Download Multinational Randomized Phase III Trial With or Without

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33
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2015
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Multinational Randomized Phase III Trial With or Without
Consolidation Chemotherapy Using Docetaxel and
Cisplatin After Concurrent Chemoradiation in Inoperable
Stage III Non–Small-Cell Lung Cancer: KCSG-LU05-04
Jin Seok Ahn, Yong Chan Ahn, Joo-Hang Kim, Chang Geol Lee, Eun Kyung Cho, Kyu Chan Lee, Ming Chen,
Dong-Wan Kim, Hoon-Kyo Kim, Young Joo Min, Jin-Hyoung Kang, Jin-Hyuck Choi, Sang-We Kim,
Guangying Zhu, Yi-Long Wu, Sung Rok Kim, Kyung Hee Lee, Hong Suk Song, Yoon-La Choi, Jong-Mu Sun,
Sin-Ho Jung, Myung-Ju Ahn, and Keunchil Park
Author affiliations appear at the end of
this article.
Published online ahead of print at
www.jco.org on July 6, 2015.
Supported in part by sanofi-aventis
Korea.
Presented in part at the 12th World Conference on Lung Cancer, Seoul, Korea,
September 2-5, 2007; the 45th Annual
Meeting of the American Society of Clinical
Oncology, Orlando, FL, May 31-June 4,
2009, and the 50th Annual Meeting of the
American Society of Clinical Oncology,
Chicago, IL, May 30-June 3, 2014.
Authors’ disclosures of potential conflicts
of interest are found in the article online at
www.jco.org. Author contributions are
found at the end of this article.
Clinical trial information: NCT00326378.
Written on behalf of the Korean Cancer
Study Group.
Corresponding author: Keunchil Park,
MD, PhD, Division of HematologyOncology, Department of Medicine,
Samsung Medical Center, Sungkyunkwan University School of Medicine, 81
Irwon-ro, Gangnam-gu, Seoul, 135-710,
Korea; e-mail: [email protected].
© 2015 by American Society of Clinical
Oncology
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Purpose
To determine the efficacy of consolidation chemotherapy (CC) with docetaxel and cisplatin (DP)
after concurrent chemoradiotherapy (CCRT) with the same agents in locally advanced non–smallcell lung cancer (LA-NSCLC).
Patient and Methods
Patients were randomly assigned to either CCRT alone (observation arm) or CCRT followed by CC
(consolidation arm). CCRT with docetaxel (20 mg/m2) and cisplatin (20 mg/m2) was administered
every week for 6 weeks with a total dose of 66 Gy of thoracic radiotherapy in 33 fractions. In the
consolidation arm, patients were further treated with three cycles of DP (35 mg/m2 each on days
1 and 8, every 3 weeks). The primary end point was 40% improvement in progression-free survival
(PFS) compared with observation.
Results
From October 2005 to April 2011, 437 patients were randomly assigned. Seventeen patients did
not start CCRT as a result of consent withdrawal or ineligibility reasons after random assignment,
leaving 420 patients for this analysis (n ⫽ 211 for observation; n ⫽ 209 for consolidation). Patient
characteristics were similar in both arms. In the consolidation arm, 143 patients (68%) received
CC, of whom 88 (62%) completed three planned cycles. The median PFS was 8.1 months in the
observation arm and 9.1 months in the consolidation arm (hazard ratio, 0.91; 95% CI, 0.73 to 1.12;
P ⫽ .36). Median overall survival times were 20.6 and 21.8 months in the observation and
consolidation arms, respectively (HR, 0.91; 95% CI, 0.72 to 1.25; P ⫽ .44).
Conclusion
CC with DP after CCRT with weekly DP in LA-NSCLC failed to further prolong PFS. CCRT alone
should remain the standard of care.
J Clin Oncol 33:2660-2666. © 2015 by American Society of Clinical Oncology
0732-183X/15/3324w-2660w/$20.00
INTRODUCTION
DOI: 10.1200/JCO.2014.60.0130
The incidence of lung cancer is still increasing in
most countries, and it remains the leading cause
of cancer death.1,2 Non–small-cell lung cancer
(NSCLC) accounts for approximately 80% to 85%
of lung cancer. Most patients with NSCLC are detected with locally advanced or metastatic disease
and have poor survival.3
Inoperable locally advanced NSCLC (LANSCLC) has shown an approximately 5% 5-year
survival rate with radiation therapy (RT) alone.4 For
the treatment of LA-NSCLC, multidisciplinary ther2660
apy has resulted in survival improvements. In the
1980s, induction chemotherapy was investigated for
LA-NSCLC, and several randomized phase III studies of induction chemotherapy and subsequent RT
have reported significant increases in survival.5-7 In the
1990s, a new approach with the concurrent administration of chemotherapy and RT was introduced and
demonstrated further improvements in survival compared with RT alone.8-10 Subsequent randomized
phase III trials have confirmed the superiority of concurrent chemoradiotherapy (CCRT) compared with
sequential chemoradiotherapy.11,12 Since then, the
standard of care for LA-NSCLC has been CCRT.
