Full text of DOI:10.1016/S0169-5002(02)00304-5

Lung Cancer 38 (2002) 303Á308
/
www.elsevier.com/locate/lungcan
Phase II study of irinotecan and carboplatin for advanced non-small
cell lung cancer
Koji Takeda *, Nobuhide Takifuji, Hisao Uejima, Naruo Yoshimura,
Kazuhiko Terakawa, Shunichi Negoro
Department of Clinical Oncology and Pulmonary Medicine, Osaka City General Hospital, 2-13-22 Miyakojimahondohri, Miyakojima-ku, 534-0021,
Osaka, Japan
Received 2 April 2002; received in revised form 19 July 2002; accepted 14 August 2002
Abstract
A phase II study was conducted to assess the activity and toxicity of irinotecan (CPT-11) and carboplatin (CBDCA) combination
chemotherapy for advanced non-small-cell lung cancer (NSCLC). Eligibility included chemo-naive advanced NSCLC patients with
measurable disease and a good performance status. CPT-11 of 50 mg/m2 was administered as a 90-min intravenous infusion on days
1, 8, and 15. CBDCA dosed to an area under the concentration-time curve of 5 mg min/ml, using Calvert’s formula, was
administered by 90-min infusion after the CPT-11 infusion on day 1. Treatment was repeated 28 days interval for at least two cycles.
Haematopoietic growth factors were not routinely used. From December 1997 to January 1999, 36 patients were entered into the
study. The overall response rate was 25.0% (95% confidence interval: 12.1Á
rate were 10.2 months and 42.2%, respectively. Major toxicity by Japan Clinical Oncology Group criteria was as follows: grade 3Á
neutropenia 76.5%; grade 3 anemia 26.5%; grade 3/4 thrombocytopenia 47.1%; grade 3 nausea/vomiting 36.1%; grade 3Á4 diarrhoea
5.9%; grade 3 alopecia 5.9%; grade 3Á4 skin rush 2.9%. Four patients developed febrile neutropenia and only one had serious
/
42.2%). The median survival time and the 1-year survival
/4
/
/
diarrhea induced by CPT-11. Actual relative delivery dose of CPT-11 to the projected one on days 8 and 15 were 0.86 and 0.43,
respectively. It seemed that CPT-11 and CBDCA was more toxic regimen than CPT-11 and CDDP in advanced NSCLC. The
relatively disappointing response rate could be related with low dose intensity of CPT-11.
# 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Phase II study; Irinotecan; Carboplatin; Non-small-cell lung cancer; Chemotherapy
1. Introduction
Carboplatin (CBDCA) is an analogue of cisplatin
(CDDP), but produces less nonhematologic toxicity. It
is active against NSCLC and its DLTs are thrombocy-
topenia and leukopenia. The area under the plasma
concentration versus the time curve (AUC) of CBDCA
correlates well with the degree of myelosuppression,
especially thrombocytopenia and with the response rates
of patients with ovarian carcinoma. CBDCA is a unique
antineoplastic agent, for which the desired AUC can be
controlled on the basis of individual renal function.
AUC-based dosing of CBDCA is a reasonable strategy
for ensuring constant drug exposure, reducing the risk
of unnecessary toxicity, and possibly improving the
response rate [5].
The recent development of new drugs for the treat-
ment of non-small-cell lung cancer (NSCLC) has made
several systemic chemotherapy regimens available for
this disease [1].
Irinotecan (CPT-11), a new derivative of camptothe-
cin, has been found to have clinical activity against
various tumors, including small cell lung cancer (SCLC)
[2], and NSCLC [3]. Its major active metabolite, 7-ethyl-
10-hydroxycamptothecin (SN-38), is also active against
these tumors [4]. The dose-limiting toxicities (DLTs) of
CPT-11 are diarrhea and leukopenia [2,3].
Furthermore, CBDCA shows no cross-resistance with
CPT-11 [6], and a synergistic effect has been observed
with combined CBDCA and CPT-11 in a preclinical
* Corresponding author. Tel.: ꢀ
1091
E-mail address: kkk-take@ga2.so-net.ne.jp (K. Takeda).
/
81-6-6929-1221; fax: ꢀ81-6-6929-
/
0169-5002/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 1 6 9 - 5 0 0 2 ( 0 2 ) 0 0 3 0 4 - 5

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K. Takeda et al. / Lung Cancer 38 (2002) 303Á308
/
study [7,8]. When compared with other chemotherapy
regimens by a cooperative group study, CBDCA was
associated with modest improvement in the 1-year
survival rate of patients with advanced NSCLC [9].
