The toxicity of paclitaxel given with cisplatin appears to be dependent on order of administration, with more severe myelosuppression occurring if cisplatin is given first. There does notappear to be any sequence dependent interaction for combination of docetaxel with carboplatin or docetaxel with cisplatin.Paclitaxel may reduce thrombocytopenia associated with carboplatin. The combination of carboplatin with paclitaxel appearsto be more neurotoxic than carboplatin with docetaxel.
Clinical evidence,mechanism, importance and management
Several clinical studies have found that severity of thrombocytopenia with combination of paclitaxel and carboplatin was less than that expected with carboplatin alone.(See reference number 1-5) This does not appear to be due to any changes in carboplatin pharmacokinetics. In one study, patients were given carboplatin as a 30-minute infusion, either alone or immediately following paclitaxel 175 mg/m(See reference number 2) as a 3-hour infusion, and it was found that pharmacokinetics of carboplatin were not significantly affected by paclitaxel.(See reference number 6) Similarly,a pharmacokinetic interaction was not noted when paclitaxel and carboplatin were given in either order in another study.(See reference number 1) Other studies found AUC of carboplatin to be similar to that predicted, despite presence of paclitaxel.(See reference number 2,5) Although one study found AUC of carboplatin to be about 12 % lower in presence of paclitaxel,(See reference number 4) same researchers also found that AUC associated with a 50 % decrease in platelet count increased by 68 % (i.e. more carboplatin is needed to cause same degree of thrombocytopenia), which suggests a pharmacodynamic basis for attenuated toxicity of combination.(See reference number 7) Other researchers also reported that AUC of carboplatin causing a 50 % reduction in platelets was about 6.3 mg/mL per minute when given with paclitaxel compared with historical data of 4 mg/mL per minute when given alone.(See reference number 8) Although thrombocytopenia may be lower than expected, myelosuppression (in form of neutropenia) is a dose-limiting toxicity of combination of carboplatin and paclitaxel.(See reference number 1-4) In one study, patients given paclitaxel with carboplatin experienced significantly greater neurotoxicity than those given docetaxel with carboplatin, but regimens were similar in efficacy.(See reference number 9)Further,there appear to be no pharmacokinetic
Early studies of combination of cisplatin and paclitaxel showed that degree of myelosuppression was sequence dependent. When cisplatin was given first,a greater degree of myelosuppression was seen (See reference number 12). Pharmacokinetic studies suggest that sequence-dependent differences in myelosuppression may be due to a 25 % reduction in paclitaxel clearance when cisplatin is given first (See reference number 12). For this reason, manufacturers recommend that paclitaxel is given before cisplatin (See reference number 13,14). There is also some evidence that myelosuppression is greater for combination when paclitaxel is given over 24 hrs as opposed to 3 hrs (See reference number 13). When paclitaxel is given with cisplatin, neurotoxicity (peripheral neuropathy) is common,(See reference number 13) and there is some evidence that this is more severe if paclitaxel is given over 3 hrs as opposed to over 24 hrs (See reference number 15). In one study,(See reference number 16) neurotoxicity was unexpectedly severe when paclitaxel alone was used in patients who had relapsed after treatment with cisplatin; however, this was not case in another similar study (See reference number 17).
In contrast to paclitaxel, early studies did not reveal any obvious sequence dependent toxicity for combination of docetaxel and cisplatin (See reference number 18). In addition,cisplatin did not cause any significant changes in docetaxel pharmacokinetics (See reference number 18,19).
Huizing MT,Giaccone G, van Warmerdam LJC, Rosing H, Bakker PJM, Vermorken JB,Postmus PE, van Zandwijk, Koolen MGJ, ten Bokkel Huinink, van der Vijgh WJF, BierhorstFJ, Lai A, Dalesio O, Pinedo HM, Veenhof CHN, Beijnen JH. Pharmacokinetics of paclitaxeland carboplatin in a dose-escalating and dose-sequencing study in patients with non-smallcell lung cancer. J Clin Oncol (1997) 15, 317–29.
Bookman MA,McGuire WP, Kilpatrick D, Keenan E, Hogan WM, Johnson SW, O’DwyerP, Rowinsky E, Gallion HH, Ozols RF. Carboplatin and paclitaxel in ovarian carcinoma: aphase I study of the Gynecologic Oncology Group. J Clin Oncol (1996) 14, 1895–1902.
