Skip to main content

Advertisement

SpringerLink
Log in

Phase I/II study of docetaxel, ifosfamide, and doxorubicin in advanced, recurrent, or metastatic soft tissue sarcoma (STS)

  • Phase I Studies
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background: Based on reports of the efficacy of docetaxel (T) in STS, we undertook a phase I/II trial to determine the response rate (RR), dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of addition of T to doxorubicin (A) and ifosfamide (I) in advanced STS.

Methods: Patients with advanced, recurrent, or metastatic STS, without prior chemotherapy, were enrolled in a dose escalation trial. Dose levels: I-A 40 mg/m2; I 4.0 gm/m2; T 40 mg/m2, II-A 50; I 5.0; T 50, III-A 60; I 6.0; T 60, and IV-A 75; I 7.5; T 75. MTD was defined as the dose producing DLTs in ≥2 of 3–6 patients treated.

Results: 21 patients were accrued. Median age: 55 (28–78) years. Histology: leiomyosarcoma 10, spindle cell sarcoma 3, synovial sarcoma 2, angiosarcoma 1, fibrous histiocytoma 1, epitheliod hemangio-endothelioma 1, and 3 not specified. MTD was level III (A 60, I 6.0, and T 60). DLT was myelosuppression. All grade 4 toxicities were hematologic. Patients received median 2 cycles (range 2–9). Eight patients (38%) achieved partial response (PR). PR occurred after six cycles in 5 patients. 18 patients died. Median overall survival: 17 months (95% CI, 9.1–33.6 months).

Conclusions: The recommended Phase II dose of this combination is level III: A 60 mg/m2, I 6.0 g/m2, T 60 mg/m2, with mesna and granulocyte-colony stimulating factor. The RR is similar to that of AI in other trials, but the survival is better than anticipated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ (2004) Cancer statistics, 2004. CA Cancer J Clin 54:8–29

    Article  PubMed  Google Scholar 

  2. van Glabbeke M, van Oosterom AT, Oosterhuis JW, Mouridsen H, Crowther D, Somers R, Verweij J, Santoro A, Buesa J, Tursz T (1999) Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: An analysis of 2,185 patients treated with anthracycline-containing first-line regimens—a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 17:150–157

    PubMed  Google Scholar 

  3. Verweij J, Mouridsen HT, Nielssen OS, Woll PJ, Somers R, van Oosterom AT, Van Glabbeke M, Tursz T (1995) The present state of the art in chemotherapy for soft tissue sarcomas in adults: The EORTC point of view. Crit Rev Oncol Hematol 20:193–201

    PubMed  CAS  Google Scholar 

  4. Edmonson JH, Ryan LM, Blum RH, Brooks JS, Shiraki M, Frytak S, Parkinson DR (1993) Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11:1269–1275

    PubMed  CAS  Google Scholar 

  5. Antman K, Crowley J, Balcerzak SP, Rivkin SE, Weiss GR, Elias A, Natale RB, Cooper RM, Barlogie B, Trump DL, Doroshow JH, Aisner J, Pugh RP, Weiss RB, Cooper BA, Clamond GH, Baker LH (1993) An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 11:1276–1285

    PubMed  CAS  Google Scholar 

  6. Borden EC, Amato DA, Rosenbaum C, Enterline HT, Shiraki MJ, Creech RH, Lerner HJ, Carbone PP (1987) Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 5:840–850

    PubMed  CAS  Google Scholar 

  7. 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 (2000) 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

    PubMed  CAS  Google Scholar 

  8. van Hoesel QG, Verweij J, Catimel G, Clavel M, Kerbrat P, van Oosterom AT, Kerger J, Tursz T, van Glabbeke M, Van Pottelsberghe C (1994) 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

    PubMed  Google Scholar 

  9. Amodio A, Carpano S, Paoletti G, Gionfra T, Rinaldi M, Manfredi C, Foggi P, Lopez M (1998) Phase II study of docetaxel in patients with advanced stage soft tissue sarcoma. Clin Ter 149:121–125

    PubMed  CAS  Google Scholar 

  10. Baker LH, Hirth JS, Carson E, Little R, Watkins PB (1998) Cytochrome P4503A activity as a predictor of docetaxel toxicity and response. Proc Am Soc Clin Oncol 718

  11. Kostler WJ, Brodowicz T, Attems Y, Hejna M, Tomek S, Amann G, Fiebiger WC, Wiltschke CH, Krainer M, Zielinski CC (2001) 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

