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
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References
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
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
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
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
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
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
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
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
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
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
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
Liu G, Franssen E, Fitch MI and Warner E (1997) Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 15: 110–115
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
McGuire WP and Ozols RF (1998) Chemotherapy of advanced ovarian cancer. Semin Oncol 25: 340–348
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
Parker SL, Tong T, Bolden S and Wingo PA (1997) Cancer statistics, 1997. CA Cancer J Clin 47: 5–27
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
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
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
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
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
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
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Gelderblom, H., Sparreboom, A., Jonge, M. et al. Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer. Br J Cancer 85, 1124–1129 (2001). https://doi.org/10.1054/bjoc.2001.2014
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DOI: https://doi.org/10.1054/bjoc.2001.2014
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