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New Clinical Strategies in Non–Small-Cell Lung Cancer

New Clinical Strategies in Non–Small-Cell Lung Cancer

ABSTRACT: In an attempt to further improve the quality of life and prognosis of patients with non–small-cell lung cancer, several clinical strategies exist to evaluate newer chemotherapy agents for this disease. Several of these pragmatic strategies are being investigated at our center and by others, and all of these represent rather classic empiric or semiempiric methods, primarily utilizing cytotoxic therapy. Three new clinical strategies are reviewed in this article: 1) the use of paclitaxel (Taxol) over a 1-hour infusion and a weekly schedule; 2) the development of triple-drug combination regimens utilizing new chemotherapeutic agents; and 3) the rationale, plans, and preliminary information regarding neoadjuvant and adjuvant therapy with the newer drug combinations. [ONCOLOGY 13(4):60-64, 1999]

Introduction

Newer chemotherapy agents have improved the survival and quality of
life for patients with non–small-cell lung cancer (eg,
paclitaxel [Taxol], docetaxel [Taxotere], gemcitabine [Gemzar],
vinorelbine [Navelbine], topotecan [Hycamtin], and irinotecan
[CPT-11; Camptosar]).[1,2] We are only beginning to appreciate the
advantages of these drugs. There are several clinical strategies to
pursue in evaluating these agents in an attempt to further improve
the quality of life and prognosis for patients with this disease.

Certainly, an understanding of basic mechanisms is critical, and
several mechanistic-based therapies may be applied successfully in
the near future. We do not yet, however, have any new practical or
efficacious therapies applicable for patients today arising from
basic research. We do have a number of new chemotherapeutic agents,
several of which show good activity in non–small-cell lung cancer.

Several pragmatic clinical strategies are currently being
investigated at our center and by others, and three of these will be
discussed in this article.

Paclitaxel Over a 1-Hour Infusion and a
Weekly Schedule

Our group was the first to shorten the infusion of paclitaxel to 1
hour.[3] We initiated a study soon after the 3-hour infusion schedule
proved to be safe and less myelosuppressive than a 24-hour schedule.
We have amply documented, and this has been confirmed by others, that
a 1-hour infusion schedule is safe, is not associated with a high
incidence of hypersensitivity reactions, and has comparable activity
to longer infusions for many paclitaxel-sensitive tumors. We have
subsequently performed many trials using paclitaxel over a 1-hour
infusion in combination with other drugs. Others have also studied
combination chemotherapy in various settings.

Although there are no randomized comparisons to definitively prove
equivalence, it does appear from multiple comparisons of phase II
trials that 1-hour paclitaxel infusions are very similar to 3-hour
infusions in reference to efficacy in lung cancer, breast cancer,
ovarian cancer, and several other malignancies. There is no apparent
difference in toxicity. There are many advantages of a 1-hour
infusion, including less time in the outpatient area or clinic and
office, less expense, ease of use when combining with other drugs,
and patient convenience. Pharmacologically, the maximum plasma
concentration is higher with a 1-hour infusion. However, in all other
respects, the pharmacokinetics are very similar to the 3-hour
infusion. Despite a considerable volume of clinical data now
available, 3-hour infusion has remained more popular.

It seems that this is mainly a reflection of historical precedence,
and certainly there is no major disadvantage of a 3-hour infusion
other than two additional hours of administration. Other than
important practical issues allowing for more efficient treatment with
less expense, this may not be viewed as a major difference.

Recently, the use of paclitaxel in a weekly schedule has been
explored. Several single-agent studies are now complete and
combination programs are in progress. Weekly administration of
paclitaxel has a very acceptable toxicity profile. Doses as high as
175 mg/m²/week have been given without severe myelosuppression
becoming the dose-limiting toxicity. However, neuropathy becomes
quite serious (grade 3/4) if patients continue treatment at these
higher dose levels. At 100 mg/m² or below, patients often
tolerate many weeks of paclitaxel without any serious neuropathy or
myelosuppression. Weekly paclitaxel has often been administered as a
1-hour infusion. Early results suggest that there is single-agent
activity in lung, breast, and ovarian cancers.

Several combination studies are ongoing. At the Sarah
Cannon–Minnie Pearl Cancer Center, weekly evaluations of
paclitaxel in several settings are being performed, as described in
Table 1
. These studies are underway and it is too early to
present any results. It is expected that paclitaxel in effective
doses, particularly with the dose-dense weekly regimen, can be given
safely with several combinations of other drugs. Hopefully, this
strategy will improve the overall cytotoxic efficacy of the
combination in sensitive tumor types, such as small-cell lung cancer,
non–small-cell lung cancer, and breast cancer.