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Consolidation Docetaxel and Cisplatin in Stage III NSCLC
Despite this progress with a combined-modality approach, the
prognosis of LA-NSCLC remains poor, with a median survival time of
15 to 18 months.13 In 2003, the Southwest Oncology Group 9504 trial,
a phase II trial for consolidation chemotherapy (CC) with docetaxel
after CCRT with etoposide and cisplatin (EP), reported promising
results with a median progression-free survival (PFS) of 16 months
and a median survival of 26 months.14
In a previous phase II study of CCRT with CC with oral etoposide
and cisplatin for LA-NSCLC, we reported promising response rates
and survival results.15 We also conducted a phase I study of weekly
docetaxel and cisplatin (DP) concurrent with thoracic RT in stage III
NSCLC16 and confirmed the feasibility of this regimen with acceptable
toxicities. On the basis of these studies, this phase III randomized trial
was designed to evaluate whether CC with these same thirdgeneration chemotherapeutic agents after CCRT with weekly DP provides survival benefit for patients with inoperable stage III NSCLC.
PATIENTS AND METHODS
Patients with histologically documented NSCLC with inoperable stage IIIA or
IIIB disease, which was proven by computed tomography (CT), magnetic
resonance imaging, and/or positron emission tomography (PET), were eligible. N2 or N3 disease must have been confirmed by pathology or PET. Patients
were age 18 years or older and had an Eastern Cooperative Oncology Group
performance status of 0 to 1 at baseline.
Eligible patients also met the following criteria: measurable disease based
on RECIST; no prior chemotherapy, RT to the chest, immunotherapy, or
biologic therapy; forced expiratory volume in 1 second ⱖ 0.8 L by spirometry;
and adequate bone marrow, renal, and hepatic function. Female patients were
also excluded if they were pregnant or lactating, had not taken a pregnancy test
within 14 days before the first administration, or had childbearing potential
and were not willing to use adequate contraception.
All patients provided written informed consent. The study was approved
by the institutional review board of every participating institution and was
performed in accordance with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice.
Study Design and Treatment
This was an international, multicenter, open, randomized, phase III
study to evaluate the effects of CC of DP after CCRT in patients with inoperable LA-NSCLC. Random assignment was performed through a computerized online system. The stratification factors were participating center and
performance status.
Eligible patients received docetaxel 20 mg/m2 intravenously and cisplatin 20 mg/m2 intravenously on days 1, 8, 15, 22, 29, and 36. All patients
received thoracic RT 5 days per week in once-daily fractions and at 2.0 Gy
per fraction. The total dose was 66 Gy in 33 fractions. The initial 46 Gy or
RT over 23 fractions covered the clinical target volume plus the margin,
and the later 20 Gy over 10 fractions covered the gross tumor volume plus
the margin. CC was conducted between 4 and 8 weeks after the completion
of CCRT in patients with no local progression or distant metastases and
adequate organ function before the start of CC. On days 1 and 8 of each
cycle, an intravenous infusion of docetaxel 35 mg/m2 for 1 hour, followed
by cisplatin 35 mg/m2 for 1 hour, was given. This regimen was repeated
every 3 weeks and continued for up to three cycles as long as there was no
unacceptable toxicity or evidence of disease progression.
History and physical examination, assessment of Eastern Cooperative
Oncology Group performance status, pulmonary function tests including
forced expiratory volume in 1 second, CBC, serum chemistries, and chest CT
were obtained at baseline. PET scans were mandated except for in T4 disease.
Brain CT or magnetic resonance imaging was mandatory at baseline.
Throughout the CCRT phase, CBC was obtained weekly and serum chemiswww.jco.org
tries were obtained every 3 weeks. Baseline CBC and serum chemistries were
obtained and repeated before each cycle during the consolidation phase in all
patients. Evaluation of response by chest CT was first carried out within 4 to 6
weeks after the completion of CCRT, then within 9 to 12 weeks after the first
tumor assessment, and continued every 3 months for the first 3 years, every 6
months for years 3 to 5, and yearly thereafter. Adverse events were collected
from the first administration of the study drug to 30 days after the last administration. The incidence of pneumonitis was observed for up to 1 year after the
completion of treatment.
