Abstract
We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with ≥ 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150–775 mg/m2infused over 24 hours, doxorubicin 165 mg/m2as a continuous infusion over 96 hours, and cyclophosphamide 100 mg kg–1. There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775 mg/m2dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan–Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51–83%) and 77% (95% CI; 64–93%). Paclitaxel up to 725 mg/m2infused over 24 hours in combination with with doxorubicin 165 mg/m2and cyclophosphamide 100 mg kg–1is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing. © 2001 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Antman KH, Rowlins PA, Vaughan WP, Pelz CJ, Fay J, Fields K, Freytes C, Gale RP, Hillner B, Holland K, Kennedy J, Klein J, Lazarus H, McCarthy P, Saez R, Spitzer G, Stadtmauer E, Williams S, Wolff S, Sobocinski K, Armitage J and Horowitz M (1997) High-dose chemotherapy with autologous hematopoietic support for breast cancer in North America. J Clin Oncol 15: 1870–1879
Bronchud MH, Howell A, Crowther D, Hopwood P, Souza L and Dexter TM (1989) The use of granulocyte colony-stimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer. Brit J Cancer 60: 121–125
Brown T, Havlin K, Weiss G, Cagnola J, Koeller J, Kuhn J, Rizzo J, Craig J, Phillips J and Von Hoff D (1991) A phase I trial of Taxol given by 6-hour intravenous infusion. J Clin Oncol 9: 1261–1267
Doroshow JH, Somlo G, Ahn C, Baker P, Rincon A, Forman S, Akman S, Chow W, Coluzzi P, Hamasaki V, Leong L, Margolin K, Molina A, Morgan R, Rashko J, Shibata S, tetef M, Yen Y and Brent J (1995) Prognostic factors predicting progression-free (PFS) and overall survival (OS) in patients (PTS) with responsive metastatic breast cancer (MBC) treated with high-dose chemotherapy (HDCT) and bone marrow stem cell reinfusion. Proceedings of Asco Vol. 14, Los Angeles, CA
Gianni L, Kearns CM, Gianni A, Capri G, Vigano L, Lacatelli A, Bonadonna G and Egorin MJ (1995) Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13: 180–190
Gianni L, Vigano L, Locatelli A, Capri G, Giani A, Tarenzi E and Bonadonna G (1997) Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in women with breast cancer. J Clin Oncol 15: 1906–1915
Gluck S, Germond C, Lopez P, Cano P, Doreen M, Koski T, Arnold A, Dulude H and Gallant G (1998) A phase I trial of high-dose paclitaxel, cyclophosphamide and mitoxantrone with autologous blood stem cell support for the treatment of metastatic breast cancer. Eur J Cancer 34: 1008–1014
Greinix H, Linkesh W, Seifert M, Kubista E, Czerwenka K, Elahi F, Zielinski C, Hoecker P, Steger G, Schulenberg A, Neumeister G, Rabitsch W, Jakesz R and Kalhs P (2000) Paclitaxel-containing high-dose chemotherapy in high-risk breast cancer patients. Acta Oncol 39: 47–52
Henderson I, Berry D, Demetri G, Cirrincione C, Goldstein L, Martino S, Ingle J, Cooper M, Canellos G, Borden E, Fleming G, Holland J, Graziano S, Carpenter J and Muss H < Norton L for CALGB, ECOG, SWOG, NCCTG (1998) Improved disease-free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer. Proceedings of Asco Vol. 17, pp. 101a, Los Angeles, CA
Holmes FA, Walters RS, Theriault RL, Forman AD, Newton LK, Raber M, Buzdar A, Frye D and Hortobagyi GN (1991) Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83: 1797–1805
Hortobagyi G, Buzdar A, Theriault R, Valero V, Booser D, Frye D, Holmes F, Giralt S, Khouri I, Andersson B, Gajewski J, Rondon G, Smith T, Singletary SE, Ames F, Sneige N, Strom E, McNeese M, Deisseroth A and Champlin R (2000) Lack of efficacy of adjuvant high-dose tandem combination chemotherapy for high-risk primary breast cancer – A randomized trial. J Natl Cancer Inst 92: 225–233
