Establishment of the Standard Regimen for Non-Small- Cell Lung Cancer in Japan

Establishment of the Standard Regimen for Non-Small- Cell Lung Cancer in Japan

ABSTRACT: Preclinical data suggest that irinotecan (Camptosar, CPT-11), a novel topoisomerase I inhibitor, has exhibited promising activity in the treatment of lung cancer. In a phase II study of non-small-cell lung cancer, irinotecan demonstrated a 32% response rate. Combinations of irinotecan and cisplatin (Platinol) have also demonstrated synergistic activity against non-small-cell lung cancer. A phase I trial of irinotecan combined with cisplatin in previously untreated non-small-cell lung cancer patients showed an encouraging response rate of 54%, with irinotecan at 60 mg/m2 on days 1, 8, and 15, plus cisplatin at 80 mg/m2. In a phase II study of chemotherapy-naive patients with stage IIIB/IV non-small-cell lung cancer, irinotecan/cisplatin yielded a response rate of 52% and a mean survival time of 44 weeks. Data from a phase III trial comparing cisplatin at 80 mg/m2 on day 1 plus vindesine at 3 mg/m2 on days 1, 8, and 15 with two irinotecan-containing regimens—cisplatin at 80 mg/m2 on day 1 plus irinotecan at 60 mg/m2 on days 1, 8, and 15, and single-agent irinotecan at 100 mg/m2 on days 1, 8, and 15—have also been reported. Responses were observed in 32%, 44%, and 21% of patients for the vindesine/cisplatin, irinotecan/cisplatin, and irinotecan arms, respectively, with corresponding median survival times of 45.6, 50.0, and 46.0 weeks; there were no significant differences in response rate or survival between treatment groups for all patients. However, subset analysis of stage IV patients indicated a significant survival advantage for irinotecan/cisplatin; the median survival time was 50 weeks for patients receiving irinotecan/cisplatin, 36.4 weeks for vindesine/cisplatin, and 42.1 weeks for irinotecan (P = .004 for the irinotecan/cisplatin arm vs vindesine/cisplatin; P = .018 for irinotecan vs vindesine/cisplatin). Another phase III study compared irinotecan/cisplatin and vindesine/cisplatin. There was no difference in overall median survival time, and the median survival times were not significantly different for stage IV patients in the respective irinotecan/cisplatin and vindesine/cisplatin arms (44.7 vs 45.3 weeks). Further studies are needed to determine whether irinotecan/cisplatin combinations improve survival in comparison with other promising platinum-containing regimens. [ONCOLOGY 15(Suppl 1):13-18, 2001]


Irinotecan (Camptosar, CPT-11) is a
semisynthetic water-soluble camptothecin analog. Its mechanism of action is inhibition of DNA topoisomerase I
through the formulation of a topoisomerase I-DNA cleavable complex.[1,2] In
preclinical studies, irinotecan has demonstrated a broad spectrum of activity
both in vitro and in vivo. These include synergistic effects that have been
observed when it is administered in combination with other active anticancer

Clinical Studies: Single-Agent Irinotecan

Japanese Phase I Studies

Single-Dose Schedule: Taguchi and coworkers reported the
first phase I trial of irinotecan in 1990.[3] The human trial was initiated at a
dose of 50 mg/m2 on a single-dose schedule based on a dose of one-fifth of the
lethal dose (LD10) in mice (52.8 mg/m2) and one-third of the toxic dose in dogs
(69.3 mg/m2). The dose-escalation schedule was carried out according to the
modified Fibonacci search method, and the study dose range was 50 to 350 mg/m2.
A total of 17 patients with refractory solid tumors were enrolled in the trial.

The dose-limiting toxicity was myelosuppression, especially
neutropenia, and the maximum tolerated dose was presumed to be 250 mg/m2 or
more. Other toxicities included nausea and vomiting, diarrhea, abdominal pain,
alopecia, and anemia. However, interpatient variability of toxic effects was
substantial. Antitumor effects were observed at a dose of  ³ 165
mg/m2 in
patients with colon cancer, gastric sarcoma, malignant melanoma, and lung
cancer. The authors suggested a dose for early phase II trials of 200 mg/m2
every 3 to 4 weeks (see Table 1).

Once-a-Week Schedule: Camptothecin and its derivatives have
demonstrated schedule-dependent antitumor activity and toxicity.[4,5] In
preclinical systems, the antitumor efficacy of irinotecan increased when it was
given by repeated administration instead of single administration of the same
total dose.[6] Hence, a once-a-week administration of irinotecan appears
superior to a once-a-month schedule in achieving a response.

Negoro and colleagues reported the results of a phase I study of
weekly IV infusion of irinotecan in patients with advanced non-small-cell lung
cancer.[7] Seventeen patients were administered a weekly schedule at doses
ranging from 50 to 150 mg/m2 (50, 100, 125, and 150
mg/m2). The dose-limiting
toxicities were leukopenia and unpredictable diarrhea. Simultaneous occurrence
of these toxicities was lethal in two patients, but it did not correlate to the
pharmacokinetics of either irinotecan or its active metabolite SN-38

Antitumor activity (partial responses of 3.2 and 4.0 months) was
observed in two previously untreated patients
at the respective doses of 100 and
125 mg/m2. The maximum tolerated dose on this schedule was 100
mg/m2, as was the
recommended dose of a weekly schedule for phase II trials, with particular
attention paid to hematologic and gastrointestinal adverse events (see Table

Japanese Phase II Studies

Single-Dose Schedule: Nakai and coworkers conducted a phase
II multi-institutional study using a single-dose schedule of irinotecan in
patients with advanced lung cancer.[8] Based on the previous phase I study of a
single-dose schedule,[3] irinotecan at 200 mg/m2 was administered to 38 eligible
patients with advanced non-small-cell lung cancer. (The total number of
eligible patients in this trial was 41, including
3 patients with small-cell lung cancer.)

