An estimated 75,000 new cases
of lung cancer were diagnosed
in Japan in 2002. Approximately
15% of these cases were diagnosed
as small-cell lung cancer
(SCLC), which is strongly associated
with tobacco use, as is non-small-cell
lung cancer (NSCLC). The clinical
characteristics of SCLC tend to be
more aggressive, but also more sensitive
to chemotherapy and radiation
therapy than those of NSCLC. Smallcell
lung cancer is usually staged as
either limited disease (LD) or extensive
Platinum-based chemotherapy remains
the mainstay of treatment regimens
for ED-SCLC. In a metaanalysis
of 19 randomized trials comparing
a cisplatin-based regimen with
a non-cisplatin-based regimen, patients
randomized to a regimen containing
cisplatin had a significantly
higher probability of response and
survival, with no significant increase
in toxicity. Berghmans et al presented
a detailed analysis of the roles
of etoposide and cisplatin in the treatment
of SCLC. Between 1980 and
1998, 36 eligible trials were performed.
These trials concluded that
the use of cisplatin and/or etoposide
offered a significant survival advantage
to patients with SCLC.
Irinotecan (Camptosar) has been
semisynthesized as a water-soluble
derivative of camptothecin, an inhibitor
of nuclear enzyme topoisomerase
I, in an attempt to reduce its toxicity
and to improve its therapeutic efficacy.[
4-8] In a phase II trial of irinote
for SCLC, the response rate was
47%.[9,10] In preclinical studies,
irinotecan and cisplatin exhibited synergistic
activities. Their toxicity pro-
files also showed a minimal overlap.[
11-16] In a phase II trial of irinotecan
and cisplatin, the response rate
was 86%. In these trials, the principal
toxicities were neutropenia and
Phase III Trial Comparing
Irinotecan and Cisplatin With
Cisplatin and Etoposide
Based on the results of the phase II
trial, the Japan Clinical Oncology
Group (JCOG) conducted a multiinstitutional
randomized phase III trial
(JCOG-9511) comparing irinotecan
and cisplatin (IP) with cisplatin
and etoposide (EP) in patients with
previously untreated ED-SCLC.
The patient characteristics in this trial
included an Eastern Cooperative Oncology
Group (ECOG) performance
status of 0-2 and age ≤ 70 years.
Patients with symptomatic central nervous
system metastases requiring radiation
or corticosteroid treatment
were excluded from the trial. The experimental
arm consisted of irinotecan
at 60 mg/m2 administered on days
1, 8, and 15 of each 4-week cycle,
along with cisplatin at 60 mg/m2 administered
on day 1 for a total of four
4-week cycles (IP). This treatment regimen
was compared with a regimen
of etoposide at 100 mg/m2 administered
on the first 3 days of each
3-week cycle along with cisplatin at
80 mg/m2 administered on day 1 for a
total of four 3-week cycles (EP).
The principal end point was overall
survival. The projected accrual for
this trial was 230 patients (115 patients
per arm). An interim analysis
conducted after 77 patients had been
accrued in each arm showed a significant
survival advantage for the IP
arm. Therefore, further enrollment in
the trial was discontinued.
The response rate was significantly
higher in the IP arm than in the EP
arm (84% vs 68%; P = .02). Additionally,
the IP arm showed a statistically
significant improvement in both
progression-free survival (6.9 vs 4.8
months; P = .003) (Figure 1) and median
overall survival (12.8 vs 9.4
months; P = .002) (Figure 2).
The results of this trial were the
most exciting to be seen in patients
with previously untreated SCLC. The
IP regimen is thus another platinumbased
combination that should be considered
for the treatment of ED-SCLC.
Appropriately, the combination of cisplatin
and irinotecan has become the
new standard treatment for patients
with ED-SCLC in Japan. However,
several points must be examined before
the IP regimen can be fully established
as the new standard
treatment for ED-SCLC. Three randomized
controlled trials comparing
the EP regimen with the IP regimen
are presently under way in Europe
and the United States.
Phase II Trial of Cisplatin,
Irinotecan, and Etoposide
Administered Weekly or
Every 4 Weeks
JCOG 9511 showed that the IP regimen
was significantly better than the
EP regimen. However, because etoposide
was still considered to be a
key drug in the treatment of SCLC, a
combination of these three drugs-
irinotecan, cisplatin, and etoposide
(IPE)-seemed to be a promising
strategy for the treatment of EDSCLC.
The recommended weekly
doses (JCOG 9507) and the dosages
for each 4-week cycle (JCOG 9512)
for IPE were decided using dose-es
calation trials. For these reasons, a
phase II trial of irinotecan, cisplatin,
and etoposide administered weekly or
every 4 weeks for ED-SCLC (JCOG
9902-DI) was performed.
