Docetaxel (Taxotere) and vinorelbine (Navelbine) are two of a number
of new third-generation chemotherapeutic agents that have become available
in recent years. A series of single-agent and combination therapy studies
are underway to determine the efficacy of these agents in the treatment
of patients with non-small-cell lung cancer. Although docetaxel and vinorelbine
are considered tubulin-binding agents, their use in combination therapy
is promising because each has different effects on microtubule assembly
Docetaxel, like other taxoids, promotes tubulin polymerization, whereas
vinorelbine, like other vinca alkaloids, promotes tubulin depolymerization.
Preclinical tests of docetaxel in combination with other vinca alkaloids
failed to demonstrate synergy in a variety of in vivo experiments. However,
docetaxel and vinorelbine, when administered either simultaneously at 100%
of the highest nontoxic dose or 24 hours apart at 80% of the highest nontoxic
dose, produced a synergistic response in the MA 16/C mammary adenocarcinoma
This review deals essentially with the safety profiles of vinorelbine
and docetaxel and presents preliminary data supporting continued investigation
aimed at defining the optimal combination regimen of these agents in patients
with non-small-cell lung cancer.
Docetaxel, like other taxoids, promotes abnormal polymerization of tubulin
into stable microtubule bundles, rather than the long filaments normally
used for the mitotic spindle and other microtubule-based structures. Unlike
the vinca alkaloids, docetaxel binds specifically with the beta-tubulin
subunit of microtubules and inhibits the disassembly of the important cytoskel-
etal protein. This results in the inhibition of microtubule depolymerization.[3-5]
Results from in vitro studies indicate that docetaxel is approximately
twice as potent as paclitaxel (Taxol) as an inhibitor of microtubular depolymerization.[3,5]
The stabilizing effect of taxoids on microtubule bundles does not stop
after concentrations of taxoids are removed. Jordan and colleagues demonstrated
that HeLa cells did not resume proliferation after removal of taxoids;
instead, the cells entered an interphase-like state. DNA degradation into
nucleosome-sized fragments characteristic of apoptosis began during drug
incubation and increased after drug removal. Cells died within 48 to 72
In contrast, vinca alkaloids bind specifically to the alpha- and beta-tubulin
subunits and block the ability of the protein to polymerize into microtubules,
leading to the inability of chromosomes to segregate correctly during mitosis,
and thereby leading to apoptosis.[7,8]
Vinorelbine departs from the traditional vinca alkaloids in both chemical
and functional characteristics. First, vinorelbine is a semisynthetic vinca
alkaloid with substitutions on the catharanthine ring instead of the vindoline
ring of the molecule (Figure 2). From
a functional perspective, the selectivity of vinorelbine for mitotic microtubules
lessens the toxicity to axonal microtubules that is typically associated
with vinblastine and vincristine.
Binet and colleagues demonstrated that vinorelbine causes complete
depolymerization of mitotic microtubules at concentrations lower than vincristine
and vinblastine. In addition, preclinical tests with intact tectal plates
from mouse embryos showed that depolymerization of axonal microtubules
with vinorelbine occurred at a dose of 40 µM/L, compared with 5 and
30 µM/L for vincristine and vinblastine, respectively. Thus, the
differences in mitotic and axonal activity imply an improved therapeutic
index of vinorelbine compared with vincristine and vinblastine.
By correlating antitumor activity with total dosage, preclinical tests
showed that docetaxel is schedule-independent.[10-12] In several cell lines
in vitro, including those resistant to conventional antineoplastic drugs,
the antitumor activity of docetaxel appeared to be largely independent
of the specific extended dosing schedule used, indicating that prolonged
drug exposures may not be required to produce maximum antitumor effect.
