Research

JAMA Oncology | Original Investigation

Prophylactic Cranial Irradiation vs Observation in Patients

With Locally Advanced Non–Small Cell Lung Cancer
A Long-term Update of the NRG Oncology/RTOG 0214 Phase 3
Randomized Clinical Trial
Alexander Sun, MD; Chen Hu, PhD; Stuart J. Wong, MD; Elizabeth Gore, MD; Gregory Videtic, MD;
Swati Dutta, MD; Mohan Suntharalingam, MD; Yuhchyau Chen, MD, PhD; Laurie E. Gaspar, MD; Hak Choy, MD

Supplemental content
IMPORTANCE Brain metastasis (BM) rates are high in locally advanced non–small cell lung
cancer (LA-NSCLC), approaching rates seen in small cell lung cancer, where prophylactic
cranial irradiation (PCI) is standard of care. Although PCI decreases the incidence of BM in
LA-NSCLC, a survival advantage has not yet been shown.

OBJECTIVE To determine if PCI improves survival in LA-NSCLC.

DESIGN, SETTING, AND PARTICIPANTS Radiation Therapy Oncology Group (RTOG) 0214 was a
randomized phase 3 clinical trial in stage III NSCLC stratified by stage (IIIA vs IIIB), histologic
characteristics (nonsquamous vs squamous) and therapy (no surgery vs surgery). The study
took place at 291 institutions in the United States, Canada, and internationally. Of 356
patients with stage III NSCLC entered onto this study, 16 were ineligible; therefore, 340
patients were randomized.

INTERVENTION FOR CLINICAL TRIALS Observation vs PCI.

MAIN OUTCOMES AND MEASURES The primary outcome was overall survival (OS). The
secondary end points were disease-free survival (DFS) and incidence of BM.

RESULTS Of the 340 total participants, mean (SD) age was 61 years; 213 of the participants
were men and 127 were women. The median follow-up time was 2.1 years for all patients, and
9.2 years for living patients. The OS for PCI was not significantly better than observation
(hazard ratio [HR], 0.82; 95% CI, 0.63-1.06; P = .12; 5- and 10-year rates, 24.7% and 17.6% vs
26.0% and 13.3%, respectively), while the DFS (HR, 0.76; 95% CI, 0.59-0.97; P = .03; 5- and Author Affiliations: Princess
Margaret Cancer Centre, Toronto,
10-year rates, 19.0% and 12.6% vs 16.1% and 7.5% for PCI vs observation) and BM (HR, 0.43;
Ontario, Canada (Sun); NRG
95% CI, 0.24-0.77; P = .003; 5- and 10-year rates, 16.7% vs 28.3% for PCI vs observation) Oncology Statistics and Data
were significantly different. Patients in the PCI arm were 57% less likely to develop BM than Management Center, Philadelphia,
those in the observation arm. Younger patients (<60 years) and patients with nonsquamous Pennsylvania (Hu); Johns Hopkins
University School of Medicine,
disease developed more BM. On multivariable analysis, PCI was associated with decreased Baltimore, Maryland (Hu); Medical
BM and improved DFS, but not improved OS. Multivariable analysis within the nonsurgical College of Wisconsin, Milwaukee
arm suggests that PCI effectively prolongs OS, DFS, and BM. (Wong, Gore); Cleveland Clinic
Foundation, Cleveland, Ohio
(Videtic); Michigan Cancer Research
CONCLUSIONS AND RELEVANCE In patients with stage III LA-NSCLC without progression of Consortium CCOP, Ann Arbor (Dutta);
disease after therapy, PCI decreased the 5- and 10-year rate of BM and improved 5- and University of Maryland Medical
10-year DFS, but did not improve OS. Although this study did not meet its primary end point, System, Baltimore (Suntharalingam);
University of Rochester, Rochester,
the long-term results reveal many important findings that will benefit future trials. Identifying New York (Chen); University of
the appropriate patient population and a safe intervention is critical. Colorado, Denver (Gaspar);
University of Texas Southwestern
Medical Center, Dallas (Choy).
TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00048997
Corresponding Author: Alexander
Sun, MD, Department of Radiation
Oncology, Princess Margaret Cancer
Centre–University Health Network,
University of Toronto, 610 University
JAMA Oncol. doi:10.1001/jamaoncol.2018.7220 Ave, Toronto, Ontario, Canada M5G
Published online March 14, 2019. 2M9 (alex.sun@rmp.uhn.on.ca).

