research article clinical evaluation and cost...

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 195692 7 pageshttpdxdoiorg1011552013195692

Research ArticleClinical Evaluation and Cost-Effectiveness Analysis ofSerum Tumor Markers in Lung Cancer

Rong Wang1 Guoqing Wang12 Nan Zhang1 Xue Li1 and Yunde Liu1

1 School of Laboratory Medicine Tianjin Medical University No 1 Guangdong Road Hexi District Tianjin 300203 China2Department of Clinical Laboratory Tianjin Stomatological Hospital Tianjin 300041 China

Correspondence should be addressed to Yunde Liu yundeliu126com

Received 30 April 2013 Accepted 22 August 2013

Academic Editor Romonia Renee Reams

Copyright copy 2013 Rong Wang et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The detection of serum tumor markers is valuable for the early diagnosis of lung cancer Tumor markers are frequently used forthe management of cancer patients However single markers are less efficient but marker combinations increase the cost which istroublesome for clinics To find an optimal serummarker combination panel that benefits the patients and themedicalmanagementsystem as well four routine lung cancer serum markers (SCCA NSE CEA and CYFRA21-1) were evaluated individually and incombination Meanwhile the costs and effects of these markers in clinical practice in China were assessed by cost-effectivenessanalysis As expected combinations of these tumor markers improved their sensitivity for lung cancer and different combinationpanels had their own usefulness NSE + CEA + CYFRA21-1 was the optimal combination panel with highest Youdenrsquos index (064)higher sensitivity (7576) and specificity (8857) which can aid the clinical diagnosis of lung cancer Nevertheless the mostcost-effective combination was SCCA + CEA which can be used to screen the high-risk group

1 Introduction

Lung cancer has the highest incidence and mortality ofany cancer worldwide In 2008 161 million new cases werereported and 138 million deaths were attributed to lungcancer The highest rates are in Europe and North AmericaIn contrast to the decliningmortality rate inmen lung cancermortality rates in women have been rising over the recentdecades [1] In China lung cancer has the highest incidenceand it is the leading cause of mortality of all cancers Thiscancer is increasing at a rapid rate and both incidence andmortality are steadily growing China will drive up globalrates of lung cancer in the foreseeable future [2]

Lung cancer patients often do not exhibit specific symp-toms particularly in early stages Therefore the majority oflung cancer patients are diagnosed at an advanced stagewhich undermines their effective treatment Currently con-ventional diagnostic tests such as chest radiographs com-puted tomography (CT) scans and fiber optic bronchoscopy(FB) are not sensitive enough for effective early detectionMeanwhile the benign pulmonary nodules and malignant

tumors cannot be distinguished by imaging methods cur-rently [3 4] Whereas the pathological and cytologicaldetections needed to obtain biopsy samples are invasive anddifficult to repeat Serum tumor markers are proteins thatcan be found in the blood and their higher-than-normalconcentrations have resulted in their widespread use inoncology [5 6]

Early studies have illustrated the significance of serumtumor markers in the detection prognosis and follow-upof lung cancer [7ndash9] Serum tumor markers such as carci-noembryonic antigen (CEA) squamous carcinoma antigen(SCCA) neuron specific enolase (NSE) and cytokeratin frag-ment (CYFRA21-1) have been investigated in patients withlung cancer SCCA is a tumor-associated antigen originallyisolated from squamous cell carcinoma of the uterine cervix[10] Serum antigen levels have been used to follow the tumorstatus of squamous cell carcinomas including those of thehead and neck oral cavity esophagus and lung [6] NSE isthe 120574120574 dimer (isoenzyme) of enolase which was first foundin brain tissue extract and has been shown to be presentin neuroendocrine cells and tumors [11] NSE is a selective

2 BioMed Research International

Table 1 Patient characteristics

Lung cancer group (132) Pulmonary benign disease group (48) Normal group (92)Gender

Male 88 28 48Female 44 20 44

Age 28sim81 (546) 22sim82 (563) 18sim82 (535)Lung cancer

HistologyAdenocarcinoma 68Squamous cell lung cancer 56Small cell lung cancer 8

NSCLC stagesIII 73IIIIV 51

SCLC stagesLimited disease 3Extensive disease 5

Pulmonary benign diseasePneumonia 14Pleural effusion 12Bronchiectasia 4Pulmonary abscess 2Phthisis 16

marker for small-cell carcinoma [12] CEAwas first identifiedby GOLD and FREEDMAN in 1965 as an antigen specificfor digestive tract adenocarcinomas [13] In comparativestudies [14ndash16] CYFRA 21-1 has proven to be the markerof choice in nonsmall cell lung cancer and also exhibitsindependent prognostic value [17] Serum biomarkers areuseful for physicians to screen diagnose and treat lungcancer

However the diagnostic value of a single marker islimited by its sensitivity and specificity [12 18] Thereforecombination marker panel is frequently chosen in the clinicHowever combination panel has increased costs China isa developing country with a large population where nearly70 of the people live in poor rural areas Hence the cost-effectiveness of each assay is an important consideration