Statistical Analysis
The primary objective was to show that the consolidation arm would
increase the median PFS by 40% from the PFS of 12 months reported from
observation by Park et al.15 PFS was defined as the time from random assignment to the first documentation of disease progression or death, whichever
came first. With a total of 434 patients (n ⫽ 217 per arm), we had 90% power
by the log-rank test with a two-sided ␣ ⫽ .05. The sample size calculation was
based on the following assumptions: 10% of attrition, 18 months of additional
follow-up, and an annual accrual of 72 patients. A preplanned interim analysis
after 50% of enrollment demonstrated no safety issues and was previously
reported in 2009.17
The secondary end points included a comparison of overall survival
(OS), overall response rate, patterns of failure, and toxicities between the two
arms. Adverse events were graded according to the Common Terminology
Criteria for Adverse Events version 3.0. Descriptive statistics used medians or
proportions with their appropriate measures of distribution. The KaplanMeier method was used to estimate the distribution of PFS and OS, and the
distribution of each end point was compared between the two treatment arms
using the log-rank test. Univariable and multivariable regression analyses were
conducted on PFS using the Cox regression method. All P values are twosided. We considered P ⬍ .05 to be significant. The exploratory end point was
to investigate the correlation of tissue expression of ERCC1 and class III
␤-tubulin with the clinical outcome.
Exploratory Biomarker Study
Formalin-fixed, paraffin-embedded, 4 ␮m-thick tissue sections were
labeled with mouse monoclonal anti-ERCC1 antibody (8F1; GeneTex, Irvine,
CA) and anti–␤3-tubulin antibody (TU-20; Santa Cruz Biotechnology, Santa
Cruz, CA). Immunostaining was performed using a Bond-max autoimmunostainer with Bond Polymer refine detection, DS9800 (Leica Biosystems,
Melbourne, Australia). Immunohistochemical evaluation was performed by a
pathologist without knowledge of the clinical data. Tumor staining intensity
was graded on a scale of 0 to 3 using adjacent nonmalignant cells as a reference
(intensity of 2). One hundred to 1,500 positive or negative tumor cells per
specimen were counted manually. The percentage of positive tumor cells was
counted for each specimen. This proportional percentage was multiplied by
the staining intensity to obtain a final semiquantitative H score (Appendix Fig
A1, online only).
RESULTS
Between October 2005 and April 2011, 459 patients from 31 centers in
Korea, China, and Taiwan were screened for the study. Among them,
437 patients were eligible and were allocated to the observation arm
(n ⫽ 219) or consolidation arm (n ⫽ 218). Eight patients from the
observation arm and nine patients from the consolidation arm did not
start CCRT because of consent withdrawal or ineligibility reasons,
leaving 420 patients in the study (n ⫽ 211 for observation; n ⫽ 209 for
consolidation). These 420 patients were included in the final analysis
cohort (Fig 1). Patient characteristics are listed in Table 1. Approximately half of the patients had adenocarcinoma histology, and approximately 80% had stage IIIB disease. Demographic baseline
characteristics were well balanced between the two groups.
© 2015 by American Society of Clinical Oncology
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2661
Ahn et al
Screened
(n = 459)
Excluded on basis
of screening
Randomly assigned
(n = 437)
n = 219
Assigned to CCRT alone
n = 218
Assigned to CCRT + consolidation
Not treated* (n = 8)
CCRT phase
Modified
intent-to-treat
cohort
(n = 211)
Not treated* (n = 9)
CCRT phase
Study stop† (n = 36)
Observation phase
(n = 171)
Consolidation phase
Treatment Exposure During Consolidation
Of the 209 patients randomly assigned to the consolidation
arm, 42.1% received all of the three planned cycles, and 54.1%
finished at least two cycles (Table 2). Sixty-six patients (31.6%) did
not receive any CC. The reasons for not receiving CC included
early death (n ⫽ 22), consent withdrawal or patient refusal (n ⫽
Table 1. Patient Demographic and Clinical Characteristics
CCRT Alone
(n ⫽ 211)
Age, years
Median
Range
Sex
Male
Female
Performance status
0
1
2
Pathologyⴱ
Adenocarcinoma
Squamous
Other
Country of origin
Korea
China
Taiwan
FEV1, L
0.8 to ⬍ 2.0
ⱖ 2.0
Stageⴱ
IIIA
IIIB
No. of
Patients
%
CCRT ⫹
Consolidation
(n ⫽ 209)
No. of
Patients
%
P
.75
61
31-79
61
35-79
.32
178
33
84.4
15.6
169
40
80.9
19.1
51
144
16
24.2
68.3
7.6
48
144
16
23.0
68.9
7.7
109
70
26
51.7
33.2
12.3
108
65
28
51.7
31.1
13.4
.97
(n = 173)
14), adverse events of CCRT (n ⫽ 12), disease progression (n ⫽
10), and other reason (n ⫽ 8).
