Docetaxel (Taxotere) is the second taxoid to be widely evaluated in
clinical trials. It has some specific apparent advantages and disadvantages
relative to the first described taxoid, paclitaxel (Taxol). Docetaxel has
been approved for the treatment of anthracycline-resistant breast cancer;
in this setting, a series of trials shows it to have clinical activity
that is at least as good as and perhaps superior to any other single agent.
Paclitaxel was discovered serendipitously 34 years ago by a program
screening natural products. The recognition of abnormal stabilization of
microtubule assembly[1,2] as paclitaxel's mechanism of action allowed for
rapid laboratory screening of related compounds. Docetaxel was discovered
during these screening programs, which were carried out in the early 1980s.
A semisynthetic product, docetaxel is derived from the European yew
(Taxus baccata). Although docetaxel and paclitaxel appear to bind
to the same site on microtubules, docetaxel seems to bind with higher affinity.
In addition, in some cell culture systems, docetaxel accumulated to higher
intracellular concentrations and had slower efflux than did paclitaxel.
This preclinical work suggested that docetaxel would be more potent than
paclitaxel but left open the question of whether it would have a more favorable
The next logical step in the development of docetaxel was evaluation
of the agent's activity against a variety of cell lines in culture. These
studies showed that docetaxel had activity against cell lines from a wide
variety of tumor types, including cell lines derived from breast, colon,
ovarian, sarcoma, and bladder cancers.[6-8] Studies using human primary
tumors showed docetaxel to have a broad range of activity and to be partially
non-cross-resistant with paclitaxel and doxorubicin.[9,10] Preclinical
evaluation has shown that overexpression of p-glycoprotein (the product
of the gene mdr-1) and tubulin alterations are two mechanisms of
resistance to docetaxel.
Docetaxel was also evaluated against a number of animal tumor models.
In these studies, docetaxel had a high level of activity against many but
not all mammary tumor models. The agent also had a high level of activity
in nude mice with human mammary tumor xenografts (MX-1).
Docetaxel has been extensively evaluated in phase I trials. The major
dose- limiting toxicities observed in these trials were mucositis and neutropenia,
with mucositis more prominent in the extended regimens (Table
1). For this reason, the schedule selected for phase II studies was
1 hour every 3 weeks, and neutropenia was expected to be the major dose-limiting
toxicity on this schedule.
Phase II studies of docetaxel with long perfusion times have not been
conducted because of the prominent mucositis that occurs with these schedules.
In the majority of phase II studies, docetaxel has been administered at
a dose of 100 mg/m² IV over 1 hour every 3 weeks.
Extensive studies of the pharmacokinetics of docetaxel have been conducted.
The most important finding of these studies is the demonstration that docetaxel,
like paclitaxel, is cleared by hepatic metabolism. These studies have shown
a markedly lower clearance of docetaxel when there was concurrent elevation
of transaminases and alkaline phosphatase. The lower clearance rate of
docetaxel in these patients has been shown to correlate with a markedly
increased risk of toxicity (Table 2 and
Table 3). Docetaxel is also more toxic
in patients with elevated bilirubin levels, and thus, is contraindicated
in patients with liver dysfunction.
The pharmacokinetic studies conducted in the phase I and II trials have
shown docetaxel to be largely protein bound. Values of maximum serum concentration
(Cmax) and area under the curve (AUC) values were proportional
to dose. Estimates of half-life (t½b) at the 100-mg/m²
dose ranged from 11.4 to 18.5 hours.
Docetaxel was taken directly into front-line studies for the treatment
of breast cancer for several reasons. The drug had shown good activity
against mammary tumors in preclinical models, and a number of responses
in breast cancer patients had been seen in phase I trials. Also, paclitaxel,
a closely related agent, is known to have excellent activity in breast
Several phase II trials have been conducted using docetaxel as front-line
therapy (Table 4). These trials found
excellent activity for docetaxel as a single agent, with an overall response
rate of 61% in the trials conducted with a dose of 100 mg/m².
Currently, docetaxel is approved in the United States for the treatment
of anthracycline-resistant breast cancer. Approval of this indication was
based largely on the results of three trials (Table
5). In all three trials, docetaxel was used to treat patients who had
anthracycline- or anthracenedione-resistant disease, defined as disease
progression during administration of one of these agents (as opposed to
simple prior exposure during adjuvant therapy). The European study (study
3) had the most rigorous definition of anthracycline resistance, allowing
only patients with intrinsic resistance and excluding those with acquired
resistance (ie, initial response to anthracyclines and then progression).