Aims of this study were (1) to further evaluate the clinicalvalue of four common serummarkers (SCCANSECEA andCYFRA21-1) in our cohort and (2) to find an optimal serummarker combination panel that benefits both patients and themedical insurance system

2 Materials and Methods

21 Patient Population Three groups of people were selectedbetween March 2008 and December 2008 from the TianjinMedical University Cancer Institute and Hospital The firstgroup comprised lung cancer patients The diagnosis of eachpatient was confirmed by clinical outcome imaging diag-nosis and histological examinations Stage and histologicalclassification were evaluated according to the World HealthOrganization (WHO) 1999 lung cancer classification Allsamples were collected before treatment The second group

was composed of patients with benign pulmonary diseasesIn-patients with pneumonia pleural effusion bronchiectasiaand pulmonary abscess diagnoses were randomly selectedPatients were confirmed by routine standard diagnosticmethods or histological examination those patients with ahistory of malignant disease digestive or kidney disease ortwo or more concomitant lung diseases were excluded Thethird group served as the healthy control group Healthy peo-ple who took a physical examination and all the examinationin the normal range were included except for those with afamily history of lung cancer Detailed patient characteristicsare described in Table 1

22 Sample Collection and Detection A 3mL fasting venousblood sample was collected from each patient in the morninginto a sterile tube The samples were then centrifuged at2500 rpm for 20min The serums were stored at +4∘C andat minus70∘C on the longterm The SCCA concentration wasdetermined by a microparticle enzyme immunoassay usingAbbott reagent sets (Abbott USA) and measured by a chem-ical luminescence analyzer (ARCHITECT i2000SR AbbottUSA) The NSE CEA and CYFRA21-1 concentrations weredetected by electrochemical luminescence (Roche Diagnos-tics Shanghai China) According to each manufacturerrsquosrecommendations the positive cut-off values for eachmarkerwere 15 ngmL for SCCA 50 ngmL for CEA 33 ngmL forCYFRA21-1 and 152 ngmL for NSE A positive sample wasconsidered to be a sample with at least one positive serummarker in the marker combination panel

23 Cost-Effectiveness Analysis The cost-effectiveness of thecombination marker panel was evaluated in lung cancer

BioMed Research International 3

Table 2 Concentrations of SCCA NSE CEA and CYFRA21-1 in serum (ngmL 119909 plusmn 119904)

Group Number SCCA NSE CEA CYFRA21-1Lung cancer 132 173 plusmn 398

lowast

1945 plusmn 1447lowastlowast995333



Pulmonary benign disease 48 038 plusmn 055 1088 plusmn 187 113 plusmn 024lowastlowast

172 plusmn 083lowastlowast

Healthy control 92 017 plusmn 010 909 plusmn 281 078 plusmn 030 103 plusmn 052

P value was calculated by Studentrsquos t-test lowastcompared to healthy control 119875 lt 005 lowastlowastcompared to healthy control 119875 lt 001995333compared to pulmonary benign disease 119875 lt 005 995333995333compared to pulmonary benign disease 119875 lt 001

Table 3 The relationship between SCCA NSE CEA and CYFRA21-1 and the clinicopathological factors (ngmL 119909 plusmn 119904)

Clinicopathological characteristics 119873 SCCA NSE CEA CYFRA21-1Histological classification

Adenocarcinoma 68 022 plusmn 026 1795 plusmn 830 3076 plusmn 4678lowast

400 plusmn 376

Squamous cell lung cancer 56 379 plusmn 556lowast

1683 plusmn 566 449 plusmn 249 1034 plusmn 938lowast

Small cell lung cancer 8 015 plusmn 007 5080 plusmn 2260lowast

181 plusmn 105 131 plusmn 030

NSCLC TNM stageIII 73 259 plusmn 492 1521 plusmn 453 744 plusmn 836 732 plusmn 901

IIIIV 51 070 plusmn 103 2194 plusmn 1915 3371 plusmn 5004lowast

565 plusmn 399

SCLC stageLimited disease (LD) 3 206 plusmn 187 2343 plusmn 1674 727 plusmn 612 711 plusmn 523

Extensive disease (ED) 5 086 plusmn 079 2502 plusmn 1090 3351 plusmn 2963lowast

592 plusmn 380

P value was calculated by Studentrsquos t-test lowastP lt 005

group The effectiveness is determined by the tumor markersensitivity and the cost depends on the expense that patientsincur for the detection According to the charge fee in thethird class A level hospital in Tianjin the cost for SCCAdetection was yen77 and detections for the other three markers(NSE CEA CYFRA21-1) were each yen100

