Phase III Study of Concurrent Versus Sequential Thoracic
Radiotherapy in Combination With Cisplatin and
Etoposide for Limited-Stage Small-Cell Lung Cancer:
Results of the Japan Clinical Oncology Group Study 9104
By Minoru Takada, Masahiro Fukuoka, Masaaki Kawahara, Takahiko Sugiura, Akira Yokoyama, Soichiro Yokota,
Yutaka Nishiwaki, Koshiro Watanabe, Kazumasa Noda, Tomohide Tamura, Haruhiko Fukuda, and Nagahiro Saijo
for the Members of the Japan Clinical Oncology Group
Purpose: To evaluate the optimal timing for thoracic
radiotherapy (TRT) in limited-stage small-cell lung can-
cer (LS-SCLC), the Lung Cancer Study Group of the Japan
Clinical Oncology Group conducted a phase III study in
which patients were randomized to sequential TRT or
concurrent TRT.
Patients and Methods: We treated 231 patients with
LS-SCLC. TRT consisted of 45 Gy over 3 weeks (1.5 Gy
twice daily), and the patients were randomly assigned
to receive either sequential or concurrent TRT. All pa-
tients received four cycles of cisplatin plus etoposide
every 3 weeks (sequential arm) or 4 weeks (concurrent
arm). TRT was begun on day 2 of the first cycle of
chemotherapy in the concurrent arm and after the
fourth cycle in the sequential arm.
Results: Concurrent radiotherapy yielded better sur-
vival than sequential radiotherapy (P ⴝ .097 by log-
MALL-CELL LUNG cancer accounts for approxi-
S mately 20% of all lung cancers,1 and it follows a more
rapid clinical course than non–small-cell lung cancer. In
contrast to non–small-cell lung cancer, however, small-cell
lung cancer is very sensitive to cytotoxic agents and
radiation therapy. Limited-stage small-cell lung cancer (LS-
SCLC) is confined to the hemithorax, clinically, and thus
the main treatment is radiotherapy and chemotherapy.
From the Osaka Prefectural Habikino Hospital, Osaka City General
Medical Center, Kinki National Hospital for Chest Disease, and
National Toneyama Hospital for Chest Disease, Osaka; Aichi Cancer
Center, Aichi; Niigata Cancer Center Hospital, Niigata; National
Cancer Center Hospital East, Chiba; Yokohama Municipal Citizen’s
Hospital and Kanagawa Cancer Center, Kanagawa; and National
Cancer Center Hospital and National Cancer Center Research Insti-
tute, Tokyo, Japan.
Submitted December 14, 2001; accepted April 15, 2002.
Supported in part by Grants-in-Aid for Cancer Research 2S-1, 5S-1,
8S-1, 11S-2, and 11S-4 and by the Second Term Comprehensive
10-Year Strategy for Cancer Control, all from the Ministry of Health,
Labor, and Welfare.
Address reprint requests to Nagahiro Saijo, MD, Division of Internal
Medicine, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku,
Tokyo 104-0045, Japan; email: nsaijo@ncc.go.jp.
© 2002 by American Society of Clinical Oncology.
0732-183X/02/2014-3054/$20.00
3054 Journal of Clinical Oncology, Vol 20, No 14 (July 15), 2002: pp 3054-3060
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Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
rank test). The median survival time was 19.7 months
in the sequential arm versus 27.2 months in the concur-
rent arm. The 2-, 3-, and 5-year survival rates for
patients who received sequential radiotherapy were
35.1%, 20.2%, and 18.3%, respectively, as opposed to
54.4%, 29.8% and 23.7%, respectively, for the patients
who received concurrent radiotherapy. Hematologic
toxicity was more severe in the concurrent arm. How-
ever, severe esophagitis was infrequent in both arms,
occurring in 9% of the patients in the concurrent arm
and 4% in the sequential arm.
Conclusion: This study strongly suggests that cispla-
tin plus etoposide and concurrent radiotherapy is more
effective for the treatment of LS-SCLC than cisplatin plus
etoposide and sequential radiotherapy.
J Clin Oncol 20:3054-3060. © 2002 by American
Society of Clinical Oncology.
A meta-analysis performed by Pignon et al2 showed that the
addition of radiotherapy to combination chemotherapy signif-
icantly improved the survival for patients with LS-SCLC, but