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 Research Original Investigation Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non–Small Cell Lung Cancer

Figure 1. Participant Enrollment Flow Diagram

356 Randomized
176 Allocated to intervention
158 Received allocated
intervention
8 Lost to follow-up
8 Patients withdrew consent to
follow-up
163 Analyzed
13 Excluded from analysis
6 Withdrew consent
5 Registered >16 weeks
from completion of
definitive therapy
1 Bone metastasis at time
of registration
1 Patient had colon cancer,
not NSCLC
NSCLC indicates non–small cell lung cancer.
180 Allocated to observation
4 Lost to follow-up
4 Patients withdrew consent
to follow-up
177 Analyzed
3 Excluded from analysis
2 Registered >16 weeks
from completion of
definitive therapy
1 Withdrew consent
Key Points
Question Does prophylactic cranial irradiation (PCI) improve
survival in patients with locally advanced non–small cell lung
cancer (LA-NSCLC) compared with observation alone?
Findings In this prospective randomized phase 3 clinical trial
including 340 evaluable patients with LA-NSCLC, PCI decreased
the 5- and 10-year rate of brain metastases and improved 5- and
10-year disease-free survival, but did not improve overall survival
compared with observation alone.
Meaning Although this study did not meet its primary end point
of overall survival, the long-term results reveal many important PCI
findings, which will benefit future trials.
patient recruitment and all patients signed approved in-
formed consents prior to trial enrollment. The trial protocol
is available in Supplement 1.
Treatment and Follow-up
Patients were stratified by stage (IIIA or B), histologic charac-
teristics (nonsquamous or squamous), and therapy (surgery
or no surgery) and then randomized to PCI or observation. Pa-
tients randomized to PCI were treated with 2 Gy/fraction, five

C
ombined-modality therapy, including chemotherapy,
irradiation, and/or surgery, has resulted in improved sur-
vival of locally advanced non–small cell lung cancer (LA-
NSCLC). This lengthened survival is associated with in-
creased incidence of brain metastases (BM),1-12 which can have
a devastating impact on survival and quality of life (QOL). Rates
of BM reported in NSCLC studies are as high as 55%,13-20 ap-
proaching rates seen in small cell lung cancer (SCLC), where
prophylactic cranial irradiation (PCI) is standard of care. Al-
though PCI decreases the incidence of BM in LA-NSCLC,21-23
a survival advantage has not yet been shown.
The NRG Oncology/Radiation Therapy Oncology Group
(RTOG) led a study of PCI in LA-NSCLC after definitive pri-
mary therapy. The primary end point of the study was overall
survival (OS), with secondary end points including disease-
free survival (DFS) and development of BM. This is an up-
dated long-term analysis of the previously reported prelimi-
nary results.24
days per week, to 30 Gy. Acute PCI toxic events were evalu-
ated using the Common Terminology Criteria (CTC) version 2.0
grading criteria. Late PCI toxic events were evaluated using the
RTOG/European Organisation for Research and Treatment of
Cancer (EORTC) Late Toxicity Criteria. Patients were fol-
lowed up 6 months from start of PCI, every 6 months for 2 years
and then yearly. Brain imaging with MRI or CT was per-
formed at 6 and 12 months and then annually thereafter.
Study Design and End Points
The primary end point of this study was OS, and secondary end
points included DFS and BM. Overall survival failure events
were defined as death due to any cause. Disease-free survival
failure events were defined as the earliest event of death due
to any cause, local progression, regional metastasis, distant me-
tastasis, or second primary. Brain metastases failure events
were defined as any evidence of BM. Time to event was mea-
sured from date of randomization to date of failure or date of
most recent follow-up if no failure occurred.

Methods
Patient Population
Patients with stage IIIA/B NSCLC without disease progres-
sion after completing definitive locoregional therapy with ir-
radiation and/or surgery with or without chemotherapy were
randomized to PCI or observation (Figure 1). Patients were re-
staged and enrolled within 16 weeks of completing definitive
therapy. Patients were restaged with a computed tomogra-
phy (CT) scan of the chest/abdomen and magnetic resonance
imaging (MRI) of the brain within six weeks of study entry.
Brain CT with contrast was allowed if MRI was contraindi-
cated. Patients could have no evidence of progressive intra-
thoracic disease, BM, or extracranial metastases. All institu-
tions obtained institutional review board approval prior to
Statistical Methods
The rates of OS and DFS were estimated using Kaplan-Meier
method,25 and BMs were estimated using cumulative inci-
dence function.26 The comparisons between PCI and obser-
vation were based on log-rank tests27,28 stratified by Ameri-
can Joint Committee on Cancer (AJCC) stage (IIIA vs IIIB); prior
surgery (no vs yes); histologic characteristics (nonsquamous
vs squamous) and Zubrod performance status (0 vs >0). Cox
proportional hazards models29 were used to evaluate the im-
pact of treatment on OS and DFS after adjusting for all these
factors and age (<60 vs ≥60 years). Cause-specific hazard ap-
proach was used to analyze BM in presence of death without
BM as a competing event. 30 Subgroup analysis was per-
formed based on prespecified stratification factors at random-
ization when the heterogeneity of treatment effects was sup-

