Twenty-Five Years of Clinical Research for Patients
with Limited-Stage Small Cell Lung Carcinoma in
Meaningful Improvements in Survival
Pasi A. Ja ¨nne, M.D., Ph.D.1
Boris Freidlin, Ph.D.2
Scott Saxman, M.D.3
David H. Johnson, M.D.4
Robert B. Livingston, M.D.5
Frances A. Shepherd, M.D.6
Bruce E. Johnson, M.D.1
1Lowe Center for Thoracic Oncology, Department
of Adult Oncology, Dana Farber Cancer Institute,
Department of Medicine, Brigham and Women’s
Hospital and Harvard Medical School, Boston,
2Biometric Research Branch, National Institutes of
Health, Bethesda, Maryland.
3Clinical Investigations Branch, National Cancer
Institute, Bethesda, Maryland.
4Vanderbilt University Medical School, Nashville,
5University of Washington, Seattle, Washington.
6Princess Margaret Hospital, Toronto, Canada.
Presented in part at the 9th Annual Meeting of the
International Association for the Study of Lung
Cancer, Tokyo, Japan, September 11–15, 2000,
and in final form at the 37th Annual Meeting of the
American Society of Clinical Oncology, San Fran-
cisco, California, May 12–15, 2001.
Address for reprints: Bruce E. Johnson, M.D., Lowe
Center for Thoracic Oncology, Dana Farber Cancer
Institute, D1234, 44 Binney St., Boston, MA
02115; Fax: 617-632-5786; E-mail: bejohnson@
Received April 8, 2002; accepted April 25, 2002.
BACKGROUND. To determine the changes in clinical trials and outcomes of patients
with limited-stage small cell lung carcinoma (SCLC) treated on Phase III random-
ized trials initiated in North America between 1972 and1992.
METHODS. Phase III trials from 1972 to 1992 for patients with limited-stage SCLC
were identified. Patients with limited-stage SCLC treated during a similar time
interval were also evaluated in the Surveillance, Epidemiology, and End Results
(SEER) database. Trends were tested in the number of trials, in the number and
gender of patients entered on trial, and in survival duration over time.
RESULTS. Thirty trials involving 6564 patients were eligible for analyses. Nineteen
trials (61%) involving 3626 patients were initiated within the first half of this time
period (1972–1981). The median of median survival times of all patients treated on
the control arms of the Phase III trials initiated between 1972 and 1981 and
between 1982 and 1992 were 12.0 months (range, 10–16 months) and 17.0 months
(range, 11–20 months), respectively (P ? 0.001). Of 26 studies available for survival
analysis, 5 (19%) showed a statistically significant survival prolongation in the
experimental arm compared with the control arm with a median prolongation of
3.4 months (range, 1–5.2 months). All five evaluated some aspect of thoracic
radiation therapy. Over a similar time period, there was a 6.4-month increase in the
median survival of limited-stage SCLC patients listed in the SEER database (P
? 0.0001) and a more than doubling of the 5-year survival from 5.2% to 12.1% (P
CONCLUSIONS. Analyses of the patients with limited-stage SCLC treated on Phase
III trials in North America initiated between 1972 and 1992 and those listed in the
SEER database show significant improvements in median survivals. Furthermore,
the 5-year survival of patients with limited-stage SCLC listed in the SEER database
has more than doubled over the last 25 years. Further research will be needed to
determine the relative contribution of improved therapy, supportive care, and
stage migration to this prolongation in survival. Cancer 2002;95:1528–38.
© 2002 American Cancer Society.
KEYWORDS: lung neoplasm, small cell lung carcinoma, limited stage, randomized.
tients with limited-stage small cell lung carcinoma (SCLC).1,2The
therapeutic approach for patients with early-stage SCLC has evolved
from attempts at surgical resection in the 1960s,3to thoracic radiation
therapy in the 1970s,4to chemotherapy plus thoracic radiation in the
ombined modality therapy using combination chemotherapy and
thoracic radiation therapy is now the standard therapy for pa-
© 2002 American Cancer Society
1980s and 1990s.1The combined modality regimens
have evolved from 1–2 years of cyclophosphamide-
based therapy5,6to four to six cycles of etoposide and
cisplatin administered concurrently with early chest
radiotherapy.2This treatment regimen for patients
meeting protocol entry criteria is partially successful
because 25% of patients are alive and free of cancer 5
years after starting treatment. However, most patients
with limited-stage SCLC treated with currently avail-
able treatments still die.
