The New England Journal of Medicine



Original Article
Volume 346:85-91

January 10, 2002

Number 2
Irinotecan plus Cisplatin Compared with Etoposide plus Cisplatin for
Extensive Small-Cell Lung Cancer
Kazumasa Noda, M.D., Yutaka Nishiwaki, M.D., Masaaki Kawahara, M.D.,
Shunichi Negoro, M.D., Takahiko Sugiura, M.D., Akira Yokoyama, M.D.,
Masahiro Fukuoka, M.D., Kiyoshi Mori, M.D., Koshiro Watanabe, M.D., Tomohide
Tamura, M.D., Seiichiro Yamamoto, Ph.D., Nagahiro Saijo, M.D., for the Japan
Clinical Oncology Group
ABSTRACT
Background Irinotecan hydrochloride, a topoisomerase I inhibitor, is
effective against small-cell lung cancer. In a phase 2 study of irinotecan
plus cisplatin in patients with extensive small-cell lung cancer, there was
a high response rate and a promising median survival time.
Methods We conducted a multicenter, randomized, phase 3 study in which we
compared irinotecan plus cisplatin with etoposide plus cisplatin in patients
with extensive (metastatic) small-cell lung cancer.
Results The planned size of the study population was 230 patients, but
enrollment was terminated early because an interim analysis found a
statistically significant difference in survival between the patients
assigned to receive irinotecan and cisplatin and those assigned to receive
etoposide and cisplatin; as a result, only 154 patients were enrolled. The
median survival was 12.8 months in the irinotecan-plus-cisplatin group and
9.4 months in the etoposide-plus-cisplatin group (P=0.002 by the unadjusted
log-rank test). At two years, the proportion of patients surviving was 19.5
percent in the irinotecan-plus-cisplatin group and 5.2 percent in the
etoposide-plus-cisplatin group. Severe or life-threatening myelosuppression
was more frequent in the etoposide-plus-cisplatin group than in the
irinotecan-plus-cisplatin group, and severe or life-threatening diarrhea was
more frequent in the irinotecan-plus-cisplatin group than in the
etoposide-plus-cisplatin group.
Conclusions Irinotecan plus cisplatin is an effective treatment for
metastatic small-cell lung cancer.
  _____

