Docetaxel/Vinorelbine Combination Therapy in Non-Small-Cell Lung Cancer

ABSTRACT: Docetaxel (Taxotere) hasdemonstrated significant activity as a single agent in the treatment ofpatients with advanced non-small-cell lung cancer. Projected median survivalin both previously untreated and treated patients is reported to be 9 months.In addition, response rates have ranged from 33% to 38% and 21% to 27%in these respective patient populations. Because vinorelbine (Navelbine)has been demonstrated to have a survival benefit in randomized trials inpatients with non-small-cell lung cancer, the potential for the combineduse of these agents is promising. In addition, the side effect profilesof docetaxel and vinorelbine are compatible for the combined use of theseagents in patients with advanced non-small-cell lung cancer. Preliminaryresults from phase I and II combination studies have shown encouragingresults, with partial responses ranging from 23% to 55%. Based on thesedata, further study into the combined use of docetaxel and vinorelbinein patients with non-small-cell lung cancer is warranted. [ONCOLOGY 11(Suppl 7):35-40,1997]

Introduction

Docetaxel (Taxotere) and vinorelbine (Navelbine) are two of a numberof new third-generation chemotherapeutic agents that have become availablein recent years. A series of single-agent and combination therapy studiesare underway to determine the efficacy of these agents in the treatmentof patients with non-small-cell lung cancer. Although docetaxel and vinorelbineare considered tubulin-binding agents, their use in combination therapyis promising because each has different effects on microtubule assembly(Figure 1).[1]

Docetaxel, like other taxoids, promotes tubulin polymerization, whereasvinorelbine, like other vinca alkaloids, promotes tubulin depolymerization.Preclinical tests of docetaxel in combination with other vinca alkaloidsfailed to demonstrate synergy in a variety of in vivo experiments.[2] However,docetaxel and vinorelbine, when administered either simultaneously at 100%of the highest nontoxic dose or 24 hours apart at 80% of the highest nontoxicdose, produced a synergistic response in the MA 16/C mammary adenocarcinomamodel.[2]

This review deals essentially with the safety profiles of vinorelbineand docetaxel and presents preliminary data supporting continued investigationaimed at defining the optimal combination regimen of these agents in patientswith non-small-cell lung cancer.

Docetaxel, like other taxoids, promotes abnormal polymerization of tubulininto stable microtubule bundles, rather than the long filaments normallyused for the mitotic spindle and other microtubule-based structures. Unlikethe vinca alkaloids, docetaxel binds specifically with the beta-tubulinsubunit 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 approximatelytwice as potent as paclitaxel (Taxol) as an inhibitor of microtubular depolymerization.[3,5]The stabilizing effect of taxoids on microtubule bundles does not stopafter concentrations of taxoids are removed. Jordan and colleagues[6] demonstratedthat HeLa cells did not resume proliferation after removal of taxoids;instead, the cells entered an interphase-like state. DNA degradation intonucleosome-sized fragments characteristic of apoptosis began during drugincubation and increased after drug removal. Cells died within 48 to 72hours.[6]

In contrast, vinca alkaloids bind specifically to the alpha- and beta-tubulinsubunits 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 chemicaland functional characteristics. First, vinorelbine is a semisynthetic vincaalkaloid with substitutions on the catharanthine ring instead of the vindolinering of the molecule (Figure 2).[7] Froma functional perspective, the selectivity of vinorelbine for mitotic microtubuleslessens the toxicity to axonal microtubules that is typically associatedwith vinblastine and vincristine.[8]

Binet and colleagues[9] demonstrated that vinorelbine causes completedepolymerization of mitotic microtubules at concentrations lower than vincristineand vinblastine. In addition, preclinical tests with intact tectal platesfrom mouse embryos showed that depolymerization of axonal microtubuleswith vinorelbine occurred at a dose of 40 µM/L, compared with 5 and30 µM/L for vincristine and vinblastine, respectively.[9] Thus, thedifferences in mitotic and axonal activity imply an improved therapeuticindex of vinorelbine compared with vincristine and vinblastine.

