Docetaxel (Taxotere) and vinorelbine (Navelbine) are two of a number of new third-generation chemotherapeutic agents that have become available in recent years. A series of single-agent and combination therapy studies are underway to determine the efficacy of these agents in the treatment of patients with non-small-cell lung cancer. Although docetaxel(Drug information on docetaxel) and vinorelbine are considered tubulin-binding agents, their use in combination therapy is promising because each has different effects on microtubule assembly (Figure 1).
Docetaxel, like other taxoids, promotes tubulin polymerization, whereas vinorelbine, like other vinca alkaloids, promotes tubulin depolymerization. Preclinical tests of docetaxel in combination with other vinca alkaloids failed to demonstrate synergy in a variety of in vivo experiments. However, docetaxel and vinorelbine, when administered either simultaneously at 100% of the highest nontoxic dose or 24 hours apart at 80% of the highest nontoxic dose, produced a synergistic response in the MA 16/C mammary adenocarcinoma model.
This review deals essentially with the safety profiles of vinorelbine and docetaxel and presents preliminary data supporting continued investigation aimed at defining the optimal combination regimen of these agents in patients with non-small-cell lung cancer.
Docetaxel, like other taxoids, promotes abnormal polymerization of tubulin into stable microtubule bundles, rather than the long filaments normally used for the mitotic spindle and other microtubule-based structures. Unlike the vinca alkaloids, docetaxel binds specifically with the beta-tubulin subunit of microtubules and inhibits the disassembly of the important cytoskel- etal protein. This results in the inhibition of microtubule depolymerization.[3-5]
Results from in vitro studies indicate that docetaxel is approximately twice as potent as paclitaxel(Drug information on paclitaxel) (Taxol) as an inhibitor of microtubular depolymerization.[3,5] The stabilizing effect of taxoids on microtubule bundles does not stop after concentrations of taxoids are removed. Jordan and colleagues demonstrated that HeLa cells did not resume proliferation after removal of taxoids; instead, the cells entered an interphase-like state. DNA degradation into nucleosome-sized fragments characteristic of apoptosis began during drug incubation and increased after drug removal. Cells died within 48 to 72 hours.
In contrast, vinca alkaloids bind specifically to the alpha- and beta-tubulin subunits and block the ability of the protein to polymerize into microtubules, leading to the inability of chromosomes to segregate correctly during mitosis, and thereby leading to apoptosis.[7,8]
Vinorelbine departs from the traditional vinca alkaloids in both chemical and functional characteristics. First, vinorelbine is a semisynthetic vinca alkaloid with substitutions on the catharanthine ring instead of the vindoline ring of the molecule (Figure 2). From a functional perspective, the selectivity of vinorelbine for mitotic microtubules lessens the toxicity to axonal microtubules that is typically associated with vinblastine(Drug information on vinblastine) and vincristine.
Binet and colleagues demonstrated that vinorelbine causes complete depolymerization of mitotic microtubules at concentrations lower than vincristine and vinblastine. In addition, preclinical tests with intact tectal plates from mouse embryos showed that depolymerization of axonal microtubules with vinorelbine occurred at a dose of 40 µM/L, compared with 5 and 30 µM/L for vincristine and vinblastine, respectively. Thus, the differences in mitotic and axonal activity imply an improved therapeutic index of vinorelbine compared with vincristine and vinblastine.
By correlating antitumor activity with total dosage, preclinical tests showed that docetaxel is schedule-independent.[10-12] In several cell lines in vitro, including those resistant to conventional antineoplastic drugs, the antitumor activity of docetaxel appeared to be largely independent of the specific extended dosing schedule used, indicating that prolonged drug exposures may not be required to produce maximum antitumor effect.
The schedule of dependency for vinorelbine was determined using P388 intraperitoneal implanted xenografts. As shown in Table 1, the ratio of survival time in treated vs control was greatest with a once-weekly dosing schedule (days 1, 7, and 13), compared with either a day 1 only, day 1 through 5, or a twice-weekly regimen (days 1, 5, and 9). The once-weekly dosing schedule resulted in an approximate threefold increase in survival as compared with controls.
Docetaxel exhibits dose-independent pharmacokinetics that are consistent with a linear, 3-compartment model, with half-lives for the alpha, beta, and gamma phases of 4 minutes, 11 minutes, and 11.1 hours, respectively. The docetaxel area under the curve was dose proportional after intravenous doses of 70 to 115 mg/m². Mean total body clearance and steady-state volume of distribution were 21 L/h/m² and 113 L, respectively. Docetaxel is extensively metabolized and is highly bound to plasma proteins (greater than 95%).
