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Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

ABSTRACT: Over the last decade, a group of new agents with differing mechanisms of action have shown great promise in early clinical studies in non–small-cell lung cancer (NSCLC). These include the taxanes docetaxel (Taxotere) and paclitaxel (Taxol); the nucleoside analog gemcitabine (Gemzar); the vinca alkaloid vinorelbine (Navelbine); the topoisomerase-I inhibitor irinotecan (Camptosar, CPT-11); and the bioreductive agent tirapazamine. Cisplatin (Platinol), which has been the “backbone” of combination chemotherapy in patients with NSCLC because of its proven single-agent activity, has been examined in combination with these agents as well as radiation and surgery in numerous trials. This article summarizes trials of these combination therapies in the treatment of NSCLC. [ONCOLOGY 14(Suppl 5):15-27, 2000]

Introduction

Lung cancer is the leading cause of cancer death. Approximately 85%
of patients diagnosed with this neoplasm die from their disease.
Complete surgical resection and cure can be considered in only 25% of
cases.[1] Of the estimated 164,100 people in the United States who
will be diagnosed with lung cancer in 2000,[2] 75% will have
non–small-cell lung cancer (NSCLC) and the majority will die
either of micrometastatic disease from tumors that initially appeared
to be surgically resectable or from surgically unresectable locally
advanced or metastatic disease.

Despite this grim picture, recent therapeutic advances may justify
cautious optimism about future gains in the battle against lung
cancer. Over the last decade, a group of new agents with differing
mechanisms of action have shown great promise in early clinical
studies in NSCLC. These include the taxanes docetaxel (Taxotere) and
paclitaxel (Taxol), the nucleoside analog gemcitabine (Gemzar), the
vinca alkaloid vinorelbine (Navelbine), the topoisomerase-I inhibitor
irinotecan (Camptosar, CPT-11), and the bioreductive agent tirapazamine.

New Chemotherapeutic Agents in Combination Therapy

Having demonstrated activity as single agents, these new agents are
now being evaluated in combination, mostly with cisplatin (Platinol,
CDDP) (Tables 1, 7).
Cisplatin has been the “backbone” of combination
chemotherapy in patients with NSCLC because of its proven
single-agent activity. In particular, therapy with cisplatin is
associated with a relative lack of myelosuppression, a unique
cytocidal mechanism of action, and the resultant possibility of
synergistic cytotoxicity when combined with other agents. The latter
has been confirmed in in vitro studies when cisplatin was used in
combination with etoposide (VePesid, VP-16).[3,4]

Paclitaxel and Cisplatin-Based Therapy

In preclinical studies of the combination of cisplatin and
paclitaxel, it was found that paclitaxel inhibited the repair of DNA
adducts formed by platinum agents.[5] Preclinical studies have proven
these agents to be synergistic when used in combination in in vitro
models.[6] Phase I and II trials determined that the combination of
cisplatin and paclitaxel was feasible. Rowinsky et al showed that
paclitaxel at doses ranging from 135 mg/m² to 170 mg/m²
administered over 24 hours with cisplatin 75 mg/m² was well
tolerated.[7] When paclitaxel was administered following cisplatin,
there was an increased incidence of grade 4 neutropenia. However,
this same response was not observed when paclitaxel was administered
prior to cisplatin and was attributed to a possible decrease in
paclitaxel clearance due to the effect of cisplatin on the cytochrome
P-450 system.[8] Subsequent trials found that paclitaxel at 200 to
250 mg/m² was tolerated and could be administered to patients
with cisplatin when given with G-CSF granulocyte colony-stimulating
factor (G-CSF, filgrastim, [Neupogen]) support (Table
2
). Phase I and II studies demonstrated that when cisplatin is
combined with paclitaxel, response rates of 31% to 47% are achieved.[9-12]

The Eastern Cooperative Oncology Group (ECOG) attempted to
corroborate these results in a randomized phase III study of the
combination of paclitaxel and cisplatin (Table
2
).[13] The ECOG study was also designed to evaluate the
dose-intensity for paclitaxel by including two doses of paclitaxel in
combination with cisplatin. For the trial, 560 patients were
randomized to one of three arms: (1) cisplatin 75 mg/m² plus
etoposide 100 mg/m² (PE) administered intravenously on days 1-3
with cycles repeated every 3 weeks; (2) cisplatin 75 mg/m² plus
paclitaxel 135 mg/m² administered over 24 hours (PT); or (3)
cisplatin 75 mg/m² plus paclitaxel 250 mg/m² given over 24
hours with G-CSF support (PT-G).

