VOLUME

30

NUMBER

19

JULY

2012

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Risk Assessment Tool for Distant Recurrence After

Platinum-Based Concurrent Chemoradiation in Patients
With Locally Advanced Cervical Cancer: A Korean
Gynecologic Oncology Group Study
Sokbom Kang, Byung-Ho Nam, Jeong-Yeol Park, Sang-Soo Seo, Sang-Young Ryu, Jae Weon Kim,
Seung-Cheol Kim, Sang-Yoon Park, and Joo-Hyun Nam
Sokbom Kang, Byung-Ho Nam, SangSoo Seo, Sang-Yoon Park, National
Cancer Center, Goyang; Jeong-Yeol
Park, Joo-Hyun Nam, Asan Medical
Center; Sang-Young Ryu, Korea Cancer
Center; Jae Weon Kim, Seoul National
University Hospital; Seung-Cheol Kim,
Ewha Womans University Medical
Center, Seoul, Republic
of Korea.
Submitted June 12, 2011; accepted
February 29, 2012; published online
ahead of print at www.jco.org on May
21, 2012.
Supported by Grant No. 0910260-3
from the National Cancer Center
of Korea.
Authors disclosures of potential conflicts of interest and author contributions are found at the end of
this article.
Corresponding author: Joo-Hyun Nam,
MD, PhD, Department of Obstetrics
and Gynecology, University of Ulsan
College of Medicine, Asan Medical
Center, 388-1, Poongnap-2 Dong,
Songpa-Gu, Seoul, 138-736, Korea;
e-mail: jhnam@amc.seoul.kr.
2012 by American Society of Clinical
Oncology
0732-183X/12/3019-2369/$20.00

Purpose
Our study aimed to develop a model to predict distant recurrence in locally advanced cervical
cancer, which can be used to select high-risk patients in enriched clinical trials.
Patients and Methods
Our study was a retrospective analysis of a multi-institutional cohort of patients treated between 2001 and 2009. According to the order of data submission, data from three institutions
were allocated to a model development cohort (n 434), and data from the remaining two
institutions were allocated to an external validation cohort (n 115). Patient information including
[18F]fluorodeoxyglucose positron emission tomography (FDG-PET) data and clinical outcome was
modeled using competing risk regression analysis to predict 5-year cumulative incidence of
distant recurrence.
Results
The competing risk analysis revealed that the following four parameters were significantly
associated with distant recurrence: pelvic and para-aortic nodal positivity on FDG-PET, nonsquamous cell histology, and pretreatment serum squamous cell carcinoma antigen levels. This
four-parameter model showed good discrimination and calibration, with a bootstrap-adjusted
concordance index of 0.70. Also, the validation set showed good discrimination with a bootstrapadjusted concordance index of 0.73. A user-friendly Web-based nomogram predicting 5-year
probability of distant recurrence was developed.
Conclusion
We have developed a robust model to predict the risk of distant recurrence in patients with locally advanced cervical cancer. Further, we discussed how the selective enrichment of the
patient population could facilitate clinical trials of systemic chemotherapy in locally advanced
cervical cancer.
J Clin Oncol 30:2369-2374. 2012 by American Society of Clinical Oncology

DOI: 10.1200/JCO.2011.37.5923

INTRODUCTION

After the National Cancer Institute issued an alert,

based on five trials,1-5 recommending concomitant
chemoradiotherapy, the paradigm of treatment for
locally advanced cervical cancer has moved toward
concurrent chemoradiotherapy. However, although
the contribution of concurrent chemoradiotherapy
to an improvement in survival outcomes of cervical
cancer has been well confirmed,6-7 the outcomes of
patients with locally advanced cervical cancer have
been unsatisfactory.
Recently, a breakthrough in the treatment of
locally advanced cervical cancer was realized in a
phase III, randomized trial.8 In the study, the au-

thors showed that gemcitabine plus cisplatin chemoradiotherapy followed by brachytherapy and
adjuvant gemcitabine/cisplatin chemotherapy improved survival outcomes. The possible mechanism
of this benefit was explained by a 50% reduction in
distant failure, as the rates of local recurrence were
not significantly different in both arms. This explanation corresponds to meta-analyses indicating that
the addition of systemic chemotherapy has a benefit
in reducing the risk of distant failure.6,9 However,
this survival gain was not free from considerable
costs. Not only were more grade 3 and 4 toxicities
observed in the study arm but there were also two
treatment-related deaths. Thus, this trade-off raised
the following questions. Can we identify patients
2012 by American Society of Clinical Oncology