    Article  PubMed  CAS  Google Scholar 

  12. Edmonson JH, Ebbert LP, Nascimento AG, Jung SH, McGaw H, Gerstner JB (1996) Phase II study of docetaxel in advanced soft tissue sarcomas. Am J Clin Oncol 19:574–576

    Article  PubMed  CAS  Google Scholar 

  13. Itoh K, Fujii H, Minami H (1997) Phase I and pharmacological study of docetaxel (Doc) combined with doxorubicin (Dox) for advanced breast cancer. Proc Am Soc Clin Oncol 16:610

    Google Scholar 

  14. Steward WP, Verweij J, Somers R, Spooner D, Kerbrat P, Clavel M, Crowther D, Rouesse J, Tursz T, Tueni E (1993) 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

    PubMed  CAS  Google Scholar 

  15. Schoenfeld DA, Rosenbaum C, Horton J, Wolter JM, Falkson G, DeConti RC (1982) A comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide versus vincristine, actinomycin-D, and cyclophosphamide for advanced sarcoma. Cancer 50:2757–2762

    Article  PubMed  CAS  Google Scholar 

  16. Pinedo HM, Bramwell VH, Mouridsen HT, Somers R, Vendrik CP, Santoro A, Buesa J, Wagener T, van Oosterom AT, van Unnik JA (1984) Cyvadic in advanced soft tissue sarcoma: A randomized study comparing two schedules. A study of the EORTC Soft Tissue and Bone Sarcoma Group. Cancer 53:1825–1832

    CAS  Google Scholar 

  17. Bodey GP, Rodriguez V, Murphy WK, Burgess A, Benjamin RS (1981) Protected environment—prophylactic antibiotic program for malignant sarcomas: Randomized trial during remission induction chemotherapy. Cancer 47:2422–2429

    Article  PubMed  CAS  Google Scholar 

  18. Le Cesne A, Antoine E, Spielmann M, Le Chevalier T, Brain E, Toussaint C, Janin N, Kayitalire L, Fontaine F, Genin J et al. (1995) High-dose ifosfamide: Circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas. J Clin Oncol 13:1600–1608

    PubMed  Google Scholar 

  19. Patel SR, Vadhan-Raj S, Papadopolous N, Plager C, Burgess MA, Hays C, Benjamin RS (1997) High-dose ifosfamide in bone and soft tissue sarcomas: Results of phase II and pilot studies–dose-response and schedule dependence. J Clin Oncol 15:2378–2384

    PubMed  CAS  Google Scholar 

  20. van Oosterom AT, Mouridsen HT, Nielsen OS, Dombernowsky P, Krzemieniecki K, Judson I, Svancarova L, Spooner D, Hermans C, van Glabbeke M, Verweij J (2002) Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer 38:2397–2406

    Article  PubMed  Google Scholar 

  21. Cerny T, Leyvraz S, von Briel T, Kupfer A, Schaad R, Schmitz SF, Honegger P, Sessa C, Brunner J, Boddy AV (1999) Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: A pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 9:1087–1094

    Article  Google Scholar 

  22. Hensley ML, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C, Sabbatini P, Tong W, Barakat R, Spriggs DR (2002) Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: Results of a phase II trial. J Clin Oncol 20:2824–2831

    Article  PubMed  CAS  Google Scholar 

  23. Leu KM, Ostruszka LJ, Shewach D, Zalupski M, Sondak V, Biermann JS, Lee JS, Couwlier C, Palazzolo K, Baker LH (2004) Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol 22:1706–1712

    Article  PubMed  CAS  Google Scholar 

  24. Rosen G, Forscher C, Lowenbraun S, Eilber F, Eckardt J, Holmes C, Fu YS (1994) Synovial sarcoma. Uniform response of metastases to high dose ifosfamide. Cancer 73:2506–2511

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk R35, Cleveland, Ohio, 44195

    Revathi Suppiah, Laura Wood & Paul Elson

  2. Department of Hematology and Medical Oncology, The Cleveland Clinic Foundation, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, R35, Cleveland, OH, 44195

    George T. Budd

Authors
  1. Revathi Suppiah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Elson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George T. Budd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Revathi Suppiah.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Suppiah, R., Wood, L., Elson, P. et al. Phase I/II study of docetaxel, ifosfamide, and doxorubicin in advanced, recurrent, or metastatic soft tissue sarcoma (STS). Invest New Drugs 24, 509–514 (2006). https://doi.org/10.1007/s10637-006-9035-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-006-9035-2

Keywords

Search

Navigation