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Risk Assessment Tool for Distant Recurrence AfterPlatinum-Based Concurrent Chemoradiation in PatientsWith Locally Advanced Cervical Cancer: A KoreanGynecologic Oncology Group StudySokbom 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, Sang-

Soo 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 con-

flicts of interest and author contribu-

tions 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: [email protected].

2012 by American Society of Clinical

Oncology

0732-183X/12/3019-2369/$20.00

DOI: 10.1200/JCO.2011.37.5923

A B S T R A C T

PurposeOur study aimed to develop a model to predict distant recurrence in locally advanced cervicacancer, which can be used to select high-risk patients in enriched clinical trials.

Patients and MethodsOur study was a retrospective analysis of a multi-institutional cohort of patients treated bet-ween 2001 and 2009. According to the order of data submission, data from three institutionswere allocated to a model development cohort (n 434), and data from the remaining twoinstitutions were allocated to an external validation cohort (n 115). Patient information including[18F]fluorodeoxyglucose positron emission tomography (FDG-PET) data and clinical outcome wasmodeled using competing risk regression analysis to predict 5-year cumulative incidence ofdistant recurrence.

ResultsThe competing risk analysis revealed that the following four parameters were significantlyassociated with distant recurrence: pelvic and para-aortic nodal positivity on FDG-PET, nonsqua-mous cell histology, and pretreatment serum squamous cell carcinoma antigen levels. Thisfour-parameter model showed good discrimination and calibration, with a bootstrap-adjustedconcordance index of 0.70. Also, the validation set showed good discrimination with a bootstrap-

adjusted concordance index of 0.73. A user-friendly Web-based nomogram predicting 5-yearprobability of distant recurrence was developed.

ConclusionWe have developed a robust model to predict the risk of distant recurrence in patients with lo-cally advanced cervical cancer. Further, we discussed how the selective enrichment of thepatient population could facilitate clinical trials of systemic chemotherapy in locally advancedcervical cancer.

J Clin Oncol 30:2369-2374. 2012 by American Society of Clinical Oncology

INTRODUCTION

After the National Cancer Institute issued an alert,

based on five trials,1-5 recommending concomitantchemoradiotherapy, 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 che-

moradiotherapy followed by brachytherapy and

adjuvant gemcitabine/cisplatin chemotherapy im-

proved survival outcomes. The possible mechanismof 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 expla-

nation corresponds to meta-analyses indicating that

theaddition of systemic chemotherapy hasa 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

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V OL UM E 3 0 N UM BE R 1 9 J UL Y 1 2 0 1 2

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

enrichour trial population with high-risk patients, candoing so facil-

itate the design and performance of trials testing the efficacy of sys-

temic agents?

To answer these questions, the Korean Gynecologic Oncology

Group undertook a multicenter, retrospective study to develop a pre-

diction model for distant recurrence in locally advanced cancer (Ko-

reanGynecologic Oncology Group1024). Recently, we reported that

[18F]fluorodeoxyglucose positron emission tomography (FDG-PET)

can be useful in the prediction of distant recurrence,10 which corre-

sponds 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-

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

Thispredictiontool wasnamed PredictionModel of Failurein Locally

Advanced Cervical Cancer (PREFACE, version 1.1).

PATIENTS AND METHODS

Patient Cohort

Five institutions participated in our retrospective study. The method ofpatient allocation was predetermined before the analysis. According to theorder of data submission, the first three institutions were allocated to a devel-opment cohort and the final two institutions were allocated to a validationcohort. Between November 2001 and August 2009, 748 patients from threeinstitutions (Asan Medical Center, Seoul, Korea; the National Cancer CenterGoyang, Korea; and Ehwa Womans University Hospital, Seoul, Korea) un-derwent definitive platinum-based chemoradiotherapy for the primary treat-ment of locally advanced cervical cancer. Among these patients, 434 patients(58%) underwent FDG-PET before chemoradiotherapy and wereincluded inthe development cohort. During the same period, 167 patients underwentchemoradiotherapy at two institutions (Seoul National University Hospital,Seoul,Korea;andKoreaCancerCenter, Seoul,Korea).Amongthesepatients, 115patients (69%)whounderwentFDG-PET wereallocated toanexternal validationcohort. The inclusion criteria were as follows: a histologic diagnosis of primarycarcinomaof uterinecervix;International Federationof GynecologyandObstet-ricsstage IIBtoIVAorIB2 toIIA bulky (greaterthan 4 cm) disease; treatment withcurative chemoradiotherapy,withor without extended-fieldradiation;and FDG-PET or positron emission tomography/computed tomography scan (PET/CT)beforethestartofchemoradiotherapy,but nomorethan4 weeksbefore.Exclusioncriteria were as follows: small-cell or neuroendocrine type histology; concomi-tant primary cancer; nonplatinum-based chemoradiotherapy; radiation doseless than 40 Gy; or application of surgery or chemotherapy before chemora-diotherapy. Application of intracavitary brachytherapy, parametrial boost