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 Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non–Small Cell Lung Cancer Original Investigation Research

Table 1. Outcome Estimates for Entire Study

PCI (n = 163) Observation (n = 177)

Event Estimate % (95% Event Estimate % (95%
Outcome by Time No. at Risk CI) No. at Risk CI) PCI vs Observation, HR (95% CI)a P Valueb
Overall survival 0.82 (0.63-1.06) .12
2y 90 56.3 (48.3-63.6) 91 53.0 (45.3-60.1)
5y 39 24.7 (18.3-31.6) 42 26.0 (19.6-32.8)
10 y 15 17.6 (12.1-23.9) 11 13.3 (8.4-19.4)
MST (95% CI) 2.4 y (2.0-2.9) 2.1 y (1.7-2.7)
No. of events 131 146
Disease-free survival 0.76 (0.59-0.97) .03
2y 58 36.1 (28.7-43.5) 55 31.5 (24.7-38.4)
5y 30 19.0 (13.3-25.4) 26 16.1 (11.0-22.0)
10 y 10 12.6 (8.0-18.3) 7 7.5 (4.0-12.5)
MST (95% CI) 1.3 y (1.0-1.6) 1.0 (0.9-1.1)
No. of events 141 159
Brain metastasis 0.43 (0.24-0.77) .003
2y 86 10.9 (6.7-17.6) 81 24.3 (18.1-32.0)
5y 39 16.7 (10.6-25.9) 37 28.3 (21.2-37.2)
10 y 15 16.7 (10.6-25.9) 11 28.3 (21.2-37.2)
MST (95% CI) Not reached Not reached
No. of events 20 40
Abbreviations: AJCC, American Joint Committee on Cancer; HR, hazard ratio; squamous) and Zubrod performance status (0 vs >0).
MST, median survival time; PCI, prophylactic cranial irradiation. b
From stratified log-rank test, stratified by AJCC stage (IIIA vs IIIB); prior surgery
a
From stratified Cox proportional hazard model, stratified by AJCC stage (IIIA vs (no vs yes); histologic characteristics (nonsquamous vs squamous) and Zubrod
IIIB); prior surgery (no vs yes); histologic characteristics (nonsquamous vs performance status (0 vs >0).

ported by tests for interaction (eg, prior surgery) or of interest
(eg, histology).31 All statistical comparisons were considered
statistically significant at a 2-sided P < .05, and no multiple
comparison adjustments were made. All statistical analyses
were run with SAS, 9.4 (SAS Institute Inc) software.
Results
This study opened on September 19, 2002, and closed owing
to poor accrual on August 30, 2007. This report includes all data
reported as of December 15, 2016. All data analysis took place
from December 1, 2017 to January 15, 2018. A total of 527 deaths
and a projected accrual of 1058 participants were targeted to
detect a 20% risk reduction (hazard ratio [HR], 0.8, observa-
tion arm as reference) in death with 80% power and a 1-sided
significance level of P = .025. The total accrual at study clo-
sure was 356 patients. Among 356 patients entered, 9 pa-
tients (7 PCI, 2 observation) were ineligible and 7 patients (6
PCI, 1 observation) withdrew consent. Therefore 340 pa-
tients were eligible for this study. The median follow-up time
was 2.1 years (range, 0.1-12.6 years) for all patients, and 9.2 years
for 63 patients still alive. The pretreatment characteristics were
evenly distributed between the 2 arms except Zubrod perfor-
mance status . The majority of patients received a platinum
doublet chemotherapy regimen.
Primary End Point
At the time of this analysis, 277 deaths had occurred in 340
evaluable patients, which provided approximately 45% power
to detect the targeted difference in OS. Patients died primar-
ily due to their lung cancer. The survival estimates and HR in-
dicated that there appeared to be no improvement in survival
with the use of PCI. Five-year and 10-year OS rates were 24.7%
and 17.6% for PCI and 26.0% and 13.3% for observation, re-
spectively (Table 1 and Figure 2). Estimated median survival
(MS) duration was 2.4 years (95% CI, 2.0-2.9) and 2.1 years (95%
CI, 1.7-2.7) for PCI and observation, respectively. The HR for
PCI vs observation was 0.82 (95% CI, 0.63-1.06; P = .12).
DFS and BM
There were 300 DFS events at the time of analysis. Five-year
and 10-year DFS rates were 19.0% and 12.6% for PCI and 16.1%
and 7.5% for observation, respectively (P = .03) (Table 1 and
Figure 2). The HR for PCI vs observation was 0.76 (95% CI, 0.59-
0.97). There were 60 BM events and the 5-year and 10-year BM
rates were 16.7% in the PCI arm and 28.3% in the observation
arm (P = .004) (Table 1 and Figure 2). The corresponding HR
was 0.43 (95% CI, 0.24-0.77). These results continued to be
statistically significant.
Prognostic Variables
Multivariable Cox proportional hazards models were per-
formed (Table 2). Surgery, Zubrod performance status, and age
were associated with OS. Surgery was associated with DFS. A
multivariable model of BM was also performed, but owing to
the limited number of events, the results should be inter-
preted with caution. Use of PCI remained strongly associated
with decreased risk of developing BM; histological character-
istics and age also appeared to be important factors. Younger

