The taxoids have generated much interest during the past several years
as important options for the treatment of various malignancies. Docetaxel
(Taxotere) is a semisynthetic taxoid synthesized from 10-deacetyl baccatin
III, a noncytotoxic taxoid precursor extracted from the renewable needles
of the European yew Taxus baccata and chemically modified with a synthetic
lipophilic side chain at C-13 (Figure 1).
Taxoids exert their cytotoxic effects by specifically promoting the assembly
of tubules into microtubules, stabilizing the microtubules, and inhibiting
the depolymerization to free tubulin.[1-3]
However, there are differences between docetaxel and paclitaxel (Taxol)
in regard to potency, cellular uptake and efflux, pharmacokinetics, specific
mechanisms of action, and activity on tumor growth in vitro and in vivo.
For example, docetaxel is approximately twice as potent as paclitaxel as
an inhibitor of microtubule depolymerization in vitro.[1,3] In addition,
docetaxel is more efficient than paclitaxel in stabilizing microtubules
against cold-induced disassembly and twice as efficient as paclitaxel in
decreasing the minimum concentration required for microtubule formation.
Schedule-dependency studies show that docetaxel demonstrates schedule-independent
antitumor effects in several cell lines in vitro. In comparison, preclinical
studies with paclitaxel indicate schedule-dependency, with repeated prolonged
exposure required for maximal antitumor effect in animal models.[5,6] These
differences have been attributed to the ester side chain at C-13 of docetaxel.
Investigations into the use of docetaxel in non-small-cell lung cancer
arose from preclinical studies demonstrating antitumor activity against
Lewis lung carcinoma in vivo, as well as from phase II study results
with 24-hour infusions of paclitaxel showing antitumor response rates of
21% to 24% in patients with non-small-cell lung cancer.[8,9] Subsequently,
six phase II clinical trials have evaluated the use of single-agent docetaxel
as first- and second-line chemotherapy in patients with advanced non-small-cell
This paper will review data from the four original phase II studies
that documented the clinical efficacy of single-agent docetaxel (100 mg/m²)
in previously untreated patients with advanced non-small-cell lung cancer.[12-15]
In addition, the article will present preliminary results from three recently
reported trials that demonstrate clinical efficacy in previously untreated
as well as previously treated patients.[16-18]
The phase II clinical experience of single-agent docetaxel (100 mg/m²)
includes data collected from a total of 160 patients with advanced non-small-cell
lung cancer who participated in four studies. Of the four studies, three
were conducted in the United States.[12-14]
These trials were all very similarly designed, with the exception of
the Memorial Sloan-Kettering trial, which allowed patients with evaluable
disease to be enrolled; all of the other trials required measurable disease.[12,14,15]
Entry criteria included patients with unresectable locally advanced or
metastatic non-small-cell lung cancer and no previous chemotherapy. Initially,
patients with abnormal liver function tests were not excluded from study
All of the eligible patients were to receive docetaxel, 100 mg/m²,
administered as a 1-hour infusion every 3 weeks in an outpatient setting.
These trials were initially designed without any premedication, antiemetics,
or growth factor support. Later protocols were amended to include a 5-day
corticosteroid regimen to reduce the incidence and severity of infusion-related
reactions, fluid retention, and cutaneous reactions.
Antitumor responses were assessed every 3 weeks by physical examination
and by chest x-ray and every 6 weeks by CT. Measurable responses were subjected
to confirmation by follow-up CT scan within 4 to 6 weeks. Major response
was defined by the status of the measurable disease (complete and partial
response); patients with evaluable disease were not included in the intent-to-treat
analysis. All major responses were reviewed by a reference radiologist
and an external review panel. Only confirmed responses were included in
the efficacy analysis.
The demographic profile of the patients is presented in Table
1. Of the 160 patients in the phase II trials, 83% had a performance
status of 0 to 1. More than three-quarters of the patients had stage IV
non-small-cell lung cancer. Approximately one-third of the patients were
women. The majority (74%) of the patients had two or more sites of disease
involvement. Adenocarcinoma, found in 55% of the patients, was the predominant
The overall response rate for all patients receiving 100 mg/m²
of docetaxel (infused over 1 hour once every 3 weeks) in the intent-to-treat
analysis for these trials was 27%, with a median duration of response of
6 months (range, 2 to 13+ months) (Table
2). The median time to progression was 3 months (range, 0 to 14+ months),
with a median of 4 cycles administered (range, 1 to 33). In addition, the
median relative dose intensity was 96%. The overall median survival for
these 160 patients was 9.2 months; the 1-year survivalrate was 39% (Figure
2), and the 2-year survival rate was 20%. The median survival for the
patients with stage IV disease was 9.2 months, and the 1-year survival
rate was 37%.