A

DistantRecurrence

Fre

e

Survival(probability)

Time (months)

1.00

0.75

0.50

0.25

0 12 24

Modeling set

Validation set

Modeling set

Validation set

36 48 60

B

CumulativeIncidenc

eof

DistantRecurrenc

e

Time (months)

.4

.3

.2

.1

0 20 40 60

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.

Table 1. Demographic and Clinical Characteristics of Model Derivationand Validation Cohorts

Characteristic

ModelDerivation

Cohort(n 434)

Validation

Cohort(n 115)

P

No. ofPatients %

No. ofPatients %

Age, years .68

Mean 54 54

Range 27-78 32-77

Stage

Bulky IB2-IIA 72 16.6 8 7.0 .009

IIB 274 63.1 71 62.8

III 70 16.1 26 22.6

IVA 18 4.2 10 8.7

Histology

Squamous cell 385 88.7 106 92.2 .005

Adeno 29 6.7 4 3.5

Adenosquamous 17 3.9 2 1.7

Unknown 3 0.7 3 2.6

Tumor size, measured by MRI

Median 4.5 5.5 .001

Range 1.6-9.0 1.5-9.5

Unknown 16 3.7 10 8.7

Serum SCC Ag level, ng/mL

Median 4.9 8.3 .001

Range 0-395 0-402

Unknown 5 1.2 0

Pelvic node status by PET

Negative 174 40.1 56 48.7 .096

Positive 260 59.9 59 51.3

Para-aortic node status by PET

Negative 346 79.7 90 78.3 .73Positive 88 20.3 25 21.7

Extended-field radiation

Not done 283 65.2 74 64.4 .15

Done 150 34.6 39 33.9

Unknown 1 0.2 2 1.7

Recurrence

Locoregional only 29 6.7 7 6.1 .31

Distant only 66 15.2 26 22.6

Locoregional plus Distant 26 6.0 6 5.2

Death 74 17.1 21 18.3 .76

Abbreviations: MRI, magnetic resonance imaging; PET, positron emissiontomography; SCC Ag, squamous cell carcinoma antigen.

Kang et al

2370 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY


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andextended-field radiation to the para-aortic areawere not considered selec-tion criteria. All clinical information was investigated after obtaining the ap-proval of theinstitutional reviewboard of eachof theparticipatinginstitutions.Clinical characteristics of modelingand validation cohorts are summarized inTable 1 and Appendix Table 1 (online-only).

Pretreatment AssessmentTumor size was measured by magnetic resonance imaging. Computed to-

mography(CT)-basedorclinically measuredtumorsizewasnotconsideredin the

analysis.If tumorsizewas reported inthree axes,thelargest diameterwasincludedasthetumorsize.Theinstrumentalsetting andthe conditionofthe processof PETscanning are summarized according to theparticipating institutions in AppendixTable 2 (online-only). The commonly applied interpretation criteria were therules proposed by the International Harmonization Project in Lymphoma.13

Briefly, a lymph node was considered positive if its FDG uptake was greaterthan that of the blood pool activity or background tissues. The steering com-mittee madethe decisionnot to performa central reviewof thedatabecauseofthe heterogeneous settings of the PET imaging, as well as because of concernsregarding the generalization of the model. Thus, all pathologic and imagingdata were interpreted locally by specialists from each institution.

Patient Follow-UpAll patientswerefollowed upevery2 to 4 months for thefirst 2 years and

then subsequentlyevery 2 to 6 months, whichvaried accordingto thepolicyof

each institution and individual patient risk. Pelvic examination and cytologictests were performed at every visit. Diagnostic imaging (CT or magneticresonance imaging) was performed every 6 or 12 months and when clinicallyindicated. Theend point was thetime from thestart of chemoradiotherapytothe earliest diagnosis of distant recurrence. Distant recurrence was defined astumor recurrence at a site beyond the pelvicradiation field. Para-aorticnodalrecurrence above the L4-L5 interspace was regarded as a distant recurrence.

