Topotecan in the treatment of refractory neuroblastoma and other malignant tumors in childhood - a phase-II-study

Abstract

Background: The topoisomerase-I-inhibitor Topotecan (TPT) has shown a broad activity in the therapy of adult malignant diseases. In pediatric oncology TPT has been rarely used. Methods: From 1/98 to 8/99 we conducted a multicenter phase-II-study of TPT (1.5 mg/m²/d in 30 min i. v. for 5 days every 21 days) in pediatric patients (pts) with malignant tumors refractory to conventional therapy (either second line or any relapse). Patients: A total of 20 pts received 81 cycles. The 7 female and 13 male pts had a median age of 10.2 years at the beginning of the TPT therapy. Results: The median number of administered TPT cycles was 4 with an interval of 23.5 days. The median administered TPT dose was 1.48 mg/m²/d . No complete responses, but 2 partial responses and 9 stable diseases were observed. In 9 pts the disease progressed. The mean duration until progression for SD was 130 and not different from PR with 131 days. The median cumulative TPT dose until progression in responders was 30 mg/m². For all study-pts the median overall survival time was 235 days with 1 pt. still alive. The main toxicity was hematological with anemia grade III/IV (10/42 % of all evaluable TPT cycles), neutropenia grade III/IV (49/18 %) and thrombopenia grade III/IV (35/36 %). Non-hematologic toxicity was mild with the exception of 4 cycles with infection grade III and 1 grade IV. No patient died of therapy-related complications. Conclusions: TPT as monotherapy has shown an antitumor activity in pediatric pts with various malignancies. Toxicity was mainly hematological and manageable. Further evaluation of TPT treatment is planned using combinations with other cytostatic drugs.

Zusammenfassung

Hintergrund: Der Topoisomerase-I-Hemmer Topotecan (TPT) zeigte in der Therapie von malignen Tumoren im Erwachsenenalter eine breite klinische Wirksamkeit. In der pädiatrischen Onkologie gab es hierzu bislang wenig Erfahrung. Methode: Von 1/98 bis 8/99 führten wir eine multizentrische Phase-II-Studie mit TPT (1,5 mg/m²/d 30 min i. v. an 5 Tagen; alle 21 Tage) bei pädiatrischen Patienten mit therapierefraktären oder rezidivierten malignen Tumoren durch. Patienten: 20 Patienten erhielten insgesamt 81 Therapiezyklen. Die 7 weiblichen und 13 männlichen Patienten hatten ein medianes Alter von 10,2 Jahren bei Therapiebeginn. Ergebnisse: Die mediane Anzahl der TPT-Zyklen war 4 in einem medianen Intervall von 23,5 Tagen. Die applizierte mediane TPT-Dosis war 1,48 mg/m²/d. Keine komplette Remission, jedoch 2 partielle Remissionen und 9 stabile Erkrankungen wurden beobachtet. Bei 9 Patienten war die Erkrankung primär progredient. Die mediane Dauer bis zur erneuten Progression war bei den Patienten mit stabiler Erkrankung (130 Tage) die gleiche wie bei Patienten mit partieller Remission (131 Tage). Die kumulative TPT-Dosis bis zur Progression betrug 30 mg/m². Die mediane Überlebenszeit für alle Patienten betrug 235 Tage, wobei ein Patient noch lebt. Die wesentliche Toxizität war hämatologisch: Anämie III/IV ° (10/42 % aller auswertbarer Zyklen), Neutropenie III/IV ° (49/18 %), Thrombopenie III/IV ° (35/36 %). Die nicht-hämatologische Toxizität war gering, bis auf Infektion III/IV in 4 bzw. 1 Zyklus. Kein Patient verstarb an therapie-assoziierten Komplikationen. Schlussfolgerung: TPT als Monotherapie zeigt eine antitumoröse Aktivität bei pädiatrisch-onkologischen Patienten. Die Toxizität war i.w. hämatologisch und beherrschbar. Weitere Studien z. B. in Kombinationstherapien sind erforderlich.

Key words

Topotecan - Neuroblastoma - Childhood tumors - Phase II study

Schlüsselwörter

Topotecan - Neuroblastom - kindliche Tumoren - Phase-II-Studie

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