Investigational New Drugs

, Volume 21, Issue 4, pp 481–486

An open label, non-comparative phase II study of topotecan as salvage treatment for patients with soft tissue sarcoma

  • Peter Reichardt
  • Karin Oechsle
  • Daniel Pink
  • Carsten Bokemeyer
  • F. Schneller
  • Rolf Issels
  • Lothar Kanz
  • Jörg Thomas Hartmann
Article

Abstract

Background: The number of effective cytotoxic agents for the treatment of patients with metastatic soft tissue sarcoma (STS) is limited, especially when patients have failed anthracyline-based chemotherapy. Patients and methods: Between 1999 and 2000 a total of 16 patients with histologically proven STS progressing during or after first-line anthracycline-based chemotherapy were entered into this open-label, noncomparative study. Topotecan was administered as a 30-min infusion at a dosage of 1.5 mg/m2 on five consecutive days every 3 weeks. All patients had received an anthracycline- or ifosfamide-based first-line chemotherapy. Results: None of the 16 included patients achieved an objective response to topotecan. Six patients achieved stable disease (38%), lasting for at least 6 weeks in four patients (25%) and for less than 6 weeks in two patients (13%). Ten patients (62%) had progressive disease. The median time to progression was 79 days calculated from the start of topotecan therapy (range, 28–230). The treatment was well tolerated; however, both anemia and thrombopenia grade III/IV occurred in 25% of the patients as well as severe neutropenia in 69% of the patients. Nonhematologic toxicities grade III/IV such as diarrhea and severe bleeding occurred only in one patient each (6%). Discussion: Topotecan is well tolerated in anthracycline-resistant patients with metastatic STS, but no objective response has been observed in this trial.