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 Research Original Investigation Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non–Small Cell Lung Cancer

in the PCI arm and 30 (23%) patients in the observation arm

Figure 2. PCI vs Observation in Patients with Locally Advanced Non–
Small Cell Lung Cancer
experienced treatment failure in the brain as the first site of
failure, of which, ten (9%) and 28 (21%) were isolated events,
A Overall survival respectively. Among patients whose treatments failed, 75 (66%)
100 in the PCI arm and 68 (52%) in the observation arm first ex-
perienced local or regional failure; 62 (54%) in the PCI arm and
75 80 (61%) in the observation arm first experienced distant fail-
Overall Survival, %

ure; 23 (20%) in the PCI arm and 17 (13%) in the observation

50 arm first experienced local/regional and distant failure; and 9
(8%) PCI and 16 (12%) observation patients developed a sec-
ond primary tumor prior to experiencing any other failure
25 PCI
(eFigure 1 in Supplement 2).
Observation
0
0 1 2 3 4 5 6 7 8 9 10 11 Subgroup Analysis
Time Since Randomization, y There were 225 patients (66%) who did not have surgery.
PCI 163 122 90 64 47 39 35 34 30 22 15 Table 3 details the OS between the PCI and observation arms
Observation 177 134 91 65 51 42 35 33 24 17 11
in this subgroup. As evidenced by the data in Table 3, there were
significant differences in OS between the 2 arms, with an MS
B Disease-free survival
of 2.3 years for PCI and 1.9 years for observation, respec-
100
tively. The rates of DFS were significantly different between
the 2 arms. For BM, the rates for PCI were significantly lower
Disease-Free Survival, %

75
than those for observation. Multivariable analysis of OS
(eTable 1 in Supplement 2) revealed PCI patients had lower risks
50 of death (HR, 0.73; 95% CI, 0.54-0.98; P = .04). Zubrod per-
formance status (>0) was found to be significantly associated
PCI
25 with increased risk of death. A lower risk of DFS events was
Observation associated with PCI (HR, 0.70; 95% CI, 0.52-0.93; P = .01). For
0 BM, PCI patients were less likely to develop BM than those in
0 1 2 3 4 5 6 7 8 9 10 11
observation (HR, 0.34; 95% CI, 0.17-0.68; P = .002). In addi-
Time Since Randomization, y
tion, younger (<60 years) patients and patients with nonsqua-
PCI 163 91 58 46 36 30 27 25 23 16 10
Observation 177 92 55 35 29 26 23 22 15 9 7 mous cancers had higher rates of BM.
For subgroup analysis of the 115 patients treated with sur-
C Brain metastasis gery, there was no difference between the 2 arms for OS, MS,
100 DFS, or BM. Multivariable analysis (eTable2 in Supplement 2)
revealed that older age (≥60 years) and stage IIIB cancer were
75 associated with increased risks of death. In addition, patients
with stage IIIB cancer had higher risk of DFS events, and pa-
tients with nonsquamous cancer had higher risk of BM.
50
There was no difference between PCI and observation
Observation among the 225 patients with nonsquamous histologic charac-
25
PCI teristics with respect to OS (eTable3 in Supplement 2). Simi-
lar to the main analysis, there was a significant benefit for DFS
0 (HR, 0.72; 95% CI, 0.53-0.98; P = .04) and BM (HR, 0.43; 95%
0 1 2 3 4 5 6 7 8 9 10 11
Time Since Randomization, y CI, 0.25-0.78; P = .01) with the use of PCI. There were 115 pa-
PCI 163 115 86 62 47 39 35 34 30 22 15
tients with squamous histologic characteristics. There was no
Observation 177 117 81 58 46 37 31 31 23 17 11 difference in OS and DFS between the 2 arms. There was an
insufficient number of events within the BM end point for sub-
PCI indicates prophylactic cranial irradiation.
group analysis in this population.