The schedule of dependency for vinorelbine was determined using P388
intraperitoneal implanted xenografts. As shown in Table
1, the ratio of survival time in treated vs control was greatest with
a once-weekly dosing schedule (days 1, 7, and 13), compared with either
a day 1 only, day 1 through 5, or a twice-weekly regimen (days 1, 5, and
9). The once-weekly dosing schedule resulted in an approximate threefold
increase in survival as compared with controls.
Docetaxel exhibits dose-independent pharmacokinetics that are consistent
with a linear, 3-compartment model, with half-lives for the alpha, beta,
and gamma phases of 4 minutes, 11 minutes, and 11.1 hours, respectively.
The docetaxel area under the curve was dose proportional after intravenous
doses of 70 to 115 mg/m². Mean total body clearance and steady-state
volume of distribution were 21 L/h/m² and 113 L, respectively. Docetaxel
is extensively metabolized and is highly bound to plasma proteins (greater
Although docetaxel pharmacokinetic characteristics are not affected
by age or gender, the clearance of docetaxel is decreased in patients with
impaired hepatic function. Docetaxel did not demonstrate sequence-dependent
effects when administered with cisplatin (Platinol).
Pharmacokinetic studies have determined that vinorelbine follows a 3-compartment
model. Intravenous administration of vinorelbine results in a rapid
distribution to peripheral tissues, with an average terminal half-life
of 27.7 ± 15.7 hours. This long half-life is advantageous for use
in combination regimens. The mean plasma clearance rate of vinorelbine
ranges from 0.97 to 1.26 L/h/kg. The steady-state volume of distribution
is large, ranging from 25.4 to 40.1 L/kg.
Vinorelbine is highly bound in blood, especially to platelets and lymphocytes,
but no drug interactions from displacement of bound drug have been reported.
The liver is the primary site of metabolism. The pharmacokinetic profile
of vinorelbine is not significantly altered in the elderly or when the
drug is administered with cisplatin. Compared with the other vinca alkaloids,
vinorelbine has a larger volume of distribution and a higher clearance.
There is an extensive safety database on the administration of 100 mg/m²
of docetaxel in patients (N = 1,435) with breast, non-small-cell lung cancer,
ovarian, and other tumor types. The dose-limiting side effect of docetaxel
was short-lasting neutropenia (less than 500 cells/mm³), which occurred
in 76% of patients. Neutropenia resolved in less than 1 week in approximately
11% of patients. Patients who developed febrile neutropenia (12%) were
effectively managed by reducing the dosage of docetaxel for subsequent
courses, without the use of colony-stimulating factors.
The other frequent hematologic adverse event was leukopenia (less than
1,000 cells/mm³), which was noted in 31% of patients. The incidence
of thrombocytopenia (less than 100,000 cells/mm³; 7.5%) and anemia
(less than 8 g/dL; 8.4%) associated with docetaxel was low.
Nonhematologic side effects associated with 100 mg/m² of docetaxel
included alopecia (80%), gastrointestinal side effects (nausea, 40%; diarrhea,
40%; vomiting, 24%), stomatitis (42%), and nail changes (28%). These were
common, but usually only grade 1 or 2 in severity. Neurosensory changes,
such as mild paresthesias, were uncommon (less than 5% of patients). In
patients receiving corticosteroid premedication, mild hypersensitivity
reactions, such as flushing and pruritus, occurred in 16% of patients,
and severe reactions were observed in only 0.9% of patients.
The safety of vinorelbine was recently reported in a prospective multicenter
trial in 216 patients with stage IV non-small-cell lung cancer. Patients
were randomized to receive either vinorelbine, 30 mg/m², infused over
20 minutes once weekly or an intravenous bolus of 425 mg/m² of fluorouracil
(5-FU) plus 20 mg/m² of leucovorin administered for 5 consecutive
days every 4 weeks. The predominant toxicity associated with the use of
single-agent vinorelbine at 30 mg/m2 was granulocytopenia (Table
Grade 3 or 4 granulocytopenia was noted in 54% of patients receiving
vinorelbine, compared with 24% of the 5-FU/leucovorin-treated patients.
