DOI: 10.1093/jnci/djr325 © The Author 2011. Published by Oxford University Press. All rights reserved.

Advance Access publication on September 8, 2011. For Permissions, please e-mail: [email protected].

ARTICLE

Sequential vs Concurrent Chemoradiation for Stage III Non–Small

Cell Lung Cancer: Randomized Phase III Trial RTOG 9410
Walter J. Curran Jr, Rebecca Paulus, Corey J. Langer, Ritsuko Komaki, Jin S. Lee, Stephen Hauser, Benjamin Movsas,
Todd Wasserman, Seth A. Rosenthal, Elizabeth Gore, Mitchell Machtay, William Sause, James D. Cox

Manuscript received June 14, 2010; revised July 22, 2011; accepted July 26, 2011.

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Correspondence to: Walter J. Curran Jr, MD, Department of Radiation Oncology and Winship Cancer Institute, Emory University, 1365C Clifton Rd, NE,
Ste C4104, Atlanta, GA 30322 (e-mail: [email protected]).

Background The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown
to confer a survival advantage for good performance status patients with stage III non–small cell lung cancer.
However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combina-
tion strategy.

Methods A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy
and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1
and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 60 Gy TRT beginning on day 50. Arm 2 used the
same chemotherapy regimen as arm 1 with 60 Gy TRT once daily beginning on day 1. Arm 3 used cisplatin at
50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6
with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall
survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan–Meier
analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All
statistical tests were two-sided.

Results Median survival times were 14.6, 17.0, and 15.6 months for arms 1–3, respectively. Five-year survival was sta-
tistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with
the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7%
to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% [22 patients],
95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3–5 nonhematologic
toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar.

Conclusion Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared
with the sequential delivery of these therapies.

 J Natl Cancer Inst 2011;103:1452–1460

Nearly 50 000 Americans are diagnosed each year with non–small of these trials used a platinating compound as one of the
cell lung cancer (NSCLC) that is confined to the thorax and not chemotherapeutic agents, there was considerable variability among
amenable to potentially curative resection because of invasion of the combined modality arms with respect to chemotherapeutic
adjacent structures and/or lymph node metastases. These patients agent selection, dosing, and schedule, dose and schedule of TRT,
have stage III disease according to both the 1992 and 2010 and the temporal relationship between chemotherapy and TRT.
American Joint Commission on Cancer (AJCC) staging system (1), Two of these trials were conducted in North America by National
and the optimal management of this large and heterogeneous Cancer Institute–sponsored cooperative groups, and both used the
population remains controversial. sequential chemoradiation regimen of two cycles of cisplatin and
At least five randomized trials (2–6) conducted since the early vinblastine followed by TRT (2,3). The survival benefit of this
1980s have demonstrated a survival advantage for good perfor- regimen compared with TRT alone and its relatively low toxicity
mance status patients with stage III NSCLC when chemotherapy helped establish sequential cisplatin-based chemoradiation as a
is combined with thoracic radiotherapy (TRT) compared with standard approach to patients with unresected stage III NSCLC.
TRT alone (2–6). The median survival time (MST) of the com- Since 1990, several phase II trials of concurrent chemoradiation
bined modality arms in these trials ranged from 12 to 14 months regimens for such patients have resulted in promising MSTs of
compared with 9 to 12 months with TRT alone. Although each 16–20 months (7,8). In addition, there are at least two randomized

1452   Articles | JNCI Vol. 103, Issue 19 | October 5, 2011

trials comparing concurrent chemoradiation to TRT alone, which
CONTEXTS AND CAVEATS
demonstrated a survival advantage favoring the concurrent therapy
arms (5,6). Although the concurrent delivery of these therapies Prior knowledge
increased both the frequency of severe hematologic and nonhema- Patients with stage III non–small cell lung cancer have been shown
tologic toxicity seen with sequential chemoradiation, the survival to benefit from a combination of chemotherapy with thoracic ra-
results were considered sufficiently promising to the Radiation diotherapy. However, it is not known if sequential or concurrent
delivery of these therapies is the more beneficial treatment
Therapy Oncology Group (RTOG) to conduct a phase III mul-
strategy.
ti-institutional trial with two promising concurrent chemoradia-
tion regimens and the sequential chemoradiation regimen tested in Study design
earlier cooperative group trials. This trial compared concurrent In a randomized phase III trial, 610 patients with inoperable stage
once-daily radiation against sequential therapy and then the better II or III non–small cell lung cancer were randomly assigned to two
of those two against concurrent twice-daily radiation to determine different concurrent regimens (chemotherapy with once-daily or

