Study Purposes: To determine the maximum-tolerated dose (MTD) of paclitaxel administered by 72-hour continuous infusion followed by bolus intravenous ifosfamide on days 4 and 5 or epirubicin on day 4, every 21 days. To assess the toxicity and preliminary activity in patients with advanced refractory solid tumors. Patients and Methods: Sixteen patients with progressive disease after standard chemotherapy for advanced disease were treated with the combination paclitaxel-ifosfamide and 10 patients with the combination paclitaxel-epirubicin. Results: In the first phase I study the MTDs were: paclitaxel 135 mg/m2 and ifosfamide 2.5 mg/m2/day; hematologic toxicity was the dose-limiting toxicity (DLT) during the first cycle of therapy at dose level 4. Paclitaxel administered at 135 mg/m2 and epirubicin 50 mg/m2 were the MTDs in the second phase I study; grade 4 stomatitis was the DLT of this combination. Conclusions: Paclitaxel by 72-hour continuous infusion followed by bolus ifosfamide was a manageable regimen with an acceptable hematologic toxicity in the absence of neurotoxicity. Preliminary activity of this combination was encouraging in a group of patients with ovarian cancer. The optimal way to combine paclitaxel and epirubicin and the best schedule relative to such a long paclitaxel infusion time in this combination regimen remain to be determined.

Keywords:
Phase I, Paclitaxel, Infusion, continuous, Ifosfamide, Epirubicin
1.
Rowinsky EK, Donehower RC: Paclitaxel. N Engl J Med 1995;332:1004–1014.
2.
Miglietta L, Amoroso D, Bruzzone M, Granetto C, Catsafados E, Mammoliti S, Guarneri D, Pedullà F, Foglia G, Ragni R, Martini MC, Brema F, Addamo G, Moraglio L, Patorino G, Boccardo F: Paclitaxel plus ifosfamide in advanced ovarian cancer: A multicenter phase II study. Oncology 1997;54:102–107.
3.
Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, Spreafico C, Laffranchi A, Caraceni A, Martini C: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer. High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 1995;13:2688–2699.
4.
Conte PF, Baldini E, Gennari A, Michelotti A, Salvadori B, Tibaldi C, Danesi R, Innocenti F, Gentile A, Dell’Anna R, Biadi O, Mariani M, Del Tacca M: Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advanced breast cacer. J Clin Oncol 1997;15:2510–2517.
5.
Beijnen JH, Huizing MT, ten Bokkel Huinink WW, Veenhof CHN, Vermorken JB, Giaccone G, Pinedo HM: Bioanalysis, pharmacokinetics and pharmacodynamics of the novel anticancer drug paclitaxel (Taxol). Semin Oncol 1994;21(suppl 8):53–62.
6.
Lopes NM, Adams EG, Pitts TW, Bhuyan BK: Cell kill kinetics and cell cycle effects of taxol on human and hamster ovarian cell lines. Cancer Chemother Pharmacol 1993;32:235–242.
7.
Wilson WH, Berg SL, Bryant G, Wittes RE, Bates S, Fojo A, Steinberg SM, Goldspiel BR, Herdt J, O’Shaughnessy J, Balis FM, Chabner BA: Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer. A phase I/II trial of 96-hour infusion. J Clin Oncol 1994;12:1621–1629.
8.
Seidman AD, Hochhauser D, Gollub M, Edelman B, Yao T-J, Hudis CA, Francis P, Fennelly D, Gilewski TA, Moynahan ME, Currie V, Baselga J, Tong W, O’Donaghue M, Salvaggio R, Auguste L, Spriggs D, Norton L: Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J Clin Oncol 1996;14:1877–1884.
9.
Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 1981;47:207–214.
10.
Holmes FA, Valero V, Buzdar AU, Booser DJ, Winn R, Tolcher A, Seidman A, Goodwin W, Beraden J, Baysinger L, Hortobagyi GN, Arbuck SA: Final results: Randomized phase III trial of paclitaxel by 3-hr versus 96-hr infusion in patients with metastatic breast cancer. The long and short of it (abstract 426). Proc Am Soc Clin Oncol 1998;17:110.
11.
Liebmann JE, Fisher J, Teague D, Cook JA: Sequence dependence of paclitaxel (Taxol) combined with cisplatin or alkylators in human cancer cells. Oncol Res 1994;6:25–31.
12.
Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, Gianni L, Myles J, van der Burg ME, Kerr I, Vermorken JB, Buser K, Colombo N: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 1994;12:2654–2666.
13.
Wilson WH, Berg S, Kang Y-K, Bates S, Fojo A, Steinberg S, Balis F, Goldspiel B, O’Shaughnessy J, Chabner B, Wittes RE: Phase I/II of taxol 96-hour infusion in refractory lymphoma and breast cancer: Pharmacodynamics and analysis of multi-drug resistance (mdr-1) (abstract 335). Proc Am Soc Clin Oncol 1993;12:134.
14.
Bunnell CA, Thompson L, Buswell L, Berkowitz R, Muto M, Sheets E, Shulman LN: A phase I trial of ifosfamide and paclitaxel with granulocyte-colony stimulating factor in the treatment of patients with refractory solid tumors. Cancer 1998;82:561–566.
15.
Tolcher AW, Cowan KH, Noone MH, Denicoff AM, Kohler DR, Goldspiel BR, Barnes CS, McCabe M, Gossard MR, Zujewski J, O’Shaughnessy JA: Phase I study of paclitaxel in combination with cyclophosphamide and granulocyte colony-stimulating factor in metastatic breast cancer patients. J Clin Oncol 1996;14:95–102.
16.
Cavaletti G, Bogliun G, Marzorati L, Zincone A, Marzola M, Colombo N, Tredici G: Peripheral neurotoxicity of taxol in patients previously treated with cisplatin. Cancer 1995;75:1141–1150.
17.
Cavaletti G, Bogliun G, Crespi V, Marzorati L, Zincone A, Marzola M, Rota S, Galli A, Tredici P, Tredici G: Neurotoxicity and ototoxicity of cisplatin plus paclitaxel in comparison to cisplatin plus cyclophosphamide in patients with epithelial ovarian cancer. J Clin Oncol 1997;15:199–206.
18.
Georgiadis MS, Schuler BS, Brown JE, Kieffer LV, Steinberg SM, Wilson WH, Takimoto CH, Kelley MJ, Johnson BE: Paclitaxel by 96-hour continuous infusion in combination with cisplatin: A phase I trial in patients with advanced lung cancer. J Clin Oncol 1997;15:735–743.
19.
Holmes FA, Madden T, Newman RA, Valero V, Theriault RL, Fraschini G, Walters RS, Booser DJ, Buzdar AU, Willey J, Hortobagyi GN: Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1996;14:2713–2721.
20.
Sledge GW, Goldstein RN, Sparano J, Cobleigh M, Maughman C, Neuberg D, Rowinsky E: Phase I trial of Adriamycin (A) + Taxol (T) in metastatic breast cancer (MBC) (abstract 421). Eur J Cancer 1993;29A(suppl 6):S81.
© 2001 S. Karger AG, Basel
2001
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.