Current Status of Vinorelbine For Breast Cancer

Introduction

Vinorelbine tartrate(Drug information on vinorelbine tartrate) (5'-noranhydro-vinblastine) is a new semisynthetic vinca alkaloid with a broad spectrum of in vitro antitumor activity demonstrated in preclinical studies. Phase I/II trials confirmed the efficacy of this drug against a variety of solid tumors, including non-small-cell lung cancer, breast cancer, head and neck cancer, and Hodgkin's lymphoma. Favorable phase III trial results led to its recent FDA approval for use as a first-line agent in ambulatory patients with advanced non-small-cell lung cancer.

After nearly a decade of clinical trials in Europe and recent studies in the United States, there is now extensive data confirming the activity of vinorelbine for metastatic breast cancer. Vinorelbine differs from other vinca alkaloids, for the drug possesses unique pharmacokinetics and a more favorable side-effect profile. This article will review the encouraging results of single agent and combination therapy trials, compare vinorelbine activity to established therapies for breast cancer, consider novel routes of administration, and discuss ongoing randomized clinical trials and future studies that may lead to the widespread use of vinorelbine for the treatment of breast cancer.

Pharmacokinetics

The chemical structure of vinorelbine differs from the other members of the vinca alkaloid family (such as vincristine or vinblastine(Drug information on vinblastine)), in that vinorelbine has a substitution on the catharine ring of the molecule instead of the vindoline nucleus. This difference imparts the unique biochemical properties of the drug, and vinorelbine pharmacokinetics thus differ from the other vinca alkaloids.

Vinorelbine is highly lipophilic, which results in more significant tissue uptake and a greater therapeutic index than the other vinca alkaloids. The excretion of vinorelbine following a dose of 30 mg/m² infused over 15 to 20 minutes has been described as triphasic, with a large volume of distribution, high systemic clearance, and prolonged terminal phase due to the slow efflux of the drug from peripheral tissue compartments [1]. The terminal half-life of vinorelbine is 27.7 to 43.6 hours, and the mean plasma clearance ranges from 0.83 to 1.26 L/h/kg [2,3].

Metabolism and Elimination

Vinorelbine is metabolized predominantly by the liver, with most of the drug and its metabolites eliminated via the biliary tract and excreted in feces. In fact, the clearance of vinorelbine approaches hepatic blood flow (1.3 L/h/kg) [1]. Renal clearance accounts for only 10% to 12% of total drug elimination [2]. To date, the effect of hepatic or renal dysfunction on vinorelbine metabolism has not been determined, but dose reduction is recommended for patients with liver function abnormalities.

The hepatic cytochrome P-450 3A enzyme system appears to be responsible for the metabolism of vinorelbine, all vinca alkaloids, and the majority of chemotherapeutic agents [4-6]. One vinorelbine metabolite, deacetylvinorelbine, has been detected in plasma and possesses antitumor activity [1]. Specific drugs have been shown to inhibit vinorelbine metabolism by competitive inhibition of P-450 3A, especially other vinca alkaloids and drugs such as doxorubicin(Drug information on doxorubicin), methotrexate(Drug information on methotrexate), and calcium-channel blockers [4-6].

Research has demonstrated large variation between patients in the pharmacokinetics of vinorelbine, but the reasons for this diversity are unknown. Although age does not appear to influence vinorelbine pharmacokinetics [1], there is growing evidence that the activity of the P-450 3A enzyme may be altered with menopause [7]. As a result, investigators are currently studying the potential impact of menopausal status on vinorelbine metabolism.

Potential Mechanisms of Resistance

Like other vinca alkaloids, vinorelbine resistance is presumably mediated by multidrug resistance (MDR) and P-glycoprotein overexpression, which results in enhanced drug efflux from tumor cells [8,9]. The precise mechanism of resistance to vinorelbline has yet to be determined, but the role of MDR is supported by evidence that there appears to be substantial cross-resistance between vinorelbine and other members of the vinca family, as well as a variety of other MDR substrates [10].