The outcome of patients with extensive-stage
SCLC has improved considerablyin the past 25 years.7
Analyses of patients with extensive-stage SCLC treated
on randomized Phase III trials in North America and
patients identified and followed in the Surveillance,
Epidemiology, and End Results (SEER) database re-
vealed that the median of median survivals for both
groups of patients had increased by 2 months between
1972 and 1990.7Furthermore, the 5-year survival rate
of patients with extensive-stage SCLC followed in the
SEER database has modestly increased from 0.8% for
those treated between 1973 and 1974 to 1.6% for pa-
tients treated between 1989 and 1990.
The majority of patients with SCLC have exten-
sive-stage disease and the modest increase in survival
for patients with extensive-stage disease is encourag-
ing. The increase in survival for patients with limited-
stage disease is potentially much more important be-
cause it improves their chance for a cure. There are
2–10-fold more 5-year survivors of limited-stage SCLC
SCLC.8–11Potential survival gains observed in Phase II
studies for patients with limited-stage SCLC may be
much more important for increasing the number of
patients who are alive and free of SCLC at 5 years.
Therefore, we decided to perform analyses similar to
Chute et al.7and Chen et al.12for patients with limit-
ed-stage SCLC treated on Phase II and Phase III trials
in North America during the past 25 years. We also
assessed the outcomes of patients with limited-stage
SCLC who were not treated as part of a clinical trial
during the last 25 years using the population-based
SEER database. This is not meant to be a review study
of SCLC but an analysis of outcomes of patients with
limited-stage SCLC treated on cooperative group
Phase III clinical trials and in a population-based reg-
istry. Whenever possible, we evaluated the pilot and
Phase II studies that were used in subsequent Phase III
studies to generate a statistical model that would be
used to determine the success of Phase II and pilot
studies when taken into a Phase III trial setting.12We
incorporated the Phase II studies into this study be-
cause there are not enough Phase II studies to warrant
a separate study.
MATERIALS AND METHODS
Phase III Trials
Phase III trials initiated for patients with limited-stage
SCLC were identified through a search of the National
Cancer Institute Cancer Therapy Evaluation Program
database from 1972 to 1992, by a computer-based
search of MEDLINE (using the keywords “lung neo-
plasm,” “carcinoma, small cell,” “limited stage,” “ran-
domized” and “phase III”), and by direct contact with
the leaders of the cooperative groups (Cancer and
Leukemia Group B, Eastern Cooperative Oncology
Group,Southeastern Oncology Group, North Central
Cancer Treatment Group [NCCTG], Southwest Oncol-
ogy Group, and the National Cancer Institute of Can-
ada Clinical Trials Group). We evaluated the random-
ized trials initiated between 1972 and 1992 and
completed by 1996 because this time period allowed
adequate time for patient enrollment into a study,
follow-up, and publication of the results of the thera-
peutic trials. Only trials that were published either in
full form or reported as a published abstract were
considered for this analysis. Trials were ineligible for
analysis if they had fewer than 20 patients per treat-
ment arm, did not separate information for limited-
stage patients, or had prophylactic cranial irradiation
(PCI) as the only study variable because the results of
PCI have been reported as a metaanalysis.13
The lung carcinoma committee chairs from each
cooperative group in North America were contacted to
inform them of this analysis and to determine whether
additional trials had been performed that were not
known to the authors. Investigators from NCCTG de-
clined to participate in this study by not providing
missing data. Information obtained from each trial
and the methods used to compute the median of
median survival times were identical to our previously
published reports.7,14Of 30 Phase III trials, 4 (13%)
published articles did not have all of this information
available. In these cases, the chairperson of the coop-
erative group or the author of the study was contacted
and additional data were obtained if available and the
author permitted its use. In studies where the median
survival was not stated in the publication, we esti-
mated the median survival from enlargements of the
figures in the published article.