The overall response rate for patients in these studies was 41%. Table
6 shows that for patients with evaluable disease, the response rate
was well maintained in patients with visceral disease sites, such as the
liver, as well as in patients with multiple disease sites. These results
are quite striking, given the generally low response rates of other single
agents and combinations in such patients.
The major dose-limiting toxicity of docetaxel, given at 100 mg/m²
over 1 hour every 3 weeks, is neutropenia. Toxicity information for docetaxel
derived from phase II studies is summarized in Tables 2 and 3. It is clear
that for patients with hepatic compromise, docetaxel at a dose of 100 mg/m²,
has unacceptable toxicity. Even in patients with normal hepatic function,
docetaxel caused more than 90% of patients to develop grade 4 neutropenia,
but the neutropenia generally lasted less than 1 week, and only 4% of patients
per cycle developed neutropenia and fever. Other severe hematologic toxicities
are rare in patients with normal hepatic function.
Several types of nonhematologic toxicities were noted in these trials.
Acute hypersensitivity reactions and neurosensory reactions were rare.
Myalgias, when they occurred, were generally mild. Some patients experienced
severe skin reactions, with peeling of the skin particularly obvious on
the palms. Some patients developed severe asthenia, and a few developed
A toxicity that at first seemed unique to docetaxel is a fluid retention
syndrome. This syndrome is the result of cumulative toxicity. It is gradual
in onset and reversible. In unpremedicated patients, the syndrome can become
severe, leading to treatment discontinuation.
The fluid retention syndrome seems to be ameliorated largely by the
present premedication regimen of dexamethasone, 8 mg bid orally, starting
the day of treatment and continuing for 5 consecutive days. Mild peripheral
edema may still occur on this regimen, but it can be easily managed with
1. Fuchs DA, Johnson RK: Cytologic evidence that taxol, an antineoplastic
agent from Taxus brevifolia acts as a mitotic spindle poison. Cancer Treat
Res 62:1219-1222, 1978.
2. Schiff PB, Horowitz SB: Taxol stabilizes microtubules in mouse fibroblast
cells. Proc Natl Acad Sci USA 77:1561-1565, 1980.
3. Bissery M-C, Nohynek G, Sanderink G-J, et al: Docetaxel (Taxotere):
A review of preclinical and clinical experience. Anticancer Drugs 6: 339-368,
4. Ringel I, Horowitz SB: Studies with RPR 56976 (Taxotere) a semisynthetic
analogue of Taxol. J Natl Cancer Inst 83: 288-291, 1991.
5. Lavelle F, Bissery MC, Combeau C, et al: Preclinical evaluation of
docetaxel (Taxotere). Semin Oncol 22(suppl 4):3-16, 1995.
6. Riou JF, Naudin A, Lavelle F: Effects of Taxotere on murine and human
cell lines. Biochem Biophys Res Commun 187:164-170, 1992.
7. Kelland LR, Abel G: Comparative in vitro cytotoxicity of Taxol and
Taxotere against cisplatin-sensitive and resistant human ovarian carcinoma
cell lines. Cancer Chemother Pharmacol 30:444-450, 1992.
8. Braakhuis BJM, Hill BT, Dietel M, et al: In vitro antiproliferative
activity of docetaxel (Taxotere), paclitaxel (Taxol) and cisplatin against
human tumors and normal bone marrow cells. Anticancer Res 14:205-208, 1994.
9. Vogel M, Hilsenbeck SG, Depenbrock H, et al: Preclinical activity
of taxotere (RP 56976, NSC 628503) against freshly explanted clonogenic
human tumour cells: comparison with taxol and conventional antineoplastic
agents. Eur J Cancer 29A(14):2009-2014, 1993.
10. Hanauske AR, Degen D, Hilsenbeck SG, et al: Effects of Taxotere
and taxol on in vitro colony formation of freshly explanted human tumor
cells. Anticancer Drugs 3:121-124, 1992.
11. Dykes DJ, Bissery MC, Gueritte-Vogelein F, et al: Response of human
tumor xenografts in athymic mice to docetaxel. Invest New Drugs 13:1-11,
12. Extra J-M, Rousseau F, Bruno R, et al: Phase I and pharmacokinetic
study of taxotere (RP 56976, NSC 628503) given as a short intravenous infusion.
