Introduction
The rationale for the use of docetaxel(Drug information on docetaxel) (Taxotere) and vinorelbine (Navelbine) in combination chemotherapy regimens is based on a number of factors. One is attributable to their mechanisms of action, because both of these agents exert complementary effects on microtubules. Docetaxel promotes abnormal polymerization of tubulin into stable microtubule bundles by binding specifically with the b-tubulin subunit of microtubules, thereby leading to the inhibition of microtubule depolymerization.[1-3] Vinorelbine, on the other hand, binds specifically to the a- and b-tubulin subunits and blocks the ability of the protein to polymerize into microtubules. This action leads to the inability of chromosomes to segregate correctly during mitosis, thereby inducing apoptosis.[4,5]
The interest in these two compounds is also generated by specific characteristics within their respective chemical classes--ie, the taxoids and Vinca alkaloids. For example, docetaxel possesses greater potency as an inhibitor of microtubular depolymerization, estimated as twice that of paclitaxel(Drug information on paclitaxel) (Taxol).[2,3] Other differentiating in vitro characteristics of docetaxel include higher binding affinities for microtubules, higher intracellular concentrations, and prolonged retention in tumor cells as compared with paclitaxel.[6,7]
It is believed that vinorelbine is less neurotoxic than other Vinca alkaloids because of the selectivity of vinorelbine for mitotic microtubules.[5] Moreover, results from preclinical tests[8] demonstrate that depolymerization of axonal microtubules with vinorelbine occurs at a concentration of 40 µM/L as compared with 5 and 30 µM/L for vincristine and vinblastine(Drug information on vinblastine), respectively. Thus, the therapeutic index of vinorelbine can potentially be greater than that of either vincristine or vinblastine, as indicated by its actions on mitotic and axonal activity.
Preclinical tests conducted by Bissery and colleagues[6] revealed that docetaxel and vinorelbine produce a synergistic response in the MA 16/C mammary adenocarcinoma model. Synergy was demonstrated whether both agents were administered simultaneously or 24 hours apart at 80% of the highest nontoxic dose.[6,9] Additional toxicity at these doses was not observed. In contrast, synergy was not demonstrated with either vincristine or vinblastine.[6] Thus, the results from preclinical studies and the well-established antitumor activity as first-line single agents in metastatic breast cancer, non-small-cell lung cancer, and a variety of other cancers support the use of docetaxel and vinorelbine in combination regimens.
Clinical Trials with Docetaxel and Vinblastine
Phase I/II Studies in Metastatic Breast Cancer
A phase I/II dose-finding study by Fumoleau and colleagues[10] established the maximum tolerated doses for the combination of docetaxel and vinorelbine, determined major pharmacokinetic parameters, and identified a recommended dose for future phase II studies. Dose-limiting toxicity was defined as febrile neutropenia of more than 3 days' duration and/or grade 4 neutropenia lasting more than 7 days and/or grade 3 to 4 nonhematologic toxicity. Patients entered in this trial had metastatic breast cancer, a World Health Organization performance status of 2 or less, and no prior chemotherapy for advanced disease.
The treatment plan included vinorelbine administered as a 30-minute intravenous infusion on days 1 and 5 followed immediately by a 1-hour intravenous infusion of docetaxel on day 1 of a 21-day cycle. The dose levels of vinorelbine/docetaxel administered were 20/60, 20/75, 22.5/ 75, 20/85, and 20/100 mg/m². All patients received premedication with 8 mg/day of dexamethasone(Drug information on dexamethasone) for 3 days starting 1 day prior to chemotherapy. Because of the potential for neurotoxicity with the use of vinorelbine, neurological examinations including nerve conduction studies were performed at baseline, and then following every 2 cycles thereafter.
Overall, responses were observed at each dose level. Two maximum tolerated doses were reached: 22.5 mg/m² of vinorelbine followed by 75 mg/m² of docetaxel and 20 mg/m² of vinorelbine followed by 100 mg/m² of docetaxel. Febrile neutropenia was observed in 37% and 11% of the cycles at the 2 dose levels. Based on these results, the authors concluded that 20 mg/m² of vinorelbine (days 1 and 5) followed by either 75 or 85 mg/m² of docetaxel on day 1 was recommended for phase II studies. At the recommended doses, 11 of 16 patients had an objective response.
Based on the results of the phase I study,[10] a multicenter phase II trial was initiated to evaluate the combination of docetaxel and vinorelbine as first-line therapy in patients with metastatic breast cancer. Patients in this ongoing trial will receive 20 mg/m² of vinorelbine administered as a 30-minute intravenous infusion on days 1 and 5 followed immediately by 85 mg/m² of docetaxel on day 1 of a 21-day cycle.
Phase I/II Studies in Non-Small-Cell Lung Cancer
Although the initial studies of docetaxel and vinorelbine combinations were performed in patients with metastatic breast cancer, subsequent studies have concentrated on non-small-cell lung cancer. Douillard and co-workers[11] conducted a phase I dose-escalation trial to determine the dose-limiting toxicity, maximum tolerated dose, and the recommended dose of docetaxel plus vinorelbine for future trials. Inclusion criteria included previously untreated patients with histologically proven advanced or metastatic non-small-cell lung cancer with at least one bidimensionally measurable lesion and who had a World Health Organization performance status less than or equal to 2.
During the 3-week cycle, vinorelbine was administered as a 30-minute intravenous infusion on days 1 and 8 followed immediately by a 1-hour intravenous infusion of docetaxel on day 8. The dose levels are shown in Table 1. Patients were premedicated with 8 mg of dexamethasone twice daily for 3 days, beginning 1 day prior to the administration of docetaxel.
To date, 26 patients have entered this ongoing trial, with evaluable data on 23 patients (Table 2). The median age is 52 years (range: 39 to 68 years) with a median World Health Organization performance status of 1. The maximum tolerated dose was 25 mg/m² of vinorelbine on days 1 and 8 and 100 mg/m² of docetaxel on day 8. At this dose, 3 patients developed dose-limiting toxicities (1 incidence of febrile neutropenia, 1 neurosensory, and 1 neutropenia with infection). Data are not yet available for patients receiving 25 and 20 mg/m² of vinorelbine on days 1 and 8, and 100 mg/m² of docetaxel on day 8. The authors concluded that the maximum tolerated dose found in this study was close to the recommended dose of each drug as a single agent.
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