The response rates were 12% for the PE control arm, 26% for the PT
arm, and 32% for the PT-G arm (P < .001). Median survivals
were 9.56 and 9.99 months for the PT and PT-G arms, respectively.
This compared favorably with median survival in the PE control arm,
which was 7.69 months (P = .091). There was no significant
difference when the low- and higher-dose paclitaxel arms were
compared. Moreover, a stronger trend for longer survival (P =
.051) was observed when the paclitaxel-treated cohort was compared
with patients treated with PE. Treatment-related mortality rates for
arms PE, PT, and PT-G were similar: 2%, 4.4%, and 5.3%, respectively.
The results of this study culminated in the combination of cisplatin
and 24-hour infused paclitaxel 135 mg/m² being designated as the
control arm for future ECOG trials in metastatic NSCLC.

Paclitaxel and Carboplatin in Combination

Several investigators have combined paclitaxel with carboplatin
(Paraplatin), a congener of cisplatin. These trials were designed to
reduce the significant nonhematologic toxicity seen with cisplatin.
Carboplatin has minimal renal toxicity, reduced neurologic toxicity,
and is less emetogenic. The principle toxicities of carboplatin
relate to its effects on bone marrow suppression, particularly
neutropenia and thrombocytopenia. The results of studies combining
carboplatin with paclitaxel as a 3- or 24-hour infusion are
summarized in Table 1. This
combination has revealed interesting activity with reported response
rates of approximately 30% to 50% in phase I or phase II trials in
small numbers of patients (n = 10 to 53).

The primary toxicity was neutropenia of short duration. There were
relatively few episodes of neutropenic fever. Patients receiving the
shorter infusion of paclitaxel experienced peripheral neuropathy,
particularly with repeated cycles of treatment. An interesting
observation with this combination is the unexpectedly low incidence
of significant thrombocytopenia.[14] Investigators have theorized
that this is attributable to the protective effect mediated by
paclitaxel against carboplatin-induced thrombocytopenia.[15] These
studies have also demonstrated that the dosing of carboplatin with
paclitaxel delivered over 24 hours is limited by myelosuppression,
whereas neurotoxicity is the dose-limiting effect when the same
combination is given over 1 or 3 hours.[16]

In most studies, the regimens were scheduled every 3 weeks, except
for a study by Johnson in which a 4-week cycle was evaluated.[17]
There appears to be an appreciable difference in response rates
between the two schedules: the 4-week schedule had a response rate of
27%, whereas the majority of the studies utilizing the 3-week
schedule had response rates of 50% or greater.[15,16,18-20] Until the
results of ongoing phase III trials are complete, however, the
optimal paclitaxel and platinum regimen cannot be defined.
Nonetheless, the conclusions reached from studies completed to date
have been interpreted as demonstrating that paclitaxel and the platin
compounds are active combinations that are well tolerated and can be
administered on an outpatient basis every 3 weeks.

The results of three recent phase III trials of platin compounds and
paclitaxel vs cisplatin and etoposide or teniposide (Vumon) have
recently been presented.[21-23] Belani et al randomized 179 patients
to 75 mg/m² cisplatin on day 1, 100 mg/m² etoposide on days
1 to 3 of a 21-day cycle, and 190 patients to carboplatin with an
area-under-curve (AUC) of 6 and 3-hour–infused paclitaxel at 225
mg/m².[21] All patients in this study had a performance status
greater than 70% and stage III or IV disease (Table
7
). Although there was no difference in the incidence of grade 3
or 4 neutropenia between the treatment arms, the incidence of grade 1
to 3 neuropathy was 4% in the taxane-containing arm and 0.6% in the
etoposide arm. The response rate was 14% for the control arm compared
to 21.6% for the carboplatin/paclitaxel arm. There was no difference
in overall survival.

In another study of 332 patients, Giaccone et al on behalf of the
European Organization for Research and Treatment of Cancer (EORTC)
compared paclitaxel (175 mg/m² infused over 3 hours) and
cisplatin (80 mg/m²) administered on day 1 of a 21-day cycle
with the same dose of cisplatin plus teniposide (100 mg/m²
administered on days 1 to 3) of a 21-day cycle.[22] The
teniposide-containing arm had a higher incidence of grade 3/4
neutropenia (83%) and thrombocytopenia (36%) than the taxane arm (55%
and 2%, respectively), whereas the taxane arm had more grade 2/3
neurotoxicity (29% vs 7%). Response rates favored the taxane arm
significantly (41% vs 28%; P = 0.18), however, this did not
translate into a survival advantage as the

1-year overall survival rate was 41% in the teniposide arm and 43% in
the taxane-containing arm. Gatzemeier compared high-dose cisplatin
(100 mg/m²) administered every 3 weeks with cisplatin (80
mg/m²) plus paclitaxel (175 mg/m²) administered every 3
weeks (Table 7).[23] In this
study of 414 patients with NSCLC, 70% had stage IV disease and 30%
had stage IIIB. Patients in the single-agent arm received a median of
three courses of treatment compared with five courses in the
combination arm. The response rate in the cisplatin alone arm was 17%
vs 26% in the combination arm (P = .0002) and the time-to-disease
progression was 2.7 months vs 4.1 months respectively (P =
.028). The median survival in the cisplatin arm was 8.6 months vs 8.1
months in the cisplatin plus paclitaxel arm (P = .826).
Peripheral neuropathy, neutropenia, and alopecia were worse in the
combination treatment arm, whereas nausea/vomiting and constipation
were more problematic in the cisplatin arm.