Antitumor Activityand Pharmacokinetics

Antitumor Activity

By correlating antitumor activity with total dosage, preclinical testsshowed that docetaxel is schedule-independent.[10-12] In several cell linesin vitro, including those resistant to conventional antineoplastic drugs,the antitumor activity of docetaxel appeared to be largely independentof the specific extended dosing schedule used, indicating that prolongeddrug exposures may not be required to produce maximum antitumor effect.

The schedule of dependency for vinorelbine was determined using P388intraperitoneal implanted xenografts.[13] As shown in Table1, the ratio of survival time in treated vs control was greatest witha once-weekly dosing schedule (days 1, 7, and 13), compared with eithera day 1 only, day 1 through 5, or a twice-weekly regimen (days 1, 5, and9). The once-weekly dosing schedule resulted in an approximate threefoldincrease in survival as compared with controls.[13]

Pharmacokinetics

Docetaxel exhibits dose-independent pharmacokinetics that are consistentwith 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.[14]The docetaxel area under the curve was dose proportional after intravenousdoses of 70 to 115 mg/m². Mean total body clearance and steady-statevolume of distribution were 21 L/h/m² and 113 L, respectively. Docetaxelis extensively metabolized and is highly bound to plasma proteins (greaterthan 95%).

Although docetaxel pharmacokinetic characteristics are not affectedby age or gender, the clearance of docetaxel is decreased in patients withimpaired hepatic function. Docetaxel did not demonstrate sequence-dependenteffects when administered with cisplatin (Platinol).[14]

Pharmacokinetic studies have determined that vinorelbine follows a 3-compartmentmodel.[15] Intravenous administration of vinorelbine results in a rapiddistribution to peripheral tissues, with an average terminal half-lifeof 27.7 ± 15.7 hours. This long half-life is advantageous for usein combination regimens. The mean plasma clearance rate of vinorelbineranges from 0.97 to 1.26 L/h/kg. The steady-state volume of distributionis 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 profileof vinorelbine is not significantly altered in the elderly or when thedrug is administered with cisplatin. Compared with the other vinca alkaloids,vinorelbine has a larger volume of distribution and a higher clearance.[15]

Safety Considerations

Docetaxel

There is an extensive safety database on the administration of 100 mg/m²of docetaxel in patients (N = 1,435) with breast, non-small-cell lung cancer,ovarian, and other tumor types. The dose-limiting side effect of docetaxelwas short-lasting neutropenia (less than 500 cells/mm³), which occurredin 76% of patients. Neutropenia resolved in less than 1 week in approximately11% of patients. Patients who developed febrile neutropenia (12%) wereeffectively managed by reducing the dosage of docetaxel for subsequentcourses, without the use of colony-stimulating factors.

The other frequent hematologic adverse event was leukopenia (less than1,000 cells/mm³), which was noted in 31% of patients. The incidenceof 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 docetaxelincluded alopecia (80%), gastrointestinal side effects (nausea, 40%; diarrhea,40%; vomiting, 24%), stomatitis (42%), and nail changes (28%). These werecommon, but usually only grade 1 or 2 in severity. Neurosensory changes,such as mild paresthesias, were uncommon (less than 5% of patients). Inpatients receiving corticosteroid premedication, mild hypersensitivityreactions, such as flushing and pruritus, occurred in 16% of patients,and severe reactions were observed in only 0.9% of patients.

Vinorelbine

The safety of vinorelbine was recently reported in a prospective multicentertrial[16] in 216 patients with stage IV non-small-cell lung cancer. Patientswere randomized to receive either vinorelbine, 30 mg/m², infused over20 minutes once weekly or an intravenous bolus of 425 mg/m² of fluorouracil(5-FU) plus 20 mg/m² of leucovorin administered for 5 consecutivedays every 4 weeks. The predominant toxicity associated with the use ofsingle-agent vinorelbine at 30 mg/m2 was granulocytopenia (Table2).[16]

Grade 3 or 4 granulocytopenia was noted in 54% of patients receivingvinorelbine, 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 relatedto granulocytopenia.