the optimal method of integrating thoracic radiotherapy (TRT)
with chemotherapy remained undefined.
During the 1980s, the cisplatin-etoposide regimen be-
came the treatment of choice, because this combination
seemed to offer better systemic therapy without intrinsic
pulmonary toxicity. Because of this, pilot studies combining
TRT with concurrent cisplatin plus etoposide therapy were
performed.3-5 The results of the trials were encouraging: a
2-year survival rate of approximately 40% was obtained
with acceptable toxicities. To evaluate the optimal timing
for TRT in LS-SCLC, the Lung Cancer Study Group of the
Japan Clinical Oncology Group (JCOG) conducted a phase
III study in which patients were randomized to sequential
TRT or concurrent TRT.
PATIENTS AND METHODS
Patients
The diagnosis of small-cell lung cancer was confirmed by the
histologic or cytologic findings in all cases. Limited stage was defined
as disease confined to one hemithorax with or without mediastinal node
metastasis and with or without bilateral supraclavicular node metasta-
sis. Additional eligibility criteria consisted of measurable or assessable
disease, age less than 75 years, Eastern Cooperative Oncology Group
DOI: 10.1200/JCO.2002.12.071
CHEMORADIOTHERAPY SEQUENCE FOR LIMITED-STAGE SCLC
performance status (PS) ⱕ 2, adequate organ function, leukocyte count
greater than 4,000/mm3, hemoglobin level greater than 11 g/dL, platelet
count greater than 100,000/mm3, serum creatinine level less than 1.5
mg/dL, serum AST and ALT levels less than two times the upper limit
of normal, serum bilirubin level less than 2.0 mg/dL, 24-hour creatinine
clearance greater than 60 mL/min/m2, and arterial oxygen pressure
greater than 70 mmHg. Patients with malignant pleural effusions or
stage I disease by the tumor-node-metastasis staging method6 were
ineligible. Patients with symptomatic cardiac disease or a history of
myocardial infarction within the previous 3 months were excluded.
Each patient underwent the following studies: chest radiography and
fiberoptic bronchoscopy, complete blood count and biochemical tests,
ECG, computed tomography scan of the thorax, abdomen, and brain,
bone marrow aspiration biopsy, and a radionuclide bone scan. All
patients were reassessed at the end of treatment in the same manner as
at the time of enrollment.
Chemotherapy
Chemotherapy was given in a 28-day cycle in the concurrent arm and
a 21-day cycle in the sequential arm. Chemotherapy consisted of
cisplatin (80 mg/m2 intravenously) on day 1 and etoposide (100 mg/m2
intravenously) on days 1, 2, and 3. If the leukocyte count had decreased
to below 3,000/mm3 or the platelet count to below 75,000/mm3 on the
first day of next cycle, chemotherapy was withheld until the counts
recovered. During cycles 3 and 4, the dose of etoposide was reduced to
75% of the initial dosage for patients who experienced grade 4
hematologic toxicity in the previous cycle. Study chemotherapy was
terminated in patients with serum creatinine levels of 2.0 mg/dL or
higher, serum bilirubin levels of 2.0 mg/dL or higher, or failure of the
hepatic transaminase level to fall below 100 IU/L after 6 weeks of the
prior cycle.
Thoracic Radiotherapy
TRT was begun on day 2 of the first cycle of chemotherapy in the
concurrent arm and after the fourth cycle of chemotherapy in the
sequential arm. It was administered twice daily (1.5 Gy per fraction,
with 4 hours or more between fractions) and directed to the primary
tumor for a total dose of 45 Gy in 3 weeks. The initial field included the
primary disease site with a 1.5-cm margin around the mass, the
ipsilateral hilum, the entire width of the mediastinum, and the supra-
clavicular lymph nodes (only if there was tumor involvement). The
initial field in the sequential arm was also based on the pretreatment
tumor volume. TRT was suspended if a patient experienced grade 4
hematologic toxicities, radiation pneumonitis or fever, a decrease in
