Download New Chemotherapy Agents for Small Cell Lung Cancer

New Chemotherapy Agents for
Small Cell Lung Cancer*
Karen Kelly, MD
Background: Approximately 45,000 new cases of
small cell lung cancer (SCLC) will be diagnosed in
the United States this year. Combination chemotherapy is the cornerstone of treatment for all stages of
this disease and results in high response rates (65 to
85%), leading to a meaningful survival advantage for
these patients. Patients with limited-stage disease
enjoy a median survival of 10 to 15 months with
chemotherapy, as compared to 3 months without
drug therapy. With addition of chest radiotherapy,
survival is further prolonged to 12 to 20 months.
Patients with extensive-stage disease experience an
average survival of 1.5 months without chemotherapy and 7 to 11 months with chemotherapy. However, no further improvement in survival has been
demonstrated since combination chemotherapy regimens were introduced in the late 1970s and early
1980s, despite evaluating numerous strategies; the
5-year survival for all patients remains dismal at 5%.
Clearly, new chemotherapy agents with novel mechanisms of action are needed.
Focus: This article will review the experience to date
with six new agents that are active against SCLC. It
includes two taxanes (paclitaxel and docetaxel), vinorelbine, two camptothecin derivatives (topotecan and irinotecan), and gemcitabine. Single-agent activity as well
as combination regimens with other agents and radiotherapy will be discussed. The role of maintenance
therapy with oral matrix metalloproteinase inhibitors
also is evaluated.
(CHEST 2000; 117:156 –162S)
Key words: carboplatin; cisplatin; gemcitabine; small cell lung
cancer; survival; taxanes; topotecan; vinorelbine
Abbreviations: AUC ⫽ area under the plasma concentration-vstime curve; CAV ⫽ cyclophosphamide, doxorubicin, and vincristine; CE ⫽ carboplatin and etoposide; CR ⫽ complete response;
ECOG ⫽ Eastern Cooperative Oncology Group; G-CSF ⫽
granulocyte colony-stimulating factor; MMP ⫽ matrix metalloproteinase; PE ⫽ cisplatin and etoposide; PR ⫽ partial response;
RTOG ⫽ Radiation Treatment Oncology Group; SCLC ⫽ small
cell lung cancer; SWOG ⫽ Southwest Oncology Group
mall cell lung cancer (SCLC) is one of the most
S aggressive
and lethal cancers in man. Approximately
45,000 new cases of SCLC will be diagnosed in the United
States this year.1 One third of patients will present with
limited-stage disease confined to the chest, and the remaining two thirds of patients will have disseminated
disease. Combination chemotherapy is the cornerstone of
treatment for these patients, yielding high initial response
*From the University of Colorado Health Sciences Center,
Denver, CO.
Correspondence to: Karen Kelly, MD, Associate Professor of
Medicine, Division of Medical Oncology B171, 4200 East Ninth
Ave, Denver, CO 80262; e-mail: [email protected]
rates of 65 to 85%, including 10 to 50% complete responses (CRs) depending on stage.2,3 Despite high response rates, relapse and progression occur in the majority
of SCLC patients, and median survival is ⬍ 1 year for
patients with extensive-stage disease. Patients with limited-stage disease receiving chemoradiotherapy sometimes
are cured, but the median survival is limited to 15 to 20
months in the majority of patients, and the 2-year survival
rate is 40%. Ten to 30% of patients with progressive
disease may respond to salvage chemotherapy regimens,
but the responses are of short duration.
Current Status of Chemotherapy
Commonly used combination chemotherapy regimens
currently used to treat SCLC include cyclophosphamide,
doxorubicin, and vincristine (CAV); cyclophosphamide,
doxorubicin, and etoposide; and cisplatin and etoposide
(PE). PE has been compared with CAV or CAV alternating with PE in two randomized trials.4,5 Investigators for
the Southeastern Cancer Study Group showed no difference in response rates (51%, 61%, and 59%, respectively)
or median survival (8.3, 8.6, and 8.1 months, respectively)
with these three treatment arms in extensive-stage disease.4 In addition, four cycles of PE had equivalent activity
to six cycles of CAV or CAV/PE. Fukuoka and coworkers5
noted a trend toward improved survival in the CAV/PE
arm, 11.8 months, vs 9.9 months in the other two arms
(p ⫽ 0.056), which was found to occur only among patients with limited-stage disease. No difference in survival
(8 to 9 months) was noted among the patients with
extensive-stage SCLC. Although nausea and vomiting
were considerable with the PE regimen, there was less
myelosuppression, neurotoxicity, and cardiac toxicity than
with CAV. Based on these results, the PE regimen has
become the most commonly used regimen to treat patients with SCLC.