The response results for the four phase II trials are listed in Table
3. For the 141 patients reported in these trials who received 100 mg/m2
of docetaxel, infused over 1 hour once every 3 weeks, 31% (95% confidence
interval, 24% to 39%) achieved a major response. Major response rates reported
in the studies by The M.D. Anderson Cancer Center and the University
of Texas Health Science Center at San Antonio were both 32%, and 38%
was reported for the Memorial Sloan-Kettering Cancer Center study.
In the European Organization for Research and Treatment of Cancer: Early
Clinical Trials Group study, 24% of the 37 patients achieved a major
Overall, docetaxel was well tolerated by most patients. The overall
incidence of febrile neutropenia in 160 previously untreated patients with
advanced non-small-cell lung cancer receiving 100 mg/m² of docetaxel
in the phase II trials was 19%. Reasons for discontinuation of study participation
included fluid retention (6%), asthenia (4%), acute hypersensitivity reaction
(4%), and paresthesia (3%). It is important to note that more of these
patients had been premedicated with corticosteroids.
The incidence of severe fluid retention in patients who did receive
corticosteroid premedication was 0.9%; and recently, 3 days of corticosteroid
treatment (oral dexamethasone, 8 mg twice daily, starting 1 day prior to
docetaxel treatment) has been shown to be as effective as 5 days.
Although formal comparisons cannot be made, it is of interest to review
the response rates of the present trials with those from other trials that
utilized either supportive care or combination chemotherapy as first-line
therapy in patients with non-small-cell lung cancer (Table
4).[20,21] The response rates achieved with single-agent docetaxel
(100 mg/m², infused over 1 hour, once every 3 weeks) appear to be
at least comparable to cisplatin-based combination regimens and more
favorable than results achieved with supportive care.
Preliminary results from three otherphase II trials of single-agent
docetaxel (100 mg/m²) in patients with advanced non-small-cell lung
cancer were recently reported.[16-18] The first study was conducted
in France, where 66 previously untreated patients with advanced non-small-cell
lung cancer received 100 mg/m² of docetaxel, over 1 hour, once every
Patients also received pretreatment with dexamethasone and diosime (Diosmil).
Of the 53 patients evaluable for response, 30% achieved a major response
with a median duration of 7.1 months. The principal adverse event was neutropenia.
Fluid retention was similar to that seen in previous trials with corticosteroid
The second trial was reported by Kath and colleagues. Docetaxel
was administered in a fashion identical to that of the French study.
Dexamethasone was administered in three doses--once prior to docetaxel
administration, once on the same day as docetaxel, and once on the day
after. Of the 25 patients recruited into the study, 23 were evaluable for
efficacy. Five patients had received previous chemotherapy. Response was
achieved in 18% of patients, with the primary adverse events being neutropenia
and peripheral neuropathy.
The third study, by Mattson and colleagues, included both previously
untreated (N = 43) and previously treated (N = 14) patients with advanced
non-small-cell lung cancer. Docetaxel was administered as described above,
with a 5-day administration of dexamethasone. The response rate reported
in this trial was 31%, with neutropenia and peripheral neuropathy being
the primary adverse events.
Docetaxel at a dose of 100 mg/m² demonstrates appreciable antitumor
activity as a single agent in previously untreated patients with advanced
non-small-cell lung cancer. Data from four phase II clinical trials reveal
a response rate of 27%, with a median survival of 9.2 months and a 1-year
survival rate of 39%. These results are very encouraging, given that cisplatin
(Platinol), vindesine (Eldisine), vinblastine, and mitomycin (Mutamycin)
produce response rates under 25% and that response rates achieved with
cisplatin-based combination regimens are comparable to that of single-agent
docetaxel at a dose of 100 mg/m².
1. Gueritte-Voegelein F, Guenard D, Lavelle F, et al: Relationships
between the structure of taxol analogues and their antimitotic activity.
J Med Chem 34:992-998, 1991.