The SEER database was also evaluated to compare
the median and 5-year survival information for all
patients with SCLC and for patients with limited-stage
SCLC versus with our analysis of patients treated on
Phase III trials over the same time period. The time
period between 1974 and 1996 was evaluated because
the starting year corresponded most closely with the
start of the cooperative group studies and 1996 corre-
Survival Improvements in Small Cell Lung Carcinoma/Ja ¨nne et al.1529
North American Phase III Trials of Limited-Stage Small Cell Lung Carcinoma
First author Study yrs
C ? TI ?/?PCI 3 ?/?C (maint)
CM ? TI ?/?PCI 3 ?/?CM (maint)
CMV ?TI ?/?PCI 3 ?/?CMV (maint)
CM(HD)V ? TI ?/?PCI 3 ?/? CM (HD) V (maint)
TI ?PCI ?CC1
V1OCA ? 8 ?TI
V1OCAP ? 8 ?TI
COMF ? 2 ?TI ?PCI 3 AC/COMF (maint)
CHO ? 2 ?TI ?PCI 3 COMF/AC (maint)
COMF ? 2? BCG ?TI ?PCI 3 COMF/AC (maint)
CHO ? 2? BCG ?TI ?PCI 3 AC/COMF (maint)
TI ?PCI 3 CAD ? 8 (if progression)
CAD ? 2 3 TI ?PCI 3 CAD ? 8
CAE 3 ?/? PCI
CAE 3 COMP1/CAE 3 ?/?PCI
P1OCC1? 2 3 TI ? PCI 3 P1OCC13 VAM (if progression)
VAM ? 3 3 TI ? PCI 3 P1OCC1/VAM
MAC1C ? 2 3 TI ? PCI 3 MAC1C ? 2 3 ?/? BCG
CC1V/AV (alt) ? 1 3 TI ? PCI 3 CC1V/AV (alt) ? 1 3
CMC1/VAP1(alt) ? 4 ? PCI
CMC1/VAP1(alt) ? 4 ? T1 ? PCI
CAV ? PCI 3 E/HMM ? 3
CAV ? TI ? PCI 3 E/HMM ? 3
VMV1AC (CR) ? TI ? PCI 3 CE ? 4 3 VMV1AC
VMV1AC (CR) ? CE ? 4 ? PCI 3 VMV1AC
VMV1AC (PR/NR) ? WVTI ? PCI 3 CE ? 4 3 VMV1AC
VMV1AC (PR/NR) ? RVTI ? PCI 3 CE ? 4 3 VMV1AC
VAC ? 3 ? TI ? PCI 3 VAC (maint)
EVAC ? 3 ? TI ? PCI 3 EVAC (maint)
CAV ? 4 3 TI (if PR) 3 PCI
CEV ? 4 3 TI (if PR) 3 PCI
C (HD)/V ? 4 3 TI (if PR) 3 PCI
CAV ?/? TI ? PCI
CAE ?/? TI ? PCI
CAV ? TI ? PCI
CAVE ? TI ? PCI
CAV ? 4 3 PCI ? TI (if PR) 3 CAV
CAVE ? 4 3 PCI ? TI (if PR) 3 CAVE
CEV ? 6 ? PCI 3 CEV/CAV (alt)
CEV ? 6 ? TI ? PCI 3 CEV/CAV (alt)
CEV ? 3 3 TI ? PCI ? CEV ? 3 3 CEV/CAV (alt)
CAV ? 3 3 EP ? 3 ? PCI 3 RT (T)
CAV/EP (alt) ? 3 ? PCI 3 RT (T)
CC1M (CR/PR) 3 TI ? PCI 3 CC1M/AV1(maint)
CC1M (CR/PR) 3 AV13 PCI 3 CC1M/AV1(maint)
CC1M (NR/LP) 3 TI 3 AV1(maint)
CC1M (NR/LP) 3 AV13 AV1(maint)
CAV ? 6 3 ?/? PE ? 2
CAV ? 6 ? TI 3 ?/? PE ? 2
EVAC ? 6 3 TI ? PCI 3 EVAC ? 6
EP/VAC (alt) ? 3 3 TI ? PCI 3 EP/VAC ? 3 (alt)
1530CANCER October 1, 2002 / Volume 95 / Number 7
sponded most closely with the year the cooperative
group trials finished their patient accrual. In this anal-
ysis, patients from the SEER database with in situ,
localized, or regional disease are termed “limited-
stage” to be consistent with the terminology used in
the cooperative group studies.
