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Combination Docetaxel/Vinorelbine for Metastatic Breast Cancer and Non-Small-Cell Lung Cancer

Combination Docetaxel/Vinorelbine for Metastatic Breast Cancer and Non-Small-Cell Lung Cancer

ABSTRACT: Docetaxel (Taxotere) and vinorelbine (Navelbine) have both demonstrated activity as single agents for the treatment of patients with metastatic breast cancer and non-small-cell lung cancer. With 100 mg/m² of docetaxel administered as a 1-hour intravenous infusion once every 3 weeks, projected median survival in previously untreated and treated patients with non-small-cell lung cancer is reported to be approximately 9 months. In addition, response rates have ranged from 23% to 36% and 17% to 21% in these respective patient populations. Preliminary studies indicate that in previously untreated patients with non-small-cell lung cancer, vinorelbine provides a survival benefit that is greater than best supportive care and similar to that of platinum-based chemotherapeutic regimens. Investigation into the use of these agents in combination is supported by synergy shown in preclinical models, nonoverlapping side-effect profiles, and the schedule independence of docetaxel. Preliminary results from phase I and II combination studies are encouraging, and no neurotoxicity has been observed. 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 8):46-49, 1997]

Introduction

The rationale for the use of docetaxel (Taxotere) and vinorelbine (Navelbine)
in combination chemotherapy regimens is based on a number of factors. One
is attributable to their mechanisms of action, because both of these agents
exert complementary effects on microtubules. Docetaxel promotes abnormal
polymerization of tubulin into stable microtubule bundles by binding specifically
with the b-tubulin subunit of microtubules, thereby leading to the inhibition
of microtubule depolymerization.[1-3] Vinorelbine, on the other hand, binds
specifically to the a- and b-tubulin subunits and blocks the ability of
the protein to polymerize into microtubules. This action leads to the inability
of chromosomes to segregate correctly during mitosis, thereby inducing
apoptosis.[4,5]

The interest in these two compounds is also generated by specific characteristics
within their respective chemical classes--ie, the taxoids and Vinca alkaloids.
For example, docetaxel possesses greater potency as an inhibitor of microtubular
depolymerization, estimated as twice that of paclitaxel (Taxol).[2,3] Other
differentiating in vitro characteristics of docetaxel include higher binding
affinities for microtubules, higher intracellular concentrations, and prolonged
retention in tumor cells as compared with paclitaxel.[6,7]

It is believed that vinorelbine is less neurotoxic than other Vinca
alkaloids because of the selectivity of vinorelbine for mitotic microtubules.[5]
Moreover, results from preclinical tests[8] demonstrate that depolymerization
of axonal microtubules with vinorelbine occurs at a concentration of 40
µM/L as compared with 5 and 30 µM/L for vincristine and vinblastine,
respectively. Thus, the therapeutic index of vinorelbine can potentially
be greater than that of either vincristine or vinblastine, as indicated
by its actions on mitotic and axonal activity.

Preclinical tests conducted by Bissery and colleagues[6] revealed that
docetaxel and vinorelbine produce a synergistic response in the MA 16/C
mammary adenocarcinoma model. Synergy was demonstrated whether both agents
were administered simultaneously or 24 hours apart at 80% of the highest
nontoxic dose.[6,9] Additional toxicity at these doses was not observed.
In contrast, synergy was not demonstrated with either vincristine or vinblastine.[6]
Thus, the results from preclinical studies and the well-established antitumor
activity as first-line single agents in metastatic breast cancer, non-small-cell
lung cancer, and a variety of other cancers support the use of docetaxel
and vinorelbine in combination regimens.

Clinical
Trials with Docetaxel and Vinblastine

Phase I/II Studies in Metastatic Breast Cancer

A phase I/II dose-finding study by Fumoleau and colleagues[10] established
the maximum tolerated doses for the combination of docetaxel and vinorelbine,
determined major pharmacokinetic parameters, and identified a recommended
dose for future phase II studies. Dose-limiting toxicity was defined as
febrile neutropenia of more than 3 days' duration and/or grade 4 neutropenia
lasting more than 7 days and/or grade 3 to 4 nonhematologic toxicity. Patients
entered in this trial had metastatic breast cancer, a World Health Organization
performance status of 2 or less, and no prior chemotherapy for advanced
disease.

The treatment plan included vinorelbine administered as a 30-minute
intravenous infusion on days 1 and 5 followed immediately by a 1-hour intravenous
infusion of docetaxel on day 1 of a 21-day cycle. The dose levels of vinorelbine/docetaxel
administered were 20/60, 20/75, 22.5/ 75, 20/85, and 20/100 mg/m².
All patients received premedication with 8 mg/day of dexamethasone for
3 days starting 1 day prior to chemotherapy. Because of the potential for
neurotoxicity with the use of vinorelbine, neurological examinations including
nerve conduction studies were performed at baseline, and then following
every 2 cycles thereafter.

Overall, responses were observed at each dose level. Two maximum tolerated
doses were reached: 22.5 mg/m² of vinorelbine followed by 75 mg/m²
of docetaxel and 20 mg/m² of vinorelbine followed by 100 mg/m²
of docetaxel. Febrile neutropenia was observed in 37% and 11% of the cycles
at the 2 dose levels. Based on these results, the authors concluded that
20 mg/m² of vinorelbine (days 1 and 5) followed by either 75 or 85
mg/m² of docetaxel on day 1 was recommended for phase II studies.
At the recommended doses, 11 of 16 patients had an objective response.

Based on the results of the phase I study,[10] a multicenter phase II
trial was initiated to evaluate the combination of docetaxel and vinorelbine
as first-line therapy in patients with metastatic breast cancer. Patients
in this ongoing trial will receive 20 mg/m² of vinorelbine administered
as a 30-minute intravenous infusion on days 1 and 5 followed immediately
by 85 mg/m² of docetaxel on day 1 of a 21-day cycle.

Phase I/II Studies in Non-Small-Cell Lung Cancer

Although the initial studies of docetaxel and vinorelbine combinations
were performed in patients with metastatic breast cancer, subsequent studies
have concentrated on non-small-cell lung cancer. Douillard and co-workers[11]
conducted a phase I dose-escalation trial to determine the dose-limiting
toxicity, maximum tolerated dose, and the recommended dose of docetaxel
plus vinorelbine for future trials. Inclusion criteria included previously
untreated patients with histologically proven advanced or metastatic non-small-cell
lung cancer with at least one bidimensionally measurable lesion and who
had a World Health Organization performance status less than or equal to
2.

During the 3-week cycle, vinorelbine was administered as a 30-minute
intravenous infusion on days 1 and 8 followed immediately by a 1-hour intravenous
infusion of docetaxel on day 8. The dose levels are shown in Table
1
. Patients were premedicated with 8 mg of dexamethasone twice daily
for 3 days, beginning 1 day prior to the administration of docetaxel.

To date, 26 patients have entered this ongoing trial, with evaluable
data on 23 patients (Table 2). The median
age is 52 years (range: 39 to 68 years) with a median World Health Organization
performance status of 1. The maximum tolerated dose was 25 mg/m² of
vinorelbine on days 1 and 8 and 100 mg/m² of docetaxel on day 8. At
this dose, 3 patients developed dose-limiting toxicities (1 incidence of
febrile neutropenia, 1 neurosensory, and 1 neutropenia with infection).
Data are not yet available for patients receiving 25 and 20 mg/m²
of vinorelbine on days 1 and 8, and 100 mg/m² of docetaxel on day
8. The authors concluded that the maximum tolerated dose found in this
study was close to the recommended dose of each drug as a single agent.

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