The usual chemotherapy for extensive small-cell lung cancer is etoposide
plus cisplatin or this combination in alternation with a regimen of
cyclophosphamide, doxorubicin, and vincristine. 1
<http://content.nejm.org/cgi/content/full/346/2/#R1> , 2
<http://content.nejm.org/cgi/content/full/346/2/#R2> , 3
<http://content.nejm.org/cgi/content/full/346/2/#R3> , 4
<http://content.nejm.org/cgi/content/full/346/2/#R4>  In preliminary
studies, irinotecan hydrochloride, a topoisomerase I inhibitor, was
effective against small-cell lung cancer, 5
<http://content.nejm.org/cgi/content/full/346/2/#R5>  and a phase 2 study of
irinotecan plus cisplatin yielded a rate of complete response of 29 percent
and an overall response rate of 86 percent (median survival, 13.2 months) in
patients with extensive small-cell lung cancer. 6
<http://content.nejm.org/cgi/content/full/346/2/#R6>  For these reasons, we
conducted a randomized, phase 3 study to compare irinotecan plus cisplatin
with etoposide plus cisplatin in patients with extensive small-cell lung
cancer.
Methods
Patients
To be included in the study, patients had to have cytologically or
histologically confirmed small-cell lung cancer; extensive disease (defined
by distant metastasis, contralateral hilar-node metastasis, or both; those
with pleural effusion alone were excluded); no prior radiotherapy,
chemotherapy, or surgery; measurable lesions; an Eastern Cooperative
Oncology Group (ECOG) performance status of 0, 1, or 2; a life expectancy of
at least three months; an age of 70 years or less; and adequate organ
function. Staging of the tumor was based on the results of physical
examination, chest radiography, fiberoptic bronchoscopy with biopsy and
cytologic examination, computed tomography (CT) of the chest and the brain,
ultrasonography or CT of the abdomen, radionuclide bone scanning, bone
marrow aspiration or biopsy, and other tests as needed. Adequate organ
function (adequate function of the bone marrow, liver, and kidney) was
defined as indicated by a leukocyte count of at least 4000 per cubic
millimeter, a platelet count of at least 100,000 per cubic millimeter, a
hemoglobin level of at least 9.5 g per deciliter (5.9 mmol per liter),
aspartate aminotransferase and alanine aminotransferase levels no higher
than 100 IU per milliliter, a serum creatinine level no higher than 1.2 mg
per deciliter (106 µmol per liter), and a creatinine clearance of at least
60 ml per minute.
The exclusion criteria were infection, diarrhea, ileus, interstitial
pneumonitis, pulmonary fibrosis, uncontrolled diabetes mellitus, myocardial
infarction within the preceding three months, massive pleural or peritoneal
effusion, symptomatic brain metastases requiring whole-brain irradiation or
administration of corticosteroids, a paraneoplastic syndrome, an active
synchronous cancer, a metachronous cancer within three disease-free years,
and pregnancy or breast-feeding.
Treatment Assignment and Drug Administration
The patients were randomly assigned to receive either a combination of
irinotecan and cisplatin or a combination of etoposide and cisplatin by the
minimization method of balancing the groups according to the institution and
the patients' performance status. Randomization was performed at the Japan
Clinical Oncology Group (JCOG) data center according to the order in which
information on enrollments was received by telephone or fax. The regimen of
irinotecan and cisplatin consisted of four four-week cycles of 60 mg of
irinotecan per square meter of body-surface area on days 1, 8, and 15 and 60
mg of cisplatin per square meter on day 1. The regimen of etoposide and
cisplatin consisted of four three-week cycles of 100 mg of etoposide per
square meter on days 1, 2, and 3 and 80 mg of cisplatin per square meter on
day 1. Both regimens required hydration and administration of antiemetic
drugs. If the leukocyte count fell below 2000 per cubic millimeter or the
neutrophil count fell below 1000 per cubic millimeter, recombinant human
granulocyte colony-stimulating factor was administered until the leukocyte
or neutrophil count was restored. Because not all patients received the
planned dose intensity (due to toxicity), we considered the planned
intensity of cisplatin to be 15 mg and 26.7 mg per square meter per week in
the irinotecan-plus-cisplatin group and the etoposide-plus-cisplatin group,
respectively.
Dose Modifications and Modifications in the Treatment Schedule
Toxic effects were graded according to the JCOG Toxicity Criteria, 7
<http://content.nejm.org/cgi/content/full/346/2/#R7>  in which a grade of 1
indicates a mild effect, grade 2 a moderate effect, grade 3 a severe effect,
and grade 4 a life-threatening effect. Administration of irinotecan was
skipped on day 8 or 15 if the leukocyte count was 2000 per cubic millimeter
or less, if the platelet count was 50,000 per cubic millimeter or less, or
if there was diarrhea. Administration of subsequent cycles of irinotecan was
allowed when the leukocyte count reached at least 3500 per cubic millimeter,
the platelet count reached at least 100,000 per cubic millimeter, and the
diarrhea had subsided. The dose of irinotecan in subsequent cycles was
reduced by 10 mg per square meter from the planned dose if there were grade
4 hematologic toxic effects or if grade 2 or 3 diarrhea developed. Treatment
was discontinued in patients with grade 4 diarrhea.
Etoposide was discontinued if the leukocyte count was 3500 per cubic
millimeter or less, if the platelet count was 75,000 per cubic millimeter or
less, or if the serum creatinine level was 1.5 mg per deciliter (132.6 µmol
per liter) or higher. In patients with grade 4 hematologic toxic effects,
the doses of etoposide and cisplatin in subsequent cycles were reduced to 75
percent of the planned doses. In both study groups, the dose of cisplatin
was reduced to 75 percent of the planned dose in patients with grade 2 renal
toxic effects. Subsequent cycles of treatment were suspended entirely in
patients with grade 2 hepatic toxic effects until the results of
liver-function tests were normal. Treatment was terminated in patients with
renal toxic effects rated grade 3 or higher, pulmonary toxic effects rated
grade 2 or higher, or hepatic toxic effects rated grade 3 or higher.
A second randomization to evaluate subsequent thoracic radiotherapy as a
means of inhibiting local relapse was canceled because of an inadequate
