Single-Agent Docetaxel in Patients With Refractory Non-Small-Cell Lung

Introduction

Advanced non-small-cell lung cancer remains relatively chemotherapy-resistant to first-line treatment.[1,2] The relative benefits of chemotherapy vs palliative treatment only are debatable. Randomized studies comparing platinum-based combination therapy to best supportive care for advanced disease have shown only a minor, although statistically significant, impact on survival.[3-6] Median survival has been reported to improve from 17 to 27 weeks, and 1-year survival rate from 5% to 15% in patients who receive platinum-based chemotherapy, as compared with palliative care only.[1]

Despite the marginal benefit associated with chemotherapy, most oncologists agree that it is reasonable to at least offer a trial of front-line systemic chemotherapy, usually with platinum-based combination regimens, to patients with advanced non-small-cell lung cancer who have an acceptable performance status.

Given the fact that the benefits of first-line platinum-based chemotherapy may be minimal in patients with non-small-cell lung cancer, the indications for second-line treatment in the patient who has not responded to initial chemotherapy are even more debatable.[3-6] Not only would these patients generally have a worse performance status than chemotherapy-naive patients, but one might expect that they would have tumors refractory to all chemotherapy due to acquired or inherent resistance. This underscores the importance of developing rational, cost-effective guidelines for the use of chemotherapy in patients with advanced non-small-cell lung cancer who have not responded to front-line therapy.

Docetaxel (Taxotere), a semisynthetic taxoid, is one of the few drugs that have been systematically investigated as a second-line option for patients with advanced non-small-cell lung cancer.[7] This paper will review the results of several phase II studies supporting the potential benefit of docetaxel(Drug information on docetaxel) in patients with advanced non-small-cell lung cancer in whom previous chemotherapy has failed. It will also discuss the implications of these data as they relate to historical controls and will describe ongoing phase III trials of docetaxel in the second-line setting.

Phase II Studies of Docetaxel in Previously Treated Patients

A total of 88 patients participated in two phase II studies[7-9] conducted at the M.D. Anderson Cancer Center[8] (44 patients) and at the University of Texas Health Sciences Center at San Antonio[9] (44 patients accrued from three sites).

Eligibility

Eligible patients had stage IV or unresectable stage III non-small-cell lung cancer, a performance status of 2 or less (Zubrod scale), and had not responded to at least one prior platinum-containing regimen, either cisplatin(Drug information on cisplatin) (Platinol) or carboplatin(Drug information on carboplatin) (Paraplatin). Patients who had received more than two prior chemotherapy regimens were excluded. Platinum-resistant patients were defined as those who had an initial response to platinum but subsequently progressed. Platinum-refractory patients were those who never showed a response to platinum therapy.

Treatment Plan

Docetaxel was administered at a dosage of 100 mg/m², as a 1-hour intravenous (IV) infusion, once every 3 weeks. In addition, most patients were premedicated with IV diphenhydramine(Drug information on diphenhydramine), 50 mg, 30 minutes prior to the administration of docetaxel.

For patients who experienced a hypersensitivity reaction, a second 50-mg dose of IV diphenhydramine was administered along with 10 mg of IV dexamethasone(Drug information on dexamethasone). Premedication for

patients with hypersensitivity reactions for subsequent docetaxel infusions included 4 mg of oral dexamethasone every 6 hours and 10 mg of IV dexamethasone plus 50 mg of IV diphenhydramine, 30 minutes before receiving docetaxel. Antiemetics and growth factors were not used.

Results

The characteristics of the 88 patients are shown in Table 1.[7-9] There were 46 men and 42 women, most of whom had a Zubrod performance score of 1 or less. The median age was 57 years (range, 29 to 71 years). The majority (84%) of patients had stage IV disease, two-thirds had adenocarcinoma, and over half had received prior radiation therapy.

In platinum-refractory/resistant patients treated with docetaxel, 100 mg/m², once every 3 weeks, 20% of the 71 evaluable patients achieved a partial response (Table 2).[7-9] A subset analysis of response rates based on the presence of adenocarcinoma revealed a trend toward higher response rates among patients with other histologies. This trend was not statistically significant, however.

The median time to response was 6 weeks, with a median response duration of 29 weeks (Table 2). The projected median survival (all patients, both studies) was 39 weeks, and the 1-year survival rate was 40% (Figure 1).

Response rates and median survival did differ between the two studies.[7-9] Patients from the M.D. Anderson Cancer Center study achieved higher response rates (21%) and longer median survival times (42 weeks) than patients participating in the University of Texas Health Sciences Center study (14% and 25 weeks, respectively) (Table 2). These differences may be related to patient selection factors during the enrollment phase of the study. At the M.D. Anderson Cancer Center, only 5% of patients were in the poor-performance status category, as compared with 23% of patients from the San Antonio site.

Safety

The toxicity profile reported from the phase II trials[8,9] was comparable with that seen in companion trials conducted in previously untreated patients with advanced non-small-cell lung cancer. The primary dose-limiting toxicity was neutropenia. At the M.D. Anderson Cancer Center, 75% of patients developed grade 3 or 4 neutropenia, with febrile neutropenia occurring in 7% of the first cycle and 16% overall.[7]

Similarly, there was not much difference in the incidence of nonhematologic side effects between the chemotherapy-naive patients and the previously treated patients, with the exception of peripheral neuropathy.[7] A greater incidence of peripheral neuropathy was noted in patients who had received prior chemotherapy, which may have been due to their prior exposure to cisplatin.[7]

Additional Phase II Studies in Platinum-Refractory Patients

Preliminary data are available from two other recently reported phase II trials on the use of docetaxel in patients with platinum-refractory non-small-cell lung cancer.[10,11] In both trials, patients were treated with 100 mg/m² of docetaxel, administered as a 1-hour IV infusion, once every 3 weeks. In addition, all patients received routine premedication with dexamethasone.