Docetaxel and Cisplatin

This combination has also been evaluated in patients with advanced or
metastatic NSCLC. The response rates (25% to 53%) were similar to
those seen when paclitaxel was given in combination with cisplatin,
with acceptable toxicity. Docetaxel was administered in doses of 75
mg/m² with 75 to 100 mg/m² cisplatin given on an
every-3-week schedule.[24-26] The principle toxicity was grade 4
neutropenia. The incidence of febrile neutropenia was approximately
10% among patients who received this combination. The accumulation of
peripheral edema appears to be ameliorated by the use of short
courses of dexamethasone administered shortly before, and for a few
days after, docetaxel.

Vinorelbine and Platinum-Based Chemotherapy

Phase I/II trials established the activity and acceptable toxicities
of this combination (Table 1).
Gebbia et al reported the results of a phase I/II study of cisplatin
80 mg/m² on day 1 and vinorelbine 25 to 30 mg/m² on days 1
and 8 of a 3-week cycle.[27] An overall response rate of 46% and a
median survival of 34 weeks was observed in 30 patients, all of whom
had good performance status and either stage III or IV disease. The
toxicities were World Health Organization (WHO) grade 3 leukopenia
(33%) and injection vein phlebitis (16%). Similar findings were noted
by Berthaud et al when vinorelbine 30 mg/m2 weekly was administered
with cisplatin 120 mg/m² every 4 to 6 weeks.[28] The median age
of the 32 patients in that study was 55 years. Most had an ambulatory
performance status with locally advanced metastatic disease. The
response rate was 33% and the median survival was 44 weeks.

Three phase III trials have demonstrated the efficacy of the
vinorelbine and cisplatin combination. In a study conducted by
LeChevalier et al, 612 patients were prospectively randomized to one
of three arms: (1) cisplatin 120 mg/m² on days 1 and 29 and then
every 6 weeks plus vinorelbine 30 mg/m² weekly; (2) cisplatin
120 mg/m² alone on days 1 and 29 and every 6 weeks plus
vindesine (Eldisine) 3 mg/m² weekly for 6 doses and then every
other week vs (3) single-agent vinorelbine 30 mg/m² weekly.[29]
Approximately 65% of the patients in this study had a performance
status of 0 or 1 and stage IV disease. The median age of patients was
60 years. The authors reported response rates favoring the cisplatin
plus vinorelbine arm, 30% vs 19% in the cisplatin plus vindesine arm (P
= .02).

A modest survival advantage was also found in favor of the
cisplatin/vinorelbine combination, with a median survival of 40 weeks
compared with 32 weeks for the cisplatin plus vindesine combination (P
= .01). Survival in the single-agent vinorelbine arm was similar to
that in the vindesine/cisplatin arm, 31 weeks vs 32 weeks,
respectively. There was increased myelosuppression with the
cisplatin/vinorelbine combination, but less neurotoxicity than with
the vindesine/cisplatin combination.

The Southwest Oncology Group (SWOG) conducted a second randomized
trial evaluating vinorelbine in combination with cisplatin.[30] In
this study, 432 patients with advanced or metastatic NSCLC and good
performance status were randomized to receive either cisplatin 100
mg/m² once every 4 weeks or cisplatin 100 mg/m² once every
4 weeks plus vinorelbine 25 mg/m² weekly. The combination of
cisplatin plus vinorelbine elicited a superior response rate compared
to single-agent cisplatin, 26% vs 12%, respectively (P =
.0002). Overall median survival and 1-year survival favored the
combination arm with a median survival of 8 months and 1-year
survival of 36% vs 6 months and 20%, respectively (P = .0018),
in the single-agent arm. As expected, the combination arm had a much
higher incidence of WHO grade 3/4 neutropenia (81%) compared with the
single-agent cisplatin arm (5%).

Based on the results of their previous randomized trial, the SWOG
conducted a second trial in 408 eligible patients with stage IIIB
(12%) and stage IV (88%) NSCLC. Patients were randomized to receive
either vinorelbine plus cisplatin (VC) or paclitaxel plus carboplatin
(PC).[31] There was no difference in response rate (27% for each
arm), median survival (8 months for each arm), or 1-year survival
(36% for VC and 33% for PC). Economic and quality-of-life parameters
were compared. The preliminary analysis revealed no differences in
quality of life, but a significant difference in pharmacoeconomic
data favoring the VC arm.

Santammagio et al have combined carboplatin with vinorelbine in a
study in 77 patients with NSCLC. The study had standard inclusion
criteria. A response rate of 31% and median survival of 9 months were
reported.[32] Toxicities included seven cases of grade 3
nausea/vomiting, two cases of grade 3 granulocytopenia, and six cases
of grade 3 anemia.

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