2369

Kang et al

Table 1. Demographic and Clinical Characteristics of Model Derivation

and Validation Cohorts

Characteristic
Age, years
Mean
Range
Stage
Bulky IB2-IIA
IIB
III
IVA
Histology
Squamous cell
Adeno
Adenosquamous
Unknown
Tumor size, measured by MRI
Median
Range
Unknown
Serum SCC Ag level, ng/mL
Median
Range
Unknown
Pelvic node status by PET
Negative
Positive
Para-aortic node status by PET
Negative
Positive
Extended-field radiation
Not done
Done
Unknown
Recurrence
Locoregional only
Distant only
Locoregional plus Distant
Death

No. of
Patients

Validation
Cohort
(n 115)
No. of
Patients

P
.68

54
27-78

54
32-77

72
274
70
18

16.6
63.1
16.1
4.2

8
71
26
10

7.0
62.8
22.6
8.7

.009

385
29
17
3

88.7
6.7
3.9
0.7

106
4
2
3

92.2
3.5
1.7
2.6

.005

5.5
1.5-9.5
10
8.7

.001

4.5
1.6-9.0
16
3.7
4.9
0-395
5
1.2

.001

8.3
0-402
0

174
260

40.1
59.9

56
59

48.7
51.3

.096

346
88

79.7
20.3

90
25

78.3
21.7

.73

283
150
1

65.2
34.6
0.2

74
39
2

64.4
33.9
1.7

.15

29
66
26
74

6.7
15.2
6.0
17.1

7
26
6
21

6.1
22.6
5.2
18.3

.31

2012 by American Society of Clinical Oncology

Patient Cohort
Five institutions participated in our retrospective study. The method of
patient allocation was predetermined before the analysis. According to the
order of data submission, the first three institutions were allocated to a development cohort and the final two institutions were allocated to a validation
cohort. Between November 2001 and August 2009, 748 patients from three
institutions (Asan Medical Center, Seoul, Korea; the National Cancer Center,
Goyang, Korea; and Ehwa Womans University Hospital, Seoul, Korea) underwent definitive platinum-based chemoradiotherapy for the primary treatment of locally advanced cervical cancer. Among these patients, 434 patients
(58%) underwent FDG-PET before chemoradiotherapy and were included in
the development cohort. During the same period, 167 patients underwent
chemoradiotherapy at two institutions (Seoul National University Hospital,
Seoul, Korea; and Korea Cancer Center, Seoul, Korea). Among these patients, 115
patients (69%) who underwent FDG-PET were allocated to an external validation
cohort. The inclusion criteria were as follows: a histologic diagnosis of primary
carcinoma of uterine cervix; International Federation of Gynecology and Obstetrics stage IIB to IVA or IB2 to IIA bulky (greater than 4 cm) disease; treatment with
curative chemoradiotherapy, with or without extended-field radiation; and FDGPET or positron emission tomography/computed tomography scan (PET/CT)
beforethestartofchemoradiotherapy,butnomorethan4weeksbefore.Exclusion
criteria were as follows: small-cell or neuroendocrine type histology; concomitant primary cancer; nonplatinum-based chemoradiotherapy; radiation dose
less than 40 Gy; or application of surgery or chemotherapy before chemoradiotherapy. Application of intracavitary brachytherapy, parametrial boost,

Modeling set
Validation set

1.00

0.75

0.50

0.25

12

24

36

60

Modeling set
Validation set

.3
.2
.1

0
.76

48

Time (months)

B
.4

Abbreviations: MRI, magnetic resonance imaging; PET, positron emission

tomography; SCC Ag, squamous cell carcinoma antigen.

2370

PATIENTS AND METHODS

Cumulative Incidence of
Distant Recurrence

Model
Derivation
Cohort
(n 434)

structed, accompanied by a user-friendly, Web-based nomogram.

This prediction tool was named Prediction Model of Failure in Locally
Advanced Cervical Cancer (PREFACE, version 1.1).

