European Journal of Cancer (2012) 48, 3396–3404

A v a i l a b l e a t w w w . s c i e nc e d i r e c t . c o m

journa l homepage : www.e j cancer . in fo

A nomogram associated with high probability of malignant nodesin the surgical specimen after trimodality therapy of patientswith oesophageal cancer

Yuki Hayashi a, Lianchun Xiao b, Akihiro Suzuki a, Mariela A. Blum a, Bradley Sabloff g,Takashi Taketa a, Dipen M. Maru d, James Welsh c, Steven H. Lin c, Brian Weston e,Jeffrey H. Lee e, Manoop S. Bhutani e, Wayne L. Hofstetter f, Stephen G. Swisher f,Jaffer A. Ajani a,⇑

a Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United Statesb Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United Statesc Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United Statesd Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United Statese Department of Hepatology and Nutrition, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United Statesf Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United Statesg Department of Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States

Available online 31 July 2012

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⇑77

KEYWORDS

NomogramTrimodality therapyOesophageal cancerPrognosis

59-8049/$ - see front matter

tp://dx.doi.org/10.1016/j.ejca.

Corresponding author: Addr030, United States.E-mail address: jajani@mda

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Abstract Background: The presence of malignant lymph nodes (+ypNodes) in the surgicalspecimen after preoperative chemoradiation (trimodality) in patients with oesophageal cancer(EC) portends a poor prognosis for overall survival (OS) and disease-free survival (DFS). Cur-rently, none of the clinical variables highly correlates with +ypNodes. We hypothesised that acombination of clinical variables could generate a model that associates with high likelihoodof +ypNodes after trimodality in EC patients.Methods: We report on 293 consecutive EC patients who received trimodality therapy. A mul-tivariate logistic regression analysis that included pretreatment and post-chemoradiation vari-ables identified independent variables that were used to construct a nomogram for +ypNodesafter trimodality in EC patients.Results: Of 293 patients, 91 (31.1%) had +ypNodes. OS (p = 0.0002) and DFS (p < 0.0001)were shorter in patients with +ypNodes compared to those with –ypNodes. In multivariableanalysis, the significant variables for +ypNodes were: baseline T-stage (odds ratio [OR], 7.145;95% confidence interval [CI], 1.381–36.969; p = 0.019), baseline N-stage (OR, 2.246; 95% CI,

lsevier Ltd. All rights reserved.

20

University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Mail Stop 426, Houston, TX

org (J.A. Ajani).

Y. Hayashi et al. / European Journal of Cancer 48 (2012) 3396–3404 3397

1.024–4.926; p = 0.044), tumour length (OR, 1.178; 95% CI, 1.024–1.357; p = 0.022), induc-tion chemotherapy (OR, 0.471; 95% CI, 0.242–0.915; p = 0.026), nodal uptake on post-chemo-radiation positron emission tomography (OR, 2.923; 95% CI, 1.007–8.485; p = 0.049) andenlarged node(s) on post-chemoradiation computerised tomography (OR, 3.465; 95% CI,1.549–7.753; p = 0.002). The nomogram after internal validation using the bootstrap method(200 runs) yielded a high concordance index of 0.756.Conclusion: Our nomogram highly correlates with the presence of +ypNodes after chemora-diation, however, considerably more refinement is needed before it can be implemented in theclinic.

� 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Primary surgical resection is still the most frequent strat-egy for treat localised oesophageal cancer (EC) but the 5-year survival rates remain poor.1,2 In an analysis of 283EC patients who underwent primary surgery at M.D.Anderson Cancer Center from 1997 to 2001, the 3-year sur-vival rates for pathologic stages IIA and III were only 44%and 6%, respectively.3 Therefore, surgery alone for ECpatients with clinical stage higher than T1bN0 is not rec-ommended. Such patients should be considered for com-bined modality therapy and preoperative chemoradiationtherapy provides the strongest evidence to date.4–7

The prognosis of patients who receive preoperativechemoradiation followed by surgery (trimodalitytherapy) depends on the degree of residual cancer inthe surgical specimen.8–10 One of the most importantprognosticators for overall survival (OS) and disease-free survival (DFS) is the presence of malignant nodes(+ypNodes) in the surgical specimen.8,11,12 Resistanceto preoperative chemoradiation is frequent with only�25% of patients achieving a complete pathologicresponse.8,10 Currently, there is not one clinical variablethat can be highly associated with +ypNodes. A modelthat can reliably be associated with the presence of+ypNodes could potentially be instructive and usefulin individualising therapy.