Kaplan EL and Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481
Lotz JP, Cure H, Janvier M, Morvan F, Legros M, Asselain B, Guillemot M, Roche H and Gisselbrecht C (1999) [Intensive chemotherapy and autograft of hematopoietic stem cells in the treatment of metastatic cancer: results of the national protocol Pegase 04]. Intensification therapeutique et autogreffe de cellules souches hematopoietiques (CSH) dans le traitment des cancers du sein metastatiques: results du programme national Pegase 04. Hematol Cell Ther 41: 71–74
Mamounas E, Brown A, Smith R, Lembersky B, Fisher B, Wickerham D, Wolmark N, Atkins J, Shibata H, Baez L, DeFusco P, Davila E, Thirwell M, Bearden J, Tipping A and Scholnick A (1998) Effect of taxol duration of infusion in advanced breast cancer: Results from NSABP B-26 trial comparing 3- to 24 hour infusion of high-dose taxol. Proceedings of Asco Vol.17, pp. 101a: Los Angeles, CA
McCloskey DE, Kaufman SH and Prestigiacomo LJ: (1996) Paclitaxel induces programmed cell death in MDA-MB-468 human breast cancer cells. Clin Cancer Res 2: 847–854
O’Shaughnessy JA, Fisherman JS and Cowan KH (1994) Combination paclitaxel (Taxol) and doxorubicin therapy for metastatic breast cancer. Sem Oncol 21: 12–23
Peters WP, Ross M, Vredenburg JJ, Meisenberg B, Marks LB, Winer E, Kurtzberg J, Bast RC Jr, Jones R, Shpall E, Wu K, Rosner G, Gilbert C, Mathias B, Coniglio D, Petros W, Henderson IC, Norton L, Weiss RB<Budman DR and Hurd D (1993) High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 11: 1132–1143
Peters W, Rosner G, Vredenburgh J, Shpall E, Crump M, Richardson P, Marks L, Cirrincione C, Wood W, Henderson I, Hurd D and Norton L for CALGB, SWOG and NCIC (1999) A prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Proceedings of Asco Vol.18, pp.1: Atlanta, GA
Reichman BS, Seidman AD, Crown JPA, Heelan R, Hakes R, Lebwohl D, Gilewski T, Surbone A, Currie V and Hudis CA, Yao T, Klecker R, Jamis-Dow C, Collins J, Quinlivan S, Berkery R, Taomasi F, Canetta R, Fisherman J, Arbuck S and Norton L (1993) Paclitaxel and recombinant human granulocyte-colony stimulating factor as initial chemotherapy for metastatic breast cancer. J Clin Oncol 11: 1943–1951
Riley CA, Crom WR and Evans WE (1985) Loop-column extraction and liquid chromatographic analysis of doxorubicin and three metabolites in plasma. Therapeutic Drug Monitoring 7: 455–460
Rizzo J, Riley C, Von Hoff D, Kuhn J, Phillips J and Brown T (1990) Analysis of anticancer drugs in biological fluids: Determination of Taxol with application to clinical pharmacokinetics. J Pharmaceut Biomed Anal 8: 159–164
Rodenhuis S, Richel D, van der Wall E, Schornagel J, Baars J, Koning C, Peterse J, Borger J, Nooijen W, Bakx R and Dalesio O (1998) A randomized trial of high-dose chemotherapy and hematopoietic progenitor cell support in operable breast cancer with extensive axillary lymph node involvement. Lancet 352: 515–521
Rodenhuis S, Bontenbal M, Beex L, van der Wall E, Richel D, Nooij M, Voest E, Hupperets P, Westermann A, Dalesio O and de Vries E (2000) Randomized phase III study of high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin in operable breast cancer with 4 or more axillary lymph nodes (2000). Proceedings of Asco Vol. 19, pp. 74a: New Orleans, LA
Somlo G, Doroshow JH, Forman SJ, Leong L, Margolin K, Morgan R Jr., Raschko J, Akman S, Ahn C, Nagasawa S, Harrison J, Stein A, Smith E, Sniecinski I and Schmidt G (1994) High-dose doxorubicin, etoposide and cyclophosphamide with stem cell reinfusion in patients with metastatic or high-risk primary breast cancer. Cancer 73: 1678–1685