Carboplatin has also been shown to be highly active
against SCLC and less toxic than cisplatin.6 In one randomized trial, the combination of carboplatin and etoposide (CE) was compared to PE in treating 143 SCLC
patients evaluable for response.7 Among 82 limited-disease patients, there was a 76% overall response rate,
including a 44% CR in the PE treatment arm vs a 37% CR
and an 86% objective response rate in the CE arm. The 62
patients with extensive-stage disease given PE had a 13%
CR rate with an overall response rate of 60%, as compared
to a 15% CR rate and a 69% objective response rate for
patients receiving CE. Overall survival was 12.5 months
for the PE group vs 11.8 months for the CE group. The
CE regimen was shown to be less toxic than PE. Thus, CE
has similar efficacy but less toxicity than PE, and is now
often employed to treat patients with SCLC.
The Search for New Agents
Since the development of these active drugs and their
addition to combination regimens, ⬎ 15 years have passed
in trying to optimize SCLC therapy. However, even novel
therapeutic programs using these agents—including maintenance therapy with more cycles of drugs, administering
higher drug doses, or using drugs in alternating sequenc-
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Multimodality Approach to Lung Cancer
therapy.11,12 In both trials, topotecan, 1.5 mg/m2, was
given for 5 days. Responses were rare among refractory
patients in both trials (2% and 6%), with higher response
rates observed in sensitive-relapse patients (14% and
38%). In the trial of Depierre et al,11 the lower response
may have been because fewer courses of topotecan were
administered. Several patients with stable disease after 2
to 3 cycles were given alternative chemotherapy. Neutropenia was the major toxicity in both trials. Perez-Soler et
al13 evaluated topotecan, 1.25 mg/m2, given to 30 patients
refractory to etoposide. Among 25 evaluable patients, 3
patients (12%) achieved a PR, and grade 3 and grade 4
neutropenia occurred in 69% of cycles. A composite of the
data revealed a response rate of 38% among untreated
patients, 24% in sensitive-relapse patients, and 5% for
refractory patients.
Based on these encouraging results, a randomized
phase III comparison of topotecan vs CAV in the treatment of patients who had relapses ⱖ 60 days after completion of first-line therapy was initiated (Table 1).14 At the
time of analysis, there were 94 evaluable patients in each
arm. Response rates, median time to progression, and
median survival were similar between the two groups
(21%, 3.3 months, and 5.8 months, respectively, for the
topotecan arm; 15%, 3 months, and 5.5 months, respectively, for the CAV arm). The rates of neutropenia and
febrile neutropenia also were similar in both arms, but
more thrombocytopenia and anemia occurred in the topotecan arm (p ⬍ 0.001 and p ⬍ 0.003, respectively).
There was no difference in the rates of nonhematologic
toxicities between the two groups. Symptom relief was
greater with topotecan than CAV. The investigators concluded that topotecan was active in this setting, and that
the increased hematologic toxicity was manageable.
Currently, single-agent topotecan is being evaluated as
part of a phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG). In this trial, untreated
es— have been disappointing, yielding no change in survival rates. Instead, the hope for the future seems to come
from six new agents having significant single-agent activity
in SCLC. Two taxanes, paclitaxel and docetaxel; another
mitotic spindle inhibitor, vinorelbine; two topoisomerase I
inhibitors, irinotecan and topotecan; and one antimetabolite, gemcitabine, are being actively evaluated. Oral matrix
metalloproteinase (MMP) inhibitors are being investigated as maintenance therapy in this disease.