Among the 38 eligible patients, the response rate was 18.4% (7
out of 38) with partial responses. The response rate in 22 patients with prior
therapy was 14% (3 out of 22), and that for previously untreated patients was
(4 out of 13). The major toxicities observed in this trial were leukopenia (³
grade 3: 18%), diarrhea (³ grade 3: 13%), nausea/vomiting (³ grade 2: 50%),
and anorexia (³ grade 2: 66%) (see Table

Once-a-Week Schedule: Fukuoka et al reported the results of
a phase II trial conducted on a weekly schedule between 1989 and 1990 in
patients with previously untreated advanced non-small-cell lung cancer.[9] A
total of 73 patients were enrolled, and all had measurable disease with an
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Of 72
evaluable patients, there were no complete responses, but 23 (31.9%) showed a
partial response (95% confidence interval [CI] = 20% to 44%). The response rates
were similar for patients with a performance status of 0 or 1 (34% [18 out of
53]) and those with a performance status of 2 (26.3% [5 out of 19]).

Ten of 32 patients (31%) with locoregional (stage I-IIIB)
disease and 13 of 40 patients (33%) with stage IV disease comprised the
responders. The median duration of response for all patients who achieved a
partial response was 15 weeks (range: 7 to 31 weeks), and that for stage IV
patients was 15 weeks (range: 7 to 31 weeks). The median survival time for all
eligible patients was 42 weeks; for stage IV patients it was 40 weeks. The
1-year survival rate was 40%, and that for stage IV patients was 32%.

The major toxicities observed in this trial were leukopenia,
diarrhea, nausea/vomiting, anemia, alopecia, and pneumonitis. Grade 4 leukopenia
occurred in 4 patients (6%), and grade 3 or 4 anemia was observed in 11 patients
(15%). Diarrhea occurred in 48 patients (67%). This toxic effect was so severe
that it was difficult to control in three patients. Nausea/vomiting was observed
in 56 patients (78%), but these reactions were controllable by anti-emetic
drugs. Pulmonary toxicity was noted in six patients (8%). Five of these patients
demonstrated a diffuse reticular nodular pattern upon chest x-ray, and one
showed an abnormality highly suggestive of interstitial infiltrates on computed
tomography of the chest;
five patients developed dyspnea on exertion and four developed fever.

Ages ranged from 56 to 74 years, with a median of 69 years for
the group exhibiting pulmonary toxicity. Five patients had no preexisting
pulmonary disease, but one had had a pulmonary fibrosis. The interval from the
beginning of irinotecan administration to the onset of pulmonary symptoms ranged
from 42 to 175 days, with a median of 61 days. The median total dose of
irinotecan in these patients was 750 mg/m2 (range: 400 to 1,000
mg/m2). Five of
six patients were treated with corticosteroids, and one died of respiratory
failure, while four improved; one patient resolved spontaneously within a week
(see Table 2).

Combinations of Irinotecan
With Cisplatin

The combination of irinotecan with cisplatin (Platinol) has been
comprehensively tested in dose-finding studies in patients with advanced lung
cancer. The rationale is multifold, including synergy between these two agents
in preclinical models, impressive cytotoxic activity when administered
individually against a wide range of tumors, and nonoverlapping principal
toxicities. Combinations of irinotecan and cisplatin have been investigated in
five phase I studies in Japan.

Irinotecan With a Fixed Dose of Cisplatin (80 mg/m2)

Masuda and colleagues[10] reported data from a dose-finding
study of irinotecan combined with a fixed dose of IV cisplatin at 80 mg/m2 on
day 1. The dose of irinotecan was increased, with a starting IV dose of 30 mg/m2
on days 1, 8, and 15; this regimen was repeated every 28 days. Twenty-seven
patients were entered into this trial, and all patients with advanced stage
III/IVB non-small-cell lung cancer had no previous therapy, had measurable
disease, and had a performance status of 0 to 2. These patients were treated at
doses of irinotecan from 30 to 70 mg/m2 (30, 40, 50, 60, and 70

Generally, remarkably little toxicity was observed at the first
three dose levels during the first course of therapy. At dose level 4, grade 3
or 4 leukopenia occurred in 3 of 10 patients. At dose level 5, which represented
a dose of 70 mg/m2 on days 1, 8, and 15, myelosuppression was more severe and
dose-limiting; two of six patients developed grade 3 leukopenia. Diarrhea did
not become a significant problem until dose level 5 was reached. At dose levels
1 to 4, grade 3 diarrhea was noted in only 2 of 58 courses. Diarrhea developed
more frequently at the highest dose level (70 mg/m2); two of six patients
experienced grade 4 diarrhea during the first course.

Of 26 assessable patients for response, there were no complete
responses, while 14 (54%) showed a partial response. The response rates were 67%
at dose level 2 (2 of 3), 80% at dose level 3 (4 of 5), 56% at dose level 4 (5
of 9), and 50% at dose level 5 (3 of 6). Based on these results, the authors
concluded that the major dose-limiting toxicities were leukopenia and diarrhea,
and the maximum tolerated dose of irinotecan was 70 mg/m2 IV on days 1, 8, and
15 plus 80 mg/m2 of cisplatin on day 1. The recommended dose for phase II
studies was irinotecan at 60 mg/m2 IV on days 1, 8, and 15 plus cisplatin at 80
mg/m2 on day 1, every 4 weeks (see Table


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