Phase II and Pilot Trials
Phase II and pilot trials that were used subsequently as
the experimental arms of Phase III trials were identi-
fied using the published Phase III clinical trials and by
searching the MEDLINE database. Only studies that
used the identical or a very similar treatment regimen
between the Phase II/pilot trials and Phase III studies
were considered for evaluation.12Information was ob-
tained on the dates of the Phase II studies, the number
and gender of patients, the chemotherapy regimens,
the chest radiotherapy treatment plan, the response
rates, the median survival, and the number of deaths
at the time of the Phase II analysis.
Least squares linear regression was used to evaluate
time trends in the Phase III data. The two-sample t
test, Wilcoxon test, and Pearson chi-square test were
used to compare data for the 1973–1987 versus the
1988–1996 periods. The trend in median and 5-year
survivals among patients with limited-stage SCLC in
the SEER database was calculated using a least
squares regression analysis. All P values corresponded
to two-sided tests.
Phase III Trials
Forty-three North American cooperative group and
institutional Phase III trials were initiated between
1972 and 1992 and completed by 1996 and comprised
7305 patients with limited-stage SCLC. Thirteen trials
did not meet the criteria for our study and were ex-
cluded.15–27Seven trials had fewer than 20 patients per
First author Study yrs
P1OC1C/V1AM (CR/PR) 3 ?/? P1OC1C/V1AM
P1OC1C/V1AM (CR/PR) 3 TI
CAVE ? 3 3 TI ? PCI 3 CAVE
CAVE ? 3 ? RA233 3 TI ? PCI 3 CAVE ? RA233
CAV/EP ? 3 ? TI (cycle 6) 3 PCI
CAV/EP ? 3 ? TI (cycle 2) 3 PCI
ACE ? 3 3 PCE ? 2 ? TI ? PCI 3 ACE ? 3
ACE ? 3 3 PCE ? 2 ? TI ? PCI ? Warfarin 3 ACE ? 3
PE ? 2 3 CAV ? 4 ? TI ? PCI 3 ?/? rIFN?
EP ? 2 3 CAV ? 4 ? TI ? PCI 3 ?/? rIFN?
E(24 h)P ? 2 3 CAV ? 4 ? TI ? PCI 3 ?/? rIFN?
E(24 h)P(24 h) ? 2 3 CAV ? 4 ? TI ? PCI 3 ?/? rIFN?
PE ? TI
PE ? TI ? GM-CSF
PE ? 4 ? TI 3 PCI
PE ? 4 ? BID TI 3 PCI
EP ? 3 3 TI ? EP ? 2 3 EP ? 1 3 PCI
EP ? 3 3 BID TI ? EP ? 2 3 EP ? 1 3 PCI
PE/CAV (alt) ? 3 ? TI
PE/CAV (alt) ? 3 ? TI ? MA
CR: complete response; PR: partial response; NA: not available; NR: no response; LP: local progression; HD: high-dose; TI: thoracic irradiation; PCI: prophylactic cranial irradiation; alt: alternating therapy; maint:
maintenance therapy; WVTI: wide-volume thoracic irradiation; RVTI: reduced-volume thoracic irradiation; BID: twice daily; C: cyclophosphamide; M: methotrexate; V,O: vincristine; C1: CCNU; A,H: doxorubicin; V1,
E: etoposide; P: cisplatin; F: 5-fluorouracil; BCG: bacillus Calmette–Guerin immunotherapy; D: DTIC; P1: procarbazine; HMMM: hexamethylmelamine; rIFN?: recombinant interferon gamma; GM-CSF: recombinant
granulocyte-macrophge–colony-stimulating factor; MA: megestrol acetate.