arterial oxygen pressure exceeding 10 mmHg, or if a patient had
difficulty swallowing a liquid diet. The maximum spinal cord dose was
limited to 30 Gy.
After TRT, prophylactic whole-brain irradiation was administered to
patients with a complete or near-complete response: a scar-like shadow
on chest films but no positive cytology and/or bronchoscopic biopsy.
The brain irradiation consisted of 24 Gy in 1.5-Gy fractions twice daily,
5 days per week.
Response and Toxicity Criteria
Tumor response and treatment toxicity were classified in accordance
with the World Health Organization criteria.7 Esophagitis was graded
as follows: grade 1, mild pain on swallowing and discomfort when
swallowing solid food; grade 2, moderate pain on swallowing but able
to swallow solid food; grade 3, severe pain on swallowing and able to
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Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
3055
swallow only a liquid diet; grade 4, intractable pain on swallowing and
oral alimentation impossible.
Study Design and Statistical Analysis
This study was designed as a multicenter, prospective, randomized
phase III study. The primary end point was overall survival, and the
secondary end points were complete and overall response rates,
progression-free survival, and toxicity. The planned sample size was
220 patients from 16 participating institutions, with a planned accrual
duration of 3.5 years and a planned follow-up time of 2 years. The
sample size was designed to provide 80% power to detect a difference
in median survival time of 18 months versus 12 months in favor of the
concurrent arm at the .05 error level with a two-sided test.8 Random-
ization was performed centrally using the minimization method of
balancing institution and PS at the JCOG Data Center.
Analysis of the trial data was based on the intention-to-treat
principle. Duration of survival was measured from the date of random-
ization to the date of death or most recent follow-up. Progression-free
survival was measured from the date of randomization to the date of the
first observation of disease progression or death. If there was no
progression or the patient had not died, progression-free survival was
censored at the date of confirmation of no progression. Survival
distributions were calculated by the Kaplan-Meier method9 and com-
pared by using the log-rank test.10 Fisher’s exact test was used for
comparisons of categorical data.11 Cox’s proportional hazards regres-
sion model was used to assess the impact on survival of treatment and
important demographic factors, such as sex, Eastern Cooperative
Oncology Group PS, age, and stage.12 All P values are based on
two-sided test.
The protocol was approved by the Clinical Trial Review Committee
of JCOG before the study activation. In accordance with policies of the
JCOG in 1991, oral or written consent was obtained from the patients
or their families before randomization.
RESULTS
Patient Characteristics
Between May 1991 and January 1995 a total of 231
patients with LS-SCLC being treated at 15 institutions were
enrolled onto the study. Three patients in the sequential arm
were ineligible, because of extensive disease in two patients
and malignant lymphoma in one patient. These three pa-
tients were excluded from the primary analyses of overall
survival, progression-free survival, and response. The char-
acteristics of the 228 eligible patients are shown in Table 1,
and they are well balanced between the arms.
Toxicity
Documentation of toxicity data was not available for nine
patients (seven in the sequential arm and two in the
concurrent arm), which left 222 patients (110 in the sequen-
tial arm and 112 in the concurrent arm) assessable for
toxicity. Hematologic and nonhematologic toxicities are
summarized in Table 2. Myelosuppression was common in
both arms but more severe in the concurrent arm. Leuko-
penia was much more frequent in the concurrent arm.
3056 TAKADA ET AL