The purpose of this trial was to
evaluate the toxicity and antitumor
effect of the combination of irinotecan,
cisplatin, and etoposide administered
according to two schedules,
weekly (arm A) and every 4 weeks
(arm B), for the treatment of previously
untreated ED-SCLC, and to select
the appropriate arm for use in
phase III trials. Patients were enrolled
in this trial if they met the following
criteria: (1) a histologic or cytological
diagnosis of SCLC; (2) no prior treatment;
(3) measurable disease; (4) extensive
disease, defined as distant
metastasis or contralateral hilar lymph
node metastasis; (5) performance status
of 0 to 2 on the ECOG scale; (6) a
life expectancy of 3 months or longer;
(7) age between 20 and 70 years;
(8) adequate organ function; and (9)
written informed consent.
The treatment schedule is shown
in Figure 3. In arm A, cisplatin at 25
mg/m2 was administered intravenously
(IV) over 60 minutes on day 1 and
at 1-week intervals for 9 weeks; irinotecan
at 90 mg/m2 was administered
IV over 90 minutes on day 1 on weeks
1, 3, 5, 7, and 9; and etoposide at 60
mg/m2 was administered by IV over
60 minutes on days 1 to 3 of weeks 2,
4, 6, and 8. Granulocyte colony-stimulating
factor (G-CSF) was administered
prophylactically on the days
when a cytotoxic drug was not given,
unless the white blood cell (WBC)
count exceeded 10.0 * 109/L.
In arm B, cisplatin at 60 mg/m2
was administered by IV over 60 minutes
on day 1; irinotecan at 60 mg/m2
was administered by IV over 90 minutes
on days 1, 8, and 15; and etoposide
at 50 mg/m2 was administered by
IV over 60 minutes on days 1 to 3.
G-CSF was injected subcutaneously
from day 5 until the day when the
WBC count exceeded 10.0 * 109/L.
This treatment was repeated every 4
weeks for a total of four cycles.
Patient characteristics are listed in
Table 1. Between August 1999 and
October 2000, 30 patients were entered
in each arm. The last follow-up
examination was performed in February
2002. All enrolled patients were
included in the toxicity, tumor response,
and patient survival analyses.
No differences in any of the listed
characteristics were observed between
the two arms.
Treatment delivery is listed in Table
2. Of the 30 patients in each arm,
22 (73%) and 21 (70%) patients in
arms A and B, respectively, received
full cycles of chemotherapy (nine cycles
in arm A and four cycles in arm
B). Therapy was stopped because of
toxicity in four (13%) patients in arm
A and in six (20%) patients in arm B.
Therapy was stopped because of tumor
progression in three (10%) patients
in each arm. The need for
treatment delay in arm A and treatment
skipping in arm B, however,
was significant. Only eight (27%) patients
in arm A completed the treatment
without delay, and only seven
(23%) patients in arm B received all
the planned doses. A total of 105 chemotherapy
cycles were administered to
30 patients in arm B, but eight (8%)
doses of irinotecan on day 8, and 33
(31%) doses of irinotecan on day 15
were omitted because of toxicity, according
to criteria in the protocol.
The median total dosages of cisplatin
and etoposide administered per
patient were maintained at the planned
dosage levels in both arms (Table 3).
The median total dosage of irinotecan
as a percentage of the scheduled dosage
(the relative total dosage) was
100% in arm A, but only 78% in arm
B, reflecting the doses of irinotecan
that were skipped on days 8 and 15.
Dose intensity was evaluated in 29
patients in arm A and 28 patients in
arm B (Table 3). The median relative
dosage intensity was well maintained
at a level of 80% or higher, except
that of irinotecan in arm B (77%).
The median actual dosage intensity
of etoposide was 70 mg/m2/wk in arm
A and 37 mg/m2/wk in arm B.
Toxicity was evaluated in all patients.
The incidences of grade 3/4
neutropenia, anemia, thrombocytopenia,
infection, and diarrhea in arm A
were 57%, 43%, 27%, 7%, and 7%,
respectively, and 87%, 47%, 10%,
13%, and 10%, respectively, in arm
B. A treatment-related death occurred
in one patient in arm A (Table 4).
Two complete responses (CRs) and
23 partial responses (PRs) were obtained
in arm A, resulting in an overall
clinical response rate of 83%,
whereas five CRs and 18 PRs were
obtained in arm B, resulting in an
overall response rate of 77% (Table
5). The median time to survival and
1-year survival rate in arm A were 8.9
months and 40%, respectively, and
12.9 months and 57%, respectively,
in arm B (Figure 4).
In this trial, the two IPE schedules
were both effective against ED-SCLC
and had an acceptable toxicity level.
Arm B was adopted as the investigational
arm in phase III trials.
The combination of cisplatin and
irinotecan has become the new standard
treatment for patients with EDSCLC
in Japan. However, SCLC is
rarely cured, although the response
rate has been improved and the survival
time extended through the use
of chemotherapy. Based on the results
of JCOG 9511 and JCOG 9902-
DI, a randomized trial comparing IP
with IPE administered every 3 weeks
in patients with previously untreated
ED-SCLC is now being performed in
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