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