Therefore, we conducted a dose escalation study of
CPT-11 combined with fixed dose of CBDCA (target
AUC; 5 mg min/ml) for advanced NSCLC [10]. The
maximum tolerated dose of CPT-11 with this regimen
was 60 mg/m2, while 50 mg/m2 could be recommended
for future use. The overall response rate of 35.3% and
the median survival time of 10.5 months were encoura-
ging.
serum electrolytes, blood urea nitrogen (BUN), creati-
nine, total protein, albumin, calcium, phosphate, uric
acid, alkaline phosphatase, total bilirubin, AST, and
ALT.
2.2. Treatment schedule
CPT-11 of 50 mg/m2 was administered as a 90-min
intravenous infusion on days 1, 8, 15. CBDCA was
administered by 90-min infusion after the CPT-11
infusion on day 1, with the dose targeted to a specific
AUC as described by Calvert et al. [5]. The dose was
determined by multiplying the targeted AUC by the sum
of the glomerular filtration rate (GFR) plus 25. The 24-h
creatinine clearance was substituted for GFR. The
target AUC of CBDCA was fixed 5 mg min/ml in this
study. This dose definition was leaded by our previous
phase I study of CPT-11 and CBDCA [10]. The regimen
was repeated every 28 days for at least 2 cycles.
The objective of this phase II study was to assess the
response and toxicity of combination chemotherapy of
CPT-11 and CDBCA in patients with advanced
NSCLC.
2. Patients and methods
CPT-11 was withdrawn if the leukocyte count was less
than 3000/ml, the platelet count was less than 100 000/ml,
or diarrhea Grade 1 or higher occurred on days 8 and
15. This withdrawn criterion was amended according to
the guideline from the Ministry of Public Welfare at that
time. In our previous phase I study, CPT-11 was
withdrawn if the leukocyte count was less than 2000/
ml, the platelet count was less than 70 000/ml, or diarrhea
Grade 2 or higher occurred on days 8 and 15 [10].
For CPT-11-induced diarrhea, high dose loperamide
treatment, as described by Abigerges et al. [12], was
administered.
2.1. Patients’ selection
Patients with histologically or cytologically documen-
ted, TNM stage IIIB or IV NSCLC according to the
criteria reported by Mountain [11] were enrolled in this
study. However, patients who had received previous
chemotherapy were excluded. Patients who had experi-
enced postoperative recurrence and those who had
received radiotherapy to metastatic sites were eligible
for the current study. A complete history and physical
examination were performed in all patients. The nature
and purpose of the study were fully explained to each
patient. All patients signed an informed consent ap-
proved by the institutional review boards of Osaka City
General Hospital.
Subsequent courses of chemotherapy were initiated
when the leukocyte and platelet counts were E
/
4000 /ml
and E100 000 /ml after day 28, respectively. If the
/
leukocyte or platelet counts had not returned normal
levels or diarrhea had not disappeared by day 1 of the
next course of chemotherapy, both drugs were withheld
until full recovery. If more than 8 weeks passed from the
time of the last treatment before these criteria were
satisfied, the patient was removed from the study.
Dose adjustments were made for both CBDCA and
CPT-11 based on toxicity. Patients who experienced
grade 4 leukopenia or grade 3 or higher diarrhea had
their CPT-11 dose reduced by 10 mg/m2 for the
subsequent cycle. Patients who experienced thrombocy-
topenia grade 4 had their target AUC of CBDCA
reduced by 1 mg min/ml for the subsequent cycle.
Haematopoietic growth factors were not administered
routinely, but were used as needed according to
published guidelines [13].
Patients were required to have measurable or asses-
sable disease, an Eastern Cooperative Oncology Group
(ECOG) performance status (PS) 0Á
/
2, an age B75
/
years, and no active concomitant malignancy. Measur-
able or assessable disease meant that the tumor was
demonstrated by conventional chest roentgenograms or
computed tomography (CT) of the whole body. In
addition, all patients underwent a routine staging
evaluation that consisted of standard radiological stu-
dies (including CT of the abdomen and brain) as well as
bone scanning.
Eligibility requirements also included the following:
white blood cell (WBC) countE
countE100 000/ml, hemoglobinE9.5 g/dl, serum
bilirubinB1.5 mg/dl, serum AST/ALT0twice the
upper limit of normal, creatinine clearanceE40 ml/
/
4000/ml, platelet
/
/
/
/
/
min. Patients with massive pleural effusion or ascitis
were excluded from this study.
2.3. Evaluation of efficacy and toxicity
Height, weight, PS, and tumor stage were recorded.