Despite the wide difference in the incidence of grade 3 or 4 granulocytopenia,
only 7% and 6% of the patients in both groups experienced infections related
Other hematologic toxicities included anemia, which was seen in 70%
of the vinorelbine-treated patients and 42% of the 5-FU/leucovorin-treated
patients. Anemia was of grade 1 or 2 severity, with 18% of vinorelbine-treated
patients and 12% of 5-FU plus leucovorin-treated patients requiring blood
Nonhematologic toxicities that occurred more frequently in vinorelbine-treated
patients than in those given 5-FU/leucovorin combination therapy included
constipation (29% vs 6%), peripheral neuropathy (20% vs 4%), and injection-site
reactions (ie, phlebitis and pain; 38% vs 1%). The incidence of grade
3 severity of the same nonhematologic toxicities was substantially lower--ie,
constipation, 2%; peripheral neuropathy, 1%; and injection site reactions,
5%. There were no grade IV nonhematologic toxicities associated with the
administration of vinorelbine.
In general, nausea, vomiting, stomatitis, anorexia, and diarrhea were
reported to occur more frequently in the 5-FU/leucovorin treatment than
in the vinorelbine treatment group. Thus, the hematologic and nonhematologic
toxicity profiles of docetaxel and vinorelbine appear to be compatible
for concomitant use in patients with non-small-cell lung cancer.
1. Gelmon K: The taxoids: Paclitaxel and docetaxel. Lancet 344:1267-1272,
2. Lavelle F, Bissery MC, Combeau C, et al: Preclinical evaluation of
docetaxel (Taxotere). Semin Oncol 22(suppl 4):3-16, 1995.
3. 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.
4. Ringel I, Horwitz SB: Studies with RP 56976 (Taxotere): A semisynthetic
analogue of taxol. J Natl Cancer Inst 83:288-291, 1991.
5. 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.
6. Jordan MA, Wendell K, Gardiner S, et al: Mitotic block induced by
HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal
mitotic exit and apoptotic cell death. Cancer Res 56:816-825, 1996.
7. Burris HA, Fields S: Summary of data from in vitro and phase I vinorelbine
(Navelbine) studies. Semin Oncol 21(suppl 10):14-21, 1994.
8. Binet S, Fellows A, Meininger V: In situ analysis of the action of
Navelbine on various types of microtubules using immunofluorescence. Semin
Oncol 16(suppl 4):5-8, 1989.
9. Binet S, Chineau E, Fellows A, et al: Immunofluorescence of the action
of Navelbine, vincristine, and vinblastine on mitotic and axonal microtubules.
Int J Cancer 46:262-266, 1990.
10. Vogal M, Hilsenbeck SG, Depenbrock H, et al: Preclinical activity
of Taxotere (RP 56976, NSC 628503) against freshly explanted clonogenic
human tumor cells: comparison with Taxol and conventional antineoplastic
agents. Eur J Cancer 29A:2009-2014, 1993.
11. 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.
12. Burris H, Irvin R, Kuhn J, et al: Phase I clinical trial of Taxotere
administration as either a 2-hour or 6-hour intravenous infusion. J Clin
Oncol 11:950-958, 1993.
13. Cros S, Wright M, Morimoto M, et al: Experimental antitumor activity
of Navelbine. Semin Oncol 16(suppl 4):15-20, 1989.
14. Bruno R, Sanderink GJ: Pharmacokinetics and metabolism of Taxotere
(docetaxel), in Workman P, Graham MA, (eds): Cancer Surveys, pp 305-313.
Plainview, New York, Cold Spring Harbor Laboratory Press, 1993.
15. Wargin WA, Lucas VS: The clinical pharmacokinetics of vinorelbine
(Navelbine). Semin Oncol 21(suppl 10):21-27, 1994.
