Abstract
The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m2). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity. © 2001 Cancer Research Campaign
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
Adinoff B, Bone GH and Linnoila M (1988) Acute ethanol poisoning and the ethanol withdrawal syndrome. Med Toxicol 3: 172–196
Cavaletti G, Bogliun G, Marzorati L, Zincone A, Marzola M, Colombo N and Tredici G (1995) Peripheral neurotoxicity of Taxol in patients previously treated with Cisplatin. Cancer 75: 1141–1150
Chang SM, Kuhn JG, Rizzo J, Robins HI, Schold SC Jr, Spence AM, Berger MS, Mehta MP, Bozik ME, Pollack I, Gilbert M, Fulton D, Rankin C, Malec M and Prados MD (1998) Phase I study of paclitaxel in patients with recurrent malignant glioma: a North American brain tumor consortium report. J Clin Oncol 16: 21888–22194
Chapuis B, Helg C, Jeannet M, Zulian G, Huber P and Gumovski P (1985) Anaphylactic reaction to intravenous cyclosporine. N Englj Med 312: 1259
Donfrancesco A, Deb G, De Sio L, De Laurentis C, Fidani P, Cozza R, Jenkner A, Castellano A and Habetswallner D (1996) Phase I–II trial of Taxol according to Q4D regimen in pediatric patients with recurrent solid tumors. Med Pediatr Oncol 27: 211 (abstr O2)
Eiseman JL, Eddington ND, Leslie J, MacAuley C, Sentz DL, Zuhowski M, Kujawa JM, Young D and Egorin MJ (1994) Plasma pharmacokinetics and tissue distribution of paclitaxel in CD2F1mice. Cancer Chemother Pharmacol 34: 465–471
Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, Gianni L, Myles J, van deBurg MEL, Kerr I, Vermorken JB, Buser K, Colombo N, Bacon M, Santabarbara P, Onetto N, Winograd B and Canetta R (1994) European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 12: 2654–2666
Ellenhorn M (1997) Alcohols and glycols. In: Medical toxicology, 2nd edn, Ellenhorn (ed) pp. 1127–1147, William and Wilkins: Baltimore
Gaspard MH, Maraninchi D, Stoppa AM, Gastaut JA, Michel G, Tubiana N, Blaise D, Novakovitch G, Rossi JF, Weiller PJ, Sainty D, Horchowski N and Carcassone Y (1988) Intensive chemotherapy with high doses of BCNU, Etoposide, Cytosine Arabinoside and Melphalan (BEAM) followed by autologous bone marrow transplantation: toxicity and antitumor activity in 26 patients with poor-risk malignancies. Cancer Chemother Pharmacol 22: 256–262
Gianni L, Kearns CM, Giani 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
Glantz MJ, Choy H, Kearns CM, Mills PC, Wahlberg LU, Zuhowski EG, Calabresi P and Egorin MJ (1995) Paclitaxel disposition in plasma and central nervous system of humans and rats with brain tumors. J Natl Cancer Inst 87: 1077–1081
Glantz MJ, Choy H, Kearns CM, Cole BF, Mills P, Zuhowski EG, Saris S, Rhodes CH, Stopa E and Egorin MJ (1996) Phase I study of weekly outpatient Paclitaxel and concurrent cranial irradiation in adults with astrocytomas. J Clin Oncol 14: 600–609
Gluck S, Germond C, Lopez P, Cano P, Dorreen 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
Huizing MT, Keung AC, Rosing H, van der Kuij V, ten Bokkel Huinink WW, Mandjes IM, Dubbelman AC, Pinedo HM and Beijnen JH (1993) Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 11: 2127–2135
Hurwitz CA, Relling MV, Weitman SD, Ravindranath Y, Vietti TJ, Strother DR, Ragab AH and Pratt CB (1993) Phase I trial of Paclitaxel in children with refractory solid tumors: a pediatric oncology group study. J Clin Oncol 11: 2324–2329
Kearns CM, Gianni L and Egorin MJ (1995) Paclitaxel pharmacokinetics and pharmacodynamics. Sem Oncol 22: 16–23
Landers DF (1983) Alcoholic coma and some associated conditions. Am Fam Physician 28: 219–222
Lansky SB, List MA, Lansky LL, Ritter-Sterr C and Miller DR (1987) The measurement of performance in childhood cancer patients. Cancer 60: 1651–1656
Litovitz T (1986) The alcohols: ethanol, methanol, isopropanol, ethylene glycol. Pediatr Clin North Am 33: 311
McLeod HL, Baker DK Jr, Pui CH and Rodman JH (1991) Somnolence, hypotension and metabolic acidosis following high-dose teniposide in children with leukaemia. Cancer Chemother Pharmacol 29: 150–154
Magalini SC, Nanni G, Agnes S, Citterio F and Castagneto M (1986) Anaphylactic reaction to first exposure to cyclosporine. Transplantation 42: 443–444
Martin N, Catalin J, Blachon MF and Durand A (1998) Assay of paclitaxel (Taxol) in plasma and urine by high-performance liquid chromatography. J Chromatogr Biomed Applic 709: 281–288
Moss MH (1970) Alcohol-induced hypoglycemia and coma caused by alcohol sponging. Pediatrics 46: 445–447
Namouni F, Doz F, Tanguy ML, Quintana E, Michon J, Pacquement H, Bouffet E, Gentet JC, Plantaz D, Lutz P, Vannier JP, Validire P, Neuenschwander S, Desjardins L and Zucker JM (1997) High dose chemotherapy with Carboplatin, Etoposide and Cyclophosphamide followed by hematopoietic stem cell rescue in patients with high risk retinoblastoma: a SFOP and SFGM study. Eur J Cancer 33: 2368–2375