Gaur et al.13 developed a nomogram that was associ-ated with +pNodes in oesophageal cancer patients whounderwent primary surgery. In that nomogram, thebaseline tumour length had the highest influence onthe presence of +pNodes. Other important factors werethe baseline T-stage and baseline N-status. This nomo-gram can be very useful for early EC to decide whetherendoscopic therapy is sufficient or surgery should be rec-ommended because of a high likelihood of +pNodes.However, since preoperative therapy is now commonlyrecommended,14 it would be important to develop amodel that is correlated with +ypNodes after preopera-tive chemoradiation. A reliable nomogram, most likely,could not be implemented immediately in the clinic butwould be informative. It could provide additional usefulclinical information that we are currently unable toobtain. In the future, it might complement other models

(e.g. biomarkers or sophisticated imaging techniques)where it could prompt surgery or avoid surgery. It isacknowledged that considerable validation will beneeded before clinical implementation. Here we presenta nomogram based on a large number of patients as afirst step towards that goal.

2. Materials and methods

2.1. Patients

We searched the prospectively maintained oesopha-geal cancer database in the Department of Gastrointesti-nal Medical Oncology at M.D. Anderson Cancer Centerand retrospectively reviewed record for patients withbiopsy-proven oesophageal or gastroesophageal junction(squamous cell carcinoma of the esophagus and adeno-carcinoma of oesophagogastric junction or oesophagus[AEG] types I and II) cancer who were treated between2002 and 2010. There were 293 consecutive patientswho received trimodality therapy (preoperative chemora-diation and surgery with or without induction chemo-therapy). Patients were included if they had completepretreatment clinical staging. No other selection criteriawere applied. The Institutional Review Board of M.D.Anderson Cancer Center approved this analysis.

2.2. Pretreatment clinical staging

Baseline tumour, node and metastasis (TNM) stagewas established using a combination of oesophagealendoscopy with endoscopic ultrasonography and fineneedle aspiration (when appropriate), computerisedtomography with oral and intravenous contrast and posi-tive emission tomography (PET). The TNM staging crite-ria used in this study were as defined in the sixth edition ofAmerican Joint Committee on Cancer TNM staging sys-tem.15 The longest cranio-caudal axial length measuredon endoscopy determined clinical tumour length.

2.3. Preoperative imaging

Experienced radiologists focused on lymph nodalinvolvement reviewed computerised tomographic

3398 Y. Hayashi et al. / European Journal of Cancer 48 (2012) 3396–3404

images and PET images. Lymph nodes were consideredpotentially malignant if the short axis was greater than10 mm on computerised tomography or the standard-ised uptake value was greater than 2.5 on PET and theanatomical distribution of nodes was consistent withthe anticipated pattern with the location of the primarytumour.

Table 1Patient and tumour characteristics.

Number of patients (n = 293)

Age at diagnosis* 61 (27–80)

2.4. Trimodality therapy

Trimodality was assigned to these patients after acomplete multidisciplinary evaluation. All patientsreceived concurrent chemotherapy with radiotherapy.Prior to chemoradiation, 129 (44.0%) patients receivedinduction chemotherapy (up to 8 weeks). The total radi-ation dose delivered was either 45 Gy in 25 fraction or50.4 Gy in 28 fractions, at 1.8 Gy per fraction deliveredonce per day, 5 days per week. Patients received a flu-oropyrimidine and either a taxane or a platinum com-pound as the second cytotoxic agent during radiation.Five to six weeks after the completion of chemoradia-tion, all patients underwent comprehensive restagingincluding blood tests, gastroesophageal endoscopy withmultiple biopsies and imaging studies including PET.Types of oesophagectomy included Ivor-Lewis, trans-thoracic, transhiatal, three-field and minimally invasiveoesophagectomy.