Development of New Triple-Drug Combination Chemotherapy

The combination of paclitaxel and carboplatin (Paraplatin) has become
extremely popular. This combination has been evaluated in phase II
trials, and phase III randomized prospective studies are currently in
progress. The combination is relatively well tolerated, and produces
less thrombocytopenia than expected from carboplatin alone at a
similar dose. In addition, the activity in non–small-cell lung
cancer is notable and most studies show a 1-year survival rate of
about 40%. A 2-year survival rate of 20% has been observed in at
least one study.[4] Most of these studies are not yet mature enough
to report long-term survival rates.

Based upon the activity of paclitaxel and carboplatin, we have
studied several three-drug combinations in phase I/II trials adding
gemcitabine, vinorelbine, and topotecan, respectively, to a
paclitaxel and carboplatin combination. The study is complete for the
three-drug combination of paclitaxel, carboplatin, and gemcitabine.
Paclitaxel has been administered as a 1-hour infusion in all of these
studies. Table 2 illustrates
the maximum tolerated dose recommended without growth factor support,
of all three agents as determined from these phase I trials.

Paclitaxel and Carboplatin Plus Gemcitabine

The first triple-drug combination with the addition of gemcitabine
was tested in a phase II trial by the Minnie Pearl Research Network,
a community oncology clinical research network. In this study, 69
previously untreated patients with stage IIIB or IV
non–small-cell lung cancer were treated. These patients had no
central nervous system metastasis, a performance status of 0 to 2,
and measurable disease with adequate bone marrow, kidney, and liver
function. All patients gave an informed consent. The median age was
60 years (range 26 to 80 years), and there were 46 men and 23 women.
Of these, 51 patients (74%) had stage IV disease, and of the 63
evaluable patients, 30 had objective responses (48%), including one
complete response and 29 partial responses. An additional 29 patients
(33%) had minor responses or stable disease. Follow-up is very short,
however; 69% of the patients remain alive after a median follow-up of
5 months. Toxicity primarily was myelosuppression.

Grade 3 or 4 leukopenia was seen in 51% of the patients, but in only
26% of the courses, and grade 3 or 4 thrombocytopenia was seen in 43%
of the patients, but in only 17% of the courses. Eleven patients were
hospitalized with neutropenia and fever, and eight patients (12%)
required platelet transfusions. Other grade 3/4 toxicity was unusual,
except fatigue, which was seen in 12% of the patients. There were no
treatment-related deaths.

The preliminary results of this study suggest that this triple-drug
combination is highly active and well tolerated in the treatment of
advanced non–small-cell lung cancer and may be superior to the
combination of paclitaxel and carboplatin. Further studies, including
randomized trials, may be necessary to document this possibility.

Paclitaxel and Carboplatin Plus Vinorelbine

The second triple-drug combination added vinorelbine to the
paclitaxel and carboplatin combination. A phase I study in patients
with lung cancer has been completed and a phase II study is now in
progress. In the phase I study, the doses of paclitaxel and
carboplatin were initially fixed at 200 mg/m² and an area under
the concentration-time curve of 6.0 (AUC in mg/mL · min),
respectively, both given over a 1-hour infusion. Vinorelbine was
initially scheduled on days 1 and 8 with doses escalated in
sequential cohorts of patients at 17.5 mg/m², 20 mg/m², and
22.5 mg/m². No cytokines were planned prophylactically. Patients
with previously untreated stage IIIB and IV non–small-cell lung
were eligible, and the entry criteria were otherwise identical to the
triplet combination study using gemcitabine.

Twenty patients were entered in this study and received a median of
five courses of chemotherapy. The dosing of vinorelbine on days 1 and
8 resulted in held or reduced doses on day 8 in 40% of patients. This
schedule was modified to allow vinorelbine to be given on either day
8 or 15, depending on the blood counts. This subsequently allowed us
to more effectively deliver 22.5 mg on day 1 and then on either day 8
or 15. At this dose level, the percentages of planned doses of
paclitaxel, carboplatin, and vinorelbine actually administered were
91%, 91%, and 73%, respectively, during the first two courses. The
dose-limiting toxicity was leukopenia. When utilizing the day 8 or 15
vinorelbine dosing, grade IV leukopenia did not occur in any patients
at 20 mg/m2, and occurred in 33% of the patients at 22.5 mg/m².

Of the 98 courses administered, eight (8%) were associated with
neutropenic fever. Grade 3/4 nonhematologic toxicity was unusual, but
did include fatigue in eight patients, emesis in two patients, and
neuropathy in one patient. There were no treatment-related deaths in
the phase I study. It was notable that of 19 evaluable patients, 13
(68%) had partial responses. The three-drug regimen was feasible and
relatively well tolerated. A phase II study is now in progress
utilizing paclitaxel at 200 mg/m², carboplatin at an AUC of 6.0,
and vinorelbine at 22.5 mg/m² given on day 1 and either day 8 or 15.

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