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twice-daily radiotherapy) or to sequential treatment with these
whether the rate of overall survival is improved by concurrent
therapies.
and/or hyperfractionated radiotherapy administration.
Contribution
Five-year survival was statistically significantly higher for patients
Methods treated with the concurrent regimen with once-daily radiotherapy
Patient Eligibility compared with the sequential treatment.
Patients with medically or surgically inoperable AJCC stage II, Implication
IIIA, or IIIB newly diagnosed histologically confirmed NSCLC Long-term survival was better for patients in the concurrent delivery
(adenocarcinoma, squamous cell carcinoma, large cell carcinoma, arms even though the rates of acute nonhematological toxic effects
or NSCLC—not otherwise specified) were eligible for the study. were higher than in the sequential arm.
Patients were required to have a Karnofsky performance status Limitations
(KPS) of 70 or greater, to have no more than 5% weight loss over Patients with lower functional status or with other comorbid condi-
3 months before enrollment, to be 18 years of age or older, and to tions were not included in the trial. Thus, the current findings may
be without evidence of metastatic disease. Patients with pleural not be applicable to these patients.
effusions with malignant cytology were ineligible as were those
From the Editors
with pleural effusions visible on chest x-ray unless the effusion
appeared only after a thoracotomy or another invasive procedure
(Figure 1). Radiological assessment included chest x-ray, comput-
erized axial tomography of the thorax and upper abdomen and American cooperative group phase III studies (2,3) that demon-
brain, and technetium-99 bone scan. All studies, including a com- strated a survival advantage for chemoradiation compared with RT
plete medical history and physical examination, required comple- alone (Figure 2) (2,3). Cisplatin chemotherapy was delivered intra-
tion within 4 weeks of study enrollment. Patients were required to venously at a dose of 100 mg/m2 over a 30- to 60-minute period on
have a hemoglobin value of 8.0 g or higher, a granulocyte count of day 1 or 2, and vinblastine was delivered at a dose of 5 mg/m2
2000/cc or higher, a platelet count of 100 000/cc or higher, a weekly for five consecutive weeks beginning on day 1. Arm 3 che-
serum creatinine level 1.5 g or less, and serum levels of bilirubin motherapy was based on the regimen piloted in an RTOG phase II
and serum glutamic oxaloacetic transaminase less than 1.5 times trial in which the encouraging MST of 19.6 months was achieved
the upper range of normal laboratory values, unless the abnor- (7). Cisplatin was delivered intravenously at 50 mg/m2 over 30–60
mality was caused by documented benign disease. Pregnant minutes on days 1, 8, 29, and 36, and oral etoposide was adminis-
women were ineligible, and patients with childbearing potential tered at a dose of 50 mg twice daily on days 1–5, 8–12, 29–33, and
were required to practice appropriate contraception. 36–40. The dosing of oral etoposide was reduced to 75 mg/d if the
Patients who underwent a complete tumor resection were inel- patient’s body surface area was less than 1.7 m2. In all three arms,
igible, as were those having received prior chemotherapy or tho- chemotherapy dose modifications were based on the granulocyte
racic or neck radiotherapy. Patients were ineligible if they could be and platelet counts. C. J. Langer reviewed chemotherapy records
enrolled on an RTOG phase III trial for patients with confirmed of all patients with RTOG data management staff. After comple-
N2 lymph node involvement evaluating the role of surgery for tion of chemotherapy, all patient charts were reviewed and assessed
such patients (RTOG 9309). All patients signed an informed con- for their adherence to protocol guidelines.
sent that was approved by their institutional review board before The TRT guidelines for arms 1 and 2 were identical except that
random assignment. Patients were randomly assigned to one of arm 1 TRT started on day 50 and arm 2 TRT began on day 1. In
three treatment arms via phone call to RTOG headquarters and both arms, the initial TRT target volume consisted of the primary
were stratified by KPS (70–80 vs 90–100) and clinical stage (II vs pulmonary tumor, the regional draining lymph nodes, and any in-
IIIA vs IIIB). trathoracic or supraclavicular lymph nodes measuring greater than
2.5 cm. TRT was delivered to this volume at a daily dose of 1.80
Treatment Gy to a total dose of 45.00 Gy over 5 weeks. The sixth and seventh
The chemotherapy regimen was identical in arms 1 and 2 and weeks of TRT were delivered to a smaller target volume encom-
identical to that delivered in the investigational arm of the two passing the primary tumor and lymph nodes known to be involved