patients (<60 years) and patients with nonsquamous cancer
were more likely to develop BM.
Patterns of First Failure
A total of 114 and 132 patients in the PCI and observation arms,
respectively, experienced some sort of treatment failure. Fail-
ing locally was defined as failure at the primary site; region-
ally was defined as the regional lymph nodes, and distantly was
any site beyond local or regional. Of these, 11 (10%) patients
PCI-Related Toxic Events
Grade 3 acute PCI toxic events occurred in 6 (4%) of the cases
in the PCI arm, which included fatigue, hematologic, ataxia,
depression, and headache. There was 1 (1%) grade 4 acute PCI
toxic event reported (depression). Five (3%) patients in the PCI
arm reported grade 3 late PCI toxic events. The only addi-
tional grade 3 late PCI toxic event, not reported initially, was
soft-tissue necrosis. Neurocognitive function findings were pre-

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 Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non–Small Cell Lung Cancer Original Investigation Research

Table 2. Cox Proportional Hazard Multivariable Analysis Results for Entire Study

Overall Survival Disease-Free Survival Brain Metastasis

Covariate Comparison HR (95% CI) P Value HR (95% CI) P Value HR (95% CI) P Value
Treatment arm PCI 0.84 (0.66-1.07) .16 0.78 .04 0.44 (0.25-0.77 .01
(0.62-0.99)
Observation (RL) 1 [Reference]
Age ≥60 years 1.39 (1.08-1.79) .01 1.14 (0.90 .29 0.57 (0.34-0.97) .04
1.45
<60 years 1 [Reference]
Zubrod >0 1.34 (1.05-1.72) .02 1.18 .17 1.00 (0.59-1.70) .99
(0.93-1.49)
0 1 [Reference]
Prior surgery Yes 0.82 (0.62-1.07) .14 0.79 .07 0.65 (0.36-1.19) .16
(0.61-1.02)
No 1 [Reference]
AJCC stage IIIB 1.17 (0.91-1.50) .22 1.23 .10 0.88 (0.51-1.54) .65
(0.96-1.56)
IIIA 1 [Reference]
Histologic Squamous 1.08 (0.84-1.39) .56 1.01 .91 0.20 (0.08-0.46) .01
characteristics (0.80-1.29)
Nonsquamous 1 [Reference]

Abbreviations: AJCC, American Joint Committee on Cancer; HR, hazard ratio; MST, median survival time; PCI, prophylactic cranial irradiation.