Other hematologic toxicities included anemia, which was seen in 70%of the vinorelbine-treated patients and 42% of the 5-FU/leucovorin-treatedpatients. Anemia was of grade 1 or 2 severity, with 18% of vinorelbine-treatedpatients and 12% of 5-FU plus leucovorin-treated patients requiring bloodproducts.

Nonhematologic toxicities that occurred more frequently in vinorelbine-treatedpatients than in those given 5-FU/leucovorin combination therapy includedconstipation (29% vs 6%), peripheral neuropathy (20% vs 4%), and injection-sitereactions (ie, phlebitis and pain; 38% vs 1%).[16] The incidence of grade3 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 theadministration of vinorelbine.

In general, nausea, vomiting, stomatitis, anorexia, and diarrhea werereported to occur more frequently in the 5-FU/leucovorin treatment thanin the vinorelbine treatment group. Thus, the hematologic and nonhematologictoxicity profiles of docetaxel and vinorelbine appear to be compatiblefor concomitant use in patients with non-small-cell lung cancer.

Docetaxel/Vinorelbine:Preclinical and Clinical Studies

Data supporting the potential for docetaxel/vinorelbine combinationtherapy in non-small-cell lung cancer come from single-agent trials aswell as preclinical studies.

Single-Agent Efficacy

Docetaxel has demonstrated significant activity as a single agent inthe treatment of patients with advanced non-small-cell lung cancer. Responserates for docetaxel administered intravenously 100 mg/m² over 60 minutes,once every 3 weeks, in patients with non-small-cell lung cancer have rangedfrom 33% to 38% in previously untreated patients, with projected mediansurvival duration of 9 months and a 1-year survival rate of 40%.[17] Inpreviously treated patients, response rates have ranged from 21% to 27%,with projected median survival duration of 9 months and a 1-year survivalrate of 34%.[17]

As reported in a recent prospective multicenter trial[16] in 216 previouslyuntreated patients with stage IV non-small-cell lung cancer, 30 mg/m²of vinorelbine, infused over 5 to 10 minutes once weekly every 21 days,produced a partial response rate of 12%, with a median survival of 30 weeksand 1-year survival rate of 25%.[16] This survival time was superior tothe control regimen of 5-FU/leucovorin (16% at 1 year) and compares favorablywith that achieved by previous combination regimens (28 weeks), as shownin Table 3.[16,18-25]

The potential for improving the survival time of vinorelbine was demonstratedby Le Chevalier and colleagues[26], who reported that survival times couldbe increased to 40 weeks when cisplatin was used in combination with vinorelbinein patients with non-small-cell lung cancer.

Preclinical/Phase I Combination Studies

Bissery and colleagues[27] reported the in vitro synergistic effectsof these agents when administered in mice bearing subcutaneous mammaryadenocarcinoma MA 16/C. The study used a 3-arm dose-response design toassess the tolerance and efficacy of the combination when administeredeither simultaneously or 24 hours apart. The highest nontoxic dose of docetaxel(100 mg/m² IV every 21 days) and vinorelbine (21 mg/m² IV oncea week) could be administered when given simultaneously. However, schedulingstudies 24 hours apart necessitated a 20% reduction in the docetaxel dose,regardless of the order in which the agents were administered.[27]

The results from this preclinical study proved to be predictive of themaximum tolerated dose in patients with breast cancer. The phase I clinicaltrial[27] performed by the same authors evaluated patients' response to20 mg/m² of vinorelbine administered intravenously on days 1 and 5followed immediately by varying doses of docetaxel (60, 75, 85, and 100mg/m²) on day 1, once every 3 weeks. Each dose level demonstratedsignificant clinical responses (31% to 34%), with the highest nontoxicdose being 85 mg/m² of docetaxel combined with 20 mg/m² of vinorelbine.These results suggest that the docetaxel/vinorelbine combination has activityin the breast cancer model.[27]