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Figure 1. CONSORT diagram for Radiation Therapy Oncology Group (RTOG) 9410 clinical trial. RT = radiotherapy.

with disease and any lymph node measuring greater than 2.0 cm. of 6–8 hours. Target volume definitions were identical to those in
This treatment was delivered in a technique avoiding the spinal arms 1 and 2, and the total dose was 50.40 Gy for the initial volume
cord at a daily dose of 2.00 Gy for nine fractions to 18.00 Gy. The and 19.20 Gy for the secondary target volume. Spinal cord dose was
total TRT dose in arms 1 and 2 to the tumor was 63.00 Gy, and also restricted to 48.00 Gy or less. W. J. Curran, R. Komaki, and
the total dose to the spinal cord was restricted to 48.00 Gy or less. RTOG dosimetry staff reviewed dosimetry, treatment plans, and
In arm 3, TRT was delivered twice daily in 20 Gy fractions to a simulation and verification films of all treatment fields for all evalu-
total dose of 69.60 Gy separated with an interfraction time interval able patients. Similarly to chemotherapy, all patients’ radiation

1454   Articles | JNCI Vol. 103, Issue 19 | October 5, 2011

 progression were censored, and those who died without progres-
Arm 1:
vinblastine 5 mg/m2 IV (starting day 50) sion were considered a competing risk. The corresponding failure
R bolus weekly first 5 weeks 63 Gy/7 wks/34 daily time was measured from the date of random assignment until the
A cisplatin 100 mg/m2 IV over fractions (1.8 Gy x 25 fx, then
30-60 minutes, days 1 & 29 2.0 Gy x 9 fx) first instance of progression or the date of last follow-up/death if
N
D Arm 2:
there was no progression.
O vinblastine 5 mg/m2 IV bolus weekly first 5 weeks Three interim analyses of the primary study endpoint of sur-
M cisplatin 100 mg/m 2 IV over 30-60 minutes, days 1 & 29 vival were performed at 50%, 67%, and 75% of the total planned
63 Gy/7 wks/34 daily fractions (1.8 Gy x 25 fx, then 2.0 Gy x 9 fx)
I accrual. The results of the blinded interim analysis were reported
Z Arm 3: to the RTOG Data Monitoring Committee. The log-rank test was
E oral etoposide 50 mg twice daily x 10 only on RT treatment days 1-5, 8-12, 29-
33 and 36-40 (75 mg/day if body surface area < 1.7 m2) used to examine differences in Kaplan–Meier curves between arms.
cisplatin 50 mg/m2 IV over 30-60 minutes on days 1 and 8 and 29 and 36 The forward selection method of Chen and Simon (12), which is
69.6 Gy/6 wks/58 x 1.2 Gy twice-daily fractions (at least 6 hours apart)
analogous to the Makuch and Simon method (9) for determining