aThese studies randomized patients based on response to induction therapy. Data from these studies have not been used to calculate trends in survival.
bTotal number of patients enrolled in induction therapy.
cSurvival worse (P ? 0.0099) in chemotherapy arm compared with both radiation arms.
Survival Improvements in Small Cell Lung Carcinoma/Ja ¨nne et al.1531
arm and were statistically unreliable,15–21one trial did
not have information separately for limited-stage pa-
tients,27and in five trials PCI was the only study vari-
able.22–26Thirty Phase III studies involving 6564 pa-
tients were available for analysis. The results of these
30 trials are listed in Table 1. Four trials are included in
the analysis of the trials but are excluded from the
survival trend analyses as the randomization in these
studies was based on response to initial therapy and
took place 1.5–9 months after initiation of treat-
ment.37,45,48,54The survival of the patients treated on
these four trials is skewed artificially as only patients
responding to initial therapy are entered on study and
evaluated for survival. Therefore, 26 Phase III studies
involving 5245 patients were available for survival
trend analyses. A summary of characteristics of the 30
trials is shown in Table 2.
Of the 26 studies used for the survival trend anal-
ysis, 6 (23%) studies examined questions regarding
radiation therapy, 14 (54%) evaluated different che-
motherapy regimens, and 6 (23%) evaluated the addi-
tion of a biologic modifier to the treatment regimen.
Of the four trials excluded from the survival trend
analysis, three evaluated radiation therapy (one com-
pared the addition of radiation therapy with the addi-
tion of chemotherapy different from the induction
regimen, one compared the addition of radiation ther-
apy with chemotherapy, and one compared daily with
twice daily radiation therapy) and one evaluated che-
motherapy sequencing and the size of the radiation
field. Twenty (77%) studies had two arms, two (8%)
studies had three arms, and four (15%) studies had
Twenty-eight of the 30 (93%) studies had informa-
tion on the staging systems used to evaluate potential
sites of metastatic disease and to select patients for
study entry. Twenty-seven (96%) studies required a
bone marrow examination. A computed tomographic
scan (CT) of the head was required in 13 of 28 (46%)
studies and it was optional in 9 of 28 (32%) studies. In
studies initiated between 1972 and 1981, a CT scan of
the head was required in 4 of 17 (24%) studies and it
was optional in 6 of 17 (35%) studies compared with
10 of 12 (82%) and 2 of 12 (18%) studies initiated
between 1982 and 1992, respectively. Magnetic nu-
clear resonance imaging scan (MRI) of the brain was
not required in any of the studies but was optional in
2 of 28 (7%) of the studies. Six of 28 (22%) studies, all
initiated between 1972 and 1981, used brain radionu-
clide scans to examine patients for central nervous
systemmetastases. CT scans of the chest and abdomen
were required in 6 of 28 (21%) and in 5 of 28 (18%)
studies, respectively. All of these studies took place in
the later time period (1982–1992).
Survival Time of Patients
The median survival of patients treated in the Phase III
studies is shown in Table 1. Nineteen trials included
data on the number of patients who had died at the
time of analysis (median percent of patients deceased
per trial at the time of data analysis beforepublication,
85; range, 54–97%). The median of median survival
times of all patients treated on the control arms of the
Phase III trials initiated between 1972 and 1981 and
between 1982 and 1992 were 12.0 months (range,
10–16 months) and 17.0 months (range, 11–20
months), respectively (P ? 0.001; Fig. 1). The increase
in median survival remained significant after adjust-
ing for the change in the proportion of female patients
during these two time periods.
