Skip to main content
SpringerLink
Log in

A Preliminary Risk-Benefit Assessment of Paclitaxel

  • Review Article
  • Risk-Benefit Assessment
  • Published:
Drug Safety Aims and scope Submit manuscript

Summary

Paclitaxel is an antineoplastic agent, first isolated and described in 1971. Despite its novel structure and apparent activity in vitro, little interest was shown in developing the compound because of its scarcity, problems with its formulation and the mistaken assumption that its mechanism of action was similar to that of the vinca alkaloids.

Approximately 10 years later, the unique mechanism of action of paclitaxel, its ability to stabilise microtubules, was discovered, and its activity against human tumour xenografts was demonstrated. Interest in the drug was reignited and clinical testing began.

Severe hypersensitivity reactions were controlled in the phase II programme with a premedication regimen consisting of dexamethasone, histamine H1-antagonists and H2-antagonists. Neutropenia was dose limiting in all studies conducted in patients with solid tumours. This toxicity was schedule-dependent, and less severe when paclitaxel was administered as a 3-hour infusion regimen. Peripheral neuropathy was mild to moderate in the initial experience, and dose-dependent. However, when bone marrow support with haemopoietic growth factors was used to allow paclitaxel dose intensification, neurotoxicity became dose limiting.

To date, substantial clinical efficacy has been demonstrated in ovarian, breast, non-small-cell lung, and head and neck cancers. Response rates were low in initial studies in melanoma, prostate, colon, cervix and renal cancer. In December 1992, US Food and Drug Administration approval was granted for the use of paclitaxel as second-line therapy in ovarian cancer patients. More recently, similar approval was granted for use in recurrent breast cancer. Nevertheless, important questions remain. Such questions include: (a) the optimal dosage and schedule; (b) the use of paclitaxel as initial therapy; (c) its role in other malignancies; and (d) the development of suitable combination chemotherapy regimens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Wani MC, Taylor HL, Wall ME, et al. Plant antitumor agents VI: the isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 1971; 93: 2325–7

    Article  PubMed  CAS  Google Scholar 

  2. Chabner BA. Taxol. In: PPO updates, cancer principles and practice of oncology. Philadelphia, PA: JB Lippincott Co., 1991: 1–10

    Google Scholar 

  3. Fuchs DA, Johnson RK. Cytologie evidence that taxol, an antineoplastic agent from Taxus brevifolia, acts as a mitotic spindle poison. Cancer Treat Rep 1978; 62: 1219–22

    PubMed  CAS  Google Scholar 

  4. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature 1979; 22: 665–7

    Article  Google Scholar 

  5. Schiff PB, Horwitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA 1980; 77: 1561–5

    Article  PubMed  CAS  Google Scholar 

  6. McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 1989; 111: 273–9

    PubMed  CAS  Google Scholar 

  7. De Furia MD, Horowitz Z. Taxol commercial supply strategy. J Natl Cancer Inst Monogr 1993; 15: 195–8

    Google Scholar 

  8. Horwitz SB. How to make taxol from scratch. Nature 1994; 367: 593–4

    Article  PubMed  CAS  Google Scholar 

  9. Nicolau KC, Yang Z, Liu JJ, et al. Total synthesis of taxol. Nature 1994; 367: 630–4

    Article  Google Scholar 

  10. Flam F. Race to synthesize taxol ends in a tie. Science 1994; 263: 911

    Article  PubMed  CAS  Google Scholar 

  11. Horwitz SB. Mechanism of action of taxol. Trends Pharmacol Sci 1992; 13: 134–6

    Article  PubMed  CAS  Google Scholar 

  12. Schiff PB, Horwitz SB. Taxol assembles tubulin in the absence of exogenous guanosine 5′-triphosphate or microtubule associated proteins. Biochemistry 1981; 20: 3242–52