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Figure 2. Flow diagram of treatment arms. Patients were stratified by sample size, was used for the primary analysis. This method com-
Karnofsky performance status and stage before being randomly pared arm 1 with arm 2 at the P = .055 level and then compared
assigned to one of three treatment arms, a control arm of sequential
chemotherapy followed by standard radiation and two experimental the superior arm of this test to arm 3 at the P = .069 level to select
arms in which chemotherapy was delivered concurrently with radia- the best arm overall. For example, if arm 1 was dropped at the in-
tion. fx = fraction; IV = intravenous; RT = Radiotherapy. terim analysis, then arm 2 would be compared with arm 3 at the P
= .040 level. Hazard ratios (HRs) with 95% confidence intervals
treatment delivery was reviewed for adherence to the protocol (CIs) were also calculated. A multivariable analysis testing for ef-
treatment guidelines. fects of pretreatment characteristics was done using the Cox pro-
portional hazards model. Proportionality was confirmed using a
Statistical Analysis Kolmogorov-type supremum test. Differences in time to progres-
The primary objective of this study was to evaluate overall survival. sion were examined using Gray test. Differences in toxicity
The survival outcome from two prior RTOG phase II trials (7,8) distributions were examined using the Wilcoxon rank sum test. All
of concurrent chemoradiation and the survival results of sequential reported P values are two-sided.
chemoradiation in the two prior phase III trials (2,3) determined
the patient sample size. RTOG 90-15 (8) used a concurrent
chemoradiation regimen identical to arm 2 except for the RT frac- Results
tionation, and the MST of patients meeting eligibility criteria of Between July 1994 and July 1998, a total of 610 patients from 153
this study was 17.5 months. RTOG 91-06 (7) used the same con- institutions located in the United States and Canada were enrolled
current chemoradiation regimen as arm 3, and the MST of these on this trial (203, 204, and 203 for arms 1, 2, and 3, respectively).
patients was 19.7 months. In both prior North American phase III The average monthly accrual rate was 11.4 patients per month,
randomized trials testing the sequential chemoradiation regimen and the three blinded interim analyses performed during the ac-
used as arm 1 in this trial, the MST was 13.8 months (2,3). The crual period of this trial did not result in any recommended
sequential regimen was considered the standard arm for this study changes by the RTOG Data Monitoring Committee. The median
(RTOG 9410). The Makuch and Simon (9) sample size formula, age of enrolled patients was 61 years (Table 1), and there were no
which assumes constant proportionality of hazards, was used to statistically significant differences among the three arms with
calculate the sample size. A total of 597 evaluable patients (199 per respect to age, performance status, sex, histological subtype, or
arm) accrued over 4.2 years and followed for a minimum of 2 years clinical stage. Thirty-three patients were deemed ineligible for the
were needed to ensure an 80% (20% type II error rate) probability trial (8, 9, and 16 for arms 1, 2, and 3, respectively). A total of 577
of detecting a 43% relative improvement in MST between the patients were eligible for analysis, constituting 95% of enrolled
worst and best regimen while rejecting the null hypothesis at the patients, and were analyzed based on the treatment arm to which
95% level (a 5% type I error rate) (10). This sample size was also they were assigned. All data received at RTOG headquarters as of
sufficient to detect an absolute 10% difference in acute grade 3 or November 4, 2009, were included in the analysis. The median
worse esophageal toxicity. Secondary endpoints included tumor follow-up time for the 28 patients not reported dead was 11 years
response and time to tumor progression. Patients were stratified by (range 0.8–14.0 years). Two patients were lost to follow-up at 10
stage (II vs IIIA vs IIIB) and KPS (90–100 vs 70–80) and were and 12 months.
randomly assigned to a given treatment arm, according to Zelen Compliance with treatment guidelines was excellent. TRT was
permuted block randomization method (11). A failure for the pri- given in compliance with guidelines or with minor deviations in
mary endpoint of overall survival was death due to any cause, and 83% of patients in arm 1, 92% in arm 2, and 81% in arm 3. Major
the corresponding event time was measured from date of random unacceptable variations were observed in only 3% of patients.
assignment to the date of death or last follow-up if the patient was Treatment interruptions in the delivery of the TRT of more than
still alive. Response to treatment was evaluated using the World 1 week were seen in 9% of patients. Chemotherapy as per protocol
Health Organization classification of response. A response was or with minor deviations was received by 97% of patients.
considered either a clinical complete response or a clinical partial There were statistically significantly higher rates of acute
response. A failure for tumor progression was considered the first esophagitis in both concurrent arms than in the sequential arm,
instance of progressive disease; patients who were alive without with grade 3 or worse rates of 4%, 22%, and 45% for arms 1, 2,