Cancer Res 53:1037-1042, 1993.
13. Tomiak E, Piccart MJ, Kerger J, et al. Phase I study of docetaxel
administered as a 1-hour intravenous infusion on a weekly basis. J Clin
Oncol 12:1458-1468, 1994.
14. Burris H, Irvin R, Kuhn J, et al: Phase I clinical trial of Taxotere
administered as either a 2-hour or 6-hour intravenous infusion. J Clin
Oncol 11:950-958, 1993.
15. Pazdur R Newman RA, Newman BM, et al: Phase I clinical study of
Taxotere: five day schedule. J Natl Cancer Inst 84:1781-1788, 1992.
16. Bisset D, Setanoians A, Cassidy J, et al: Phase I and pharmacokinetic
study of Taxotere (RP 56976) administered as a 24 hour infusion. Cancer
Res 53:523-527, 1993.
17. Bruno R, Hille D, Thomas L, et al: Population pharmacokinetics/pharmacodynamics
of docetaxel (Taxotere) in phase II studies. Proc Annu Meet Am Soc Clin
Oncol 14:A1471, 1995.
18. Hudis CA, Seidman AD, Crown JP, et al: Phase II and pharmacologic
study of docetaxel as initial chemotherapy for metastatic breast cancer.
J Clin Oncol14:58-65, 1996.
19. Trudeau ME, Eisenhauer EA, Higgins BP, et al: Docetaxel in patients
with metastatic breast cancer: A phase II study of the national Cancer
Institute of Canada Clinical Trials Group. J Clin Oncol 14:422-428, 1996.
20. Dieras V, Chevallier B, Kerbrat P, et al: A multicentre phase II
study of docetaxel 75 mg m-2 as first-line chemotherapy for patients with
advanced breast cancer: Report of the Clinical Screening Group of the EORTC.
Br J Cancer 74:650-656, 1996.
21. ten Bokkel-Huinink WW, Prove AM, Piccart M, et al: A phase II trial
with docetaxel (Taxotere) in second line treatment with chemotherapy for
advanced breast cancer. A study of the EORTC Early Clinical Trials Group.
Ann Oncol 5:527-532, 1994.
22. Hudis CA, Seidman AD, Crown JP, et al: Phase II and pharmacologic
study of docetaxel as initial chemotherapy for metastatic breast cancer.
J Clin Oncol 14:58-65, 1996.
23. Chevallier B, Fumoleau P, Kerbrat P, et al: Docetaxel is a major
cytotoxic drug for the treatment of advanced breast cancer: a phase II
trial of the Clinical Screening Co-operative Group of the EORTC. J Clin
Oncol 13:314-322, 1995.
24. Krakowsky I, Rios M, Fumoleau P, et al: Phase II first line chemotherapy
study with docetaxel (Taxotere) and prophylactic premedication of fluid
retention in patients with metastatic or locally advanced breast cancer.
EORTC Clinical Screening Group (abstract). Proc Am Soc Clin Oncol 14(87):97,
25. Valero V, Holmes FA, Walters RS, et al. Phase II trial of docetaxel:
a new highly effective antineoplastic agent in the management of patients
with anthracycline resistant metastatic breast cancer. J Clin Oncol 13:
26. Ravdin PM, Burris HA, Cook G: Phase II trial of docetaxel in advanced
anthracycline-resistant or anthracenedione resistant breast cancer. J Clin
Oncol 13:2879-2885, 1995.
27. Guastalla JP, Bonneterre J, Fumoleau P, et al: A phase II trial
of docetaxel in patients with anthracycline resistant metastatic breast
cancer. 8th European Conference on Clinical Oncology and Cancer Nursing
(ECCO). Paris, October 1995.
28. Bissery MC, Nohynek G, Sanderink GJ, et al: Docetaxel (Taxotere):
a review of preclinical and clinical experience. Anticancer Drugs 6:339-355,
29. Kalla S, Boureois H, Gruia G: Docetaxel in combination with doxorubicin
as 1st line CT of metastatic breast cancer: A phase I dose finding study--Final
results. Ann Oncol 7:124, 1996.
30. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion
in combination with bolus doxorubicin in women with untreated metastatic
breast cancer: high anti tumor efficacy and cardiac effects in a dose-finding
and sequence-finding study. J Clin Oncol 13:2688-2699,1995.