Of the 26 Phase III trials, 5 (19%) showed a statis-
tically significant difference in survival time when the
patient cohort received the experimental therapy
compared with the control group (absolute differences
in the experimental arm compared with the control
arm: 1, 2.5, 3.4, 4, and 5 months; median, 3.4
months).2,5,6,36,50A sixth study showed a significant
survival prolongation in the control arm compared
with only one of the three experimental arms.52All five
of the studies with a significant survival prolongation
in the experimental arms compared with the control
arm(s) evaluated some aspect of radiation therapy.
Three of the studies compared chemotherapy alone
with a combination of chemotherapy and thoracic
radiation therapy,5,6,36one study compared early ver-
sus late thoracic radiation therapy,50and one study
compared daily versus twice daily thoracic radiation
therapy.2Only one other study available for survival
trend analysis evaluated the addition of thoracic radi-
ation therapy to chemotherapy.46Although not statis-
tically different, the median survival in this study was
greater for those patients who received thoracic radi-
ation compared with those treated with chemotherapy
alone (Table 1). However, the randomization in this
study was terminated prematurely due to significant
toxicities in the combined modality arm. As a result,
the final number of patients randomized to that arm
Summary of Phase III Trials in Limited-Stage Small
Cell Lung Carcinoma
No. of studies
No. of patients
Median no. of patients enrolled
Median no. of patients per arm
P ? 0.025
P ? 0.047
1532CANCER October 1, 2002 / Volume 95 / Number 7
(n ? 147) was less than the projected statistical esti-
mate (n ? 166), which may account for the survival
findings. Of the 26 studies, 20 (76%) showed no sur-
vival benefit in the experimental arm(s) compared
with the control arm (Table 1).
Phase II and Pilot Trials
We identified nine Phase II trials that led subsequently
to a Phase III study. We excluded five Phase II trials
because we found differences between the Phase II
and Phase III studies in the chemotherapy drugs
used,17,56the chemotherapy drug schedule,57the
Phase II study did not include thoracic radiation al-
though it was administered in the subsequent Phase
III trial,58or the Phase II study did not report results
separately for limited-stage patients.59Table 3 com-
pares the number of patients, the response rate, and
the median survival between the Phase II and Phase III
trials. All four of the Phase II studies were performed
in the later time period (1982–1992). The median re-
sponse rates in the Phase II studies (median, 90.5%;
range, 85–96%) were slightly better than in the Phase
III studies (median, 86%; range, 77–89%). In one of
four studies, the median survival was longer in the
Phase II study than in the Phase III study.60However,
in three of the four studies, the median survival was
actually longer in the Phase III study than in the Phase
II study.61–63These four Phase II trials and their cor-
responding Phase III studies are insufficient to con-
struct a statistically reliable model to determine the
success of the Phase III studies based on the Phase II
results. To generate such a model, approximately 10
Phase II studies with corresponding Phase III studies
will be required.
Information on the median and 5-year survival times
of patients with limited-stage SCLC is available in the
SEER population database. SEER survival data are re-
corded from the time of diagnosis, rather than from
the initiation of therapy as has been done in the stud-
ies reported in the current study. Therefore, the data
on median survival are not directly comparable to the
survival data from the Phase III cooperative group
studies. In the SEER database, the median survival of
patients with limited-stage SCLC increased from a
median of 9.1 months between 1973 and 1974 to 15.5
months in patients diagnosed between 1995 and 1996
(P ? 0.0001 for trend; Fig. 2a). There has also been
more than a doubling in the 5-year survival rate from
5.2% between 1975 and 1976 to 12.1% between 1991
and 1992 (P ? 0.0001; Fig. 2b).
The median and 5-year survivals of all patients
with SCLC were also evaluated in the SEER database
because of the potential for stage migration. Between
1973 and 1981, 43% of patients listed in the SEER
database were classified as having limited disease.
Between 1982 and 1992, this value decreased to 35%.