Distant RecurrenceFree
Survival (probability)

who may benefit from the addition of systemic chemotherapy? If we

enrich our trial population with high-risk patients, can doing so facilitate the design and performance of trials testing the efficacy of systemic agents?
To answer these questions, the Korean Gynecologic Oncology
Group undertook a multicenter, retrospective study to develop a prediction model for distant recurrence in locally advanced cancer (Korean Gynecologic Oncology Group1024). Recently, we reported that
[18F]fluorodeoxyglucose positron emission tomography (FDG-PET)
can be useful in the prediction of distant recurrence,10 which corresponds with prior evidence.11-12 We hypothesized that the prediction
of the risk of distant recurrence may be useful in the design of clinical
trials or in the individualization of treatment. Thus, a prediction
model for distant recurrence in locally advanced cancer was con-

20

40

60

Time (months)
Fig 1. (A) Kaplan-Meier estimate of distant-recurrence free survival probability of
the model development and the validation cohorts. (B) Cumulative incidence of
distant-recurrence estimated by competing risk analysis.
JOURNAL OF CLINICAL ONCOLOGY

Predicting Distant Failure in Locally Advanced Cervical Cancer

according to the Fine and Gray method, was performed using Cox regression.15 The first observed distant metastasis was considered an event. Both
locoregional recurrence and death before recurrence were regarded as competing risks. To handle missing data, the complete-case method was applied.
Although many predictor-selection strategies exist, the strategy we chose
to use was as follows. We began developing a risk model by fitting the Cox
proportional hazards model, using all predictors that had P value less than .25
in single predictor analysis. A reduced model was also created from parameters
showing a P value of less than .25 in the full model. Only variables showing
significant P values ( .05) in the reduced model were regarded as viable
predictors. The significance of all predictors was internally validated using the
jackknife method. The possible interactions between variables were tested
within the variables selected for the final model.
The discrimination ability of the model was evaluated by Harrells concordance index.16-17 The discrimination ability of the final model was internally
validated using estimation of bootstrap-adjusted concordance index with 200
bootstrap resamples. Calibration of the model was assessed by plotting the observed incidence rate of distant recurrence estimated by the Kaplan-Meier method
and the predicted probability of distant recurrence in three risk groups partitioned
according to the distribution of the predicted risk. In addition, a nomogram was
constructed, based on the Cox proportional hazards model, and was converted
into a user-friendly Web-based program. All statistical analyses were performed using the STATA computer program, version 11.0 (STATA, College
Station, TX; Computing Resource Center, Santa Monica, CA).

and extended-field radiation to the para-aortic area were not considered selection criteria. All clinical information was investigated after obtaining the approval of the institutional review board of each of the participating institutions.
Clinical characteristics of modeling and validation cohorts are summarized in
Table 1 and Appendix Table 1 (online-only).
Pretreatment Assessment
Tumor size was measured by magnetic resonance imaging. Computed tomography(CT)-basedorclinicallymeasuredtumorsizewasnotconsideredinthe
analysis. If tumor size was reported in three axes, the largest diameter was included
as the tumor size. The instrumental setting and the condition of the process of PET
scanning are summarized according to the participating institutions in Appendix
Table 2 (online-only). The commonly applied interpretation criteria were the
rules proposed by the International Harmonization Project in Lymphoma.13
Briefly, a lymph node was considered positive if its FDG uptake was greater
than that of the blood pool activity or background tissues. The steering committee made the decision not to perform a central review of the data because of
the heterogeneous settings of the PET imaging, as well as because of concerns
regarding the generalization of the model. Thus, all pathologic and imaging
data were interpreted locally by specialists from each institution.
Patient Follow-Up
All patients were followed up every 2 to 4 months for the first 2 years and
then subsequently every 2 to 6 months, which varied according to the policy of
each institution and individual patient risk. Pelvic examination and cytologic
tests were performed at every visit. Diagnostic imaging (CT or magnetic
resonance imaging) was performed every 6 or 12 months and when clinically
indicated. The end point was the time from the start of chemoradiotherapy to
the earliest diagnosis of distant recurrence. Distant recurrence was defined as
tumor recurrence at a site beyond the pelvic radiation field. Para-aortic nodal
recurrence above the L4-L5 interspace was regarded as a distant recurrence.