Huizing MT,van Warmerdam LJC, Rosing H, Schaefers MCW, Lai A, Helmerhorst TJM,Veenhof CHN, Birkhofer MJ, Rodenhuis S, Beijnen JH, ten Bokkel Huinink WW. Phase Iand pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer. J Clin Oncol (1997) 15, 1953–64.
Belani CP,Kearns CM, Zuhowski EG, Erkmen K, Hiponia D, Zacharski D, Engstrom C, Ramanathan RK, Capozzoli MJ, Aisner J, Egorin MJ. Phase I trial, including pharmacokineticsand pharmacodynamic correlations, of combination paclitaxel and carboplatin in patientswith metastatic non-small-cell lung cancer. J Clin Oncol (1999) 17, 676–84.
Siddiqui N,Boddy AV, Thomas HD, Bailey NP, Robson L, Lind MJ, Calvert AH. A clinicaland pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelialovarian cancer. Br J Cancer (1997) 75, 287–94.
Obasaju CK,Johnson SW, Rogatko A, Kilpatrick D, Brennan JM, Hamilton TC, Ozols RF,O’Dwyer PJ, Gallo JM. Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel. Clin Cancer Res (1996) 2, 549–52.
Kearns CM,Belani CP, Erkmen K, Zuhowski M, Hiponia D, Ergstrom C, Ramanthan R,Trenn M, Aisner J, Ergorin MJ. Reduced platelet toxicity with combination carboplatin & paclitaxel: pharmacodynamic modulation of carboplatin associated thrombocytopenia. Proc Am Soc Clin Oncol (1995) 14, 170.
van Warmerdam LJC,Huizing MT, Giaccone G, Postmus PE, ten Bokkel Huinink WW, vanZandwijk N, Koolen MGJ, Helmerhorst TJM, van der Vijgh WJF, Veenhof CHN, BeijnenJH. Clinical pharmacology of carboplatin administered in combination with paclitaxel. Semin Oncol (1997) 24 (Suppl 2), S2-97–S2-104.
Kaye SB,Vasey PA. Docetaxel in ovarian cancer: phase III perspectives and future development. Semin Oncol (2002) 29 (3 Suppl 12) 22–7.
Oka M,Fukuda M, Nagashima S, Fukuda M, Kinoshita A, Soda H, Doi S, Narasaki F, Suenaga M, Takatani H, Nakamura Y, Kawabata S, Tsurutani J, Kanda T, Kohno S. Phase I studyof second-line chemotherapy with docetaxel and carboplatin in non-small-cell lung cancer.Cancer Chemother Pharmacol (2001) 48, 446–50.
Ando M,Saka H, Ando Y, Minami H, Kuzuya T, Yamamoto M, Watanabe A, Sakai S,Shimokata K, Hasegawa Y. Sequence effect of docetaxel and carboplatin on toxicity, tumorresponse and pharmacokinetics in non-small-cell lung cancer patients: a phase I study of two sequences. Cancer Chemother Pharmacol (2005) 55, 552–8.
Rowkinsky EK,Gilbert M, McGuire WP, Noe DA, Grochow LB, Forastiere AA, EttingerDS, Lubejko BG, Clarke B, Sartorius SE, Cornblath DR, Hendricks CB, Donehower RC. Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol (1991) 9, 1692–1703.
Taxol (Paclitaxel). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary of productcharacteristics,August 2005.
Taxol (Paclitaxel). Bristol-Myers Squibb Company. US Prescribing information,March2003.
Connelly E,Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J. Paclitaxeldelivered as a 3-hr infusion with cisplatin in patients with gynecologic cancers: unexpectedincidence of neurotoxicity. Gynecol Oncol (1996) 62, 166–8.
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, 1141–50.
McGuire WP,Rowinsky EK, Rosenhein NB, Grumbine FC, Ettinger DS, Armstrong DK,Donehower RC. Taxol: a unique antineoplastic agent with significant activity in advancedovarian epithelial neoplasms. Ann Intern Med (1989) 111, 273–9.
Pronk LC,Schellens JHM, Planting AST, van den Bent MJ, Hilkens PHE, van der BurgMEL, de Boer-Dennert M, Ma J, Blanc C, Harteveld M, Bruno R, Stoter G, Verweij J. PhaseI and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors.J Clin Oncol (1997) 15, 1071–9.
Millward MJ,Zalcberg J, Bishop JF, Webster LK, Zimet A, Rischin D, Toner GC, Laird J,Cosolo W, Urch M, Bruno R, Loret C, James R, Blanc C. Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer. J Clin On-col (1997) 15, 750–8.