advanced soft tissue sarcoma topotecan topoisomerase-I-inhibitor second-line chemotherapy 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Patel SR: Systemic chemotherapy, In Pollock RE (ed) Soft tissue sarcomas, Hamilton, Ontario, Canada, 2002, pp. 323–328Google Scholar
  2. 2.
    Benjamin RS, Legha SS, Patel SR, Nicaise C: Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the M.D. Anderson experience. Cancer Chemother Pharmacol 31(suppl 2): S174–S179, 1993Google Scholar
  3. 3.
    Borden EC, Amato DA, Rosenbaum C, Enterline HT, Shiraki MJ, Creech RH, Lerner HJ, Carbone PP: Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 5: 840–850, 1987Google Scholar
  4. 4.
    Lopez M, Vici P, Di Lauro L, Carpano S: Increasing single epirubicin doses in advanced soft tissue sarcomas. J Clin Oncol 20: 1329–1334, 2002Google Scholar
  5. 5.
    Cure H, Krakowski I, Adenis A, Tubiana N, Kerbrat P, Roche H, Chevallier B, Lentz MA, Fumoleau P, Chollet P: Results of a phase II trial with second-line cystemustine at 60 mg/m2 in advanced soft tissue sarcoma: a trial of the EORTC Early Clinical Studies Group. Eur J Cancer 34: 422–423, 1998Google Scholar
  6. 6.
    Hartmann JT, Oechsle K, Mayer F, Kanz L, Bokemeyer C: Phase II trial of trofosfamide in patients with advanced pretreated soft tissue sarcomas. Anticancer Res, 2003 Mar–Apr; 23(2C): 1899–1901. PM1D: 12820475[Pubmed-indexed for MEDLINE].Google Scholar
  7. 7.
    Spath-Schwalbe E, Genvresse I, Koschuth A, Dietzmann A, Grunewald R, Possinger K: Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas. Anticancer Drugs 11: 325–329, 2000Google Scholar
  8. 8.
    Papai Z, Bodoky G, Szanto J, Poller I, Rahoty P, Eckhardt S, Lang I, Szendroi M: The efficacy of a combination of etoposide, ifosfamide, and cisplatin in the treatment of patients with soft tissue sarcoma. Cancer 89: 177–180, 2000Google Scholar
  9. 9.
    O'Reilly S, Rowinsky EK, Slichenmyer W, Donehower RC, Forastiere AA, Ettinger DS, Chen TL, Sartorius S, Grochow LB: Phase I and pharmacologic study of topotecan in patients with impaired renal function. J Clin Oncol 14: 3062–3073, 1996Google Scholar
  10. 10.
    Bramwell VH, Eisenhauer EA, Blackstein M, Boos G, Knowling M, Jolivet J, Bogues W: Phase II study of topotecan (NSC 609 699) in patients with recurrent or metastatic soft tissue sarcoma. Ann Oncol 6: 847–849, 1995Google Scholar
  11. 11.
    Saylors RL, III, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a pediatric oncology group phase II study. J Clin Oncol 19: 3463–3469, 2001Google Scholar
  12. 12.
    WHO (ed): International classification of diseases, 10th edn (ICD-10). Geneva, 1996Google Scholar
  13. 13.
    Fleming TR: One-sample multiple testing procedure for phase II clinical trials. Biometrics 38: 143–151, 1982Google Scholar
  14. 14.
    Kaplan EL, Maier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481, 1958Google Scholar
  15. 15.
    Bokemeyer C, Franzke A, Hartmann JT, Schober C, Arseniev L, Metzner B, Link H, Kanz L, Schmoll HJ: A phase I/II study of sequential, dose-escalated, high dose ifosfamide plus doxorubicin with peripheral blood stem cell support for the treatment of patients with advanced soft tissue sarcomas. Cancer 80: 1221–1227, 1997Google Scholar
  16. 16.
    Frustaci S, Buonadonna A, Galligioni E, Favaro D, De Paoli A, Lo RG, Sorio R, Tumolo S, Monfardini S: Increasing 4′-epidoxorubicin and fixed ifosfamide doses plus granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: a pilot study. J Clin Oncol 15: 1418–1426, 1997Google Scholar
  17. 17.
    Reichardt P, Tilgner J, Hohenberger P, Dorken B: Dose-intensive chemotherapy with ifosfamide, epirubicin, and filgrastim for adult patients with metastatic or locally advanced soft tissue sarcoma: a phase II study. J Clin Oncol 16: 1438–1443, 1998Google Scholar
  18. 18.
    Steward WP, Verweij J, Somers R, Spooner D, Kerbrat P, Clavel M, Crowther D, Rouesse J, Tursz T, Tueni E: Granulocyte-macrophage colony-stimulating factor allows safe escalation of dose-intensity of chemotherapy in metastatic adult soft tissue sarcomas: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 11: 15–21, 1993Google Scholar
  19. 19.
    Patel SR, Vadhan-Raj S, Burgess MA, Plager C, Papadopolous N, Jenkins J, Benjamin RS: Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol 21: 317–321, 1998Google Scholar
  20. 20.