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Table 1. Demographics of enrolled patients*

Patient characteristic Arm 1 (n = 195) Arm 2 (n = 195) Arm 3 (n = 187) Total (n = 577)
Age, No. (%)
<60,y 82 (42) 90 (46) 72 (39) 244 (42)
≥60,y 113 (58) 105 (54) 115 (62) 333 (58)
Median 63 60 63 62
Range 33–79 33–79 35–80 33–80
Sex, No. (%)
Men 122 (63) 125 (64) 124 (66) 371 (64)
Women 73 (37) 70 (36) 63 (34) 206 (36)
KPS, No. (%)
70–80 45 (23) 47 (24) 45 (24) 137 (24)
90–100 150 (77) 148 (76) 142 (76) 440 (76)

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Histology, No. (%)
Squamous 75 (38) 75 (38) 70 (37) 220 (38)
Adenocarcinoma 53 (27) 73 (37) 52 (28) 178 (31)
Large Cell 29 (15) 27 (14) 23 (12) 79 (14)
Combined 2 (1) 2 (1) 8 (4) 12 (2)
Carcinoma NOS 34 (17) 18 (9) 30 (16) 82 (14)
Other 2 (1) 0 (0) 4 (2) 6 (1)
AJCC stage, No. (%)
II 4 (2) 3 (2) 4 (2) 11 (2)
IIIA 81 (42) 84 (43) 75 (40) 240 (42)
IIIB 110 (56) 108 (55) 108 (58) 326 (57)
Race, No. (%)
White 167 (86) 171 (88) 161 (86) 499 (86)
Hispanic 3 (2) 2 (1) 2 (1) 7 (1)
Black or African American 20 (10) 19 (10) 17 (9) 56 (10)
Asian 3 (2) 2 (1) 5 (3) 10 (2)
Native American 0 (0) 1 (<1) 1 (<1) 2 (<1)
Other 2 (1) 0 (0) 1 (<1) 3 (1)

* Arm 1 was the sequential arm. Arm 2 used the same chemotherapy regimen as arm 1 with 60 Gy thoracic radiotherapy beginning on day 1. Arm 3 used cisplatin
at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2-Gy twice-daily
fractions beginning on day 1. AJCC = American Joint Commission on Cancer staging; KPS = Karnofsky performance status; NOS = not otherwise specified.