Table 1. Characteristics of Patients According to Treatment Arm: Eligible Patients

Sequential Arm (n ⫽ 114)* Concurrent Arm (n ⫽ 114)

Characteristic No. of Patients % No. of Patients % P

Age, years
Median 64 65 .46
Range 30-74 39-74
Sex
Male 93 82 91 80 .87
Female 21 18 23 20
PS
0 33 29 25 22 .49
1 75 66 83 73
2 6 5 6 5
Weight loss
⬍ 10% 102 89 104 91 .86
ⱖ 10% 8 7 6 5
Not reported 4 4 4 4
Stage
II 10 9 7 6 .54
IIIA 57 50 65 57
IIIB 47 41 42 37

*Three patients in the sequential arm were ineligible because of being in the extensive stage in two patients and having lymphoma in one patient. They were
excluded from Table 1.

Thrombocytopenia was infrequent and mild in both arms.
Two patients in the concurrent arm died of sepsis. Grade 3
or 4 esophagitis occurred in 10 patients in the concurrent
arm and four patients in the sequential arm, but none of
these patients developed a permanent stricture. There
were no marked differences in nonhematologic toxicity
between the arms. There were three treatment-related
deaths in the concurrent arm (sepsis in two patients and
pyothorax in one patient) and four in the sequential arm
(radiation pneumonitis in three patients and acute cardiac
failure in one patient).
Tumor Response
Table 3 shows tumor response according to treatment
arm. The overall response rate was 92% (27% complete
response rate and 65% partial response rate) in the

Table 2. Incidence of Toxic Effects According to Treatment Arm: Patients Assessable for Toxicity*
Sequential Arm (n ⫽ 110) Concurrent Arm (n ⫽ 112)

Toxic Effect/Grade No. of Patients % No. of Patients % P

Hematologic toxicity ⱖ grade 3

Leukopenia 59 54 99 88 ⬍ .001
Grade 3 49 57
Grade 4 10 42
Thrombocytopenia 29 26 41 37 .11
Grade 3 14 33
Grade 4 15 8
Anemia
Grade 3 46 42 60 54 .08
Nonhematologic toxicity ⱖ grade 3
Nausea/vomiting 21 19 12 11 .09
Esophagitis 4 4 10 9 .17
Alopecia† 14 13 13 12 .99
Fever 2 2 2 2 .99
Infection 1 1 6 5 .12
Arrhythmias 0 0 2 2 .50
Treatment-related death 4 4 3 3 .72

*Data were not available for seven patients in the sequential arm and two patients in the concurrent arm.
†Data on alopecia were available for 109 patients in the sequential arm and 109 patients in the concurrent arm.

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CHEMORADIOTHERAPY SEQUENCE FOR LIMITED-STAGE SCLC 3057

Table 3. Tumor Response According to Treatment Arm: Eligible Patients

Sequential Arm (n ⫽ 114) Concurrent Arm (n ⫽ 114)

Result No. of Patients % No. of Patients % P

Response
Complete 31 27 45 40 .07
Partial 74 65 65 57
Overall 105 92 110 96 .25
No change 3 3 1 1
Progressive 4 4 1 1
Could not be evaluated 2 2 2 2

sequential arm and 97% (40% complete response and
65% partial response) in the concurrent arm. There was a
trend for a higher complete response rate in the concur-
rent arm (P ⫽ .07).
Treatment Delivery and Dose-Intensity
One hundred (88%) of the 114 eligible patients in the
sequential arm and 98 (86%) of the 114 in the concurrent
arm completed four cycles of chemotherapy. The median
chemotherapy interval was 21 days in the sequential arm
and 28 days in the concurrent arm. Planned and actual
dose-intensities are shown in Table 4. The actual dose-
intensity as a proportion of the planned dose-intensity was
greater than 90% in both arms. Actual dose-intensities for
both cisplatin and etoposide were 1.3 times higher in the
sequential arm. More than 80% of patients in both arms
completed thoracic radiotherapy of 45 Gy.
Survival
The formal final analysis of the study was performed in
May 1998, and updated survival follow-up was performed
on August 2000. Figure 1 shows the updated survival curves
for eligible patients analyzed on August 2000. The median
survival time of all eligible patients was 19.7 months in the
sequential arm (95% confidence interval [CI], 15.8 to 23.3
months) and 27.2 months (95% CI, 18.4 to 31.0 months) in
the concurrent arm. The 2-, 3-, and 5-year survival rates
were 35.1%, 20.2%, and 18.3%, respectively, in the sequen-
tial arm versus 54.4%, 29.8%, and 23.7% in the concurrent
arm (P ⫽ .097 for eligible patients and .086 for all
randomized patients by log-rank test). Overall survival in
the concurrent arm tended to be superior to that in the
sequential arm. After adjustments for the prognostic factors
performance status, age, and stage, by Cox proportional
hazards regression model, the hazard ratio for death in the
concurrent arm to death in the sequential arm was 0.70
(95% CI, 0.52 to 0.94, P ⫽ .02) (Table 5).
Progression-Free Survival
Figure 2 shows the estimated progression-free survival
distribution of eligible patients at the analysis on May 1998.
Progression-free survival in the concurrent arm was also
superior to that in the sequential arm. The distribution of the
first progression sites was similar in both the arms (Table 6).
Brain metastasis was experienced as the first progression in
27% of the patients in the sequential arm and 19% in the
concurrent arm. The first local failure rate within the thorax
was low, only 18% in both arms.