RESULTS

Survival Analysis in Training Set

In the model development cohort, the median follow-up period
of surviving patients was 49 months (range, 1 to 114 months). In the
validation cohort, the median follow-up period of surviving patients

Statistical Analysis
Survival distributions were estimated by the Kaplan-Meier method, with
reverse meaning of the status indicator.14 Competing risk regression analysis,

Table 2. Competing Risk Analysis of Time to Distant Recurrence in Locally Advanced Cervical Cancer
Multiple Predictor Analysis
Single Predictor Analysis
Characteristic
Age, years (continuous)
40
70
Stage
Bulky IB-IIA
IIB
III
IVA
III-IVA v I-II
Histology
Squamous cell
Adeno
Adenosquamous
Squamous v adeno plus adenosquamous
Tumor size by MRI, cm (continuous)
4 cm v 4 cm
Serum SCC Ag, ng/mL
SUVmax cervix by PET
Pelvic node by PET
Para-aortic node by PET
Extended-field radiation

Full Model

Reduced Model

SHR

95% CI

SHR

95% CI

1.00
1.51
1.00

0.98 to 1.02
0.85 to 2.68
0.47 to 2.11

.76
.16
.99

1.50

0.71 to 3.13

.29

Reference
1.48
1.69
1.19
1.15

0.78 to 2.78
0.79 to 3.60
0.33 to 4.21
0.70 to 1.90

.23
.18
.79
.57

1.72
1.38
0.64

0.76 to 3.93
0.47 to 4.03
0.13 to 3.08

.20
.56
.56

Reference
1.82
1.53
1.71
1.19
1.87
1.01
1.02
2.54
2.98
1.78

0.94 to 3.53
0.60 to 3.90
0.97 to 3.00
1.06 to 1.33
1.15 to 3.04
1.00 to 1.01
0.99 to 1.05
1.56 to 4.13
1.95 to 4.56
1.17 to 2.69

.37
.062
.003
.012
.001
.21
.001
.001
.007

2.82
1.15

1.48 to 5.34
1.00 to 1.33

.002
.052

1.01
0.99
2.04
1.98
1.26

1.00 to 1.01
0.95 to 1.03
1.10 to 3.80
1.06 to 3.72
0.78 to 2.20

.005
.64
.024
.032
.34

SHR

95% CI

Jack-knifed P

2.30
1.08
1.31
1.00

1.28 to 4.14
0.94 to 1.23
0.78 to 2.22
1.00 to 1.01

.006
.276
.305
.026

.008

1.95
2.36

1.15 to 3.33
1.49 to 3.72

.014
.001

.017
.001

.024

Abbreviations: MRI, magnetic resonance imaging; PET, positron emission tomography; SCC Ag, squamous cell carcinoma antigen; SHR, subdistribution hazard
ratio; SUV, standardized uptake value.

www.jco.org

2012 by American Society of Clinical Oncology

2371

Kang et al

Model Validation
Internal validation of predictive accuracy was performed using
200 times of bootstrap resampling. In the modeling cohort, the
bootstrap-adjusted corrected concordance index was 0.70 (95% CI,
0.64 to 0.75), which exceeded that of the International Federal of
Gynecology and Obstetrics stage (0.57; 95% CI, 0.52 to 0.62). In the
external validation set (n 113), the model showed a good discrimination performance (concordance index, 0.73) and the bootstrapadjusted concordance index was 0.73 (95% CI, 0.65 to 0.81). A
calibration curve for the validation set is illustrated in Figure 2B.
Finally, a nomogram was constructed from the coefficients of
this model. For easier use, a computerized version of the nomogram was created. This Web-based software tool is available for use
at the Korean Gynecologic Oncology Group Web site (Appendix
Fig 2, online-only).
Utility of Our Prediction Model
Figure 3A shows how the model could be used to design a clinical
trial to test the efficacy of systemic chemotherapy to reduce the risk of
distant failure after chemoradiotherapy. We assumed a 50% risk reduction by systemic chemotherapy on the basis of a recent report. If a
trial included all patients without any selection criteria, then 86% of
patients would receive unnecessary treatment and suffer from severe
complications. However, a scenario can be suggested based on our risk
model. If we enrolled cases with an estimated risk of more than 25%,
then the percentage of unnecessarily treated patients and the required
size of the study population would both be reduced by 60%, whereas
the proportion of benefited patients among enrolled patients would
increase by 43%.
DISCUSSION

