Abstract
Purpose
Paclitaxel, when combined with carboplatin, exhibits a platelet-sparing effect. Paclitaxel is formulated in Cremophor EL (CrEL), which has been shown in preclinical models to reduce haematological toxicity from radiotherapy and chemotherapy. We sought to determine the effect of a 3-h infusion of 20 ml/m2 (equivalent to 175 mg/m2 paclitaxel) CrEL on myelosuppression following carboplatin chemotherapy, and the effect of CrEL on carboplatin pharmacokinetics.
Methods
A total of 16 patients with locally advanced or metastatic cancer were randomized to receive either CrEL or saline over 3 h prior to carboplatin (area under the curve, AUC, 5–7). Each patient was subsequently crossed over to the other treatment. Blood samples were collected at selected time-points for estimation of platinum AUC and 24-h platinum levels. Full blood counts were obtained three times per week.
Results
Of the 16 patients randomized, 15 were evaluable. Myelosuppression was measured by percentage fall at nadir and nadir levels. No significant differences were obtained when comparing CrEL and saline with respect to the above end-points after adjusting for multiple testing. There was no evidence to indicate that CrEL altered the pharmacokinetics of carboplatin.
Conclusion
CrEL at this dose and schedule does not appear to be a major contributory factor to the platelet-sparing effect of paclitaxel when combined with carboplatin, nor does it alter the pharmacokinetics of carboplatin.
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References
Badary OA, Abdel-Naim AB, Khalifa AE, Hamada FM (2000) Differential alteration of cisplatin cytotoxicity and myelotoxicity by the paclitaxel vehicle cremophor EL. Naunyn Schmiedebergs Arch Pharmacol 361:339
Belani CP, Kearns CM, Zuhowski EG, Erkmen K, Hiponia D, Zacharski D, Engstrom C, Ramanathan RK, Capozzoli MJ, Aisner J, Egorin MJ (1999) Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer. J Clin Oncol 17:676
Bertoncello I, Kriegler AB, Woodcock DM, Williams B, Barber L, Nilsson SK (1995) Haematopoietic radioprotection by Cremophor EL: a polyethoxylated castor oil. Int J Radiat Biol 67:57
Blommaert FA, van Dijk-Knijnenburg HC, Dijt FJ, den Engelse L, Baan RA, Berends F, Fichtinger-Schepman AM (1995) Formation of DNA adducts by the anticancer drug carboplatin: different nucleotide sequence preferences in vitro and in cells. Biochemistry 34:8474
Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME, Wiltshaw E (1989) Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748
Eschalier A, Lavarenne J, Burtin C, Renoux M, Chapuy E, Rodriguez M (1988) Study of histamine release induced by acute administration of antitumor agents in dogs. Cancer Chemother Pharmacol 21:246
Fujiwara K, Yamauchi H, Suzuki S, Ishikawa H, Tanaka Y, Fujiwara M, Kohno I (2001) The platelet-sparing effect of paclitaxel is not related to changes in the pharmacokinetics of carboplatin. Cancer Chemother Pharmacol 47:22
Gelderblom H, Sparreboom A, de Jonge MJ, Loos WJ, Wilms E, Mantel MA, Hennis B, Camlett I, Verweij J, van der Burg ME (2001) Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer. Br J Cancer 85:1124
Gelderblom H, Loos WJ, Verweij J, van der Burg ME, de Jonge MJ, Brouwer E, Nooter K, Stoter G, Sparreboom A (2002) Modulation of cisplatin pharmacodynamics by Cremophor EL: experimental and clinical studies. Eur J Cancer 38:205
de Graaff M, Maliepaard M, Pluim D, Floot BJ, Slaper-Cortenbach IC, Schellens JH (1999) In vitro antagonistic cytotoxic interactions between platinum drugs and taxanes on bone marrow progenitor cell CFU-GM. Anticancer Drugs 10:213
Guminski AD, Harnett PR, deFazio A (2001) Carboplatin and paclitaxel interact antagonistically in a megakaryoblast cell line—a potential mechanism for paclitaxel-mediated sparing of carboplatin-induced thrombocytopenia. Cancer Chemother Pharmacol 48:229
Isla D, Rosell R, Sanchez JJ, Carrato A, Felip E, Camps C, Artal A, Gonzalez-Larriba JL, Azagra P, Alberola V, Martin C, Massuti B (2001) Phase II trial of paclitaxel plus gemcitabine in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 19:1071