The data published by Bissery and colleagues,[27] as well as Fumoleauand co-workers,[28] provided a basis for testing various schedules of docetaxelplus vinorelbine in patients with non-small-cell lung cancer. Monnier andcolleagues[29] reported the results of a French multicenter, phase II trialthat evaluated the use of docetaxel/vinorelbine in 39 patients with locallyadvanced or metastatic non-small-cell lung cancer, 80% of whom had a performancestatus of 0 to 1. The initial dose was 75 mg/m²of docetaxel administeredintravenously on day 1 followed by vinorelbine, 20 mg/m² administeredintravenously on days 1 and 5, once every 3 weeks. Patients also receivedpremedication with prednisone, diosmine, and antiemetics on an outpatientbasis.

The dose-limiting toxicity was grade 4 neutropenia, which was seen in77% of the patients (Table 4).[29] Febrileneutropenia was experienced by 42% of patients. Grade 3 to 4 stomatitisand severe asthenia occurred in 11% of the patients. Partial responseswere achieved in 23% of the patients.

The authors concluded that additional studies are needed to determinewhether the efficacy documented in this study is similar to that of docetaxelalone.[17] In addition, the regimen did not include colony-stimulatinggrowth support, which may be appropriate for inclusion in future studiesbecause of the 42% incidence of febrile neutropenia reported in this study.[29]

Other Trials

A second trial, by Kourousis and colleagues[30], examined the combinationregimen of 100 mg/m² of docetaxel (as a 3-hour infusion with premedication)and 25 mg/m² of vinorelbine, both administered intravenously onceevery 21 days, in 43 patients with non-small-cell lung cancer. Patientsin this study also received growth factor support in the form of 5 mg/kgof granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen])beginning on days 4 through 15 to reduce the expected neutropenia. Themajority (70%) of patients had stage IV disease, and 81% had a performancestatus of 0 to 1.[30]

The addition of G-CSF minimized the magnitude of grade 3 or 4 neutropenia,which was noted in 19% of patients (Table4).[30] Further, only 6% of patients experienced febrile neutropenia.The incidence of grade 2 to 3 neurotoxicity was also low, at 8%. Partialresponse was documented in 47% of patients, with a median survival timeof over 6 months (range, 2 to 10 months). The authors noted that the additionof G-CSF to docetaxel/vinorelbine resulted in an active, well-toleratedregimen with acceptable toxicity.[30]

A third approach to the combination of docetaxel and vinorelbine inpatients with non-small-cell lung cancer was reported by Viallet and colleagues.[31]In this study, 45 patients with stage IIIB or IV non-small-cell lung cancerreceived 100 mg/m² of docetaxel on day 1, 100 mg/m² of cisplatinon day 21, and 30 mg/m² of vinorelbine on days 21, 28, and 35 of a6-week cycle. A maximum of 3 cycles was given to patients with stable diseaseand a maximum of 2 cycles beyond maximal response to responding patients.Growth factor support was not administered in this study.

Febrile neutropenia was noted in 4 patients; 63 cycles were administered(Table 4).[31] A response rate of 55%(15 of 27 patients) was documented, with stable disease being achievedin an additional 5 patients.

Recently, Early and colleagues[32] reported preliminary results froma phase I/II trial in patients with stage IIIB and IV non-small-cell lungcancer who received escalating doses of vinorelbine (15 to 37.5 mg/m²)administered intravenously over 10 minutes followed by a 1-hour intravenousinfusion of docetaxel, 50 mg/m². The cycle was repeated every 2 weeks.Patients also received prophylactic G-CSF support and dexamethasone premedication.

Two episodes of febrile neutropenia were noted in the 83 cycles administered.Antitumor activity has been noted in 5 of the 17 patients enrolled to datein this ongoing study.[32]

Conclusions

The optimal regimen for the combination of docetaxel and vinorelbinein patients with non-small-cell lung cancer remains to be determined. Anumber of preliminary studies of this combination have had encouragingresults in terms of efficacy as well as tolerability. Future studies needto address the role of supportive therapy with G-CSF and whether dose intensificationwith a docetaxel/vinorelbine regimen can be achieved in patients with non-small-celllung cancer.

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