Mechanism of Action

Vinorelbine inhibits microtubule assembly, and thus, is cell-cycle-specific. Like other vinca alkaloids, vinorelbine blocks formation of the mitotic spindle apparatus at metaphase and prevents cell division. This is in contrast to the taxanes, such as paclitaxel(Drug information on paclitaxel) (Taxol), which promote and stabilize the assembly of microtubules after spindle formation has occurred.

One of the most promising aspects of vinorelbine relates to this selective effect on microtubules. Peripheral neuropathy is common with most vinca alkaloids, and is believed to result from a direct effect on the microtubules in peripheral nerves. However, in vitro immunofluorescence experiments have demonstrated that vinorelbine is selective for nonneural microtubules [11]. Additional studies have confirmed that toxicity against axonal microtubules typically occurs at a significantly higher vinorelbine concentration (30 to 40 mol/L) than is required for maximal antitumor effect (5 mol/L) [11,12]. Therefore, as expected from preclinical data, vinorelbine has a wide therapeutic window, which has resulted in reduced neurotoxicity in clinical trials compared to the other vinca alkaloids.

Toxicity

Extensive clinical studies have been conducted to elucidate the safety profile of vinorelbine. Table 1 lists the major toxiciticies of vinorelbine reported in three North American clinical trials involving 222 women with metastatic breast cancer [13,14].

Hematologic Effects

The majority of the adverse events reported in these trials were hematologic. Neutropenia was the most commonly reported toxicity, with 96% of women having an absolute neutrophil count (ANC) < 2,000/mm³ with single-agent treatment and 41% of women experiencing an ANC < 500/mm³. Fever and neutropenia were reported in 9% of treatment cycles. Recovery from hematologic toxicity is rapid, with nadirs typically occurring at 7 to 10 days and complete recovery 1 to 2 weeks later in most cases.

Although neutropenia remains the most frequent cause of dose adjustment or treatment delay in patients who receive weekly vinorelbine administration, growth factor support has not been routinely recommended for weekly 30-mg/m² doses of vinorelbine when used as a single agent. However, combination regimens that include vinorelbine may require granulocyte colony-stimulating factor (G-CSF; filgrastim(Drug information on filgrastim) [Neupogen]) to minimize this additive toxicity and to maintain the dosage schedule.

Vinorelbine also resulted in mild anemia in clinical trials, with 87% of women with breast cancer having a hemoglobin of less than 11 mg/dL. Despite the frequency of this adverse effect, however, transfusion was seldom necessary. Finally, thrombocytopenia was rarely reported; fewer than 10% of administered cycles were associated with platelet counts below 100,000/mm³.

Nonhematologic Effects

In contrast to its significant myelosuppression, vinorelbine is associated with only modest nonhematologic toxicity. The drug produced mild elevations of serum liver function tests, with abnormal serum glutamic-oxaloacetic transaminase (SGOT) noted more commonly than an increased total bilirubin. However, clinical symptoms or frank hepatic toxicity has not been reported.

Vinorelbine is only mildly emetogenic, and coadministration of potent serotonin antagonist antiemetics is not routinely required. The predominant gastrointestinal side effects included nausea (50%), vomiting (23%), constipation (38%), and diarrhea (20%).

Vinorelbine is a mild vesicant, and local reactions involving phlebitis or pain at the infusion site were reported in approximately 20% of patients. Peripheral neuropathy, characterized by mild to moderate, reversible paresthesias or hypoesthesias, occurred in 30% of women. No grade III or grade IV neurotoxicity was seen, and loss of deep-tendon reflexes was noted in fewer than 5% of patients.

Dyspnea occurred in 9% of patients within hours after vinorelbine administration, and yet pulmonary symptoms were rarely severe and most likely represent an allergic reaction. Finally, alopecia was reported in 12% of women.

In summary, vinorelbine is well tolerated, with the major toxicity involving neutropenia.