Table 4. Mean Dose-Intensity According to Treatment Arm: Eligible

Patients
Sequential Concurrent Ratio of
Arm Arm Sequential to
Variable (n ⫽ 114) (n ⫽ 114) Concurrent

Cisplatin
Planned dose-intensity, mg/m2/wk 26.7 20.0 1.33
Actual dose-intensity, mg/m2/wk 24.4 18.8 1.30
Percent of planned dose 91.2 94.1
Etoposide
Planned dose-intensity, mg/m2/wk 100.0 75.0 1.33
Actual dose-intensity, mg/m2/wk 90.3 69.3 1.30 Fig 1. Overall survival of patients with LS-SCLC who were assigned to
treatment with sequential chemoradiotherapy or concurrent chemo-
Percent of planned dose 90.4 92.5
radiotherapy.

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3058 TAKADA ET AL

Table 5. Risk of Death Adjusted for Prognostic Variables: All

Randomized

Variable Hazard Ratio 95% CI P

Treatment arm
Sequential v concurrent 0.70 0.52-0.94 .02
Performance status
0v1 1.58 1.10-2.29 .01
0v2 3.60 1.79-7.22 ⬍ .001
Stage
II v IIIA 2.65 1.28-5.51 .01
II v IIIB 3.34 1.60-7.01 .001
Age* 1.03 1.01-1.05 .004
Sex Fig 2. Progression-free survival of patients with LS-SCLC who were
assigned to treatment with sequential chemoradiotherapy or concurrent
Male v female 0.76 0.51-1.12 .17
chemoradiotherapy.
*The relationship of age to the risk of death was modeled by using age as
a continuous variable.
A 50% increase in median survival from 1219 to 18 months
was considered a clinically significant survival improve-
DISCUSSION ment. In view of this, we conducted a phase III study of
The standard treatment for LS-SCLC is combined-mo- sequential versus concurrent TRT combined with cisplatin
dality therapy consisting of TRT and systemic chemother- plus etoposide for patients with LS-SCLC.
apy. However, there have been many unresolved problems Comparison of overall- and progression-free survival in
with regard to combined therapy: the radiation dose, frac- this study suggested that concurrent radiotherapy was more
tionation, chemotherapy regimen, and the timing of TRT. advantageous than sequential radiotherapy, but the differ-
With regard to fractionation, Turrisi et al13 had determined ence was not statistically significant (P ⫽ .097). In view of
that accelerated hyperfractionation, which is the same the baseline characteristics, there seemed to be a slight
method used in this study, was superior to standard frac- imbalance in PS and stage between the arms; however,
tionation in an intergroup phase III study. Early administra- adjustment with Cox regression analysis suggested a
tion of TRT may eliminate localized populations of chemo- greater benefit of concurrent radiotherapy than simple
therapy-resistant tumor cells that might be responsible for comparison. We think that the imbalance in baseline
treatment failure if permitted to disseminate systemically. characteristics would result in a more conservative esti-
This would be an obvious advantage of early administration mation of the benefit of concurrent radiotherapy in the
of TRT. Although concurrent use of the two modalities intent-to-treat primary analysis.
seemed to be more effective, many doxorubicin-based or One of the major reasons that this study could not
cyclophosphamide-based regimens could not be combined demonstrate a statistically significant result was a relatively
with full doses of TRT concurrently because of increased small sample size of 220 patients. The design called for a
pulmonary toxicity. 50% increase in median survival from 12 to 18 months.
Cisplatin plus etoposide was found to be the optimal Actually, median survival times in both arms were greater
regimen for combination with concurrent TRT, since it than 18 months. The United States Intergroup study re-
hardly accelerates toxicity at all and there is no recall quired over 400 patients and took many years to show a
phenomenon.14-16 The median survival time for patients significant advantage in twice-daily thoracic radiotherapy.13
treated with this regimen and concurrent twice-daily TRT in However, accrual of 65 to 75 patients per year was the limit
the various phase II studies has been 18 to 22 months.4,17,18 of our study group at the time. Another reason may be the

Table 6. First Progression Site According to Treatment Arm: Eligible Patients

Sequential Arm (n ⫽ 114) Concurrent Arm (n ⫽ 114)

Site No. of Patients % No. of Patients % P

Progression-free 26 23 33 29 .29
Within the thorax 21 18 20 18 .86
Outside the thorax 56 49 52 46 .60
Within and outside the thorax 11 10 9 8 .64
Brain 31 27 22 19 .16