2. Ringel I, Horwitz SB: Studies with RP 56976 (Taxotere): A semisynthetic
analogue of taxol. J Natl Cancer Inst 83:288-291, 1991.
3. Diaz JF, Andreu JM: Assembly of purified GDP-tubulin into microtubules
induced by Taxol and Taxotere: Reversibility, ligand stoichiometry, and
competition. Biochemistry 32:2747-2755, 1993.
4. Vogal M, Hilsenbeck SG, Depenbrock H et al: Preclinical activity
of Taxotere (RP 56976, NSC 628503) against freshly explantedclonogenic
human tumor cells: comparison with Taxol and conventional antineoplastic
agents. Eur J Cancer 29A:2009-2014, 1993.
5. Arbuck SG, Canetta R, Onetto N, et al: Current dosage and schedule
issues in the development of paclitaxel (Taxol). Semin Oncol 20(suppl 3):31-39,
6. Rose WC: Taxol-based combination chemotherapy and other in vivo preclinical
antitumor studies. Monogr Natl Cancer Inst 15:47-53, 1993.
7. Bissery MC, Guenard D, Gueritte- Voegelein F, et al: Experimental
antitumor activity of taxotere (RP 56976, NSC 628503), a Taxol analogue.
Cancer Res 51:4845-4852, 1991.
8. Chang AY, Kim K, Glick J, et al: Phase II study of taxol, merbarone,
and piroxantrone in stage IV non-small-cell lung cancer: The Eastern Cooperative
Oncology Group results. J Natl Cancer Inst 85:388-394, 1993.
9. Murphy WK, Fossella FV, Winn RJ, et al: Phase II study of taxol in
patients with untreated advanced non-small-cell lung cancer. J Natl Cancer
Inst 85:384-388, 1993.
10. Rigas JR: Docetaxel in stage III and IV non-small cell lung cancer.
Eur J Cancer 31A(suppl 4):S18-S20, 1995.
11. Fossella FV, Lee JS, Berille J, et al: Summary of phase II data
of docetaxel (Taxotere), an active agent in the first-line and second-line
treatment of advanced non-small cell lung cancer. Semin Oncol 22(suppl
12. Fossella FY, Lee JS, Murphy WK, et al: Phase II study of docetaxel
for recurrence or metastatic non-small cell lung cancer. J Clin Oncol 12:1238-1244,
13. Francis PA, Rigas JR, Kris MG, et al: Phase II trial of docetaxel
in patients with stage III and IV non-small cell lung cancer. J Clin Oncol
14. Burris HA, Eckardt J, Fields S, et al: Phase II trials of Taxotere
in patients with non-small cell lung cancer (abstract 1116). Proc Am Soc
Clin Oncol 12:335, 1993.
15. Cerny T, Kaplan S, Pavlidis N,et al: Docetaxel (Taxotere) is active
in non-small cell lung cancer: A phase II trial ofthe EORTC early clinical
trials group (ECTG). Br J Cancer 70:384-387, 1994.
16. Robinet G, Thomas P, Perol M, et al: Phase II study of Taxotere
(docetaxel) in advanced metastatic non-small cell lung cancer (NSCLC) previously
treated with platinum (abstract 458P). Ann Oncol 7(suppl 5):96, 1996.
17. Kath R, Blumenstengel K, Fricke HJ et al: Preliminary report of
chemotherapy results with docetaxel in advanced non-small cell lung cancer
(NSCLC) (abstract 473P). Ann Oncol 7(suppl 5):100, 1996.
18. Mattson K, Le Chevalier T, Stupp R, et al: Preliminary report of
a phase IIstudy of docetaxel (Taxotere) in locally advancedor metastatic
non-small cell lung cancer (NSCLC) (abstract 473P). Ann Oncol 7(suppl 5):90,
19. Riva A, Fumoleau P, Roche H, et al: Efficacy and safety of different
corticosteroid (C) premedications (P) in breast cancer patients (PTS) treated
with Taxotere (T) (abstract 660). Proc Am Soc Clin Oncol 16:188a, 1997.
20. Le Chevalier T, Brisgand D, Douillard JY, et al: Randomized study
of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine
alone in advanced non-small-cell lung cancer: Results of a European multicenter
trial including 612 patients. J Clin Oncol 12:360-367, 1994.
21. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in
non-small cell lung cancer: A meta-analysis using updated data on individual
patients from 52 randomised clinical trials. Br Med J 311:899-909, 1995.