Topotecan
Topotecan is the most extensively studied compound to
date for the treatment of SCLC. Phase I testing identified
myelosuppression as the dose-limiting toxicity and 1.5 mg/m2
IV over 30 min for 5 days every 21 days as the recommended dosage and schedule for phase II testing.8 Table
1 presents results from several phase II trials evaluating
topotecan in SCLC.9 –13 In the first trial, Schiller et al9 gave
topotecan, 2 mg/m2, to 48 untreated patients with extensive-stage SCLC, adding granulocyte colony-stimulating
factor (G-CSF) after the first 13 patients due to a high rate
of grade 4 neutropenia (77%). The addition of growth
factor reduced the neutropenia to 29%. Febrile neutropenia occurred in 8% of patients not receiving growth factor,
and 11% of those were administered G-CSF. After treatment, 19 patients (39%) had a partial response (PR),
median survival was 10 months, and 1-year survival rate
was 39%. Watanabe et al10 administered dosages of 0.8 to
1.2 mg/m2/d for 5 days to 6 untreated and 15 previously
treated patients, yielding responses in 2 of 6 untreated
(33%) and 4 of 15 (27%) previously treated patients.
Grade 4 neutropenia occurred only in previously treated
SCLC patients (27%).
Two studies involved patients with refractory disease—
defined as progressive disease while receiving first-line
treatment or within 90 days of treatment— or sensitive
relapse—progressive disease at least 90 days after first-line
Table 1—Phase II/III Clinical Trials With Topotecan in SCLC*
Authors
Dose,
mg/m2
Schiller et al9
Watanabe et al10
2
0.8–1.2
Depierre et al11
1.5
Ardizzoni et al12
1.5
Perez-Soler et al13
Schiller et al14
1.25
1.5
Patients, No.
Response, %
48
6
15†
41R
57S
47R
45S
25R
94#
39
33
27
2
17
6
38
12
21
Median
Survival, mo
1-Yr
Survival, %
Grade 4
Neutropenia, %
10
NR
NR
5.4§
39
NR
NR
NR
NR
NR
NR
NR
NR
77 (G-CSF)
0‡
27‡
89 (G 3/4)
70㛳
47㛳
4.7
6.9
NR
5.8
69¶
64
*R ⫽ refractory to previous treatment: progressed on first-line treatment or failed within 90 d of treatment; S ⫽ sensitive to previous treatment:
progressed after 90 d of stopping first-line treatment; NR ⫽ not reported; G 3/4 ⫽ grade 3 and 4 neutropenia.
†Leukopenia.
‡Previously treated.
§All patients.
㛳Percentage of cycles.
¶Percentage of cycles with grade 3 and grade 4.
#Failed first-line treatment after 60 d.
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patients with extensive-stage SCLC receive four cycles of
PE and are then randomized to four cycles of topotecan or
observation. Results are awaited. Combination trials incorporating topotecan into active regimens are also underway.
Two institutions are performing a phase I trial of topotecan with PE, and a promising regimen of topotecan plus
paclitaxel is discussed below.
Taxanes
Two phase II studies established the efficacy of paclitaxel in SCLC (Table 2).15,16 In an ECOG study, Ettinger
and colleagues15 administered paclitaxel, 250 mg/m2 by
24-h infusion, to achieve a 53% response rate (11 of 32
untreated patients) and an 11-month median survival. The
North Central Cancer Treatment Group conducted a
similar trial and reported a 68% response rate in 37
patients and a median survival of 7.3 months.16 Grade 4
leukopenia was the major toxicity seen in both studies.
To improve on the results with single-agent paclitaxel,
several groups have combined paclitaxel with the platinum
agents, cisplatin or carboplatin (Table 2).17–25 Nair et al17
assigned patients with untreated extensive-stage SCLC to
treatment with paclitaxel, 135 mg/m2 or 175 mg/m2, plus
cisplatin, 75 mg/m2 on day 1. Fifteen of 21 evaluable
patients receiving the lower dose of paclitaxel responded
(71%), as did 39 of 44 patients (89%) on the higher dose
arm. Median survival was 8.5 months vs 9.5 months and
1-year survival was 24% vs 38% on the low-dose and
higher-dose paclitaxel arms, respectively, suggesting a
dose-response effect for paclitaxel. Only one patient (2%)
receiving the high-dose paclitaxel regimen experienced
grade 4 neutropenia. Georgiadis et al18 conducted a
dose-escalating trial of a 96-h infusion of paclitaxel plus
cisplatin in patients with advanced lung cancer. Four of six
patients (67%) with SCLC achieved an objective response.
The maximally tolerated dose without growth factor support was paclitaxel, 120 mg/m2, with cisplatin, 80 mg/m2.
