The taxoids have generated much interest during the past several years as important options for the treatment of various malignancies. Docetaxel(Drug information on docetaxel) (Taxotere) is a semisynthetic taxoid synthesized from 10-deacetyl baccatin III, a noncytotoxic taxoid precursor extracted from the renewable needles of the European yew Taxus baccata and chemically modified with a synthetic lipophilic side chain at C-13 (Figure 1). Taxoids exert their cytotoxic effects by specifically promoting the assembly of tubules into microtubules, stabilizing the microtubules, and inhibiting the depolymerization to free tubulin.[1-3]
However, there are differences between docetaxel and paclitaxel(Drug information on paclitaxel) (Taxol) in regard to potency, cellular uptake and efflux, pharmacokinetics, specific mechanisms of action, and activity on tumor growth in vitro and in vivo. For example, docetaxel is approximately twice as potent as paclitaxel as an inhibitor of microtubule depolymerization in vitro.[1,3] In addition, docetaxel is more efficient than paclitaxel in stabilizing microtubules against cold-induced disassembly and twice as efficient as paclitaxel in decreasing the minimum concentration required for microtubule formation.
Schedule-dependency studies show that docetaxel demonstrates schedule-independent antitumor effects in several cell lines in vitro. In comparison, preclinical studies with paclitaxel indicate schedule-dependency, with repeated prolonged exposure required for maximal antitumor effect in animal models.[5,6] These differences have been attributed to the ester side chain at C-13 of docetaxel.
Investigations into the use of docetaxel in non-small-cell lung cancer arose from preclinical studies demonstrating antitumor activity against Lewis lung carcinoma in vivo, as well as from phase II study results with 24-hour infusions of paclitaxel showing antitumor response rates of 21% 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 docetaxel as first- and second-line chemotherapy in patients with advanced non-small-cell lung cancer.[10,11]
This paper will review data from the four original phase II studies that 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 recently reported trials that demonstrate clinical efficacy in previously untreated as 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-cell lung cancer who participated in four studies. Of the four studies, three were conducted in the United States.[12-14]
These trials were all very similarly designed, with the exception of the Memorial Sloan-Kettering trial, which allowed patients with evaluable disease to be enrolled; all of the other trials required measurable disease.[12,14,15] Entry criteria included patients with unresectable locally advanced or metastatic non-small-cell lung cancer and no previous chemotherapy. Initially, patients with abnormal liver function tests were not excluded from study participation.
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-day corticosteroid regimen to reduce the incidence and severity of infusion-related reactions, fluid retention, and cutaneous reactions.
Antitumor responses were assessed every 3 weeks by physical examination and by chest x-ray and every 6 weeks by CT. Measurable responses were subjected to confirmation by follow-up CT scan within 4 to 6 weeks. Major response was defined by the status of the measurable disease (complete and partial response); patients with evaluable disease were not included in the intent-to-treat analysis. All major responses were reviewed by a reference radiologist and an external review panel. Only confirmed responses were included in the efficacy analysis.
The demographic profile of the patients is presented in Table 1. Of the 160 patients in the phase II trials, 83% had a performance status of 0 to 1. More than three-quarters of the patients had stage IV non-small-cell lung cancer. Approximately one-third of the patients were women. The majority (74%) of the patients had two or more sites of disease involvement. Adenocarcinoma, found in 55% of the patients, was the predominant histologic subtype.
The overall response rate for all patients receiving 100 mg/m² of docetaxel (infused over 1 hour once every 3 weeks) in the intent-to-treat analysis for these trials was 27%, with a median duration of response of 6 months (range, 2 to 13+ months) (Table 2). 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, the median relative dose intensity was 96%. The overall median survival for these 160 patients was 9.2 months; the 1-year survivalrate was 39% (Figure 2), and the 2-year survival rate was 20%. The median survival for the patients with stage IV disease was 9.2 months, and the 1-year survival rate was 37%.
The response results for the four phase II trials are listed in Table 3. For the 141 patients reported in these trials who received 100 mg/m2 of docetaxel, infused over 1 hour once every 3 weeks, 31% (95% confidence interval, 24% to 39%) achieved a major response. Major response rates reported in the studies by The M.D. Anderson Cancer Center and the University of 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: Early Clinical Trials Group study, 24% of the 37 patients achieved a major response.
Overall, docetaxel was well tolerated by most patients. The overall incidence of febrile neutropenia in 160 previously untreated patients with advanced non-small-cell lung cancer receiving 100 mg/m² of docetaxel in the phase II trials was 19%. Reasons for discontinuation of study participation included fluid retention (6%), asthenia (4%), acute hypersensitivity reaction (4%), and paresthesia (3%). It is important to note that more of these patients had been premedicated with corticosteroids.
The incidence of severe fluid retention in patients who did receive corticosteroid premedication was 0.9%; and recently, 3 days of corticosteroid treatment (oral dexamethasone(Drug information on dexamethasone), 8 mg twice daily, starting 1 day prior to docetaxel treatment) has been shown to be as effective as 5 days.
Although formal comparisons cannot be made, it is of interest to review the response rates of the present trials with those from other trials that utilized either supportive care or combination chemotherapy as first-line therapy in patients with non-small-cell lung cancer (Table 4).[20,21] The response rates achieved with single-agent docetaxel (100 mg/m², infused over 1 hour, once every 3 weeks) appear to be at least comparable to cisplatin(Drug information on cisplatin)-based combination regimens and more favorable than results achieved with supportive care.Preliminary Results of Other Phase II Studies of Single-Agent Docetaxel in Advanced Disease
Preliminary results from three otherphase II trials of single-agent docetaxel (100 mg/m²) in patients with advanced non-small-cell lung cancer were recently reported.[16-18] The first study was conducted in France, where 66 previously untreated patients with advanced non-small-cell lung cancer received 100 mg/m² of docetaxel, over 1 hour, once every 3 weeks.
Patients also received pretreatment with dexamethasone and diosime (Diosmil). Of the 53 patients evaluable for response, 30% achieved a major response with a median duration of 7.1 months. The principal adverse event was neutropenia. Fluid retention was similar to that seen in previous trials with corticosteroid premedication.
The second trial was reported by Kath and colleagues. Docetaxel was administered in a fashion identical to that of the French study. Dexamethasone was administered in three doses--once prior to docetaxel administration, once on the same day as docetaxel, and once on the day after. Of the 25 patients recruited into the study, 23 were evaluable for efficacy. Five patients had received previous chemotherapy. Response was achieved in 18% of patients, with the primary adverse events being neutropenia and peripheral neuropathy.
The third study, by Mattson and colleagues, included both previously untreated (N = 43) and previously treated (N = 14) patients with advanced non-small-cell lung cancer. Docetaxel was administered as described above, with a 5-day administration of dexamethasone. The response rate reported in this trial was 31%, with neutropenia and peripheral neuropathy being the primary adverse events.
Docetaxel at a dose of 100 mg/m² demonstrates appreciable antitumor activity as a single agent in previously untreated patients with advanced non-small-cell lung cancer. Data from four phase II clinical trials reveal a response rate of 27%, with a median survival of 9.2 months and a 1-year survival rate of 39%. These results are very encouraging, given that cisplatin (Platinol), vindesine(Drug information on vindesine) (Eldisine), vinblastine(Drug information on vinblastine), and mitomycin(Drug information on mitomycin) (Mutamycin) produce response rates under 25% and that response rates achieved with cisplatin-based combination regimens are comparable to that of single-agent docetaxel at a dose of 100 mg/m².