Single-Agent Docetaxel in Patients With Refractory Non
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Single-Agent Docetaxel in Patients With Refractory
Non-Small-Cell Lung
Review Article [1] | July 01, 1997
By Frank V. Fossella, MD [2]
There are few options available for the patient with advanced non-small-cell lung cancer in whom
first-line chemotherapy has failed. Docetaxel (Taxotere), a semisynthetic taxoid, is one of the few
drugs that has been systematically investigated as a second-line option for patients with advanced
non-small-cell lung cancer.
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
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 (Platinol) or 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
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every 3 weeks. In addition, most patients were premedicated with IV 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. 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.
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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 (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 (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 (Camptosar),[21,22] and others--have been similarly
disappointing.
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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.
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