24 Statistical Analysis Statistical analysis was performedusing SPSS Statistics 190 (SPSS Inc Chicago IL) Theassociation between serum markers and lung cancer charac-teristics including stage and histological classification werecompared by Studentrsquos t-test The data were described bymeans plusmn standard deviation The sensitivity specificity andYoudenrsquos index of single markers and combination markerswere calculated Receiver operation characteristic (ROC)curves were used to estimate the diagnostic efficiency ofeach marker Three levels are stratified into no diagnosticvalue (lt05) lower accuracy (05ndash07) higher accuracy (07ndash09) and highest accuracy (gt09) Based on the statistics theaccuracy of the diagnostic assay is enhanced as the area underthe ROC curve increases [19 20] A similar trend is exhibitedbyYoudenrsquos index [21] the accuracy of the diagnostic strengthincreases with the index Cost-effectiveness was analyzed bya cost-benefit ratio

3 Results

31 Comparison of the SCCA NSE CEA and CYFRA21-1 Concentrations in the Lung Cancer Group Benign LungDisease Group and Healthy Control Group Table 2 showedthat the four markers were more abundant in the lungcancer group than in the healthy control group NSE CEAand CYFRA21-1 were dramatically increased (119875 lt 001)

The concentrations of CEA and CYFRA21-1 were higher inthe benign disease group than in the healthy group (119875 lt001)The SCCA concentrationwas not significantly differentbetween the cancer and benign disease groups but theremaining three markers were significantly different in thetwo groups

32 Comparison of the SCCA NSE CEA and CYFRA21-1 Concentrations among Each Clinicopathological Factor inthe Cancer Group Table 3 showed a significant increase inthe concentrations of SCCA and CYFRA21-1 in squamouscell carcinoma an increased NSE concentration in smallcell carcinoma and an increased CEA concentration inadenocarcinoma (119875 lt 005)

With respect to TNM stage only CEA was dramaticallyincreased in stages IIIIV when compared to stages III(119875 lt 005) while no differences were observed in theconcentrations of the SCCA NSE and CYFRA21-1 markersbetween the two stages Similar to the trend in TNM stageCEA demonstrated a higher concentration in the extensivedisease group than in the limited disease No significantdifference was observed in the remaining three markers

33 Comparison on ROC Curves of SCCA NSE CEA andCYFRA21-1 Figure 1 demonstrated that the sensitivities ofNSE CEA and CYFRA21-1 (119875 lt 005) were better thanthose of SCCAThe areas under the curves of NSE CEA andCYFRA21-1 were 0928 plusmn 0034 0957 plusmn 0026 and 0964 plusmn0023 respectively

34 Comparison of the Sensitivity Specificity and YoudenrsquosIndex of the Four Markers Individually and in Combination


Table 4 The sensitivity specificity and Youdenrsquos index of the four markers individually and in combination

Tumor markers Sensitivity () Specificity () Youdenrsquos index

AdenocarcinomaSquamouscell lungcancer

Small celllung cancer Lung cancer

SCCA 735 (568) 5000 (2856) 1250 (18) 2576 (34132) 9429 (132140) 020NSE 4706 (3268) 5000 (2856) 5000 (48) 4848 (64132) 9143 (128140) 040CEA 5882 (4068) 3571 (2056) 000 (08) 4545 (60132) 8929 (125140) 035CYFRA21-1 2941 (2068) 7143 (4056) 1250 (18) 4621 (61132) 9714 (136140) 043SCCA + NSE 4706 (3268) 6786 (3856) 6250 (58) 5682 (75132) 9143 (128140) 048SCCA + CEA 5882 (4068) 6964 (3956) 1250 (18) 6061 (80132) 8929 (125140) 050SCCA + CYFRA21-1 2941 (2068) 7143 (4056) 2500 (28) 4697 (62132) 9071 (127140) 038NSE + CEA 6618 (4568) 7143 (4056) 5000 (48) 6742 (89132) 8929 (125140) 057NSE + CYFRA21-1 5294 (3668) 7857 (4456) 6250 (58) 6439 (85132) 8857 (124140) 053CEA + CYFRA21-1 5882 (4068) 7857 (4456) 1250 (18) 6439 (85132) 8929 (125140) 054SCCA + NSE + CEA 6765 (4668) 7500 (4256) 6250 (58) 7045 (93132) 8929 (125140) 060SCCA + NSE + CYFRA21-1 5294 (3668) 7857 (4456) 7500 (68) 6515 (86132) 8857 (124140) 054SCCA + CEA + CYFRA21-1 5882 (4068) 9107 (5156) 2500 (28) 7045 (93132) 8929 (125140) 060NSE + CEA + CYFRA21-1 6618 (4568) 8929 (5056) 6250 (58) 7576 (100132) 8857 (124140) 064SCCA + NSE + CEA + CYFRA21-1 6765 (4668) 9107 (5156) 7500 (68) 7803 (103132) 8500 (119140) 063

In descending order of individual sensitivity the tumormarkers were NSE (4848) gt CYFRA21-1(4621) gt CEA(4545) gt SCCA (2576) (Table 4) The combination oftumor markers can improve the sensitivity and the com-bination of NSE+CEA+CYFRA21-1 ranked the highest inYoudenrsquos index (064) with higher sensitivity (7576) andspecificity (8857)