viously published,32,33 however, with longer follow-up, there
was insufficient data for further analysis.
Discussion
The NRG Oncology/RTOG 0214 randomized clinical trial was
developed to address the apparent increasing incidence of BM
in patients who are living longer with improved control of lo-
coregional disease with advanced radiation and surgery tech-
niques and who are experiencing fewer extracranial distant me-
tastases with multidrug chemotherapy. Studies have shown
t h at t h o s e w it h a d e n o c a r c i n o m a o r n o n s q u a m o u s
disease16,18,34,35 were at higher risk of BM. Higher BM rates are
also associated with greater extent of disease.5,17,36,37 Addi-
tionally, studies with trimodality therapy including surgery re-
ported the highest rates of BM.2,3,5-7,9,10,12 The NRG Oncology/
RTOG 0214 trial was therefore stratified by histologic
characteristics (squamous or nonsquamous), stage (IIIA or IIIB),
and therapy for primary disease (surgery or no surgery) to mini-
mize potential bias in estimating overall treatment effect due
to any heterogeneous treatment effects within these sub-
groups. Although this study was closed prematurely owing to
poor accrual, it still represents the largest randomized clini-
cal trial to evaluate PCI in LA-NSCLC to our knowledge. With
one-third of the planned sample size, the current long-term
report was only able to provide approximately 45% power to
detect the hypothesized effect size in OS. Not surprisingly, this
long-term analysis failed to show a statistically significant im-
provement in OS, although the observed magnitude (HR, 0.82)
was numerically similar to the hypothesized (HR, 0.8). In ad-
dition, with more events than the initial report, this study
shows that PCI improves DFS and decreases the risk of BM by
57%. A number of randomized and nonrandomized studies
have consistently shown that PCI is associated with de-
creased risk of BM in patients with LA-NSCLC.2,7,9,10,12,21-23,38,39
On multivariable analysis, observation, nonsquamous can-
cer, and age (<60 years) were associated with higher risk of BM,
while performance status, surgery, and stage were not. There
was no difference in BM rates between patients with stage IIIA
and IIIB disease. However, data regarding volume of disease
and extent of nodal involvement were not available. Ceresoli
et al5 reported borderline significance of bulky mediastinal dis-
ease (nodes >2 cm) and the incidence of BM. Robnett et al17
reported 2-year actuarial incidence of BM of 36% with stage
IIIB disease and 29% with stage II/IIIA disease. Wang et al34
conducted a more extensive analysis of impact of nodal dis-
ease on BM in 223 patients treated surgically with stage IIIA/B
disease. Brain metastases were greater in patients with more
lymph nodes and nodal regions involved.
In multivariable analysis of the patients studied by Cer-
esoli et al,5 age younger than 60 years was associated with an
increased risk of BM (31% vs 9%, P = .03). Carolan et al14 showed
that 25.6% of patients younger than 60 years experienced first
failure in the brain compared with 11.4% of patients 60 years
or older. In a review of 4 SWOG studies, patients younger than
50 years of age were at increased risk for developing BM with
a hazard ratio of 1.8 (P = .046).13 Review of the Metropolitan
Detroit Cancer Surveillance System showed the highest inci-
dence of BM in patients with lung cancer occurred in patients
between the ages of 40 and 49 years.40 Other series have not
shown an increased risk of BM with young age.1,17
The reliability of subset analyses in this trial are limited by
the low numbers, although the results are informative and may
guide future trials. The rates of OS and DFS were evaluated in
subsets of patients with nonsquamous cancer, with surgery,
and without surgery for primary disease. Patients with nons-
quamous disease had more BMs than those with squamous dis-
ease. The use of PCI significantly decreased the risk of BM (HR,
0.43; 95% CI, 0.24-0.78; P = .01) and a DFS event (HR, 0.72;
95% CI, 0.53-0.98; P = .04). Perhaps there was no difference
between PCI and observation among the 225 patients with non-

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 Research Original Investigation Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non–Small Cell Lung Cancer

Table 3. Outcome Estimates, by Prior Surgery Status

Event Estimate % (95% Event Estimate % (95%
Outcome by Time No. at Risk CI) No. at Risk CI) PCI vs Observation HR (95% CI)a P Valueb
No Prior Surgery
PCI (n = 106) Observation (n = 119)
Overall survival 0.70 (0.52-0.96) .03
2y 60 58.3 (48.2-67.1) 54 47.7 (38.3-56.4)
5y 23 22.8 (15.2-31.3) 21 19.5 (12.7-27.3)
10 y 9 16.6 (10.1-24.5) 5 8.9 (4.2-15.7)
MST (95% CI) 2.3 y (2.0-3.0) 1.9 (1.4-2.2)
No. of events 85 102
Disease-free survival 0.69 (0.51-0.93) .01
2y 38 36.6 (27.5-45.8) 28 24.0 (16.7-32.0)
5y 18 17.8 (11.1-25.8) 12 10.7 (5.9-17.1)
10 y 6 11.7 (6.4-18.9) 3 4.9 (1.8-10.2)
MST (95% CI) 1.1 y (0.8-1.6) 1.0 (0.6-1.0)
No. of events 92 110
Brain metastasis 0.36 (0.18-0.72) .01
2y 57 9.5 (5.0-17.5) 47 27.0 (19.2-37.2)
5y 23 13.0 (7.3-22.8) 19 31.0 (22.1-42.3)
10 y 9 13.0 (7.3-22.8) 5 31.0 (22.1-42.3)
MST (95% CI) Not reached Not reached
No. of events 11 29
Prior Surgery
PCI (n = 57) Observation (n = 58)
Overall survival 1.15 (0.72-1.84) .56
2y 30 52.6 (39.0-64.6) 37 63.8 (50.1-74.7)
5y 16 28.1 (17.2-40.0) 21 38.9 (26.3-51.2)
10 y 6 19.3 (10.3-30.4) 6 22.1 (11.9-34.4)
MST (95% CI) 2.5 y (1.4-3.4) 3.1 y (2.2-5.3)
No. of events 46 44
Disease-free survival 0.95 (0.60-1.51) .84
2y 20 35.1 (23.1-47.4) 27 46.6 (33.4-58.7)
5y 12 21.1 (11.6-32.4) 14 27.0 (16.2-38.9)
10 y 4 14.0 (6.6-24.3) 4 12.9 (5.1-24.4)
MST (95% CI) 1.5 y (1.0-1.6) 1.6 y (1.0-2.6)
No. of events 49 49
Brain metastasis 0.66 (0.24-1.84) .43
2y 29 13.6 (6.3-28.0) 34 19.1 (10.7-32.7)
5y 16 22.6 (11.3-42.0) 18 23.1 (13.1-39.0)
10 y 6 22.6 (11.3-42.0) 6 23.1 (13.1-39.0)
MST (95% CI) Not reached Not reached
No. of events 8 11
Abbreviations: AJCC, American Joint Committee on Cancer; HR, hazard ratio; performance status (0 vs >0).
MST, median survival time; PCI, prophylactic cranial irradiation. b
From stratified log-rank test, stratified by AJCC stage (IIIA vs IIIB); histologic
a
From stratified Cox proportional hazard model, stratified by AJCC stage (IIIA vs characteristics (nonsquamous vs squamous) and Zubrod performance status
IIIB); histologic characteristics (nonsquamous vs squamous) and Zubrod (0 vs >0).

