Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Phase I study of high-dose cisplatin, ifosfamide, and etoposide


To test the feasibility of a regimen of high-dose cisplatin, ifosfamide, and etoposide (VP-16; VIPP regimen), we registered 15 patients with advanced non-small-cell lung cancer in a phase I trial of the Northern California Oncology Group. One cycle of treatment consisted of high-dose cisplatin given at 100 mg/m2 i.v. on days 1 and 8, VP-16 given at 60–75 mg/m2 i.v. on days 1–3, plus ifosfamide given at 1.0–1.2 g/m2 i.v. on days 1–3; cycles were repeated every 28 days. There were 13 men and 2 women; the median age was 59 years (range, 47–72 years). The median Karnofsky performance status (KPS) was 90 (range, 70–100). All patients were assessable for toxicity and response. The median number of cycles delivered per patient was two (range, one to four). Hematologic toxicity was dose-limiting and required de-escalation of the ifosfamide and VP-16 doses. Ten patients developed a white blood count of <1000/mm3 and seven patients developed a platelet count of <50,000/mm3. The duration of cytopenia increased progressively with each subsequent cycle of therapy. Two patients required antibiotics for neutropenic fever with documented infections (pneumonia, bacteremia). Seven patients received red blood cell transfusions for a hemoglobin level of <8 gm/dl. Grade III or IV non-hematologic toxicities were uncommon and involved one patient each with grade 3 ototoxicity and grade 3 neurotoxicity. Five patients developed laboratory evidence of renal salt wasting. The overall response rate was 33% (5/15) with a complete response being achieved by two patients (13%) and a partial response being attained by three (20%). The overall median survival was 44 weeks. We conclude that although this regimen demonstrated activity, hematologic toxicity limited its use in the palliative treatment of non-small-cell lung cancer. Using hemopoietic growth-factor support to permit dose escalation, this schedule of VIPP may be of interest in a number of different chemotherapy-sensitive tumor types.

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


  1. 1.

    Bakowski MT, Creech JC (1983) Chemotherapy of non-small-cell lung cancer: a reappraisal and look to the future. Cancer Treat Rev 10: 159–172

  2. 2.

    Brock N (1989) Oxazaphosphorine cytostatics: past-present-future. Cancer Res 49: 1–7

  3. 3.

    Constanzi JJ, Morgan LR, Hokanson J (1982) Ifosfamide in the treatment of extensive non-oat cell carcinoma of the lung. Semin Oncol 9: 61–65

  4. 4.

    Drings P (1988) European experience with ifosfamide in non-small-cell lung cancer. Semin Oncol 16 [Suppl 3]: 22–30

  5. 5.

    Ettinger DS (1989) Ifosfamide in the treatment of non-small-cell lung cancer. Semin Oncol 16 [Suppl 3]: 31–38

  6. 6.

    Gandara DR, Perez EA, Wold HG, Lawrence HJ, DeGregorio MW (1989) Evaluation of cisplatin dose-intensity: current status and future prospects. Anticancer Res 9: 1121–1128

  7. 7.

    Gandara DR, Wold HG, Perez EA, Deisseroth A, Doroshow J, Meyers F, McWhirter K, Hannigan J, DeGregorio M (1989) Cis-platin dose intensity in non-small-cell lung cancer. Phase II results of a day 1 and 8 high-dose regimen. J Natl Cancer Inst 81: 790–794

  8. 8.

    Gandara DR, Perez EA, Wold H, Caggiano V, Malec M, Ahn DK, Meyers F, Carlson RW (1990) High-dose cisplatin and mitomycin C in advanced non-small-cell lung cancer. A phase II study of the Northern California Oncology Group. Cancer Chemother Pharmacol 27: 243–247

  9. 9.

    Gandara DR, Crowley J, Livingston RB, Perez EA, Taylor CW, Weiss G, Neele JR, Barlogie B, Laufman LR, Grunberg SM, Braun TJ, Balcerzak SP (1993) Evaluation of cisplatin dose intensity in metastatic non-small-cell lung cancer. A phase III study of the Southwest Oncology Group. J Clin Oncol 11: 873–878

  10. 10.