35 Cost-Effectiveness Analysis In the cost-effectivenessanalysis only the combination markers whose sensitivityexceeded 50 were included The combination of SCCAand NSE was taken as the healthy control group because itexhibited the lowest sensitivity and the lowest cost Table 5demonstrated that the most cost-effective combination wasSCCA+CEA given that its cost was the lowest furthermoreits cost was the lowest per 1 of sensitivity When the cost ofthe assays was decreased by 10 the cost of the SCCA+CEAcombination was still the lowest as well as the ratio of cost tosensitivity

4 Discussion

In this study four common serum markers (SCCA NSECEA and CYFRA21-1) in lung cancer were evaluated indi-vidually and in combination In addition to sensitivity andspecificity the ROC curve and Youdenrsquos index were appliedwhich are more accurate effective and comprehensiveindexes for validation Compared to SCCA the markersNSE CEA and CYFRA21-1 were more accurate accordingto both higher Youdenrsquos indexes (040 035 043) and largerareas under ROC curves (0928 plusmn 0034 0957 plusmn 0026and 0964 plusmn 0023) However the sensitivities of all fourindividual markers in our investigation were lower than 50Table 4 demonstrates that the combination of tumor markers

is one way to improve their sensitivities The combinationof NSE+CEA+CYFRA21-1 might be an optimal choice dueto the highest Youdenrsquos index (064) with higher sensitivity(7576) and specificity (8857) Furthermore differentcombination panels can assist to differentiate histologicalsubtype of lung cancer The combination of SCCA NSEand CEA with the highest sensitivity (6765) and higherspecificity (8929) can help in the diagnosis of AC SCCACEA and CYFRA21-1 (9107 and 8929) can aid to thediagnosis of SCC and SCCA NSE and CYFRA21-1 (7500and 8857) can assist in the diagnosis of SCLCThese resultsare associated to the unique function of each marker inprevious reports

Enolase molecules in mammalian tissues are dimerscomposed of three immunologically distinct subunits (120572 120573and 120574) The 120574 subunit which has been designated as neuron-specific enolase (NSE) is highly concentrated in neuronsneuroendocrine cells and neurogenic tumors [11] NSE canbe taken as a distinguishing marker between SCLC andNSCLC given that SCLC is a neurosecretion tumor thatresults in NSE expressing highly in SCLC patients [22 23]High serum levels of NSE in patients with suspicion of malig-nancy suggest the presence of SCLC with high probabilityPrevious studies have indicated that approximately 70 of450 SCLC patients have elevated serum concentrations ofNSE while only 14 of 190 NSCLC patients show this [6]Consistent with this conclusion the concentration of NSE inSCLC is higher than that in SCC and AC (119875 lt 005) in ourstudy Contrary to our results no difference was observedbetween LD and ED high pretreatment values of NSE werenoted in 38ndash71 of SCLC patients with LD and in 83ndash98 ofthose with ED and were summarized in Ferrignorsquos review [6]

Compared to NSE the CEA CYFRA21-1 and SCCAare more specific to NSCLC in our investigation CEA is


Table 5 Cost-effectiveness analysis of different combinations of tumor markers at the current cost and with a 10 decrease in cost

Group Cost (C)yen Effectiveness (E) 119862119864 Δ119862Δ119864

SCCA + NSE 177 (1593) 5682 312 (280) 000 (000)SCCA + CEA 177 (1593) 6061 292 (263) 000 (000)NSE + CEA 200 (180) 6742 297 (267) 217 (195)NSE + CYFRA21-1 200 (180) 6439 311 (280) 304 (273)CEA + CYFRA21-1 200 (180) 6439 311 (280) 304 (273)SCCA + NSE + CEA 277 (2493) 7045 393 (354) 734 (660)SCCA + NSE + CYFRA21-1 277 (2493) 6515 425 (383) 1200 (1080)SCCA + CEA + CYFRA21-1 277 (2493) 7045 393 (354) 734 (660)NSE + CEA + CYFRA21-1 300 (270) 7576 396 (356) 649 (584)SCCA + NSE + CEA + CYFRA21-1 377 (3393) 7803 483 (435) 943 (849)

1

08

06

04

02

00 02 04 06 08 1

Sens

itivi

ty

Source of the curvesSCCANSECEA

CYFRA21-1Reference line

1minus specificity

Figure 1 Receiver operation characteristic curves (ROCs) for thetumormarkers in serum for the discrimination between lung cancerand healthy control SCCA 0578 plusmn 0077 (95CI 0427sim0728)NSE0928 plusmn 0034 (95 CI 0861sim0994) CEA 0957 plusmn 0026 (95 CI0905sim1008) and CYFRA21-1 0964 plusmn 0023 (95 CI 0919sim101)

produced by the secretion cells of the normal adult gas-trointestinal tract [24] It is a marker for monitoring colonand rectal cancers Recently CEA has become the markerof choice for lung AC [25] Meanwhile several studies havereported increased CEA values in advanced bronchogeniccancers of various histological types [26 27] Generally CEAlevels vary in accordance with obvious changes in diseasestatus or they may precede their clinical recognition Ourdata show that CEA has elevated levels (119875 lt 005) andhigher sensitivity (5882) in lung AC Furthermore it mayhave a role in monitoring therapy in advanced stages In thepresent study CEA is correlated with TNM stage and tumorinvasion In stages IIIIV CEA is observed at higher levels

than in stages IIIThe same event occurs to the extensive lungcancer However the SCCA NSE and CYFRA21-1 do notshow the correlationwith TNMstage and extent of disease Inaddition the AUC for CEA in our study is higher than thosein the literature where they range from 069 to 079 [28ndash31]whichmight be caused by samples in advanced stages or thoseincluding distant metastases