FIGURE 1. Median survival time of patients treated in the control arms of
Phase III studies. Each study is represented by a circle, the size of which is
proportional to the sample size of the treated patients (univariate analysis; P
Phase II and Corresponding Phase III Studies of Limited-Stage Small Cell Lung Carcinoma
Phase II/Phase III
Goodman et al.60Goodman et al.47
Murray et al.41/Murray et al.50
Aisner et al.52/Maurer et al.51
Turrisi et al.63/Turrisi et al.2
EVAC ? 6 3 TI ? PCI 3 EVAC ? 6
CAV/EP ? 3 ? TI (cycle 2) 3 PCI
ACE ? 3 3 PCE ? 2 ? TI ? PCI ? Warfarin 3 ACE ? 3
PE ? 4 ? BID TI 3 PCI
CR: complete response; PR: partial response.
aSee explanation of regimens in Table 1 footnote.
Survival Improvements in Small Cell Lung Carcinoma/Ja ¨nne et al.1533
Between 1973 and 1974, 12.3% of patients with lung
carcinoma listed in the SEER database were classified
as having SCLC. This number increased slightly to 15%
between 1995 and 1996. The median survival of all
patients with SCLC increased from a median of 7.3
months between 1973 and 1974 to 9.5 months be-
tween 1995 and 1996 (P ? 0.001; Fig. 3a). Similarly,
there was a statistically significant increase in the
5-year survival of all patients with SCLC from 3.0 %
between 1973 and 1974 to 5.1 % between 1991 and
1992 (P ? 0.001; Fig. 3b).
Analyses of Phase III therapeutic trials for limited-
stage SCLC during the past 25 years show significant
improvements in patient outcomes. The median of
median survivals in Phase III studies increased by 5
months from 12.0 months in the initial time period
evaluated (1972–1981) to 17.0 months in the later time
period (1982–1992). This improvement is not limited
to patients fitting the criteria for entry into clinical
trials as it closely parallels the 6.4-month increase in
the median survival observed in the SEER database
over a similar time period. The potential explanations
for the prolongation in survival include improvements
in the treatment modalities of SCLC, improvements in
supportive care during the same time period, and
more sensitive staging techniques so that fewer pa-
tients who have less severe disease are identified as
having limited disease. However, the increase in the
median and 5-year survival times for all patients with
SCLC makes these findings unlikely due to stage mi-
gration alone. In addition, the survival trend for lim-
ited-stage SCLC patients continues to increase in a
linear fashion even in the later time period (1982–
1992). During this period more sensitive staging tech-
niques were employed. Over the same time period, the
proportion of SCLC patients in the SEER database
diagnosed with limited-stage disease decreased as did
the number of all SCLC patients in other population
registries.64One possibility for these findings, as re-
flected in the studies from the later time period (1982–
1992), is the introduction of routine CT scans of the
chest and abdomen as well as CT and MRI scans of the
head. The percentage of patients with limited-stage
SCLC available for clinical studies may further de-
crease with the advent of more sensitive staging stud-
ies such as positron emission tomography scans,
which may lead to longer survival.65,66
The concordance in survival is similar to previous
findings among patients with extensive-stage SCLC
and advanced-stage nonsmall cell lung carcinoma
(NSCLC).In the Phase III studies and in the SEER
database, a 2-month and a 2-week prolongation in
FIGURE 2. The median (a) and 5-year
(b) survivals of patients with limited-
stage small cell lung carcinoma as re-
corded in the Surveillance, Epidemiol-
ogy, and End Results database. Each dot
represents the median survival for a
2-year period beginning with 1973 and
1974 (linear regression for median and
5-year survivals, P ? 0.0001 and P
? 0.0001, respectively).
FIGURE 3. The median (a) and 5-year
(b) survivals of all patients with small
cell lung carcinoma as recorded in the
Surveillance, Epidemiology, and End Re-
sults database. Each dot represents the
median survival for a 2-year period be-
ginning with 1973 and 1974 (linear re-
gression for both median and 5-year
survivals, P ? 0.001).
1534CANCER October 1, 2002 / Volume 95 / Number 7
median survival was observed, respectively.7,14The
similar increases in survivals among patients with
three types or stages of lung carcinoma suggest that
the outcomes of patients have improved to a similar
extent whether they were treated on a clinical trial in
North America or in one of the SEER tumor registries
in 11 different states.
