The large number of patients with metastatic breast cancer resistant
to anthracyclines suggests a need to develop nonanthracycline combination
chemotherapies. The differing mechanisms of action of docetaxel (Taxotere)
and vinorelbine (Navelbine) suggest a rationale for their use in combination.
Docetaxel promotes tubulin polymerization and stabilizes the formed microtubules.
In contrast, vinorelbine inhibits the polymerization of tubulin into microtubules.
Both compounds have demonstrated high antitumor activity as first-line
chemotherapy in metastatic breast cancer, with overall response rates of
61% for docetaxel and 41% to 50% for vinorelbine.
In addition, preclinical research has shown a therapeutic synergy between
the two drugs in mice bearing subcutaneous transplantable tumors. Moreover,
the combination toxicity index was between 1.8 and 1.55, indicating that
approximately 78% to 90% of the maximum tolerated dose of the two drugs
could be administered together without additional toxicity.
These observations led to a phase I dose-finding study of the combination
of docetaxel and vinorelbine, conducted at Centre René Gauducheau,
Nantes, France. Ongoing and future research will compare the docetaxel/vinorelbine
combination with other regimens routinely used as first-line therapy for
patients with advanced breast cancer or as second-line therapy after the
failure of anthracycline treatment.
The objectives of this phase I study were to determine the dose-limiting
toxicities and the recommended dose for further phase II trials. A secondary
objective was to define the major pharmacokinetic parameters in order to
assess potential interactions between the two drugs when administered in
All patients had evaluable and/or measurable metastatic breast cancer,
with no prior chemotherapy for advanced disease. Previous adjuvant chemotherapy
was allowed, provided that there was a 1-year interval between the end
of adjuvant chemotherapy and entry into the study. Performance status on
the Eastern Cooperative Oncology Group (ECOG) scale was 2 or less, with
normal hematologic, liver, and renal function. All patients gave written
Vinorelbine was administered as a 20-minute intravenous infusion on
days 1 and 5, followed by docetaxel as a 1-hour infusion on day 1, repeated
every 3 weeks. Vinorelbine doses were 20 or 22.5 mg/m², while docetaxel
doses increased from 60 to 100 mg/m². At least three patients were
accrued at each dose level (Table 1).
Patients received 3 days of corticosteroid premedication (8 mg of oral
dexamethasone every 6 hours, starting the day before therapy and continuing
through the day after). They also received 500 mg of diosime (Daflon),
2 g/d, starting the day before the first infusion and continuing through
the entire course of therapy. (Diosime is a flavonoid approved in France
as a "vascular tonic" to stabilize capillary endothelium.)
Dose-limiting toxicities were defined as grade 4 absolute neutrophil
count for more than 7 days, febrile neutropenia for more than 3 days, grade
3 or 4 infection, grade 4 thrombocytopenia, and/or any other grade 3 or
4 adverse event, except anemia or alopecia. The maximum tolerated dose
was defined as the dose at which a dose-limiting toxicity occurred in two
or more of three patients entered, or in three or more of six patients
Neurologic function was evaluated prospectively by the same neurologist
at baseline, every two cycles during the study, and at the end of the study.
This included a clinical examination and measurement of nerve conduction
Over 1 year, 29 patients were enrolled in the study. The majority of
patients had visceral disease, mainly liver involvement.
Table 1 summarizes the overall safety
results. The incidence of grade 4 neutropenia was high at all dose levels,
with febrile neutropenia highest at level III. Grade 3 or 4 mucositis occurred
in two patients at level III and in one patient each at levels IV and V.
Symptomatic peripheral neuropathy was not observed. Neurologic adverse
events were no higher than grade 1. The treatment regimen, which included
corticosteroid prophylaxis, resulted in only mild fluid retention.
Table 2 summarizes the dose-limiting
toxicities, which were first observed at level III. At level III, three
(75%) of the four patients had dose-limiting toxicities. Dose-limiting
toxicities were also high at level V (four of six patients; 67%).