Race

Caucasian 264 (90.1%)African American 6 (2.0%)Hispanic 18 (19.4%)Asian 5 (1.7%)Gender (Male: Female) 256 (87.4): 37 (12.6%)Siewert class

Oesophagus 25 (8.5%)AEGI 166 (56.7%)AEGII 102 (34.8%)Baseline T stage

T1 1 (0.3%)T2 35 (11.9%)T3 254 (86.7%)T4 3 (1.0%)Baseline N 1 178 (60.8%)Baseline M 1 14 (4.8%)Clinical Stage

I 1 (0.3%)II 121 (41.3%)III 157 (53.6%)IVa 14 (4.8%)Length of tumour (cm)* 5 (1–14)Histology

Adenocarcinoma 267 (91.1%)Squamous cell Carcinoma 23 (7.8%)Others 3 (1.0%)Tumour grade

Well 2 (6.8%)Moderately 131 (44.7%)Poorly 160 (54.6%)Induction chemo 129 (44.0%)

* Median (range). AEG, Adenocarcinoma in the lower esophagus orat the gastrooesophageal junction (2 patients had squamous cell car-cinoma at these locations in our cohort).

2.5. Statistical analysis

Univariate and multivariate logistic regression mod-els were used to evaluate the association of +ypNodeswith baseline demographic and clinical variables.Regarding multivariate analysis, initially a full multivar-iate logistic regression model, including all variableswith a p value less than 0.15 in the univariate analysis,was fit. Then the backward variable selection procedurewas performed to determine the independent covariates.The multivariate logistic model with independent covar-iates was used to construct nomogram. The Kaplan–Meier method and log rank test were used for survivalanalysis.

The performance of the nomogram was quantified bydiscrimination and calibration.16 To reduce the overfitbias, the nomogram was subjected to 200 bootstrap res-amples for internal validation. The bootstrap estimatedcorrected concordance index (C-index) was calculated.This index estimates the probability of concordancebetween the observed presence of +ypNodes and pres-ence of +ypNodes that are predicted from the model.The concordance index ranges from 0 to 1, with 1 indi-cating perfect concordance, 0.5 indicating no better con-cordance than chance, and 0 indicating perfectdiscordance. All analyses were performed using SAS(Statistical Analysis System) software 9.2 (Cary, NC)and R package, version 2.12.1, with the design library.

3. Results

3.1. Patients and tumour Characteristics

Tables 1 and 2 summarise patients and tumour char-acteristics of the study population. The median age was61 years (range, 27–80 years), and the majority of thepatients were men (87.4%) and Caucasian (90.1%). Atbaseline, the majority of the tumours were T3(86.7%) and N positive (60.8%). Main histology wasadenocarcinoma (91.1%) and others include squamouscell carcinoma or undifferentiated carcinoma after thesurgery, 91 patients (31.1%) had +ypNodes in the sur-gical specimen and the median number of +ypNodeswas 2 (range, 1–20). Median number of nodes evalu-ated was 21 (range, 0–52).

Sixteen patients (5.5%) had transhiatal oesophagec-tomy, while 226 patients (77.1%) had transthoracicapproaches. Pathological complete response wasnoted in 65 patients (22.2%) consistent with theliterature.17

Table 2Surgical and pathologic characteristics.