Two small studies have evaluated this specific is-
sue in patients with SCLC. Cottin et al.67evaluated the
characteristics of 57 patients (of 178 total [31%]) ex-
cluded from three SCLC clinical trials. In one of these
studies, they found that the median survival for 37
SCLC patients (4 limited, 33 extensive) excluded from
that study was 6 months compared with 9 months in
73 patients (20 limited, 53 extensive) treated on study
(P ? 0.01). In contrast, Quoix et al.68evaluated the
outcomes of 171 patients (60 limited, 111 extensive)
treated off protocol compared with 44 patients (21
limited, 23 extensive) treated on six clinical trials. They
found no difference in the median survivals of limited-
stage disease patients (12 months for patients on pro-
tocol vs. 13 months for patients off protocol; P ? NS)
but found a worse survival for patients with extensive-
stage SCLC (7.5 months vs. 3.5 months, respectively; P
? 0.05). Although we did not analyze individual pa-
tient data, our results on outcomes of patients with
both stages of SCLC do not agree with these findings
and show similar outcomes for patients treated on a
Phase III clinical trial and in a population-based reg-
The number of Phase III trials that showed a sta-
tistically significant improvement in survival in this
analysis (5 of 26 studies [19%]) is similar to the num-
ber of studies showing improvement for extensive-
stage SCLC (5 of 21 studies [24%]) and advanced-stage
NSCLC (5 of 33 studies [15%]).7,14Most of the Phase III
clinical trials for all three diseases have shown no
statistically significant survival improvement in the
experimental arms compared with the control arms.
These findings should be considered when planning
future randomized Phase III studies. The need for
adequate sample size in designing a clinical trial can-
not be overstated. The observed differences in median
survival times between experimental and control arms
in patients with limited-stage SCLC have been modest.
Only one of the five positive trials had a difference of
more than 4 months, indicating that in the future,
survival improvements in excess of 4 months may be
unlikely.2This information should be considered in
designing future trials for patients with limited-stage
SCLC. For example, a sample size of 1000 patients is
required for a trial with 90% power to detect a
4-month improvement in median survival, a 24% in-
crease, assuming a median survival of 17 months in
the control arm. Given the decrease in the number of
patients with SCLC and especially those with limited-
stage disease, careful selection of future studies with
the greatest likelihood of success is warranted. A sta-
tistical model to aid in the selection of chemotherapy
regimens for Phase III clinical studies based on Phase
II and pilot studies in extensive-stage SCLC was de-
veloped recently.12,69,70For limited-stage SCLC, only
four Phase II studies were identified retrospectively
(Table 3), which is insufficient to generate an accurate
model.60–63Due to the inherent differences in the
treatments and outcomes of patients with limited-
stage SCLC compared with extensive-stage SCLC, the
model generated from studies of extensive-stage SCLC
is not applicable to limited-stage SCLC studies.
The only clinical studies that have shown a statis-
tically significant prolongation in survival in the ex-
perimental arms have evaluated questions involving a
combination of radiation therapy and chemotherapy.
No studies involving chemotherapy, given either be-
fore radiation therapy, concurrently with radiation
therapy, or in maintenance therapy, have shown su-
periority over the control arm. These findings are of
importance when planning future studies in SCLC and
should prompt the need to perform additional Phase
II clinical trials before proceeding with large Phase III
studies. Median survival rather than response rate is
likely to be a better predictor of the success of a Phase
II trial when taken into a Phase III setting as has been
determined for extensive-stage SCLC.12However, for
limited-stage SCLC, a minimum of 2–3 years of follow-
up is needed to assess median survival in a Phase II
trial. Information generated from patients with exten-
sive-stage SCLC, the statistical model based on Phase
II and pilot studies, and the current study will be
useful in planning future Phase III trials in SCLC uti-
lizing data obtained from Phase II studies and incor-
porating the projected cost-benefits of new agents
into the standard treatment regimens.
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