    Ghosn M, Droz JP, Theodore C, Pico JL, Baume D, Spielmann M, Ostronoff M, Moran A, Salloum E, Kramar A, Hayat M (1988) Salvage chemotherapy in refractory germ cell tumors with etoposide (vp-16) plus ifosfamide plus high-dose cisplatin. Cancer 62: 24–27

  11. 11.

    Golden A (1982) Ifosfamide in experimental tumor systems. Semin Oncol 9: 14–23

  12. 12.

    Hryniuk WM (1987) Average relative dose intensity and the impact on design of clinical trials. Semin Oncol 14: 65–74

  13. 13.

    Hutchinson F, Perez EA, Gandara DR, Lawrence HJ, Kaysen GA (1988) Renal salt wasting in patients treated with cisplatin. Ann Intern Med 108: 21–25

  14. 14.

    Ifosfamide and mesna. (1989) Med Lett Drugs Ther 31: 98–99

  15. 15.

    Ihde DC (1992) Chemotherapy of lung cancer. N Engl J Med 327: 1434–1441

  16. 16.

    Livingston RB (1988) Treatment of advanced non-small-cell lung cancer. A Southwest Oncology Group experience. Semin Oncol 15 [Suppl 7]: 37

  17. 17.

    Loehrer PJ, Lauer R, Roth BJ, Williams SD, Kalasinski LA, Einhorn LH (1988) Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 109: 540–546

  18. 18.

    Mortimer JE, Schulman S, MacDonald JS, Kopecky K, Goodman G (1990) High-dose cisplatin in disseminated melanoma: a comparison of two schedules. Cancer Chemother Pharmacol 25: 373–376

  19. 18a.

    Moutain CF (1986) A new international staging system for lung cancer. Chest 89: 2255–2335

  20. 19.

    Paccagnella A, Favretto A, Brandes A, Ghiono C, Fornasiero A, Volpi A, Pappagello G, Fest G, Cipriani A, Vinante O, Chiaron-Sileni V, Fiorentio MV (1990) Cisplatin, etoposide and ifosfamide in non-small-cell lung carcinoma. A phase II randomized study with cisplatin and etoposide as the control arm. Cancer 65: 2631–2634

  21. 20.

    Patterson WP, Khojasteh A (1989) Ifosfamide-induced renal tubular defects. Cancer 63: 649–651

  22. 21.

    Perez EA, Gandara DR (1989) Cisplatin dose intensity: evaluation of current trials and future prospects (monograph). Bristol-Myers Printing, Evansville, Indiana

  23. 22.

    Perez EA, Putney JD, Gandara DR (1989) In vitro dose-response relationship to cisplatin in human non-small-cell lung cancer cell lines. Proc Am Assoc Cancer Res 30: 459

  24. 23.

    Quezado ZM, Wilson WH, Cumnion RE, Parker MM, Reda D, Bryant G, Ognibene FP (1993) High-dose ifosfamide is associated with severe, reversible cardiac dysfunction. Ann Intern Med 118: 31–36

  25. 24.

    Shirinian M, Lee JS, Dhingra HH, Greenberg J, Hong WK (1992) Phase II study of cisplatin, ifosfamide with mesna and etoposide (PIE) chemotherapy for advanced non-small-cell lung cancer. Sem Oncol 19 [Suppl 1]: 49–53

  26. 25.

    Weiss RB (1991) Ifosfamide vs cyclophosphamide in cancer therapy. Oncology 5: 67–86

  27. 26.

    Zalupski M, Baker LH (1988) Ifosfamide. J Natl Cancer Inst 80: 556–566

Download references

Author information

Correspondence to Edith A. Perez.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Perez, E.A., Sowray, P.C., Gardner, S.L. et al. Phase I study of high-dose cisplatin, ifosfamide, and etoposide. Cancer Chemother. Pharmacol. 34, 331–334 (1994).

Download citation

Key words

  • Cisplatin
  • Ifosfamide
  • Phase I