number of eligible patients.
Evaluations
All the patients underwent weekly evaluations that included an assessment of
symptoms, a physical examination, chest radiography, a complete blood count,
blood-chemistry studies (including measurements of aspartate
aminotransferase and alanine aminotransferase, lactate dehydrogenase,
bilirubin, serum creatinine, blood urea nitrogen, total protein, serum
albumin, serum electrolytes, and calcium), and urinalysis. Tumor response
was evaluated according to World Health Organization criteria 8
<http://content.nejm.org/cgi/content/full/346/2/#R8>  and was assessed by
chest radiography or chest CT and by the same tests used initially to stage
the tumor. A complete response was defined as the disappearance of all
clinical and radiologic evidence of tumor for at least four weeks; a partial
response was defined as a decrease of 50 percent or more in the sum of the
products of the longest perpendicular diameters of all measurable lesions
for at least four weeks; and progressive disease was defined as an increase
of more than 25 percent in the sum of the products of the perpendicular
diameters of all measurable lesions or the appearance of new lesions. All
other circumstances were considered to indicate no change. All the observed
responses were reviewed by an extramural panel at regular study-group
meetings. A planned quality-of-life study 9
<http://content.nejm.org/cgi/content/full/346/2/#R9>  was terminated because
of poor compliance.
Study Design and Statistical Analysis
This trial was designed as a multicenter, prospective, randomized phase 3
study. The study protocol was approved by the Clinical Trial Review
Committee of JCOG and the institutional review board of each participating
institution before the initiation of the study, and all the patients
provided written informed consent before randomization in accordance with
the policies of JCOG in effect in 1995, when enrollment began. The primary
end point was overall survival, and the secondary end points were the rates
of complete and overall response, progression-free survival, sites of
relapse, and toxicity. The sample size initially planned was 230 patients
from 54 participating sites, with 115 patients in each group. The planned
duration of accrual was 3 years, and the planned follow-up time was 1.5
years. This sample size was designed to provide the study with 80 percent
power to detect an improvement of 9 months in the median survival of the
patients in the etoposide-plus-cisplatin group and an improvement of 13
months in the median survival of patients in the irinotecan-plus-cisplatin
group (hazard ratio, 0.69) with a one-sided type I error of 0.05.
All comparisons of patients' characteristics, prognostic variables, response
rates, and rates of toxic effects were performed with Fisher's exact test,
except for age, for which the t-test was used. Survival was measured as the
date of randomization to the date of death or the date of the most recent
follow-up. Progression-free survival was measured as the date of
randomization to the date of the first observation of disease progression or
the date of death from any cause if there had been no progression. If there
was no progression and if the patient had not died, data on progression-free
survival were censored as of the date that the absence of progression was
confirmed. If a patient died without information on progression, data on
progression-free survival were censored as of the last date on which
progression could be ruled out by review of follow-up forms. Survival curves
were calculated by the Kaplan–Meier method 10
<http://content.nejm.org/cgi/content/full/346/2/#R10>  and compared with use
of the log-rank test.
Two interim analyses were planned, with adjustment for multiple comparisons
taken into account by the method of Lan and DeMets. 11
<http://content.nejm.org/cgi/content/full/346/2/#R11>  The O'Brien–Fleming
type alpha spending function was used. The first interim analysis was
planned for the date on which half the planned number of patients had been
enrolled, and the second for the date on which all the patients had been
enrolled. The boundaries were calculated with the use of computer programs
provided by Reboussin et al. 12
<http://content.nejm.org/cgi/content/full/346/2/#R12>  The current study was
designed and conducted on the basis of one-sided testing, but the results
are presented with two-sided P values. Unadjusted P values are reported
because of the conservative spending function used.
All patient-information forms were collected and managed at the data center.
In-house interim monitoring was performed at the data center to ensure the
submission of data, the eligibility of the patients, compliance with the
protocol, safety, and progress of the study on schedule. The monitoring
reports were submitted to and reviewed by an independent monitoring
committee semiannually.
Results
Enrollment in the study began in November 1995. The first interim analysis,
performed in August 1998, suggested a difference in overall survival between
the two study groups; the monitoring committee therefore recommended that
the second interim analysis be performed earlier than planned. The second
analysis, performed in December 1998, found a significant difference in
overall survival between the two groups (P<0.001), and the monitoring
committee therefore recommended termination of the study. Enrollment was
discontinued and the study was terminated in January 1999.
Between November 1995 and November 1998, 154 patients were enrolled in the
study at 27 sites among the 54 institutions planned, with 77 randomly
assigned to receive irinotecan and cisplatin and 77 randomly assigned to
receive etoposide and cisplatin ( Table 1
<http://content.nejm.org/cgi/content/full/346/2/#T1> ). All the enrolled
patients were included in the analyses of survival, progression-free
survival, and tumor response. However, two patients in the
irinotecan-plus-cisplatin group were given no chemotherapy, one because of
rapid progression of disease and the other because of an acute gastric ulcer
that was diagnosed immediately after randomization. Both of these patients
were excluded from the analysis of toxicity. The average follow-up time was
16.8 months in the irinotecan-plus-cisplatin group and 11.7 months in the
etoposide-plus-cisplatin group. None of the patients were lost to follow-up.