Although docetaxel pharmacokinetic characteristics are not affected by age or gender, the clearance of docetaxel is decreased in patients with impaired hepatic function. Docetaxel did not demonstrate sequence-dependent effects when administered with cisplatin(Drug information on cisplatin) (Platinol).
Pharmacokinetic studies have determined that vinorelbine follows a 3-compartment model. Intravenous administration of vinorelbine results in a rapid distribution to peripheral tissues, with an average terminal half-life of 27.7 ± 15.7 hours. This long half-life is advantageous for use in combination regimens. The mean plasma clearance rate of vinorelbine ranges from 0.97 to 1.26 L/h/kg. The steady-state volume of distribution is large, ranging from 25.4 to 40.1 L/kg.
Vinorelbine is highly bound in blood, especially to platelets and lymphocytes, but no drug interactions from displacement of bound drug have been reported. The liver is the primary site of metabolism. The pharmacokinetic profile of vinorelbine is not significantly altered in the elderly or when the drug is administered with cisplatin. Compared with the other vinca alkaloids, vinorelbine has a larger volume of distribution and a higher clearance.
There is an extensive safety database on the administration of 100 mg/m² of docetaxel in patients (N = 1,435) with breast, non-small-cell lung cancer, ovarian, and other tumor types. The dose-limiting side effect of docetaxel was short-lasting neutropenia (less than 500 cells/mm³), which occurred in 76% of patients. Neutropenia resolved in less than 1 week in approximately 11% of patients. Patients who developed febrile neutropenia (12%) were effectively managed by reducing the dosage of docetaxel for subsequent courses, without the use of colony-stimulating factors.
The other frequent hematologic adverse event was leukopenia (less than 1,000 cells/mm³), which was noted in 31% of patients. The incidence of thrombocytopenia (less than 100,000 cells/mm³; 7.5%) and anemia (less than 8 g/dL; 8.4%) associated with docetaxel was low.
Nonhematologic side effects associated with 100 mg/m² of docetaxel included alopecia (80%), gastrointestinal side effects (nausea, 40%; diarrhea, 40%; vomiting, 24%), stomatitis (42%), and nail changes (28%). These were common, but usually only grade 1 or 2 in severity. Neurosensory changes, such as mild paresthesias, were uncommon (less than 5% of patients). In patients receiving corticosteroid premedication, mild hypersensitivity reactions, such as flushing and pruritus, occurred in 16% of patients, and severe reactions were observed in only 0.9% of patients.
The safety of vinorelbine was recently reported in a prospective multicenter trial in 216 patients with stage IV non-small-cell lung cancer. Patients were randomized to receive either vinorelbine, 30 mg/m², infused over 20 minutes once weekly or an intravenous bolus of 425 mg/m² of fluorouracil(Drug information on fluorouracil) (5-FU) plus 20 mg/m² of leucovorin administered for 5 consecutive days every 4 weeks. The predominant toxicity associated with the use of single-agent vinorelbine at 30 mg/m2 was granulocytopenia (Table 2).
Grade 3 or 4 granulocytopenia was noted in 54% of patients receiving vinorelbine, compared with 24% of the 5-FU/leucovorin-treated patients. Despite the wide difference in the incidence of grade 3 or 4 granulocytopenia, only 7% and 6% of the patients in both groups experienced infections related to granulocytopenia.
Other hematologic toxicities included anemia, which was seen in 70% of the vinorelbine-treated patients and 42% of the 5-FU/leucovorin-treated patients. Anemia was of grade 1 or 2 severity, with 18% of vinorelbine-treated patients and 12% of 5-FU plus leucovorin-treated patients requiring blood products.
Nonhematologic toxicities that occurred more frequently in vinorelbine-treated patients than in those given 5-FU/leucovorin combination therapy included constipation (29% vs 6%), peripheral neuropathy (20% vs 4%), and injection-site reactions (ie, phlebitis and pain; 38% vs 1%). The incidence of grade 3 severity of the same nonhematologic toxicities was substantially lower--ie, constipation, 2%; peripheral neuropathy, 1%; and injection site reactions, 5%. There were no grade IV nonhematologic toxicities associated with the administration of vinorelbine.
In general, nausea, vomiting, stomatitis, anorexia, and diarrhea were reported to occur more frequently in the 5-FU/leucovorin treatment than in the vinorelbine treatment group. Thus, the hematologic and nonhematologic toxicity profiles of docetaxel and vinorelbine appear to be compatible for concomitant use in patients with non-small-cell lung cancer.