squamous cancer with respect to OS; as in a subgroup of pa-
tients, targeted therapies can be effective as salvage treat-
ment, including for BM, especially new-generation targeted
agents.41-46
Although it was expected that patients with surgery for
treatment of primary disease would have a higher rate of BM
and would therefore be more likely to benefit from PCI, this
was not shown in this trial. Contrary to what was anticipated,
subset analyses showed that patients with surgery had a rela-
tively low rate of BM, and the risk did not appear to be influ-
enced by PCI. A possible explanation is that patients in the NRG
Oncology/RTOG 0214 trial who were undergoing surgery had
more favorable disease than in reported trimodality trials. The
proportion of patients with subclinical or gross N2 disease is
not known, although it is likely that patients treated surgi-
cally had lower-volume disease, including bulk of nodal dis-

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 Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non–Small Cell Lung Cancer
ease and number of nodal stations, relative to the nonsurgi-
cal patients in this trial.
Subset analysis of patients treated nonsurgically showed
higher incidence of BM in the observation arm at 5 and 10 years
(31%) than in the observation arm of the surgery group (23%).
This may be owing to higher risk of BM in the nonsurgical group
owing to disease burden. Median OS (2.3 years vs 1.9 years,
P = .03) and DFS (1.1 years vs 1.0 years; P = .01) were better with
PCI in nonsurgical patients. On multivariable analysis, PCI and
favorable performance status were associated with improved
OS, and PCI was associated with improved DFS in the nonsur-
gical subset. The therapeutic effect of PCI, if any, appears to
be mainly driven by patients treated without surgery. Multi-
variable analysis within this patient population suggests that
PCI effectively prolongs OS (HR, 0.73; P = .04) and DFS (HR,
0.70; P = .01), and decreases BM (HR, 0.34; P = .002). The origi-
nal study design assumed the MS time for operable and inop-
erable patients as 38 and 17 months, respectively, and hypoth-
esized detection of a 20% relative risk reduction among both
operable and inoperable patients (HR, 0.8, observation arm as
reference level). Had all patients in this study been treated with-
out surgery, the corresponding subgroup analysis suggests that
PCI would have effectively reduced the relative risk of death
by 30% (HR, 0.70). We had hypothesized that the incidence
rates of BM would improve from 23.4% to 15.0% by using PCI.
This long-term analysis supports this hypothesis in both the
overall population (28.3% to 16.7%, HR, 0.43) and in patients
treated without surgery (31.0% to 13.0%, HR, 0.36).
Of the patients who experienced failure, 10% in the PCI arm
and 23% in the observation arm experienced failure in the brain
as the first site of failure, of which 9% and 21% were isolated
events, respectively. With the advent of stereotactic radiosur-
gery for BM, it is likely that many of these patients were treated
with stereotactic radiosurgery, thereby potentially confound-
ing the OS results, more so in the observation arm. Further-
more, the decrease in BM, especially as the first site of fail-
ure, likely contributed to the improvement in DFS seen in the
PCI arm. Since BMs have such a profound impact on QOL, it is
likely that this benefit in DFS would translate into improved
QOL. Unfortunately, we do not have enough long-term data
on QOL to confirm this potentially important finding.
The main difference between the preliminary analysis and
this long-term update is the improvement in DFS. With lon-
ger follow-up, DFS of PCI patients became statistically signifi-
cantly better than observation (HR, 0.76, 95% CI, 0.59-0.97;
P = .03; 5- and 10-year rates 19.0% and 12.6% vs 16.1% and 7.5%
for PCI vs observation). Although OS was also improved with
longer follow-up, it was not significant.(HR, 0.82; 95% CI, 0.63-
1.06; P = .12; 5- and 10-year rates, 24.7% and 17.6% vs 26.0%
and 13.3%, for PCI vs observation) The lack of patients ac-
crued likely contributed to the lack of OS benefit. Unfortu-
nately, it is unlikely with even longer follow-up that OS will
show a difference in this study because of the limited num-
bers of patients still alive.
