Cancer Chemotherapy and Pharmacology

, Volume 18, Supplement 2, pp S13–S16 | Cite as

Cyclophosphamide versus ifosfamide: preliminary report of a randomized phase II trial in adult soft tissue sarcomas

  • Vivien H. C. Bramwell
  • H. T. Mouridsen
  • A. Santoro
  • G. Blackledge
  • R. Somers
  • D. Thomas
  • R. Sylvester
  • Allan Van Oosterom
  • European Organization for Research in Treatment of Cancer Soft Tissue and Bone Sarcoma Group
International Satellite Symposium to the 3rd European Conference on Clinical Oncology Stockholm, June 1985 Recent Experience with Ifosfamide/Mesna in Solid Tumor Cyclophosphamide vs. Ifosfamide, Soft Tissue Sarcomas


One hundred and seventy-one patients with advanced soft tissue sarcoma entered a randomized crossover phase II study comparing cyclophosphamide (CYCLO) with a new analogue, ifosfamide (IFOS), both administered as 24 h i.v. infusions every 3 weeks. The doses used were CYCLO 1.5 g/m2 and IFOS 5 g/m2, with provision for dose escalation. All patients received mesna 400 mg/m2 as an i.v. bolus 4 hourly x 9 doses, commencing at the start of the oxazophosphorine infusion. Patients who had received previous chemotherapy were eligible provided this did not include a classical alkylating agent. There were 22 patients who were ineligible, and response could not be evaluated in 12 additional patients. IFOS produced two complete and ten partial remissions, for an overall response rate of 18%. CYCLO was significantly (P=0.04) less active, producing one complete and five partial remissions, an overall response rate of 9%. Stabilization of disease was similar in both arms (27% and 24% respectively), but fewer patients showed progression on IFOS. The response rate was higher (20% vs 5%) for patients who had not received previous chemotherapy, and also for female compared with male patients (21% vs 5%). When only patients who had not received previous chemotherapy were considered, the respective response rates for IFOS and CYCLO were 24% and 15%. There were no responses in previously treated patients receiving CYCLO. There were four partial responses in 33 patients crossing from CYCLO to IFOS, but no responses in 18 patients receiving CYCLO after IFOS. Leucopenia was significantly more pronounced (P=0.0004) with CYCLO, both after the first course and throughout treatment, although the incidence of severe infections, 6%, was the same in both arms. Nausea and vomiting were more severe with IFOS (P=0.022), but other toxicities were mild. Grade 1 or 2 bladder (haematuria) or renal (rise in serum creatinine) toxicity was slightly more frequent with IFOS (7 vs 3 patients) and was a reason for stopping treatment for one patient in each arm. Three episodes of mild to moderate drowsiness after IFOS were reported, but no severe encephalopathy. A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination with such active agents as adriamycin.