CYFRA 21-1 is a sensitive tumor marker for NSCLCparticularly in squamous cell tumors Because CYFRA 21-1determines only fragments of cytokeratin 19 the test showsa higher specificity than tissue polypeptide antigen (TPA)which determines a mixture of cytokeratins 8 18 and 19CK-19 is a protein component of the intermediate filamentprotein in epithelial cells [32]When epithelial cells transforminto malignant cells the keratin content is increased Due tonecrosis of tumor cells the soluble fragment CYFRA21-1 ofCK-19 is released into the blood However no organ tissue-specific and tumor-specific epithelial cytokeratins existtherefore it cannot be used as a tumor diagnosis indicatorHowever CYFRA21-1 in serum will increase when epithelialcells transform into cancerous tumor cells especially squa-mous epithelial cells of the lung and bladder transitional cells[32] The results of this study indicate that the CYFRA21-1 concentration in the lung cancer group was significantlyhigher than that in the normal control and benign lungdisease groups (119875 lt 001) and the concentration in thebenign lung disease group was significantly higher than thatin the normal control group (119875 lt 001) Therefore itsmeasurement may be helpful in the differential diagnosis ofsuspicious lung masses but it can also be used as a goodindicator for distinguishing between benign lung disease andnormal group Moreover Table 3 shows that the expressionof CYFRA21-1 in NSCLC was higher than that in SCLCCYFRA21-1 and SCCA in SCC were more sensitive thanthose in AC and SCLC (119875 lt 005) which is consistent withother reports [33 34] In descending order of CYFRA21-1sensitivity each pathological types are SCC (7143) gt AC(2941)gt SCLC (1250)Thismight be caused by theCK-19expression in SCC and AC while CK-18 is always expressedin SCLC Taken together CYFRA21-1 has a high diagnosticvalue in SCC

SCCA is a purified subfraction of the tumor antigen Ele-vated SCCA serum levels were found in many types of SCCincluding the uterine cervix bronchus and nasopharynx


[6 10] In 1988 Mino et al [35] found higher SCCA serumlevels in patients with lung squamous carcinoma comparedto healthy subjects or those with benign pulmonary diseasesOur data are in partial agreement with this result a higherlevel of SCCA is found in lung cancer but it is onlysignificantly different from the healthy control group andnot different from the benign pulmonary group Moreovergiven that SCCA yielded the lowest sensitivity (2576) andthe lowest Youdenrsquos index (020) in addition to exhibitingno significant difference from the control group by the ROCcurve SCCA may not be a good marker for lung cancerscreening but it might be useful as a marker for histologicalsubtyping However because of its significantly reducedsensitivity SCCA would preferably be used in combinationwith CYFRA 21-1 which is also specific for SCC

Although the combination of tumormarkers can improvethe sensitivity the specificity will decrease with increasingsensitivitymeanwhile the cost will increase aswell Presentlysome hospitals and clinics prefer to take the four mark-ers together (SCCA+NSE+CEA+CYFRA21-1) In realityour results indicate that Youdenrsquos index and specificityof four marker panel are lower than three marker panel(NSE+CEA+CYFRA21-1) for the diagnosis of lung cancerChina is a developing country and therefore the optimalcost should be considered The best marker combinationpanel is useful not only for promoting the efficiency ofdiagnosis but also for reducing the economic load for thepatient and health management department Some reports[36ndash38] indicate that an analysis of cost-effectiveness is anappropriate evaluation of tumormarker combinations In thisstudy we perform an analysis of cost-effectiveness for thetumormarker combinationsThe results demonstrate that thecost of SCCA+CEA is the lowest per 1 sensitivity Howevermany variables will affect the cost-effectiveness analysis Forinstance cost discount rate and depreciation of fixed assetsmay contribute to cost-effectiveness If one of the variablesvaries the result may change Therefore Δ119862Δ119864 (119862 cost119864 effectiveness) is applied to evaluate the result due to thevariables With the advancement of laboratory medicine andinstruments the cost will decreaseWe decreased the expenseby 10 and reassessed the tumor marker cost-effectivenessThe results remained unchanged Hence compared to otherpanels the combination of SCCA and CEA is the best choiceto implement screening program in high-risk group