Statistical AnalysisSurvivaldistributions wereestimatedby theKaplan-Meiermethod, with

reverse meaning of the status indicator.14 Competing risk regression analysis,

according to the Fine and Gray method, was performed using Cox regres-sion.15 The first observed distant metastasis was considered an event. Bothlocoregional recurrence and death before recurrence were regarded as com-peting risks. To handle missing data, the complete-case method was applied.

Althoughmany predictor-selectionstrategies exist, the strategy we choseto use was as follows. We began developing a risk model by fitting the Coxproportional hazards model, using all predictors that hadPvalue less than .25in singlepredictor analysis. A reducedmodelwas alsocreatedfrom parametersshowing aPvalue of less than .25 in the full model. Only variables showingsignificant Pvalues ( .05) in the reduced model were regarded as viablepredictors. The significance of all predictors was internally validated using the

jackknife method. The possible interactions between variables were testedwithin the variables selected for the final model.

The discrimination ability of the model was evaluated by Harrells concor-dance index.16-17 The discrimination ability of the final model was internallyvalidated using estimation of bootstrap-adjusted concordance index with 200bootstrap resamples. Calibration of the model was assessed by plotting the ob-servedincidencerateofdistantrecurrenceestimatedby theKaplan-Meiermethodandthe predictedprobabilityof distantrecurrence inthree riskgroupspartitionedaccording to the distribution of the predictedrisk. In addition, a nomogram wasconstructed, based on the Coxproportionalhazardsmodel,andwas convertedinto a user-friendly Web-based program. All statistical analyses were per-formed using the STATA computer program, version 11.0 (STATA, College

Station, TX; Computing Resource Center, Santa Monica, CA).

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

Table 2.Competing Risk Analysis of Time to Distant Recurrence in Locally Advanced Cervical Cancer

Characteristic

Single Predictor Analysis

Multiple Predictor Analysis

Full Model Reduced Model

SHR 95% CI P SHR 95% CI P SHR 95% CI P Jack-knifed P

Age, years (continuous) 1.00 0.98 to 1.02 .76

40 1.51 0.85 to 2.68 .16 1.50 0.71 to 3.13 .29

70 1.00 0.47 to 2.11 .99

Stage

Bulky IB-IIA Reference

IIB 1.48 0.78 to 2.78 .23 1.72 0.76 to 3.93 .20

III 1.69 0.79 to 3.60 .18 1.38 0.47 to 4.03 .56

IVA 1.19 0.33 to 4.21 .79 0.64 0.13 to 3.08 .56

III-IVA v I-II 1.15 0.70 to 1.90 .57

Histology

Squamous cell ReferenceAdeno 1.82 0.94 to 3.53

Adenosquamous 1.53 0.60 to 3.90 .37

Squamous vadeno plus adenosquamous 1.71 0.97 to 3.00 .062 2.82 1.48 to 5.34 .002 2.30 1.28 to 4.14 .006 .008

Tumor size by MRI, cm (continuous) 1.19 1.06 to 1.33 .003 1.15 1.00 to 1.33 .052 1.08 0.94 to 1.23 .276

4 cm v 4 cm 1.87 1.15 to 3.04 .012 1.31 0.78 to 2.22 .305

Serum SCC Ag, ng/mL 1.01 1.00 to 1.01 .001 1.01 1.00 to 1.01 .005 1.00 1.00 to 1.01 .026 .024

SUVmax cervix by PET 1.02 0.99 to 1.05 .21 0.99 0.95 to 1.03 .64

Pelvic node by PET 2.54 1.56 to 4.13 .001 2.04 1.10 to 3.80 .024 1.95 1.15 to 3.33 .014 .017

Para-aortic node by PET 2.98 1.95 to 4.56 .001 1.98 1.06 to 3.72 .032 2.36 1.49 to 3.72 .001 .001

Extended-field radiation 1.78 1.17 to 2.69 .007 1.26 0.78 to 2.20 .34

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

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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 single-

predictor 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 squa-

mous 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%; andhigh

risk, 40% or more; AppendixFig A1,online-only).According to these

risk groups, observed incidences of distant recurrence were plotted

againstpredicted incidencesof distantrecurrence forcalibrationof themodel (Fig 2A).