    Article  Google Scholar 

  13. Kumar N. Taxol-induced polymerization of purified tubulin. J Biol Chem 1981; 256: 10435–41

    PubMed  CAS  Google Scholar 

  14. Donehower RC, Rowinsky EK. Anticancer drugs derived from plants. In: De Vita VT, Hellman S, Rosemberg SA, editors. Cancer principles and practice of oncology. 4th ed. Philadelphia, PA: JB Lippincott Co., 1993: 409–17

    Google Scholar 

  15. De Brabandauer M, Geneus G, Nuydeus R, et al. Taxol induces the assembly of free microtubules in living cells and blocks the organizing capacity of centrosomes and kinetochores. Proc Natl Acad Sci USA 1981; 78: 5608–12

    Article  Google Scholar 

  16. Jordan MA, Toso RJ, Throwes D. Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations. Proc Natl Acad Sci USA 1993; 90: 9552–6

    Article  PubMed  CAS  Google Scholar 

  17. Roy SN, Horwitz SB. A phosphoglycoprotein associated with taxol-resistance in J774.2 cells. Cancer Res 1985; 45: 3856–63

    PubMed  CAS  Google Scholar 

  18. Schibler MJ, Cabral F. Taxol-dependent mutants of Chinese hamster ovary cells with alterations in α- or β-tubulin. J Cell Biol 1986; 102: 1552–61

    Article  Google Scholar 

  19. Hamel E, Lim CM, Johns DG. Tubulin-dependent biochemical assay for the antineoplastic agent taxol and applications to measurements of the drug in the serum. Cancer Treat Rep 1982; 66: 1381–6

    PubMed  CAS  Google Scholar 

  20. Wiernik PH, Schwatz EL, Strauman JJ, et al. Phase I clinical and pharmacokinetic study of taxol. Cancer Res 1987; 47: 2486–93

    PubMed  CAS  Google Scholar 

  21. Grem JL, Tutsch KD, Simon KJ, et al. Phase I study of taxol administered as a short IV infusion daily for 5 days. Cancer Treat Rep 1987; 71: 1179–84

    PubMed  CAS  Google Scholar 

  22. Rowinsky EK, Burke PJ, Karp JE, et al. Phase I study of taxol in refractory adult acute leukemia. Cancer Res 1989; 49: 4640–7

    PubMed  CAS  Google Scholar 

  23. Kohler DR, Goldspiel BR. Paclitaxel (taxol): evaluation of new drugs. Pharmacotherapy 1994; 14: 3–34

    PubMed  CAS  Google Scholar 

  24. Wiernik PH, Schwartz EL, Einzig A, et al. Phase I trial of taxol given as a 24 hour infusion every 21 days. J Clin Oncol 1987; 5: 1232–9

    PubMed  CAS  Google Scholar 

  25. Brown T, Halvin K, Weiss G. A phase I trial of taxol given by 6-hour intravenous infusion. J Clin Oncol 1991; 9: 1261–7

    PubMed  CAS  Google Scholar 

  26. Walle T, Bhalla KN, Walle UK, et al. Taxol disposition in humans after tritium-labelled drug [abstract]. Proc Am Soc Clin Oncol 1994; 13: 152

    Google Scholar 

  27. Rahman A, Korzekwa KR, Grogan J, et al. Selective biotransformation of taxol to 6-hydroxytaxol by human cytochrome P450 2C8. Cancer Res 1994; 54: 5543–6

    PubMed  CAS  Google Scholar 

  28. Harris JW, Rahman A, Guengerich FP, et al. Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res 1994; 54: 4026–35

    PubMed  CAS  Google Scholar 

  29. Swenerton K, Eisenhauer E, ten Bokkel Huinink W, et al. Taxol in relapsed ovarian cancer: high vs low dose and short vs long infusion. A European-Canadian study coordinated by the NCI Canada Trials Group [abstract]. Proc Am Soc Clin Oncol 1993; 12: 256

    Google Scholar 

  30. Keung ACF, Kaul S, Pinedo HM, et al. Pharmacokinetics of taxol given by 3 hrs or 24 hrs infusion to patients with ovarian cancer [abstract]. Proc Am Soc Clin Oncol 1993; 12: 130