One multicenter trial, reported by Gandara and colleagues,[10] showed a response rate of 16% in 77 patients with non-small-cell lung cancer who were refractory to platinum treatment. The median survival duration and 1-year survival rates noted by these authors were 7 months and 25%, respectively. The most commonly reported serious adverse event was neutropenia (19%).

Kleisbauer and coworkers[11] conducted a multicenter phase II study in 18 platinum-refractory patients with advanced non-small-cell lung cancer. This study, which is currently ongoing, reports a preliminary response rate of 22% to 100 mg/m² of docetaxel. Information on median survival and 1-year survival rates is not yet available.

Second-Line Docetaxel Therapy vs Historical Controls

Recently, the investigators from the M.D. Anderson Cancer Center performed a retrospective analysis comparing data from the 44 patients who received docetaxel, 100 mg/m², in the second-line phase II study with a comparable historical-control patient

population. The objective was to determine whether the favorable survival seen in the M.D. Anderson Cancer Center trial was truly due to the efficacy of docetaxel in that setting or simply reflected selection bias, given that 95% of patients in that trial had a good performance status and might be expected to do well regardless of second-line therapy.

Using a computerized protocol database, a cohort of 36 non-small-cell lung cancer patients who matched the entry criteria for the docetaxel study were identified for the historical-control group. These patients had received first-line chemotherapy from one of 18 different phase I protocols conducted at the M.D. Anderson Cancer Center between 1988 and 1991. Thus, patients selected for the historical-control cohort had stage IV or unresectable stage III non-small-cell lung cancer, had not responded to at least one prior chemotherapy regimen (which was platinum-based in all but one patient), and were taxoid-naive.

Both groups were well balanced with regard to age, gender, stage, histology, number of prior chemotherapy cycles, and their response to front-line combination chemotherapy. One important difference between the two groups was performance status. There were significantly fewer patients (5%) with a performance status of 2 in the docetaxel group than in the control group (19%).

The partial response rate was 21% in the patients who participated in the docetaxel phase II study at the M.D. Anderson Cancer Center, as compared with 0% in the historical-control group (Table 3). Median survival was 42 weeks for the docetaxel-treated patients vs 16 weeks for the historical-control group, and the 1-year survival rate was 41% vs 16% (P = .003).

Because the control group had more patients with a performance status of 2 (which might have skewed the survival in favor of the docetaxel arm), we calculated survival for patients with good performance status (ie, 0 to 1). The analysis of patients with good performance status also showed a significant improvement in survival for docetaxel: for the 42 patients in this group, median survival duration and 1-year survival rates were 43 weeks and 42%, respectively, as compared with 16 weeks and 16%, respectively, for the 29 historical-control group patients with good performance status (P = .018).

Although there are limitations to this type of retrospective analysis, it does provide some insight into the relative advantage of using 100 mg/m² of docetaxel (infused over 1 hour, once every 3 weeks) as a second-line treatment in patients with non-small-cell lung cancer in whom platinum-based chemotherapy has failed.

Ongoing Studies After First-Line Platinum-Based Chemotherapy Failure

Two large, randomized phase III studies are currently evaluating the use of docetaxel in patients with good performance status and advanced disease who have not responded to at least one prior platinum-containing regimen. The first study is comparing the efficacy of docetaxel at doses of 75 and 100 mg/m² administered as an IV infusion over 1 hour, once every 3 weeks, with best supportive care.

In the second study, patients are being randomized to receive either 75 mg/m² of docetaxel, 100 mg/m² of docetaxel, or in the control arm, vinorelbine (Navelbine) or ifosfamide(Drug information on ifosfamide) (Ifex). The primary end point of both studies is survival, with secondary end points being quality of life and response rate. Preliminary results from these studies are anticipated by the end of 1997.

Conclusions

Four phase II studies have now demonstrated that docetaxel at a dose of 100 mg/m², administered over 1 hour, once every 3 weeks, has activity in platinum-resistant or platinum-refractory non-small-cell lung cancer. Partial responses have ranged from 14% to 22%, and median survival duration is in the range of 30 to 42 weeks.

A retrospective analysis conducted at the M.D. Anderson Cancer Center[8] suggests that there may be a clinically meaningful survival advantage of docetaxel, 100 mg/m², in the second-line setting as well, with an improvement in median survival from 16 to 42 weeks and an increase in 1-year survival rate from 16% to 41%. It should be noted, however, that most of the patients from the M.D. Anderson Cancer Center had excellent performance status, despite the fact that they had already received extensive prior therapy. Two large, randomized trials are currently ongoing to better define the role of docetaxel as a second-line therapy.

The related taxoid, paclitaxel(Drug information on paclitaxel) (Taxol), has not been studied as systematically in the second-line setting. Data from the six studies that have been conducted are conflicting.[12-17] One trial suggests that paclitaxel--at a dose of 200 mg/m², administered over 1 hour--may have activity in platinum-resistant patients. However, the results are of limited value because the cohort of patients studied was small and survival data were not reported.[17] In contrast, five other small studies have reported no or minimal activity of paclitaxel in this setting.[12-16] Finally, available data on other drugs--including vinorelbine,[18-20] irinotecan(Drug information on irinotecan) (Camptosar),[21,22] and others--have been similarly disappointing.

Based on available clinical data, it would be reasonable to offer a trial of second-line docetaxel therapy in patients with advanced non-small-cell lung cancer who have failed first-line, platinum-based therapy. However, because most of the data are derived from patients with good performance status, such treatment should generally used in patients who have a performance status of 0 to 1. Additional prospective randomized trials are underway to further define the role of docetaxel as second-line therapy for previously treated non-small-cell lung cancer patients.