Efficacy
With a median follow-up time of 50.7 months, there were 349
events in total, 180 in the observation arm and 169 in the consolidation arm. There was no difference in PFS between the two arms, with
a median PFS of 8.1 months (95% CI, 7.6 to 8.9 months) in the
observation arm and 9.1 months (95% CI, 7.9 to 10.9 months) in the
consolidation arm (hazard ratio [HR], 0.91; 95% CI, 0.73 to 1.12; P ⫽
.36; Fig 2A). In subgroup analysis, none of the factors except age (⬎ 60
years old) were significant (Appendix Fig A2, online only).
There were 279 deaths, 145 in the observation arm and 134 in the
consolidation arm. Median OS also did not differ between the two
arms, with a median OS of 20.6 months (95% CI, 17.6 to 26.3 months)
in the observation arm and 21.8 months (95% CI, 17.7 to 24.7
months) in the consolidation arm (HR, 0.91; 95% CI, 0.72 to 1.25; P ⫽
.44; Fig 2B).
The overall response rate was 38.4% (with 4.3% complete response) in the observation arm versus 43.1% (with 2.9% complete
response) in the consolidation arm without a significant difference
.90
Table 2. Compliance of Consolidation Chemotherapy
CCRT ⫹ Consolidation (n ⫽ 209)
1.00
171
37
3
81.0
17.5
1.4
179
36
3
81.3
17.2
1.4
63
148
29.9
70.1
70
139
33.5
66.5
53
157
25.1
74.4
40
168
19.1
80.4
.42
.16
Abbreviations: CCRT, concurrent chemoradiotherapy; FEV1, forced expiratory
volume in 1 second.
ⴱ
There are some missing data.
2662
Fig 1. CONSORT diagram. Patients
were enrolled from October 2005 to April
2011. CCRT, concurrent chemoradiotherapy. (*) Consent withdrawn, ineligible patient. (†) Consent withdrawn, disease
progression, follow-up loss, death.
(n = 209)
Study stop† (n = 40)
Characteristic
(n = 22)
© 2015 by American Society of Clinical Oncology
Cycle and Day
Cycle 3
Day 8
Day 1
Cycle 2
Day 8
Day 1
Cycle 1
Day 8
Day 1
No consolidation
No. of Patients
%
88
4
42.1
1.9
21
5
10.1
2.4
15
10
66
7.2
4.8
31.6
Abbreviation: CCRT, concurrent chemoradiotherapy.
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2015
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Consolidation Docetaxel and Cisplatin in Stage III NSCLC
Progression-Free Survival
(proportion)
1.0
B
CCRT alone
CCRT + consolidation
0.8
Patients Events
CCRT alone
211
CCRT + consolidation 209
0.6
180
169
mPFS (95% CI)
8.05 (7.56 to 8.90)
9.10 (7.92 to 10.94)
Hazard ratio = 0.906
(95% CI, 0.734 to 1.119)
P = .410
0.4
0.2
0
1.0
Overall Survival
(proportion)
A
CCRT alone
CCRT + consolidation
0.8
Patients Events
CCRT alone
211
CCRT + consolidation 209
0.6
145
134
mOS (95% CI)
20.63 (17.58 to 26.28)
21.78 (17.71 to 24.74)
Hazard ratio = 0.911
(95% CI, 0.720 to 1.253)
P = .438
0.4
0.2
12
24
36
48
60
72
0
84
12
24
Time (months)
36
48
60
72
84
Time (months)
Fig 2. (A) Progression-free survival. (B) Overall survival. CCRT, concurrent chemoradiotherapy; mOS, median overall survival; mPFS, median progression-free
survival.
(P ⫽ .33). The disease control rate was approximately 58% in both
arms (Appendix Table A1, online only).
At the time of this analysis, the sites of treatment failure were
known in approximately half of the patients. Both arms showed similar locoregional or distant failure rates with no significant differences.
The remaining or contralateral lung was the most common site of the
first relapse followed by the brain, pleura, bone, and liver (Appendix
Table A2, online only).
