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Docetaxel/Vinorelbine Combination Therapy in Non-Small-Cell Lung Cancer

Docetaxel/Vinorelbine Combination Therapy in Non-Small-Cell Lung Cancer

ABSTRACT: Docetaxel (Taxotere) has demonstrated significant activity as a single agent in the treatment of patients with advanced non-small-cell lung cancer. Projected median survival in both previously untreated and treated patients is reported to be 9 months. In addition, response rates have ranged from 33% to 38% and 21% to 27% in these respective patient populations. Because vinorelbine (Navelbine) has been demonstrated to have a survival benefit in randomized trials in patients with non-small-cell lung cancer, the potential for the combined use of these agents is promising. In addition, the side effect profiles of docetaxel and vinorelbine are compatible for the combined use of these agents in patients with advanced non-small-cell lung cancer. Preliminary results from phase I and II combination studies have shown encouraging results, with partial responses ranging from 23% to 55%. Based on these data, further study into the combined use of docetaxel and vinorelbine in patients with non-small-cell lung cancer is warranted. [ONCOLOGY 11(Suppl 7):35-40, 1997]

Introduction

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
(Figure 1).[1]

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.[2] 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
model.[2]

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[6] 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
hours.[6]

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).[7] 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.[8]

Binet and colleagues[9] 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.[9] Thus, the
differences in mitotic and axonal activity imply an improved therapeutic
index of vinorelbine compared with vincristine and vinblastine.

Antitumor Activity
and Pharmacokinetics

Antitumor Activity

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.[13] 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.[13]

Pharmacokinetics

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.[14]
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
than 95%).

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).[14]

Pharmacokinetic studies have determined that vinorelbine follows a 3-compartment
model.[15] 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.[15]

Safety Considerations

Docetaxel

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.

Vinorelbine

The safety of vinorelbine was recently reported in a prospective multicenter
trial[16] 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
2
).[16]

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
to granulocytopenia.

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
products.

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%).[16] 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.

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