We have developed and validated a robust prediction model that can

be used to predict the risk of distant recurrence in patients with locally
2372

2012 by American Society of Clinical Oncology

Observed 5-Year Probability

of Distant Recurrence

0.8

0.6

0.4

0.2

0.2

0.4

0.6

0.8

Expected 5-Year Probability of Distant Recurrence

B
Observed 5-Year Probability
of Distant Recurrence

was 42 months (range, 10 to 92 months). For both development and

validation cohorts, distant recurrence-free survival and cumulative
incidence function of distant recurrence are illustrated in Figures 1A
and 1B. Using the candidate predictors obtained from a singlepredictor analysis, a full model and a reduced model were created
(Table 2). The reduced model yielded four statistically significant
predictors: positive pelvic and para-aortic nodes detected by PET; a
nonsquamous cell histologic subtype; and pretreatment serum squamous cell carcinoma antigen (SCC, ng/mL). All the four predictors
remained significant (P .05) after the internal validation using the
jackknife method. No significant interaction between the selected
predictors was observed (Appendix Table 3; online-only).
Because the concordance index of the full model was 0.72 (95%
CI, 0.66 to 0.77) and was not significantly better than that of the
reduced model, 0.70 (95% CI, 0.64 to 0.75), the reduced model was
finally selected for parsimonious purposes. From the distribution of
predicted cumulative incidence, we could identify three distinct risk
groups (low risk, 0% to 20%; intermediate risk, 20% to 40%; and high
risk, 40% or more; Appendix Fig A1, online-only). According to these
risk groups, observed incidences of distant recurrence were plotted
against predicted incidences of distant recurrence for calibration of the
model (Fig 2A).

0.8

0.6

0.4

0.2

0.2

0.4

0.6

0.8

Expected 5-Year Probability of Distant Recurrence

Fig 2. Model calibration. The predicted and observed 5-year incidence rate of
distant failure in (A) the model development cohort and (B) the validation cohort.
Patients were grouped according to the predicted risk (low-risk, 0% to 20%;
intermediate risk, 20% to 40%; high-risk, 40% or more). Vertical bars are
95% CIs.

advanced cervical cancer who underwent definitive chemoradiotherapy. Furthermore, we built a Web-based nomogram for easier access.
We believe these tools can help select candidates for trials designed to
evaluate the efficacy of systemic therapy. The relevance of our predictors corresponds well with previous reports.10-12,18-21
Survival outcomes in locally advanced cervical cancer have
been improved with the inclusion of systemic chemotherapy as a
multimodal treatment.6,22 Obviously, one of the main mechanisms
of improved outcome is the reduction of distant recurrence.6,9 A
recent randomized trial successfully indicated that aggressive systemic therapy may improve outcomes by reducing the rate of
distant failure. It is not difficult to expect that currently ongoing
international trials, such as the ANZGOG (Australian New Zealand Gynaelogical Oncology Group) -0902 study, will be stimulated by this success, and more trials will be launched to test the
efficacy of systemic treatment in locally advanced cervical cancer.23
However, not all patients with locally advanced disease bear the
same risk of distant recurrence. It has been argued that not all
patients with locally advanced cervical cancer are candidates for
systemic chemotherapy.11,24-25 Moreover, although the investigators in a recent randomized trial claimed that increased toxicity
JOURNAL OF CLINICAL ONCOLOGY

Predicting Distant Failure in Locally Advanced Cervical Cancer

Reduced risk of distant failure

Cumulative Incidence of
Distant Recurrence (%)