Safety
During the CCRT phase, the hematologic toxicities were as expected. In patients assigned to the consolidation arm, there was
slightly more febrile neutropenia and grade 3 or 4 neutropenia (Table
3). Table 4 lists the nonhematologic toxicities. During the CCRT
phase, esophagitis was observed in 79% of patients with 9.5% grade 3
or 4 toxicities. Grade 3 or 4 infections developed in 6.4% of patients
with some treatment-related mortality (TRM). Radiation pneumonitis was less frequently observed, but one patient died of radiation
pneumonitis. During the consolidation phase, 2.3% of patients experienced grade 3 or 4 infection, and 1.2% of patients had grade 3 or 4
radiation pneumonitis with some ensuing TRM. The overall TRM
rate was 3.6% during the CCRT phase and 2.9% during the consolidation phase.
Exploratory Biomarker Study
The median H scores for ERCC1 (n ⫽ 97) and class III ␤-tubulin
(n ⫽ 97) were 240 and 30, respectively. ERCC1 expression had no
significant correlation with PFS or OS (P ⫽ .40 and P ⫽ .53, respectively). Class III ␤-tubulin expression was also not correlated with PFS
or OS (P ⫽ .97 and P ⫽ .44, respectively).
DISCUSSION
Most studies that have investigated the role of CC after CCRT have
been small phase I/II trials; few large randomized phase III trials have
been conducted. In each trial, there have been differences in patient
characteristics, CCRT backbones, or CC regimens, and none of the
trials were designed for a specific subset of patients by incorporating
molecular biomarkers.18 Our randomized phase III trial, which is the
largest reported to date, failed to demonstrate that CC with DP after
completing CCRT with the same agents improved survival. This is in
line with a recent report on the pooled analysis of 41 studies, which
failed to provide evidence that CC yield significant survival benefit for
patients with LA-NSCLC.19
While this study was being conducted, a phase III study by the
Hoosier Oncology Group (HOG), which included 203 patients using
single-agent docetaxel as CC after CCRT, was prematurely terminated
as a result of futility analysis. Compared with the HOG study, we had
stricter criteria for N2 or N3 disease, which needed to be proven by
pathology or PET. More patients were staged by PET in our study than
in the HOG study (92% v 67%, respectively). The most striking difference in study design was the random assignment point. Our patients were randomly assigned before the start of CCRT. We thought
Table 3. Hematologic Toxicities
% of Patients
CCRT Phase (n ⫽ 420)
Observation (n ⫽ 171)
Consolidation (n ⫽ 173)
Toxicity
Grade 2
Grade 3
Grade 4
Grade 2
Grade 3
Grade 4
Grade 2
Grade 3
Grade 4
Anemia
Neutropenia
Febrile neutropenia
Thrombocytopenia
7.9
1.9
NA
1.9
5.2
2.6
0.7
0.5
0.2
0
0.2
0
12.9
2.9
NA
0
1.2
0.6
0
1.2
2.3
2.3
0
2.3
28.3
7.5
NA
1.7
1.7
4.6
1.2
0.6
0.6
2.3
0.6
1.2
Abbreviations: CCRT, concurrent chemoradiotherapy; NA, not applicable.
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2015
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2663
Ahn et al
Table 4. Nonhematologic Toxicities
% of Patients
CCRT Phase (n ⫽ 420)
Observation (n ⫽ 171)
Consolidation (n ⫽ 173)
Toxicity
All Grades
Grade 3 to 4
All Grades
Grade 3 to 4
All Grades
Grade 3 to 4
Anorexia
Nausea
Vomiting
Diarrhea
Constipation
Esophagitis
Fatigue/asthenia
Infection
Radiation pneumonitis
Hypersensitivity reaction
Treatment-related death
70.2
58.3
20.7
14.3
23.3
79.3
35.5
17.6
2.4
3.6
4.0
1.7
1.2
1.4
1.0
9.5
3.6
6.4
0
0
20.5
1.8
2.3
3.5
3.5
26.9
8.2
5.8
5.8
0
1.2
0
0.6
0
0
1.8
0
2.9
1.2
0
42.8
31.8
14.5
9.8
10.4
35.3
31.2
8.7
13.3
1.7
3.5
1.7
2.3
1.2
0
1.2
4.6
2.3
1.2
0.6
3.6 (n ⫽ 15)
0.0
2.9 (n ⫽ 5)
Abbreviation: CCRT, concurrent chemoradiotherapy.
this would result in minimal data loss and less bias. We used DP during
CCRT instead of the more common regimen of EP to investigate
whether these newer agents were any superior to older ones. Docetaxel
has been tested in CCRT with cisplatin in many phase I/II trials with
promising response rates,16,20-22 and a recent phase III trial showed
that CCRT with DP had better efficacy in the early follow-up period.23
We also used a DP doublet in the consolidation phase to maximize the
effects of additional treatment.
