Four phase II trials have beenconducted to evaluate the efficacy and tolerability of single-agent docetaxel
ABSTRACT: Four phase II trials have beenconducted to evaluate the efficacy and tolerability of single-agent docetaxel(Taxotere) in the treatment of previously untreated patients with advancednon-small-cell lung cancer. This paper presents data from 160 patientswho received 100 mg/m² of docetaxel administered over 1 hour, onceevery 3 weeks. In the intent-to-treat analysis, overall, major responseswere achieved in 27% of previously untreated patients with advanced non-small-celllung cancer. Median survival was 9.2 months, with a 1-year survival rateof 39%. Neutropenia was the most common adverse event. Nonhematologic adverseevents included alopecia, fluid retention, asthenia, infusion-related reaction,and rash. Single-agent docetaxel demonstrates significant antitumor activityin previously untreated patients with advanced non-small-cell lung cancer.The response rate and survival benefit achieved with single-agent docetaxelare comparable to those of cisplatin (Platinol)-based combination regimensand higher than those observed with best supportive care. Additional investigationswith docetaxel, alone and in combination with other chemotherapeutic agentsactive in non-small-cell lung cancer, are warranted. [ONCOLOGY 11(Suppl 7):17-21,1997]
The taxoids have generated much interest during the past several yearsas important options for the treatment of various malignancies. Docetaxel(Taxotere) is a semisynthetic taxoid synthesized from 10-deacetyl baccatinIII, a noncytotoxic taxoid precursor extracted from the renewable needlesof the European yew Taxus baccata and chemically modified with a syntheticlipophilic side chain at C-13 (Figure 1).Taxoids exert their cytotoxic effects by specifically promoting the assemblyof tubules into microtubules, stabilizing the microtubules, and inhibitingthe depolymerization to free tubulin.[1-3]
However, there are differences between docetaxel and paclitaxel (Taxol)in regard to potency, cellular uptake and efflux, pharmacokinetics, specificmechanisms of action, and activity on tumor growth in vitro and in vivo.For example, docetaxel is approximately twice as potent as paclitaxel asan inhibitor of microtubule depolymerization in vitro.[1,3] In addition,docetaxel is more efficient than paclitaxel in stabilizing microtubulesagainst cold-induced disassembly and twice as efficient as paclitaxel indecreasing the minimum concentration required for microtubule formation.
Schedule-dependency studies show that docetaxel demonstrates schedule-independentantitumor effects in several cell lines in vitro. In comparison, preclinicalstudies with paclitaxel indicate schedule-dependency, with repeated prolongedexposure required for maximal antitumor effect in animal models.[5,6] Thesedifferences have been attributed to the ester side chain at C-13 of docetaxel.
Investigations into the use of docetaxel in non-small-cell lung cancerarose from preclinical studies demonstrating antitumor activity againstLewis lung carcinoma in vivo, as well as from phase II study resultswith 24-hour infusions of paclitaxel showing antitumor response rates of21% to 24% in patients with non-small-cell lung cancer.[8,9] Subsequently,six phase II clinical trials have evaluated the use of single-agent docetaxelas first- and second-line chemotherapy in patients with advanced non-small-celllung cancer.[10,11]
This paper will review data from the four original phase II studiesthat documented the clinical efficacy of single-agent docetaxel (100 mg/m²)in previously untreated patients with advanced non-small-cell lung cancer.[12-15]In addition, the article will present preliminary results from three recentlyreported trials that demonstrate clinical efficacy in previously untreatedas well as previously treated patients.[16-18]
The phase II clinical experience of single-agent docetaxel (100 mg/m²)includes data collected from a total of 160 patients with advanced non-small-celllung cancer who participated in four studies. Of the four studies, threewere conducted in the United States.[12-14]
These trials were all very similarly designed, with the exception ofthe Memorial Sloan-Kettering trial, which allowed patients with evaluabledisease to be enrolled; all of the other trials required measurable disease.[12,14,15]Entry criteria included patients with unresectable locally advanced ormetastatic non-small-cell lung cancer and no previous chemotherapy. Initially,patients with abnormal liver function tests were not excluded from studyparticipation.
All of the eligible patients were to receive docetaxel, 100 mg/m²,administered as a 1-hour infusion every 3 weeks in an outpatient setting.These trials were initially designed without any premedication, antiemetics,or growth factor support. Later protocols were amended to include a 5-daycorticosteroid regimen to reduce the incidence and severity of infusion-relatedreactions, fluid retention, and cutaneous reactions.
Antitumor responses were assessed every 3 weeks by physical examinationand by chest x-ray and every 6 weeks by CT. Measurable responses were subjectedto confirmation by follow-up CT scan within 4 to 6 weeks. Major responsewas defined by the status of the measurable disease (complete and partialresponse); patients with evaluable disease were not included in the intent-to-treatanalysis. All major responses were reviewed by a reference radiologistand an external review panel. Only confirmed responses were included inthe efficacy analysis.