    Balcerzak SP, Benedetti J, Weiss GR, Natale RB: A phase II trial of paclitaxel in patients with advanced soft tissue sarcomas. A Southwest Oncology Group study. Cancer 76: 2248–2252, 1995Google Scholar
  21. 21.
    Svancarova L, Blay JY, Judson IR, van Hoesel QG, van Oosterom AT, le Cesne A, Keizer HJ, Hermans C, Van Glabbeke M, Verweij J, Hogendoorn PC, Nielsen OS: Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 38: 556–559, 2002Google Scholar
  22. 22.
    Okuno S, Edmonson J, Mahoney M, Buckner JC, Frytak S, Galanis E: Phase II trial of gemcitabine in advanced sarcomas. Cancer 94: 3225–3229, 2002Google Scholar
  23. 23.
    Patel SR, Gandhi V, Jenkins J, Papadopolous N, Burgess MA, Plager C, Plunkett W, Benjamin RS: Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 19: 3483–3489, 2001Google Scholar
  24. 24.
    Hensley ML, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C, Sabbatini P, Tong W, Barakat R, Spriggs DR: Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 20: 2824–2831, 2002Google Scholar
  25. 25.
    van Hoesel QG, Verweij J, Catimel G, Clavel M, Kerbrat P, van Oosterom AT, Kerger J, Tursz T, Van Glabbeke M, van Pottelsberghe C: Phase II study with docetaxel (taxotere) in advanced soft tissue sarcomas of the adult. EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol 5: 539–542, 1994Google Scholar
  26. 26.
    Kostler WJ, Brodowicz T, Attems Y, Hejna M, Tomek S, Amann G, Fiebiger WC, Wiltschke CH, Krainer M, Zielinski CC: Docetaxel as rescue medication in anthracycline-and ifosfamide-resistant locally advanced or metastatic soft tissue sarcoma: results of a phase II trial. Ann Oncol 12: 1281–1288, 2001Google Scholar
  27. 27.
    Edmonson JH, Ebbert LP, Nascimento AG, Jung SH, McGaw H, Gerstner JB: Phase II study of docetaxel in advanced soft tissue sarcomas. Am J Clin Oncol 19: 574–576, 1996Google Scholar
  28. 28.
    Verweij J, Lee SM, Ruka W, Buesa J, Coleman R, van Hoessel R, Seynaeve C, di Paola ED, Van Glabbeke M, Tonelli D, Judson IR: Randomized phase II study of docetaxel versus doxorubicin in first-and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: a study of the european organization for research and treatment of cancer soft tissue and bone sarcoma group. J Clin Oncol 18: 2081–2086, 2000Google Scholar
  29. 29.
    Delaloge S, Yovine A, Taamma A, Riofrio M, Brain E, Raymond E, Cottu P, Goldwasser F, Jimeno J, Misset JL, Marty M, Cvitkovic E: Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients—preliminary evidence of activity. J Clin Oncol 19: 1248–1255, 2001Google Scholar
  30. 30.
    Demetri GD: ET-743: the US experience in sarcomas of soft tissues. Anticancer Drugs 13(suppl 1): S7–S9, 2002Google Scholar
  31. 31.
    Kollmannsberger C, Brugger W, Hartmann JT, Maurer F, Bohm P, Kanz L, Bokemeyer C: Phase II study of oral trofosfamide as palliative therapy in pretreated patients with metastatic soft-tissue sarcoma. Anticancer Drugs 10: 453–456, 1999Google Scholar
  32. 32.
    Blomqvist C, Wiklund T, Pajunen M, Virolainen M, Elomaa I: Oral trofosfamide: an active drug in the treatment of soft-tissue sarcoma. Cancer Chemother Pharmacol 36: 263–265, 1995Google Scholar
  33. 33.
    Budd GT, Rankin C, Hutchins LF, Wong L, Petruska PJ, Antman K: Phase II trial of topotecan by continuous infusion in patients with advanced soft tissue sarcomas, a SWOG study. Southwest Oncology Group. Invest New Drugs 20: 129–132, 2002Google Scholar
  34. 34.
    Raney RB, Anderson JR, Barr FG, Donaldson SS, Pappo AS, Qualman SJ, Wiener ES, Maurer HM, Crist WM: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 23: 215–220, 2001Google Scholar
  35. 35.
    Van Glabbeke M, Verweij J, Judson I, Nielsen OS: Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer 38: 543–549, 2002Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Peter Reichardt
    • 1
  • Karin Oechsle
    • 2
  • Daniel Pink
    • 1
  • Carsten Bokemeyer
    • 2
  • F. Schneller
    • 3
  • Rolf Issels
    • 4
  • Lothar Kanz
    • 2
  • Jörg Thomas Hartmann
    • 2
  1. 1.Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Robert-Roessle-Klinik, Helios-Klinikum BerlinUniversitätsklinikum CharitéeBerlinGermany
  2. 2.Medizinische Klinik IIUniversitätsklinikum, Eberhard-Karls-UniversityTuebingenGermany
  3. 3.Medizinische Klinik IIIKlinikum rechts der IsarMunichGermany
  4. 4.Medizinische Klinik IIILMU Grosshadern und GSF-Institut für Molekulare Immunologie, KKG HTMunichGermany

Personalised recommendations