Number of patients (n = 293)

Type of surgery

Ivor-Lewis oesophagectomy 189 (64.5%)Transthoracic oesophagectomy 16 (5.5%)Three-field oesophagectomy 21 (7.2%)Transhiatal oesophagectomy 16 (5.5%)Minimally-invasive oesophagectomy 38 (13.0%)Others 13 (4.4%)Pathological T stage

T0 73 (24.9%)T1 44 (15.0%)T2 50 (17.1%)T3 118 (40.3%)T4 8 (2.7%)+ypNodes 91 (31.1%)ypM1 1 (3.4%)ypStage

0 65 (22.2%)I 35 (11.9%)II 127 (43.3%)III 65 (22.2%)IV 1 (3.4%)pathCR 65 (22.2%)Number of +ypNodes* 2 (1–20)Number of total nodes* 21 (0–52)

* Median (range), pathCR denotes pathologic complete response.

Y. Hayashi et al. / European Journal of Cancer 48 (2012) 3396–3404 3399

3.2. Preoperative therapy

The total radiation dose delivered was either 45 or50.4 Gy. Of 293 patients, 291 (99.3%) received a fluoro-pyrimidine and 286 patients (97.6%) received either ataxane or a platinum compound as the second cytotoxicagent during radiation. Of 293 patients, 129 (44.0%)received induction chemotherapy.

Path

Time (

% A

live

0 20 40

0.0

0.2

0.4

0.6

0.8

1.0

Fig. 1a. Kaplan–Meier overall survival plots for patient with +ypNodes a

3.3. Imaging after preoperative chemoradiation

Sensitivities for +ypNodes by computerised tomogra-phy only and by PET only were 41.6% and 21.6%,respectively. However, the specificities individually forthese two modalities were 85.7% and 93.7%,respectively.

3.4. +ypNodes and survival

The presence of +ypNodes reduced OS of patientssignificantly (p = 0002; Fig. 1a). The presence of+ypNodes also reduced DFS significantly (p < 0.0001;Fig. 1b). OS was significantly affected for patients with –ypNodes, median number (two) of +ypNodes, and >2+ypNodes (p = 0.0002; Fig. 2a) and similarly DFSwas affected as well (p < 0.0001; Fig. 2b).

3.5. Logistic regression model and nomogram

Logistic regression analysis was performed to evalu-ate the relationship between pretreatment and post che-moradiation clinical variables and +ypNodes (Table 3).In the multivariate analyses, +ypNodes was indepen-dently associated with baseline T3/4 stage (odds ratio[OR] 7.145, p = 0.019), baseline N+ stage (OR 2.246,p = 0.044), longer tumour (OR 1.178, p = 0.022),absence of induction chemotherapy (OR 0.471,p = 0.026), post-chemoradiation enlarged (>10 mm)nodes by computerised tomography (OR 3.465,p = 0.002) and avid nodes by post-chemoradiationPET (OR 2.923, p = 0.049). The post-chemoradiationPET SUVmax, results of the post-chemoradiationbiopsy of primary tumour, age, gender, tumour location

Node

Months)

60 80 100

pN0: death/N =57/202pN1: death/N=35/91

P value = 0.0002

nd –ypNodes. pN0 means no +ypNodes and pN1 means +ypNodes.

Path Node

Time (Months)

% A

live

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

None: death/N =57/2021-2: death/N=17/49>2: death/N=18/42

P value = 0.0002

Fig. 2a. Kaplan–Meier overall survival plots for patient with –ypNodes (red curve), median number of +ypNodes (black curve) or >mediannumber of +ypNodes (green curve).

Path Node

Time (Months)

% R

ecur

renc

e-fr

ee s

urvi

val

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

pN0: event/N =69/201pN1: event/N=54/90

P value < 0.0001

Fig. 1b. Kaplan–Meier relapse-free survival plots for patient with +ypNodes and –ypNodes. pN0 means no +ypNodes and pN1 means +ypNodes.

3400 Y. Hayashi et al. / European Journal of Cancer 48 (2012) 3396–3404

and histology were not associated with +ypNodes. Onthe basis of the six variables that were independentlyassociated with +ypNodes, we constructed a nomogram(Fig. 3). Internal validation using the bootstrap method(200 runs) showed that the concordance-index for themodel was 0.756.

