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Current Status of Vinorelbine For Breast Cancer

Current Status of Vinorelbine For Breast Cancer

ABSTRACT: Vinorelbine tartrate (Navelbine) is a new semisynthetic vinca alkaloid with efficacy against a variety of solid tumors, including non-small-cell lung cancer, breast cancer, head and neck cancer, and Hodgkin's lymphoma. Recently approved by the FDA for the first-line treatment of advanced non-small-cell lung cancer, vinorelbine is also under review by the FDA for use in patients with metastatic breast cancer. There is now extensive data confirming the activity of vinorelbine in metastatic breast cancer, with second-line response rates of 17% to 36% and first-line response rates of 40% to 44%. Investigators have combined vinorelbine with other active drugs against breast cancer to produce response rates exceeding 50% for first-line therapy. Numerous centers are now conducting randomized trials comparing vinorelbine to established second-line therapies for advanced breast cancer, such as paclitaxel (Taxol). Future research is needed to further define the precise role of vinorelbine as a component of combination therapy for metastatic breast cancer. [ONCOLOGY 9(8):767-779, 1995]

Introduction

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),
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,
methotrexate, and calcium-channel blockers [4-6].

Research has demonstrated large variation between patientsin 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 (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
[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.

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