Initial laboratory data obtained included a complete
blood count, differential WBC count, platelet count,
For the assessment of response and toxicity, the
following tests were done once a week during treatment:
complete blood count, AST, ALT, alkaline phospha-

K. Takeda et al. / Lung Cancer 38 (2002) 303Á
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305
tase, lactate dehydrogenase, bilirubin, creatinine, BUN,
serum electrolytes, urinalysis, and chest X-ray film.
WHO response criteria [14] were used for efficacy
analysis; responses were assessed in alternate therapy
cycles with CT scan or radiologic and ultrasound
evaluation of the lesions.
Toxicity was evaluated in accordance with Japan
Cooperative Oncology Group (JCOG) toxicity criteria
[15].
Thirty-two (88.9%) had an ECOG PS of 0 or 1. Two
patient (5.6%) was in TNM stage IIIA, 7 (19.4%) had
stage IIIB, and 27 (75.0%) had stage IV disease at the
enrollment. Twenty-two patients (61.1%) had no prior
therapy, and 14 had prior therapy including lobectomy
for primary lesion, whole brain irradiation, gamma
knife, or craniotomy for brain metastasis, and chest
radiotherapy for residual mediastinum lymph node after
surgery.
Survival was calculated on the basis of the period
from the start of treatment to death or the last follow-up
evaluation. Survival curves were drawn using the
3.2. Drug delivery
KaplanÁMeier method [16].
/
A total of 78 cycles of CPT-11 and CBDCA were
administered. The median number of cycles received was
This phase II study was conducted using a two-stage
design [17]. Twenty patients were to be treated, if two or
fewer responses were observed, accrual would terminate.
This would ensure, with 95% confidence interval (CI),
two (range 1Á/4), with a median cycle interval of 34 days
(range 28Á50). Cycle delays were almost due to prolon-
/
gation of neutropenia. Nine (25%) of 36 patients were
given at only first cycle for the following reasons: tumor
that the combination had a response rate B30%.
/
progression (nꢁ
/
5), severe toxicity (nꢁ3), and patient
/
refusal (nꢁ1). Four patients were adjusted the doses of
/
CPT-11 and CBDCA over the subsequent cycle accord-
ing to the previous described criteria. An actual
delivered dose of CPT-11 compared to the projected
one was shown in Fig. 1.
3. Results
3.1. Patients characteristics
In 27 patients treated with two or more cycles, the
achieved dose intensity compared to the projected one of
CPT-11 and CBDCA were 26.5 mg/m2/wk and 1.1
mg min/ml/wk, respectively, considering both the dose
adjustment and the treatment interval. Furthermore, the
achieved dose intensity of CPT-11 and CBDCA were
0.71 and 0.89, respectively.
From December 1997 to January 1999, 36 patients
were entered into this study. The main clinical char-
acteristics of the 36 eligible patients are listed in Table 1.
Table 1
Patients characteristics
No. of patients entered
Eligible
Male/female
36
36
(100%)
3.3. Toxicity
26/10
Age (year)
Median
Range
The major toxicity was myelosuppression (Table 2). A
dose reduction was required in four and two patients at
the second and third cycles, respectively. Recombinant
human granulocyte colony-stimulating factor (rhG-
CSF) support was used in seven treatment cycles
(9.0%). The median number of days required rhG-CSF
66
42Á74
/
Performance Status (ECOG)
0
1
2
9
23
4
(25.0%)
(63.9%)
(11.1%)
Histology
support was seven (range, 3Á13). Four patients occurred
with grade 3 or 4 febrile neutropenia were given
/
Adenocarcinoma
Squamous cell carcinoma
Unclassified carcinoma
20
14
2
(55.6%)
(38.9%)
(5.6%)
Stage
IIIA
IIIB
IV
2
7
(5.6%)
(19.4%)
(75.0%)
27
Prior therapy
No
Yes
22
14
(61.1%)
(38.9%)
Surgery alone
7
1
5
1
Chest radiotherapy after surgery
Gamma knife or WBI
Craniotomy
ECOG; Eastern Cooperating Oncology Group, WBI; whole brain
irradiation.
Fig. 1. Relative dose intensity of CPT-11 on days 1, 8, and 15. Relative
dose of CPT-11ꢁactual delivered CPT-11/projected dose of CPT-11.