There have been four studies in which investigators
added paclitaxel to the active regimen of PE. Kelly et al19
recently completed a phase I trial in which escalating
doses of paclitaxel, 135 to 200 mg/m2 IV over 3 h; cisplatin,
50 to 80 mg/m2; and etoposide, 50 to 80 mg/m2 IV day 1,
with 100 to 160 mg/m2 orally on days 2 and 3, was given to
untreated patients with extensive-stage SCLC. With this
regimen, 19 of 23 evaluable patients (83%) achieved a
response. The median survival for all 28 patients was 10.8
months, and the 1-year survival rate was 46%. Doselimiting neuropathy occurred with paclitaxel, 200 mg/m2;
cisplatin, 80 mg/m2; and etopside, 80 to 160 mg/m2. Grade
4 neutropenia was frequent in cycle 1 (82%), but febrile
neutropenia was uncommon. Based on these encouraging
results, the Southwest Oncology Group (SWOG) is enroll-
Table 2—Phase I/II Trials With Paclitaxel in SCLC*
Treatments/Authors
Paclitaxel
Ettinger et al15
Kirschling et al16
Paclitaxel plus cisplatin
Nair et al17
Dose/Schedule
Patients, No.
Response, %
Median
Survival, Mo
1-Yr
Survival, %
Grade 4
Neutropenia, %
34
37
53
68
11
7.3
37
NR
56†
19‡
21
44
6
71
89
67
8.5
9.5
NR
24
38
NR
0
2
NR
23
26
8
8§
83
96
88
100
10.8
15.5
NR
NR
46
NR
NR
NR
82
48‡
0
50㛳
23
15§
38
41§
20
35
65
93
84
98
85
86
7
17
10
⬎ 16
NR
NR
NR
NR
NR
NR
NR
NR
8¶
12
92
NR
50
51‡
6
83
NR
NR
NR
250 mg/m2, 24 h
250 mg/m2, 24 h
135 mg/m2
175 mg/m2
Georgiadis et al18
100–120 mg/m2, 96 h
Paclitaxel plus cisplatin plus etoposide
Kelly et al19
135–200 mg/m2, 3 h
30 mg/m2, 3 h
Glisson et al20
Levitan et al21
135–200 mg/m2, 3 h
Bremnes et al22
175 mg/m2
Paclitaxel plus carboplatin plus etoposide
Hainsworth et al23
135 mg/m2, 1 h
200 mg/m2, 1 h
Neill et al24
200–175 mg/m2
Gatzemeier et al25
175 mg/m2, 3 h
Paclitaxel plus topotecan
Jett et al26
135 mg/m2
Paclitaxel plus carboplatin plus etoposide plus ifosfamide
Strauss et al27
75–225 mg/m2
38¶
24
31
*See Table 1 for abbreviation.
†Leukopenia.
‡Percent of cycles.
§Patients with limited-stage disease.
㛳Grade 3 and grade 4 leukopenia.
¶Grade 3 and grade 4 neutropenia occurring in all patients.
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Multimodality Approach to Lung Cancer
ing SCLC patients in a phase II trial to receive paclitaxel,
175 mg/m2; cisplatin, 80 mg/m2; and etopside, 80 to 160
mg/m2 with G-CSF.
In a similar design, Glisson et al20 administered paclitaxel, 130 mg/m2 by a 3-h infusion, on day 1, plus cisplatin,
75 mg/m2, and etoposide, 80 mg/m2 IV, on days 2 to 4. In
this setting, 25 of 26 patients (96%) achieved a response,
including 5 patients (19%) with a CR. The estimated
median overall survival was 15.5 months. Grade 4 neutropenia was frequent (48% of courses), but febrile neutropenia occurred in only 6% of courses.
Levitan et al21 administered paclitaxel, 135 to 200
mg/m2, with cisplatin, 60 mg/m2 on day 1, and etoposide,
80 mg/m2 on days 1 to 3, to eight patients with extensivestage SCLC. Among seven evaluable patients, one experienced a CR and six had a PR, for an overall response rate
of 88%. Bremnes et al22 also treated eight SCLC patients
with paclitaxel, 175 mg/m2 IV over 1 h; cisplatin, 50 mg/m2;
and etoposide, 100 mg/m2 IV day 1 and 100 mg orally bid
on days 2 to 5. All patients had limited-stage disease and
received concurrent radiation beginning with cycle 3.