Kenward MG, Jones B (1987) The analysis of data from 2×2 cross-over trials with baseline measurements. Stat Med 6:911
Kris MG, O’Connell JP, Gralla RJ, Wertheim MS, Parente RM, Schiff PB, Young CW (1986) Phase I trial of taxol given as a 3-hour infusion every 21 days. Cancer Treat Rep 70:605
Kroep JR, Giaccone G, Voorn DA, Smit EF, Beijnen JH, Rosing H, van Moorsel CJ, van Groeningen CJ, Postmus PE, Pinedo HM, Peters GJ (1999) Gemcitabine and paclitaxel: pharmacokinetic and pharmacodynamic interactions in patients with non-small-cell lung cancer. J Clin Oncol 17:2190
Millward MJ, Webster LK, Toner GC, Bishop JF, Rischin D, Stokes KH, Johnston VK, Hicks R (1996) Carboplatin dosing based on measurement of renal function—experience at the Peter MacCallum Cancer Institute. Aust N Z J Med 26:372
O’Shaughnessy JNS, Albain K (2003) Gemcitabine plus paclitaxel (GT) versus paclitaxel (T) as first line treatment for anthracycline pre-treated metastatic breast cancer (MBC): interim results of a global phase III study. Proc Am Soc Clin Oncol Chicago 7
Pertusini E, Ratajczak J, Majka M, Vaughn D, Ratajczak MZ, Gewirtz AM (2001) Investigating the platelet-sparing mechanism of paclitaxel/carboplatin combination chemotherapy. Blood 97:638
Reck M, von Pawel J, Macha HN, Kaukel E, Deppermann KM, Bonnet R, Ulm K, Hessler S, Gatzemeier U (2003) Randomized phase III trial of paclitaxel, etoposide, and carboplatin versus carboplatin, etoposide, and vincristine in patients with small-cell lung cancer. J Natl Cancer Inst 95:1118
Rinaldi DA, Lormand NA, Brierre JE, Cole JL, Stagg MP, Fontenot MF, Buller EJ, Rainey JM (2002) Phase I trial of gemcitabine, administered as a standard and constant dose-rate infusion, in combination with paclitaxel in patients with advanced solid tumors (LOA-2). Am J Clin Oncol 25:523
Rischin D, Webster LK, Millward MJ, Linahan BM, Toner GC, Woollett AM, Morton CG, Bishop JF (1996) Cremophor pharmacokinetics in patients receiving 3-, 6-, and 24-hour infusions of paclitaxel. J Natl Cancer Inst 88:1297
Scialli AR, DeSesso JM, Rahman A, Husain SR, Goeringer GC (1995) Embryotoxicity of free and liposome-encapsulated taxol in the chick. Pharmacology 51:145
Shord SS, Faucette SR, Gillenwater HH, Pescatore SL, Hawke RL, Socinski MA, Lindley C (2003) Gemcitabine pharmacokinetics and interaction with paclitaxel in patients with advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 51:328
Sparreboom A, Verweij J, van der Burg ME, Loos WJ, Brouwer E, Vigano L, Locatelli A, de Vos AI, Nooter K, Stoter G, Gianni L (1998) Disposition of Cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo. Clin Cancer Res 4:1937
de Vos AI, Nooter K, Verweij J, Loos WJ, Brouwer E, de Bruijn P, Ruijgrok EJ, van der Burg ME, Stoter G, Sparreboom A (1997) Differential modulation of cisplatin accumulation in leukocytes and tumor cell lines by the paclitaxel vehicle Cremophor EL. Ann Oncol 8:1145
Wagner JG (1993) Pharmacokinetics for the pharmaceutical scientist. Technomic, Lancaster, PA
Woodcock DM, Jefferson S, Linsenmeyer ME, Crowther PJ, Chojnowski GM, Williams B, Bertoncello I (1990) Reversal of the multidrug resistance phenotype with cremophor EL, a common vehicle for water-insoluble vitamins and drugs. Cancer Res 50:4199
Woodcock DM, Linsenmeyer ME, Chojnowski G, Kriegler AB, Nink V, Webster LK, Sawyer WH (1992) Reversal of multidrug resistance by surfactants. Br J Cancer 66:62
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The authors are grateful for the conscientious sample collection by nursing staff at Peter MacCallum Cancer Centre.
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Loi, S., Rischin, D., Michael, M. et al. A randomized cross-over trial to determine the effect of Cremophor EL on the pharmacodynamics and pharmacokinetics of carboplatin chemotherapy. Cancer Chemother Pharmacol 54, 407–414 (2004). https://doi.org/10.1007/s00280-004-0792-3
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DOI: https://doi.org/10.1007/s00280-004-0792-3