/

306
K. Takeda et al. / Lung Cancer 38 (2002) 303Á308
/
Table 2
Major toxicity in 36 eligible patients
JCOG grade
1
2
3
4
3Á/4(%)
Neutropenia
Thrombocytopenia
Leukopenia
Anemia
5
6
4
8
4
7
12 14*
76.5
47.1
44.1
26.5
8.8
5.9
5.9
2.9
2.9
0
8
8
1
15 14
15
9
3
1
2
1
0
0
0
Á
Á/
/
Nausea/vomiting
Diarrhoea
15 10
10
11
2
3
5
2
2
1
2
1
Alopecia
Skin rash
Á/
0
Constipation
Creatinine
AST/ALT
1
1
0
0
2
Fig. 2. KaplanÁMeier curve for time to death.
/
4
0
* Including 4 febrile neutropenia.
either alone or in combination with CDDP, versus
vindesine (VDS) and CDDP, the reference arm, was
conducted [18]. A total of 385 evaluable patients
enrolled, 246 of who had stage IV disease. Patients
were randomized to one of three arms: (1) VDS at 3 mg/
m2 days 1, 8, and 15 and CDDP at 80 mg/m2 day 1 every
4 weeks; (2) CPT-11 at 60 mg/m2 days 1, 8, and 15 and
CDDP 80 mg/m2 day 1 every 4 weeks; or (3) CPT-11 at
100 mg/m2 days 1, 8, and 15 every 4 weeks. Overall
response rate were observed in 32, 44 and 21% of
patients for VDS and CDDP, CPT-11 and CDDP, and
CPT-11 alone arm, 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, when the subset of stage IV patients was
analyzed separately, the survival advantage for CPT-11
and CDDP was significant; the median survival time
was 50 weeks for patients receiving CPT-11 and CDDP,
36.4 weeks for VDS and CDDP, and 42.1 weeks for
antibiotics intravenously, and two of them were also
required rhG-CSF support. All of them had recovered
until 4 days. Grade 3 anemia occurred in nine patients
(26.5%), and 4 patients required a total of 24 units of
packed RBCs. Grade 4 thrombocytopenia was devel-
oped in eight patients, and nine patients, including one
of grade 3 thrombocytopenia, required a total 200 units
of platelet transfusions. There was no episode of
bleeding tendency.
Nonhaematological toxicities were generally modest.
However, diarrhea induced CPT-11 was sometimes
serious. One patient developed grade 4 diarrhea with
grade 4 neutropenia and infections, and subsequently
ileus of grade 4 was documented. These series were very
serious and life-threatening toxicities. Another patient
developed a temporary grade 3 diarrhea. No treatment
related death had been experienced in this study.
3.4. Response and survival
CPT-11 alone (Pꢁ
/
0.004 for CPT-11 and CDDP arm vs
VDS and CDDP; Pꢁ
/
0.018 for CPT-11 vs VDS and
Among 36 eligible patients, there were no complete
and 9 partial responses, for an overall response rate of
CDDP). This established CPT-11, along with vinorel-
bine [19] and paclitaxel [20], as one of three ‘new’ drugs,
which, in combination with CDDP, has proven superior
to ‘standard’ older CDDP combinations. However, a
separate phase III study comparing CPT-11 and CDDP
to VDS and CDDP in 210 patients with advanced
NSCLC failed to show a survival difference [21].
Recently reported from the JCOG, CPT-11 plus
CDDP is more effective treatment than etoposide plus
CDDP for extensive SCLC [22].
25.0% (95%CI, 12.1Á42.2%). Nineteen patients experi-
/
enced stable disease, and 8 had progressive disease.
Seven responses were apparent after the first cycle, and
two responses were the initial two cycles of therapy.
With a minimum follow-up duration of 26 months,
the median survival time is 10.2 months and 1- and 2-
year survival rate are 42.2 and 20.5%, respectively. The
survival curve was shown in Fig. 2.
Among the numerous drugs evaluated over the 10
years, only CBDCA has achieved similar survival
prolongation as a single agent in advanced NSCLC
[9]. These findings, coupled with the excellent toxicity
profile of CPT-11 and CBDCA in combination,
prompted us investigated this regimen in advanced
NSCLC.
4. Discussion
Over the past few years, a number of new drugs have
been shown to posses good activity against NSCLC,
including paclitaxel, docetaxel, vinorelbine, gemcita-
bine, and CPT-11. CPT-11 combined with CDDP has
been defined to be one of the most aggressive regimens
against NSCLC. In Japan, a phase III trial of CPT-11,
Our previous dose escalation study of CPT-11 com-
bined with fixed dose of CBDCA (target AUC; 5

K. Takeda et al. / Lung Cancer 38 (2002) 303Á
/308
307
mg min/ml) for advanced NSCLC was conducted. The
maximum tolerated dose of CPT-11 was 60 mg/m2,
while 50 mg/m2 could be recommended for this phase II
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