and 3, respectively (Table 2). A comparison of severe acute esopha- longer in arm 2 compared with arm 3 (HR of death = 0.93, 95%
gitis by the Wilcoxon test demonstrated significant differences CI = 0.75 to 1.14, P = .046, log-rank test, Figure 4). Multivariable
between arms 1 and 2 (P < .001) and arms 3 and 2 (P < .001). Of analysis using treatment, age, KPS, sex, histology, stage, and race/
interest was the lack of difference in late esophagitis rates among ethnicity showed that, after controlling for treatment, only age,
these arms, with rates of 1%–4% among the three arms. Grade 3 KPS, and stage were statistically significantly associated with survival
or worse acute pulmonary toxicity was higher for the sequential (P = .001, .007, and .02, respectively).
arm than either concurrent arm, and although no difference in late Response rate was highest in arm 2 at 70% (95% CI = 63% to
toxicity was observed, the grade 3–5 late pulmonary toxicities 76%). This included a clinical complete response (cCR) rate of
ranged between 13% and 17% for the three arms. The rates of 42% (95% CI = 35% to 49%). Arm 1 had a 61% response rate
grade 3 or worse granulocyte level depressions were highest in (95% CI = 54% to 68%) and a cCR of 30% (95% CI = 24% to
arms 1 and 2, which included vinblastine (arm 1, 77%; arm 2, 81%; 37%). Arm 3 had a 65% response rate (95% CI = 58% to 71%)
and arm 3, 53%). A total of 14 patients (2%) experienced acute and a cCR of 33% (95% CI = 27% to 40%). The response rate
fatal toxicity; 13 were attributable to neutropenic sepsis. Of the in arm 2 was statistically significantly higher (P < .05) compared
eight late fatal toxicities, seven were pulmonary in nature, and one with arm 1, but arms 2 and 3 were not statistically significantly
was infectious. No differences between the arms were noted in the different in response rate. Local tumor failure rate (progression of
rates of these grade 5 toxicities. tumor within the full dose radiation region) was highest in arm 1
MSTs were 14.6 months (95% CI = 12.1 to 17.0 months) in (39%, 95% CI = 32 to 46 at 2 years) and lower in arm 2 (30%,
arm 1, 17.0 months (95% CI = 14.0 to 20.2 months) in arm 2, and 95% CI = 23 to 36) and arm 3 (29%, 95% CI = 22 to 35). The
15.6 months (95% CI = 13 to 18 months) in arm 3. Overall 5-year differences in local tumor failure rates between arms 2 and 1 and
survival rates were 10% (20 patients, 95% CI = 7% to 15%) for between arms 1 and 3 were not statistically significant (P = .09 and
arm 1, 16% (31 patients, 95% CI = 11% to 22%) for arm 2, and .053, respectively).
13% (22 patients, 95% CI = 9% to 18%) for arm 3. Overall survival Patterns of disease progression were defined for all patients as
was not statistically significantly longer in arm 2 compared with occurring “infield,” distant, or both (Table 3). There was no dif-
arm 1 (HR of death = 0.81, 95% CI = 0.66 to 0.996, P = .46, log- ference in the pattern of occurrence of first sites of disease failure
rank test, Figure 3) Overall survival was statistically significantly between arms 1 and 2. There were, however, fewer patients in arm

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Table 2. Chemotherapy and acute and late toxicities*

Grade
Toxicity 3 4 5 3 4 5 3 4 5
Chemotherapy and acute Arm 1 (n = 195) Arm 2 (n = 193) Arm 3 (n = 187)
   radiotherapy toxicities, No. (%)
Granulocytopenia 37 (19) 111 (57) 2 (1) 40 (21) 114 (59) 3 (2) 51 (27) 46 (25) 3 (2)
Leukopenia 68 (35) 42 (22) 1 (<1) 64 (33) 94 (49) 4 (2) 76 (40) 51 (27) 1 (<1)
Thrombocytopenia 4 (2) 5 (3) 0 11 (6) 6 (3) 1 (<1) 14 (7) 16 (9) 0
Worst hematological 40 (21) 114 (58) 2 (1) 46 (24) 117 (61) 4 (2) 77 (41) 53 (28) 3 (2)
Pulmonary 13 (7) 2 (1) 2 (1) 6 (3) 1 (<1) 0 3 (2) 1 (<1) 0
Esophagus 7 (4) 0 0 40 (21) 3 (2) 0 78 (42) 6 (3) 0
Cardiac 2 (1) 1 (<1) 0 0 0 1 (<1) 4 (2) 3 (2) 0
Mucositis 2 (1) 0 0 21 (11) 0 0 39 (21) 3 (2) 0

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Nausea/Vomiting 22 (11) 7 (4) 0 36 (19) 7 (4) 1 (<1) 31 (17) 14 (7) 0
Anemia 13 (7) 1 (<1) 0 20 (10) 3 (2) 0 31 (17) 4 (2) 0
Other nonhematological 21 (11) 7 (4) 5 (3) 33 (17) 9 (5) 1 (<1) 42 (22) 8 (4) 3 (2)
Worst nonhematological 47 (24) 14 (7) 7 (4) 82 (42) 20 (10) 1 (<1) 90 (48) 31 (17) 3 (2)
Worst overall toxicity 47 (24) 114 (57) 7 (4) 50 (26) 121 (63) 4 (2) 79 (42) 75 (40) 3 (2)