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 discrimi-

nation performance (concordance index, 0.73) and the bootstrap-

adjusted 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 ofthis model. For easier use, a computerized version of the nomo-

gram 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 howthe modelcould 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 re-

duction 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 scenariocan be suggested based on ourrisk

model. If we enrolled cases with an estimated risk of more than 25%,

then the percentage of unnecessarily treated patientsand 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 therisk of distant recurrence in patientswith locally

advanced cervical cancer who underwent definitive chemoradiother-

apy. 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 predic-

tors 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, oneof themain mechanisms

of improved outcome is the reduction of distant recurrence.6,9 A

recent randomized trial successfully indicated that aggressive sys-

temic 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 Zea-

land Gynaelogical Oncology Group) -0902 study, will be stimu-

lated 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 investiga-

tors in a recent randomized trial claimed that increased toxicity

A

Observed5

-YearProbability

ofDistan

tRecurrence

Expected 5-Year Probability of Distant Recurrence

0.8

0.6

0.4

0.2

0 0.2 0.4 0.6 0.8

B

Observed

5-

YearPro

bability

ofDistantRecurre

nce

Expected 5-Year Probability of Distant Recurrence

0.8

0.6

0.4

0.2

0 0.2 0.4 0.6 0.8

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.

Kang et al



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was manageable,8 the physical and economical burden of the sys-

temic chemotherapy might be unnecessary in the patients with a

low risk of distant failure.

Thus, with thecurrent prediction model,we suggestedthe 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 nota newconcept andhas 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

reduceunnecessarytreatment 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

enrolled all interested patients, it would require 318 patients for

each arm at a power of90%andan alpha error of.25. However,if we

enrolled only high patients with a probability greater than 25%, then

therequiredsample size woulddecrease to114 patientsfor eacharmat

the same power. To enroll this number of patients, 333 patients with

locally advanced disease should be screened, which is not very differ-

ent 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 thecostof screening. Ofcourse,thisscenario wasconstructed

based on several assumptions. However, the above calculation sug-

geststhat ourmodel isworthbeing tested inclinical trials to reduce the

number of unnecessarily treatedpatients andto facilitateclinical 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 accuratepredic-

tion of distant recurrence. Although FDG-PET/CT is the most accu-

rate imaging tool for the assessment of nodal status in cervica

cancer,27-28 its accuracy is far from satisfactory, especially in terms of

sensitivity.28-30Thus, futureresearchshouldtest whetheritspredictive

performance can be enhanced by incorporating surgical staging or

assessment of sentinel nodes.31-33

There areseveral limitations to thisstudy.Dueto itsretrospective

nature, extended-field radiation was not assigned in a randomized

fashion. Althoughthis feature may introduce a bias,our modelincor-

porated 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.How-

ever, 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 distantrecurrence in locally advanced cervical cancer. Our model will allow

theselection of a patient population at high risk for distant recurrence

and thus will facilitate the design of clinical trials for systemic chemo-

therapy in locally advanced cervical cancer.

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design:Sokbom KangFinancial support:Sokbom KangAdministrative support:Sokbom KangProvision of study materials or patients:Sokbom Kang, Sang-Soo Seo,Sang-Young Ryu, Jae Weon Kim, Seung-Cheol Kim, Sang-Yoon Park,Joo-Hyun NamCollection 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 NamData analysis and interpretation:Sokbom Kang, Byung-Ho NamManuscript writing:All authorsFinal approval of manuscript:All authors

Reduced risk of distant failure

Unnecessarily treated patients

No. of patients enrolled

Possibly benefited patients/

enrolled patients

Required sample size

Population size to be screened

A

Trea

tall

comers

>5%

>10

%

>15

%

>20

%

>25

%

>30

%

>35

%

>40

%

Cumulat

iveIncidenceof

Distant

Recurrence(%)

100

90

80

70

60

50

40

30

20

10

0

B

Trea

tall

comers

>5%

>10

%

>15

%

>20

%

>25

%

>30

%

>35

%

>40

%

No.ofPatien

ts

500

450

400

350

300

250

200

150

100

50

0

Fig 3. Graph showing how the prediction model could be used to design a

clinical trial testing the efficacy of systemic chemotherapy in locally advancedcervical 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).

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