The combination of vinorelbine tartrate (Navelbine) and paclitaxel
(Taxol) appears promising for the treatment of patients with metastatic
breast cancer, including some patients who had previously receivedanthracycline-based
adjuvant therapy, according to researchers at the M. D. Anderson
Cancer Center in Houston. Preliminary results of the phase I study
were recently reported at the annual meeting of the American Association
of Cancer Research (AACR).
The phase I study, the first to combine these two drugs to treat
advanced breast cancer, was conducted to evaluate dosing and the
combined effect of vinorelbine and paclitaxel on 25 patients untreated
for metastatic breast cancer. In previous preclinical studies,
the two drugs, when added simultaneously to breast and lung cancer
tissue cultures, had synergistic antitumor effects, despite exhibiting
different mechanisms of action on the cell division process.
"This is a progress report for a combination that has great
potential as an effective treatment option for advanced breast
cancer, especially as an alternative for patients that are resistant
to standard therapy such as doxorubicin or the combination of
Cytoxan, methotrexate, and fluorouracil (CMF)," said lead
investigator Gabriel Hortobagyi, MD, Department of Breast and
Gynecologic Medical Oncology at M. D. Anderson. "Individually,
both Navelbine and Taxol are exciting in treating breast cancer.
We are hopeful this combination will improve the treatment of
these patients substantially," Dr. Hortobagyi added.
The agents were given simultaneously by 3-hour infusion on the
first day of treatment and repeated every 21 days, with doses
starting at 36 mg/m² for vinorelbine, 175 mg/m² for
paclitaxel. The maximum tolerated dose was 25 mg/m² for vinorelbine
and 150 mg/m² for paclitaxel. At this dose and schedule,
the combination therapy was moderately well-tolerated. Neutropenic
fever was encountered during 19 of the 115 courses (16%). Two
patients experienced reversible grade 3 pelvic floor pain, and
grade 3 paresthesia of the hands and feet was reported in five
patients. Granulocyte colony-stimulating factor (G-CSF) support
was not given prophylactically with the initial treatment.
"As a first step, the combination at this dosage and schedule
is reasonably well-tolerated and effective," said Dr. Hortobagyi.
"As we continue its evaluation, our next step is to develop
a schedule that will enable us to intensify treatment and increase
efficacy while maintaining its safety profile."
Researchers also determined the combination's maximum-tolerated
dose when combined with G-CSF:vinorelbine at 36mg/m2 and paclitaxel
at 150mg/m2 when given every 3 weeks.
Evaluation is ongoing to determine the flexibility of this dosage
given on a 2-week schedule.
Vinorelbine is a semi-synthetic vinca alkaloid. In December 1994,
the FDA approved vinorelbine for marketing as a first-line treatment
for ambulatory patients with unresectable, advanced non-small-cell
lung cancer. Paclitaxel is a chemotherapeutic agent in the taxane
Granulocytopenia, a reversible decrease in the white blood cell
count, is the dose-limiting toxicity for both drugs. As with other
cancer drugs that suppress white blood cell counts, vinorelbine
and paclitaxel are associated with an increased risk of infection,
which may require hospitalization and can sometimes be fatal.
In previous clinical studies with vinorelbine as a single agent,
granulocytopenia is the most commonly reported and important side
effect, and is usually manageable with patient monitoring and
reductions or delays in dosing.
Overall, vinorelbine has been found to have a favorable side effect
profile in clinical trials. Side effects often considered to be
of greatest importance and concern to patients, such as nausea,
vomiting, and alopecia, were reported as mild to moderate in intensity.
Other clinical studies are also ongoing in lung, breast, ovarian,
and prostate cancer.