5 Conclusions

Lung cancer is the most common and lethal malignantneoplasm inmost of thewestern countries and it is becomingone of the major health problems in undeveloped countriesThe above data may explain several limitations in the clinicaluse of serum tumor markers Although the four markersin our investigation are quick objective comparable andreproducible none of the single serummarkers has sufficientsensitivity for the screening and diagnosis of lung cancerCombination tumor markers could be a choice to improvethe clinical effectiveness in the diagnosis of lung cancerFurthermore different combination panels have their ownusefulness In our investigation the optimal marker panel

with NSE CEA and CYFRA21-1 can assist to the diagnosisof lung cancer and SCCA+NSE+CEA can help in thediagnosis of AC SCCA+CEA+CYFRA21-1 can aid to thediagnosis of SCC and SCCA+NSE+CYFRA21-1 can assistin the diagnosis of SCLC In addition from an economicviewpoint SCCA+CEA might be a cost-effective combina-tion for screening program However a large cohort valida-tion and other tumor markers would be valuable researchundertakings in the future

List of Abbreviations

CEA Carcinoembryonic antigenNSE Neuron-specific enolaseSCCA Squamous cell carcinoma antigenNSCLC Non-small cell lung cancerSCLC Small cell lung cancerSCC Squamous cell carcinomaAC AdenocarcinomaED Extensive diseaseLD Limited diseaseROC Receiver operating characteristicAUC Area under ROC curveTNM TNM classification of malignant tumors

Authorsrsquo Contribution

Rong Wang and Guoqing Wang contributed equally to thisarticle

Acknowledgment

This work was supported by the Tianjin Municipal HealthBureau Project (09KZ04)

References

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[2] S Chang M Dai J S Ren Y H Chen and L W Guo ldquoEsti-mates and prediction on incidence mortality and prevalence oflung cancer in China in 2008rdquo Zhonghua Liu Xing Bing Xue ZaZhi vol 33 no 4 pp 391ndash394 2012

[3] X Xie Y Zhao R A Snijder et al ldquoSensitivity and accuracyof volumetry of pulmonary nodules on low-dose 16- and 64-row multi-detector CT an anthropomorphic phantom studyrdquoEuropean Radiology vol 23 no 1 pp 139ndash147 2013

[4] C I Henschke and D F Yankelevitz ldquoCT screening for lungcancer update 2007rdquo Oncologist vol 13 no 1 pp 65ndash78 2008

[5] R J Pamies and D R Crawford ldquoTumor markers an updaterdquoMedical Clinics of North America vol 80 no 1 pp 185ndash1991996

[6] D Ferrigno G Buccheri and A Biggi ldquoSerum tumourmarkersin lung cancer history biology and clinical applicationsrdquoEuropean Respiratory Journal vol 7 no 1 pp 186ndash197 1994

[7] J S de Cos Escuin and J H Hernandez ldquoTumor markers andlung cancer Whatrsquos newrdquo Archivos de Bronconeumologıa vol40 supplement 6 pp 35ndash40 2004


[8] D E Niewoehner and J B Rubins ldquoClinical utility of tumormarkers in the management of non-small cell lung cancerrdquoMethods in Molecular Medicine vol 75 pp 135ndash141 2003

[9] N Vinolas R Molina M C Galan et al ldquoTumor markersin response monitoring and prognosis of non-small cell lungcancer preliminary reportrdquo Anticancer Research vol 18 no 1Bpp 631ndash634 1998

[10] H Kato K Tamai T Magaya et al ldquoClinical value of SCC-antigen a subfraction of tumor antigen TA-4 in the manage-ment of cervical cancerrdquo Gan no Rinshos vol 31 supplement 6pp 594ndash599 1985

[11] E H Cooper T A Splinter D A Brown M F Muers M DPeake and S L Pearson ldquoEvaluation of a radioimmunoassay forneuron specific enolase in small cell lung cancerrdquoBritish Journalof Cancer vol 52 no 3 pp 333ndash338 1985

[12] L G M Joslashrgensen K Osterlind J Genolla et al ldquoSerumneuron-specific enolase (S-NSE) and the prognosis in small-celllung cancer (SCLC) a combined multivariable analysis on datafrom nine centresrdquo British Journal of Cancer vol 74 no 3 pp463ndash467 1996

[13] S Hammarstrom ldquoThe carcinoembryonic antigen (CEA) fam-ily structures suggested functions and expression in normaland malignant tissuesrdquo Seminars in Cancer Biology vol 9 no2 pp 67ndash81 1999

[14] J Grenier J L Pujol F Guilleux J P Daures H Pujol and FB Michel ldquoCyfra 21-1 a new marker of lung cancerrdquo NuclearMedicine and Biology vol 21 no 3 pp 471ndash476 1994

[15] M Muraki Y Tohda T Iwanaga H Uejima Y Nagasaka andS Nakajima ldquoAssessment of serum CYFRA 21-1 in lung cancerrdquoCancer vol 77 no 7 pp 1274ndash1277 1996

[16] A van der Gaast C H H Schoenmakers T C Kok B GBlijenberg F Cornillie and T A W Splinter ldquoEvaluation ofa new tumour marker in patients with non-small-cell lungcancer Cyfra 211rdquo British Journal of Cancer vol 69 no 3 pp525ndash528 1994