16. Crawford J, O'Rourke M, Schiller JH, et al: Randomized trial of
vinorelbine compared with fluorouracil plus leucovorin in patients with
stage IV non-small cell lung cancer. J Clin Oncol 14:2774-2784, 1996.
17. Fossella FV, Lee JS, Berille J, et al: Summary of phase II data
of docetaxel (Taxotere), an active agent in the first- and second-line
treatment of advanced non-small cell lung cancer. Semin Oncol 22(suppl
18. Ganz PA, Figlin RA, Haskell CM, et al: Supportive care versus supportive
care and combination chemotherapy in metastatic non-small cell lung cancer.
CA Cancer J Clin 63:1271-1278, 1989.
19. Kaasa S, Lund E, Thorud E, et al: Symptomatic treatment versus combination
chemotherapy for patients with extensive non-small cell lung cancer. CA
Cancer J Clin 67:2443-2447, 1991.
20. Woods RL, Williams CJ, Levi J, et al: A randomized trial of cisplatin
and vindesine versus supportive care only in advanced non-small cell lung
cancer. Br J Cancer 61:608-611, 1990.
21. Quoix E, Dietemann A, Charbonneau J, et al: La chimiothérapie
comportant du cisplatine est-elle utile dans le cancer bronchique non microcellulaire
au stade IV? Résultats d' une étude randomisée. Bull
Cancer 78:341-346, 1991.
22. Comier Y, Bergeron D, La Forge, et al: Benefits of polychemotherapy
in advanced non-small cell bronchogenic carcinoma. CA Cancer J Clin 50:845-849,
23. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survival
in patients with advanced non-small cell lung cancer: Report of a Canadian
multicenter randomized trial. J Clin Oncol 6:633-641, 1988.
24. Cellerino R, Tummarello D, Guidi F, et al: A randomized trial of
alternating chemotherapy versus best supportive care in advanced non-small
cell lung cancer. J Clin Oncol 9:387-395, 1985.
25. Cartei G, Cartei F, Cantone A, et al: Cisplatin-cyclophosphamide-mitomycin
combination chemotherapy with supportive care versus supportive care alone
for treatment of metastatic non-small cell lung cancer. J Natl Cancer Inst
26. Le Chevalier T, Brisgand D, Douillard J, 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.
27. Bissery MC, Azli N, Fumoleau P: Docetaxel in combination with vinorelbine:
Preclinical-clinical correlation (abstract 1550). Proc Am Soc Clin Oncol
28. Fumoleau P, Delecroix V, Perrocheau G, et al: Docetaxel (D) in combination
with vinorelbine (V) as 1st line CT in PTS with metastatic breast cancer
(MBC): Final results (abstract 232). Proc Am Soc Clin Oncol 15:142, 1996.
29. Monnier A, Riviere A, Douillard JY, et al: Phase II study of docetaxel
(Taxotere) and vinorelbine in chemotherapy naive patients with advanced
non-small-cell lung carcinoma (NSCLC) (abstract 1129). Proc Am Soc Clin
Oncol 15:378, 1996.
30. Kourousis C, Kakolyris S, Androullakis N, et al: First line treatment
on non-small cell lung carcinoma with docetaxel and vinorelbine: A phase
II study (abstract 1234). Proc Am Soc Clin Oncol 15:405, 1996.
31. Viallet J, Laberge F, Martins H, et al: Docetaxel alternating with
cisplatin and vinorelbine: Early evidence of additive activity in a phase
II trial of non-small-cell lung cancer (NSCLC) (abstract 1115). Proc Am
Soc Clin Oncol 15:375, 1996.
32. Early E, Miller, VA, Grant SC, et al: Phase I/II trial of docetaxel
(DTX) and vinorelbine (VNR) with filgrastim (G-CSF) in patients (PTS) with
advanced non-small cell lung cancer (NSCLC) (abstract 1678). Proc Am Soc
Clin Oncol 16:467a, 1997.