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Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
CHEMORADIOTHERAPY SEQUENCE FOR LIMITED-STAGE SCLC
difference in chemotherapy intervals between two arms.
The chemotherapy was given at 4-week intervals in the
concurrent arm and at 3-week intervals in the sequential
arm. An increase in the chemotherapy interval from 3 weeks
to 4 weeks results in a decrease in dose-intensity of 33% in
the concurrent arm, which may be responsible for the
unusual shape of the survival curves. One might accept a
4-week interval only for the first cycle to mitigate the
toxicity of concurrent chemoradiotherapy. However, we had
considered that chemotherapy by 3-week intervals could not
be administered for subsequent chemotherapy courses based
on the results of our previous study.20
Interestingly, local control was the same in both arms, yet
survival was better in the concurrent arm. It may suggest
two hypotheses: (1) local control is achieved earlier in the
concurrent arm, preventing distant dissemination beyond
the confines of the radiation field, and (2) clinical ability to
assess local control is still poor in both arms. The fact that
there was more brain metastasis in the sequential arm (Table
6) may support hypothesis 1.
Hematologic toxicity and esophagitis were more severe
in the concurrent arm; however, there was no increase in
pulmonary toxicity in the concurrent arm. Treatment was
well tolerated by most patients, and the frequency of
radiation esophagitis in this study was lower than previously
reported. In other studies, chemotherapy was administered
in 3-week cycles in the concurrent arm. The 4-week cycle of
cisplatin plus etoposide with concurrent radiotherapy
seemed to reduce the frequency of radiation esophagitis.
Five randomized trials of thoracic irradiation timing in
LS-SCLC, including this study,21-24 have been reported, and
REFERENCES
1. Elias AD: Small cell lung cancer: State-of-the-art therapy in
1996. Chest 112:251S-258S, 1997
2. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of
thoracic radiotherapy for small-cell lung cancer. N Engl J Med
327:1618-1624, 1992
3. Frytak S, Shaw E, Eagan R: Accelerated hyperfractionated
split course thoracic radiotherapy and infusion cisplatin based
chemotherapy for small-cell lung cancer. Lung Cancer 7:157, 1991
(suppl, abstr)
4. Johnson BE, Bridges JD, Sobczeck M, et al: Patients with limited-
stage small-cell lung cancer treated with concurrent twice-daily chest
radiotherapy and etoposide/cisplatin followed by cyclophosphamide,
doxorubicin, and vincristine. J Clin Oncol 14:806-813, 1996
5. Turrisi AT III: Platinum combined with radiation therapy in small
cell lung cancer: Focusing like a laser beam on crucial issues. Semin
Oncol 21:36-42, 1994
6. Hermanek P, Sobin Le: TNM Classification of Malignant Tumors
(ed 4). Berlin, Germany, Springer-Verlag, 1987
7. World Health Organization: Handbook for Reporting Results of
Cancer Treatment (WHO Offset Publication No. 48). Geneva, Swit-
zerland, World Health Organization, 1979
Downloaded from ascopubs.org by 139.167.0.60 on November 13, 2016 from 139.167.000.060
Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
3059
three of them,21,22 including this study, have shown the
superiority of early thoracic irradiation over delayed tho-
racic irradiation. The two studies23,24 that failed to show the
superiority of early thoracic irradiation used cyclophospha-
mide-based chemotherapy, and the decrease in dose-inten-
sity because of the accelerated toxicity of the combined-
modality therapy may be the main reason for this. Long-
term survival after early irradiation consistently exceeds
20% at 5 years, 21,22 and delayed irradiation has never
approached the 20% long-term survival milestone. The data
available from these trials strongly suggest the superiority
of early irradiation over delayed irradiation. However, the
possibility that concurrent radiotherapy in the middle of
chemotherapy course (eg, with the third cycle of chemo-
therapy) is equally or more effective than immediate con-
current radiotherapy is still remains to be investigated.