Seven patients had a CR, and one had a PR (100%). Four
patients developed grade 3 or grade 4 leukopenia after
cycle 1, three patients had reversible grade 3 peripheral
neuropathy, and one patient experienced grade 3 esophagitis from the radiation. Presently, the Radiation Treatment Oncology Group (RTOG) and ECOG are conducting phase II trials with paclitaxel, cisplatin, and etoposide
plus concurrent radiation to treat patients with limitedstage disease. In the RTOG study, the concurrent therapy
begins on day 1; in the ECOG study, it begins with cycle 3.
Hainsworth et al23 have conducted the largest trial
combining paclitaxel with CE in the treatment of SCLC.
Their study included 38 patients, 15 with limited-stage
disease and 23 with extensive-stage disease who received
paclitaxel, 135 mg/m2 IV over 1 h; carboplatin, at an area
under the plasma concentration-vs-time curve (AUC) of 5;
and etoposide, 50 mg alternating with 100 mg orally on
days 1 through 10. Patients with limited-stage disease
received concurrent radiation beginning with cycle 3. This
regimen resulted in an objective response in 14 patients
(93%) with limited-stage disease and 15 patients (65%)
with extensive-stage disease. Median survival was 17
months and 7 months in limited- and extensive-stage
SCLC, respectively. The regimen was extremely well
tolerated: only 8% of courses resulted in grade 3 or grade
4 neutropenia. Thus, an additional 79 patients were
treated with the paclitaxel dose escalated to 200 mg/m2,
resulting in objective responses in 40 of 41 patients (98%)
with limited-stage SCLC and 32 of 38 patients (84%) with
extensive-stage SCLC. Median survival was 10 months for
patients with extensive-stage disease, and has not been
reached for those with limited-stage disease. Grade 3 and
grade 4 neutropenia increased to 38% of courses with the
higher dose of paclitaxel.
Neill et al24 are conducting a trial of paclitaxel, 200
mg/m2 IV over 3 h; carboplatin, AUC of 6; and etoposide,
80 to 100 mg/m2 IV on days 1 to 3 plus growth factor, in
patients with advanced lung cancer. Seventeen of 20
patients with SCLC obtained a major response (85%).
Grade 4 neutropenia developed in 24% of patients. Gatze-
meier and coworkers25 have reported preliminary results
with a similar three-drug combination for limited-stage
SCLC. Patients received paclitaxel, 175 mg/m2 by 1-h infusion; carboplatin, AUC of 5; and oral etoposide, 100 mg on
days 2 to 8. Thirty-one of 35 patients (86%) achieved a
response, including 13 CRs (37%). Grade 4 neutropenia
occurred in 31% of patients. Significant thrombocytopenia,
peripheral neuropathy, and other nonhematologic toxicities
were infrequent in all three trials.
Paclitaxel in combination with platinum-based chemotherapy regimens appears to produce a higher response
rate in SCLC than previously observed. Thus, the Intergroup plans to initiate a trial comparing paclitaxel plus PE
to the standard regimen of PE for extensive-stage SCLC
to determine if there is a survival benefit with the
three-drug regimen.
Other combinations with paclitaxel are under investigation. Jett et al26 are evaluating paclitaxel, 130 mg/m2 IV
over 24 h on day 5, plus topotecan, 1 mg/m2 IV on days 1
to 5, with G-CSF support when administered to previously
untreated patients with extensive-stage SCLC (Table 2).
Among 12 evaluable patients receiving this combination,
there were two CRs (17%) and nine PRs (75%), for an
overall response rate of 92%. The 1-year rate was 50%.
Grade 3 or grade 4 leukopenia occurred in 51% of courses,
but other toxicities were minimal. In a phase I trial,
Strauss and colleagues27 are testing the combination of
24-h infusional paclitaxel, 75 to 225 mg/m2; ifosfamide,
2,000 mg/m2 on days 1 to 3; carboplatin, 300 mg/m2 on day
2; and etoposide, 75 mg/m2 on days 2 to 3 with G-CSF
support, for the treatment of advanced lung cancer (Table
2). Among the six patients with SCLC, the investigators
observed two CRs and three PRs (83%). Perez28 is
evaluating the efficacy of paclitaxel, 150 mg/m2 given on
day 10, plus oral etoposide, 50 mg bid for 10 days. With 16
of the 50 planned patients entered in the study, the
regimen appears to be well tolerated and the response rate
is encouraging.
Studies with the other taxane, docetaxel, are limited.