The major obstacle in this trial was that many patients could not
complete the three planned cycles of CC, as in other trials.19 Approximately one third of the patients (32%) did not even start CC, and only
approximately half of the patients could complete ⱖ two cycles of CC.
Approximately half of the patients failed to start CC because of disease
progression or death before the consolidation phase. Another major
reason was related to incomplete recovery from the adverse effects of
CCRT. A full-dose doublet regimen of CC in our trial might have
further reduced the rate of completing the three planned cycles of CC.
Hematologic toxicities during both the CCRT and consolidation
phases were not so severe, perhaps because of the weekly administration of DP. Several phase III trials and a meta-analysis of weekly
docetaxel as second-line chemotherapy for advanced NSCLC showed
significant benefit in grade 3 to 4 neutropenia compared with administering docetaxel every 3 weeks.24-27 Nonhematologic toxicities during the CCRT phase were as expected and similar to conventional
CCRT with EP. In brief, CCRT with weekly DP is a feasible regimen
with acceptable toxicities.
It is of interest that there was a significant benefit with CC for
patients older than age 60 years (HR, 0.72). In a population-based
study from National Cancer Institute’s Surveillance, Epidemiology,
and End Results database in elderly patients with LA-NSCLC, CCRT
alone is associated with the greatest mortality risk compared with
either induction chemotherapy or CC with CCRT, suggesting that
more gradual strategies may be more appropriate for the elderly population.28 In addition, in the combined analysis of five Cancer and
Leukemia Group B trials, age was not an independent predictive factor
of outcome.29 However, the exact reason why patients older than age
60 benefited in this study remains unexplained. There was no difference in baseline characteristics between patients older than 60 and
patients ⱕ 60 years.
2664
© 2015 by American Society of Clinical Oncology
ERCC1 is a component of the nucleotide excision repair pathway, which is essential for the repair of platinum-DNA adducts and is
associated with cellular resistance to platinum compounds. Low
ERCC1 expression has been correlated with superior PFS and OS in
patients with advanced NSCLC treated with cisplatin.30-32 In a smallscale retrospective study, immunohistochemistry for ERCC1 was useful for predicting survival in patients with LA-NSCLC receiving CCRT
with DP.33 The International Adjuvant Lung Cancer Trial Collaborative Group has demonstrated a survival benefit with adjuvant
cisplatin-based chemotherapy in patients whose tumors were negative
for ERCC1 expression.34 However, the ERCC1 immunohistochemistry results were not reproducible.35,36 Small comparative studies have
also shown that overexpression of class III ␤-tubulin is correlated with
resistance to tubulin-binding agents, taxanes, and vinorelbine and has
resulted in poor prognosis in metastatic NSCLC.37-39 In contrast, high
levels of class III ␤-tubulin were associated with an adverse prognosis
but also seemed to be associated with increased benefit from adjuvant cisplatin/vinorelbine chemotherapy in patients with operable
NSCLC.40 In our exploratory biomarker study, the expression of
ERCC1 and class III ␤-tubulin was not correlated with either PFS or
OS. Until now, no biomarker has been validated to predict benefit or
resistance to currently available cytotoxic chemotherapy.41
Given that almost half of the patients could not receive CC after
CCRT as a result of early progression and/or toxicities, we need to develop
better tolerated regimens without the loss of efficacy. Several new agents
are under investigation. PROCLAIM, a phase III study of pemetrexed,
cisplatin,andRTfollowedbyconsolidationpemetrexedversusEPandRT
followed by a CC of choice in patients with stage III NSCLC of nonsquamous histology, was prematurely terminated based on the planned interim futility analysis.42 The role of cetuximab is being evaluated in the
Radiation Therapy Oncology Group 0617 trial, which randomly assigned
patients to standard-dose or high-dose RT or carboplatin and paclitaxel
alone,withorwithoutcetuximabconcurrentwithRT.Theinferiorresults
of high-dose RT were already presented, and the effect of cetuximab
awaits further follow-up.43 L-BLP25 is a MUC1 antigen-specific cancer
immunotherapy. A phase III trial (START [Stimulating Targeted Antigenic Response to Non-Small-Cell Lung Cancer]) investigating L-BLP25
in patients who have finished CCRT was completed. L-BLP25 maintenance therapy, however, did not significantly prolong OS.44 Given the
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Consolidation Docetaxel and Cisplatin in Stage III NSCLC
high locoregional failure and the presence of distant metastases, newer RT
techniques are needed including hypofractionation, stereotactic body RT,
adaptive RT, or proton therapy.
