Serial Intense Chemotherapy Combining Topotecan, Etoposide, Carboplatin and Cyclophosphamide (TECC) Followed by Autologous Hematopoietic Stem Cell Support in Patients with High Risk Soft Tissue Sarcoma (STS)

Abstract

In nine patients (pts) with soft tissue sarcoma refractory to conventional therapy (incomplete response or relapse) intensified chemotherapy was administered combining 0.75 mg/m² topotecan, 100 mg/m² etoposide, 100 mg/m² carboplatin and 200 mg/m² cyclophosphamide on day 1-5 (TECC). To avoid prolonged intervals between the serial TECC courses autologous hematopoietic stem cell supports (median 1.0×10⁶ CD34+ cells per kg body weight (bw), range 0.5-2.8×10⁶ CD34+ cells/kg bw, SD 0.6×10⁶ CD34+ cells/kg bw) were given on day 7. All pts received granulocyte colony stimulating factor (GCSF) from day 8 in addition. All together 39 TECC courses (minimum 2 courses, maximum 6 courses per pt) were administered, with a median interval of 32 (range 21-52) days until recovery. Leukopenia (<1000/μl) occurred 9 days (range 3-13 days; SD 2.4 days) after end of chemotherapy and persisted for 9 (range 3-15 days; SD 3 days) days. In 31/39 TECC courses readmission to hospital was required for supportive therapy mainly due to neutropenic fever. In this period pts received 0.83 (range 0-1) red blood cell units and 2.35 (range 1-4) platelet units. C-reactive protein in neutropenic pts as an indicator for infection after TECC chemotherapy was detectable after 36 of 39 chemotherapy courses leading to further supportive therapy (median 10.4 mg/dl, range 1.1-28.3 mg/dl; SD 6.67 mg/dl). Duration of total inpatient treatment per TECC course including supportive therapy was in median 13.5 days (range 7-53 days; SD 4.3 days). Only two children had a prolonged infection (77 and 100 days). Clinical and objective tumor responses, defined as complete remission, very good partial response and partial response were observed in 9/9 pts at eight weeks after the last TECC course and were maintained at six months in 7/9 pts. Median time to progression and median overall survival time after TECC chemotherapy were 20.3 months and 25.2 months, respectively.

These data provide evidence that in very high risk pts refractory to standard high risk therapy, a combination of TECC chemotherapy and stem cell support is feasible in pts with incomplete remission respectively relapsed STS pts and demonstrates promising antineoplastic activity. Therefore, this regimen warrants further investigation in prospective trials.

Zusammenfassung

Neun Patienten mit refraktären Weichteilsarkomen nach protokollgemäßer Hochrisiko-Therapie wurden mit einer intensivierten Chemotherapie (TECC), bestehend aus Topotecan (0.75 mg/m²), Etoposid (100 mg/m²), Carboplatin (100 mg/m²) und Cyclophosphamid (200 mg/m²) an den Tagen 1-5 behandelt. Um verlängerte Intervalle zwischen den konsekutiven TECC Kursen zu vermeiden, wurden autologe hämatopoetische Stammzellen (median 1.0×10⁶ CD34+ Zellen pro kg Körpergewicht (KG), range 0.5-2.8×10⁶ CD34+ Zellen/kg KG, SD 0.6×10⁶ CD34+ Zellen/kg KG) an Tag 7 transfundiert. Alle Patienten erhielten ab Tag 8 eine Therapie mit GCSF. Insgesamt wurden 39 TECC Kurse (min. 2, max. 6 Kurse pro Patient) verabreicht; das mittlere Intervall betrug aus medizinischen Gründen 32 Tage (range 21-52). Eine Leukopenie (<1000/μl) trat im Mittel 9 Tage (range 3-13 Tage, SD 2,4 Tage) nach Ende der Chemotherapie auf und dauerte im Mittel 9 Tage an (range 3-15 Tage; SD 3 Tage). Nach 31/39 TECC Kursen wurde eine stationäre Wiederaufnahme zur Supportivtherapie erforderlich, während der Antibiotika und Blutprodukte (im Mittel 0.83 Erythrozytenkonzentrate (range 0-1) und im Mittel 2.35 Thrombozytenkonzentrate (range 1-4)) verabreicht werden mussten. Die stationäre Aufenthaltsdauer der Patienten pro TECC Kurs und Supportivtherapie betrug median 13,5 Tage (range 7-53 Tage, SD 4,3 Tage). Nur 2 Kinder hatten eine anhaltenden Infektion, deren Behandlung 77 und 100 Tage dauerte.

Ein Tumoransprechen, definiert als komplette Remission, sehr gute Teilremission und partielle Remission wurde bei 9/9 Patienten acht Wochen nach dem letzten TECC Chemotherapiekurs beobachtet und bestand bei 7/9 Patienten auch noch 6 Monate nach Therapieende. Die mediane Zeit bis zur Progression und das mediane Überleben nach TECC Chemotherapie betrug 20,3 bzw. 25,2 Monate.

Diese Ergebnisse zeigen, dass die TECC Chemotherapie mit Stammzellsupport bei Patienten mit refraktären Weichteilsarkomen durchführbar ist und zu einem guten therapeutischen Ansprechen führt. Eine Prüfung dieser Therapie im Rahmen einer prospektiven Studie ist deshalb gerechtfertigt.

high-risk soft tissue sarcoma - autologous hematopoietic stem cell support - TECC chemotherapy

refraktäre Weichteilsarkome - autologer hämatopoetischer Stammzellsupport - TECC Chemotherapie

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