[17] H-J Yan R-BWang K-L Zhu et al ldquoCytokeratin 19 fragmentantigen 21-1 as an independent predictor for definitive chemora-diotherapy sensitivity in esophageal squamous cell carcinomardquoChinese Medical Journal vol 125 no 8 pp 1410ndash1415 2012

[18] M Plebani D Basso F Navaglia M de Paoli A Tommasiniand A Cipriani ldquoClinical evaluation of seven tumour markersin lung cancer diagnosis can any combination improve theresultsrdquo British Journal of Cancer vol 72 no 1 pp 170ndash1731995

[19] B J McNeil E Keeler and S J Adelstein ldquoPrimer on certainelements ofmedical decisionmakingrdquoTheNewEngland Journalof Medicine vol 293 no 5 pp 211ndash215 1975

[20] J A Hanley and B J McNeil ldquoThe meaning and use of thearea under a receiver operating characteristic (ROC) curverdquoRadiology vol 143 no 1 pp 29ndash36 1982

[21] N J Perkins and E F Schisterman ldquoThe inconsistency ofldquooptimalrdquo cutpoints obtained using two criteria based on thereceiver operating characteristic curverdquo American Journal ofEpidemiology vol 163 no 7 pp 670ndash675 2006

[22] H Satoh H Ishikawa K Kurishima Y T Yamashita MOhtsuka andK Sekizawa ldquoCut-off levels ofNSE to differentiateSCLC fromNSCLCrdquoOncology Reports vol 9 no 3 pp 581ndash5832002

[23] S Ando H Kimura N Iwai et al ldquoOptimal combinationof seven tumour markers in prediction of advanced stage atfirst examination of patients with non-small cell lung cancerrdquoAnticancer Research vol 21 no 4B pp 3085ndash3092 2001

[24] V L Go H V Ammon K H Holtermuller E Krag and SF Phillips ldquoQuantification of carcinoembryonic antigen likeactivities in normal human gastrointestinal secretionsrdquo Cancervol 36 supplement 6 pp 2346ndash2350 1975

[25] P FoaM Fornier RMiceli et al ldquoTumourmarkers CEA NSESCC TPA and CYFRA 211 in resectable non-small cell lungcancerrdquoAnticancer Research vol 19 no 4C pp 3613ndash3618 1999

[26] G Plavec M Ninkovic G Kozlovacki A Lazarov and VTatic ldquoTumor markers in pleural effusions in bronchogeniccarcinoma and tuberculosisrdquoVojnosanitetski Pregled vol 59 no1 pp 23ndash28 2002

[27] T Rasmuson G R Bjork L Damber et al ldquoTumor markers inbronchogenic carcinoma An evaluation of carcinoembryonicantigen tissue polypeptide antigen placental alkaline phos-phatase and pseudouridinerdquo Acta Radiologica vol 22 no 3 pp209ndash214 1983

[28] B Nisman J Lafair N Heching et al ldquoEvaluation of tissue pol-ypeptide specific antigen CYFRA 21-1 and carcinoembryonicantigen in nonsmall cell lung carcinoma does the combineduse of cytokeratin markers give any additional informationrdquoCancer vol 82 no 10 pp 1850ndash1859 1998

[29] M Takada N Masuda E Matsuura et al ldquoMeasurement ofcytokeratin 19 fragments as a marker of lung cancer by CYFRA21-1 enzyme immunoassayrdquoBritish Journal of Cancer vol 71 no1 pp 160ndash165 1995

[30] B Bergman F-T Brezicka C-P Engstrom and S LarssonldquoClinical usefulness of serum assays of neuron-specific enolasecarcinoembryonic antigen and CA-50 antigen in the diagnosisof lung cancerrdquo European Journal of Cancer A vol 29 no 2 pp198ndash202 1993

[31] D Moro D Villemain J P Vuillez C A Delord and CBrambilla ldquoCEA CYFRA21-1 and SCC in non-small cell lungcancerrdquo Lung Cancer vol 13 no 2 pp 169ndash176 1995

[32] P Stieber H Dienemann U Hasholzner et al ldquoComparisonof CYFRA 21-1 TPA and TPS in lung cancer urinary bladdercancer and benign diseasesrdquo International Journal of BiologicalMarkers vol 9 no 2 pp 82ndash88 1994

[33] M Tomita T Shimizu T Ayabe A Yonei and T OnitsukaldquoPrognostic significance of tumour marker index based onpreoperative CEA and CYFRA 21-1 in non-small cell lungcancerrdquo Anticancer Research vol 30 no 7 pp 3099ndash3102 2010

[34] R-S Lai H-K Hsu J-Y Lu L-P Ger and N-S Lai ldquoCYFRA21-1 enzyme-linked immunosorbent assay evaluation as atumor marker in non-small cell lung cancerrdquo Chest vol 109 no4 pp 995ndash1000 1996