In summary, this study confirms that the current strategy of
consolidation treatment with cytotoxic chemotherapy after CCRT
does not improve survival in patients with LA-NSCLC. In future trials,
CCRT without CC should remain the reference arm. Given that distant failure is the most common pattern of failure after CCRT in
LA-NSCLC and the treatment outcome remains poor, we strongly
believe that the concept of consolidation therapy needs to be further
explored using less toxic, better tolerated agents.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
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www.jco.org
AUTHOR CONTRIBUTIONS
Conception and design: Jin Seok Ahn, Yong Chan Ahn, Hoon-Kyo Kim,
Sin-Ho Jung, Myung-Ju Ahn, Keunchil Park
Provision of study materials or patients: Jin Seok Ahn, Yong Chan Ahn,
Joo-Hang Kim, Chang Geol Lee, Eun Kyung Cho, Kyu Chan Lee, Ming
Chen, Hoon-Kyo Kim, Young Joo Min, Jin-Hyoung Kang, Jin-Hyuk
Choi, Sang-We Kim, Yi-Long Wu, Sung Rok Kim, Kyung Hee Lee, Hong
Suk Song, Jong-Mu Sun, Myung-Ju Ahn, Keunchil Park
Collection and assembly of data: Jin Seok Ahn, Yong Chan Ahn,
Joo-Hang Kim, Chang Geol Lee, Eun Kyung Cho, Kyu Chan Lee, Ming
Chen, Dong-Wan Kim, Hoon-Kyo Kim, Young Joo Min, Jin-Hyuk Choi,
Sang-We Kim, Guangying Zhu, Yi-Long Wu, Sung Rok Kim, Kyung Hee
Lee, Hong Suk Song, Myung-Ju Ahn, Keunchil Park
Data analysis and interpretation: Jin Seok Ahn, Yong Chan Ahn,
Dong-Wan Kim, Jin-Hyoung Kang, Yi-Long Wu, Yoon-La Choi,
Jong-Mu Sun, Sin-Ho Jung, Myung-Ju Ahn, Keunchil Park
Manuscript writing: All authors
Final approval of manuscript: All authors
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Affiliations
Jin Seok Ahn, Yong Chan Ahn, Yoon-La Choi, Jong-Mu Sun, Myung-Ju Ahn, and Keunchil Park, Samsung Medical Center,
Sungkyunkwan University School of Medicine; Joo-Hang Kim and Chang Geol Lee, Yonsei Cancer Center, Yonsei University Health System;
Dong-Wan Kim, Seoul National University Hospital; Jin-Hyoung Kang, Catholic University Seoul St Mary’s Hospital; Sung Rok Kim, Inje
University Sanggye Paik Hospital; Sang-We Kim, Asan Medical Center, University of Ulsan College of Medicine; Sin-Ho Jung, Samsung
Medical Center, Office of Biomedical Science, Seoul; Eun Kyung Cho and Kyu Chan Lee, Gachon University Gil Medical Center, Incheon;
Hoon-Kyo Kim, Catholic University St Vincent’s Hospital; Jin-Hyuck Choi, Ajou University Hospital, Suwon; Young Joo Min, Ulsan
University Hospital, Ulsan; Kyung Hee Lee, Yeungnam University Medical Center; Hong Suk Song, Keimyung University Dongsan Medical
Center, Daegu, Korea; Ming Chen, Sun Yat-Sen University Cancer Center, Guangzhou; Guangying Zhu, Beijing Cancer Hospital, Beijing; YiLong Wu, Guandong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong,
China.
