary leak syndrome [16
19
], and cardiopulmonary [20
], hepatic [21
] or renal [22
] dysfunction are the most frequently reported side-effects. Life-threatening toxicities include cardiac arrhythmias, episodes of ventricular tachycardia and transient cardiac ischemia [23
]. Most of these toxicities are rapidly reversible after stopping IL-2 therapy.
The present study was designed to evaluate the feasibility of high-dose IL-2 therapy in children with advanced solid malignancies. The primary objective was to characterize clinical effects and side-effects. Secondary objectives included the measurement of several different laboratory parameters and assessment of an inflammatory profile during IL-2 therapy.
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Patients and methods |
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During IL-2 infusion patients were monitored by daily clinical examination including measurement of blood pressure, heart and respiratory rates, body temperature, fluid intake and excretion. Measurement of body weight was done twice daily. Oral fluid intake was restricted to 1500 ml/m2/day. Deficits were corrected by intravenous infusion of normal saline supplemented with 5% human serum albumin. Paracetamol (10 mg/kg body weight per dose) was given as antipyretic medication three to four times daily. Treatment-related side-effects were graduated according to WHO criteria.
Laboratory investigations
Peripheral blood samples for complete blood counts, renal and hepatic function tests, alkaline phosphatase (AP), lactate dehydrogenase, C-reactive protein (CRP), glucose, protein and albumin were taken from all patients prior to the start of IL-2 infusion and once daily until 2 days after completion of IL-2 treatment.
Flow cytometry (fluorescence-activated cell sorting)
During each cycle of IL-2 therapy lymphocyte subsets were measured by immunofluorescence an average of five times per cycle. Peripheral blood samples were lysed and stained with phycoerythrin (PE) and fluoresceinisothiocyanate conjugated markers for CD3/4/8/25/45RA/45RO/56 (Becton Dickinson, San Jose, CA, USA) after incubation with mouse IgG to block non-specific binding to the Fc-receptors according to the manufacturer's recommendations. PE-conjugated mouse isotype controls were used for assessment of non-specific binding. Absolute numbers of cells were calculated using CellQuest software (Becton Dickinson).
Cytokine investigations
During IL-2 therapy, serum concentrations of soluble IL-2, IL-2 receptor alpha-chain (CD25, TAC), tumor necrosis factor (TNF)-, TNF-ß, TNF receptor and IL-7 levels were determined using commercially available ELISA kits.
Statistics
Data were entered into a computerized database and analyzed. They are displayed as median, with minimum and maximum in parentheses. To determine the statistical significance of differences between two repeated measures the Wilcoxon signed-rank test was used. For the comparison of more than two measures we conducted a two-way analysis of ranks (Friedman test). All analyses were carried out using the statistical package SPSS for Windows, version 12.0. P <0.05 was considered significant.
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Results |
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Numbers of T lymphocytes (CD3+), T lymphocytes co-expressing IL-2 receptor (CD3+/CD25+), cytotoxic T lymphocytes (CD3+/CD56+) and natural killer (NK) cells (CD3/CD56+) declined during each course of IL-2 therapy, but reached normal values within 2 days after the end of treatment. Difference of absolute numbers of T cells and their subsets between day 1 and day 7 did not reach statistical significance. The ratio of CD4+/CD8+ T lymphocytes and the ratio of CD3+/45RA+/RO+ T lymphocytes remained unchanged during therapy (Figure 3).
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Discussion |
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Immunotherapy with IL-2 is considered a reasonable alternative treatment option for selected adult cancer patients with progressive or recurrent disease. Promising antitumor activity has been demonstrated against a variety of solid tumors in adult patients [10, 25
, 26
]. Response rates vary from 4% in non-small-lung cancer patients [9
] to 85% in patients with pancreatic head carcinoma [11
]. IL-2 therapy for pediatric cancer patients, however, is controversial. A number of serious side-effects seem to neutralize the potential benefit of IL-2. Life-threatening toxicities of IL-2 therapy in adult patients [22
, 27
] can also be expected in children. Negrier et al. [28
] reported therapy-related deaths in children when IL-2 was infused together with LAK cells. Adverse effects of IL-2 result from release of secondary cytokines by cells targeted by IL-2. No direct toxicity of IL-2 has been documented so far.
The aim of the present study was to evaluate the safety and toxicity as well as the efficacy during high-dose IL-2 treatment in children with advanced solid neoplasms. Toxicity during IL-2 therapy was severe in all patients and included gastrointestinal (nausea, vomiting, diarrhea), cardiac (tachycardia, hypotension) and constitutional (fatigue, anorexia) side-effects. In two patients IL-2 administration had to be discontinued owing to life-threatening capillary leak syndrome and acute renal failure, respectively. All symptoms, however, completely resolved within few days after completion of IL-2 therapy.
Although our data show substantial changes of laboratory parameters during each single cycle of IL-2 therapy, a difference over the whole period of treatment was observed only for WBC and AP levels. All other parameters normalized shortly after IL-2 administration.
The main effect of IL-2 is stimulation of T lymphocytes leading to an increase of the number of circulating activated T-lymphocyte subsets. Interestingly, in our study numbers of CD3+ T cells and T-cell subsets (CD3+/CD56+ cytotoxic T cells, CD3/CD56+ NK cells and CD3+/CD25+ T cells) declined during IL-2 administration, followed by a sharp increase starting 2 days after discontinuation of treatment (Figure 3). This rebound phenomenon was limited and values normalized prior to the next cycle. In addition, CD3+/45RA+/RO+ ratios were constantly low, indicating low numbers of circulating immature T cells and little thymic output. However, these findings might not reflect potential activity of primed T cells in tissues and residual tumor sites. Furthermore, the general ability to induce immunologic responses might have been reduced in these heavily pretreated cancer patients.
Considering the poor prognosis of our patients, the fact that five out of 10 patients are still in CR is promising. However, owing to the low number of patients in our study, these results must be interpreted with caution. Future studies are needed to answer the question of whether IL-2 can improve prognosis of children with advanced or metastatic solid tumors.
In conclusion, the results of this study demonstrated that high-dose IL-2 treatment in pediatric cancer patients is associated with clinically significant serious, but mostly reversible, side-effects. In selected pediatric cancer patients with refractory disease IL-2 might be able to induce long-term remissions, particularly when given after debulking tumor surgery.
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Acknowledgements |
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Received for publication February 1, 2005. Revision received February 23, 2005. Accepted for publication February 24, 2005.
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