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Table 1. Characteristics of the Patients.

Toxicity
Hematologic toxic effects are shown in Table 2
<http://content.nejm.org/cgi/content/full/346/2/#T2> . JCOG grade 3 or 4
leukopenia and neutropenia and grade 3 or 4 thrombocytopenia were more
frequent in the etoposide-plus-cisplatin group than in the
irinotecan-plus-cisplatin group. Grade 3 or 4 diarrhea occurred in 16.0
percent of the irinotecan-plus-cisplatin group and in none of the
etoposide-plus-cisplatin group (P<0.001). Grade 1 or 2 diarrhea was also
frequent in the irinotecan-plus-cisplatin group. The incidence of nausea and
vomiting and other nonhematologic toxic effects did not differ significantly
between the two groups.


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Table 2. Toxic Effects, According to Study Group and JCOG Grade of Toxicity.

Major deviations from the protocol were the failure to reduce the dose of
chemotherapy despite the presence of grade 4 neutropenia (in six patients in
the irinotecan-plus-cisplatin group and seven in the
etoposide-plus-cisplatin group), administration of irinotecan despite the
presence of grade 1 or 2 diarrhea (in nine patients in the
irinotecan-plus-cisplatin group), continuation of the study treatment
despite grade 2 or 3 pulmonary toxic effects (in three patients in the
irinotecan-plus-cisplatin group and six in the etoposide-plus-cisplatin
group), and continuation of the study treatment despite grade 3 hepatic
toxic effects (in one patient in the irinotecan-plus-cisplatin group and
three in the etoposide-plus-cisplatin group).
There were four treatment-related deaths, three in the
irinotecan-plus-cisplatin group and one in the etoposide-plus-cisplatin
group. In the irinotecan-plus-cisplatin group, a 63-year-old man died of
bleeding from a metastatic site in the lung, a 62-year-old man died of
sepsis associated with neutropenia and diarrhea, and a 64-year-old woman
died of pneumonia associated with neutropenia. In the
etoposide-plus-cisplatin group, a 69-year-old man died of radiation
pneumonitis after completion of subsequent thoracic radiotherapy.
Delivery of Treatment
There were no significant differences between the two groups in the delivery
of treatment ( Table 3
<http://content.nejm.org/cgi/content/full/346/2/#T3> ). The proportion of
patients who received the planned four cycles of chemotherapy was
approximately 70 percent in each group. More patients in the
etoposide-plus-cisplatin group (38 percent) than in the
irinotecan-plus-cisplatin group (29 percent) completed their assigned study
treatment with no modifications in the doses or delivery schedule. The dose
intensity (the actual dose delivered as a proportion of the planned dose)
was 80.4 percent for irinotecan and 95.3 percent for cisplatin in the group
assigned to receive irinotecan plus cisplatin and was 83.9 percent for
etoposide and 84.6 percent for cisplatin in the group assigned to receive
etoposide plus cisplatin. The actual intensity of the dose of cisplatin in
the etoposide-plus-cisplatin group was 1.58 times that in the
irinotecan-plus-cisplatin group (22.6 vs. 14.3 mg per square meter per week,
respectively).