Smyth et al29 administered docetaxel, 100 mg/m2, to 28
previously treated patients with SCLC and reported a 25%
response rate. Grade 4 neutropenia developed in 71% of
patients. Burris et al30 treated 46 chemotherapy-naive
patients with docetaxol, 100 mg/m2, to achieve eight PRs
(17%) and a median survival of 9 months. Grade 4
leukopenia was noted in 8% of patients. The University of
Colorado is conducting a phase I clinical trial using
docetaxel in a combination regimen for the treatment of
limited-stage SCLC. Eligible patients receive two cycles of
carboplatin, AUC of 5, day 1, and etoposide, 50 mg/m2 IV
on day 1 and 100 mg/m2 orally on days 2 to 3, with
escalating doses of docetaxel starting at 50 mg/m2, day 1,
before and after chemoradiotherapy.
Gemcitabine
Gemcitabine is a new potent antimetabolite shown to
be active against SCLC. Cormier and coworkers31 used
gemcitabine, 1,000 to 1,250 mg/m2 administered weekly
for 3 of 4 weeks, to treat 29 previously untreated patients
with SCLC. They observed a 27% response rate (7 of 26)
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among evaluable patients, a median duration of response
of 12.5 weeks, and a 12-month median survival. Toxicities
were mild, with only 18% of courses (13 of 72) leading to
grade 3 or grade 4 myelosuppression.
Studies in non-small cell lung cancer combining gemcitabine with cisplatin have shown an acceptable toxicity
profile. SWOG, therefore, is currently conducting a phase
II trial involving untreated patients with extensive-stage
SCLC who will receive gemcitabine, 1,250 mg/m2 on days
1 and 8, plus cisplatin, 75 mg/m2 on day 1, given every 21
days.32,33
Vinorelbine
Vinorelbine, a semisynthetic vinca alkaloid, has been
evaluated as a single agent for the treatment of SCLC by
five investigators, as shown in Table 3.34 –38 Depierre et al34
administered vinorelbine, 30 mg/m2 weekly, to 30 patients
with untreated advanced disease, achieving a PR in 8 of 30
patients (27%). Myelosuppression was observed in 12
patients (40%) as was the dose-limiting toxicity; 3 patients
experienced grade 3 or grade 4 constipation. In a smaller
trial by Tummarello and coworkers,35 vinorelbine, 25
mg/m2 weekly, yielded no responses among six previously
untreated patients. In previously treated patients, Furuse
and colleagues36 noted responses in 3 of 24 patients (13%)
treated with vinorelbine, 25 mg/m2, and 60% of patients
developed grade 3 or grade 4 leukopenia. In a similar
population, Jassem et al37 treated 26 sensitive-relapse
patients with vinorelbine, 30 mg/m2 weekly. Four of 25
evaluable patients (16%) achieved an objective response.
Neutropenia—the predominant toxicity— occurred in
32% of patients. Finally, Lake and colleagues38 evaluated
the activity of vinorelbine, 30 mg/m2 every week for 3 of 4
weeks, when administered to 34 sensitive-relapse patients.
Five of 31 patients with measurable disease had documented PR (15%), with a median survival of 5 months.
Grade 4 neutropenia was noted in 40% of patients.
In a phase II trial, vinorelbine was combined with PE to
treat 14 previously untreated patients with limited-stage
(n ⫽ 9) and extensive-stage (n ⫽ 5) SCLC (Table 4).39
Patients received the combination of cisplatin, 75 mg/m2
on day 1; etoposide, 60 mg/m2 on days 1 to 3; and
vinorelbine, 20 mg/m2 on days 1 and 8, repeated every 28
days. Patients with limited-stage disease received concurrent radiation beginning with cycle 3. All patients were
evaluable for response and toxicity. In this setting, seven of
nine patients (78%) with limited-stage SCLC, and two of
five patients (40%) with extensive-stage SCLC achieved a
response. Median survival was 13.4 months and 7 months,
respectively, for limited-stage and extensive-stage patients.
Neutropenia was observed in 7% of patients.
In Italy, a phase II trial was designed to evaluate the
activity of carboplatin plus vinorelbine in extensive-stage
SCLC (Table 4).40 Treatment with carboplatin, 300 mg/m2
on day 1, and vinorelbine, 25 mg/m2 on days 1 and 8,
repeated every 4 weeks, yielded an objective response in
23 patients (70%), with 24% having a CR. Treatment was
well tolerated, with 4% grade 4 neutropenia and 4% grade
3 thrombocytopenia.