    Google Scholar 

  31. Sonnichsen DS, Hurwittz C, Pratt CB, et al. Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumors. J Clin Oncol 1994; 12: 532–8

    PubMed  CAS  Google Scholar 

  32. Rowinsky EK. Clinical pharmacology of taxol. J Nat Cancer Inst Monogr 1993; 15: 25–37

    Google Scholar 

  33. Rowinsky EK, Gilbert M, McGuire WP, et al. Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol 1991; 9: 1692–703

    PubMed  CAS  Google Scholar 

  34. Onetto N, Canetta R, Winograd B, et al. Overview of taxol safety. J Natl Cancer Inst Monogr 1993; 15: 131–9

    PubMed  Google Scholar 

  35. Link CJ, Bicher A, Kohn E, et al. Flexible G-CSF dosing in ovarian cancer patients receiving dose intense taxol therapy. Blood 1994; 83: 1188–92

    PubMed  Google Scholar 

  36. Thigpen JT, Blessing JA, Ball H, et al. Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol 1994; 12: 1748–53

    PubMed  CAS  Google Scholar 

  37. Einzig AI, Wiernik PH, Sasloff J, et al. Phase II study and long term follow up of patients treated with taxol for advanced ovarian adenocarcinoma. J Clin Oncol 1992; 10: 1748–53

    PubMed  CAS  Google Scholar 

  38. Swenerton K, Eisenhauer E, ten Bokkel Huinink WW, et al. Taxol in relapsed ovarian cancer: a European-Canadian study coordinated by the NCI Canada Clinical Trials Group [abstract]. Proc Am Soc Clin Oncol 1993; 12: 256

    Google Scholar 

  39. Holmes FA, Walters RS, Theriault RL, et al. Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 1991; 83: 1797–805

    Article  PubMed  CAS  Google Scholar 

  40. Seidman A, Reichman B, Crown J, et al. Activity of taxol with recombinant granulocyte colony-stimulating factor as first chemotherapy of patients with metastatic breast cancer [abstract]. Proc Am Soc Clin Oncol 1992; 11: 59

    Google Scholar 

  41. Sarosy G, Kohn E, Stone DA, et al. Phase I study of taxol and granulocyte colony-stimulating factor in patients with refractory ovarian cancer. J Clin Oncol 1992; 10: 1165–70

    PubMed  CAS  Google Scholar 

  42. ten Bokkel Huinink WW, Eisenhauer E, Swenerton K, et al. Preliminary evaluation of a multicenter, randomized comparative study of taxol (paclitaxel) dose and infusion length in platinum-treated ovarian cancer. Cancer Treat Rev 1993; 19 Suppl.: 79–86

    Article  PubMed  Google Scholar 

  43. Rowinsky EK, Chaudhry V, Forastiere A, et al. Phase I study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting. J Clin Oncol 1993; 11: 2010–20

    PubMed  CAS  Google Scholar 

  44. Rowinsky EK, Chaudhry V, Cornblath DR, et al. Neurotoxicity of taxol. J Natl Cancer Inst Monogr 1993; 15: 107–15

    PubMed  Google Scholar 

  45. Jerian SM, Sarosy GA, Link Jr CJ, et al. Incapacitating autonomic neuropathy precipitated by taxol. Gynecol Oncol 1993; 51: 277–80

    Article  PubMed  CAS  Google Scholar 

  46. Arbuck SG, Strauss H, Rowinsky EK, et al. A reassessment of cardiac toxicity associated with taxol. J Natl Cancer Inst Monogr 1993; 15: 117–30

    PubMed  Google Scholar 

  47. Kohn EC, Sarosy G, Bicher A, et al. Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst 1994; 86: 18–24

    Article  PubMed  CAS  Google Scholar 

  48. Donehower RC, Rowinsky EK. An overview of experience with taxol (paclitaxel) in the USA. Cancer Treat Rev 1993; 19: 63–78