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Table 3. Number of Cycles of Treatment and Actual Doses Delivered.

Rates of Response
The rate of complete response and the overall response rate were 2.6 percent
(95 percent confidence interval, 0.3 to 9.1 percent) and 84.4 percent (95
percent confidence interval, 74.4 to 91.7 percent), respectively, in the
irinotecan-plus-cisplatin group and 9.1 percent (95 percent confidence
interval, 3.7 to 17.8 percent) and 67.5 percent (95 percent confidence
interval, 55.9 to 77.8 percent), respectively, in the
etoposide-plus-cisplatin group ( Table 4
<http://content.nejm.org/cgi/content/full/346/2/#T4> ). The rate of overall
response in the irinotecan-plus-cisplatin group was significantly higher
than that in the etoposide-plus-cisplatin group (P=0.02).


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Table 4. Objective Tumor Response.

Overall Survival
As of March 2001, when the final analysis was conducted, the median overall
survival was 12.8 months (95 percent confidence interval, 11.7 to 15.2) in
the irinotecan-plus-cisplatin group and 9.4 months (95 percent confidence
interval, 8.1 to 10.8) in the etoposide-plus-cisplatin group; 70 patients in
the irinotecan-plus-cisplatin group and 74 in the etoposide-plus-cisplatin
group died (P=0.002 by the log-rank test) ( Figure 1
<http://content.nejm.org/cgi/content/full/346/2/#F1> ). The rate of overall
survival in the irinotecan-plus-cisplatin group was 58.4 percent (95 percent
confidence interval, 47.4 to 69.4 percent) at one year and 19.5 percent (95
percent confidence interval, 10.6 to 28.3 percent) at two years; in the
etoposide-plus-cisplatin group, the rates of overall survival at these time
points were 37.7 percent (95 percent confidence interval, 26.8 to 48.5
percent) and 5.2 percent (95 percent confidence interval, 0.2 to 10.2
percent). The risk of death in the irinotecan-plus-cisplatin group relative
to that in the etoposide-plus-cisplatin group was 0.60 (95 percent
confidence interval, 0.43 to 0.83). Similar results were obtained in
analyses that adjusted for age, sex, performance status, and weight loss and
in an analysis that excluded the 23 patients randomly assigned to the
radiotherapy portion of the study, which was canceled.


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Figure 1. Overall Survival of Patients with Extensive Small-Cell Lung Cancer
Who Were Assigned to Treatment with Irinotecan plus Cisplatin or Etoposide
plus Cisplatin.
The tick marks indicate patients whose data were censored.

Progression-free Survival
The median known progression-free survival was 6.9 months (95 percent
confidence interval, 6.1 to 7.3) in the irinotecan-plus-cisplatin group and
4.8 months (95 percent confidence interval, 4.3 to 5.5) in the
etoposide-plus-cisplatin group. The rate of known progression-free survival
in the irinotecan-plus-cisplatin group was 65.3 percent (95 percent
confidence interval, 54.3 to 76.3 percent) at six months and 12.5 percent
(95 percent confidence interval, 4.9 to 20.1 percent) at one year; in the
etoposide-plus-cisplatin group the rates of progression-free survival at
these time points were 35.6 percent (95 percent confidence interval, 24.8 to
46.3 percent) and 7.9 percent (95 percent confidence interval, 1.8 to 14.0
percent), respectively (P=0.003 by the log-rank test) ( Figure 2
<http://content.nejm.org/cgi/content/full/346/2/#F2> ). Progression was
known to have occurred in 68 patients in the irinotecan-plus-cisplatin group
and 75 patients in the etoposide-plus-cisplatin group. The relative risk of
disease progression in the irinotecan-plus-cisplatin group as compared with
that in the etoposide-plus-cisplatin group was 0.61 (95 percent confidence
interval, 0.44 to 0.84). The estimates of progression-free survival,
however, may be biased because information on progression was not monitored
continuously and because there were 10 instances of early censoring because
of death without data on progression (8 instances in the
irinotecan-plus-cisplatin group and 2 in the etoposide-plus-cisplatin
group).