Irinotecan
Irinotecan is a camptothecin derivative similar to topotecan with single-agent activity in SCLC (Table 4).41– 44
Negoro and coworkers41 treated 35 patients (27 had
received previous therapy) with irinotecan, 100 mg/m2
weekly. Nine previously treated patients (33%) and four of
eight untreated patients (50%) responded. When Masuda
et al42 administered the same dose and schedule to 16
patients with relapses, 7 of 15 achieved an objective
response (47%). Le Chevalier and colleagues43 used a
3-week schedule of irinotecan, 350 mg/m2, to treat 32
chemotherapy-naive SCLC patients. An objective response was observed in five patients (16%), and the
Table 3—Phase II Trials of Vinorelbine in SCLC*
Treatments/Authors
Dose, mg/m2
Vinorelbine
Depierre et al34
30
Tummarello et al35
25
Furuse et al36
25
Jassem et al37
30
Lake et al38
30
Vinorelbine plus cisplatin plus etoposide
Richardet et al39
20
Vinorelbine plus carboplatin
Gridelli et al40
25
Patients, No.
Response, %
Median
Survival, Mo
1-Yr
Survival, %
Grade 4
Neutropenia, %
30
6
24§
26§
34§
27
0
13
16
15
NR
NR
NR
NR
5
NR
NR
NR
NR
NR
40†
16‡
60㛳
32㛳
40
9¶
5
78
40
13.4
7
NR
NR
7
33
70
NR
NR
3.5#
*See Table 1 for abbreviation.
†Grade 3 and grade 4.
‡Percent of cycles with grade 3 and grade 4.
§Sensitive-relapse patients.
㛳Grade 3 and grade 4 leukopenia.
¶Limited-stage patients.
#Leukopenia.
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Multimodality Approach to Lung Cancer
Table 4 —Phase II Trials of Irinotecan in SCLC*
Dose, mg/m2
Treatments/Authors
Irinotecan
Negoro et al41
Masuda et al42
Le Chevalier et al43
Irinotecan plus cisplatin
Japan
100
100
350 every 3 wk
80
Patients, No.
Response, %
Median
Survival, Mo
1-Yr
Survival, %
Grade 4
Neutropenia, %
27†
8
15
32†
33
50
47
16
NR
NR
6.8
4.5
NR
NR
NR
NR
NR
NR
NR
58‡
40§
35
83
80
NR
NR
NR
NR
NR
NR
*See Table 1 for abbreviation.
†Previously treated patients.
‡Grade 3 and grade 4.
§Limited-stage patients.
median survival was 4.5 months. The major toxicities in all
trials were neutropenia and diarrhea.
One Japanese phase II combination trial (investigators
brochure) examined irinotecan, 80 mg/m2 on days 1, 8,
and 15; and cisplatin, 60 mg/m2 on day 1, every 28 days to
treat 75 previously untreated patients with SCLC. Among
40 patients with limited-stage SCLC, the response rate
was 83% (33 of 40 patients), including 12 CRs (30%). The
response rate in 35 patients with extensive-stage SCLC
was 86% (30 of 35 patients), with 10 CRs (29%).
MMP Inhibitors
The MMP inhibitors are a new class of drugs that break
down extracellular matrix and disrupt tissue architecture
that is associated with tumor progression.44 Specific
MMPs, MMP-2 and MMP-9, have been isolated in lung
tumors. MMP inhibitors have been shown to inhibit tumor
invasion in vitro and in vivo and block tumor-induced
neovascularization.
Two MMP inhibitors are being examined in SCLC as
maintenance therapy in phase III clinical trials. Responding patients with limited- or extensive-stage SCLC are
randomly assigned to an oral MMP inhibitor or placebo
treatment. In one study, patients take the medication for a
maximum of 18 months, while the other study allows patients
to take the medication until the cancer progresses. In phase
I testing, MMPs are extremely well tolerated, with the major
side effects being myalgias, arthralgias, and headache.
Conclusion
In conclusion, the antitumor activity of these new agents
against SCLC has renewed our optimism that survival can be
prolonged for this group of patients. Perhaps most encouraging is the possibility that patients with limited-stage disease
might be cured with new agents in combination with radiotherapy. Defining the optimum combinations of these new
agents to impact survival is just beginning, but the future
appears promising.
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Multimodality Approach to Lung Cancer