Late radiotherapy toxicities, No. (%) Arm 1 (n = 176) Arm 2 (n = 184) Arm 3 (n = 171)
Granulocytopenia 1 (1) 0 0 0 1 (1) 0 1 (1) 0 0
Leukopenia 0 1 (1) 0 1 (1) 1 (1) 0 0 0 0
Thrombocytopenia 0 1 (1) 0 0 0 0 1 (1) 0 0
Worst hematological 1 (1) 2 (1) 0 1 (1) 1 (1) 0 2 (1) 0 0
Pulmonary 20 (11) 4 (2) 2 (1) 20 (11) 0 3 (2) 24 (14) 3 (2) 2 (1)
Esophagus 1 (1) 0 0 5 (3) 1 (1) 0 6 (4) 0 0
Cardiac 1 (1) 0 0 3 (2) 1 (1) 0 7 (4) 1 (1) 0
Nausea/Vomiting 1 (1) 0 0 1 (1) 0 0 0 0 0
Anemia 1 (1) 0 0 1 (1) 0 0 2 (1) 1 (1) 0
Other nonhematological 1 (1) 1 (1) 0 8 (4) 2 (1) 0 4 (2) 0 1 (1)
Worst nonhematological 24 (14) 5 (3) 2 (1) 29 (16) 4 (2) 3 (2) 31 (18) 4 (2) 3 (2)
Worst overall toxicity 25 (14) 7 (4) 2 (1) 30 (16) 5 (3) 3 (2) 32 (19) 4 (2) 3 (2)

* Arm 1 was the sequential arm. Arm 2 used the same chemotherapy regimen as arm 1 with 60 Gy thoracic radiotherapy beginning on day 1. Arm 3 used cisplatin
at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2-Gy twice-daily
fractions beginning on day 1.

3 with disease progression within the TRT target volume as com- before or during TRT statistically significantly improved survival
pared with arm 1 (P = .03). The time to infield disease progression in this patient cohort to MST of 13–15 months and 3-year survival
was also compared between arms 1 and 2 and between arms 1 and rates of 15%–20% (2–6). The magnitude of benefit from the addi-
3. No difference was observed between arms 1 and 2; however, tion of chemotherapy to TRT was similar among these trials, and
infield disease progression rates were reduced in arm 3 compared the optimal sequencing of chemotherapy and TRT for these
with arm 1 (P = .01). patients remained uncertain.
In 1994, the RTOG initiated this trial after observing encour-
aging phase II results with two concurrent chemoradiation regi-
Discussion mens. The MST of 17.5 months and 19.6 months seen among
The long-term results of this large phase III trial confirm the hy- patients with good performance status and low weight loss in these
pothesis generated by the promising results from one of two prior phase II trials appeared to compare favorably with the 13.8-month
phase II multi-institutional trials that the concurrent delivery of MST observed with sequential chemoradiation in two large phase
cisplatin-based chemotherapy with TRT improves survival com- III trials (7,8). These phase II regimens were therefore used as the
pared with the sequential delivery of such therapies (7). The acute basis for the investigational arms (2,3) in this trial.
toxicity, particularly esophagitis, is statistically significantly worse The statistically significant long-term survival benefit observed
with concurrent therapy, but long-term toxicity and treatment- in arm 2 compared with arm 1 supports the hypothesis that the
related mortality are equivalent. concurrent delivery of cisplatin-based chemoradiation provides an
The management of patients with locally advanced unresected improved outcome in comparison to the sequential delivery of the
NSCLC has undergone considerable change since 1990 when 60 same therapies. The promising phase II results observed in a prior
Gy TRT alone was the standard of care. TRT alone resulted in RTOG trial of delivering concurrent cisplatin-based chemoradio-
MST of 10–12 months and 3-year survival rates of 10%–15% therapy have been confirmed in this phase III randomized trial.
among patients with a good performance status and low levels of The only therapeutic variable between arms 1 and 2 was the timing
disease-related weight loss (2,3,13). The past two decades have of TRT, and no other factors such as the selection of chemother-
witnessed the maturation of at least five major randomized trials apeutic agents or the dose and schedule of any therapy have con-
demonstrating that the addition of platinum-based chemotherapy founded this result. It is likely that the radiosensitizing antitumor