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Figure 2. Progression-free Survival of Patients with Extensive Small-Cell
Lung Cancer Who Were Assigned to Treatment with Irinotecan plus Cisplatin or
Etoposide plus Cisplatin.
The tick marks indicate patients whose data were censored.

Discussion
The current standard chemotherapy for extensive small-cell lung cancer — a
regimen of etoposide and cisplatin or this combination alternating with a
combination of cyclophosphamide, doxorubicin, and vincristine — yields a
median survival of 8 to 10 months and a 2-year survival rate of 10 percent.
In this phase 3 study, 77 patients with metastatic small-cell lung cancer
who were treated with irinotecan plus cisplatin had a median survival of
12.8 months, whereas the group that received etoposide plus cisplatin had a
median survival of 9.4 months (P=0.002). The overall rates of survival in
these two groups at two years were 19.5 percent and 5.2 percent,
respectively.
Myelosuppression was the most frequent toxic effect in both groups and was
more frequent in the etoposide-plus-cisplatin group than in the
irinotecan-plus-cisplatin group. There was, however, a significantly higher
incidence of grade 3 or 4 diarrhea among the patients who received
irinotecan than among those who received etoposide.
The three treatment-related deaths in the irinotecan-plus-cisplatin group
occurred during the first or second cycle of treatment and were attributed
to hematologic toxic effects of the first cycle. Severe hematologic toxic
effects, as well as diarrhea, during the initial cycles of chemotherapy
should therefore be managed carefully. All cases of grade 1 to 4 diarrhea
occurred during the first and second cycles of irinotecan-plus-cisplatin
treatment, but early suspension of treatment prevented death associated with
diarrhea in all but one case, which involved a protocol violation in which
the patient was given irinotecan on day 8 of the first cycle despite the
presence of grade 1 diarrhea. We administered loperamide hydrochloride or a
Chinese herbal drug such as hange-shashin-to to ameliorate the diarrhea at
the discretion of the attending physicians.
The proportion of patients who received all four cycles of chemotherapy was
similar in the two groups (approximately 70 percent), and thus the observed
difference in survival is not thought to be attributable to a difference in
the actual delivery of treatment.
Our study had several weaknesses. The planned second randomization to allow
us to assess the benefit of subsequent thoracic radiotherapy was not
completed; the planned quality-of-life study was not completed; and full
information concerning treatment after disease progression was not
available. The estimates of overall survival, however, should be highly
reliable because, as of March 2001 (the final analysis), no patient had been
lost to follow-up.
We consider that the trend toward a higher complete-response rate in the
etoposide-plus-cisplatin group than in the irinotecan-plus-cisplatin group
is due to chance. Although it is possible that these results occurred by
chance, we believe that the decision to terminate the trial early was based
on generally accepted scientific and ethical principles and that, despite
the small sample size, we can conclude that the combination of irinotecan
and cisplatin is an attractive option for patients with metastatic
small-cell lung cancer who have a good performance status.
Supported in part by grants-in-aid for cancer research and for the
Second-Term Comprehensive 10-Year Strategy for Cancer Control from the
Ministry of Health, Labor, and Welfare (Tokyo).
We are indebted to Ms. M. Imai and Ms. M. Niimi for data management; to Dr.
K. Yoshimura for analyses during periodic interim monitoring; and to Dr. H.
Fukuda for direction of the JCOG data center and oversight of management of
the study.
* Other participating institutions and investigators are listed in the
Appendix. <http://content.nejm.org/cgi/content/full/346/2/#RFN1>