The demographic profile of the patients is presented in Table1. Of the 160 patients in the phase II trials, 83% had a performancestatus of 0 to 1. More than three-quarters of the patients had stage IVnon-small-cell lung cancer. Approximately one-third of the patients werewomen. The majority (74%) of the patients had two or more sites of diseaseinvolvement. Adenocarcinoma, found in 55% of the patients, was the predominanthistologic subtype.
The overall response rate for all patients receiving 100 mg/m²of docetaxel (infused over 1 hour once every 3 weeks) in the intent-to-treatanalysis for these trials was 27%, with a median duration of response of6 months (range, 2 to 13+ months) (Table2). The median time to progression was 3 months (range, 0 to 14+ months),with a median of 4 cycles administered (range, 1 to 33). In addition, themedian relative dose intensity was 96%. The overall median survival forthese 160 patients was 9.2 months; the 1-year survivalrate was 39% (Figure2), and the 2-year survival rate was 20%. The median survival for thepatients with stage IV disease was 9.2 months, and the 1-year survivalrate was 37%.
The response results for the four phase II trials are listed in Table3. For the 141 patients reported in these trials who received 100 mg/m2of docetaxel, infused over 1 hour once every 3 weeks, 31% (95% confidenceinterval, 24% to 39%) achieved a major response. Major response rates reportedin the studies by The M.D. Anderson Cancer Center and the Universityof Texas Health Science Center at San Antonio were both 32%, and 38%was reported for the Memorial Sloan-Kettering Cancer Center study.In the European Organization for Research and Treatment of Cancer: EarlyClinical Trials Group study, 24% of the 37 patients achieved a majorresponse.
Overall, docetaxel was well tolerated by most patients. The overallincidence of febrile neutropenia in 160 previously untreated patients withadvanced non-small-cell lung cancer receiving 100 mg/m² of docetaxelin the phase II trials was 19%. Reasons for discontinuation of study participationincluded fluid retention (6%), asthenia (4%), acute hypersensitivity reaction(4%), and paresthesia (3%). It is important to note that more of thesepatients had been premedicated with corticosteroids.
The incidence of severe fluid retention in patients who did receivecorticosteroid premedication was 0.9%; and recently, 3 days of corticosteroidtreatment (oral dexamethasone, 8 mg twice daily, starting 1 day prior todocetaxel treatment) has been shown to be as effective as 5 days.
Although formal comparisons cannot be made, it is of interest to reviewthe response rates of the present trials with those from other trials thatutilized either supportive care or combination chemotherapy as first-linetherapy in patients with non-small-cell lung cancer (Table4).[20,21] The response rates achieved with single-agent docetaxel(100 mg/m², infused over 1 hour, once every 3 weeks) appear to beat least comparable to cisplatin-based combination regimens and morefavorable than results achieved with supportive care.
PreliminaryResults of Other Phase II Studies of Single-Agent Docetaxel in AdvancedDisease
Preliminary results from three otherphase II trials of single-agentdocetaxel (100 mg/m²) in patients with advanced non-small-cell lungcancer were recently reported.[16-18] The first study was conductedin France, where 66 previously untreated patients with advanced non-small-celllung cancer received 100 mg/m² of docetaxel, over 1 hour, once every3 weeks.
Patients also received pretreatment with dexamethasone and diosime (Diosmil).Of the 53 patients evaluable for response, 30% achieved a major responsewith a median duration of 7.1 months. The principal adverse event was neutropenia.Fluid retention was similar to that seen in previous trials with corticosteroidpremedication.
The second trial was reported by Kath and colleagues. Docetaxelwas administered in a fashion identical to that of the French study.Dexamethasone was administered in three doses--once prior to docetaxeladministration, once on the same day as docetaxel, and once on the dayafter. Of the 25 patients recruited into the study, 23 were evaluable forefficacy. Five patients had received previous chemotherapy. Response wasachieved in 18% of patients, with the primary adverse events being neutropeniaand peripheral neuropathy.
The third study, by Mattson and colleagues, included both previouslyuntreated (N = 43) and previously treated (N = 14) patients with advancednon-small-cell lung cancer. Docetaxel was administered as described above,with a 5-day administration of dexamethasone. The response rate reportedin this trial was 31%, with neutropenia and peripheral neuropathy beingthe primary adverse events.
Docetaxel at a dose of 100 mg/m² demonstrates appreciable antitumoractivity as a single agent in previously untreated patients with advancednon-small-cell lung cancer. Data from four phase II clinical trials reveala response rate of 27%, with a median survival of 9.2 months and a 1-yearsurvival rate of 39%. These results are very encouraging, given that cisplatin(Platinol), vindesine (Eldisine), vinblastine, and mitomycin (Mutamycin)produce response rates under 25% and that response rates achieved withcisplatin-based combination regimens are comparable to that of single-agentdocetaxel at a dose of 100 mg/m².
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