4. Discussion

One can argue that the value of a model that is highlyassociated with the presence of +ypNodes could be lim-ited. Argument would be that one would still proceedwith surgery. Currently, we do not have such a model

Path Node

Time (Months)

% R

ecur

renc

e-fr

ee s

urvi

val

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

None: event/N =69/2011-2: event/N=28/49>2: event/N=26/41

P value < 0.0001

Fig. 2b. Kaplan–Meier relapse-free survival plots for patient with –ypNodes (red curve), median number of +ypNodes (black curve) or >mediannumber of +ypNodes (green curve).

Table 3Logistic regression analysis.

Variables N Univariate Multivariate

Odds Ratio 95% Confidenceinterval (CI)

P value Odds Ratio 95% Confidenceinterval (CI)

P value

Age 0.996 0.972–1.020 0.753Gender (Female) 37 0.575 0.252–1.312 0.189Siewert class 0.483Oesophageal 25 1.000AEG 1 166 1.612 0.609–4.213 0.336AEG 2 102 1.258 0.456–3.466 0.657Baseline T (T3/4) 257 9.006 2.114–38.344 0.003 7.145 1.381–36.969 0.019Baseline N (N1) 178 4.505 2.457–8.258 <0.0001 2.246 1.024–4.926 0.044Baseline M (M1) 14 1.247 0.406–3.830 0.700Baseline Stage <0.0001I/II 122 1.000III 157 4.843 2.653–8.837 <0.0001IV 14 3.431 1.026–11.475 0.045tumour length (cm) 1.275 1.140–1.426 <0.0001 1.178 1.024–1.357 0.022Histology (non-adeno) 26 0.985 0.412–2.357 0.973tumour Grade (Poorly) 160 1.723 1.036–2.865 0.036Induction Chemo 129 0.587 0.352–0.979 0.041 0.471 0.242–0.915 0.026SUV uptake of tumour (pre CRT) 1.014 0.986–1.044 0.329SUV uptake of tumour (post CRT) 1.042 0.981–1.108 0.179Nodal uptake by post CTRT PET 31 4.085 1.883–8.860 0.0004 2.923 1.007–8.485 0.049>10 mm node(s) by post CTRT CT 57 4.267 2.295–7.933 <0.0001 3.465 1.549–7.753 0.002Post CTRT tumour on biopsy 59 1.468 0.806–2.676 0.210

CTRT, chemoradiation; CT, computerised tomography; PET, positron emission tomography; AEG, adenocarcinoma of the oesophagus orgastroesophageal junction.

Y. Hayashi et al. / European Journal of Cancer 48 (2012) 3396–3404 3401

and it would only provide additional information but itmay not be actionable, however, such information can-not be obtained by any other source at the moment. Itsusefulness would be established if the model is validated

and if it would complement other strategies (biomarkersor more sophisticated imaging techniques). Upon vali-dation, it is conceivable that the information generatedby this model can be shared with members of the

Points0 10 20 30 40 50 60 70 80 90 100

Baseline TT1/T2

T3/T4

Baseline NN0

N1

Tumor length (cm)1 2 3 4 5 6 7 8 9 10 11 12 13 14

Induction ChemoYes

No

L/N mets by post CRTPET No

Yes

L/N mets by post CRTCT No

Yes

Total Points0 50 100 150 200 250 300 350 400

Probability of Lymph mets0.01 0.05 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 0.95

Fig. 3. Nomogram to assess the possibility of +ypNodes after preoperative chemoradiation in patients with oesophageal cancer undergoingsurgery.

3402 Y. Hayashi et al. / European Journal of Cancer 48 (2012) 3396–3404

multidisciplinary team and could be a tool to communi-cate with a surgery-eligible patient (with a high probabil-ity of +ypNodes), who is undecided to undergo surgery.

