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. 1991 Jul;117(Suppl 4):S208–S213. doi: 10.1007/BF01613229

Escalating doses of carboplatin with high-dose ifosfamide using autologous bone marrow as support: a phase I study

Anthony D Elias 1,2,✉, Lois J Ayash 1,2, J Paul Eder 1,2, Cathy Wheeler 1,2, Joan Deary 1,2, Lisa Weissman 1,2, Myla Hunt 1,2, John Critchlow 1,2, Lowell Schnipper 1,2, Emil Frei III 1,2, Karen H Antman 1,2
PMCID: PMC12200037  PMID: 1795009

Abstract

In this phase I study, 16 adult cancer patients were treated with concurrent 4-day continuous infusions of ifosfamide at 12 g/m2 and escalating doses of carboplatin (400–1600 mg/m2) to determine the major non-haematological dose-limiting toxicity of the combination. Mesna was given by continuous infusion over 5 days for uroprotection (total dose per course=15 g/m2). Autologous bone marrow support, which was mandated for subsequent dose levels once granulocytes remained below 500/μl for more than 14 days in at least 2 patients entered at a given dose level, was used at dose levels above 400 mg/m2 carboplatin. Renal toxicity became doselimiting at the maximum tolerated dose level of 1600 mg/ m2 carboplatin. Temporary creatinine elevations above 2 mg/dl (median peak 2.6 mg/dl) were observed in 3 and irreversible renal toxicity occurred in 1 (peak creatinine 6.9 mg/dl, chronic creatinine 5–6 mg/dl) of the 5 patients entered at this dose level. Severe confusion and lethargy associated with rising creatinine developed in 2 patients. Two complete and four partial responses were documented in 14 heavily pretreated evaluable patients. The complete responses continue at 14+ and 20+ months in a patient with germ cell carcinoma and Ewing's sarcoma, respectively. Carboplatin appears to contribute to the renal toxicity of ifosfamide. Nevertheless, the combination of carboplatin and ifosfamide at 80% and 75% of the single-agent maximal tolerated doses respectively produced acceptable non-haematological toxicity. Further studies in the treatment of sarcoma, germ cell, ovarian and lung carcinomas with this combination are warranted.

Key words: High-dose ifosfamide, Carboplatin, Bonemarrow

Footnotes

Supported in part by a grant from the Mathers Foundation and by Public Health Service Grant CA 13849 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. A.D.E. and J.P.E. are recipients of American Cancer Society Career Development Awards