Source Information
From Kanagawa Cancer Center, Yokohama (K.N.); National Cancer Center
Hospital East, Chiba (Y.N.); National Kinki Central Hospital for Chest
Diseases, Osaka (M.K.); Osaka City General Hospital, Osaka (S.N.); Aichi
Cancer Center, Nagoya (T.S.); Niigata Cancer Center Hospital, Niigata
(A.Y.); Kinki University School of Medicine, Osaka (M.F.); Tochigi Cancer
Center, Tochigi (K.M.); Yokohama Municipal Citizen's Hospital, Yokohama
(K.W.); National Cancer Center Central Hospital, Tokyo (T.T., N.S.); and the
Cancer Information and Epidemiology Division, National Cancer Center
Research Institute, Tokyo (S.Y.) — all in Japan.
Address reprint requests to Dr. Saijo at the National Cancer Center, Tsukiji
5-1-1, Chuo-ku, Tokyo 104-0045, Japan, or at [log in to unmask]
<mailto:[log in to unmask]> .
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Appendix
This study was coordinated by the Japan Clinical Oncology Group (M.
Shimoyama, former chairperson) and was performed with the cooperation of the
following institutions and investigators: National Dohoku Hospital, Hokkaido
(T. Fujikane, K. Takahashi, and Y. Yamazaki); Hokkaido Keiaikai
Minami-ichijo Hospital, Hokkaido (A. Fujita); Asahikawa Medical College
Hospital, Hokkaido (Y. Osaki and Y. Nishizaki); Yamagata Prefectural Central
Hospital, Yamagata (T. Tsukamoto); Tsukuba University Hospital, Ibaragi (S.
Hasegawa and M. Tajima); Tochigi Cancer Center, Tochigi (T. Hirose, S.
Machida, and M. Noda); National Nishi-Gunma Hospital, Gunma (S. Tsuchiya and
H. Nakano); Saitama Cancer Center, Saitama (S. Yoneda, H. Sakai, T. Ikeda,
and K. Kobayashi); National Cancer Center Hospital East, Chiba (F. Houjo, R.
Kakinuma, Y. Ohe, T. Matsumoto, H. Ohmatsu, K. Kodama, E. Moriyama, and Y.
Hosomi); National Cancer Center Central Hospital, Tokyo (T. Shinkai, H.
Kunitoh, K. Kubota, and I. Sekine); International Medical Center of Japan,
Tokyo (K. Kudo and Y. Takeda); Kanagawa Cancer Center, Yokohama (I. Nomura,
K. Yamada, F. Oshita, Y. Kato, and M. Kondo); Yokohama Municipal Citizen's
Hospital, Yokohama (H. Kunikane and A. Nagatomo); Niigata Cancer Center
Hospital, Niigata (H. Tsukada, S. Mitsuma, and Y. Ichikawa); Aichi Cancer
Center, Nagoya (K. Yoshida and T. Hida); National Nagoya Hospital, Nagoya
(K. Nishiwaki and M. Hiraiwa); National Kinki Central Hospital for Chest
Diseases, Osaka (M. Ogawara, T. Tsuchiyama, N. Kodama, K. Moriya, K.
Okishio, N. Naka, S. Nobuyama, and S. Yamamoto); Kinki University School of
Medicine, Osaka (N. Yamamoto, K. Nakagawa, T. Nogami, Y. Ieda, and M.
Yoshida); Osaka Prefectural Habikino Hospital, Osaka (I. Kawase, N. Masuda,
T. Nitta, and M. Kobayashi); Osaka City General Hospital, Osaka (K. Takeda,
N. Yoshimura, H. Uejima, N. Nishikubo, T. Nitta, N. Takifuji, R. Miyaguchi,
and K. Sugioka); National Toneyama Hospital for Chest Diseases, Osaka (H.
Nishikawa and K. Shinkawa); Hyogo Medical Center for Adults, Hyogo (Y.
Takada and T. Kadoh); Hyogo Medical College, Hyogo (K. Higashino and A.
Tonomura); Wakayama Rohsai Hospital, Wakayama (T. Hoso and H. Minakada);
Sasebo Municipal General Hospital, Nagasaki (J. Araki, K. Yamaguchi, and K.
Ohba); Kumamoto Chuo Hospital, Kumamoto (T. Kiyama and Y. Yoshioka); and
Kumamoto Regional General Hospital, Kumamoto (H. Senba and T. Seto).


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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.