The nomogram generated by our data has a highreproducibility with cross-validation and produced aconcordance index 0.756. The current staging evaluationafter chemoradiation is useful but has low sensitivityand specificity for its association with a specific out-come, such as +ypNodes.18,19 In our study, sensitivitiesof computerised tomography and PET for their associa-tion with +ypNodes were low and thus not very reliable.The major factor in computerised tomographic studies isthe size of the node, however, in a retrospective studywith 2969 dissected nodes from 186 oesophageal or gas-troesophageal junction cancer patients treated with pre-operative chemoradiation, Gu et al.20 reported that thesize of +ypNodes measured from 0.5 to 18 mm in great-est dimension. Furthermore, Bollschweiler et al.21

showed that nodes after trimodality were significantlysmaller than those identified after primary surgery(p = 0.031). From these studies, we can assume that cer-tain malignant nodes are likely to be less than 10 mmand would not be suspected by imaging studies. It isnot surprising that the sensitivity of computerisedtomography for predicting +ypNodes is low. Similarcomments can be made for PET. At the 2011 AmericanSociety of Clinical Oncology Annual Meeting, Waldronet al.22 used PET to predict +ypNodes in head and neckcancer patients, and found that the sensitivity and spec-ificity were 53% and 65%, respectively. Interestingly,they included only patients who had more than 10 mmnodes by computerised tomography, meaning the truesensitivity would be even lower.

We used six independent variables that emerged inthe logistic regression analysis (tumour length, baselineT-stage, baseline N-stage, induction chemotherapy,computerised tomography after chemoradiation andPET after chemoradiation). All these parameters canbe easily assessed in the clinic making our model practi-cal and transportable. If a patient achieves a score of 250or higher, the chance of having +ypNodes is more than60%. Another example could be a patient with a 6 cmlong tumour with baseline T2N1 stage, the score byour nomogram would be 120 if the nodes are notenlarged or avid by imaging and regardless of inductionchemotherapy; this patient’s probability of +ypNodeswould be less than 10%. This type of probability wouldbe difficult to obtain from other clinical sources. Pre-treatment tumour depth, node status and tumour lengthwere also used for the nomogram predicting +pNodeswith surgery as primary therapy13 and suggests thatthese three variables are quite important and at playwith trimodality therapy as well. It is interesting thatT-stage scores higher points than the length of theprimary.

The fact that induction chemotherapy was an inde-pendent variable is interesting and needs further evalua-tion. There were 40 patients who had +ypNodes out of174 patients who had no evidence of node enlargementor avidity by post-chemoradiaiton imaging. Addition-ally and more intriguingly, 139 patients who had a clin-ical complete response,23 28 had +ypNodes. Thenumber of +ypNodes also had an impact on OS andDFS. We acknowledge that there is an ongoing debateregarding the value of induction chemotherapy fortrimodality-eligible patients. Results of our completed

Y. Hayashi et al. / European Journal of Cancer 48 (2012) 3396–3404 3403

randomised trial that addresses this very issue will beforthcoming.

Our study has the following limitations: it is a retro-spective study, it has only cross-validation and not inde-pendent validation, the results cannot be implemented inthe clinic, it cannot predict the number of +ypNodes,and although the number 294 is decent, patients withtwo histologic subtypes have been included, a largercohort of patients might produce more reliable results.The strength of our study is that it generated a relativelysturdy nomogram with high concordance index, it is thefirst proposal of a nomogram for +ypNodes in trimo-dality population and all patients were uniformly staged.

In conclusion, we have developed a nomogram thatuses practical clinical variables and can be highly associ-ated with +ypNodes. Further refinements and valida-tion might lead into its clinical utility in the future forindividualising therapy in EC patients.

Conflict of interest statement

The authors have no conflict of interest or financialdisclosures.

Acknowledgements

Supported in part by generous gifts by Caporella,Park, Dallas, Smith, Cantu, Sultan, Frazier and Oaksfamilies. Also supported by the Kevin Fund.

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