Regular Article

British Journal of Cancer (2001) 85, 1124–1129. doi:10.1054/bjoc.2001.2014 www.bjcancer.com
Published online 16 October 2001

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer

H Gelderblom1,5, A Sparreboom1, M J A de Jonge1, W J Loos1, E Wilms2, M A Mantel1, B Hennis3, I Camlett4, J Verweij1 and M E L van der Burg1

  1. 1Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 AE Rotterdam, The Netherlands
  2. 2Department of Pharmacy, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 AE Rotterdam, The Netherlands
  3. 3SmithKline Beecham Pharmaceuticals, Zeist, The Netherlands
  4. 4Glaxo SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (South), Third Avenue, Harlow, Essex CM19 5AW, UK
  5. 5Department of Clinical Oncology, Leiden University Medical Centre, KI-p, PO Box 9600, 2300 RC Leiden, The Netherlands

Received 16 February 2001; Revised 11 June 2001; Accepted 5 July 2001.

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Abstract

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m–2d–1on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m–2d–1, experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m–2d–1) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m–2d–1). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m–2d–1in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords:

cisplatin, oral topotecan, cremophor EL, ovarian cancer

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References

  1. Badary OA, Abdel-Naim AB, Khalifa AE and Hamada FMA (2000) Differential alteration of cisplatin cytotoxicity and myelotoxicity by the vehicle Cremophor EL. Naunyn-Schmiedeberg Arch Pharmacol 361: 339–334
  2. Chou TC, Motze RJ, Tong Y and Bosl GJ (1994) Computerised quantitation of synergism and antagonism of Taxol, Topotecan and Cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst 86: 1517–1524 | Article | PubMed | ChemPort |
  3. Ciesielski-Carlucci C, Leong P and Jacobs C (1997) Case report of anaphylaxis from cisplatin/paclitaxel and a review of their hypersensitivity reaction profiles. Am J Clin Oncol (CCT) 20: 373–375
  4. Creemers GJ, Bolis G, Gore M, Scarfone G, Lacave AJ, Guastalla JP, Despax R, Favalli G, Kleinberg R, van Belle S, Hudson I, Verweij J and ten Bokkel Huinink WW (1994) Topotecan, an active drug in the second line treatment of epithelian ovarian cancer: Results of a large European Phase II study. J Clin Oncol 12: 1748–1753 | PubMed | ISI | ChemPort |
  5. de Jonge MJA, Loos WJ, Gelderblom HJ, Planting AST, van der Burg MEL, Sparreboom A, Brouwer E, van Beurden V, Mantel M, Doyle E, Hearn S, Ross G and Verweij J (2000) Phase I and pharmacological study of oral topotecan and intravenous cisplatin: sequence-dependent haematologic side effects. J Clin Oncol 18: 2104–2115 | PubMed | ISI | ChemPort |
  6. de Vos Al, Nooter K, Verweij J, Loos WJ, Brouwer E, de Bruijn E, Ruijgrok EJ, van der Burg MEL, Stoter G and Sparreboom A (1997) Differential modulation of cisplatin accumulation in leukocytes and tumour cell lines by the paclitaxel vehicle Cremophor EL. Ann Oncol 8: 1145–1150 | Article | PubMed | ISI | ChemPort |
  7. Gelderblom H, Loos WJ, Verweij J, Brouwer E, van der Burg MEL and Sparreboom A (2000a). Modulation of cisplatin pharmacodynamics by Cremophor EL: Experimental and clinical studies, Submitted
  8. Gelderblom H, Loos WJ, de Jonge MJA, Sparreboom A, Planting AST, van der Burg MEL, Brouwer E, Verheij C, Ouwens L, Hearn S and Verweij J (2000b) Phase I and pharmacological study of increased dose oral topotecan in combination with intravenous cisplatin. Ann Oncol 11: 1205–1207
  9. Gerrits CJH, Burris H, Schellens JHM, Planting AST, van der Burg MEL, Rodriguez GL, van Beurden V, Loos WJ, Hudson I, Fields S, Verweij J and Von Hoff DD (1998) Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours. Eur J of Cancer 34: 1030–1035
  10. Gore M, Rustin G, Calvert H, Bezwoda W, Carmichael J, Oza A, Kaye S, ten Bokkel Huinink W, Malfetano J, Falkson G, Clarke-Pearson D, Ross GA, Dane GC and Fields SZ (1998) A multicentre randomized phase III study of topotecan administered intravenously or orally for advanced epithelial ovarian carcinoma. Proc ASCO 17: 1346
  11. Hochster H, Liebes L, Speyer J, Sorich J, Taubes B, Oratz R, Wernz J, Chachoua A, Blum RH and Zeleniuch-Jacquotte A (1994) Phase 1 trial of low continuous topotecan infusion in patients with cancer: An active and well tolerated regimen. J Clin Oncol 12: 553–559 | PubMed | ChemPort |
  12. Liu G, Franssen E, Fitch MI and Warner E (1997) Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 15: 110–115 | PubMed | ISI | ChemPort |
  13. Ma J, Verweij J, Planting AST, Kolker HJ, Loos WJ, de Boer-Dennert M, van der Burg MEL, Stoter G and Schellens JHM (1996) Docetaxel and paclitaxel inhibit DNA adduct formation and intracellular accumulation of cisplatin in human leukocytes. Cancer Chemother Pharmacol 36: 382–382
  14. McGuire WP and Ozols RF (1998) Chemotherapy of advanced ovarian cancer. Semin Oncol 25: 340–348 | PubMed | ChemPort |
  15. Miller AA, Hargis BJ, Lilenbaum RC, Fields SZ, Rosner GL and Schilsky RL (1994) Phase 1 study of topotecan and cisplatin in patients with advanced solid tumours: a cancer and leukemia group B study. J Clin Oncol 12: 2743–2750 | PubMed | ISI | ChemPort |
  16. Parker SL, Tong T, Bolden S and Wingo PA (1997) Cancer statistics, 1997. CA Cancer J Clin 47: 5–27 | PubMed | ISI | ChemPort |
  17. Romanelli S, Perego P, Pratesi G, Carenini N, Tortoreto M and Zunino F (1998) In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems. Cancer Chemother Pharmacol 41: 385–390 | Article | PubMed | ChemPort |
  18. Rowinsky EK, Kaufmann SH, Baker SD, Grochow LB, Chen T-L, Peereboom D, Bowling MK, Sartorius SE, Ettinger DS, Forastiere AA and Donehower RC (1996) Sequences of topotecan and cisplatin: Phase 1, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 14: 3074–3084 | PubMed | ISI | ChemPort |
  19. Swisher EM, Mutch DG, Rader JS, Elbendary A and Herzog TJ (1997) Topotecan in Platinum-and Paclitaxel-resistant ovarian cancer. Gyn Oncol 66: 480–486
  20. ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I, Broom C, Scarabelli C, Davidson N, Spanczynski M, Bolis G, Malmstrom H, Coleman R, Fields SC and Heron JF (1997) Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 15: 2183–2193 | PubMed | ChemPort |
  21. van der Burg MEL, Logmans A, de Wit R, van Lent M, Kruit WJH, Stoter G and Verweij J (1996) Weekly high dose cisplatin and oral vepesid: a highly active regimen for ovarian cancer failing on or relapsing after conventional platinum containing combination chemotherapy. Proc ASCO 15: 722
  22. van der Burg MEL, de Wit R, Stoter G and Verweij J (1998) Phase 1 study of weekly cisplatin and weekly or 4-weekly taxol: a highly active regimen in advanced epithelian cancer. Proc ASCO 17: 1370