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Figure 3. Five-year survival results for
patients assigned to receive standard

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radiation with concurrent chemotherapy
compared with patients assigned to
receive sequential chemotherapy and
radiotherapy. Hazard ratio for death =
0.812, 95% confidence interval = 0.663 to
0.996, P = .046, two-sided log-rank test.
Total dead at any time: Arm 1 = 189 and
Arm 2 = 185. Slash marks indicate cen-
sored observations.

effect of the chemotherapy in arm 2 contributed to the improve- Of note is another report (14) of a phase III comparison of
ment in patient survival seen in this treatment arm. The promising concurrent vs sequential cisplatin-based chemoradiation for
phase II results for the arm 3 regimen have not been supported in patients with stage III NSCLC, in which a survival advantage was
this trial. Although the reasons for this result are not clear, it is also noted. In a 314-patient trial conducted by the West Japan
possible that the higher rates of acute nonhematologic toxicity Lung Cancer Oncology Group, MST was 17 vs 13 months and
observed in this arm may have diminished the benefit of this 5-year survival was 16% vs 9% (P = .039), with concurrent chemo-
aggressive concurrent regimen. radiation compared with sequential treatment (14). The remarkable

Figure 4. Five-year survival results for

patients assigned to receive standard
radiation with concurrent chemotherapy
(arm 2) compared with patients assigned
to receive hyperfractionated radiation
with concurrent chemotherapy (arm 3).
Hazard ratio for death = 0.925, 95% con-
fidence interval = 0.752 to 1.138, P = .46,
two-sided log-rank test. Total dead at
any time: Arm 2 = 185 and Arm 3 = 175.
Slash marks indicate a censored
observation.

1458   Articles | JNCI Vol. 103, Issue 19 | October 5, 2011

Table 3. Patterns of failure* lung cancer: first analysis of a randomized trial in 353 patients. J Natl
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Arm 1 Arm 2 Arm 3 concomitant cisplatin and radiotherapy in inoperable non-small cell lung
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6. Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Hyperfractionated
Primary tumor 65 (33) 56 (29) 47 (25)
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Thoracic lymph nodes (infield) 34 (17) 24 (12) 18 (10)
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Thoracic lymph nodes (out of field) 4 (2) 8 (4) 3 (2)
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Brain metastases 24 (12) 28 (14) 24 (13)
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Other metastases 65 (33) 64 (33) 60 (32)
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Future approaches to patients with locally advanced NSCLC
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jnci.oxfordjournals.org   JNCI | Articles 1459

Notes Center, Houston, TX (RK, JDC); Lung Cancer Branch, National Cancer Center,
The funders did not have any involvement in the design of the study; the Kyonggi, Korea (JSL); Formerly of University of California at San Francisco, San
collection, analysis, and interpretation of the data; the writing of the article; or Francisco, CA (SH); Department of Radiation Oncology, Hartford Hospital Gray
the decision to submit the article for publication. Cancer Center, Hartford, CT (SH); Formerly of Fox Chase Cancer Center,
Philadelphia, PA (BM); Department of Radiation Oncology, Henry Ford Hospital,
Detroit, MI (BM); Department of Radiation Oncology, Washington University,
Affiliations of authors: Department of Radiation Oncology and Winship St Louis, MO (TW); Radiological Associates of Sacramento, Sacramento, CA
Cancer Institute, Emory University, Atlanta, GA (WJC); Radiation Therapy (SAR); Department of Radiation Oncology, Medical College of Wisconsin,
Oncology Group Statistical Center, Philadelphia, PA (RP); Abramson Cancer Milwaukee, WI (EG); Department of Radiation Oncology, Case Western
Center, University of Pennsylvania Medical Center, Philadelphia, PA (CJL); Reserve University School of Medicine, Cleveland, OH (MM); Department
Division of Radiation Oncology, University of Texas MD Anderson Cancer of Radiation Oncology, Intermountain Medical Center, Murray, UT (WS).

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1460   Articles | JNCI Vol. 103, Issue 19 | October 5, 2011