References

  1. Alberts DS, Mason-Liddil N (1989) Carboplatin in the treatment of ovarian cancer. Semin Oncol 16 [Suppl 5]:19–26 [PubMed] [Google Scholar]
  2. Alberts D, Green S, Hannigan E et al. (1989) Improved efficacy of carboplatin (carbo P)/cyclophosphamide (CPA) vs cisplatin (cisP)/CPA: preliminary report of a phase III randomized trial in stages III–IV, suboptimal ovarian cancer (OV CA). Proc Am Soc Clin Oncol 8:151 [C-588] [Google Scholar]
  3. Allen LM, Creaven PJ (1972) Effect of microsomal activation on interaction between ifosfamide and DNA. J Pharm Sci 61:2009–2011 [DOI] [PubMed] [Google Scholar]
  4. Antman KH, Ryan L, Elias A, Sherman D, Grier HE (1989) Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 7:126–131 [DOI] [PubMed] [Google Scholar]
  5. Araujo C, Cervellino J, Tessler J (1982) Combined modality therapy with DTIC (D), cyclophosphamide (C), methotrexate (M) vs. D, ifosfamide and M in non-squamous cell lung cancer (abstract). In: Proc. 13th International Cancer Congress, Seattle, p 351
  6. Bramwell V, Mouridsen H, Santoro G et al. (1987) Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcoma. Eur J Cancer Clin Oncol 23:311–321 [DOI] [PubMed] [Google Scholar]
  7. Brock N (1972) Pharmacological studies with ifosfamide -a new oxazaphosphorine compound. In: Semonsky M, Heizler M, Masak S (eds) Advances in antimicrobial and antineoplastic chemotherapy, vol 2. University Park Press, Baltimore, pp 749–756 [Google Scholar]
  8. Brock N, Pohl J, Stekar J, Scheef W (1982) Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention: III. Profile of action of sodium 2-mercaptoethane sulfonate (mesna). Eur J Cancer Clin Oncol 18:1377–1387 [DOI] [PubMed] [Google Scholar]
  9. Canetta R, Bragman K, Smaldone L et al. (1988) Carboplatin: current status and future prospects. Cancer Treat Rev 15 [Suppl B]:17–32 [DOI] [PubMed] [Google Scholar]
  10. Case DC, Anderson J, Ervin TJ, Gottlieb A (1988) Phase II trial of ifosfamide and mesna in previously treated patients with non-Hodgkin's lymphoma: Cancer and Acute Leukemia Group B Study 8552. Med Pediatr Oncol 16:182–186 [DOI] [PubMed] [Google Scholar]
  11. Costanzi JJ, Gagliano R, Loukas D, Panettiere FJ, Hokanson JA (1978) Ifosfamide in the treatment of recurrent or disseminated lung cancer. A phase II study of two dose schedules. Cancer 41:1715–1719 [DOI] [PubMed] [Google Scholar]
  12. Curt GA, Grygiel JJ, Corden BJ et al. (1983) A phase I and pharmacokinetic study of diamminecyclobutane-dicarboxylatoplatinum (NSC 241240). Cancer Res 43:4470–4473 [PubMed] [Google Scholar]
  13. Drings P (1987) Ifosfamide in the treatment of bronchial carcinoma. Contrib Oncol 26:294–318 [Google Scholar]
  14. Druckrey H (1973) Krebs — Experimentelle Ursachenforschung und Chemotherapie. Z Krebsgeschehen 5:73 [Google Scholar]
  15. Elias AD, Ryan L, Sulkes A, Collins J, Aisner J, Antman KH (1989) The response of 108 previously untreated patients with metastatic or unresectable sarcoma to mesna, Adriamycin, ifosfamide and dacarbazine (MAID). J Clin Oncol 7:1208–1216 [DOI] [PubMed] [Google Scholar]
  16. Elias AD, Eder JP, Shea T, Begg CB, Frei E III, Antman KH (1990) High-dose ifosfamide with mesna uroprotection: a phase I study. J Clin Oncol 8:93–100 [DOI] [PubMed] [Google Scholar]
  17. Goldin A (1987) Ifosfamide in experimental tumor systems. Semin Oncol 9:14–23 [PubMed] [Google Scholar]
  18. Goren MP, Wright RK, Pratt CB, Pell E (1986) Dechloroethylation of ifosfamide and neurotoxicity. Lancet II, 1219–1220 [DOI] [PubMed] [Google Scholar]
  19. Goren MP, Wright RK, Horowitz ME, Pratt CB (1987a) Ifosfamide —induced subclinical tubular nephrotoxicity despite mesna. Cancer Treat Rep 71:127–130 [PubMed] [Google Scholar]
  20. Goren MP, Wright RK, Pratt CB et al. (1987b) Potentiation of ifosfamide neurotoxicity, hematopoietic toxicity and tubular nephrotoxicity by prior cisplatin therapy. Cancer Res 47:1457–1460 [PubMed] [Google Scholar]
  21. Klastersky J (1988) Cisplatin and carboplatin in combination with etoposide as a treatment for NSCLC: the experience of the EORTC Lung Cancer Working Party. Cancer Treat Rev 15 [Suppl B]:33–40 [DOI] [PubMed] [Google Scholar]
  22. Meanwell C, Blackledge G, Mould J et al. (1987) Studies of chemotherapy in cervical cancer. Contrib Oncol 26:176–192 192 [Google Scholar]
  23. Mehta CR, Patel NR, Tsiatis AA (1984) Exact significance testing to establish treatment equivalence with ordered categorical data. Biometrics 40:819–825 [PubMed] [Google Scholar]
  24. Motzer RH, Bosl GH, Tauer K et al. (1987) Phase II trial of carboplatin in patients with advanced germ cell tumors refractory to cisplatin. Cancer Treat Rep 71:197–198 [PubMed] [Google Scholar]
  25. Pratt CB, Green AA, Horowitz M et al. (1986) Central nervous system toxicity following treatment of pediatric subjects with ifosfamide/mesna. J Clin Oncol 4:1253–1261 [DOI] [PubMed] [Google Scholar]
  26. Posey LE, Morgan LE, Carter RD et al. (1978) A comparison of cyclophosphamide and ifosfamide in advanced bronchogenic carcinoma. Proc Am Soc Clin Oncol 19:388 [C-326] [Google Scholar]
  27. Shea TC, Flaherty M, Elias A, Eder JP, Antman K, Begg C, Schnipper L, Frei E III, Henner WD (1989) A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support. J Clin Oncol 7:651–661 [DOI] [PubMed] [Google Scholar]
  28. Smith IE et al. (1985) Carboplatin: a very new active cisplatin analog in the treatment of small cell lung cancer. Cancer Treat Rep 69:43–46 [PubMed] [Google Scholar]
  29. Sutton GP, Blessing JA, Homesley HD, Berman ML, Malfetano J (1989) Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 7:1672–1676 [DOI] [PubMed] [Google Scholar]
  30. Wheeler BM, Loehrer PJ, Williams SD, Einhorn LD (1986) Ifosfamide in refractory male germ tumors. J Clin Oncol 4:28–34 [DOI] [PubMed] [Google Scholar]
  31. Wiltshaw E, Evans B, Harland S (1985) Phase III randomized tiral of cisplatin versus JM8 (carboplatin) in 112 ovarian cancer patients, stages III and IV. Proc Am Soc Clin Oncol 4:121 [Google Scholar]
  32. Wiltshaw E, Perren TJ, Fryatt ID, Blake PR, Harper P, Slevin M for the London Gynaecological Oncology Group (1990) Carboplatin and ifosfamide in ovarian cancer: Phase II and III trials. Cancer Chemother Pharmacol 26 [Suppl]:48–50 [DOI] [PubMed] [Google Scholar]

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