Two maximum tolerated doses were reached. The first, at 75 mg/m²
of docetaxel and 22.5 mg/m² of vinorelbine, included the dose-limiting
toxicities of febrile neutropenia plus mucositis (two patients) or febrile
neutropenia alone (one patient). The second maximum tolerated dose was
reached at 100 mg/m² of docetaxel and 20 mg/m² of vinorelbine;
dose-limiting toxicities were febrile neutropenia, febrile neutropenia
plus mucositis, febrile neutropenia plus sepsis, or grade 4 mucositis (one
From these results, the recommended doses for phase II studies were
determined to be 75 to 85 mg/m² of docetaxel on day 1 and 20 mg/m²
of vinorelbine on days 1 and 5, every 3 weeks (level IV); at these doses,
only one dose-limiting toxicity occurred in 10 patients.
Pharmacokinetics and Efficacy
Based on the maximum concentration, bioavailability, and clearance data,
the pharmacokinetics of docetaxel and vinorelbine were not altered by combining
them at the doses and schedule studied. The data indicate that under these
conditions the two drugs can be administered together without any relevant
The responses observed were promising, with an 80% overall response
rate at the higher recommended dose, 85 mg/m² of docetaxel on day
1 and 20 mg/m² of vinorelbine on days 1 and 5, and a 67% overall response
rate at 75 mg/m²of docetaxel and 20 mg/m² of vinorelbine at the
same schedule. At all dose levels, the overall response rate was 66%. It
is noteworthy that in the 11 patients with evaluable liver metastases,
the overall response rate was 82%, with one complete response.
These results correlate well with the preclinical data. Bissery et al[2,3]
performed three experiments in mice: one in the MA/16 model and two with
MA 13/C to determine the mean combination toxicity index; ie, the sum of
the percentages of the highest nontoxic doses of each of the agents used
in the combination. They found a mean combination toxicity index of 1.79
When considering the recommended dose in humans--ie, 75 to 85 mg/m²
of docetaxel on day 1 and 20 mg/m² of vinorelbine on days 1 and 5
of a 21-day course--the combined dosages correspond to 87% of the actual
dose intensity of docetaxel (98 mg/m² every 3 weeks) and 95% of the
actual dose intensity of vinorelbine (21 mg/m²/wk). This corresponds
to an overall combined toxicity index of 1.82, which correlates well with
the preclinical data.
Future study designs will continue to investigate the combination of
docetaxel and vinorelbine, as first-line therapy for patients with advanced
breast cancer, and as second-line therapy after the failure of an anthracycline-containing
Future investigations may attempt to raise the rate of complete responses
by increasing the dose density to every 14 days, dosing with additional
granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) or
by administering several therapies alternately or sequentially.
Based on the results of this trial, the recommended dosage regimen for
the docetaxel/vinorelbine combination in phase II studies is docetaxel,
75 to 85 mg/m²on day 1, and vinorelbine, 20 mg/m² on days 1 and
5, every 3 weeks. This combination will play an important role in the treatment
of patients with advanced breast cancer.
1. Gelmon K: The taxoids: Paclitaxel and docetaxel. Lancet 344:1267-1272,
2. Bissery MC, Azli N, Fumoleau P, et al: Docetaxel in combination with
vinorelbine: preclinical-clinical correlation (abstract). Proc Am Soc Clin
Oncol 15:487 1550, 1996.
3. Bissery MC, Vrignaud P, Bayssas M, et al: Docetaxel (RP 56976, docetaxel)
efficacy as a single agent or in combination against mammary tumors in
mice (abstract 1946). Proc Am Assoc Cancer Res 35:327, 1994.
4. Fumoleau P, Delecroix V, Perrocheau G, et al: Final results of a
phase I dose finding and pharmacokinetic (P.K.) study of docetaxel in combination
with vinorelbine in metastatic breast cancer (abstract 606P). Ann Oncol
7(suppl 5):126, 1996.