Cyclophosphamide Partial Response Active Agent Soft Tissue Sarcoma Dose Escalation 
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  1. 1.
    Antman KH, Montella D, Rosenbaum C, Schwen M (1985) Phase II trial of Ifosfamide with Mesna in previously treated metastatic sarcoma. Cancer Treat Rep 69:499–504Google Scholar
  2. 2.
    Bonadonna, G, Santoro A (1982) Bone and soft tissue sarcomas. in: Pinedo HM (ed) Cancer chemotherapy 1982, chap 22, The EORTC Cancer Chemotherapy Annual, vol 4, Excerpta Medica, Amsterdam, pp 373–396Google Scholar
  3. 3.
    Bonadonna G, Santoro A (1983) Bone and soft tissue sarcomas. In: Pinedo HM, Chabner BA (eds) Cancer chemotherapy, chap 24, The EORTC Cancer Chemotherapy Annual, vol 5. Elsevier, Amsterdam, pp 430–445Google Scholar
  4. 4.
    Bonadonna G, Santoro A (1984) Bone and soft tissue sarcomas. In: Pinedo HM, Chabner BA (eds) Cancer chemotherapy, chap 25, The EORTC Cancer Chemotherapy Annual, vol 6. Elsevier, Amsterdam, pp 436–449Google Scholar
  5. 5.
    Bonadonna G, Beretta G, Tancini G, Brambilla, C, Bajetta, E, De Palo GM, De Lena M, Fossati-Bellani F, Gasparini M, Valagussa, P, Veronesi U (1975) Adriamycin (NSC-123127) studies at the Istituto Nazionale Tumori Milan. CancerGoogle Scholar
  6. 6.
    Brade WP, Herdrich K, Varini M (1985) Ifosfamide-pharmacology, safety and therapeutic potential. Cancer Treat Rev 12:1–47Google Scholar
  7. 7.
    Bramwell VHC, Pinedo HM (1979) Bone and soft tissue sarcomas. In: Pinedo HM (ed) Cancer chemotherapy 1979, chap 20, The EORTC Cancer Chemotherapy Annual, vol 1. Excerpta Medica, Amsterdam, pp 424–450Google Scholar
  8. 8.
    Bramwell VHC, Pinedo HM (1980) Bone and soft tissue sarcomas. In: Pinedo HM (ed) Cancer chemotherapy 1980, chap 21, The EORTC Cancer Chemotherapy Annual, vol 2. Excerpta Medica, Amsterdam, pp 393–414Google Scholar
  9. 9.
    Bramwell VHC, Pinedo HM (1981) Bone and soft tissue sarcomas. In: Pineda HM (ed) Cancer chemotherapy 1981, chap 21, The EORTC Cancer Chemotherapy Annual, vol 3. Excerpta Medica, Amsterdam, pp 409–424Google Scholar
  10. 10.
    Bramwell VHC, Mouridsen HT, Mulder JH, Somers R, Van Oosterom AT, Santoro A, Thomas D, Sylvester R, Markham D (1983) Carminomycin vs Adriamycin in advanced soft tissue sarcomas: an EORTC randomized phase II study. Eur J Cancer Clin Oncol 19:1097–1104Google Scholar
  11. 11.
    Bramwell VHC, Crowther D, Deakin DPD, Swindell R, Harris M (1985) Combined modality management of local and disseminated adult soft tissue sarcomas: a review of 257 cases seen over 10 years at the Christie Hospital & Holt Radium Institute, Manchester. Br J Cancer 51:301–318Google Scholar
  12. 12.
    Brock N, Pohl J (1983) Detoxification as a principle to increase the drug's therapeutic range in cancer chemotherapy, Ifosamide and Mesna. In: 13th Interntional Congress on Chemotherapy, Vienna, Austria, 1983, pp 123–137Google Scholar
  13. 13.
    Czownicki A, Utracka-Hutka B (1977) Contribution to the treatment of malignant tumors with Ifosfamide. In: Burkert H, Voight HC (eds) Proceedings, International Holoxan Symposium, Düsseldorf. Asta-Werke, Bielefeld, pp 109–111Google Scholar
  14. 14.
    Hoefer-Janker H, Scheef W, Günther U, Hüls W (1975) Erfahrungen mit der fraktionierten Ifosfamide Stoßtherapie bei generalisierten malignen Tumoren. Med Welt 26:972–979Google Scholar
  15. 15.
    Klein HO (1982) High dose Ifosfamide and Mesna continuous infusion over 5 days — a phase I/II trial. In: Proceedings, 13th International Cancer Congress, 1982Google Scholar
  16. 16.
    Meanwell CA, Blake AE, Blackledge G, Blake DR, Honisberger L, Williams AC, Latief TN, Mould JJ, Shaw IC, Spooner D, Jones SR (1985) Encephalopathy associated with Ifosfamide/Mesna therapy. Lancet 1:406–407Google Scholar
  17. 17.
    Mouridsen HT, Somers R, Santoro A, Mulder JH, Bramwell VHC, Van Oosterom AT, Sylvester R, Thomas D (1984) Adriamycin vs 4'epiadriamycin in advanced soft tissue sarcomas: An EORTC randomized phase II study. In: Bonadonna G (ed) Advances in anthracycline chemotherapy: epirubicin. Masson Italia, Milan, pp 105–109Google Scholar
  18. 18.
    Pinedo HM, Kenis Y (1977) Chemotherapy of advanced soft tissue sarcoma in adults. Cancer Treat Rev 4:67–86Google Scholar
  19. 19.
    Scheef W, Klein HO, Brock N, Burkert H, Günther U, Hoeferjanker, H, Mitrenga D, Schnitker J, Voigtman R (1979) Controlled clinical studies with an antidote against the urotoxicity of oxazaphosphorines: preliminary results. Cancer Treat Rep 63:501–505Google Scholar
  20. 20.
    Scheef W, Soemer G (1981) The treatment of solid malignant tumors with holoxan and uromitexan. In: Burkert H, Nagel GA (eds) New experience with the oxazophosphamines, with special reference to the uroprotector uromitexan. Karger, Basel, pp 12–20Google Scholar
  21. 21.
    Stuart-Jarris RC, Harper PG, Parsons CA (1983) High-dose alkylation therapy using Ifosfamide infusion with Mesna in the treatment of adult advanced soft tissue sarcoma. Cancer Chemother Pharmacol 11:69–72Google Scholar
  22. 22.
    World Health Organization (1979) Handbook for reporting results of cancer treatment. WHO, Geneva (Offset publication no 48)Google Scholar

Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • Vivien H. C. Bramwell
    • 1
  • H. T. Mouridsen
    • 2
  • A. Santoro
    • 3
  • G. Blackledge
    • 4
  • R. Somers
    • 5
  • D. Thomas
    • 6
  • R. Sylvester
    • 6
  • Allan Van Oosterom
    • 7
  • European Organization for Research in Treatment of Cancer Soft Tissue and Bone Sarcoma Group
  1. 1.Christie HospitalManchesterEngland
  2. 2.Finsen InstituteCopenhagenDenmark
  3. 3.Istituto Nazionale Dei TumoriMilanItaly
  4. 4.Queen Elizabeth HospitalBirminghamEngland
  5. 5.Antoni Van LeeuwenhoekAmsterdamThe Netherlands
  6. 6.EORTC Data CentreBrussellsBelgium
  7. 7.Department of Clinical OncologyUniversity Hospital AntwerpEdegemBelgium

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