Somlo G, Doroshow JH, Forman SJ, Odom-Maryon T, Lee J, Chow W, Hamasaki V, Leong L, Morgan R Jr, Margolin K, Raschko J, Shibata S, Tetef M, Yen Y, Simpson J and Molina A (1997a) High-dose chemotherapy and stem cell rescue in the treatment or high-risk breast cancer: Prognostic indicators of progression-free and overall survival. J Clin Oncol 15: 2882–2893
Somlo G, Sniecinski I, Odom-Maryon T, Nowicki B, Chow W, Hamasaki V, Leong L, Margolin K, Morgan, Jr R, Raschko J, Shibata S, Tetef M, Molina A, Berenson R, Forman S and Doroshow JH (1997b) The effect of CD34 + selection and various schedules of stem cell reinfusion and priming on hematopoietic recovery following high-dose chemotherapy for breast cancer. Blood 89: 1521–1528
Sonnichsen D, Hurwitz C, Pratt C, Shuster J and Relling MV (1994) Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumors. J Clin Oncol 12: 532–538
Stadtmauer E, O'Neill A, Goldstein L, Criley P, Mangan K, Ingle J, Brodsky I, Martino S, Lazarus H, Erban J, Sickles C, Glick J and the Philadelphia Transplant Group (2000) Conventional-dose chemotherapy compared to high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 342: 1069–1076
Stemmer S, Cagnoni PJ, Shpall EJ, Bearman S, Matthes S, Dufton C, Day T, Taffs S, Hami L, Martinez C, Purdy M, Arron J and Jones RB (1996) High-dose paclitaxel, cyclophosphamide and cisplatin with autologous hematopoietic support: a phase I trial. J Clin Oncol 14: 1463–1472
Synold TW and Doroshow JH (1996) Anthracycline dose intensity: clinical pharmacology and pharmacokinetics of high-dose doxorubicin administered as a 96-hour continuous intravenous infusion. J Infusional Chemother 6: 69–73
Vahdat LT, Papadopuoloski K, Balmaceda C, McGovern T, Dunleavy J, Kaufman E, Fung B, Garrett T, Savage D, Tiersten A, Ayello J, Bagiella E, Heitjan D, Antman K and Hesdorffer C (1998) Phase I trial of sequential high-dose chemotherapy with escalating dose paclitaxel, melphalan and cyclophosphamide, thiotepa and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer. Clin Cancer Res 4: 1689–1695
Williams SF, Mick R, Desser R, Golick J, Beschorner J and Bitran J (1989) High-dose consolidation therapy with autologous stem cell rescue in stage IV breast cancer. J Clin Oncol 7: 1824–1830
Wilson WH, Berg SL, Bryant G, Wittes R, Bates S, Fojo A, Steinberg S, Goldspiel B, Herdt J, O’Shaughnessy J, Balis F and Chabner B (1994) Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: A phase I/II trial of 96 hour infusion. J Clin Oncol 12: 1621–1629
Wood WC, Budman DR, Korzun AH, Cooper M, Younger J, Hart R, Moore A, Ellerton J, Norton L, Ferree C, Ballow A, Frei E III and Henderson I (1994) Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330: 1253–1259
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Somlo, G., Doroshow, J., Synold, T. et al. High-dose paclitaxel in combination with doxorubicin, cyclophosphamide and peripheral blood progenitor cell rescue in patients with high-risk primary and responding metastatic breast carcinoma: toxicity profile, relationship to paclitaxel pharmacokinetics and short-term outcome. Br J Cancer 84, 1591–1598 (2001). https://doi.org/10.1054/bjoc.2001.1835
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.1835
This article is cited by
-
Paclitaxel Induces Acute Pain via Directly Activating Toll like Receptor 4
Molecular Pain (2015)
-
Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity
The Pharmacogenomics Journal (2011)
-
Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer
The Pharmacogenomics Journal (2011)
-
Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer
The Pharmacogenomics Journal (2007)
-
Short- and long-term cause-specific survival of patients with inflammatory breast cancer
BMC Cancer (2005)