The 24% 5-year survival in this study was impressive and
consistent with the 26% reported by Turrisi et al13 in a large
intergroup trial. The results of the two trials have updated
the recommendation for treatment of patients with LS-
SCLC to cisplatin plus etoposide and early, concurrent,
twice-daily thoracic radiotherapy. This combined-modality
treatment yielded a median survival time of 23 to 27 months
and 24% to 26% long-term survivors.
ACKNOWLEDGMENT
We thank JCOG Data Center (Miyuki Niimi, Naoki Ishizuka, and
their colleagues) and other participating institutions: Osaka Adult and
Cancer Center (Harumichi Ikegami), Nagasaki Municipal Hospital
(Seishin Nakano), National Nishi-Gunma Hospital (Ryusei Saitou),
Tochigi Cancer Center (Kiyoshi Mori), and Hyogo Medical Center for
Adults (Katsuki Takada).
8. Rubinstein LV, Gail MH, Santner TJ: Planning the duration of a
comparative clinical trial with loss to follow-up and a period of
continued observation. J Chronic Dis 34:469-479, 1981
9. Kaplan E, Meier P: Nonparametric estimation from incomplete
observations. J Am Stat Assoc 53:457-481, 1958
10. Peto R, Pike M: Conservatism of the approximation S(O-E)2/E
in the log-rank test for survival data or tumour incidence data.
Biometrics 29:759-784, 1973
11. Cox D, Snell E: Analysis of binary data. (ed 2). London, United
Kingdom, Chapman & Hall, 1989
12. Cox DR: Regression models and life table. J R Stat Soc B
34:181-220, 1972
13. Turrisi AT III, Kim K, Blum R, et al: Twice-daily compared
with once-daily thoracic radiotherapy in limited small-cell lung cancer
treated concurrently with cisplatin and etoposide. N Engl J Med
340:265-271, 1999
14. Bunn PA Jr, Lichter AS, Makuch RW, et al: Chemotherapy
alone or chemotherapy with chest radiation therapy in limited stage
small cell lung cancer: A prospective, randomized trial. Ann Intern
Med 106:655-662, 1987
3060
15. Greco FA, Brereton HD, Kent H, et al: Adriamycin and
enhanced radiation reaction in normal esophagus and skin. Ann Intern
Med 85:294-298, 1976
16. Perez CA, Einhorn L, Oldham RK, et al: Randomized trial of
radiotherapy to the thorax in limited small-cell carcinoma of the lung
treated with multiagent chemotherapy and elective brain irradiation: A
preliminary report. J Clin Oncol 2:1200-1208, 1984
17. McCracken JD, Janaki LM, Crowley JJ, et al: Concurrent
chemotherapy/radiotherapy for limited small-cell lung carcinoma: A
Southwest Oncology Group study. J Clin Oncol 8:892-898, 1990
18. Turrisi AT, Glover DJ, Mason BA: A preliminary report:
Concurrent twice-daily radiotherapy plus platinum-etoposide chemo-
therapy for limited small cell lung cancer. Int J Radiat Oncol Biol Phys
15:183-187, 1988
19. Fukuoka M, Furuse K, Saijo N, et al: Randomized trial of
cyclophosphamide, doxorubicin, and vincristine versus cisplatin and
etoposide versus alternation of these regimens in small-cell lung
cancer. J Natl Cancer Inst 83:855-861, 1991
Downloaded from ascopubs.org by 139.167.0.60 on November 13, 2016 from 139.167.000.060
Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
TAKADA ET AL
20. Ariyoshi Y, Fukuoka M, Saijo N, et al: Concurrent cisplatin-
etoposide chemotherapy plus thoracic radiotherapy for limited-stage
small cell lung cancer. Jpn J Clin Oncol 24:275-281, 1994
21. Jeremic B, Shibamoto Y, Acimovic L, et al: Initial versus
delayed accelerated hyperfractionated radiation therapy and concurrent
chemotherapy in limited small-cell lung cancer: A randomized study.
J Clin Oncol 15:893-900, 1997
22. Murray N, Coy P, Pater JL, et al: Importance of timing for
thoracic irradiation in the combined modality treatment of limited-stage
small-cell lung cancer: The National Cancer Institute of Canada
Clinical Trials Group. J Clin Oncol 11:336-344, 1993
23. Perry MC, Eaton WL, Propert KJ, et al: Chemotherapy with or
without radiation therapy in limited small-cell carcinoma of the lung.
N Engl J Med 316:912-918, 1987
24. Work E, Nielsen OS, Bentzen SM, et al: Randomized study of
initial versus late chest irradiation combined with chemotherapy in
limited-stage small-cell lung cancer: Aarhus Lung Cancer Group.
J Clin Oncol 15:3030-3037, 1997