ARTICLE INFORMATION Published Online: March 14, 2019.
Accepted for Publication: November 30, 2018. doi:10.1001/jamaoncol.2018.7220
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Original Investigation Research
It is the risk-benefit ratio that helps to determine the ad-
visability of a particular treatment. The risks of PCI are mainly
related to the effects on neurocognitive function, which we and
others have previously reported.2,7,32,33,47-50 Effective strate-
gies to decrease these risks include the use of the neuropro-
tectant memantine51 and PCI with hippocampal avoidance.52-55
Both of these strategies have shown promising results when
treating known BM with whole brain radiotherapy. Prospec-
tive randomized phase 2/3 studies will be addressing these
same strategies in SCLC, where PCI is part of standard of
care56-59 and may be appropriate for select patients with LA-
NSCLC and high risk of BM.
The challenge in the future is to exploit the therapeutic ra-
tio of benefits vs risks. Patients most likely to benefit from PCI
are those at highest risk of developing BM. These patients
would include those treated without surgery or with poor risk
features such as nonsquamous cancer, young age, and high-
volume disease. To minimize the risk, promising strategies in-
clude hippocampal avoidance radiotherapy techniques and/or
neuroprotectants (memantine). Furthermore, as the stan-
dard treatment of unresectable stage III disease is in the pro-
c e s s o f c h a nge w it h t h e a dd it i o n o f c o n s o l i d at i o n
immunotherapy,60,61 this has to be taken into account for fu-
ture trials.
Limitations
The main limitation of this study was the lack of patient ac-
crual, which likely contributed to the lack of OS benefit for the
entire cohort. If the planned sample size had been accrued, then
there may have been enough statistical power to detect the hy-
pothesized effect size in OS, as the observed magnitude (HR,
0.82) was numerically similar to the hypothesized (HR, 0.8).
This study, the largest randomized phase 3 clinical trial to evalu-
ate PCI in LA-NSCLC to our knowledge, is currently part of an
international collaborative effort, which is performing an in-
dividual patient data meta-analysis of similar randomized stud-
ies. It is hoped that this meta-analysis will have the power to
detect an OS advantage for PCI, as was the case for the estab-
lishment of PCI in SCLC.56
Conclusions
In conclusion, this final analysis did not show an overall sur-
vival benefit, although PCI improved DFS and decreased the
risk of BM in patients with LA-NSCLC. It is very unlikely that
a single definitive study with and without PCI for NSCLC will
ever be completed, although establishing an accepted means
of prevention of BM remains important. Currently, the most
effective therapy to prevent BMs is PCI. Identifying the ap-
propriate patient population and a safe intervention is criti-
cal.
Author Contributions: Dr Sun had full access to all
of the data in the study and takes responsibility for
(Reprinted) JAMA Oncology Published online March 14, 2019 E7
 Research Original Investigation
the integrity of the data and the accuracy of the
data analysis..
Study concept and design: Sun, Hu, Gore, Choy.
Acquisition, analysis, or interpretation of data: Sun,
Hu, Wong, Gore, Videtic, Dutta, Suntha, Chen,
Gaspar.
Drafting of the manuscript: Sun, Hu, Gore.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Sun, Hu.
Obtained funding: Choy.
Administrative, technical, or material support: Sun,
Wong, Gore, Choy.
Study supervision: Sun, Hu, Gore, Choy.
Conflict of Interest Disclosures: Dr Choy reports
stock/ownership interest in Texas Radiotherapy
Innovation and Optimization, consulting/advisory
role with Vertex Pharmaceutical and Boehringer
Ingelheim, and research funding from Celgene. No
other disclosures are reported.
Funding/Support: This project was supported by
RTOG grant U10 CA21661, CCOP grant U10
CA37422, and Stat grant U10 CA32115 from the
National Cancer Institute (NCI). This manuscript’s
contents are solely the responsibility of the authors
and do not necessarily represent the official views
of the National Cancer Institute.
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Data Sharing Statement: See Supplement 3.
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