    Article  PubMed  Google Scholar 

  49. Trimble EL, Adams JD, Vena D, et al. Paclitaxel for platinumrefractory ovarian cancer: results from the first 1000 patients registered to NCI Treatment Referral Center 9103. J Clin Oncol 1993; 11: 2405–10

    PubMed  CAS  Google Scholar 

  50. Kavanaugh JJ, Kudelka AT, Edwards CL, et al. A randomized crossover trial of parenteral hydroxyurea v. high dose taxol in cisplatin/carboplatin resistant epithelial ovarian cancer [abstract]. Proc Am Soc Clin Oncol 1993; 12: 259

    Google Scholar 

  51. McGuire WP, Hoskins WJ, Brady MF, et al. A phase III trial comparing cisplatin/cytoxan and cisplatin/taxol in advanced ovarian cancer [abstract]. Proc Am Soc Clin Oncol 1993; 12: 255

    Google Scholar 

  52. Holmes AF, Valero V, Walters RS, et al. The MD Anderson experience with taxol in metastatic breast cancer. J Natl Cancer Inst Monogr 1993; 15: 161–70

    PubMed  Google Scholar 

  53. Fisherman J, McCabe M, Noone M, et al. Phase I study of taxol, doxorubicin, plus granulocyte colony-stimulating factor in patients with metastatic breast cancer. J Natl Cancer Inst Monogr 1993; 15: 189–94

    PubMed  Google Scholar 

  54. Forastiere AA, Neuberg D, Taylor SG, et al. Phase II evaluation of taxol in advanced head and neck cancer. J Natl Cancer Inst Monogr 1993; 15: 181–3

    PubMed  Google Scholar 

  55. Ettinger DS, Finkelstein DM, Sarma R, et al. Phase II study of taxol in patients with extensive-stage small cell lung cancer: an Eastern Cooperative Oncology Group study [abstract]. Proc Am Soc Clin Oncol 1993; 12: 329

    Google Scholar 

  56. Murphy WK, Fosella FV, Winn RJ, et al. A phase II study of taxol in patients with non-small cell lung cancer. J Natl Cancer Inst 1993; 85: 384–7

    Article  PubMed  CAS  Google Scholar 

  57. Einzig AI, Hochster H, Wiernik PH, et al. A phase II study of taxol in patients with malignant melanoma. Invest New Drugs 1991; 9: 59–64

    Article  PubMed  CAS  Google Scholar 

  58. Legha SS, Ring S, Papadopoulus N, et al. A phase II trial of taxol in patients with metastatic melanoma. Cancer 1990; 65: 2478–81

    Article  PubMed  CAS  Google Scholar 

  59. Geard CR, Jones J, Schiff P. Taxol and radiation. J Natl Cancer Inst Monogr 1993; 15: 89–93

    PubMed  Google Scholar 

  60. Parker RJ, Dabholkar MD, Lee KB, et al. Taxol effect on cisplatin cellular accumulation in human ovarian cancer cells. J Natl Cancer Inst Monogr 1993; 15: 83–8

    PubMed  Google Scholar 

  61. Reed E, Kohn EC, Sarosy G, et al. Paclitaxel, cisplatin, and cyclophosphamide in human ovarian cancer: molecular rationale and early clinical results. Semin Oncol. In press

  62. Young RC, Perez CA, Hoskins WJ. Cancer of the ovary. In: De Vita VT, Hellman S, Rosemberg SA, editors. Cancer principles and practice of oncology. 4th ed. Philadelphia, PA: JB Lippincott Co., 1993: 1226–62

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 12C103, 9000 Rockville Pike, Bethesda, Maryland, 20892, USA

    Roberto J. Bitton &  Eddie Reed

  2. Laboratory of Clinical Pharmacokinetics, Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    William D. Figg

Authors
  1. Roberto J. Bitton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William D. Figg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eddie Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bitton, R.J., Figg, W.D. & Reed, E. A Preliminary Risk-Benefit Assessment of Paclitaxel. Drug-Safety 12, 196–208 (1995). https://doi.org/10.2165/00002018-199512030-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199512030-00005

Keywords

Search

Navigation