[35] N Mino A Iio and K Hamamoto ldquoAvailability of tumor-antigen 4 as a marker of squamous cell carcinoma of the lungand other organsrdquo Cancer vol 62 no 4 pp 730ndash734 1988

[36] A J Atherly and D R Camidge ldquoThe cost-effectiveness ofscreening lung cancer patients for targeted drug sensitivitymarkersrdquoBritish Journal of Cancer vol 106 no 6 pp 1100ndash11062012

[37] J-X Hou X-Q Yang C Chen Q Jiang G-L Yang and YLi ldquoScreening the gastric cancer related tumor markers frommulti-tumor markers protein chip with kappa coefficient andcost-effectiveness analysisrdquo Hepato-Gastroenterology vol 58no 106 pp 632ndash636 2011

[38] W F McGhan C R Rowland and J L Bootman ldquoCost-benefitand cost-effectiveness methodologies for evaluating innovativepharmaceutical servicesrdquo American Journal of Hospital Phar-macy vol 35 no 2 pp 133ndash140 1978

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Table 1 Patient characteristics

Lung cancer group (132) Pulmonary benign disease group (48) Normal group (92)Gender

Male 88 28 48Female 44 20 44

Age 28sim81 (546) 22sim82 (563) 18sim82 (535)Lung cancer

HistologyAdenocarcinoma 68Squamous cell lung cancer 56Small cell lung cancer 8

NSCLC stagesIII 73IIIIV 51

SCLC stagesLimited disease 3Extensive disease 5

Pulmonary benign diseasePneumonia 14Pleural effusion 12Bronchiectasia 4Pulmonary abscess 2Phthisis 16

marker for small-cell carcinoma [12] CEAwas first identifiedby GOLD and FREEDMAN in 1965 as an antigen specificfor digestive tract adenocarcinomas [13] In comparativestudies [14ndash16] CYFRA 21-1 has proven to be the markerof choice in nonsmall cell lung cancer and also exhibitsindependent prognostic value [17] Serum biomarkers areuseful for physicians to screen diagnose and treat lungcancer

However the diagnostic value of a single marker islimited by its sensitivity and specificity [12 18] Thereforecombination marker panel is frequently chosen in the clinicHowever combination panel has increased costs China isa developing country with a large population where nearly70 of the people live in poor rural areas Hence the cost-effectiveness of each assay is an important consideration

Aims of this study were (1) to further evaluate the clinicalvalue of four common serummarkers (SCCANSECEA andCYFRA21-1) in our cohort and (2) to find an optimal serummarker combination panel that benefits both patients and themedical insurance system

2 Materials and Methods

21 Patient Population Three groups of people were selectedbetween March 2008 and December 2008 from the TianjinMedical University Cancer Institute and Hospital The firstgroup comprised lung cancer patients The diagnosis of eachpatient was confirmed by clinical outcome imaging diag-nosis and histological examinations Stage and histologicalclassification were evaluated according to the World HealthOrganization (WHO) 1999 lung cancer classification Allsamples were collected before treatment The second group

was composed of patients with benign pulmonary diseasesIn-patients with pneumonia pleural effusion bronchiectasiaand pulmonary abscess diagnoses were randomly selectedPatients were confirmed by routine standard diagnosticmethods or histological examination those patients with ahistory of malignant disease digestive or kidney disease ortwo or more concomitant lung diseases were excluded Thethird group served as the healthy control group Healthy peo-ple who took a physical examination and all the examinationin the normal range were included except for those with afamily history of lung cancer Detailed patient characteristicsare described in Table 1

22 Sample Collection and Detection A 3mL fasting venousblood sample was collected from each patient in the morninginto a sterile tube The samples were then centrifuged at2500 rpm for 20min The serums were stored at +4∘C andat minus70∘C on the longterm The SCCA concentration wasdetermined by a microparticle enzyme immunoassay usingAbbott reagent sets (Abbott USA) and measured by a chem-ical luminescence analyzer (ARCHITECT i2000SR AbbottUSA) The NSE CEA and CYFRA21-1 concentrations weredetected by electrochemical luminescence (Roche Diagnos-tics Shanghai China) According to each manufacturerrsquosrecommendations the positive cut-off values for eachmarkerwere 15 ngmL for SCCA 50 ngmL for CEA 33 ngmL forCYFRA21-1 and 152 ngmL for NSE A positive sample wasconsidered to be a sample with at least one positive serummarker in the marker combination panel

23 Cost-Effectiveness Analysis The cost-effectiveness of thecombination marker panel was evaluated in lung cancer




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400 plusmn 376







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592 plusmn 380




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Acknowledgment


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Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




lowast











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565 plusmn 399



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3 Results















4 Discussion









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itivi

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5 Conclusions







Acknowledgment


References















































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology









4 Discussion









1

08

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ty



1minus specificity









5 Conclusions







Acknowledgment


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Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





1

08

06

04

02

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Sens

itivi

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5 Conclusions







Acknowledgment


References















































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




5 Conclusions







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References















































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

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