■ ■ ■
2666
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Consolidation Docetaxel and Cisplatin in Stage III NSCLC
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Multinational Randomized Phase III Trial With or Without Consolidation Chemotherapy Using Docetaxel and Cisplatin After Concurrent
Chemoradiation in Inoperable Stage III Non–Small-Cell Lung Cancer: KCSG-LU05-04
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Jin Seok Ahn
Honoraria: Eli Lilly, Pfizer, Roche
Guangying Zhu
No relationship to disclose
Yong Chan Ahn
No relationship to disclose
Yi-Long Wu
Honoraria: AstraZeneca, Eli Lilly, Pfizer, Roche
Joo-Hang Kim
Research Funding: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Pfizer
Sung Rok Kim
No relationship to disclose
Chang Geol Lee
No relationship to disclose
Kyung Hee Lee
No relationship to disclose
Eun Kyung Cho
Consulting or Advisory Role: Celltrion
Hong Suk Song
No relationship to disclose
Kyu Chan Lee
No relationship to disclose
Yoon-La Choi
No relationship to disclose
Ming Chen
No relationship to disclose
Jong-Mu Sun
No relationship to disclose
Dong-Wan Kim
Consulting or Advisory Role: Novartis
Sin-Ho Jung
No relationship to disclose
Hoon-Kyo Kim
No relationship to disclose
Myung-Ju Ahn
No relationship to disclose
Young Joo Min
No relationship to disclose
Keunchil Park
Honoraria: Astellas Pharma, AstraZeneca, AVEO, Clovis Oncology, Eli
Lilly, Hanmi, Kyowa Hakko Kirin, Novartis, Ono Pharmaceutical, Roche
Consulting or Advisory Role: Astellas Pharma, AstraZeneca, AVEO,
Boehringer Ingelheim, Clovis Oncology, Daiichi Sankyo, Eli Lilly,
Hanmi, Kyowa Hakko Kirin, Novartis, Ono Pharmaceutical, Roche
Speakers’ Bureau: Eli Lilly
Research Funding: AstraZeneca, Sanofi
Jin-Hyoung Kang
No relationship to disclose
Jin-Hyuk Choi
No relationship to disclose
Sang-We Kim
No relationship to disclose
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2015
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Ahn et al
Appendix
Table A1. Overall Response to CCRT
Response
CCRT Alone (n ⫽ 211)
No. of Patients (%)
CCRT ⫹ Consolidation (n ⫽ 209)
No. of Patients (%)
P
9 (4.3)
72 (34.1)
43 (20.4)
44 (20.9)
43 (24ⴱ)
81 (38.4)
124 (58.8)
6 (2.9)
84 (40.2)
32 (15.3)
44 (21.1)
43 (22ⴱ)
90 (43.1)
122 (58.4)
.3297
.9346
CR
PR
SD
PD
NE
RR
DCR
Abbreviations: CCRT, concurrent chemoradiotherapy; CR, complete response; DCR, disease control rate; NE, not evaluable; PD, progressive disease; PR, partial
response; RR, response rate; SD, stable disease.
ⴱ
No. of patients with unconfirmed CR or PR.
Table A2. Pattern of Failure
Treatment Failure
Patients with treatment failure
Locoregional failure
Distant failure
Local and distant failure
Site of distant failureⴱ
Lung
Pleura
Liver
Brain
Bone
CCRT Alone (n ⫽ 211)
No. of Patients (%)
CCRT ⫹ Consolidation (n ⫽ 209)
No. of Patients (%)
P
115 (54.5)
57 (49.6)
50 (43.5)
8 (7.0)
112 (53.6)
50 (44.6)
56 (50.0)
6 (5.4)
.42
.55
.59
17
4
8
14
9
18
11
4
16
6
Abbreviation: CCRT, concurrent chemoradiotherapy.
ⴱ
Select sites; multiple sites in some patients.
A
B
C
D
Fig A1. Immunohistochemical staining of ERCC1 and class III ␤-tubulin protein in lung cancer tissues. Examples of the expression of each protein are shown. (A)
ERCC1 H score of 300. (B) ERCC1 H score of 40. (C) Class III ␤-tubulin H score of 280. (D) Class III ␤-tubulin H score of 20.
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Consolidation Docetaxel and Cisplatin in Stage III NSCLC
No. of
Patients
PFS
Hazard Ratio (95% CI)
HR
95% CI
P
Age, years
≤ 60
195
1.15
0.85 to 1.55
.376
> 60
225
0.72
0.53 to 0.97
.030
347
0.92
0.73 to 1.15
.451
73
0.89
0.52 to 1.53
.671
135
271
0.88
0.94
0.60 to 1.30
0.72 to 1.22
.523
.639
ECOG PS
0
99
1.08
0.69 to 1.71
.731
1
288
0.86
0.67 to 1.11
.254
FEV1
≥ 2.0 L
287
0.88
0.60 to 1.29
.526
< 2.0 L
133
0.93
0.72 to 1.20
.586
Sex
Male
Female
Pathology
Squamous
Nonsquamous
Stage
IIIA
93
1.17
0.74 to 1.84
.498
IIIB
325
0.85
0.67 to 1.08
.184
420
0.91
0.73 to 1.12
.360
Total
Favors consolidation
1
Favors observation
Fig A2. Subgroup analysis for progression-free survival (PFS). ECOG PS, Eastern Cooperative Oncology Group performance status; FEV1, forced expiratory volume
in 1 second; HR, hazard ratio.
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