The combination of vinorelbine tartrate(Drug information on vinorelbine tartrate) (Navelbine) and paclitaxel(Drug information on 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(Drug information on doxorubicin) or the combination of Cytoxan, methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on 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 class.
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.