Nolte H, Carstensen H and Hertz H (1988) VM-26 (teniposide)-induced hypersensitivity and degranulation of basophils in children. Am J Pediatr Hematol Oncol 10: 308–312
Rischin D, Webster LK, Millward MJ, Linahan BM, Toner GC, Woollett AM, Morton CG and Bishop JF (1996) Cremophor pharmacokinetics in patients receiving 3-, 6- and 24-hour infusions of paclitaxel. J Natl Cancer Inst 18: 1297–1301
Rowinsky EK and Donehower RC (1995) Paclitaxel (Taxol). N Engl J Med 332: 1004–1014
Schiller JH, Storer B, Tutsch K, Arzoomanian R, Alberti D, Feierabend C and Spriggs D (1994) Phase I trial of 3-hour infusion of paclitaxel with or without granulocyte colony-stimulating factor in patients with advanced cancer. J Clin Oncol 12: 241–248
Seibel NL, Blaney SM, O’Brien M, Krailo M, Hutchinson R, Mosher RB, Balis FM and Reaman GH (1999) Phase I trial of docetaxel with filgrastim support in pediatric patients with refractory solid tumors: a collaborative Pediatric Oncology Branch, National Cancer Institute and Children’s Cancer Group trial. Clin Cancer Res 5: 733–737
Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J, Kakes T, Baselga J, Sklarin N, Moynihan ME, Tong W, Egorin M, Kearns C, Spriggs D and Norton L (1995) Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol 13: 2575–2581
Sellers EM and Kalant H (1976) Alcohol intoxication and withdrawal. N Engl J Med 294: 757–762
Sonnichsen DS and Rellin MV (1994) Clinical pharmacokinetics of paclitaxel. Clin Pharmacokinet 27: 256–269
Sonnichsen DS, Hurwitz CA, Pratt CB, Shuster JJ and Relling MV (1994) Saturable pharmacokinetics and Paclitaxel pharmacodynamics in children with solid tumors. J Clin Oncol 12: 532–538
Sparreboom A, Van Tellingen O, Huizing MT, Nooijen WJ and Beijnen JH (1996a) Determination of polyoxyethyleneglycerol triricinoleate 35 (Cremophor EL) in plasma by pre-column derivatization and reversed-phase high-performance liquid chormatography. J Chromatogr B Biomed Appl 681: 355–361
Sparreboom A, van Tellingen O, Nooijen WJ and Beijnen JH (1996b) Nonlinear pharmacokinetcs of paclitaxel in mice results from the pharmaceutical vehicle cremophor EL. Cancer Res 56: 2112–2115
Sparreboom A, van Zuylen L, Brouwer E, Loss WJ, de Bruijn P, Gelderblom H, Pillay M, Nooter K, Stoter G and Verweij J (1999) Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinica pharmacokinetic implications. Cancer Res 59: 1454–1457
Theis JG, Liau-Chu M, Chan HS, Doyle J, Greenberg ML and Koren G (1995) Anaphylactoid reaction in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance: the causative role of improper dissolution of Cremophor EL. J Clin Oncol 13: 2508–2516
van Tellingen O, Huizing MT, Panday VR, Schellens JH, Nooijen WJ and Beijnen JH (1999) Cremophor EL causes (pseudo-) non linear pharmacokinetics of paclitaxel in patients. Br J Cancer 81: 330–335
Vassilomanolakis M, Tsoussis S and Efremedis A (1998) Long lasting, grade IV, orthosatic hypotension after a single cycle combination chemotherapy with paclitaxel and cisplatin. Eur J Cancer 34: 1295
Webster LK, Crinis NA, Morton CG and Millward MJ (1996) Plasma alcohol concentrations in patients following paclitaxel infusion. Cancer Chemother Pharmacol 37: 499–501
Wilson DB, Beck TM and Gundlach CA (1997) Paclitaxel formulation as a cause of ethanol intoxication. Ann Pharmacother 31: 873–875
Windebank AJ, Blexrud MD and De Groen PC (1994) Potential neurotoxicity of the solvent vehicle for cyclosporine. J Pharmacol Exp Ther 268: 1051–1056
Younes A, Sarris A, Melnyk A, Romaguera J, McLaughlin P, Swan F, Rodriguez MA, Hagemeister F, Moore D, North L, Smith TL and Cabanillas F (1995) Three-hour paclitaxel infusion in patients with refractory and relapsed non-Hodgkin’s lymphoma. J Clin Oncol 13: 583–587
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
Doz, F., Gentet, J., Pein, F. et al. Phase I trial and pharmacological study of a 3-hour paclitaxel infusion in children with refractory solid tumours: a SFOP study. Br J Cancer 84, 604–610 (2001). https://doi.org/10.1054/bjoc.2000.1637
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2000.1637
Keywords
This article is cited by
-
Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles
Scientific Reports (2016)
-
Nephronophthisis: should we target cysts or fibrosis?
Pediatric Nephrology (2016)
-
New Adaptive Method for Phase I Trials in Oncology
Clinical Pharmacology & Therapeutics (2008)
-
A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours
British Journal of Cancer (2006)
-
Survival in extra-orbital metastatic retinoblastoma: treatment results
Clinical and Translational Oncology (2006)