100

Unnecessarily treated patients

90

No. of patients enrolled

80

Possibly benefited patients/

enrolled patients

70
60
50
40
30
20
10

40

%
35

>

>

>

30

%
25

>

20

%
>

15

%
>

10
>

5%

Tr
ea

ta

ll
c

>

om

er
s

Required sample size

Population size to be screened

500

No. of Patients

450
400
350
300
250
200
150
100
50

>

40

%
35
>

%
30
>

>

25

%
20
>

%
15
>

%
10
>

>

Tr
ea

ta

ll

co

er

5%

Fig 3. Graph showing how the prediction model could be used to design a
clinical trial testing the efficacy of systemic chemotherapy in locally advanced
cervical cancer. (A) Using the risk of subsequent distant recurrence as a cutoff
(x-axis), patients at high risk can be selected and enrolled onto the clinical trial. As
the threshold for enrollment increases, the number of patients enrolled (gray line)
and unnecessarily treated (red dash) would be dramatically decreased, whereas
the proportion of benefited patients among the enrolled study population would
be increased. Note that the reduced risk of distant failure also gradually
decreases (blue dash). A 50% risk reduction by systemic chemotherapy was
assumed. (B) Graph showing the required sample size (blue dash) and the size of
the population that needs to be screened to obtain the required sample size (red
line) at the error of .05 and the power of 90% (for each arm).

enrolled all interested patients, it would require 318 patients for

each arm at a power of 90% and an alpha error of .25. However, if we
enrolled only high patients with a probability greater than 25%, then
the required sample size would decrease to 114 patients for each arm at
the same power. To enroll this number of patients, 333 patients with
locally advanced disease should be screened, which is not very different from the sample size of a nonselective trial. Thus, our prediction
model may help to reduce the resources required for trials, even if we
consider the cost of screening. Of course, this scenario was constructed
based on several assumptions. However, the above calculation suggests that our model is worth being tested in clinical trials to reduce the
number of unnecessarily treated patients and to facilitate clinical trials.
Our prediction model is heavily dependent on the status of
lymph node involvement. It suggests that the accurate assessment of
metastatic lymph nodes is crucially important for the accurate prediction of distant recurrence. Although FDG-PET/CT is the most accurate imaging tool for the assessment of nodal status in cervical
cancer,27-28 its accuracy is far from satisfactory, especially in terms of
sensitivity.28-30 Thus, future research should test whether its predictive
performance can be enhanced by incorporating surgical staging or
assessment of sentinel nodes.31-33
There are several limitations to this study. Due to its retrospective
nature, extended-field radiation was not assigned in a randomized
fashion. Although this feature may introduce a bias, our model incorporated it as a predictor, and we observed no influence on the risk of
distant failure. Secondly, our model was validated only in an Asian
population in Korea. Therefore, further validation using cohorts of
different ethnicities or geographic locations would be recommended.
Finally, the discrimination accuracy of our model is not perfect. However, the 95% CI of the concordance index of our model is similar to
other cancer-prediction models, which show concordance indices
between 0.6 and 0.8.34-36
In conclusion, we have developed a prediction model and a
user-friendly, Web-based nomogram for the prediction of distant
recurrence in locally advanced cervical cancer. Our model will allow
the selection of a patient population at high risk for distant recurrence
and thus will facilitate the design of clinical trials for systemic chemotherapy in locally advanced cervical cancer.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.

was manageable, the physical and economical burden of the systemic chemotherapy might be unnecessary in the patients with a
low risk of distant failure.
Thus, with the current prediction model, we suggested the risk
prediction model for distant failure, and this model may be useful
in candidate selection for clinical trials. The risk-based enrollment
of candidates is not a new concept and has been used successfully in
other trials.26 Our illustrations show how our prediction models
can be applied in clinical trials (Fig 3A). In our scenario, we could
reduce unnecessary treatment by 60% using a probability of 25% as
a cutoff for study enrollment. Moreover, this selective enrollment
strategy could also reduce the number of patients to be enrolled by
60%. In addition, we can estimate the changes in the required
sample size and in the population size to be screened (Fig 3B). If we
www.jco.org

AUTHOR CONTRIBUTIONS
Conception and design: Sokbom Kang
Financial support: Sokbom Kang
Administrative support: Sokbom Kang
Provision of study materials or patients: Sokbom Kang, Sang-Soo Seo,
Sang-Young Ryu, Jae Weon Kim, Seung-Cheol Kim, Sang-Yoon Park,
Joo-Hyun Nam
Collection and assembly of data: Sokbom Kang, Jeong-Yeol Park,
Sang-Soo Seo, Sang-Young Ryu, Jae Weon Kim, Seung-Cheol Kim,
Sang-Yoon Park, Joo-Hyun Nam
Data analysis and interpretation: Sokbom Kang, Byung-Ho Nam
Manuscript writing: All authors
Final approval of manuscript: All authors
2012 by American Society of Clinical Oncology

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Kang et al

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